Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans

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Preisinger Rudolf

2010-01-01

Full Text Available Abstract Background Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Methods Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR. These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV. Results Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. Conclusions The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift.

Interleukin-10 overexpression promotes Fas-ligand-dependent chronic macrophage-mediated demyelinating polyneuropathy.

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Dru S Dace

Full Text Available BACKGROUND: Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome or chronic forms. Interleukin-10 (IL-10, although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. PRINCIPAL FINDINGS: Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL-mediated Schwann cell death. SIGNIFICANCE: These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP or Guillain-Barré syndrome.

A recurrence of Guillain-Barr and eacute; syndrome or a case of acute-onset chronic inflammatory demyelinating polyneuropathy in the course of chronic hepatitis B?

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Guner Celik Koyuncu

2016-12-01

Full Text Available Chronic inflammatory demyelinating polyneuropathy is a demyelinating polyneuropathy characterized by distal/proximal weakness, which shows gradual progression over a period of 8 weeks or longer. Guillan-Barre Syndrome is a condition characterized by acute monophasic paralysis typically following an infectious assault, and it usually peaks in severity over 3-4 weeks at most. Although rare, there are acute-onset chronic inflammatory demyelinating polyneuropathy cases that show progression over a period shorter than 4 weeks, as is the case in Guillan-Barre Syndrome .This report discusses a case of chronic inflammatory demyelinating polyneuropathy in a HBsAg-positive patient, which started as Guillan-Barre Syndrome but showed 3 recurrences within 6 months, each with rapidly progressing quadriplegia, respiratory arrest, and elevated liver enzymes and HBV DNA. [Cukurova Med J 2016; 41(4.000: 782-786

Analysis of relationship between demyelinating lesions and myelin basic protein in pancreatic encephalopathy

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HUANG Boru

2015-05-01

Full Text Available Pancreatic encephalopathy (PE is one of the severe complications of severe acute pancreatitis (SAP. Early diagnosis mostly depends on the history of disease as well as clinical symptoms and signs. PE progresses rapidly and is often complicated by multiple organ dysfunction, and it may finally develop into multiple organ failure with a high fatality rate if not treated in time. It is currently known that demyelination is one of the important pathological features of this disease, with fat-soluble demyelination of cerebral gray matter and white matter, as well as inflammatory changes such as hemorrhage and edema. The target antigen of demyelinating lesions, however, is myelin basic protein (MBP. This paper reviews the changes in MBP levels in the demyelinating lesions of the central nervous system among PE patients, with the purpose of providing clues for the early diagnosis and prognostic study of demyelinating lesions in PE.

Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy

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Markvardsen, Lars Høj; Debost, J-C; Harbo, Thomas

2013-01-01

BACKGROUND AND PURPOSE: We hypothesized that subcutaneous administration of immunoglobulins (SCIG) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is feasible, safe and superior to treatment with saline for the performance of muscle strength. METHODS: Thirty patients with motor...... Research Council (MRC) score, grip strength, standardized electrophysiological recordings from three nerves, and plasma IgG levels were evaluated. RESULTS: SCIG treatment was well tolerated in all 14 patients. Six patients complained of mild side-effects at the injection site. In the SCIG group...

Chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus

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Farzad Fatehi

2013-01-01

Full Text Available Various forms of neuropathy are seen diabetic patients; chronic inflammatory demyelinating polyneuropathy (CIDP seems not to be infrequent neuropathy in patients suffering from diabetes and it seems to be more common than in the general population; on the contrary, some authorities do not support pathogenetic association between diabetes mellitus (DM and CIDP. Also, there are some controversies on the subject of CIDP treatment in diabetic patients. Some studies showed that patients with CIDP-DM considerably had recovered following treatment with immunotherapeutic modalities like (Intravenous immunoglobulin IVIG and conversely, some else have argued against the prescription of IVIG in this group and recommend treatment with corticosteroids and provided that resistant, rituximab may be beneficial. The main limitation in most studies is the inadequate number of cases and as a result, problematic decision making in treatment. This article represents an inclusive review of diabetic CIDP presentation and treatment.

Blood-brain barrier hyperpermeability precedes demyelination in the cuprizone model.

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Berghoff, Stefan A; Düking, Tim; Spieth, Lena; Winchenbach, Jan; Stumpf, Sina K; Gerndt, Nina; Kusch, Kathrin; Ruhwedel, Torben; Möbius, Wiebke; Saher, Gesine

2017-12-01

In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.

Thrombocytosis distinguishes POEMS syndrome from chronic inflammatory demyelinating polyneuropathy.

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Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay; Mauermann, Michelle L

2015-10-01

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) syndrome may be mistaken for chronic inflammatory demyelinating polyneuropathy (CIDP). Differentiating the 2 entities is crucial, as there are major treatment implications. We compared platelet counts in 136 POEMS patients and 67 CIDP controls. Of the patients with POEMS, 53.7% had thrombocytosis, compared with 1.5% of those with CIDP (P < 0.0001). The median platelet count in patients with POEMS was 467,000/μl compared with 275,000/μl in those with CIDP (P < 0.0001). Thrombocytosis is a helpful indicator to prompt clinicians to consider the diagnosis of POEMS syndrome in patients who are thought to have CIDP, and is an important reminder of the increased risk of thrombotic events in POEMS syndrome. © 2015 Wiley Periodicals, Inc.

A Mechanism of Virus-Induced Demyelination

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Jayasri Das Sarma

2010-01-01

Full Text Available Myelin forms an insulating sheath surrounding axons in the central and peripheral nervous systems and is essential for rapid propagation of neuronal action potentials. Demyelination is an acquired disorder in which normally formed myelin degenerates, exposing axons to the extracellular environment. The result is dysfunction of normal neuron-to-neuron communication and in many cases, varying degrees of axonal degeneration. Numerous central nervous system demyelinating disorders exist, including multiple sclerosis. Although demyelination is the major manifestation of most of the demyelinating diseases, recent studies have clearly documented concomitant axonal loss to varying degrees resulting in long-term disability. Axonal injury may occur secondary to myelin damage (outside-in model or myelin damage may occur secondary to axonal injury (inside-out model. Viral induced demyelination models, has provided unique imminent into the cellular mechanisms of myelin destruction. They illustrate mechanisms of viral persistence, including latent infections, virus reactivation and viral-induced tissue damage. These studies have also provided excellent paradigms to study the interactions between the immune system and the central nervous system (CNS. In this review we will discuss potential cellular and molecular mechanism of central nervous system axonal loss and demyelination in a viral induced mouse model of multiple sclerosis.

Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis.

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Raddatz, Barbara B; Sun, Wenhui; Brogden, Graham; Sun, Yanyong; Kammeyer, Patricia; Kalkuhl, Arno; Colbatzky, Florian; Deschl, Ulrich; Naim, Hassan Y; Baumgärtner, Wolfgang; Ulrich, Reiner

2016-01-01

High dietary fat and/or cholesterol intake is a risk factor for multiple diseases and has been debated for multiple sclerosis. However, cholesterol biosynthesis is a key pathway during myelination and disturbances are described in demyelinating diseases. To address the possible interaction of dyslipidemia and demyelination, cholesterol biosynthesis gene expression, composition of the body's major lipid repositories and Paigen diet-induced, systemic hypercholesterolemia were examined in Theiler's murine encephalomyelitis (TME) using histology, immunohistochemistry, serum clinical chemistry, microarrays and high-performance thin layer chromatography. TME-virus (TMEV)-infected mice showed progressive loss of motor performance and demyelinating leukomyelitis. Gene expression associated with cholesterol biosynthesis was overall down-regulated in the spinal cord of TMEV-infected animals. Spinal cord levels of galactocerebroside and sphingomyelin were reduced on day 196 post TMEV infection. Paigen diet induced serum hypercholesterolemia and hepatic lipidosis. However, high dietary fat and cholesterol intake led to no significant differences in clinical course, inflammatory response, astrocytosis, and the amount of demyelination and remyelination in the spinal cord of TMEV-infected animals. The results suggest that down-regulation of cholesterol biosynthesis is a transcriptional marker for demyelination, quantitative loss of myelin-specific lipids, but not cholesterol occurs late in chronic demyelination, and serum hypercholesterolemia exhibited no significant effect on TMEV infection. © 2015 International Society of Neuropathology.

Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

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Honegger Paul

2009-05-01

Full Text Available Abstract Background Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS. Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ and lipopolysaccharide (LPS. Peroxisome proliferator-associated receptor (PPAR pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE, an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS. Methods Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG. The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, inducible NO synthase (i-NOS, PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP, myelin basic protein (MBP, and high molecular weight neurofilament protein (NF-H. GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4 and ED1 labeling. Results GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL

Gliopathy of Demyelinating And Non-Demyelinating Strains Of Mouse Hepatitis Virus.

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Lawrence Charles Kenyon

2015-12-01

Full Text Available Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59 and non-demyelinating (RSMHV2 viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white matter, but infected oligodendrocytes were restricted to white matter. In contrast, RSMHV2 infection was restricted to gray matter neurons and was not localized to oligodendrocytes. In vitro, RSA59 can infect both oligodendrocyte precursors and differentiated oligodendrocytes, whereas RSMHV2 can infect oligodendrocyte precursors but not differentiated oligodendrocytes. Viral spreading through axonal means to white matter and release of the demyelinating strain MHV at the nerve end is critical for oligodendrocytes infection and subsequent demyelination. Understanding the mechanisms by which known viruses effect demyelination in this animal model has important therapeutic implications in the treatment of human demyelinating disease.

A 17 year-old girl with a demyelinating disease requiring mechanical ventilation: a case report

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Katsenos Chrysostomos

2013-01-01

Full Text Available Abstract Background Demyelinating diseases cause destruction of the myelin sheath, while axons are relatively spared. Pathologically, demyelination can be the result of an inflammatory process, viral infection, acquired metabolic derangement and ischemic insult. Three diseases that can cause inflammatory demyelination of the CNS are: Multiple sclerosis (MS, Acute disseminated encephalomyelitis (ADEM and Acute hemorrhagic leucoencephalitis. Differentiation is not always easy and there is considerable overlaping. Data about adults with acute demyelination requiring ICU admission is limited. Case presentation A 17 year old Greek female was hospitalised in the ICU because of acute respiratory failure requiring mechanical ventilation. She had a history of febrile disease one month before, acute onset of paraplegia, diplopia, progressive arm weakness and dyspnea. Her consciousness was not impaired. A demyelinating central nervous system (CNS disease, possibly post infectious encephalomyelitis (ADEM was the underlying condition. The MRI of the brain disclosed diffused expanded cerebral lesions involving the optic nerve, basal ganglia cerebellum, pons and medulla oblongata. There was also extended involvement of the cervical and thoracic part of the spinal cord. CSF leukocyte count was elevated with lymphocyte predominance. The patient required mechanical ventilation for two months. Then she was transferred to a rehabilitation centre. Three years later she remains paraplegic. Since then she has not suffered any other demyelination attack. Conclusions Demyelinating diseases can cause acute respiratory failure when the spinal cord is affected. Severe forms of these diseases, making necessary ICU admission, is less frequently reported. Intensivists should be aware of the features of these rare diseases.

Transcriptional changes in canine distemper virus-induced demyelinating leukoencephalitis favor a biphasic mode of demyelination.

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Reiner Ulrich

Full Text Available Canine distemper virus (CDV-induced demyelinating leukoencephalitis in dogs (Canis familiaris is suggested to represent a naturally occurring translational model for subacute sclerosing panencephalitis and multiple sclerosis in humans. The aim of this study was a hypothesis-free microarray analysis of the transcriptional changes within cerebellar specimens of five cases of acute, six cases of subacute demyelinating, and three cases of chronic demyelinating and inflammatory CDV leukoencephalitis as compared to twelve non-infected control dogs. Frozen cerebellar specimens were used for analysis of histopathological changes including demyelination, transcriptional changes employing microarrays, and presence of CDV nucleoprotein RNA and protein using microarrays, RT-qPCR and immunohistochemistry. Microarray analysis revealed 780 differentially expressed probe sets. The dominating change was an up-regulation of genes related to the innate and the humoral immune response, and less distinct the cytotoxic T-cell-mediated immune response in all subtypes of CDV leukoencephalitis as compared to controls. Multiple myelin genes including myelin basic protein and proteolipid protein displayed a selective down-regulation in subacute CDV leukoencephalitis, suggestive of an oligodendrocyte dystrophy. In contrast, a marked up-regulation of multiple immunoglobulin-like expressed sequence tags and the delta polypeptide of the CD3 antigen was observed in chronic CDV leukoencephalitis, in agreement with the hypothesis of an immune-mediated demyelination in the late inflammatory phase of the disease. Analysis of pathways intimately linked to demyelination as determined by morphometry employing correlation-based Gene Set Enrichment Analysis highlighted the pathomechanistic importance of up-regulated genes comprised by the gene ontology terms "viral replication" and "humoral immune response" as well as down-regulated genes functionally related to "metabolite and energy

Transcriptional changes in canine distemper virus-induced demyelinating leukoencephalitis favor a biphasic mode of demyelination.

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Ulrich, Reiner; Puff, Christina; Wewetzer, Konstantin; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang

2014-01-01

Canine distemper virus (CDV)-induced demyelinating leukoencephalitis in dogs (Canis familiaris) is suggested to represent a naturally occurring translational model for subacute sclerosing panencephalitis and multiple sclerosis in humans. The aim of this study was a hypothesis-free microarray analysis of the transcriptional changes within cerebellar specimens of five cases of acute, six cases of subacute demyelinating, and three cases of chronic demyelinating and inflammatory CDV leukoencephalitis as compared to twelve non-infected control dogs. Frozen cerebellar specimens were used for analysis of histopathological changes including demyelination, transcriptional changes employing microarrays, and presence of CDV nucleoprotein RNA and protein using microarrays, RT-qPCR and immunohistochemistry. Microarray analysis revealed 780 differentially expressed probe sets. The dominating change was an up-regulation of genes related to the innate and the humoral immune response, and less distinct the cytotoxic T-cell-mediated immune response in all subtypes of CDV leukoencephalitis as compared to controls. Multiple myelin genes including myelin basic protein and proteolipid protein displayed a selective down-regulation in subacute CDV leukoencephalitis, suggestive of an oligodendrocyte dystrophy. In contrast, a marked up-regulation of multiple immunoglobulin-like expressed sequence tags and the delta polypeptide of the CD3 antigen was observed in chronic CDV leukoencephalitis, in agreement with the hypothesis of an immune-mediated demyelination in the late inflammatory phase of the disease. Analysis of pathways intimately linked to demyelination as determined by morphometry employing correlation-based Gene Set Enrichment Analysis highlighted the pathomechanistic importance of up-regulated genes comprised by the gene ontology terms "viral replication" and "humoral immune response" as well as down-regulated genes functionally related to "metabolite and energy generation".

Transcriptional Changes in Canine Distemper Virus-Induced Demyelinating Leukoencephalitis Favor a Biphasic Mode of Demyelination

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Ulrich, Reiner; Puff, Christina; Wewetzer, Konstantin; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang

2014-01-01

Canine distemper virus (CDV)-induced demyelinating leukoencephalitis in dogs (Canis familiaris) is suggested to represent a naturally occurring translational model for subacute sclerosing panencephalitis and multiple sclerosis in humans. The aim of this study was a hypothesis-free microarray analysis of the transcriptional changes within cerebellar specimens of five cases of acute, six cases of subacute demyelinating, and three cases of chronic demyelinating and inflammatory CDV leukoencephalitis as compared to twelve non-infected control dogs. Frozen cerebellar specimens were used for analysis of histopathological changes including demyelination, transcriptional changes employing microarrays, and presence of CDV nucleoprotein RNA and protein using microarrays, RT-qPCR and immunohistochemistry. Microarray analysis revealed 780 differentially expressed probe sets. The dominating change was an up-regulation of genes related to the innate and the humoral immune response, and less distinct the cytotoxic T-cell-mediated immune response in all subtypes of CDV leukoencephalitis as compared to controls. Multiple myelin genes including myelin basic protein and proteolipid protein displayed a selective down-regulation in subacute CDV leukoencephalitis, suggestive of an oligodendrocyte dystrophy. In contrast, a marked up-regulation of multiple immunoglobulin-like expressed sequence tags and the delta polypeptide of the CD3 antigen was observed in chronic CDV leukoencephalitis, in agreement with the hypothesis of an immune-mediated demyelination in the late inflammatory phase of the disease. Analysis of pathways intimately linked to demyelination as determined by morphometry employing correlation-based Gene Set Enrichment Analysis highlighted the pathomechanistic importance of up-regulated genes comprised by the gene ontology terms “viral replication” and “humoral immune response” as well as down-regulated genes functionally related to “metabolite and energy

Diagnostic transcranial magnetic stimulation in children with acute inflammatory demyelinating polyneuropathy

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V. B. Voitenkov

2016-01-01

Full Text Available Objective of our work was to evaluate MEPs characteristics in children with acute inflammatory demyelinating polyneuropathy and evaluate usefulness of TMS as an additional diagnostic method in this disorder.Methods. 20 healthy children (7–14 years old, average 12 years, 7 females, 13 males without any signs of neurological disorders were enrolled as controls and 37 patients (8–13 years old, average 11 years, 19 females, 18 males with AIDP were enrolled as the main group. EMG and TMS were performed on 3–7 day from the onset of the first symptoms. Cortical and lumbar MEP`s latencies, shapes and amplitudes and CMCT were averaged and analyzed.Results. Significant differences between children with AIDP and controls on latencies of both cortical and lumbar MEPs were registered. Cortical MEPs shapes were disperse in 100% of the cases, and lumbar MEPs were disperse in 57% of the cases. Amplitudes changes for both lumbar and cortical MEPs were not significant.Conclusions. Diagnostic transcranial magnetic stimulation on the early stage of the acute demyelinating polyneuropathy in children may be implemented as the additional tool. Main finding in this population is lengthening of the latency of cortical and lumbar motor evoked potentials. Disperse shape of the lumbar MEPs may also be used as the early sign of the acute demyelization of the peripheral nerves.

Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy

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Markvardsen, Lars Høj; Harbo, Thomas; Sindrup, Søren Hein

2014-01-01

evaluated after 3, 6 and 12 months. Primary end-points were changes in muscle strength evaluated by isokinetic dynamometry in four affected muscle groups and a composite score of muscle performance and function tests, including Medical Research Council (MRC) score, grip strength, 40-m walking test (40-MWT......BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is superior to placebo treatment for maintenance of muscle strength during 12 weeks in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). The present study evaluated whether SCIG preserves muscle strength for 1 year......) and nine-hole peg test (9-HPT). Secondary end-points were changes of each of the listed parameters at each time point as well as an overall disability sum score (ODSS). RESULTS: The dose of SCIG was significantly unaltered during the follow-up period. Overall the isokinetic dynamometry value increased by 7...

Cerebrospinal fluid analysis in the context of CNS demyelinating diseases

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Sandro Luiz de Andrade Matas

2013-09-01

Full Text Available The central nervous system demyelinating diseases are a group of disorders with different etiologies, characterized by inflammatory lesions that are associated with loss of myelin and eventually axonal damage. In this group the most studied ones are multiple sclerosis (MS, neuromyelitis optic (NMO and acute disseminated encephalomyelitis (ADEM. The cerebrospinal fluid is essential to differentiate between these different syndromes and to define multiple sclerosis, helping to assess the probability of Clinical Isolated Syndrome turn into multiple sclerosis.

Unusual features in chronic inflammatory demyelinating polyneuropathy: Good outcome after prolonged ventilatory support

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Sanjeev Jha

2011-01-01

Full Text Available Severe respiratory muscle paralysis and ventilatory failure is rare in chronic inflammatory demyelinating polyneuropathy (CIDP. We report a 14 year child who presented with respiratory failure, bulbar and multiple cranial nerves involvement along with bilateral phrenic nerve paralysis. He was diagnosed with CIDP after electrophysiological evaluation. He required AMBU ventilation for about 4 months (including domiciliary use, after which he recovered significantly. Along with several unusual features of CIDP, this report highlights good example of steady basic intensive care to save lives and rewarding outcome of prolonged respiratory support, provided by AMBU ventilation which is a rather primitive, but inexpensive device.

Sildenafil (Viagra Protective Effects on Neuroinflammation: The Role of iNOS/NO System in an Inflammatory Demyelination Model

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Catarina Raposo

2013-01-01

Full Text Available We recently demonstrated that sildenafil reduces the expression of cytokines, COX-2, and GFAP in a demyelinating model induced in wild-type (WT mice. Herein, the understandings of the neuroprotective effect of sildenafil and the mediation of iNOS/NO system on inflammatory demyelination induced by cuprizone were investigated. The cerebella of iNOS−/− mice were examined after four weeks of treatment with cuprizone alone or combined with sildenafil. Cuprizone increased GFAP, Iba-1, TNF-α, COX-2, IL-1β, and IFN-γ expression, decreased expression of glutathione S-transferase pi (GSTpi, and damaged myelin in iNOS−/− mice. Sildenafil reduced Iba-1, IFN-γ, and IL-1β levels but had no effect on the expression of GFAP, TNF-α, and COX-2 compared to the cuprizone group. Sildenafil elevated GSTpi levels and improved the myelin structure/ultrastructure. iNOS−/− mice suffered from severe inflammation following treatment with cuprizone, while WT mice had milder inflammation, as found in the previous study. It is possible that inflammatory regulation through iNOS-feedback is absent in iNOS−/− mice, making them more susceptible to inflammation. Sildenafil has at least a partial anti-inflammatory effect through iNOS inhibition, as its effect on iNOS−/− mice was limited. Further studies are required to explain the underlying mechanism of the sildenafil effects.

Treatment of pediatric chronic inflammatory demyelinating polyneuropathy: Challenges, controversies, and questions

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Jay Desai

2015-01-01

Full Text Available Pediatric chronic inflammatory demyelinating polyneuropathy (CIDP is an uncommon acquired disorder of unknown cause, presumed to have an immunological basis. We report 20 patients seen at Children′s Hospital Los Angeles over a period of 10 years. The outcome of our patients was favorable in a vast majority with good response to various treatments instituted. However, residual neurologic deficit was common. The choice of treatment modality was empirical and selected by the treating neurologist. Intravenous immunoglobulin (IVIG and corticosteroids were most commonly utilized for treatment. Plasmapheresis, mycophenolate mofetil, rituximab, cyclophosphamide, azathioprine, and abatacept were added if the patients were refractory to IVIG or became corticosteroid dependent. The spectrum of disease severity ranged from a single monophasic episode, to multiphasic with infrequent relapses with good response to IVIG, to progressive disease refractory to multiple therapies.

Alemtuzumab in the treatment of IVIG-dependent chronic inflammatory demyelinating polyneuropathy.

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Marsh, E A

2010-06-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an idiopathic immune mediated neuropathy causing demyelination and conduction block thought to occur as the result of an aberrant autoimmune response resulting in peripheral nerve inflammation mediated by T cells and humoral factors. Diagnosis commonly prompts initial treatment with steroids or intravenous immunoglobulin (IVIG) on which 5-35% subsequently become dependent to maintain function. Despite a number of small scale trials, the role for alternative long-term immunosuppression remains unclear. Alemtuzumab is a humanised monoclonal antibody targeting the CD52 antigen present on the surface of lymphocytes and monocytes. A single intravenous infusion results in rapid and profound lymphopoenia lasting >12 months. We report its use and clinical outcome in a small series of patients with severe IVIG-dependent CIDP. Seven patients (4 Males; 3 Females) who had failed to respond to conventional immunosuppression were treated in 5 centres receiving 9 courses of alemtuzumab (dose range 60-150 mg). Following treatment, mean monthly IVIG use fell 26% from 202 to 149 g and IVIG administration frequency from 22 to 136 days. Two patients had prolonged remission, two patients had a partial response and no clear benefit was observed in the remaining three patients (2 Males, 1 Females). Responding patients had a younger age at onset (19.5 years) and shorter disease duration than non-responders. Three patients developed autoimmune disease following treatment. Alemtuzumab may offer an alternative treatment for a subset of early onset IVIG dependent CIDP patients failing conventional immunosuppressive agents, but concerns about toxicity may limit its use.

Diffusion-weighted imaging in acute demyelinating myelopathy

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Zecca, Chiara; Cereda, Carlo; Tschuor, Silvia; Staedler, Claudio; Nadarajah, Navarajah; Bassetti, Claudio L.; Gobbi, Claudio; Wetzel, Stephan; Santini, Francesco

2012-01-01

Diffusion-weighted imaging (DWI) has become a reference MRI technique for the evaluation of neurological disorders. Few publications have investigated the application of DWI for inflammatory demyelinating lesions. The purpose of the study was to describe diffusion-weighted imaging characteristics of acute, spinal demyelinating lesions. Six consecutive patients (two males, four females; aged 28-64 years) with acute spinal cord demyelinating lesions were studied in a prospective case series design from June 2009 to October 2010. We performed magnetic resonance imaging studies from 2 to 14 days from symptom onset on the patients with relapsing remitting multiple sclerosis (n = 3) or clinically isolated syndrome (n = 3). Main outcome measures were diffusion-weighted imaging and apparent diffusion coefficient pattern (ADC) of acute spinal cord demyelinating lesions. All spinal lesions showed a restricted diffusion pattern (DWI+/ADC-) with a 24% median ADC signal decrease. A good correlation between clinical presentation and lesion site was observed. Acute demyelinating spinal cord lesions show a uniform restricted diffusion pattern. Clinicians and neuro-radiologists should be aware that this pattern is not necessarily confirmatory for an ischaemic aetiology. (orig.)

Diffusion-weighted imaging in acute demyelinating myelopathy

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Zecca, Chiara; Cereda, Carlo; Tschuor, Silvia; Staedler, Claudio; Nadarajah, Navarajah; Bassetti, Claudio L.; Gobbi, Claudio [Ospedale Regionale di Lugano, Servizio di Neurologia e Neuroradiologia, Neurocenter of Southern Switzerland, Lugano (Switzerland); Wetzel, Stephan [Swiss Neuro Institute (SNI), Abteilung fuer Neuroradiologie, Hirslanden Klinik Zuerich, Zuerich (Switzerland); Santini, Francesco [University of Basel Hospital, Division of Radiological Physics, Basel (Switzerland)

2012-06-15

Diffusion-weighted imaging (DWI) has become a reference MRI technique for the evaluation of neurological disorders. Few publications have investigated the application of DWI for inflammatory demyelinating lesions. The purpose of the study was to describe diffusion-weighted imaging characteristics of acute, spinal demyelinating lesions. Six consecutive patients (two males, four females; aged 28-64 years) with acute spinal cord demyelinating lesions were studied in a prospective case series design from June 2009 to October 2010. We performed magnetic resonance imaging studies from 2 to 14 days from symptom onset on the patients with relapsing remitting multiple sclerosis (n = 3) or clinically isolated syndrome (n = 3). Main outcome measures were diffusion-weighted imaging and apparent diffusion coefficient pattern (ADC) of acute spinal cord demyelinating lesions. All spinal lesions showed a restricted diffusion pattern (DWI+/ADC-) with a 24% median ADC signal decrease. A good correlation between clinical presentation and lesion site was observed. Acute demyelinating spinal cord lesions show a uniform restricted diffusion pattern. Clinicians and neuro-radiologists should be aware that this pattern is not necessarily confirmatory for an ischaemic aetiology. (orig.)

Changes in spatiotemporal gait parameters following intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy.

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Vo, Mary L; Chin, Russell L; Miranda, Caroline; Latov, Norman

2017-10-01

Gait impairment is a common presenting symptom in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, gait parameters have not previously been evaluated in detail as potential independent outcome measures. We prospectively measured changes in spatiotemporal gait parameters of 20 patients with CIDP at baseline and following treatment with intravenous immunoglobulin (IVIG), using GAITRite® a computerized walkway system with embedded sensors. Overall, study patients showed significant improvements in gait velocity, cadence, stride length, double support time, stance phase, and swing phase following IVIG treatment. Mean changes in velocity, stance phase, and swing phase, exhibited the greatest statistical significance among the subgroup that exhibited clinically meaningful improvement in Inflammatory Neuropathy Cause and Treatment disability score, Medical Research Council sum score, and grip strength. Assessment of gait parameters, in particular velocity, step phase and swing phase, is a potentially sensitive outcome measure for evaluating treatment response in CIDP. Muscle Nerve 56: 732-736, 2017. © 2017 Wiley Periodicals, Inc.

Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions.

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Steve Lacroix

Full Text Available The adult mammalian spinal cord has limited regenerative capacity in settings such as spinal cord injury (SCI and multiple sclerosis (MS. Recent studies have revealed that ependymal cells lining the central canal possess latent neural stem cell potential, undergoing proliferation and multi-lineage differentiation following experimental SCI. To determine whether reactive ependymal cells are a realistic endogenous cell population to target in order to promote spinal cord repair, we assessed the spatiotemporal dynamics of ependymal cell proliferation for up to 35 days in three models of spinal pathologies: contusion SCI using the Infinite Horizon impactor, focal demyelination by intraspinal injection of lysophosphatidylcholine (LPC, and autoimmune-mediated multi-focal demyelination using the active experimental autoimmune encephalomyelitis (EAE model of MS. Contusion SCI at the T9-10 thoracic level stimulated a robust, long-lasting and long-distance wave of ependymal proliferation that peaked at 3 days in the lesion segment, 14 days in the rostral segment, and was still detectable at the cervical level, where it peaked at 21 days. This proliferative wave was suppressed distal to the contusion. Unlike SCI, neither chemical- nor autoimmune-mediated demyelination triggered ependymal cell proliferation at any time point, despite the occurrence of demyelination (LPC and EAE, remyelination (LPC and significant locomotor defects (EAE. Thus, traumatic SCI induces widespread and enduring activation of reactive ependymal cells, identifying them as a robust cell population to target for therapeutic manipulation after contusion; conversely, neither demyelination, remyelination nor autoimmunity appears sufficient to trigger proliferation of quiescent ependymal cells in models of MS-like demyelinating diseases.

Anti-Ma2–associated limbic encephalitis with coexisting chronic inflammatory demyelinating polyneuropathy in a patient with non-Hodgkin lymphoma

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Ju, Weina; Qi, Baochang; Wang, Xu; Yang, Yu

2017-01-01

Abstract Rationale: We report the rare case of a 74-year-old man with anti-Ma2–associated paraneoplastic neurologic syndrome (PNS), and review and analyze the clinical manifestations, diagnosis, and treatment of the disease. Patient concerns: The patient presented with a 5-month history of muscle weakness, progressive body aches, and weakness and numbness in both lower extremities. Before his hospitalization, he had experienced cognitive function decline; ptosis, inward gaze, and vertical gaze palsy in the right eye; and occasional visual hallucinations. Brain and spinal cord magnetic resonance imaging (MRI) yielded normal results. Anti-Ma2 antibodies were detected in both serum and cerebrospinal fluid. A 4-hour electroencephalogram showed irregular sharp slow waves and δ waves in the temporal region. Electromyography showed peripheral nerve demyelination. Positron-emission tomography/computed tomography (PET-CT) examination revealed hypermetabolism in the lymph nodes of the whole body. Biopsy of the lymph nodes showed non-Hodgkin lymphoma. Diagnosis: A clinical diagnosis of lymphoma and PNS was made. Interventions: The patient was treated with intravenous dexamethasone (15 mg/day) for 3 days. Lessons: We have presented a rare case of a PNS involving both the central and peripheral nervous systems. The clinical features of this case indicated anti-Ma2–associated encephalitis and chronic inflammatory demyelinating polyneuropathy. PET-CT played a critical role in enabling early diagnosis and prompt treatment in this case. PMID:28984777

Nerve sonography in multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy

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D. S. Druzhinin

2016-01-01

Full Text Available The quantitative ultrasound characteristics (USC of the median, ulnar nerve at different levels and the spinal nerves in patients with multifocal motor neuropathy (MMN; n=13; 40,4 ± 12,6 years old and chronic inflammatory demyelinating polyneuropathy (CIDP; n = 7; 47,3 ± 11,2 year old did not reveal statistical difference in cross sectional area (CSA between analyzed groups. Patients with MMN have more pronounced asymmetry of CSA in comparison with CIDP patients which have a symmetrical pattern of diffuse nerve involvement. Quantitative USC has shown to be not informative enough in differentiation of MMN and CIDP. The qualitative analysis (QA according to 3 described types of nerve changes has shown that CIDP is characterized by the prevalence of type 3 pattern (85.8 % while MMN – by type 2 (69.2 %. The sensitivity and specificity of proposed QA patterns in nerve USC need to be analyzed in additional investigations. 

Anti-Ma2-associated limbic encephalitis with coexisting chronic inflammatory demyelinating polyneuropathy in a patient with non-Hodgkin lymphoma: A case report.

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Ju, Weina; Qi, Baochang; Wang, Xu; Yang, Yu

2017-10-01

We report the rare case of a 74-year-old man with anti-Ma2-associated paraneoplastic neurologic syndrome (PNS), and review and analyze the clinical manifestations, diagnosis, and treatment of the disease. The patient presented with a 5-month history of muscle weakness, progressive body aches, and weakness and numbness in both lower extremities. Before his hospitalization, he had experienced cognitive function decline; ptosis, inward gaze, and vertical gaze palsy in the right eye; and occasional visual hallucinations. Brain and spinal cord magnetic resonance imaging (MRI) yielded normal results. Anti-Ma2 antibodies were detected in both serum and cerebrospinal fluid. A 4-hour electroencephalogram showed irregular sharp slow waves and δ waves in the temporal region. Electromyography showed peripheral nerve demyelination. Positron-emission tomography/computed tomography (PET-CT) examination revealed hypermetabolism in the lymph nodes of the whole body. Biopsy of the lymph nodes showed non-Hodgkin lymphoma. A clinical diagnosis of lymphoma and PNS was made. The patient was treated with intravenous dexamethasone (15 mg/day) for 3 days. We have presented a rare case of a PNS involving both the central and peripheral nervous systems. The clinical features of this case indicated anti-Ma2-associated encephalitis and chronic inflammatory demyelinating polyneuropathy. PET-CT played a critical role in enabling early diagnosis and prompt treatment in this case.

Quantifying Demyelination in NK venom treated nerve using its electric circuit model.

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Das, H K; Das, D; Doley, R; Sahu, P P

2016-03-02

Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination.

Quantifying Demyelination in NK venom treated nerve using its electric circuit model

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Das, H. K.; Das, D.; Doley, R.; Sahu, P. P.

2016-03-01

Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination.

Patient with neuromyelitis optica and inflammatory demyelinating lesions comprising whole spinal cord from C2 level till conus: case report

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Pavlisa Goran

2009-10-01

Full Text Available Abstract Background Neuromyelitis optica (NMO is an idiopathic, severe, inflammatory demyelinating disease of the central nervous system, that causes severe optic neuritis and myelitis attacks. Early discrimination between multiple sclerosis (MS and NMO is important, as optimum treatment for both diseases may differ considerably. Case Presentation We report a case of a patient who initially presented as longitudinally extensive transverse myelitis (LETM, having spastic upper extremities diparesis and spastic paraplegia, C2/C3 sensory level and urinary incontinence, as well as extensive inflammatory spinal cord lesions from C2 level to conus. After 5 months the patient had another attack of transverse myelitis, had electrophysiological findings consistent with optic neuritis, was seropositive for NMO-IgG (aquaporin-4 IgG and thus fulfilled NMO diagnostic criteria. Following treatment of disease attacks with pulse corticosteroid therapy and intravenous immunoglobulins, we included oral azathioprine in a combination with oral prednisone in the therapy. Since there was no significant clinical improvement, we decided to use cyclophosphamide therapy, which resulted in good clinical improvement and gradual decrease of cord swelling. Conclusion In this NMO case report we wanted to emphasize the extensiveness of inflammatory spinal cord changes in our patient, from C2 level to conus. In the conclusion it is important to say that accurate, early diagnosis and distinction from MS is critical to facilitate initiation of immunosuppressive therapy for attack prevention.

Disease Type- and Status-Specific Alteration of CSF Metabolome Coordinated with Clinical Parameters in Inflammatory Demyelinating Diseases of CNS.

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Soo Jin Park

Full Text Available Central nervous system (CNS inflammatory demyelinating diseases (IDDs are a group of disorders with different aetiologies, characterized by inflammatory lesions. These disorders include multiple sclerosis (MS, neuromyelitis optica spectrum disorder (NMOSD, and idiopathic transverse myelitis (ITM. Differential diagnosis of the CNS IDDs still remains challenging due to frequent overlap of clinical and radiological manifestation, leading to increased demands for new biomarker discovery. Since cerebrospinal fluid (CSF metabolites may reflect the status of CNS tissues and provide an interfacial linkage between blood and CNS tissues, we explored multi-component biomarker for different IDDs from CSF samples using gas chromatography mass spectrometry-based metabolite profiling coupled to multiplex bioinformatics approach. We successfully constructed the single model with multiple metabolite variables in coordinated regression with clinical characteristics, expanded disability status scale, oligoclonal bands, and protein levels. The multi-composite biomarker simultaneously discriminated four different immune statuses (a total of 145 samples; 54 MS, 49 NMOSD, 30 ITM, and 12 normal controls. Furthermore, systematic characterization of transitional metabolic modulation identified relapse-associated metabolites and proposed insights into the disease network underlying type-specific metabolic dysfunctionality. The comparative analysis revealed the lipids, 1-monopalmitin and 1-monostearin were common indicative for MS, NMOSD, and ITM whereas fatty acids were specific for the relapse identified in all types of IDDs.

Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.

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di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X; Villoslada, Pablo

2013-01-01

Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines

Application of the 2012 revised diagnostic definitions for paediatric multiple sclerosis and immune-mediated central nervous system demyelination disorders

NARCIS (Netherlands)

van Pelt, E. Danielle; Neuteboom, Rinze F.; Ketelslegers, Immy A.; Boon, Maartje; Catsman-Berrevoets, Coriene E.; Hintzen, Rogier Q.

Background Recently, the International Paediatric Multiple Sclerosis Study Group (IPMSSG) definitions for the diagnosis of immune-mediated acquired demyelinating syndromes (ADS) of the central nervous system, including paediatric multiple sclerosis (MS), have been revised. Objective To evaluate the

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain.

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Berghoff, Stefan A; Gerndt, Nina; Winchenbach, Jan; Stumpf, Sina K; Hosang, Leon; Odoardi, Francesca; Ruhwedel, Torben; Böhler, Carolin; Barrette, Benoit; Stassart, Ruth; Liebetanz, David; Dibaj, Payam; Möbius, Wiebke; Edgar, Julia M; Saher, Gesine

2017-01-24

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes.

Microglial recruitment, activation, and proliferation in response to primary demyelination

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Remington, Leah T; Babcock, Alicia A; Zehntner, Simone P

2007-01-01

We have characterized the cellular response to demyelination/remyelination in the central nervous system using the toxin cuprizone, which causes reproducible demyelination in the corpus callosum. Microglia were distinguished from macrophages by relative CD45 expression (CD45(dim)) using flow cyto...

Chronic Inflammatory Demyelinating Polyneuropathy in Children: A Review of Clinical Characteristics and Recommendations for Treatment

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Narges Karimi

2015-07-01

Full Text Available Context: Chronic inflammatory demyelinating polyradiculopathy (CIDP is an acquired and autoimmune neuropathy, characterized by a chronic, rapidly progressive, symmetric weakness. In children, abnormal gait is as a first symptom of muscle weakness. Evidence Acquisition: The diagnosis of CIDP is on the basis of clinical characteristics, electrodiagnostic that shows the severity of the disease, lumbar puncture and spine magnetic resonance imaging (MRI. Results: The first-line treatments in childhood CIDP are intravenous immunoglobulin (IVIG, corticosteroids, and plasmapheresis. Response to first-line therapies is usually satisfactory; nevertheless, recommendations regarding the choice of second-line therapy can only be prepared on the basis of the existing practice described in some of the case reports. Conclusions: This review demonstrated the clinical presentation, diagnosis, and treatment of childhood CIDP.

Astrogliosis During Acute and Chronic Cuprizone Demyelination and Implications for Remyelination

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Norah Hibbits

2012-10-01

Full Text Available In multiple sclerosis, microglia/macrophage activation and astrocyte reactivity are important components of the lesion environment that can impact remyelination. The current study characterizes these glial populations relative to expression of candidate regulatory molecules in cuprizone demyelinated corpus callosum. Importantly, periods of recovery after acute or chronic cuprizone demyelination are examined to compare conditions of efficient versus limited remyelination, respectively. Microglial activation attenuates after early demyelination. In contrast, astrocyte reactivity persists throughout demyelination and a 6-week recovery period following either acute or chronic demyelination. This astrocyte reaction is characterized by (a early proliferation, (b increased expression of GFAP (glial fibrillary acidic protein, Vim (vimentin, Fn1 (fibronectin and CSPGs (chondroitin sulphate proteoglycans and (c elaboration of a dense network of processes. Glial processes elongated in the axonal plane persist throughout lesion areas during both the robust remyelination that follows acute demyelination and the partial remyelination that follows chronic demyelination. However, prolonged astrocyte reactivity with chronic cuprizone treatment does not progress to barrier formation, i.e. dense compaction of astrocyte processes to wall off the lesion area. Multiple candidate growth factors and inflammatory signals in the lesion environment show strong correlations with GFAP across the acute cuprizone demyelination and recovery time course, yet there is more divergence across the progression of chronic cuprizone demyelination and recovery. However, differential glial scar formation does not appear to be responsible for differential remyelination during recovery in the cuprizone model. The astrocyte phenotype and lesion characteristics in this demyelination model inform studies to identify triggers of non-remyelinating sclerosis in chronic multiple sclerosis

Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

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di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

2013-01-01

Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. Conclusion The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of

Nerve Ultrasound Predicts Treatment Response in Chronic Inflammatory Demyelinating Polyradiculoneuropathy-a Prospective Follow-Up.

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Härtig, Florian; Ross, Marlene; Dammeier, Nele Maria; Fedtke, Nadin; Heiling, Bianka; Axer, Hubertus; Décard, Bernhard F; Auffenberg, Eva; Koch, Marilin; Rattay, Tim W; Krumbholz, Markus; Bornemann, Antje; Lerche, Holger; Winter, Natalie; Grimm, Alexander

2018-04-01

As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naïve. At baseline, clinical scores correlated with NCSS (r 2  = 0.397 and r 2  = 0.443, p  50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned-out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification of disease state and may predict treatment response.

Apoptosis of infiltrating T cells in the central nervous system of mice infected with Theiler's murine encephalomyelitis virus

International Nuclear Information System (INIS)

Oleszak, Emilia L.; Hoffman, Brad E.; Chang, J. Robert; Zaczynska, Ewa; Gaughan, John; Katsetos, Christos D.; Platsoucas, Chris D.; Harvey, Nile

2003-01-01

Theiler murine encephalomyelitis virus (TMEV), DA strain, induces in susceptible strain of mice a biphasic disease consisting of early acute disease followed by late chronic demyelinating disease. Both phases of the disease are associated with inflammatory infiltrates of the central nervous system (CNS). Late chronic demyelinating disease induced by TMEV serves as an excellent model to study human demyelinating disease, multiple sclerosis. During early acute disease, the virus is partially cleared from the CNS by CD3 + T cells. These T cells express Fas, FasL, negligible levels of Bcl-2 proteins and undergo activation-induced cell death as determined by TUNEL assay leading to resolution of the inflammatory response. In contrast, during late chronic demyelinating disease, and despite dense perivascular and leptomeningeal infiltrates, only very few cells undergo apoptosis. Mononuclear cells infiltrating the CNS express Bcl-2. It appears that the lack of apoptosis of T cells during late chronic demyelinating disease leads to the accumulation of these cells in the CNS. These cells may play a role in the pathogenesis of the demyelinating disease

Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic

DEFF Research Database (Denmark)

Theibich, Ali; Dreyer, Lene; Magyari, Melinda

2014-01-01

Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling...... multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after...... treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all...

Acute Demyelinating Disease after Oral Therapy with Herbal Extracts

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Alex Kostianovsky

2011-06-01

Full Text Available Central nervous system demyelinating processes such as multiple sclerosis and acute disseminated encephalomyelitis constitute a group of diseases not completely understood in their physiopathology. Environmental and toxic insults are thought to play a role in priming autoimmunity. The aim of the present report is to describe a case of acute demyelinating disease with fatal outcome occurring 15 days after oral exposure to herbal extracts.

Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy

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Markvardsen, L H; Sindrup, S H; Christiansen, I

2017-01-01

BACKGROUND AND PURPOSE: Subcutaneous immunoglobulin (SCIG) is effective as maintenance treatment in chronic inflammatory demyelinating polyneuropathy (CIDP). We investigated whether multiple subcutaneous infusions are as effective as conventional therapy with intravenous loading doses in treatment...... treatment arm and followed for a further 10 weeks. All participants were evaluated at weeks 0, 2, 5 and 10 during both therapies. Primary outcome was combined isokinetic muscle strength (cIKS). Secondary outcomes were disability, clinical evaluation of muscle strength and the performance of various function...... tests. RESULTS: All participants received both therapies, 14 completing the protocol. Overall, cIKS increased by 7.4 ± 14.5% (P = 0.0003) during SCIG and by 6.9 ± 16.8% (P = 0.002) during IVIG, the effect being similar (P = 0.80). Improvement of cIKS peaked 2 weeks after IVIG and 5 weeks after SCIG...

Immunological Demyelination Triggers Macrophage/Microglial Cells Activation without Inducing Astrogliosis

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Frank Cloutier

2013-01-01

Full Text Available The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP. Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells.

Metallothionein expression in the central nervous system of multiple sclerosis patients

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Penkowa, M; Espejo, C; Ortega-Aznar, A

2003-01-01

Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS...

CD8+ T cells in inflammatory demyelinating disease

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Weiss, Hanne A; Millward, Jason M; Owens, Trevor

2007-01-01

We review the contribution made by CD8+ T cells to inflammation in the central nervous system (CNS) in Multiple Sclerosis (MS), and discuss their role in the animal model Experimental Autoimmune Encephalomyelitis (EAE). We show that the inflammatory cytokines interferon-gamma and interleukin-17...... are differentially regulated in CNS-infiltrating CD4+ and CD8+ T cells in EAE, and that CD8+ T cells regulate disease. In MS, CD8+ T cells appear to play a role in promotion of disease, so cytokine regulation is likely different in CD8+ T cells in MS and EAE...

Long-Lasting Cranial Nerve III Palsy as a Presenting Feature of Chronic Inflammatory Demyelinating Polyneuropathy

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Rossella Spataro

2015-01-01

Full Text Available We describe a patient with chronic inflammatory demyelinating polyneuropathy (CIDP in which an adduction deficit and ptosis in the left eye presented several years before the polyneuropathy. A 52-year-old man presented with a 14-year history of unremitting diplopia, adduction deficit, and ptosis in the left eye. At the age of 45 a mild bilateral foot drop and impaired sensation in the four limbs appeared, with these symptoms showing a progressive course. The diagnostic workup included EMG/ENG which demonstrated reduced conduction velocity with bilateral and symmetrical sensory and motor involvement. Cerebrospinal fluid studies revealed a cytoalbuminologic dissociation. A prolonged treatment with corticosteroids allowed a significant improvement of the limb weakness. Diplopia and ptosis remained unchanged. This unusual form of CIDP presented as a long-lasting isolated cranial nerve palsy. A diagnostic workup for CIDP should therefore be performed in those patients in which an isolated and unremitting cranial nerve palsy cannot be explained by common causes.

Inhibition of GABA A receptor improved special memory impairment in the local model of demyelination in rat hippocampus.

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Mousavi Majd, Alireza; Ebrahim Tabar, Forough; Afghani, Arghavan; Ashrafpour, Sahand; Dehghan, Samaneh; Gol, Mohammad; Ashrafpour, Manouchehr; Pourabdolhossein, Fereshteh

2018-01-15

Cognitive impairment and memory deficit are common features in multiple Sclerosis patients. The mechanism of memory impairment in MS is unknown, but neuroimaging studies suggest that hippocampal demyelination is involved. Here, we investigate the role of GABA A receptor on spatial memory in the local model of hippocampal demyelination. Demyelination was induced in male Wistar rats by bilaterally injection of lysophosphatidylcholine (LPC) 1% into the CA1 region of the hippocampus. The treatment groups were received daily intraventricular injection of bicuculline (0.025, 0.05μg/2μl/animal) or muscimol (0.1, 0.2μg/2μl/animal) 5days after LPC injection. Morris Water Maze was used to evaluate learning and memory in rats. We used Luxol fast blue staining and qPCR to assess demyelination extention and MBP expression level respectively. Immunohistochemistry (IHC) for CD45 and H&E staining were performed to assess inflammatory cells infiltration. Behavioral study revealed that LPC injection in the hippocampus impaired learning and memory function. Animals treated with both doses of bicuculline improved spatial learning and memory function; however, muscimol treatment had no effect. Histological and MBP expression studies confirmed that demylination in LPC group was maximal. Bicuculline treatment significantly reduced demyelination extension and increased the level of MBP expression. H&E and IHC results showed that bicuculline reduced inflammatory cell infiltration in the lesion site. Bicuculline improved learning and memory and decreased demyelination extention in the LPC-induced hippocampal demyelination model. We conclude that disruption of GABAergic homeostasis in hippocampal demyelination context may be involved in memory impairment with the implications for both pathophysiology and therapy. Copyright © 2017. Published by Elsevier B.V.

Regional oligodendrocytopathy and astrocytopathy precede myelin loss and blood-brain barrier disruption in a murine model of osmotic demyelination syndrome.

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Bouchat, Joanna; Couturier, Bruno; Marneffe, Catherine; Gankam-Kengne, Fabrice; Balau, Benoît; De Swert, Kathleen; Brion, Jean-Pierre; Poncelet, Luc; Gilloteaux, Jacques; Nicaise, Charles

2018-03-01

The osmotic demyelination syndrome (ODS) is a non-primary inflammatory disorder of the central nervous system myelin that is often associated with a precipitous rise of serum sodium concentration. To investigate the physiopathology of ODS in vivo, we generated a novel murine model based on the abrupt correction of chronic hyponatremia. Accordingly, ODS mice developed impairments in brainstem auditory evoked potentials and in grip strength. At 24 hr post-correction, oligodendrocyte markers (APC and Cx47) were downregulated, prior to any detectable demyelination. Oligodendrocytopathy was temporally and spatially correlated with the loss of astrocyte markers (ALDH1L1 and Cx43), and both with the brain areas that will develop demyelination. Oligodendrocytopathy and astrocytopathy were confirmed at the ultrastructural level and culminated with necroptotic cell death, as demonstrated by pMLKL immunoreactivity. At 48 hr post-correction, ODS brains contained pathognomonic demyelinating lesions in the pons, mesencephalon, thalamus and cortical regions. These damages were accompanied by blood-brain barrier (BBB) leakages. Expression levels of IL-1β, FasL, TNFRSF6 and LIF factors were significantly upregulated in the ODS lesions. Quiescent microglial cells type A acquired an activated type B morphology within 24 hr post-correction, and reached type D at 48 hr. In conclusion, this murine model of ODS reproduces the CNS demyelination observed in human pathology and indicates ambiguous causes that is regional vulnerability of oligodendrocytes and astrocytes, while it discards BBB disruption as a primary cause of demyelination. This study also raises new queries about the glial heterogeneity in susceptible brain regions as well as about the early microglial activation associated with ODS. © 2017 Wiley Periodicals, Inc.

A novel paraneoplastic syndrome with acquired lipodystrophy and chronic inflammatory demyelinating polyneuropathy in an adolescent male with craniopharyngioma.

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Lockemer, Hillary Elizabeth; Sumpter, Kathryn Maria; Cope-Yokoyama, Sandy; Garg, Abhimanyu

2018-03-28

Acquired lipodystrophy, craniopharyngioma and chronic inflammatory demyelinating polyneuropathy (CIDP) are individually rare disorders, and have never before been reported in a single patient. A 15-year-7 month old Caucasian male presented with lower extremity weakness, frequent falls and abnormal fat distribution occurring over the previous 1 year. He was diagnosed with CIDP, craniopharyngioma and acquired lipodystrophy. The patient underwent tumor debulking and cranial irradiation for the craniopharyngioma, and received monthly intravenous immunoglobulin for the CIDP. The patient initially had some resolution of the lipodystrophy phenotype, but subsequently the abnormal fat distribution recurred and the patient developed additional systemic abnormalities, including mild pancytopenia and hepatic fibrosis. Our patient represents a novel association of acquired lipodystrophy, craniopharyngioma, and CIDP, possibly due to an as yet unidentified paraneoplastic autoantibody.

Diagnostic criteria of chronic inflammatory demyelinating polyneuropathy in diabetes mellitus.

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Lotan, I; Hellman, M A; Steiner, I

2015-10-01

The possibility of co-association between diabetes mellitus (DM) and chronic inflammatory demyelinating polyneuropathy (CIDP) has long been a focus of interest as well as of clinical significance. As CIDP is a potentially treatable condition, it is diagnosis in the context of DM is of great importance. However, diagnostic criteria to identify CIDP in patients with diabetes are not available. We propose a diagnostic tool that should help clinicians to decide what is the probability that a patient with diabetes might have CIDP. We list several clinical, electrophysiological, and laboratory parameters that, when combined, have the power of discriminating an immune-mediated neuropathy in patients with DM. By summing the points assigned to each of these parameters, we define four levels of probability for a patient with diabetes to have CIDP. To analyze the validity of the diagnostic toll, we applied it in three different patient populations: (i) Patients with diabetes with peripheral neuropathy, (ii) Patients with CIDP without DM, and (iii) Patients with diabetes with CIDP. The scores of patients with diabetes without CIDP ranged from -7 to 2, while those of patients with DM-CIDP ranged from 2 to 20. The scores of non-diabetic patients with CIDP were similar to those of patients with DM-CIDP and ranged from 6 to 16. The mean score of patients with DM-CIDP was 9.083, while the score of patients with CIDP was 11.16 and that of patients with diabetic polyneuropathy was -3.59. These results show that this diagnostic tool is able to identify patients with diabetes with overlapping CIDP. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Relapsing and Progressive Tumefactive Demyelinating Form of Central Nervous System Involvement in a Patient with Progressive Systemic Sclerosis

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Kim, Ho Kyun; Lee, Hui Joong

2013-01-01

White matter hyper intensities (WMHI) on MRI are not rare in patients with progressive systemic sclerosis (PSS). In this presentation, WMHI were developed in both middle cerebellar peduncles and temporal white matter in a patient with PSS, and regressed after medication of high dose steroid. However, new lesions were developed in the subcortices of both precentral gyri, and progressed rapidly to tumefactive hyperintensity on MRI. We report an unusual relapsing and progressive tumefactive demyelinating form of central nervous system involvement in PSS.

Demyelinating diseases in Asia.

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Ochi, Hirofumi; Fujihara, Kazuo

2016-06-01

The present review aims to discuss the recent advances in inflammatory demyelinating diseases of the central nervous system in Asia. Prevalence of multiple sclerosis (MS) in Asia is lower than that in Western countries, although it has been increasing recently. Meanwhile, there seems to be no major difference in neuromyelitis optica (NMO) prevalence in various regions or ethnicities. Thus, the ratios of NMO/NMO spectrum disorder (NMOSD) to MS are higher in Asia as compared with Western countries, indicating that the differential diagnosis between NMO/NMOSD and MS is a major challenge in Asia. Although the detection of aquaporin-4 (AQP4)-antibody is critical in distinguishing NMO/NMOSD from MS, some patients with NMO/NMOSD phenotype are seronegative for AQP4-antibody, and a fraction of those patients possess autoantibody against myelin oligodendrocyte glycoprotein. The clinical profile of Asian MS seems to be essentially similar to that in Western MS after careful exclusion of NMO/NMOSD, although some unique genetic and/or environmental factors may modify the disease in Asians. MS prevalence has been low but is increasing in Asia. In contrast, NMO/NMOSD prevalence seems relatively constant in the world. Asian MS is not fundamentally different from Western MS, but some genetic and/or environmental differences may cause some features unique to Asian patients.

Demyelinating disease masquerading as a surgical problem: a case series

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Awang Saufi M

2009-08-01

Full Text Available Abstract Introduction We report three cases of demyelinating disease with tumor-like presentation. This information is particularly important to both neurosurgeons and neurologists who should be aware that inflammatory demyelinating diseases can present as a mass lesion, which is indistinguishable from a tumor, both clinically and radiologically, especially when there is no evidence of temporal dissemination of this disease. Case presentation The first patient was a 42-year-old Malay woman who developed subacute onset of progressive quadriparesis with urinary incontinence. Magnetic resonance imaging of her spine showed an intramedullary lesion at the C5-C7 level. She was operated on and biopsy was suggestive of a demyelinating disease. Retrospective history discovered two episodes of acute onset of neurological deficits with partial recovery and magnetic resonance imaging of her brain revealed demyelinating plaques in the centrum semiovale. The second patient was a 16-year-old Malay boy who presented with symptoms of raised intracranial pressure. A computed tomography brain scan revealed obstructive hydrocephalus with a lesion adjacent to the fourth ventricle. An external ventricular drainage was inserted. Subsequently, a stereotactic biopsy was taken and histopathology was reported as demyelination. Retrospective history revealed similar episodes with full recovery in between episodes. The third case was a 28-year-old Malay man who presented with acute bilateral visual loss and confusion. Magnetic resonance imaging of his brain showed a large mass lesion in the right temporoparietal region. Biopsy was consistent with demyelinating disease. Reexamination of the patient revealed bilateral papillitis and not papilledema. Visual evoked potential was prolonged bilaterally. In all three cases, lumbar puncture for cerebrospinal fluid study was not carried out due to lack of patient consent. Conclusions These cases illustrate the importance of

B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination.

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Kavitha Kothur

Full Text Available Myelin oligodendrocyte glycoprotein antibody (MOG Ab associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination.To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS and -negative (NEG groups.We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8, transverse myelitis (TM = 2 n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9 demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls.The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19 as well as some of Th17 related cytokines (IL-6 AND G-CSF compared to MOG Ab NEG group (all p<0.01. In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies.Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets.

Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study.

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Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

2013-09-15

to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy.

Corpus callosum demyelination associated with acquired stuttering.

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Decker, Barbara McElwee; Guitar, Barry; Solomon, Andrew

2018-04-21

Compared with developmental stuttering, adult onset acquired stuttering is rare. However, several case reports describe acquired stuttering and an association with callosal pathology. Interestingly, these cases share a neuroanatomical localisation also demonstrated in developmental stuttering. We present a case of adult onset acquired stuttering associated with inflammatory demyelination within the corpus callosum. This patient's disfluency improved after the initiation of immunomodulatory therapy. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Resistance training and aerobic training improve muscle strength and aerobic capacity in chronic inflammatory demyelinating polyneuropathy.

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Markvardsen, Lars H; Overgaard, Kristian; Heje, Karen; Sindrup, Søren H; Christiansen, Ingelise; Vissing, John; Andersen, Henning

2018-01-01

We investigated the effects of aerobic and resistance exercise in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Eighteen CIDP patients treated with subcutaneous immunoglobulin performed 12 weeks of aerobic exercise and 12 weeks of resistance exercise after a run-in period of 12 weeks without exercise. Three times weekly the participants performed aerobic exercise on an ergometer bike or resistance exercise with unilateral training of knee and elbow flexion/extension. Primary outcomes were maximal oxygen consumption velocity (VO 2 -max) and maximal combined isokinetic muscle strength (cIKS) of knee and elbow flexion/extension. VO 2 -max and muscle strength were unchanged during run-in (-4.9% ± 10.3%, P = 0.80 and -3.7% ± 10.1%, P = 0.17, respectively). Aerobic exercise increased VO 2 -max by 11.0% ± 14.7% (P = 0.02). Resistance exercise resulted in an increase of 13.8% ± 16.0% (P = 0.0004) in cIKS. Aerobic exercise training and resistance exercise training improve fitness and strength in CIDP patients. Muscle Nerve 57: 70-76, 2018. © 2017 Wiley Periodicals, Inc.

Osmotic demyelination syndrome with recent chemotherapy in normonatremic patient: A case report

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Lee, Sungjae; Baek, Hye Jin; Jung, Hyun Kyung; Kim, Seon Jeong; Lee, Yedaun; Lee, Kwaghwi; Ryu, Ji Hwa; Kim, Hong Dae [Dept. of Radiology, Haeundae Paik Hospital, Inje University College of Medicine, Busan (Korea, Republic of)

2014-11-15

Osmotic demyelination syndrome (ODS), an acquired demyelinating condition of the central pons and/or other regions of the brain, is frequently associated with rapid correction of hyponatremia. There are several reports of ODS in other clinical setting such as malnutrition, alcoholism, transplantation, malignancy, and chronic debilitating illness. However, cases of ODS associated with chemotherapy have not been frequently reported. Here, we describe a case of ODS in a normonatremic patient recently underwent chemotherapy for colon cancer. The diagnosis was confirmed by MRI showing a typical T2 hyperintensity in the central pons. This case suggests that ODS is not always associated with hyponatremia and that ODS can have a favorable clinical and radiologic prognosis.

Progesterone therapy induces an M1 to M2 switch in microglia phenotype and suppresses NLRP3 inflammasome in a cuprizone-induced demyelination mouse model.

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Aryanpour, Roya; Pasbakhsh, Parichehr; Zibara, Kazem; Namjoo, Zeinab; Beigi Boroujeni, Fatemeh; Shahbeigi, Saeed; Kashani, Iraj Ragerdi; Beyer, Cordian; Zendehdel, Adib

2017-10-01

Demyelination of the central nervous system (CNS) has been associated to reactive microglia in neurodegenerative disorders, such as multiple sclerosis (MS). The M1 microglia phenotype plays a pro-inflammatory role while M2 is involved in anti-inflammatory processes in the brain. In this study, CPZ-induced demyelination mouse model was used to investigate the effect of progesterone (PRO) therapy on microglia activation and neuro-inflammation. Results showed that progesterone therapy (CPZ+PRO) decreased neurological behavioral deficits, as demonstrated by significantly decreased escape latencies, in comparison to CPZ mice. In addition, CPZ+PRO caused a significant reduction in the mRNA expression levels of M1-markers (iNOS, CD86, MHC-II and TNF-α) in the corpus callosum region, whereas the expression of M2-markers (Trem-2, CD206, Arg-1 and TGF-β) was significantly increased, in comparison to CPZ mice. Moreover, CPZ+PRO resulted in a significant decrease in the number of iNOS + and Iba-1 + /iNOS + cells (M1), whereas TREM-2 + and Iba-1 + /TREM-2 + cells (M2) significantly increased, in comparison to CPZ group. Furthermore, CPZ+PRO caused a significant decrease in mRNA and protein expression levels of NLRP3 and IL-18 (~2-fold), in comparison to the CPZ group. Finally, CPZ+PRO therapy was accompanied with reduced levels of demyelination, compared to CPZ, as confirmed by immunofluorescence to myelin basic protein (MBP) and Luxol Fast Blue (LFB) staining, as well as transmission electron microscopy (TEM) analysis. In summary, we reported for the first time that PRO therapy causes polarization of M2 microglia, attenuation of M1 phenotype, and suppression of NLRP3 inflammasome in a CPZ-induced demyelination model of MS. Copyright © 2017 Elsevier B.V. All rights reserved.

A rare presentation of atypical demyelination: tumefactive multiple sclerosis causing Gerstmann’s syndrome

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2014-01-01

Background Tumefactive demyelinating lesions are a rare manifestation of multiple sclerosis (MS). Differential diagnosis of such space occupying lesions may not be straightforward and sometimes necessitate brain biopsy. Impaired cognition is the second most common clinical manifestation of tumefactive MS; however complex cognitive syndromes are unusual. Case presentation We report the case of a 30 year old woman who presented with Gerstmann’s syndrome. MRI revealed a large heterogeneous contrast enhancing lesion in the left cerebral hemisphere. Intravenous corticosteroids did not stop disease progression. A tumour or cerebral lymphoma was suspected, however brain biopsy confirmed inflammatory demyelination. Following diagnosis of tumefactive MS treatment with natalizumab effectively suppressed disease activity. Conclusions The case highlights the need for clinicians, radiologists and surgeons to appreciate the heterogeneous presentation of tumefactive MS. Early brain biopsy facilitates rapid diagnosis and management. Treatment with natalizumab may be useful in cases of tumefactive demyelination where additional evidence supports a diagnosis of relapsing MS. PMID:24694183

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

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Akutsu, Yuko; Shirai, Kentaro; Takei, Akira; Goto, Yudai; Aoyama, Tomohiro; Watanabe, Akimitu; Imamura, Masatoshi; Enokizono, Takashi; Ohto, Tatsuyuki; Hori, Tetsuo; Suzuki, Keiko; Hayashi, Masaharu; Masumoto, Kouji; Inoue, Ken

2018-05-01

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations. © 2018 Wiley Periodicals, Inc.

Curcumin-loaded nanoparticles ameliorate glial activation and improve myelin repair in lyolecithin-induced focal demyelination model of rat corpus callosum.

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Naeimi, Reza; Safarpour, Fatemeh; Hashemian, Mona; Tashakorian, Hamed; Ahmadian, Seyed Raheleh; Ashrafpour, Manouchehr; Ghasemi-Kasman, Maryam

2018-05-01

Curcumin has been introduced as effective anti-inflammatory agent in treatment of several inflammatory disorders. Despite the wide range pharmacological activities, clinical application of curcumin is restricted mainly due to the low water solubility of this substance. More recently, we could remarkably improve the aqueous solubility of curcumin by its encapsulation in chitosan-alginate-sodium tripolyphosphate nanoparticles (CS-ALG-STPP NPs). In this study, the anti-inflammatory and myelin protective effects of curcumin-loaded NPs were evaluated in lysolecithin (LPC)-induced focal demyelination model. Pharmacokinetic of curcumin was assessed using high performance liquid chromatography (HPLC). Local demyelination was induced by injection of LPC into corpus callosum of rats. Animals were pre-treated with intraperitoneal (i.p.) injections of curcumin or curcumin-loaded NPs at dose of 12.5 mg/kg, 10 days prior to LPC injection and the injections were continued for 7 or 14 days post lesion. Hematoxylin and eosin (H&E) staining and immunostaining against activated glial cells including astrocytes and microglia were carried out for assessment of inflammation level in lesion site. Myelin specific staining was performed to evaluate the effect of curcumin-loaded NPs on myelination of LPC receiving animals. HPLC results showed the higher plasma concentration of curcumin after administration of NPs. Histological evaluation demonstrated that, the extent of demyelination areas was reduced in animals under treatment of curcumin-loaded NPs. Furthermore, treatment with curcumin-loaded NPs effectively attenuated glial activation and inflammation in LPC-induced demyelination model compared to curcumin receiving animals. Overall; these findings indicate that treatment with curcumin-loaded NPs preserve myelinated axons through amelioration of glial activation and inflammation in demyelination context. Copyright © 2018 Elsevier B.V. All rights reserved.

The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice

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Siegert, Elise; Paul, Friedemann; Rothe, Michael; Weylandt, Karsten H.

2017-01-01

Background There is a large body of experimental evidence suggesting that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are capable of modulating immune function. Some studies have shown that these PUFAs might have a beneficial effect in patients suffering form multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). This could be due to increased n-3 PUFA-derived anti-inflammatory lipid mediators. In the present study we tested the effect...

Effects of aquatic exercises in a rat model of brainstem demyelination with ethidium bromide on the beam walking test.

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Nassar, Cíntia Cristina Souza; Bondan, Eduardo Fernandes; Alouche, Sandra Regina

2009-09-01

Multiple sclerosis is a demyelinating disease of the central nervous system associated with varied levels of disability. The impact of early physiotherapeutic interventions in the disease progression is unknown. We used an experimental model of demyelination with the gliotoxic agent ethidium bromide and early aquatic exercises to evaluate the motor performance of the animals. We quantified the number of footsteps and errors during the beam walking test. The demyelinated animals walked fewer steps with a greater number of errors than the control group. The demyelinated animals that performed aquatic exercises presented a better motor performance than those that did not exercise. Therefore aquatic exercising was beneficial to the motor performance of rats in this experimental model of demyelination.

Biology of the repair of central nervous system demyelinated lesions: an appraisal Biologia da reparação de lesões desmielinizantes do sistema nervoso central: uma avaliação

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L. A. V Peireira

1996-06-01

Full Text Available The integrity of myelin sheaths is maintained by oligodendrocytes and Schwann cells respectively in the central nervous system (CNS and in the peripheral nervous system. The process of demyelination consisting of the withdrawal of myelin sheaths from their axons is a characteristic feature of multiple sclerosis, the most common human demyelinating disease. Many experimental models have been designed to study the biology of demyelination and remyelination (repair of the lost myelin in the CNS, due to the difficulties in studying human material. In the ethidium bromide (an intercalating gliotoxic drug model of demyelination, CNS remyelination may be carried out by surviving oligodendrocytes and/or by cells differentiated from the primitive cell lines or either by Schwann cells that invade the CNS. However, some factors such as the age of the experimental animals, intensity and time of exposure to the intercalating chemical and the topography of the lesions have marked influence on the repair of the tissue.A integridade da bainha de mielina é fornecida pelos oligodendrócitos e pelas células de Schwann, no sistema nervoso central (SNC e no sistema nervoso periférico, respectivamente. O fenômeno de desmielinização refere-se à remoção das bainhas de mielina de axônios e este fato é característico na esclerose múltipla, a doença desmielinizante do SNC mais comum no homem. Muitos modelos experimentais têm sido utilizados para o estudo da biologia da desmielinização e remielinização no SNC, face à dificuldade de estudo de material humano. No modelo experimental da droga intercalate, gliotóxica, brometo de etídio, a remielinização do SNC pode ser efetuada por oligodendrócitos sobreviventes à lesão e/ou oriundos de diferenciação de linhagens celulares mais primitivas e por células de Schwann que invadem o SNC. No entanto, fatores como a idade dos animais, a intensidade, e o tempo de exposição ao agente intercalante e a

Magnetic resonance imaging of the cauda equina in chronic inflammatory demyelinating polyneuropathy

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A. F. Vasilenko

2017-01-01

Full Text Available Background. Chronic inflammatory demyelinating polyneuropathy (CIDP is a treatable disimmune neuropathy, which accurate diagnostics and treatment are essential to improve a long-lasting  prognosis and prevent invalidization. In atypical cases and  differential diagnosis extra investigations are needed, including neuroimaging.Objective. Evaluating the diagnostic role of the cauda equina magnetic resonance imaging (MRI in CIDP.Materials and methods. 8 patients with CIDP according to European Federation of Neurological Societies and Peripheral Nerve Society criteria were originally included in the main cohort: 6  patients with definitive CIDP, 1 patient – with possible CIDP; in 1  patient later mixed crioglobulinemia, associated with hepatitis C was  later diagnosed. MRI with contrast enhancement of the cauda equina was performed in all primary included patients in the main cohort  and in 8 controls with metabolic polyneuropathy. In 12 months MRI was repeated in the main cohort patients.Results. The enlargement of the nerve roots of the cauda equina and nodular hypertrophy was demonstrated in all CIDP patients, and in none of the control subjects. The extensiveness of qualitative  changes correlated with disease duration. All CIDP patients with root hypertrophy had gadolinium enhancement and its severity did not  correlate with disease activity. Contrast enhancement in roots of the  control group patients was explained by the medullary artery phenomenon.Conclusion. MRI of the cauda equina with contrast improves the diagnostic of CIDP, but does not depict the activity of the disease. MRI in CIDP is a promissing technique, requiring further investigation and standardization.

Occipital neuralgia associates with high cervical spinal cord lesions in idiopathic inflammatory demyelinating disease.

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Kissoon, Narayan R; Watson, James C; Boes, Christopher J; Kantarci, Orhun H

2018-01-01

Background The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. Methods We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. Results The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. Conclusions A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment.

Experimental models of demyelination and remyelination.

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Torre-Fuentes, L; Moreno-Jiménez, L; Pytel, V; Matías-Guiu, J A; Gómez-Pinedo, U; Matías-Guiu, J

2017-08-29

Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary. We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models. Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study. Copyright © 2017 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice.

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Martin, Nellie A; Molnar, Viktor; Szilagyi, Gabor T; Elkjaer, Maria L; Nawrocki, Arkadiusz; Okarmus, Justyna; Wlodarczyk, Agnieszka; Thygesen, Eva K; Palkovits, Miklos; Gallyas, Ferenc; Larsen, Martin R; Lassmann, Hans; Benedikz, Eirikur; Owens, Trevor; Svenningsen, Asa F; Illes, Zsolt

2018-01-01

reduced in the demyelinating corpus callosum of the KO mice. During demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.

[Local demyelination in amyotrophic lateral sclerosis].

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Kvirkvelia, N; Shakarishvili, R

2013-02-01

It is well known that the demyelination of peripheral nerves can be diffuse or local. Pathogenesis of acute or chronic inflamentary demyelination polyneurophathy is based on diffuse demyelination. Local demyelination occured by conduction block with electoneuromyographic (ENMG) researches. It is the main characteristic of multifocal motor neuropathy (MMN). Generally it is considered, that conduction block is not usual for amyotrophic lateral sclerosis (ALS). More over, its existance excludes this diagnosis. The article discribes 3 cases of ALS with conduction block verified with ENMG researches. Article also deals with pathogenetic mechanisms of conduction block in ALS and MMN. In addition it observes the issues of differential diagnosis between ALS and MMW.

Hereditary motor and sensory neuropathy with hypertrophy of the cauda equina and concomitant demyelinating white matter lesions

International Nuclear Information System (INIS)

Ertl-Wagner, B.B.; Staebler, A.; Reiser, M.

2005-01-01

Hereditary motor and sensory neuropathy (HMSN) is thought to almost exclusively affect the peripheral nervous system. We report the case of a 48-year-old patient with a longstanding history of HMSN type I who developed signs and symptoms of a cauda equina compression and of a central nervous system relapsing-remitting demyelinating white matter disease. Gross enlargement of the cauda equina fibers was detected by MR imaging of the lumbar spine. Cranial MR imaging revealed demyelinating white matter lesions. This case suggests that peripheral neuropathic mechanisms may also affect the central myelin in HMSN type I

Hereditary motor and sensory neuropathy with hypertrophy of the cauda equina and concomitant demyelinating white matter lesions

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Ertl-Wagner, B.B.; Staebler, A.; Reiser, M. [Univ. Muenchen (Germany). Inst. fuer Klinische Radiologie; Helmchen, C. [Univ. Luebeck (Germany). Klinik fuer Neurologie; Fassmann, F. [Zentrum fuer Radiologie und Nuklearmedizin, Erlangen-Nuernberg (Germany)

2005-07-01

Hereditary motor and sensory neuropathy (HMSN) is thought to almost exclusively affect the peripheral nervous system. We report the case of a 48-year-old patient with a longstanding history of HMSN type I who developed signs and symptoms of a cauda equina compression and of a central nervous system relapsing-remitting demyelinating white matter disease. Gross enlargement of the cauda equina fibers was detected by MR imaging of the lumbar spine. Cranial MR imaging revealed demyelinating white matter lesions. This case suggests that peripheral neuropathic mechanisms may also affect the central myelin in HMSN type I.

Multiple sclerosis deep grey matter: the relation between demyelination, neurodegeneration, inflammation and iron.

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Haider, Lukas; Simeonidou, Constantina; Steinberger, Günther; Hametner, Simon; Grigoriadis, Nikolaos; Deretzi, Georgia; Kovacs, Gabor G; Kutzelnigg, Alexandra; Lassmann, Hans; Frischer, Josa M

2014-12-01

In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities. We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls. In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed. MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration. Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages. Lesions developed on the background of inflammation. Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions. Demyelination and neurodegeneration were associated with oxidative injury. Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination. In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration. This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons. Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron. Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Reported Changes in Dietary Behavior Following a First Clinical Diagnosis of Central Nervous System Demyelination.

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Russell, Rebecca D; Lucas, Robyn M; Brennan, Vanessa; Sherriff, Jill L; Begley, Andrea; Black, Lucinda J

2018-01-01

Although the current evidence is insufficient to recommend a special diet for people with multiple sclerosis (MS), dietary advice for people with MS is prolific online and in the media. This study aimed to describe dietary changes made in the year following a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. We used follow-up data from the Ausimmune Study, a multicentre matched case-control study examining the environmental risk factors for a FCD. A total of 244 cases (60 male, 184 female) completed a 1-year follow-up interview, which included a question about dietary changes. We described the number and proportion (%) of participants who reported making dietary changes and the type of change made. We investigated independent predictors of making a dietary change using a multivariable logistic regression model. A total of 38% ( n  = 92) of participants at the 1-year follow-up reported making at least one dietary change over the last year. There were no statistically significant independent associations between any participant characteristic and odds of making a dietary change. Of those who made at least one dietary change, the most common changes were increasing fruit and/or vegetable intake (27%, n  = 25) and following a low-fat diet (25%, n  = 23). A considerable proportion of the study population reported making at least one dietary change in the year following a FCD, with the majority of changes being toward a healthier diet. Further research is warranted to investigate the reasons behind any dietary changes adopted by people with a FCD or with MS, and whether making a dietary change has benefits for the progression of demyelinating diseases, e.g., to a diagnosis of MS, as well as for general health and well-being.

Reported Changes in Dietary Behavior Following a First Clinical Diagnosis of Central Nervous System Demyelination

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Rebecca D. Russell

2018-03-01

Full Text Available Background/objectivesAlthough the current evidence is insufficient to recommend a special diet for people with multiple sclerosis (MS, dietary advice for people with MS is prolific online and in the media. This study aimed to describe dietary changes made in the year following a first clinical diagnosis of central nervous system demyelination (FCD, a common precursor to MS.Subjects/methodsWe used follow-up data from the Ausimmune Study, a multicentre matched case-control study examining the environmental risk factors for a FCD. A total of 244 cases (60 male, 184 female completed a 1-year follow-up interview, which included a question about dietary changes. We described the number and proportion (% of participants who reported making dietary changes and the type of change made. We investigated independent predictors of making a dietary change using a multivariable logistic regression model.ResultsA total of 38% (n = 92 of participants at the 1-year follow-up reported making at least one dietary change over the last year. There were no statistically significant independent associations between any participant characteristic and odds of making a dietary change. Of those who made at least one dietary change, the most common changes were increasing fruit and/or vegetable intake (27%, n = 25 and following a low-fat diet (25%, n = 23.ConclusionA considerable proportion of the study population reported making at least one dietary change in the year following a FCD, with the majority of changes being toward a healthier diet. Further research is warranted to investigate the reasons behind any dietary changes adopted by people with a FCD or with MS, and whether making a dietary change has benefits for the progression of demyelinating diseases, e.g., to a diagnosis of MS, as well as for general health and well-being.

Outcome in chronic inflammatory demyelinating polyneuropathy from a Malaysian centre over sixteen years.

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Hiew, Fu Liong; Ong, Jun-Jean; Viswanathan, Shanthi; Puvanarajah, Santhi

2018-04-01

Long-term outcome in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is very limited, especially from Asian countries. We aimed to determine the outcome of our cohort of CIDP patients and to define the relevant clinical, electrophysiological and laboratory determinants of disease activity, progression and treatment response. We retrospectively reviewed records of 23 CIDP patients attending our Neurology service at Kuala Lumpur Hospital, Malaysia between January 2000 and December 2016. We analysed data on neurological deficits, electrophysiological and laboratory parameters to determine diagnostic characteristics, correlation with disease activity and clinical outcomes following treatment. Included were 15 (65%) males and 8 (35%) females with a mean age of 42.7 years (SD 14.4). Mean duration of follow-up visit was 66 months (range 6-134 months). The cohort consists of 19 classical (sensory-motor) CIDP and 4 MADSAM. Large majority of patients (66%) had either stable active disease (CDAS 3, 44%) or were in remission (CDAS class 2, 22%) following treatment with standard immunotherapies (Intravenous Immunoglobulins, steroids or immunosuppressants). The proportion of CIDP patients in each CDAS class was comparable to published cohorts from North America and Europe. Medical Research Council (MRC) sum score was the only clinical score that differed across CDAS classes (p = .010) with significant inverse correlation (Spearman's rho -0.664, p = .001). In conclusion, treatment outcomes of our CIDP cohort was comparable to those of published series. Further studies with larger cohort of patients from other parts of Asia are important to determine the long-term outcome of this heterogenous disease in this region. Copyright © 2018 Elsevier Ltd. All rights reserved.

Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

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Nellie A. Martin

2018-03-01

Iba1+ macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice.ConclusionDuring demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.

Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice.

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Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B E; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P; Shields, Christopher B

2013-04-01

Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and associated functional recovery in animal model

Hypothalamic demyelination causing panhypopituitarism.

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Dixon-Douglas, Julia; Burgess, John; Dreyer, Michael

2018-05-01

Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic-pituitary axis in patients with demyelinating conditions have rarely been reported. We present two cases of MS/NMOSD with associated hypothalamic-pituitary involvement and subsequent hypopituitarism, including the first report of a patient with hypothalamic demyelination causing panhypopituitarism. Differential diagnoses, including alemtuzumab-related and primary pituitary pathology are discussed. © 2018 Royal Australasian College of Physicians.

Polimiosite associada à arterite linfocítica do sistema nervoso central Polymyositis associated with lymphocytic arteritis of the central nervous system

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Izaias Pereira da Costa

2010-02-01

Full Text Available Complicações do Sistema Nervoso Central (SNC raramente são descritas em miopatias inflamatórias idiopáticas. Os autores relatam o caso de uma paciente de 48 anos com diagnóstico de polimiosite com autoanticorpo anti-Jo-1 positivo que, após cinco anos de evolução, apresentou extensa lesão desmielinizante do SNC associada à arterite linfocítica.Central Nervous System (CNS complications in idiopathic inflammatory myopathies are seldom reported. The authors describe the case of a 48-year old female with polymyositis and positive anti-Jo-1 autoantibody who, after five years of evolution, developed extensive CNS demyelinating injury associated with lymphocytic arteritis.

Acute Demyelination in a Person with Amphetamine Abuse

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Serge Weis

2011-01-01

Full Text Available We report the case of a 31-year-old woman, admitted to the hospital for chest pain, dying a few days later from septic multiorgan failure, and showing at autopsy foci of acute demyelination in the occipital lobe. Gas chromatography/mass spectrometry analysis revealed the presence of amphetamine in the demyelinated area, which might be considered as the pathogenic agent, since other causes for demyelination could be excluded. This case represents the first report showing a demyelinating process due to a street drug.

Dynamic impact of brief electrical nerve stimulation on the neural immune axis-polarization of macrophages toward a pro-repair phenotype in demyelinated peripheral nerve.

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McLean, Nikki A; Verge, Valerie M K

2016-09-01

Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546-1561. © 2016 Wiley Periodicals, Inc.

Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis.

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Huang, Yu-Hwa; Zozulya, Alla L; Weidenfeller, Christian; Metz, Imke; Buck, Dorothea; Toyka, Klaus V; Brück, Wolfgang; Wiendl, Heinz

2009-08-01

We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS). Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB). HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS. In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.

An Occult Malignancy Behind a Demyelinating Disease

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Saberio Lo Presti MD

2016-10-01

Full Text Available We report a case of a 38-year-old man presenting with bilateral lower extremity weakness and paresthesias that progressed during a 4-month period to severe polyneuropathy forcing the patient to be bed bound. Throughout his multiple hospitalizations, he was treated erroneously for chronic inflammatory demyelinating polyneuropathy, without significant improvement in his symptoms. In addition, he developed hepatosplenomegaly (organomegaly; endocrinopathies such as diabetes mellitus, central hypogonadism, and hypothyroidism; monoclonal spike evidenced in the serum electrophoresis; and hyperpigmentation of skin, altogether consistent with POEMS syndrome. During his last hospitalization he developed excruciating pain on his left hip, and imaging revealed the presence of a 9 × 6 cm osteolytic mass with sclerotic rim in the left acetabulum. Biopsy of the mass confirmed an isolated IgG lambda plasmacytoma. The patient received radiation to his left acetabular lesion followed by left hip replacement. Subsequently, the patient underwent autologous bone marrow transplant. Eighteen months after his initial presentation, he had satisfactory clinical response and is functional without significant limitations. POEMS syndrome is a rare paraneoplastic syndrome secondary to an underlying plasma cell disorder, which can oftentimes be overlooked and misdiagnosed. The median age of presentation is 51 years, and only 31% of the cases occur in fairly young patients under the age of 45 as evidenced in this case. As clinicians, we should be aware of the constellation of features associated with POEMS syndrome and be able to recognize them promptly.

Demyelinating diseases and potential repair strategies

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Radtke, C.; Spies, M.; Sasaki, M.; Vogt, PM; Kocsis, J. D.

2009-01-01

Demyelination is associated with a number of neurological disorders including multiple sclerosis (MS), spinal cord injury and nerve compression. MS lesions often show axon loss and therefore reparative therapeutic goals include remyelination and neuroprotection of vulnerable axons. Experimental cellular transplantation has proven successful in a number of demyelination and injury models to remyelinate and improve functional outcome. Here we discuss the remyelination and neuroprotective potential of several myelin-forming cells types and their behavior in different demyelination and injury models. Better understanding of these models and current cell-based strategies for remyelination and neuroprotection offer exciting opportunities to develop strategies for clinical studies. PMID:17408905

Fatigue, Pain, Anxiety and Depression in Guillain-Barré Syndrome and Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

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Merkies, Ingemar S J; Kieseier, Bernd C

2016-01-01

In the clinical evaluation of patients with Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), scant attention is paid to symptoms such as fatigue, pain and anxiety/depression. We aimed at addressing seminal studies that focused on the burden of these symptoms and their impact on quality of life (QoL) in these conditions. Fatigue, pain, and anxiety/depression are increasingly being recognized in patients with GBS and CIDP, although their pathophysiological provenance remains unknown. Fatigue and pain are significant in terms of prevalence and intensity, may be a presenting symptom, and can persist for years after apparent functional recovery, suggesting residual injury. Anxiety/depression has also been examined although studies are limited. Despite their negative impact on QoL, the long-term dynamics of these symptoms in patients with GBS and particularly CIDP receiving therapy in routine clinical practice have not been systematically evaluated. Such observations formed the basis for the ongoing (GAMEDIS) studies evaluating the effect of Gamunex on fatigue and depression in patients with CIDP, of which some preliminary data are presented. Strength and sensory deficits are the main areas of focus in patients with GBS and CIDP, but they do not explain the total reduction in QoL, suggesting the possible role of other complaints. A more comprehensive approach to patient care demands that factors such as pain, fatigue and anxiety/depression receive greater attention. The non-interventional GAMEDIS studies are expected to provide valuable insight into the long-term effectiveness of Gamunex in everyday practice. © 2016 S. Karger AG, Basel.

Differential local tissue permissiveness influences the final fate of GPR17-expressing oligodendrocyte precursors in two distinct models of demyelination.

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Coppolino, Giusy T; Marangon, Davide; Negri, Camilla; Menichetti, Gianluca; Fumagalli, Marta; Gelosa, Paolo; Dimou, Leda; Furlan, Roberto; Lecca, Davide; Abbracchio, Maria P

2018-05-01

Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17-iCreER T2 xCAG-eGFP mice) allowing to follow the final fate of GPR17 + cells by tamoxifen-induced GFP-labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP + cells at damaged areas. However, only in the cuprizone model reacting GFP + cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP + cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor-1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti-inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. © 2018 The Authors GLIA Published by Wiley Periodicals, Inc.

Open-ring enhancement sign in diagnosing demyelinating pseudotumor

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Fang Liting; Wang Zhiping; Wang Linyou

2010-01-01

Objective: To describe open-ring enhancement sign on MRI of demyelinating pseudotumor. Methods: Contrast-enhanced MRI of histologically confirmed demyelinating pseudotumors (14 patients) and astrocytomas (21) was reviewed. Results: Of the 14 cases of demyelinating pseudotumor, open-ring enhancement pattern was observed in 6; closed ring enhancement in 2; nodular enhancement in 3; patchy enhancement in 1; slight enhancement in 1; and no enhancement in 1. Of the 21 cases of astrocytoma, there was complete ring or lace-like enhancement in 13, no contrast enhancement in 6, patchy enhancement in 2, and none with open-ring enhancement pattern. Conclusion: Open-ring enhancement is a valuable sign in differential diagnosis between demyelinating pseudotumor and astrocytoma. (authors)

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

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Coppolino, Giusy T.; Marangon, Davide; Negri, Camilla; Menichetti, Gianluca; Fumagalli, Marta; Gelosa, Paolo; Dimou, Leda; Furlan, Roberto; Lecca, Davide

2018-01-01

Abstract Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17‐iCreERT2xCAG‐eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen‐induced GFP‐labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor‐1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti‐inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery. PMID:29424466

Modern MRI tools for the characterization of acute demyelinating lesions: value of chemical shift and diffusion-weighted imaging

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Kueker, W.; Mehnert, F.; Mader, I.; Naegele, T.; Ruff, J.; Gaertner, S.

2004-01-01

Acute demyelinating lesions occur in various inflammatory disorders of the CNS. Apart from multiple sclerosis, most cases can be attributed to an overshooting immunological response to infectious agents called acute disseminated encephalomyelitis (ADEM). ADEM, which is mostly characterized by a monophasic course, has a multiphasic variant (MDEM). The early application of corticosteroids has been shown to be beneficial for the outcome; thus, an early diagnosis is highly desirable. Furthermore, the differential diagnosis ruling out neoplastic disorders may be difficult using conventional MRI alone. The potential diagnostic value of advanced MR techniques such as chemical shift imaging (CSI) and diffusion-weighted imaging (DWI) was investigated in a patient with MDEM, who had a new lesion in continuity with the initial disease manifestation. CSI was performed at 1.5 T with a long echo time of 135 ms for the evaluation of N-acetyl-aspartate (NAA) and choline (Cho) and with short TE of 30 ms for macromolecules (mm) and myo-Inositol (mI). DWI was performed using a single-shot isotropic EPI sequence. Whereas acute and chronic areas of demyelination were neither distinguishable on T2- nor on contrast-enhanced T1-weigted images, CSI and DWI revealed different metabolite concentrations and diffusion characteristics within the composite lesion, clearly separating acute from chronic areas of demyelination. In conclusion, the addition of CSI and DWI may add to the diagnostic power of MRI in the setting of demyelinating disorders by identifying areas of acute and chronic demyelination, even in the absence of contrast enhancement. (orig.)

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

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Chamberlain, Kelly A; Chapey, Kristen S; Nanescu, Sonia E; Huang, Jeffrey K

2017-02-08

Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in adenosine triphosphate (ATP) buffering, in oligodendrocyte function. We found that creatine increased mitochondrial ATP production directly in oligodendrocyte lineage cell cultures and exerted robust protection on oligodendrocytes by preventing cell death in both naive and lipopolysaccharide-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase ( Gamt ) did not affect oligodendrocyte precursor cell recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in central nervous system (CNS) lesions. Remarkably, creatine administration into Gamt -deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination. SIGNIFICANCE STATEMENT We report that creatine enhances oligodendrocyte mitochondrial function and protects against caspase-dependent oligodendrocyte apoptosis during CNS remyelination. This work has important implications for the development of therapeutic targets for diseases characterized by

Inflammatory lesions of the spinal cord and the nerve roots in magnetic resonance imaging

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Sartoretti-Schefer, S.; Wichmann, W.; Valavanis, A.

1996-01-01

The MRI examinations of 52 patients with proven inflammatory lesions (39 patients) or tumorous/postactinic lesions of the spinal cord (6 patients) and vasuclar malformations of the spinal cord (7 patients) were retrospectively analyzed. All examinations were performed on a 1.5 T MR unit, using bi- or triplanar T1-w pre- and postcontrast as well as T2-w SE sequences. Clinical and radiological examinations allow a subdivision of inflammations of the spinal cord and the nerve roots into (mening-oradiculo) myelitis and meningoradiculo (myelitis). The MRI patterns of these two inflammatory subtypes vary: Meningoradiculitis presents with an enhancement of the nerve roots and the leptomeninges; myelitis itself is characterized by single or multiple, diffuse or multifocal, with or without nodular, patchy or diffusely enhancing intramedullary lessions, with or without thickening of the cord and leptomeningeal inflammation. The immunologically suppressed patient suffers from viral infections (especially herpes simplex, varicella-zoster virus, cytomegalovirus), bacterial infections (tuberculosis), but rarely viral infections, sarcoidosis and demyelinating diseases. Idiopathic myelitis is also common. Secondary ischemic and demyelinating processes result in a complex morphology of inflammatory lesions on MRI, and therefore the whole spectrum of demyelinating, ischemic and inflammatory lesions has to be included in the differential diagnosis. Even tumors may imitate inflammatory myelitis and radiculitis. Most commonly, meningoradiculitis can be separated from myelitis. A reliable diagnosis of a specific inflammatory lesion is difficult and is mostly achieved in patients with multiple sclerosis and in patients with HIV-associated cytomegalovirus infection. (orig.) [de

Beneficial effects of minocycline on cuprizone induced cortical demyelination.

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Skripuletz, Thomas; Miller, Elvira; Moharregh-Khiabani, Darius; Blank, Alexander; Pul, Refik; Gudi, Viktoria; Trebst, Corinna; Stangel, Martin

2010-09-01

In this study, we investigated the potential of minocycline to influence cuprizone induced demyelination in the grey and white matter. To induce demyelination C57BL/6 mice were fed with cuprizone for up to 6 weeks and were analysed at different timepoints (week 0, 4, 5, 6). Mice treated with minocycline had less demyelination of the cortex and corpus callosum compared with sham treated animals. In the cortex decreased numbers of activated and proliferating microglia were found after 6 weeks of cuprizone feeding, while there were no significant effects for microglial infiltration of the corpus callosum. In addition to the beneficial effects on demyelination, minocycline prevented from motor coordination disturbance as shown in the beam walking test. For astrogliosis and the numbers of OPC and oligodendrocytes no treatment effects were found. In summary, minocycline treatment diminished the course of demyelination in the grey and white matter and prevented disturbances in motor coordination.

Acute abdominal pain as the only symptom of a thoracic demyelinating lesion in multiple sclerosis.

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Nomura, Shohei; Shimakawa, Shuichi; Kashiwagi, Mitsuru; Tanabe, Takuya; Fukui, Miho; Tamai, Hiroshi

2015-11-01

Multiple sclerosis (MS) is a syndrome characterized by complex neurological symptoms resulting from demyelinating lesions in the central nervous system. We report a child with a relapse of MS whose only presenting symptom was severe abdominal pain. Dysfunctional intestinal mobility was assessed by abdominal computed tomography. Findings resembled paralytic ileus resulting from peritonitis. However, the patient demonstrated no other symptoms of peritonitis. A T2-weighted magnetic resonance image revealed a new demyelinating lesion localized to thoracic segments T4-T12. The lesion presumably affected autonomic efferents involved in intestinal mobility. Treatment with a pulse of methylprednisolone reduced both abdominal pain and lesion size. To our knowledge, this is the first reported case of a pediatric MS patient with a demyelinating lesion associated with an autonomic symptom of altered intestinal mobility in the absence of neurological symptoms. This atypical presentation of MS highlights the need for physicians' vigilance when treating this patient population. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Spectroscopic magnetic resonance imaging of a tumefactive demyelinating lesion

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Law, M.; Meltzer, D.E.; Cha, S. [MRI Department, Department of Radiology, New York University Medical Center, Schwartz Building, Basement HCC, 530 First Avenue, New York, NY 10016 (United States)

2002-12-01

Tumefactive demyelinating lesions can present with features similar, clinically and radiologically, to those of brain tumours. Proton MR spectroscopy has been increasingly used to characterize intracranial pathology. As the underlying pathophysiology of neoplasms is different from that of demyelinating disease, one may expect the metabolic composition of neoplasms to be significantly different from that of demyelinating lesions. We report a 49-year-old woman in whom the neurologic and radiologic findings were highly suggestive of a high-grade brain tumor, and the spectroscopic features were sufficiently similar to that of a tumor to convince the neurosurgeon to operate. This case emphasizes the need for caution when confronted with a patient who presents with a differential diagnosis of demyelinating lesion versus neoplasm. (orig.)

Demyelination versus remyelination in progressive multiple sclerosis

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Bramow, Stephan; Frischer, Josa M; Lassmann, Hans

2010-01-01

The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive...... multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination...... compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ~18% higher than in primary progressive multiple sclerosis after adjustments...

Imaging of demyelinating and degenerative diseases of the brain

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Drayer, B.P.

1987-01-01

The emergence of cross-sectional brain imaging in the past decade has greatly expanded the role of imaging as a primary diagnostic modality for demyelinating and degenerative brain disorders. To remain an effective neurologic consultant, the radiologist must better understand the neuropathology and functional significance of these disorders. MR imaging has become the dominant imaging modality for multiple sclerosis and all demyelinating and dysmyelinating disorders. Detection is most sensitive with intermediate and T2-weighted spin-echo pulse sequences. Although increased signal intensity in the white matter is a sensitive but nonspecific finding, a knowledge of the patient's history and disease pathoanatomy greatly improves diagnostic specificity. Since an increasing proportion of the population is over 65 years of age, the distinction of normal versus pathologic aging becomes critical. The role of imaging in dementing illness is to distinguish primary degenerative dementia from normal aging changes, vascular medullary artery distribution disease, microangiopathic leukoencephalopathy, communicating hydrocephalus, and mass lesions. The role of MR imaging, including brain iron mapping, is analyzed in bradykinetic, choreiform, and dystonic disorders. The complications of chronic ethanol abuse, including vermian atrophy, central pontine myelinolysis, and Wernicke encephalopathy, are also reviewed

Quercetin treatment regulates the Na+,K+-ATPase activity, peripheral cholinergic enzymes, and oxidative stress in a rat model of demyelination.

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Carvalho, Fabiano B; Gutierres, Jessié M; Beckmann, Diego; Santos, Rosmarini P; Thomé, Gustavo R; Baldissarelli, Jucimara; Stefanello, Naiara; Andrades, Amanda; Aiello, Graciane; Ripplinger, Angel; Lucio, Bruna M; Ineu, Rafael; Mazzanti, Alexandre; Morsch, Vera; Schetinger, Maria Rosa; Andrade, Cinthia M

2018-07-01

Quercetin is reported to exert a plethora of health benefits through many different mechanisms of action. This versatility and presence in the human diet has attracted the attention of the scientific community, resulting in a huge output of in vitro and in vivo (preclinical) studies. Therefore, we hypothesized that quercetin can protect Na + ,K + -ATPase activity in the central nervous system, reestablish the peripheral cholinesterases activities, and reduce oxidative stress during demyelination events in rats. In line with this expectation, our study aims to find out how quercetin acts on the Na + ,K + -ATPase activity in the central nervous system, peripheral cholinesterases, and stress oxidative markers in an experimental model of demyelinating disease. Wistar rats were divided into 4 groups: vehicle, quercetin, ethidium bromide (EB), and EB plus quercetin groups. The animals were treated once a day with vehicle (ethanol 20%) or quercetin 50 mg/kg for 7 (demyelination phase, by gavage) or 21 days (remyelination phase) after EB (0.1%, 10 μL) injection (intrapontine).The encephalon was removed, and the pons, hypothalamus, cerebral cortex, hippocampus, striatum, and cerebellum were dissected to verify the Na + ,K + -ATPase activity. Our results showed that quercetin protected against reduction in Na + ,K + -ATPase in the pons and cerebellum in the demyelination phase, and it increased the activity of this enzyme in the remyelination phase. During the demyelination, quercetin promoted the increase in acetylcholinesterase activity in whole blood and lymphocytes induced by EB, and it reduced the increase in acetylcholinesterase activity in lymphocytes in the remyelination phase. On day 7, EB increased the superoxide dismutase and decreased catalase activities, as well as increased the thiobarbituric acid-reactive substance levels. Taken together, these results indicated that quercetin regulates the Na + ,K + -ATPase activity, affects the alterations of redox state

Demyelinating Disease following Anti-TNFa Treatment: A Causal or Coincidental Association? Report of Four Cases and Review of the Literature

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E. Andreadou

2013-01-01

Full Text Available Tumor necrosis factor antagonists (anti-TNFa are an established therapeutic option for several autoimmune and inflammatory bowel diseases. Despite their clinical effectiveness, neurological adverse events have been reported and literature data suggest a potential role of anti-TNFa in the induction of demyelination of the CNS. We present four patients treated with anti-TNFa who developed symptoms suggestive of CNS demyelination. The first patient, a 17-year-old male who received etanercept for psoriatic arthritis for eight months, presented with dysesthesias up to T4 level. The second patient, a 30-year-old male treated with adalimumab for three years due to ankylosing spondylitis, presented with right unilateral tinnitus. The third case, a 47-year-old female, received etanercept for four years because of psoriatic arthritis and developed persistent headache and left-sided face and head numbness. Finally, the fourth patient, a 57-years-old female treated with etanercept for six years due to ankylosing spondylitis, presented with difficulty in speech, swallowing, and ptosis of the right corner of the mouth. In all cases, brain MRI showed lesions suggestive of demyelination, while positive oligoclonal bands were detected in the CSF. Anti-TNFa treatments were discontinued and patients showed clinical improvement with pulsed intravenous corticosteroid therapy. CNS demyelination following anti-TNFa treatment represents a relatively rare but potential serious complication. Close follow-up and MRI monitoring of these patients is mandatory to elucidate whether the clinical manifestations represent adverse events occurring during anti-TNFa therapy or a first demyelinating episode.

Aggregation of MBP in chronic demyelination.

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Frid, Kati; Einstein, Ofira; Friedman-Levi, Yael; Binyamin, Orli; Ben-Hur, Tamir; Gabizon, Ruth

2015-07-01

Misfolding of key disease proteins to an insoluble state is associated with most neurodegenerative conditions, such as prion, Parkinson, and Alzheimer's diseases. In this work, and by studying animal models of multiple sclerosis, we asked whether this is also the case for myelin basic protein (MBP) in the late and neurodegenerative phases of demyelinating diseases. To this effect, we tested whether MBP, an essential myelin component, present prion-like properties in animal models of MS, as is the case for Cuprizone-induced chronic demyelination or chronic phases of Experimental Autoimmune Encephalomyelitis (EAE). We show here that while total levels of MBP were not reduced following extensive demyelination, part of these molecules accumulated thereafter as aggregates inside oligodendrocytes or around neuronal cells. In chronic EAE, MBP precipitated concomitantly with Tau, a marker of diverse neurodegenerative conditions, including MS. Most important, analysis of fractions from Triton X-100 floatation gradients suggest that the lipid composition of brain membranes in chronic EAE differs significantly from that of naïve mice, an effect which may relate to oxidative insults and subsequently prevent the appropriate insertion and compaction of new MBP in the myelin sheath, thereby causing its misfolding and aggregation. Prion-like aggregation of MBP following chronic demyelination may result from an aberrant lipid composition accompanying this pathological status. Such aggregation of MBP may contribute to neuronal damage that occurs in the progressive phase of MS.

Membrane attack complex of complement is not essential for immune mediated demyelination in experimental autoimmune neuritis.

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Tran, Giang T; Hodgkinson, Suzanne J; Carter, Nicole M; Killingsworth, Murray; Nomura, Masaru; Verma, Nirupama D; Plain, Karren M; Boyd, Rochelle; Hall, Bruce M

2010-12-15

Antibody deposition and complement activation, especially membrane attack complex (MAC) formation are considered central for immune mediated demyelination. To examine the role of MAC in immune mediated demyelination, we studied experimental allergic neuritis (EAN) in Lewis rats deficient in complement component 6 (C6) that cannot form MAC. A C6 deficient Lewis (Lewis/C6-) strain of rats was bred by backcrossing the defective C6 gene, from PVG/C6- rats, onto the Lewis background. Lewis/C6- rats had the same C6 gene deletion as PVG/C6- rats and their sera did not support immune mediated haemolysis unless C6 was added. Active EAN was induced in Lewis and Lewis/C6- rats by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant (CFA), and Lewis/C6- rats had delayed clinical EAN compared to the Lewis rats. Peripheral nerve demyelination in Lewis/C6- was also delayed but was similar in extent at the peak of disease. Compared to Lewis, Lewis/C6- nerves had no MAC deposition, reduced macrophage infiltrate and IL-17A, but similar T cell infiltrate and Th1 cytokine mRNA expression. ICAM-1 and P-selectin mRNA expression and immunostaining on vascular endothelium were delayed in Lewis C6- compared to Lewis rats' nerves. This study found that MAC was not required for immune mediated demyelination; but that MAC enhanced early symptoms and early demyelination in EAN, either by direct lysis or by sub-lytic induction of vascular endothelial expression of ICAM-1 and P-selectin. Copyright © 2010 Elsevier B.V. All rights reserved.

A Case of Paraneoplastic Demyelinating Motor Polyneuropathy

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Sohrab Mostoufizadeh

2012-04-01

Full Text Available Peripheral neuropathy is commonly accompanied by cancer but demyelinating ones are not commonly reported. We report the clinical, neurophysiological, and biological characteristics of an 82-year-old patient who presented with a demyelinating motor neuropathy and high titre of anti-ganglioside antibodies associated with oesophageal cancer. The neurological course worsened rapidly despite immunotherapy, leading to a bedridden status. We propose to suspect a paraneoplastic origin in older patients or when the clinical course progresses rapidly within a few weeks or months.

Influence of type I IFN signaling on anti-MOG antibody-mediated demyelination

DEFF Research Database (Denmark)

Berg, Carsten Tue; Khorooshi, Reza M. H.; Asgari, Nasrin

2017-01-01

Background Antibodies with specificity for myelin oligodendrocyte glycoprotein (MOG) are implicated in multiple sclerosis and related diseases. The pathogenic importance of anti-MOG antibody in primary demyelinating pathology remains poorly characterized. Objective The objective of this study...... is to investigate whether administration of anti-MOG antibody would be sufficient for demyelination and to determine if type I interferon (IFN) signaling plays a similar role in anti-MOG antibody-mediated pathology, as has been shown for neuromyelitis optica-like pathology. Methods Purified IgG2a monoclonal anti...... demyelination in wild-type and IFNAR1-KO mice. Conclusions Anti-MOG antibody and complement was sufficient to induce callosal demyelination, and pathology was dependent on type I IFN. Induction of EAE in IFNAR1-KO mice overcame the dependence on type I IFN for anti-MOG and complement-mediated demyelination....

The effect of omega-3 fatty acids on central nervous system remyelination in fat-1 mice.

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Siegert, Elise; Paul, Friedemann; Rothe, Michael; Weylandt, Karsten H

2017-01-24

There is a large body of experimental evidence suggesting that omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are capable of modulating immune function. Some studies have shown that these PUFAs might have a beneficial effect in patients suffering form multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). This could be due to increased n-3 PUFA-derived anti-inflammatory lipid mediators. In the present study we tested the effect of an endogenously increased n-3 PUFA status on cuprizone-induced CNS demyelination and remyelination in fat-1 mice versus their wild-type (wt) littermates. Fat-1 mice express an n-3 desaturase, which allows them to convert n-6 PUFAs into n-3 PUFAs. CNS lipid profiles in fat-1 mice showed a significant increase of eicosapentaenoic acid (EPA) levels but similar docosahexaenoic acid levels compared to wt littermates. This was also reflected in significantly higher levels of monohydroxy EPA metabolites such as 18-hydroxyeicosapentaenoic acid (18-HEPE) in fat-1 brain tissue. Feeding fat-1 mice and wt littermates 0.2% cuprizone for 5 weeks caused a similar degree of CNS demyelination in both groups; remyelination was increased in the fat-1 group after a recovery period of 2 weeks. However, at p = 0.07 this difference missed statistical significance. These results indicate that n-3 PUFAs might have a role in promotion of remyelination after toxic injury to CNS oligodendrocytes. This might occur either via modulation of the immune system or via a direct effect on oligodendrocytes or neurons through EPA-derived lipid metabolites such as 18-HEPE.

Suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

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Dhong Hyun Lee

2017-05-01

Full Text Available We have established two mouse models of central nervous system (CNS demyelination that differ from most other available models of multiple sclerosis (MS in that they represent a mixture of viral and immune triggers. In the first model, ocular infection of different strains of mice with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2 causes CNS demyelination. In the second model, depletion of macrophages causes CNS demyelination in mice that are ocularly infected with wild-type (WT HSV-1. In the present study, we found that the demyelination in macrophage-intact mice infected with HSV-IL-2 was blocked by depletion of FoxP3-expressing cells, while concurrent depletion of macrophages restored demyelination. In contrast, demyelination was blocked in the macrophage-depleted mice infected with wild-type HSV-1 following depletion of FoxP3-expressing cells. In macrophage-depleted HSV-IL-2-infected mice, demyelination was associated with the activity of both CD4+ and CD8+ T cells, whereas in macrophage-depleted mice infected with WT HSV-1, demyelination was associated with CD4+ T cells. Macrophage depletion or infection with HSV-IL-2 caused an imbalance of T cells and TH1 responses as well as alterations in IL-12p35 and IL-12p40 but not other members of the IL-12 family or their receptors. Demyelination was blocked by adoptive transfer of macrophages that were infected with HSV-IL-12p70 or HSV-IL-12p40 but not by HSV-IL-12p35. These results indicate that suppression of IL-12p70 formation by IL-2 or following macrophage depletion causes T-cell autoreactivity leading to CNS demyelination in HSV-1-infected mice.

Polirradiculoneuropatia desmielinizante inflamatória crônica: estudo de 18 pacientes Chronic inflammatory demyelinating polyradiculoneuropathy: study of 18 patients

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Leandro C. Calia

1997-01-01

Full Text Available Neste estudo prospectivo, analisamos as características clínicas, evolução e resposta terapêutica de 18 pacientes com a forma idiopática de polirradiculoneuropatia desmielinizante inflamatória crônica, que foram acompanhados por período que variou de 4 a 127 meses. O sexo masculino predominou sobre o feminino (1,25:1 e a idade de início dos sintomas variou de 6 a 85 anos. Observamos a preponderância da forma de evolução progressiva (61,1% sobre a forma recidivante (38,9%, bem como a baixa ocorrência de fatores predisponentes (16,7%. Todos os pacientes apresentavam comprometimento sensitivo e motor, associado a hipo ou arreflexia, enquanto apenas três (16,7% apresentavam comprometimento de nervos cranianos. No exame do liquor, as taxas de proteínas estavam elevadas em 88,9% dos pacientes, com média de 203,4 mg/dl. A eletroneuromiografia mostrou alterações desmielinizantes em todos os pacientes, associadas a alterações axonais em 94,4% deles. Em todos os sete pacientes submetidos a biopsia de nervo sural encontramos alterações compatíveis com desmielinização/remielinização. A análise com imunofluorescência, realizada em três pacientes foi normal em um e evidenciou depósito de anticorpos anti-CD3 em dois e anti-HLA-Dr em um. Optamos pela prednisona como tratamento inicial em todos os pacientes, sendo mantida posteriormente em doses reduzidas e em dias alternados em 72,2% deles. Dois pacientes (11,1% estão assintomáticos mesmo após retirada total da medicação e introduzimos azatioprína, associada ou não ao corticóide, nos quatro pacientes com má resposta à prednisona. Até a última avaliação, 16 pacientes (88,9% evoluíram com melhora funcional.This is a prospective study that describes 18 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, idiopathic type. The patients have been followed for a period of 4 to 127 months. We evaluated the clinical characteristics, the evolution

Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

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Sahel, Aurélia; Ortiz, Fernando C.; Kerninon, Christophe; Maldonado, Paloma P.; Angulo, María Cecilia; Nait-Oumesmar, Brahim

2015-01-01

Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders. PMID:25852473

Atypical idiopathic inflammatory demyelinating lesions (IIDL): Conventional and diffusion-weighted MR imaging (DWI) findings in 42 cases

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Koelblinger, Claus; Fruehwald-Pallamar, Julia [Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna (Austria); Kubin, Klaus [CT/MRI Institut Dr. Klaus Kubin, Salzburg (Austria); Wallner-Blazek, Mirja [Department of Neurology, Medical University Graz, Graz (Austria); Hauwe, Luc van den [Department of Radiology, Medical University of Antwerp, Antwerp (Belgium); Macedo, Leonardo [Department of Radiology, CEDIMAGEM, Centro - Juiz de Fora (Brazil); Puchner, Stefan B. [Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna (Austria); Thurnher, Majda M., E-mail: majda.thurnher@meduniwien.ac.at [Department of Biomedical Imaging and Image-Guided Therapy, Medical University Vienna, Vienna (Austria)

2013-11-01

Introduction: The purpose of this study was to evaluate MR imaging characteristics with conventional and advanced MR imaging techniques in patients with IIDL. Methods: MR images of the brain in 42 patients (20 male, 22 female) with suspected or known multiple sclerosis (MS) from four institutions were retrospectively analyzed. Lesions were classified into five different subtypes: (1) ring-like lesions; (2) Balo-like lesions; (3) diffuse infiltrating lesions; (4) megacystic lesions; and (5) unclassified lesions. The location, size, margins, and signal intensities on T1WI, T2WI, and diffusion-weighted images (DWI), and the ADC values/ratios for all lesions, as well as the contrast enhancement pattern, and the presence of edema, were recorded. Results: There were 30 ring-like, 10 Balo-like, 3 megacystic-like and 16 diffuse infiltrating-like lesions were detected. Three lesions were categorized as unclassified lesions. Of the 30 ring-like lesions, 23 were hypointense centrally with a hyperintense rim. The mean ADC, measured centrally, was 1.50 ± 0.41 × 10{sup −3} mm{sup 2}/s. The mean ADC in the non-enhancing layers of the Balo-like lesions was 2.29 ± 0.17 × 10{sup −3} mm{sup 2}/s, and the mean ADC in enhancing layers was 1.03 ± 0.30 × 10{sup −3} mm{sup 2}/s. Megacystic lesions had a mean ADC of 2.14 ± 0.26 × 10{sup −3} mm{sup 2}/s. Peripheral strong enhancement with high signal on DWI was present in all diffuse infiltrating lesions. Unclassified lesions showed a mean ADC of 1.43 ± 0.13 mm{sup 2}/s. Conclusion: Restriction of diffusion will be seen in the outer layers of active inflammation/demyelination in Balo-like lesions, in the enhancing part of ring-like lesions, and at the periphery of infiltrative-type lesions.

The frequencies of Killer immunoglobulin-like receptors and their HLA ligands in chronic inflammatory demyelinating polyradiculoneuropathy are similar to those in Guillian Barre syndrome but differ from those of controls, suggesting a role for NK cells in pathogenesis.

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Blum, Stefan; Csurhes, Peter; McCombe, Pamela

2015-08-15

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired inflammatory neuropathy, which has similar clinical and pathological features to Guillain-Barré Syndrome (GBS), but differs in time course. We investigated the frequency of genes encoding Killer immunoglobulin-like receptors and their HLA ligands in subjects with CIDP, in subjects with GBS and in healthy controls. There were no differences in KIR gene frequency among the 3 groups. The gene frequencies for HLA-B Bw4-I were significantly greater in CIDP than HC, but did not differ from GBS. The frequency of the combination of 3DL1/HLA-B Bw4I was greater in CIDP than HC, but did not differ from that of GBS. These data raise the possibility of NK cell function being an important factor in the pathogenesis of CIDP. Copyright © 2015 Elsevier B.V. All rights reserved.

Cellular sources and targets of IFN-γ-mediated protection against viral demyelination and neurological deficits

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Murray, Paul D.; McGavern, Dorian B.; Pease, Larry R.; Rodriguez, Moses

2017-01-01

IFN-γ is an anti-viral and immunomodulatory cytokine critical for resistance to multiple pathogens. Using mice with targeted disruption of the gene for IFN-γ, we previously demonstrated that this cytokine is critical for resistance to viral persistence and demyelination in the Theiler’s virus model of multiple sclerosis. During viral infections, IFN-γ is produced by natural killer (NK) cells, CD4+ and CD8+ T cells; however, the proportions of lymphocyte subsets responding to virus infection influences the contributions to IFN-γ-mediated protection. To determine the lymphocyte subsets that produce IFN-γ to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFN-γ-production. We demonstrate that IFN-γ production by both CD4+ and CD8+ T cell subsets is critical for resistance to Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelination and neurological disease, and that CD4+ T cells make a greater contribution to IFN-γ-mediated protection. To determine the cellular targets of IFN-γ-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFN-γ receptor. We demonstrate that IFN-γ receptor must be present on central nervous system glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to TMEV-induced demyelination. PMID:11857334

The nervous system in genital herpes simplex virus type 2 infections in mice. Lethal panmyelitis or nonlethal demyelinative myelitis or meningitis.

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Martin, J R; Stoner, G L

1984-11-01

Female mice were inoculated vaginally with the MS strain of herpes simplex virus type 2, and serially positive vaginal cultures were used to confirm infection. The proportion of mice infected and the mortality rate in infected mice decreased with increasing age. In mice 12 weeks old, clinical, neuropathologic, and virologic criteria defined four patterns of disease. Moribund mice had severe genital lesions, hindleg paralysis, and urinary and fecal retention, and most died during the second week of infection. These mice had a panmyelitis with a decreasing gradient of both viral antigen and lesions extending rostrally from the lumbosacral cord into the brain stem. Lesions were about equally distributed in gray and white matter and were characterized by neuronal loss and axonal demyelination, respectively. By contrast, mice with nonfatal infections had mild or no evident genital lesions and a small proportion had mild hindleg weakness. Of these, some mice had demyelinative lesions, particularly in the lower spinal cord but also at higher cord and brain stem levels, whereas others had leptomeningitis. Both of these groups had sacral sensory root abnormalities. A third group of survivors lacked both sensory root and central nervous system abnormalities. This report defines a broader spectrum of disease patterns following infection by a natural route than has been previously appreciated. It provides the first evidence that nonfatal herpes simplex virus type 2 infection by a peripheral route can produce central nervous system demyelination. It indicates that in aseptic meningitis with this agent, the route of virus spread to the central nervous system is neural and not hematogenous. Finally, the antigenic and pathologic observations presented here complement and confirm the virus isolation data and pathologic findings of others that genital herpes simplex virus type 2 infection causes ascending infection in the peripheral and central nervous system.

Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition

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Voss, S.D.; Hall, F.M. [Dept. of Radiology, Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Murphey, M.D. [Dept. of Radiologic Pathology, Armed Forces Institute of Pathology, Washington, DC (United States); Dept. of Radiology and Nuclear Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD (United States); Department of Radiology, University of Maryland School of Medicine, Baltimore, Maryland (United States)

2001-09-01

A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance. (orig.)

A review of MRI evaluation of demyelination in cuprizone murine model

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Krutenkova, E., E-mail: len--k@yandex.ru; Pan, E.; Khodanovich, M., E-mail: khodanovich@mail.tsu.ru [National Research Tomsk State University, Lenina pr., 36, Tomsk (Russian Federation)

2015-11-17

The cuprizone mouse model of non-autoimmune demyelination reproduces some phenomena of multiple sclerosis and is appropriate for validation and specification of a new method of non-invasive diagnostics. In the review new data which are collected using the new MRI method are compared with one or more conventional MRI tools. Also the paper reviewed the validation of MRI approaches using histological or immunohistochemical methods. Luxol fast blue histological staining and myelin basic protein immunostaining is widespread. To improve the accuracy of non-invasive conventional MRI, multimodal scanning could be applied. The new quantitative MRI method of fast mapping of the macromolecular proton fraction is a reliable biomarker of myelin in the brain and can be used for research of demyelination in animals. To date, a validation of MPF method on the CPZ mouse model of demyelination is not performed, although this method is probably the best way to evaluate demyelination using MRI.

Is distal motor and/or sensory demyelination a distinctive feature of anti-MAG neuropathy?

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Lozeron, Pierre; Ribrag, Vincent; Adams, David; Brisset, Marion; Vignon, Marguerite; Baron, Marine; Malphettes, Marion; Theaudin, Marie; Arnulf, Bertrand; Kubis, Nathalie

2016-09-01

To report the frequency of the different patterns of sensory and motor electrophysiological demyelination distribution in patients with anti-MAG neuropathy in comparison with patients with IgM neuropathy without MAG reactivity (IgM-NP). Thirty-five anti-MAG patients at early disease stage (20.1 months) were compared to 23 patients with IgM-NP; 21 CIDP patients and 13 patients with CMT1a neuropathy were used as gold standard neuropathies with multifocal and homogeneous demyelination, respectively. In all groups, standard motor and sensory electrophysiological parameters, terminal latency index and modified F ratio were investigated. Motor electrophysiological demyelination was divided in four profiles: distal, homogeneous, proximal, and proximo-distal. Distal sensory and sensorimotor demyelination were evaluated. Anti-MAG neuropathy is a demyelinating neuropathy in 91 % of cases. In the upper limbs, reduced TLI is more frequent in anti-MAG neuropathy, compared to IgM-NP. But, predominant distal demyelination of the median nerve is encountered in only 43 % of anti-MAG neuropathy and is also common in IgM-NP (35 %). Homogeneous demyelination was the second most frequent pattern (31 %). Concordance of electrophysiological profiles across motor nerves trunks is low and median nerve is the main site of distal motor conduction slowing. Reduced sensory conduction velocities occurs in 14 % of patients without evidence of predominant distal slowing. Simultaneous sensory and motor distal slowing was more common in the median nerve of anti-MAG neuropathy than IgM-NP. Electrophysiological distal motor demyelination and sensory demyelination are not a distinctive feature of anti-MAG reactivity. In anti-MAG neuropathy it is mainly found in the median nerve suggesting a frequent nerve compression at wrist.

22q11.2q13 duplication including SOX10 causes sex-reversal and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease.

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Falah, Nadia; Posey, Jennifer E; Thorson, Willa; Benke, Paul; Tekin, Mustafa; Tarshish, Brocha; Lupski, James R; Harel, Tamar

2017-04-01

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., (2004); AJMGA 127: 149-151], of an individual with 22q duplication and sex-reversal syndrome. The subject's phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain of function rather than dominant negative activity underlies PCWH. © 2017 Wiley Periodicals, Inc.

Behaviour of oligodendrocytes and Schwann cells in an experimental model of toxic demyelination of the central nervous system Comportamento de oligodendrócitos e células de Schwann em modelo experimental de desmielinização tóxica do sistema nervoso central

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Dominguita Lühers Graça

2001-06-01

Full Text Available Oligodendrocytes and Schwann cells are engaged in myelin production, maintenance and repairing respectively in the central nervous system (CNS and the peripheral nervous system (PNS. Whereas oligodendrocytes act only within the CNS, Schwann cells are able to invade the CNS in order to make new myelin sheaths around demyelinated axons. Both cells have some limitations in their activities, i.e. oligodendrocytes are post-mitotic cells and Schwann cells only get into the CNS in the absence of astrocytes. Ethidium bromide (EB is a gliotoxic chemical that when injected locally within the CNS, induce demyelination. In the EB model of demyelination, glial cells are destroyed early after intoxication and Schwann cells are free to approach the naked central axons. In normal Wistar rats, regeneration of lost myelin sheaths can be achieved as early as thirteen days after intoxication; in Wistar rats immunosuppressed with cyclophosphamide the process is delayed and in rats administered cyclosporine it may be accelerated. Aiming the enlightening of those complex processes, all events concerning the myelinating cells in an experimental model are herein presented and discussed.Oligodendrócitos e células de Schwann realizam a produção e manutenção das bainhas de mielina, respectivamente no sistema nervoso central (SNC e periférico (SNP. As células de Schwann, à diferença dos oligodendrócitos, são capazes de invadir o SNC para remielinizar axônios desmielinizados, sempre que os astrócitos tenham sido destruídos. O brometo de etídio é uma droga gliotóxica usada para induzir desmielinização com o desaparecimento precoce de astrócitos, de modo que as células de Schwann têm liberdade para invadir o SNC. Em ratos Wistar normais, a remielinização é detectada treze dias após desmielinização; em ratos Wistar imunossuprimidos com ciclofosfamida a reparação do tecido é tardia, enquanto que em animais tratados com ciclosporina ela �

Pain and spinal cord imaging measures in children with demyelinating disease

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Nadia Barakat

2015-01-01

Full Text Available Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI and magnetization transfer imaging (MTI measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1 pediatric demyelinating conditions affecting the spinal cord; (2 their distinguishing features; and (3 current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis.

Comparison of electrophysiological findings in axonal and demyelinating Guillain-Barre syndrome

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Yadegari, Samira; Nafissi, Shahriar; Kazemi, Neda

2014-01-01

Background: Incidence and predominant subtype of Guillain-Barre syndrome (GBS) differs geographically. Electrophysiology has an important role in early diagnosis and prediction of prognosis. This study is conducted to determine the frequent subtype of GBS in a large group of patients in Iran and compare nerve conduction studies in axonal and demyelinating forms of GBS. Methods: We retrospectively evaluated the medical records and electrodiagnostic study (EDS) of 121 GBS patients who were managed in our hospital during 11 years. After regarding the exclusion criteria, patients classified as three groups: acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor sensory axonal neuropathy (AMSAN). The most frequent subtype and then electrophysiological characteristic based on the time of EDS and their cerebrospinal fluid (CSF) profile were assessed. Results: Among 70 patients finally included in the study, 67% were men. About 63%, 23%, and 14% had AIDP, AMAN, and AMSAN, respectively. AIDP patients represented a wider range of ages compared with other groups. Higher levels of CSF protein, abnormal late responses and sural sparing were more frequent in AIDP subtype. Five AMSAN patients also revealed sural sparing. Conduction block (CB) was observed in one AMAN patient. Prolonged F-wave latency was observed only in AIDP cases. CB and inexcitable sensory nerves were more frequent after 2 weeks, but reduced F-wave persistency was more prominent in the early phase. Conclusion: AIDP was the most frequent subtype. Although the electrophysiology and CSF are important diagnostic tools, classification should not be made based on a distinct finding. PMID:25422732

Interactions Between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma on Neuroinflammation, Demyelination, and Remyelination in Multiple Sclerosis.

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Vallée, Alexandre; Vallée, Jean-Noël; Guillevin, Rémy; Lecarpentier, Yves

2018-05-01

Multiple sclerosis (MS) is marked by neuroinflammation and demyelination with loss of oligodendrocytes in the central nervous system. The immune response is regulated by WNT/beta-catenin pathway in MS. Activated NF-kappaB, a major effector of neuroinflammation, and upregulated canonical WNT/beta-catenin pathway positively regulate each other. Demyelinating events present an upregulation of WNT/beta-catenin pathway, whereas proper myelinating phases show a downregulation of WNT/beta-catenin pathway essential for the promotion of oligodendrocytes precursors cells proliferation and differentiation. The activation of WNT/beta-catenin pathway results in differentiation failure and impairment in remyelination. However, PI3K/Akt pathway and TCF7L2, two downstream targets of WNT/beta-catenin pathway, are upregulated and promote proper remyelination. The interactions of these signaling pathways remain unclear. PPAR gamma activation can inhibit NF-kappaB, and can also downregulate the WNT/beta-catenin pathway. PPAR gamma and canonical WNT/beta-catenin pathway act in an opposite manner. PPAR gamma agonists appear as a promising treatment for the inhibition of demyelination and the promotion of proper remyelination through the control of both NF-kappaB activity and canonical WNT/beta-catenin pathway.

Increased demyelination and axonal damage in metallothionein I+II-deficient mice during experimental autoimmune encephalomyelitis

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Penkowa, M; Espejo, C; Martínez-Cáceres, E M

2003-01-01

Metallothioneins I+II (MT-I+II) are antioxidant, neuroprotective factors. We previously showed that MT-I+II deficiency during experimental autoimmune encephalomyelitis (EAE) leads to increased disease incidence and clinical symptoms. Moreover, the inflammatory response of macrophages and T cells......, oxidative stress, and apoptotic cell death during EAE were increased by MT-I+II deficiency. We now show for the first time that demyelination and axonal damage are significantly increased in MT-I+II deficient mice during EAE. Furthermore, oligodendroglial regeneration, growth cone formation, and tissue...... repair including expression of trophic factors were significantly reduced in MT-I+II-deficient mice during EAE. Accordingly, MT-I+II have protective and regenerative roles in the brain....

Myelin activates FAK/Akt/NF-kappaB pathways and provokes CR3-dependent inflammatory response in murine system.

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Xin Sun

2010-02-01

Full Text Available Inflammatory response following central nervous system (CNS injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS and its animal model, experimental autoimmune encephalomyelitis (EAE, there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI, i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-kappaB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-kappaB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin and myelin basic protein (MBP, one of the major proteins of myelin are not able to activate NF-kappaB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.

Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?

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Thomas Vorup-Jensen

2012-11-01

Full Text Available Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin αMβ2 (also called Mac-1, complement receptor 3, or CD11b/CD18 and perspectives on the GA co-polymers as an influence on the function of the innate immune system.

Role of T cell – glial cell interactions in creating and amplifying Central Nervous System inflammation and Multiple Sclerosis disease symptoms

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Eric S. Huseby

2015-08-01

Full Text Available Multiple Sclerosis (MS is an inflammatory disease of the Central Nervous System (CNS that causes the demyelination of nerve cells and destroys oligodendrocytes, neurons and axons. Historically, MS has been thought of as a T cell-mediated autoimmune disease of CNS white matter. However, recent studies have identified gray matter lesions in MS patients, suggesting that CNS antigens other than myelin proteins may be involved during the MS disease process. We have recently found that T cells targeting astrocyte-specific antigens can drive unique aspects of inflammatory CNS autoimmunity, including the targeting of gray matter and white matter of the brain and inducing heterogeneous clinical disease courses. In addition to being a target of T cells, astrocytes play a critical role in propagating the inflammatory response within the CNS through cytokine induced NF-ΚB signaling. Here, we will discuss the pathophysiology of CNS inflammation mediated by T cell – glial cell interactions and its contributions to CNS autoimmunity.

Central pontine and extrapontine myelinolysis in an infant associated with the treatment of craniopharyngioma: case report.

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Tsutsumi, Satoshi; Yasumoto, Yukimasa; Ito, Masanori

2008-08-01

A 3-year-old girl presented with osmotic demyelination syndrome after undergoing uneventful neuroendoscopic cystostomy for a growing cystic suprasellar craniopharyngioma following microscopic subtotal resection 1 year previously. Endocrinopathy had well been controlled by hormone replacement therapy and administration of 1-amino-8-d-arginine-vasopressin with serum sodium concentration within the normal range. She presented generalized seizure and fever on postoperative day 7, with hyponatremia beginning on postoperative day 4 and deteriorating despite frequent correction. The serum sodium concentration began to fluctuate on the same day, in the range 111-164 mEq/l, which lasted for 2 weeks, refractory for intense management. Her body temperature also fluctuated between hypo- and hyperthermia not correlated with serum inflammatory markers. Her conscious disturbance progressively deteriorated with spastic paraparesis. T(2)-weighted magnetic resonance (MR) imaging taken on postoperative day 19 revealed hyperintense areas in the pons, external capsule, bilateral thalami, and basal nuclei, which had not been recognized before, suggesting osmotic demyelination syndrome causing central pontine and extrapontine myelinolysis. MR imaging taken on postoperative days 230 and 360 showed some diminished lesions but others persisted and resulted in a cavity. The patient's depressed conscious level did not improve. Suprasellar craniopharyngioma with long-standing hypothalamic dysfunction may be associated with severe osmotic demyelination syndrome even after less invasive surgery, so serum sodium derangement after surgery should be promptly corrected even if only subtle signs are present.

Autoimmune Demyelinating Polyneuropathy as a Manifestation of Chronic Graft-versus-Host Disease after Adult Cord Blood Transplantation in a Patient with Chronic Lymphocytic Leukemia

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Fredrick Hogan

2014-01-01

Full Text Available Immune mediated demyelinating disease after allogeneic stem cell transplantation is a rare entity with unclear etiology. Acute inflammatory demyelinating polyneuropathy (AIDP has been reported after related and adult unrelated allogeneic stem cell transplantation but no such case has been reported after unrelated cord blood transplantation. We hereby present the first case of AIDP after double umbilical cord blood transplantation (DUCBT. A 55-year-old man with chronic lymphocytic leukemia (CLL received a cord blood transplant for relapsed refractory disease with high risk cytogenetics. On day 221, patient presented with skin rash, tingling in both lower extremites, and ascending paralysis that progressed rapidly over the course of 2 days. The workup resulted in a diagnosis of AIDP and administration of intravenous immunoglobulins plus steroids was initiated. Motor and sensory powers were fully recovered and his chronic GVHD was managed for several months with single agent sirolimus.

Phosphatidylcholine 36:1 concentration decreases along with demyelination in the cuprizone animal model and post-mortem of multiple sclerosis brain tissue.

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Trépanier, Marc-Olivier; Hildebrand, Kayla D; Nyamoya, Stella D; Amor, Sandra; Bazinet, Richard P; Kipp, Markus

2018-03-25

Multiple sclerosis (MS) is a demyelinating and inflammatory disease. Myelin is enriched in lipids, and more specifically, oleic acid. The goal of this study was to evaluate the concentration of oleic acid following demyelination and remyelination in the cuprizone model, test if these changes occurred in specific lipid species, and whether differences in the cuprizone model correlate with changes observed in post-mortem human brains. Eight-week-old C57Bl/6 mice were fed a 0.2% cuprizone diet for 5 weeks and some animals allowed to recover for 11 days. Demyelination, inflammation, and lipid concentrations were measured in the corpus callosum. Standard fatty acid techniques and liquid chromatography combined with tandem mass spectrometry were performed to measure concentrations of fatty acids in total brain lipids and a panel of lipid species within the phosphatidylcholine (PC). Similar measurements were conducted in post-mortem brain tissues of MS patients and were compared to healthy controls. Five weeks of cuprizone administration resulted in demyelination followed by significant remyelination after 11 days of recovery. Compared to control, oleic acid was decreased after 5 weeks of cuprizone treatment and increased during the recovery phase. This decrease in oleic acid was associated with a specific decrease in the PC 36:1 pool. Similar results were observed in human post-mortem brains. Decreases in myelin content in the cuprizone model was accompanied with decreases in oleic acid concentration and is associated with PC 36:1 suggesting that specific lipids could be a potential biomarker for myelin degeneration. The biological relevance of oleic acid for disease progression remains to be verified. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

CSF free light chain identification of demyelinating disease: comparison with oligoclonal banding and other CSF indexes.

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Gurtner, Kari M; Shosha, Eslam; Bryant, Sandra C; Andreguetto, Bruna D; Murray, David L; Pittock, Sean J; Willrich, Maria Alice V

2018-02-19

Cerebrospinal fluid (CSF) used in immunoglobulin gamma (IgG) index testing and oligoclonal bands (OCBs) are common laboratory tests used in the diagnosis of multiple sclerosis. The measurement of CSF free light chains (FLC) could pose as an alternative to the labor-intensive isoelectric-focusing (IEF) gels used for OCBs. A total of 325 residual paired CSF and serum specimens were obtained after physician-ordered OCB IEF testing. CSF kappa (cKFLC) and lambda FLC (cLFLC), albumin and total IgG were measured. Calculations were performed based on combinations of analytes: CSF sum of kappa and lambda ([cKFLC+cLFLC]), kappa-index (K-index) ([cKFLC/sKFLC]/[CSF albumin/serum albumin]), kappa intrathecal fraction (KFLCIF) {([cKFLC/sKFLC]-[0.9358×CSF albumin/serum albumin]^[0.6687×sKFLC]/cKFLC)} and IgG-index ([CSF IgG/CSF albumin]/[serum IgG/serum albumin]). Patients were categorized as: demyelination (n=67), autoimmunity (n=53), non-inflammatory (n=50), inflammation (n=38), degeneration (n=28), peripheral neuropathy (n=24), infection (n=13), cancer (n=11), neuromyelitis optica (n=10) and others (n=31). cKFLC measurement used alone at a cutoff of 0.0611 mg/dL showed >90% agreement to OCBs, similar or better performance than all other calculations, reducing the number of analytes and variables. When cases of demyelinating disease were reviewed, cKFLC measurements showed 86% clinical sensitivity/77% specificity. cKFLC alone demonstrates comparable performance to OCBs along with increased sensitivity for demyelinating diseases. Replacing OCB with cKFLC would alleviate the need for serum and CSF IgG and albumin and calculated conversions. cKFLC can overcome challenges associated with performance, interpretation, and cost of traditional OCBs, reducing costs and maintaining sensitivity and specificity supporting MS diagnosis.

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

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Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

2017-08-08

The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Lesser-known myelin-related disorders: focal tumour-like demyelinating lesions.

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Jiménez Arango, J A; Uribe Uribe, C S; Toro González, G

2015-03-01

Focal tumour-like demyelinating lesions are defined as solitary demyelinating lesions with a diameter greater than 2 cm. In imaging studies, these lesions may mimic a neoplasm or brain abscess; as a result, invasive diagnostic and therapeutic measures may be performed that will in some cases increase morbidity. Our aim was to analyse and characterise these lesions according to their clinical, radiological, and pathological characteristics, and this data in addition to our literature review will contribute to a better understanding of these lesions. This descriptive study includes 5 cases with pathological diagnoses. We provide subject characteristics gathered through reviewing their clinical, radiology, and pathology reports. Patients' ages ranged from 12 to 60 years; 3 patients were female. The time delay between symptom onset and hospital admission was 3 to 120 days. Clinical manifestations were diverse and dependent on the location of the lesion, pyramidal signs were found in 80% of patients, there were no clinical or radiological signs of spinal cord involvement, and follow-up times ranged from 1 to 15 years. Brain biopsy is the gold standard for the diagnosis of demyelinating tumour-like lesions; however, their clinical features, along with several magnetic resonance imaging features such as open ring enhancement, venular enhancement, the presence of glutamate in spectroscopy, and others, may be sufficient to differentiate neoplastic lesions from focal tumour-like demyelinating lesions. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Cerebrospinal fluid inflammatory markers in patients with multiple sclerosis: a pilot study.

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Matejčíková, Z; Mareš, J; Přikrylová Vranová, H; Klosová, J; Sládková, V; Doláková, J; Zapletalová, J; Kaňovský, P

2015-02-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Autoimmune inflammation is common in the early stages of MS. This stage is followed by the neurodegenerative process. The result of these changes is axon and myelin breakdown. Although MS is according to McDonald's revised diagnostic criteria primarily a clinical diagnosis, paraclinical investigation methods are an important part in the diagnosis of MS. In common practice, magnetic resonance imaging of the brain and spinal cord, examination of cerebrospinal fluid (CSF) and examination of visual evoked potentials are used. There are an increasing number of studies dealing with biomarkers in CSF and their role in the diagnosis and treatment of MS. We hypothesized that the levels of some markers could be changed in MS in comparison with controls. We studied five inflammatory markers [interleukin-6 (IL-6), interleukin-8, interleukin-10 (IL-10), beta-2-microglobulin, orosomucoid]. CSF and serum levels of inflammatory markers were assessed in 38 patients with newly diagnosed MS meeting McDonald's revised diagnostic criteria and in 28 subjects as a control group (CG). Levels of beta-2-microglobulin and interleukin-8 in CSF were found to be significantly higher in MS patients in comparison to CG (p < 0.001 resp. p = 0.007). No differences in other CSF markers (IL-6, IL-10 and orosomucoid) and serum levels of all markers between both groups were found. The levels of two studied inflammatory markers were found to be increased at the time of first clinical symptoms of MS. Research on the role of inflammatory and neurodegenerative markers in MS should continue.

Central Pontine and Extrapontine Myelinolysis: The Great Masquerader—An Autopsy Case Report

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Sajish Jacob

2014-01-01

Full Text Available Central pontine myelinolysis is a demyelinating disorder characterized by the loss of myelin in the center of the basis pontis usually caused by rapid correction of chronic hyponatremia. The clinical features vary depending on the extent of involvement. Demyelination can occur outside the pons as well and diagnosis can be challenging if both pontine and extrapontine areas are involved. We herein report a case of myelinolysis involving pons, lateral geniculate bodies, subependymal region, and spinal cord. To the best of our knowledge, this case represents the second case of spinal cord involvement in osmotic demyelination syndrome and the first case of involvement of thoracic region of spinal cord.

Central Pontine and Extrapontine Myelinolysis: The Great Masquerader—An Autopsy Case Report

Science.gov (United States)

Jacob, Sajish; Nikolic, Dejan; Gundogdu, Betul; Ong, Shirley

2014-01-01

Central pontine myelinolysis is a demyelinating disorder characterized by the loss of myelin in the center of the basis pontis usually caused by rapid correction of chronic hyponatremia. The clinical features vary depending on the extent of involvement. Demyelination can occur outside the pons as well and diagnosis can be challenging if both pontine and extrapontine areas are involved. We herein report a case of myelinolysis involving pons, lateral geniculate bodies, subependymal region, and spinal cord. To the best of our knowledge, this case represents the second case of spinal cord involvement in osmotic demyelination syndrome and the first case of involvement of thoracic region of spinal cord. PMID:24716023

Desmielinização e remielinização após múltiplas injeções intramedulares de brometo de etídio em ratos Wistar Demyelination and remyelination after multiple intramedullary injections of ethidium bromide in Wistar rats

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Cristina Gevehr Fernandes

1997-09-01

Full Text Available O modelo de desmielinização do brometo de etídio foi utilizado para estudar a reação do sistema nervoso central frente a múltiplos episódios de desmielinização tóxica. Foram utilizados 27 ratos Wistar, submetidos a 2,3 ou 4 injeções de 1μl de solução 0,1 % de brometo de etídio (19 ratos ou de solução salina 0,9% (8 ratos em diferentes pontos da medula espinhal. Os intervalos entre as injeções variaram de 28 a 42 dias. Dez dias após a última injeção os animais foram perfundidos com glutaraldeído 2,5%. As medulas espinhais foram avaliadas pela macroscopia, microscopia óptica de cortes semifinos e microscopia eletrônica de transmissão. As lesões foram caracterizadas por desmielinização primária focal, com preservação das estruturas vasculares, e variavam em tamanho e características histológicas. Remielinização pode ser observada, ou não, de acordo com o tipo de lesão. Como conseqüência das injeções múltiplas e seqüenciais de brometo de etídio, o sistema nervoso central pareceu modificar sua capacidade de responder a um estímulo inflamatório, mas não variou seu padrão de remielinização.The ethidium bromide model of demyelination has been employed to study the central nervous system response to several episodes of demyelination. Twenty-seven Wistar rats received 2 to 4 intraspinal injections of lμl of either 0.1% ethidium bromide in normal saline (19 rats or saline 0.9% (8 rats in different anatomical locations. The intervals between the injections ranged from 28 to 42 days. Ten days after the last injection all the rats were perfused with 2.5% glutaraldehyde. The spinal sections were evaluated macroscopically and by light and transmission electron microscopy. The lesions were typical of focal primary demyelination with preserved vascular structures and followed by remyelinization and varied in size and histological aspects. After multiple sequential ethidium bromide injections, the central

Regulatory effect of triiodothyronine on brain myelination and astrogliosis after cuprizone-induced demyelination in mice.

Science.gov (United States)

Zendedel, Adib; Kashani, Iraj Ragerdi; Azimzadeh, Maryam; Pasbakhsh, Parichehr; Omidi, Negar; Golestani, Abolfazl; Beyer, Cordian; Clarner, Tim

2016-04-01

Chronic demyelination and plaque formation in multiple sclerosis is accompanied by persisting astrogliosis, negatively influencing central nervous system recovery and remyelination. Triiodothyronin (T3) is thought to enhance remyelination in the adult brain by the induction of oligodendrocyte maturation. We investigated additional astrocyte-mediated mechanisms by which T3 might promote remyelination in chronically demyelinated lesions using the cuprizone mouse model. C57BL/6 mice were fed cuprizone for 12 weeks to induce lesions with an impaired remyelination capacity. While the expression of oligodenrocyte progenitor markers, i.e., platelet derived growth factor-α receptor was not affected by T3 administration, myelination status, myelin protein expression as well as total and adult oligodendrocyte numbers were markedly increased compared to cuprizone treated controls. In addition to these effects on oligodendrocyte numbers and function, astrogliosis but not microgliosis was ameliorated by T3 administration. Intermediate filament proteins vimentin and nestin as well as the extracellular matrix component tenascin C were significantly reduced after T3 exposure, indicating additional effects of T3 on astrocytes and astrogliosis. Our data clearly indicate that T3 promotes remyelination in chronic lesions by both enhancing oligodendrocyte maturation and attenuating astrogliosis.

In vitro analysis of the oligodendrocyte lineage in mice during demyelination and remyelination

International Nuclear Information System (INIS)

Armstrong, R.; Friedrich, V.L. Jr.; Holmes, K.V.; Dubois-Dalcq, M.

1990-01-01

A demyelinating disease induced in C57B1/6N mice by intracranial injection of a coronavirus (murine hepatitis virus strain A59) is followed by functional recovery and efficient CNS myelin repair. To study the biological properties of the cells involved in this repair process, glial cells were isolated and cultured from spinal cords of these young adult mice during demyelination and remyelination. Using three-color immunofluorescence combined with [3H]thymidine autoradiography, we have analyzed the antigenic phenotype and mitotic potential of individual glial cells. We identified oligodendrocytes with an antibody to galactocerebroside, astrocytes with an antibody to glial fibrillary acidic protein, and oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells with the O4 antibody. Cultures from demyelinated tissue differed in several ways from those of age-matched controls: first, the total number of O-2A lineage cells was strikingly increased; second, the O-2A population consisted of a higher proportion of O4-positive astrocytes and cells of mixed oligodendrocyte-astrocyte phenotype; and third, all the cell types within the O-2A lineage showed enhanced proliferation. This proliferation was not further enhanced by adding PDGF, basic fibroblast growth factor (bFGF), or insulin-like growth factor I (IGF-I) to the defined medium. However, bFGF and IGF-I seemed to influence the fate of O-2A lineage cells in cultures of demyelinated tissue. Basic FGF decreased the percentage of cells expressing galactocerebroside. In contrast, IGF-I increased the relative proportion of oligodendrocytes. Thus, O-2A lineage cells from adult mice display greater phenotypic plasticity and enhanced mitotic potential in response to an episode of demyelination. These properties may be linked to the efficient remyelination achieved in this demyelinating disease

Work ability in multiple sclerosis : the impact of immunomodulating treatments and adjusted working conditions

OpenAIRE

Wickström, Anne

2015-01-01

Background Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease affecting the central nervous system (CNS) and is considered to be of autoimmune origin. The prevalence in Sweden is estimated to be about 1 in 500. The inflammation leads to demyelination as well as neurodegeneration and with time the patients often suffer from increasing neurological disability. The young age of onset makes MS one of the major causes of reduced ability to work in the Western society. Several...

Demyelinating polyneuropathy with focally folded myelin sheaths in a family of Miniature Schnauzer dogs.

Science.gov (United States)

Vanhaesebrouck, An E; Couturier, Jérôme; Cauzinille, Laurent; Mizisin, Andrew P; Shelton, G Diane; Granger, Nicolas

2008-12-15

A spontaneous demyelinating polyneuropathy in two young Miniature Schnauzer dogs was characterized clinically, electrophysiologically and histopathologically. Both dogs were related and a third dog, belonging to the same family, had similar clinical signs. On presentation, clinical signs were restricted to respiratory dysfunction. Electrophysiological tests showed a dramatic decrease in both motor and sensory nerve conduction velocities. Microscopic examination of peripheral nerve biopsies (light and electron microscopy, teased nerve fibers), showed that this neuropathy was characterized by segmental demyelination and focally folded myelin sheaths. Various clinical syndromes associated with tomacula or focal thickening of the myelin sheath of the peripheral nerves have been described in humans and shown to be caused by gene mutations affecting the myelin proteins, such as the hereditary neuropathy with liability to pressure palsies or the demyelinating forms of Charcot-Marie-Tooth disease. In animals, a tomaculous neuropathy has been reported in cattle and chickens but not in carnivores. Here we report a demyelinating peripheral neuropathy with tomacula in two Miniature Schnauzer dogs.

Hypersensitivity Responses in the Central Nervous System

DEFF Research Database (Denmark)

Khorooshi, Reza; Asgari, Nasrin; Mørch, Marlene Thorsen

2015-01-01

of pathology in neuromyelitis optica (NMO), a central nervous system (CNS) demyelinating disease where activated neutrophils infiltrate, unlike in MS. The most widely used model for MS, experimental autoimmune encephalomyelitis, is an autoantigen-immunized disease that can be transferred to naive animals...

EFNS guidelines on diagnosis and management of neuromyelitis optica

DEFF Research Database (Denmark)

Sellner, J; Boggild, M; Clanet, M

2010-01-01

Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct from multiple sclerosis...

Leukemia inhibitory factor tips the immune balance towards regulatory T cells in multiple sclerosis

NARCIS (Netherlands)

Janssens, K.; Van den Haute, C.; Baekelandt, V.; Lucas, S.; van Horssen, J.; Somers, V.; Van Wijmeersch, B.; Stinissen, P.; Hendriks, J.J.A.; Slaets, H.; Hellings, N.

2015-01-01

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), for which current treatments are unable to prevent disease progression. Based on its neuroprotective and neuroregenerating properties, leukemia inhibitory factor (LIF), a member of the interleukin-6

EFNS guidelines on diagnosis and management of neuromyelitis optica

NARCIS (Netherlands)

Sellner, J.; Boggild, M.; Clanet, M.; Hintzen, R.Q.; Illes, Z.; Montalban, X.; Du Pasquier, R.A.; Polman, C.H.; Sorensen, P.S.; Hemmer, B.

2010-01-01

Background and purpose: Neuromyelitis optica (NMO) or Devic's disease is a rare inflammatory and demyelinating autoimmune disorder of the central nervous system (CNS) characterized by recurrent attacks of optic neuritis (ON) and longitudinally extensive transverse myelitis (LETM), which is distinct

Histological characterization and quantification of cellular events following neural and fibroblast(-like) stem cell grafting in healty and demyelinated CNS tissue

OpenAIRE

Praet, J.; SANTERMANS, Eva; Reekmans, K.; de Vocht, N.; Le Blon, D.; Hoornaert, C.; Daans, J.; Goossens, H.; Berneman, Z.; HENS, Niel; Van der Linden, A.; Ponsaerts, P.

2014-01-01

Preclinical animal studies involving intracerebral (stem) cell grafting are gaining popularity in many laboratories due to the reported beneficial effects of cell grafting on various diseases or traumata of the central nervous system (CNS). In this chapter, we describe a histological workflow to characterize and quantify cellular events following neural and fibroblast(-like) stem cell grafting in healthy and demyelinated CNS tissue. First, we provide standardized protocols to isolate and cult...

Treatment of Multiple Sclerosis

OpenAIRE

Bošnjak-Pašić, Marija; Vidrih, Branka; Miškov, Snježana; Demarin, Vida

2009-01-01

Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system, characterized by multifocal inflammatory destruction of myelin, axonal damage and loss of oligodendrocytes. The disease is carried through two stages: inflammatory and degenerative. The most common form of disease in approximately 85% of the cases is RRMS (relapsing-remitting form). The treatment of MS is divided into: treatment of the acute phase of illness, prevention of new relapses and di...

Constitutive expression of a costimulatory ligand on antigen-presenting cells in the nervous system drives demyelinating disease

DEFF Research Database (Denmark)

Zehntner, Simone P; Brisebois, Marcel; Tran, Elise

2003-01-01

that transgenic mice constitutively expressing the costimulatory ligand B7.2/CD86 on microglia in the central nervous system (CNS) and on related cells in the proximal peripheral nervous tissue spontaneously develop autoimmune demyelinating disease. Disease-affected nervous tissue in transgenic mice showed...... recipients but not into non-transgenic recipients. These data provide evidence that B7/CD28 interactions within the nervous tissue are critical determinants of disease development. Our findings have important implications for understanding the etiology of nervous system autoimmune diseases such as multiple...

A systematic analysis of the complement pathways in patients with neuromyelitis optica indicates alteration but no activation during remission

DEFF Research Database (Denmark)

Veszeli, Nóra; Füst, György; Csuka, Dorottya

2014-01-01

Neuromyelitis optica (NMO) is an autoimmune demyelinating inflammatory disorder, mediated by pathogenic autoantibodies against aquaporin 4 (AQP4), the main water channel of the central nervous system (CNS). NMO is characterized by local IgG deposition and complement activation within the CNS...

Female Gender and Reproductive Factors Affecting Risk, Relapses and Progression in Multiple Sclerosis

NARCIS (Netherlands)

D'hooghe, M. B.; D'Hooghe, T.; De Keyser, J.

2013-01-01

Multiple sclerosis (MS), a chronic inflammatory demyelinating and degenerative disease of the central nervous system, is a frequent cause of neurological disability in young adults. Female predominance has increased over the last decades. Although female gender carries a higher risk of developing

RNase L mediated protection from virus induced demyelination.

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Derek D C Ireland

2009-10-01

Full Text Available IFN-alpha/beta plays a critical role in limiting viral spread, restricting viral tropism and protecting mice from neurotropic coronavirus infection. However, the IFN-alpha/beta dependent mechanisms underlying innate anti-viral functions within the CNS are poorly understood. The role of RNase L in viral encephalomyelitis was explored based on its functions in inhibiting translation, inducing apoptosis, and propagating the IFN-alpha/beta pathway through RNA degradation intermediates. Infection of RNase L deficient (RL(-/- mice with a sub-lethal, demyelinating mouse hepatitis virus variant revealed that the majority of mice succumbed to infection by day 12 p.i. However, RNase L deficiency did not affect overall control of infectious virus, or diminish IFN-alpha/beta expression in the CNS. Furthermore, increased morbidity and mortality could not be attributed to altered proinflammatory signals or composition of cells infiltrating the CNS. The unique phenotype of infected RL(-/- mice was rather manifested in earlier onset and increased severity of demyelination and axonal damage in brain stem and spinal cord without evidence for enhanced neuronal infection. Increased tissue damage coincided with sustained brain stem infection, foci of microglia infection in grey matter, and increased apoptotic cells. These data demonstrate a novel protective role for RNase L in viral induced CNS encephalomyelitis, which is not reflected in overall viral control or propagation of IFN-alpha/beta mediated signals. Protective function is rather associated with cell type specific and regional restriction of viral replication in grey matter and ameliorated neurodegeneration and demyelination.

Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions

Science.gov (United States)

Pezet, Sophie; Marchand, Fabien; D'Mello, Richard; Grist, John; Clark, Anna K.; Malcangio, Marzia; Dickenson, Anthony H.; Williams, Robert J.; McMahon, Stephen B.

2010-01-01

Here we show that phosphatidylinositol 3-kinase (PI3K) is a key player in the establishment of central sensitization, the spinal cord phenomenon associated with persistent afferent inputs and contributing to chronic pain states. We demonstrated electrophysiologically that PI3K is required for the full expression of spinal neuronal wind-up. In an inflammatory pain model, intrathecal administration of LY294002, a potent PI3K inhibitor, dose-dependently inhibited pain related behavior. This effect was correlated with a reduction of the phosphorylation of extracellular signal-regulated kinase (ERK) and CaMKinase II. In addition, we observed a significant decrease in the phosphorylation of the NMDA receptor subunit NR2B, decreased translocation to the plasma membrane of the GluR1 AMPA receptor subunit in the spinal cord and a reduction of evoked neuronal activity as measured using c-Fos immunohistochemistry. Our study suggests that PI3K is a major factor in the expression of central sensitization after noxious inflammatory stimuli. PMID:18417706

Central Pontine Myelinolysis and Localized Fluorodeoxyglucose Uptake Seen on 18F-FDG PET/CT

DEFF Research Database (Denmark)

Rønne, Frederik; Tfelt-Hansen, Peer Carsten; Rørdam, Lene

2017-01-01

Case report describing the finding of central pontine myelinolysis (CPM) using combined fluorine-18 ( 18F)-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). The patient was a known alcoholic who, during admission was under treatment for hyponatremia, showed...... a significant decline in both motor and cognitive function. Combined 18F-FDG PET/CT showed localized FDG uptake in the pons, consistent with the finding of CPM observed on magnetic resonance imaging (MRI). CPM is a demyelinating lesion of the pons, resulting in several neurological symptoms. The exact cause...... of CPM is not clear, but a strong relations between loss of myelin and osmotic stress exists, especially during rapid correction of hyponatremia. The osmotic stress is thought to induce disruption of the blood-brain barrier, allowing access for inflammatory mediators in extravascular brain tissue, which...

Diffusion Tensor Imaging as a Biomarker to Differentiate Acute Disseminated Encephalomyelitis From Multiple Sclerosis at First Demyelination.

Science.gov (United States)

Aung, Wint Yan; Massoumzadeh, Parinaz; Najmi, Safa; Salter, Amber; Heaps, Jodi; Benzinger, Tammie L S; Mar, Soe

2018-01-01

There are no clinical features or biomarkers that can reliably differentiate acute disseminated encephalomyelitis from multiple sclerosis at the first demyelination attack. Consequently, a final diagnosis is sometimes delayed by months and years of follow-up. Early treatment for multiple sclerosis is recommended to reduce long-term disability. Therefore, we intend to explore neuroimaging biomarkers that can reliably distinguish between the two diagnoses. We reviewed prospectively collected clinical, standard MRI and diffusion tensor imaging data from 12 pediatric patients who presented with acute demyelination with and without encephalopathy. Patients were followed for an average of 6.5 years to determine the accuracy of final diagnosis. Final diagnosis was determined using 2013 International Pediatric MS Study Group criteria. Control subjects consisted of four age-matched healthy individuals for each patient. The study population consisted of six patients with central nervous system demyelination with encephalopathy with a presumed diagnosis of acute disseminated encephalomyelitis and six without encephalopathy with a presumed diagnosis of multiple sclerosis or clinically isolated syndrome at high risk for multiple sclerosis. During follow-up, two patients with initial diagnosis of acute disseminated encephalomyelitis were later diagnosed with multiple sclerosis. Diffusion tensor imaging region of interest analysis of baseline scans showed differences between final diagnosis of multiple sclerosis and acute disseminated encephalomyelitis patients, whereby low fractional anisotropy and high radial diffusivity occurred in multiple sclerosis patients compared with acute disseminated encephalomyelitis patients and the age-matched controls. Fractional anisotropy and radial diffusivity measures may have the potential to serve as biomarkers for distinguishing acute disseminated encephalomyelitis from multiple sclerosis at the onset. Copyright © 2017 Elsevier Inc. All

Grey matter OPCs are less mature and less sensitive to IFN gamma than white matter OPCs : consequences for remyelination

NARCIS (Netherlands)

Lentferink, Dennis H; Jongsma, Jacomien M; Werkman, Inge; Baron, Wia

2018-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by the formation of demyelinated lesions in the central nervous system. At later stages of the disease repair in the form of remyelination often fails, which leads to axonal degeneration and neurological disability. For the

Global and 3D Spatial Assessment of Neuroinflammation in Rodent Models of Multiple Sclerosis

DEFF Research Database (Denmark)

Gupta, Shashank; Utoft, Regine Egeholm; Hasseldam, Henrik

2013-01-01

Multiple Sclerosis (MS) is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS). T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE) animal models for the disease. A te...

Simvastatin affects cell motility and actin cytoskeleton distribution of microglia

NARCIS (Netherlands)

Kuipers, HF; Rappert, Angelika A.C.; Mommaas, AM; Van Haastert, ES; Van der Valk, P; Boddeke, HWGM; Biber, KPH; Van den Elsen, PJ

2006-01-01

Statin treatment is proposed to be a new potential therapy for multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system. The effects of statin treatment on brain cells, however, are hardly understood. We therefore evaluated the effects of simvastatin treatment on

Study of Low-grade Chronic Inflammatory Markers in Men with Central Obesity: Cathepsin S was Correlated with Waist Circumference

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Adriana Todingrante

2013-08-01

Full Text Available BACKGROUND: There is a prevalence increase of overweight and obesity in Indonesia. Central obesity can lead a variety of chronic diseases through the inflammatory process. There are some markers for low-grade chronic inflammatory, such as cathepsin S, high sensitivity C-reactive protein (hs-CRP, interleukin-1- beta (IL-1β. To our current interest that central obesity can lead to various chronic diseases through the inflammatory process, we conducted a study to investigate correlation of Cathepsin S, hs-CRP, IL-1β in men with central obesity. METHODS: A cross-sectional study was conducted. Seventy-eight selected subjects were examined to collect anthropometric data and prepared for sample collection. Collected samples were processed for the following biochemical analyses: fasting glucose, high density lipoprotein (HDL-cholesterol, triglyceride, serum glutamic oxaloacetic transaminase (SGOT, serum glutamate pyruvate transaminase (SGPT, cathepsin S, hs-CRP, and IL-1β. Data distribution and variable correlation were then statistically analyzed. RESULTS: There were significant correlations between waist circumference (WC and cathepsin S (p=0.030; r=0.214, hs-CRP and cathepsin S (p=0.007; r=0.276, triglyceride and IL-1β (p=0.019; r=-0.235, WC and systolic blood pressure (SBP (p=0.003; r=-0.312, WC and fasting glucose (p=0.000; r=0.380, WC and body mass index (BMI (p=0.000; r=0.708. CONCLUSIONS: Our study showed that cathepsin S was correlated with central obesity, suggesting that cathepsin S could be a potential inflammatory marker in central obesity in the future. KEYWORDS: obesity, inflammation, hs-CRP, cathepsin S, IL-1β, waist circumference.

Deep gray matter demyelination detected by magnetization transfer ratio in the cuprizone model.

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Sveinung Fjær

Full Text Available In multiple sclerosis (MS, the correlation between lesion load on conventional magnetic resonance imaging (MRI and clinical disability is weak. This clinico-radiological paradox might partly be due to the low sensitivity of conventional MRI to detect gray matter demyelination. Magnetization transfer ratio (MTR has previously been shown to detect white matter demyelination in mice. In this study, we investigated whether MTR can detect gray matter demyelination in cuprizone exposed mice. A total of 54 female C57BL/6 mice were split into one control group ( and eight cuprizone exposed groups ([Formula: see text]. The mice were exposed to [Formula: see text] (w/w cuprizone for up to six weeks. MTR images were obtained at a 7 Tesla Bruker MR-scanner before cuprizone exposure, weekly for six weeks during cuprizone exposure, and once two weeks after termination of cuprizone exposure. Immunohistochemistry staining for myelin (anti-Proteolopid Protein and oligodendrocytes (anti-Neurite Outgrowth Inhibitor Protein A was obtained after each weekly scanning. Rates of MTR change and correlations between MTR values and histological findings were calculated in five brain regions. In the corpus callosum and the deep gray matter a significant rate of MTR value decrease was found, [Formula: see text] per week ([Formula: see text] and [Formula: see text] per week ([Formula: see text] respectively. The MTR values correlated to myelin loss as evaluated by immunohistochemistry (Corpus callosum: [Formula: see text]. Deep gray matter: [Formula: see text], but did not correlate to oligodendrocyte density. Significant results were not found in the cerebellum, the olfactory bulb or the cerebral cortex. This study shows that MTR can be used to detect demyelination in the deep gray matter, which is of particular interest for imaging of patients with MS, as deep gray matter demyelination is common in MS, and is not easily detected on conventional clinical MRI.

Enhanced accumulation of Kir4.1 protein, but not mRNA, in a murine model of cuprizone-induced demyelination.

Science.gov (United States)

Nakajima, Mitsunari; Kawamura, Takuya; Tokui, Ryuji; Furuta, Kohei; Sugino, Mami; Nakanishi, Masayuki; Okuyama, Satoshi; Furukawa, Yoshiko

2013-11-06

Two channel proteins, inwardly rectifying potassium channel 4.1 (Kir4.1) and water channel aquaporin-4 (AQP4), were recently identified as targets of an autoantibody response in patients with multiple sclerosis and neuromyelitis optica, respectively. In the present study, we examined the expression patterns of Kir4.1 and AQP4 in a mouse model of demyelination induced by cuprizone, a copper chelator. Demyelination was confirmed by immunohistochemistry using an anti-proteolipid protein antibody in various brain regions, including the corpus callosum, of cuprizone-fed mice. Activation of microglial and astroglial cells was also confirmed by immunohistochemistry, using an anti-ionized calcium binding adapter molecule and a glial fibrillary acidic protein antibody. Western blot analysis revealed the induction of Kir4.1 protein, but not AQP4, in the cortex of cuprizone-fed mice. Immunohistochemical analysis confirmed the Kir4.1 protein induction in microvessels of the cerebral cortex. Real-time polymerase chain reaction analysis revealed that mRNA levels of Kir4.1 and AQP4 in the cortex did not change during cuprizone administration. These findings suggest that enhanced accumulation of Kir4.1 protein in the brain with an inflammatory condition facilitates the autoantibody formation against Kir4.1 in patients with multiple sclerosis. © 2013 Published by Elsevier B.V.

[Demyelinating disease and vaccination of the human papillomavirus].

Science.gov (United States)

Álvarez-Soria, M Josefa; Hernández-González, Amalia; Carrasco-García de León, Sira; del Real-Francia, M Ángeles; Gallardo-Alcañiz, M José; López-Gómez, José L

2011-04-16

Primary prevention by prophylactic vaccination against the major cause of cervical cancer, the carcinogenic human papillomavirus (HPV) types 16 and 18, is now available worldwide. Postlicensure adverse neurological effects have been described. The studies realized after the license are descriptive and limited by the difficulty to obtain the information, despite most of the statistical indexes show that the adverse effects by the vaccine of the HPV are not upper compared with other vaccines, the substimation must be considered. We describe the cases of four young women that developed demyelinating disease after the vaccination of the HPV, with a rank of time between the administration of the dose and the development of the clinical of seven days to a month, with similar symptoms with the successive doses. We have described six episodes coinciding after the vaccination. Have been described seizures, autoimmune disorders such as Guillain-Barre syndrome, transverse myelitis, or motor neuron disease, probably adverse effects following immunization by HPV vaccine. So we suggest that vaccine may trigger an immunological mechanism leading to demyelinating events, perhaps in predisposed young.

Rare association of central pontine myelinolysis with infantile tremor syndrome

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Kalpana Datta

2012-01-01

Full Text Available Central pontine myelinolysis (CPM is an acute demyelination within the central basis pontis. Though exact mechanism is not known it is seen commonly with rapid correction of hyponatremia and also with pontine ischemia or infarction, demyelinating diseases, pontine neoplasm and different metabolic diseases. We report a rare association of CPM in a patient of Infantile Tremor Syndrom (ITS. ITS is a syndrome of tremor, mental and physical retardation, pigmentary changes of hair and skin and anemia in malnourished children. Though first reported in Indian subcontinent many identical cases were reported from around the world. Our case is a 15 month old child with generalized tremor, mild hepatosplenomegaly with features of grade II malnutrition including skin and hair changes. All the signs and symtoms of tremor improved after treatment with the World Health Organization (WHO protocol for protein energy malnutrition (PEM and administration of propranolol without any side effects.

Diffusion tensor imaging can be used to detect lesions in peripheral nerves in patients with chronic inflammatory demyelinating polyneuropathy treated with subcutaneous immunoglobulin

Energy Technology Data Exchange (ETDEWEB)

Markvardsen, Lars H.; Andersen, Henning [Aarhus University Hospital, Department of Neurology, Aarhus C (Denmark); Vaeggemose, Michael [Aarhus University Hospital, Department of Neurology, Aarhus C (Denmark); Aarhus University Hospital, Department of Diagnostic Imaging: MR Research Centre, Aarhus (Denmark); Ringgaard, Steffen [Aarhus University Hospital, Department of Diagnostic Imaging: MR Research Centre, Aarhus (Denmark)

2016-08-15

Magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) has shown that fractional anisotropy (FA) is lower in peripheral nerves in chronic inflammatory demyelinating polyneuropathy (CIDP). We examined whether DTI correlates to muscle strength or impairment. MRI of sciatic and tibial nerves was performed on 3-T MR scanner by obtaining T2- and DTI-weighted sequences with fat saturation. On each slice of T2-weighted (T2w) and DTI, the tibial and sciatic nerves were segmented and served for calculation of signal intensity. On DTI images, pixel-by-pixel calculation of FA and apparent diffusion coefficient (ADC) was done. Muscle strength at knee and ankle was determined by isokinetic dynamometry and severity of CIDP by neuropathy impairment score (NIS). Fourteen CIDP patients treated with subcutaneous immunoglobulin were compared to gender- and age-matched controls. T2w values expressed as a nerve/muscle ratio (nT2w) were unchanged in CIDP versus controls 0.93 ± 0.21 versus 1.02 ± 0.21 (P = 0.10). FA values were lower in CIDP compared to controls 0.38 ± 0.07 versus 0.45 ± 0.05 (P < 0.0001), and ADC values were higher in CIDP versus controls 1735 ± 232 versus 1593 ± 116 x 10{sup -6} mm{sup 2}/s (P = 0.005). In CIDP, FA values correlated to clinical impairment (NIS) (r = -0.57, P = 0.03), but not to muscle strength. FA value in the sciatic nerve distinguishes CIDP from controls with a sensitivity and a specificity of 92.9 %. CIDP patients have unchanged nT2w values, lower FA values, and higher ADC values of sciatic and tibial nerves compared to controls. FA values correlated to NIS but were unrelated to muscle strength. DTI of sciatic nerves seems promising to differentiate CIDP from controls. (orig.)

Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination.

Science.gov (United States)

Vidal, Marie; Maniglier, Madlyne; Deboux, Cyrille; Bachelin, Corinne; Zujovic, Violetta; Baron-Van Evercooren, Anne

2015-06-01

It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system. We compared them in vitro and in vivo to the well-characterized adult spinal cord-NPCs derived from the same donors. Using micro-dissection and neurosphere cultures, we demonstrate that adult DRG-NPCs have quasi unlimited self-expansion capacities without compromising their tissue specific molecular signature. Moreover, they differentiate into multiple peripheral lineages in vitro. After transplantation, adult DRG-NPCs generate pericytes in the developing forebrain but remyelinating Schwann cells in response to spinal cord demyelination. In addition, we show that axonal and endothelial/astrocytic factors as well astrocytes regulate the fate of adult DRG-NPCs in culture. Although the adult DRG-NPC multipotency is restricted to the neural crest lineage, their dual responsiveness to developmental and lesion cues highlights their impressive adaptive and repair potentials making them valuable targets for regenerative medicine. © 2015 AlphaMed Press.

Interferon-gamma in progression to chronic demyelination and neurological deficit following acute EAE

DEFF Research Database (Denmark)

Renno, T; Taupin, V; Bourbonnière, L

1998-01-01

The cytokine interferon-gamma (IFNgamma) is implicated in the induction of acute CNS inflammation, but it is less clear what role if any IFNgamma plays in progression to chronic demyelination and neurological deficit. To address this issue, we have expressed IFNgamma in myelinating oligodendrocytes....... In contrast to control mice, which remit from EAE with resolution of glial reactivity and leukocytic infiltration, transgenics showed chronic neurological deficits. While activated microglia/macrophages persisted in demyelinating lesions for over 100 days, CD4(+) T lymphocytes were no longer present in CNS...

Spinal cord demyelination combined with hyperhomocysteinemia: a case report

Directory of Open Access Journals (Sweden)

Hao MM

2014-11-01

Full Text Available Meimei Hao, Yan Zhang, Shuangxing Hou, Yanling Chen, Ming Shi, Gang Zhao, Yanchun Deng Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China Abstract: Hyperhomocysteinemia (HHcy has been recognized as an independent risk factor for atherosclerotic vascular disease. Here we report a patient who suffered from spinal cord demyelination combined with HHcy. The patient was admitted to our hospital with a diagnosis of acute myelitis. However, hormone therapy was ineffective. Further investigations revealed that he had HHcy and a homozygous mutation of the gene encoding methylenetetrahydrofolate reductase (MTHFR c.677C>T, which is a key enzyme involved in homocysteine metabolism. In view of these findings, we treated the patient with B vitamins and his symptoms gradually improved. Spinal magnetic resonance imaging performed 3 months after onset showed near recovery of the lesion. To our knowledge, similar reports are rare. Keywords: demyelination, hyperhomocysteinemia, homocysteine, methylenetetrahydrofolate reductase, methylation

Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis

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Nichole M Miller

2015-08-01

Full Text Available Multiple sclerosis (MS is an autoimmune disease of the central nervous system (CNS mediated by T helper (h1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE, indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on the strong EAE data this view is being reevaluated by some investigators in the field.

Differential intrathecal inflammatory markers in acute optic neuritis and later conversion to multiple sclerosis

DEFF Research Database (Denmark)

Olesen, Mads Nikolaj; Soelberg, Kerstin; Nilsson, Anna Christine

Background: Optic neuritis (ON) is often an early inflammatory, demyelinating event of multiple sclerosis (MS). We proffer that cytokine and chemokine profiles may (a) differ between patients with MS-related ON and those with non-MS-related ON and (b) predict conversion to MS in patients presenting......-up compared to those who had not. These findings are of potential relevance to our understanding of the pathogenesis of MS and may predict conversion of ON to MS....

Interferon beta-1a in chronic inflammatory demyelinating polyneuropathy: case report Interferon beta en polineuropatía crónica inflamatoria desmienlinizante: caso clínico

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Andrés Maria Villa

2004-09-01

Full Text Available Chronic inflammatory demyelinating polyneuropathy (CIDP is an acquired immune-mediated neuropathy. It presents with a course of progression which may be slow and steady or step-wise or relapsing. Sensory ataxic polyneuropathy may be the only clinical manifestation of this disease. Treatment with interferon beta1a (INF beta1a has been tried with different results in patients who were refractory to other, more conventional, immunomodulatory therapies. Here we report on a patient who had a relapsing form of pure sensory ataxic CIDP and who failed to respond to intravenous human immunoglobulin. He was put on INF beta1a for 3 years. During this period he suffered no relapses while his condition stabilized.La polineuropatía crónica inflamatoria desmielinizante (PCID es una neuropatía inmuno-mediada, que presenta un curso clínico primariamente progresivo o en forma de recaídas. Las manifestaciones sensoriales pueden ser su unica forma de expresión clínica. El tratamiento con interferon beta 1a (IFN beta1a ha sido ensayado en varias oportunidades, con diferentes respuestas terapéuticas, en pacientes refractarios a las terapias inmunomoduladoras convencionales. Nosotros comunicamos un paciente con una forma ataxica recurrente de PCID, que no respondió al tratamiento con inmunoglobulina endovenosa. Posteriormente fue tratado con IFN beta 1 a por tres años. Durante el período de seguimiento no mostró nuevas recaídas y su cuadro neurológico se estabilizó.

Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves.

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Nikki A McLean

Full Text Available Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.

Delayed nerve stimulation promotes axon-protective neurofilament phosphorylation, accelerates immune cell clearance and enhances remyelination in vivo in focally demyelinated nerves.

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McLean, Nikki A; Popescu, Bogdan F; Gordon, Tessa; Zochodne, Douglas W; Verge, Valerie M K

2014-01-01

Rapid and efficient axon remyelination aids in restoring strong electrochemical communication with end organs and in preventing axonal degeneration often observed in demyelinating neuropathies. The signals from axons that can trigger more effective remyelination in vivo are still being elucidated. Here we report the remarkable effect of delayed brief electrical nerve stimulation (ES; 1 hour @ 20 Hz 5 days post-demyelination) on ensuing reparative events in a focally demyelinated adult rat peripheral nerve. ES impacted many parameters underlying successful remyelination. It effected increased neurofilament expression and phosphorylation, both implicated in axon protection. ES increased expression of myelin basic protein (MBP) and promoted node of Ranvier re-organization, both of which coincided with the early reappearance of remyelinated axons, effects not observed at the same time points in non-stimulated demyelinated nerves. The improved ES-associated remyelination was accompanied by enhanced clearance of ED-1 positive macrophages and attenuation of glial fibrillary acidic protein expression in accompanying Schwann cells, suggesting a more rapid clearance of myelin debris and return of Schwann cells to a nonreactive myelinating state. These benefits of ES correlated with increased levels of brain derived neurotrophic factor (BDNF) in the acute demyelination zone, a key molecule in the initiation of the myelination program. In conclusion, the tremendous impact of delayed brief nerve stimulation on enhancement of the innate capacity of a focally demyelinated nerve to successfully remyelinate identifies manipulation of this axis as a novel therapeutic target for demyelinating pathologies.

Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models.

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O'Neill, Jessica; Sikandar, Shafaq; McMahon, Stephen B; Dickenson, Anthony H

2015-09-01

Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of

Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews.

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Oaklander, Anne Louise; Lunn, Michael Pt; Hughes, Richard Ac; van Schaik, Ivo N; Frost, Chris; Chalk, Colin H

2017-01-13

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic progressive or relapsing and remitting disease that usually causes weakness and sensory loss. The symptoms are due to autoimmune inflammation of peripheral nerves. CIPD affects about 2 to 3 per 100,000 of the population. More than half of affected people cannot walk unaided when symptoms are at their worst. CIDP usually responds to treatments that reduce inflammation, but there is disagreement about which treatment is most effective. To summarise the evidence from Cochrane systematic reviews (CSRs) and non-Cochrane systematic reviews of any treatment for CIDP and to compare the effects of treatments. We considered all systematic reviews of randomised controlled trials (RCTs) of any treatment for any form of CIDP. We reported their primary outcomes, giving priority to change in disability after 12 months.Two overview authors independently identified published systematic reviews for inclusion and collected data. We reported the quality of evidence using GRADE criteria. Two other review authors independently checked review selection, data extraction and quality assessments.On 31 October 2016, we searched the Cochrane Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects (in theCochrane Library), MEDLINE, Embase, and CINAHL Plus for systematic reviews of CIDP. We supplemented the RCTs in the existing CSRs by searching on the same date for RCTs of any treatment of CIDP (including treatment of fatigue or pain in CIDP), in the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL Plus. Five CSRs met our inclusion criteria. We identified 23 randomised trials, of which 15 had been included in these CSRs. We were unable to compare treatments as originally planned, because outcomes and outcome intervals differed. CorticosteroidsIt is uncertain whether daily oral prednisone improved impairment compared to no treatment because the quality of the

The Prevalence of Anti-Aquaporin 4 Antibody in Patients with Idiopathic Inflammatory Demyelinating Diseases Presented to a Tertiary Hospital in Malaysia: Presentation and Prognosis

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S. Abdullah

2017-01-01

Full Text Available Background. There have been inconsistent reports on the prevalence and pathogenicity of anti-Aquaporin 4 (AQP4 in patients presented with idiopathic inflammatory demyelinating diseases (IIDDs. Objective. To estimate the prevalence of anti-AQP4 antibody in patients with IIDDs presented to University Malaya Medical Centre in terms of patients’ clinical and radiological presentations and prognoses. Methods. Retrospective data review of IIDDs patients presented from 2005 to 2015. Patients were classified into classical multiple sclerosis (CMS, opticospinal (OS presentation, optic neuritis (ON, transverse myelitis (TM, brainstem syndrome (BS, and tumefactive MS. Anti-Aquaporin 4 antibody was tested using the Indirect Immunofluorescence Test (IIFT cell-based assay. Statistical analysis was done using the SPSS version 20. Results. Anti-AQP4 antibody was detected in 53% of patients presented with IIDDs. CMS was more common in the seronegative group, 27/47 (57.45%; p<0.001. Conversely, OS involvement was more common in the seropositive group, 26/53 (49.06%; p<0.001. Longitudinally extensive spinal cord lesions (LESCLs on MRI were also more common in the seropositive group, 29/40 (72.50%; p=0.004. Only 2/40 (5.00% had MRI evidence of patchy or multiple short-segment spinal cord lesions in the AQP4-positive group (p=0.003. The relapse rate and Expanded Disability Status Scale (EDSS were also higher in the seropositive group (5.43 versus 3.17, p=0.005; 4.07 versus 2.51, p=0.006, resp.. Typical clinical presentations that defined NMO were also seen in the seronegative patients, but in a lower frequency. Conclusion. Our cohort of patients had a higher prevalence of seropositivity of anti-AQP4 antibody as compared to those in Western countries. This was also associated with a more typical presentation of opticospinal involvement with LESCLs on MRI, a higher rate of relapse, and EDSS.

Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice

OpenAIRE

Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B.E.; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P.; Shields, Christopher B.

2014-01-01

Objective Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG1...

Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions

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Saadoun, Samira; Bridges, Leslie R.; Verkman, A. S.; Papadopoulos, Marios C.

2013-01-01

Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement-dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin + cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin + cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell-mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica. PMID:23108041

Expression of extracellular matrix components and their receptors in the central nervous system during experimental Toxoplasma gondii and Trypanosoma cruzi infection

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Silva A.A.

1999-01-01

Full Text Available Alterations in extracellular matrix (ECM expression in the central nervous system (CNS usually associated with inflammatory lesions have been described in several pathological situations including neuroblastoma and demyelinating diseases. The participation of fibronectin (FN and its receptor, the VLA-4 molecule, in the migration of inflammatory cells into the CNS has been proposed. In Trypanosoma cruzi infection encephalitis occurs during the acute phase, whereas in Toxoplasma infection encephalitis is a chronic persisting process. In immunocompromised individuals such as AIDS patients, T. cruzi or T. gondii infection can lead to severe CNS damage. At the moment, there are no data available regarding the molecules involved in the entrance of inflammatory cells into the CNS during parasitic encephalitis. Herein, we characterized the expression of the ECM components FN and laminin (LN and their receptors in the CNS of T. gondii- and T. cruzi-infected mice. An increased expression of FN and LN was detected in the meninges, leptomeninges, choroid plexus and basal lamina of blood vessels. A fine FN network was observed involving T. gondii-free and T. gondii-containing inflammatory infiltrates. Moreover, perivascular spaces presenting a FN-containing filamentous network filled with a4+ and a5+ cells were observed. Although an increased expression of LN was detected in the basal lamina of blood vessels, the CNS inflammatory cells were a6-negative. Taken together, our results suggest that FN and its receptors VLA-4 and VLA-5 might be involved in the entrance, migration and retention of inflammatory cells into the CNS during parasitic infections.

Flavonoids inhibit myelin phagocytosis by macrophages; a structure-activity relationship study

NARCIS (Netherlands)

Hendriks, Jerome J. A.; de Vries, Helga E.; van der Pol, Susanne M. A.; van den Berg, Timo K.; van Tol, Eric A. F.; Dijkstra, Christine D.

2003-01-01

Demyelination is a characteristic hallmark of the neuro-inflammatory disease multiple sclerosis. During demyelination, macrophages phagocytose myelin and secrete inflammatory mediators that worsen the disease. Here, we investigated whether flavonoids, naturally occurring immunomodulating compounds,

Inflammatory lesions of the spinal cord and the nerve roots in magnetic resonance imaging; Entzuendliche Erkrankungen des Rueckenmarks und der Nervenwurzeln in der MRT

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Sartoretti-Schefer, S. [Inst. fuer Neuroradiologie, Universitaetsspital Zuerich (Switzerland); Wichmann, W. [Inst. fuer Neuroradiologie, Universitaetsspital Zuerich (Switzerland); Valavanis, A. [Inst. fuer Neuroradiologie, Universitaetsspital Zuerich (Switzerland)

1996-11-01

The MRI examinations of 52 patients with proven inflammatory lesions (39 patients) or tumorous/postactinic lesions of the spinal cord (6 patients) and vasuclar malformations of the spinal cord (7 patients) were retrospectively analyzed. All examinations were performed on a 1.5 T MR unit, using bi- or triplanar T1-w pre- and postcontrast as well as T2-w SE sequences. Clinical and radiological examinations allow a subdivision of inflammations of the spinal cord and the nerve roots into (mening-oradiculo) myelitis and meningoradiculo (myelitis). The MRI patterns of these two inflammatory subtypes vary: Meningoradiculitis presents with an enhancement of the nerve roots and the leptomeninges; myelitis itself is characterized by single or multiple, diffuse or multifocal, with or without nodular, patchy or diffusely enhancing intramedullary lessions, with or without thickening of the cord and leptomeningeal inflammation. The immunologically suppressed patient suffers from viral infections (especially herpes simplex, varicella-zoster virus, cytomegalovirus), bacterial infections (tuberculosis), but rarely viral infections, sarcoidosis and demyelinating diseases. Idiopathic myelitis is also common. Secondary ischemic and demyelinating processes result in a complex morphology of inflammatory lesions on MRI, and therefore the whole spectrum of demyelinating, ischemic and inflammatory lesions has to be included in the differential diagnosis. Even tumors may imitate inflammatory myelitis and radiculitis. Most commonly, meningoradiculitis can be separated from myelitis. A reliable diagnosis of a specific inflammatory lesion is difficult and is mostly achieved in patients with multiple sclerosis and in patients with HIV-associated cytomegalovirus infection. (orig.) [Deutsch] Entzuendliche Erkrankungen des Rueckenmarks und der Nervenwurzeln werden aus klinischer und radiologischer Sicht in eine (Meningo)-Myeloradikulitis und eine Meningoradikulo-(Myelitis) beim immunsupprimierten

CT and MRI 'ring sign' may be due to demyelination: diagnostic pitfall.

LENUS (Irish Health Repository)

Kamel, M H

2012-02-03

We report a case of acute demyelinating encephalomyelitis (ADEM) in which both CT and MRI showed multiple ring-enhancing lesions suggestive of abscesses or brain tumour. This is a relatively rare phenomenon.

IL-1 signal affects both protection and pathogenesis of virus-induced chronic CNS demyelinating disease

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Kim Byung S

2012-09-01

Full Text Available Abstract Background Theiler’s virus infection induces chronic demyelinating disease in mice and has been investigated as an infectious model for multiple sclerosis (MS. IL-1 plays an important role in the pathogenesis of both the autoimmune disease model (EAE and this viral model for MS. However, IL-1 is known to play an important protective role against certain viral infections. Therefore, it is unclear whether IL-1-mediated signaling plays a protective or pathogenic role in the development of TMEV-induced demyelinating disease. Methods Female C57BL/6 mice and B6.129S7-Il1r1tm1Imx/J mice (IL-1R KO were infected with Theiler’s murine encephalomyelitis virus (1 x 106 PFU. Differences in the development of demyelinating disease and changes in the histopathology were compared. Viral persistence, cytokine production, and immune responses in the CNS of infected mice were analyzed using quantitative PCR, ELISA, and flow cytometry. Results Administration of IL-1β, thereby rending resistant B6 mice susceptible to TMEV-induced demyelinating disease, induced a high level of Th17 response. Interestingly, infection of TMEV into IL-1R-deficient resistant C57BL/6 (B6 mice also induced TMEV-induced demyelinating disease. High viral persistence was found in the late stage of viral infection in IL-1R-deficient mice, although there were few differences in the initial anti-viral immune responses and viral persistent levels between the WT B6 and IL-1R-deficiecent mice. The initial type I IFN responses and the expression of PDL-1 and Tim-3 were higher in the CNS of TMEV-infected IL-1R-deficient mice, leading to deficiencies in T cell function that permit viral persistence. Conclusions These results suggest that the presence of high IL-1 level exerts the pathogenic role by elevating pathogenic Th17 responses, whereas the lack of IL-1 signals promotes viral persistence in the spinal cord due to insufficient T cell activation by elevating the production of

Actualización en el tratamiento de la neuropatía óptica inflamatoria desmielinizante Updating on the treatment of the demyelinating inflammatory optical neuropathy

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Yaimara Hernández Silva

2011-06-01

Full Text Available Se realizó una revisión bibliográfica con el objetivo de proporcionar una actualización de las drogas que se emplean para retrasar la aparición de esclerosis múltiple en el manejo de la neuropatía óptica inflamatoria desmielinizante. El artículo presenta el origen y la justificación de la terapia esteroidea en este grupo de enfermedad, así como los mecanismos de acción y beneficios de tratamientos más modernos como los inmunomoduladores e inmunosupresores. El trabajo también introduce muchas de las drogas con efectos neuroprotectores que se encuentran en fases experimentales, cuyo uso prevendría la neurodegeneración que se produce a nivel de las células ganglionares retinianas en esta enfermedad neurológica. Las opciones terapéuticas actuales ofrecen variantes de tratamiento adicionales a pacientes con mayores probabilidades de desarrollo de esclerosis múltiple y retrasan la aparición de un segundo brote, así como las secuelas invalidantes que esta suele originar.A bibliographic review was conducted to provide an updating of drugs used to retard the appearance of multiple sclerosis in the management of the demyelinating inflammatory optical neuropathy. Present paper shows the origin and the justification of the steroid therapy in this disease, as well as the mechanisms of action and benefits of more recent treatments, e.g. the ongoing immunomodulations and immunosuppressive ones and also to introduce many drugs in experimental phase having neuroprotection effects whose use will prevent the neurodegenerative effect produced at level of the retinal ganglion cells in this neurologic disease. The current therapeutical options offer variants of additional treatment to those patients with greater possibilities to development multiple sclerosis and retarding the appearance of a second outbreak, as well as its disabling sequelae.

ONGOING OXIDATIVE STRESS CAUSES SUBCLINICAL NEURONAL DYSFUNCTION IN THE RECOVERY PHASE OF EAE

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Helena eRadbruch

2016-03-01

Full Text Available Most multiple sclerosis patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in multiple sclerosis is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic multiple sclerosis. Here, we employ intravital NAD(PH fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1-4, DUOX1,2 and, thus, to identify the cellular source of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET-FLIM, providing a possible mechanism of disease progression in multiple sclerosis.

Central endoscopy reads in inflammatory bowel disease clinical trials: The role of the imaging core lab.

Science.gov (United States)

Ahmad, Harris; Berzin, Tyler M; Yu, Hui Jing; Huang, Christopher S; Mishkin, Daniel S

2014-08-01

Clinical trials in inflammatory bowel disease (IBD) are evolving at a rapid pace by employing central reading for endoscopic mucosal assessment in a field that was, historically, largely based on assessments by local physicians. This transition from local to central reading carries with it numerous technical, operational, and scientific challenges, many of which can be resolved by imaging core laboratories (ICLs), a concept that has a longer history in clinical trials in a number of diseases outside the realm of gastroenterology. For IBD trials, ICLs have the dual goals of providing objective, consistent assessments of endoscopic findings using central-reading paradigms whilst providing important expertise with regard to operational issues and regulatory expectations. This review focuses on current approaches to using ICLs for central endoscopic reading in IBD trials. © The Author(s) 2014. Published by Oxford University Press and the Digestive Science Publishing Co. Limited.

Different Mechanisms of Inflammation Induced in Virus and Autoimmune-Mediated Models of Multiple Sclerosis in C57BL6 Mice

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Abhinoy Kishore

2013-01-01

Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease of the human central nervous system (CNS. Neurotropic demyelinating strain of MHV (MHV-A59 or its isogenic recombinant strain RSA59 induces MS-like disease in mice mediated by microglia, along with a small population of T cells. The mechanism of demyelination is at least in part due to microglia-mediated myelin stripping, with some direct axonal injury. Immunization with myelin oligodendrocyte glycoprotein (MOG induces experimental autoimmune encephalomyelitis (EAE, a mainly CD4+ T-cell-mediated disease, although CD8+ T cells may play a significant role in demyelination. It is possible that both autoimmune and nonimmune mechanisms such as direct viral toxicity may induce MS. Our study directly compares CNS pathology in autoimmune and viral-induced MS models. Mice with viral-induced and EAE demyelinating diseases demonstrated similar patterns and distributions of demyelination that accumulated over the course of the disease. However, significant differences in acute inflammation were noted. Inflammation was restricted mainly to white matter at all times in EAE, whereas inflammation initially largely involved gray matter in acute MHV-induced disease and then is subsequently localized only in white matter in the chronic disease phase. The presence of dual mechanisms of demyelination may be responsible for the failure of immunosuppression to promote long-term remission in many MS patients.

Neuromyelitis optica-IgG testing in an Indian cohort with neuromyelitis optica and related demyelinating disorders: Our experience

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Narayanan Unni

2013-01-01

Full Text Available Background: Neuromyelitis optica (NMO is an immune-mediated inflammatory demyelinating disorder of the central nervous system with a predilection for the optic nerves and the spinal cord. Immunopathological evidence suggests that the target antigen of the disease is aquaporin-4. An IgG antibody against this protein has been explored as a molecular marker for the disease and as a diagnostic tool due to its high sensitivity and specificity in various populations. Objective: To assess the value of NMO-IgG testing in Indian patients with clinical and magnetic resonance imaging features consistent with NMO and longitudinally extensive transverse myelitis (LETM. Materials and Methods: Forty-five patients with clinical and magnetic resonance imaging features consistent with NMO, LETM, and MS were tested for serum NMO-IgG. Of these patients, 22 patients satisfied revised (2006 Wingerchuk criteria for NMO (excluding NMO-IgG status and 11 patients had LETM. Twelve patients satisfied the revised (2010 McDonald criteria for multiple sclerosis (MS. Results: Of the 21 patients, satisfying the criteria for NMO and for whom the test results were available, 17 were positive for NMO-IgG (80.9%, and of the 11 patients having LETM, 6 (54.5% were positive for NMO-IgG. In one patient with NMO, the test result was not available. None of the 12 patients satisfying McDonald criteria for MS showed NMO-IgG seropositivity. Conclusion: Our study suggests that it is worthwhile to pursue NMO-IgG testing as a diagnostic tool for patients with clinical and Magnetic Resonance Imaging (MRI features consistent with NMO and LETM in the Indian population.

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System.

Science.gov (United States)

Lochhead, Jeffrey J; Ronaldson, Patrick T; Davis, Thomas P

2017-07-01

A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB's ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB's permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS.

A mutation in the gene encoding mitochondrial Mg²+ channel MRS2 results in demyelination in the rat.

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Takashi Kuramoto

2011-01-01

Full Text Available The rat demyelination (dmy mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg²+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg²+ homeostasis in CNS mitochondria is essential for the maintenance of myelin.

Absence of Multiple Sclerosis and Demyelinating Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico

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Jose Flores

2012-01-01

Full Text Available Multiple Sclerosis (MS is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants.

Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis.

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Seehusen, Frauke; Al-Azreg, Seham A; Raddatz, Barbara B; Haist, Verena; Puff, Christina; Spitzbarth, Ingo; Ulrich, Reiner; Baumgärtner, Wolfgang

2016-01-01

In demyelinating diseases, changes in the quality and quantity of the extracellular matrix (ECM) may contribute to demyelination and failure of myelin repair and axonal sprouting, especially in chronic lesions. To characterize changes in the ECM in canine distemper demyelinating leukoencephalitis (DL), histochemical and immunohistochemical investigations of formalin-fixed paraffin-embedded cerebella using azan, picrosirius red and Gomori`s silver stain as well as antibodies directed against aggrecan, type I and IV collagen, fibronectin, laminin and phosphacan showed alterations of the ECM in CDV-infected dogs. A significantly increased amount of aggrecan was detected in early and late white matter lesions. In addition, the positive signal for collagens I and IV as well as fibronectin was significantly increased in late lesions. Conversely, the expression of phosphacan was significantly decreased in early and more pronounced in late lesions compared to controls. Furthermore, a set of genes involved in ECM was extracted from a publically available microarray data set and was analyzed for differential gene expression. Gene expression of ECM molecules, their biosynthesis pathways, and pro-fibrotic factors was mildly up-regulated whereas expression of matrix remodeling enzymes was up-regulated to a relatively higher extent. Summarized, the observed findings indicate that changes in the quality and content of ECM molecules represent important, mainly post-transcriptional features in advanced canine distemper lesions. Considering the insufficiency of morphological regeneration in chronic distemper lesions, the accumulated ECM seems to play a crucial role upon regenerative processes and may explain the relatively small regenerative potential in late stages of this disease.

Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia

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Murtaza F Dhrolia

2014-01-01

Full Text Available Osmotic demyelination syndrome (ODS is a dreadful, irreversible and well-recognized clinical entity that classically occurs after rapid correction of hyponatremia. However, it has been observed that when hyponatremia is rapidly corrected in azotemic patients by hemodialysis (HD, patients do not necessarily develop ODS. We studied the effect of inadvertent rapid correction of hyponatremia with HD in patients with azotemia. Fifty-two azotemic patients, who underwent HD at the Sindh Institute of Urology and Transplantation, having pre-HD serum sodium level <125 mEq/L and post-HD serum sodium levels that increased by ≥12 mEq/L from their pre-dialysis level, were studied. Serum sodium was analyzed before and within 24 h after a HD session. HD was performed using bicarbonate solution, with the sodium concentration being 140 meq/L. The duration of the dialysis session was based on the discretion of the treating nephrologist. Patients were examined for any neurological symptoms or signs before and after HD and for up to two weeks. Magnetic resonance imaging was performed in required cases. None of the 52 patients with azotemia, despite inadvertent rapid correction of hyponatremia with HD, developed ODS. This study suggests that patients with azotemia do not develop ODS on rapid correction of hyponatremia by HD, which suggests a possible protective role of azotemia on the brain from osmotic demyelination. However, the mechanism by which azotemia protects the brain from demyelination in humans is largely hypothetical and further studies are needed to answer this question.

Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling

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Jay S. Coggan

2015-09-01

Full Text Available Despite intense research, few treatments are available for most neurological disorders. Demyelinating diseases are no exception. This is perhaps not surprising considering the multifactorial nature of these diseases, which involve complex interactions between immune system cells, glia and neurons. In the case of multiple sclerosis, for example, there is no unanimity among researchers about the cause or even which system or cell type could be ground zero. This situation precludes the development and strategic application of mechanism-based therapies. We will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. By making testable predictions and revealing critical gaps in existing knowledge, such models can help direct research and will provide a rigorous framework in which to integrate new data as they are collected. Nowadays, there is no shortage of data; the challenge is to make sense of it all. In that respect, computational modeling is an invaluable tool that could, ultimately, transform how we understand, diagnose, and treat demyelinating diseases.

[Correlation between demyelinating lesions and executive function decline in a sample of Mexican patients with multiple sclerosis].

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Aldrete Cortez, V R; Duriez-Sotelo, E; Carrillo-Mora, P; Pérez-Zuno, J A

2013-09-01

Multiple Sclerosis (MS) is characterised by several neurological symptoms including cognitive impairment, which has recently been the subject of considerable study. At present, evidence pointing to a correlation between lesion characteristics and specific cognitive impairment is not conclusive. To investigate the presence of a correlation between the characteristics of demyelinating lesions and performance of basic executive functions in a sample of MS patients. We included 21 adult patients with scores of 0 to 5 on the Kurtzke scale and no exacerbations of the disease in at least 3 months prior to the evaluation date. They completed the Stroop test and the Wisconsin Card Sorting Test (WCST). The location of the lesions was determined using magnetic resonance imaging (MRI) performed by a blinded expert in neuroimaging. Demyelinating lesions were more frequently located in the frontal and occipital lobes. The Stroop test showed that as cognitive demand increased on each of the sections in the test, reaction time and number of errors increased. On the WCST, 33.33% of patients registered as having moderate cognitive impairment. No correlation could be found between demyelinating lesion characteristics (location, size, and number) and patients' scores on the tests. Explanations of the causes of cognitive impairment in MS should examine a variety of biological, psychological, and social factors instead of focusing solely on demyelinating lesions. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

Effects of aquatic exercises in a rat model of brainstem demyelination with ethidium bromide on the beam walking test Efeitos de exercícios aquáticos no desempenho motor de ratos submetidos a um modelo de desmielização com brometo de etídio

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Cíntia Cristina Souza Nassar

2009-09-01

Full Text Available Multiple sclerosis is a demyelinating disease of the central nervous system associated with varied levels of disability. The impact of early physiotherapeutic interventions in the disease progression is unknown. We used an experimental model of demyelination with the gliotoxic agent ethidium bromide and early aquatic exercises to evaluate the motor performance of the animals. We quantified the number of footsteps and errors during the beam walking test. The demyelinated animals walked fewer steps with a greater number of errors than the control group. The demyelinated animals that performed aquatic exercises presented a better motor performance than those that did not exercise. Therefore aquatic exercising was beneficial to the motor performance of rats in this experimental model of demyelination.A esclerose múltipla é uma doença desmielinizante do sistema nervoso central que se associa a graus variados de incapacidade. Não se sabe se a realização de intervenções fisioterapêuticas precoces têm impacto na evolução dessa doença. Utilizamos um modelo experimental de desmielinização com o gliotóxico brometo de etídio e a aplicação de exercícios aquáticos precoces para avaliar o desempenho motor dos animais. Foram quantificados o número de passos e os erros executados durante a travessia da barra elevada. Os animais desmielinizados apresentaram menor número de passos e maior quantidade de erros em comparação aos grupos-controle. Os animais desmielinizados que realizaram exercícios aquáticos apresentaram melhor desempenho motor que os animais desmielinizados que não foram submetidos à intervenção. Portanto, a realização de exercícios aquáticos mostrou-se benéfica no desempenho motor dos animais submetidos ao modelo experimental do brometo de etídio.

Acute disseminated encephalomyelitis: a case report of effective early immunotherapy

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Ritarwan, K.; Ramayani, O. R.; Eyanoer, P.

2018-03-01

Acute disseminated encephalomyelitis (ADEM) is a monophasic acute non-vasculitic inflammatory demyelinating disorder of the central nervous system characterized by diffuse neurologic signs and symptoms coupled with evidence of multifocal lesions of demyelination on neuroimaging. Despite the long-standing recognition of ADEM as a specific entity, no consensus definition of ADEM had been reached until recently. Historically, different definitions of ADEM have been in published cases of pediatric and adult patients, which varied as to whether events required (1) monofocal or multifocal clinical features, (2) a change in mental status, and (3) a documentation of previous infection or immunization. The treatment has been given to the patient such as supportive therapy and high dose corticosteroids.

Combining Diffusion Tensor Metrics and DSC Perfusion Imaging: Can It Improve the Diagnostic Accuracy in Differentiating Tumefactive Demyelination from High-Grade Glioma?

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Hiremath, S B; Muraleedharan, A; Kumar, S; Nagesh, C; Kesavadas, C; Abraham, M; Kapilamoorthy, T R; Thomas, B

2017-04-01

Tumefactive demyelinating lesions with atypical features can mimic high-grade gliomas on conventional imaging sequences. The aim of this study was to assess the role of conventional imaging, DTI metrics ( p:q tensor decomposition), and DSC perfusion in differentiating tumefactive demyelinating lesions and high-grade gliomas. Fourteen patients with tumefactive demyelinating lesions and 21 patients with high-grade gliomas underwent brain MR imaging with conventional, DTI, and DSC perfusion imaging. Imaging sequences were assessed for differentiation of the lesions. DTI metrics in the enhancing areas and perilesional hyperintensity were obtained by ROI analysis, and the relative CBV values in enhancing areas were calculated on DSC perfusion imaging. Conventional imaging sequences had a sensitivity of 80.9% and specificity of 57.1% in differentiating high-grade gliomas ( P = .049) from tumefactive demyelinating lesions. DTI metrics ( p : q tensor decomposition) and DSC perfusion demonstrated a statistically significant difference in the mean values of ADC, the isotropic component of the diffusion tensor, the anisotropic component of the diffusion tensor, the total magnitude of the diffusion tensor, and rCBV among enhancing portions in tumefactive demyelinating lesions and high-grade gliomas ( P ≤ .02), with the highest specificity for ADC, the anisotropic component of the diffusion tensor, and relative CBV (92.9%). Mean fractional anisotropy values showed no significant statistical difference between tumefactive demyelinating lesions and high-grade gliomas. The combination of DTI and DSC parameters improved the diagnostic accuracy (area under the curve = 0.901). Addition of a heterogeneous enhancement pattern to DTI and DSC parameters improved it further (area under the curve = 0.966). The sensitivity increased from 71.4% to 85.7% after the addition of the enhancement pattern. DTI and DSC perfusion add profoundly to conventional imaging in differentiating tumefactive

Pediatric-onset multiple sclerosis and other acquired demyelinating syndromes of the central nervous system in Denmark during 1977-2015

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Boesen, Magnus Spangsberg; Magyari, Melinda; Koch-Henriksen, Nils

2018-01-01

BACKGROUND: The incidence of acquired demyelinating syndromes (ADS) including multiple sclerosis (MS) has never been investigated in a Danish pediatric population. OBJECTIVES: We estimated the nationwide age- and sex-specific incidence of pediatric ADS including MS. METHODS: Data were sourced from...... the Danish Multiple Sclerosis Registry, providing cases of pediatric MS for 1977-2015, and the National Patient Register, providing cases of ADS during 2008-2015. All medical records were reviewed to validate the register-based diagnoses. RESULTS: We identified 364 cases of pediatric MS occurring during 1977......-2015 (incidence rate = 0.79 per 100,000 person-years). MS was exceptionally rare before puberty, but the incidence rose considerably from 9 years in girls and 11 years in boys. The female-to-male ratio was 2.5; the median age at onset was 16 years (range = 7-17 years). The MS incidence rate was relatively stable...

Antibody-Mediated Rejection of the Heart in the Setting of Autoimmune Demyelinating Polyneuropathy: A Case Report and Review of the Literature

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Kathryn J. Lindley

2012-01-01

Full Text Available Background. Antibody-mediated rejection (AMR is caused by the production of donor-specific antibodies (DSA which lead to allograft injury in part via complement activation. The inflammatory demyelinating polyneuropathies (IDP are inflammatory disorders of the nervous system, involving both cellular and humoral immune mechanisms directed against myelin. Case Report. A 58-year-old man five years after heart transplant presented with progressive dyspnea, imbalance, dysphagia, and weakness. Nerve conduction studies and electromyogram were consistent with IDP. Plasmapheresis and high-dose steroids resulted in improvement in neurologic symptoms. Within two weeks, he was readmitted with anasarca and acute renal failure, requiring intravenous furosemide and inotropic support. Echocardiogram and right heart catheterization revealed reduced cardiac function and elevated filling pressures. DSA was positive against HLA DR53, and endomyocardial biopsy revealed grade 1R chronic inflammation, with strong capillary endothelial immunostaining for C4d. Plasmapheresis and intravenous immunoglobulin (IVIG were initiated. His anasarca and renal failure subsequently resolved, echocardiogram showed improved function off inotropes, and anti-DR53 MFI was reduced by 57%. Conclusions. This is an example of a single immune-mediated process causing concurrent IDP and AMR. The improvement in cardiac function and neurologic symptoms with plasmapheresis, IVIG, and high-dose steroids argues for a unifying antibody-mediated mechanism.

Demyelinating syndrome in SLE: review of different disease subtypes and report of a case series

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E. Chessa

2017-12-01

Full Text Available Demyelinating syndrome (DS is a rare manifestation of systemic lupus erythematosus (SLE (1% with high clinical heterogeneity and potentially severe prognosis. It can represent a diagnostic and therapeutic challenge for clinicians. A recent study described 5 different patterns of demyelinating disease presentation, characterised by specific clinical, laboratory and brain and spine magnetic resonance imaging abnormalities: 1 neuromyelitis optica; 2 neuromyelitis optica spectrum disorders; 3 DS prevalently involving the brain; 4 DS prevalently involving the brainstem; 5 clinically isolated syndrome. In this review we briefly discuss typical characteristics of each DS presentation in SLE and we describe 5 illustrative clinical cases, one for each subset of DS, considering both diagnostic and therapeutic options.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

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... and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart ... and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart ...

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination.

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Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas

2017-08-01

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

Nogo-A is a reliable oligodendroglial marker in adult human and mouse CNS and in demyelinated lesions

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Kuhlmann, Tanja; Remington, Leah; Maruschak, Brigitte

2007-01-01

to be strongly expressed in mature oligodendrocytes in vivo. In the present investigation we analyzed the expression patterns of Nogo-A in adult mouse and human CNS as well as in demyelinating animal models and multiple sclerosis lesions. Nogo-A expression was compared with that of other frequently used...... oligodendroglial markers such as CC1, CNP, and in situ hybridization for proteolipid protein mRNA. Nogo-A strongly and reliably labeled oligodendrocytes in the adult CNS as well as in demyelinating lesions and thus represents a valuable tool for the identification of oligodendrocytes in human and mouse CNS tissue...

Ongoing Oxidative Stress Causes Subclinical Neuronal Dysfunction in the Recovery Phase of EAE

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Radbruch, Helena; Bremer, Daniel; Guenther, Robert; Cseresnyes, Zoltan; Lindquist, Randall; Hauser, Anja E.; Niesner, Raluca

2016-01-01

Most multiple sclerosis (MS) patients develop over time a secondary progressive disease course, characterized histologically by axonal loss and atrophy. In early phases of the disease, focal inflammatory demyelination leads to functional impairment, but the mechanism of chronic progression in MS is still under debate. Reactive oxygen species generated by invading and resident central nervous system (CNS) macrophages have been implicated in mediating demyelination and axonal damage, but demyelination and neurodegeneration proceed even in the absence of obvious immune cell infiltration, during clinical recovery in chronic MS. Here, we employ intravital NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX1–4, DUOX1, 2) and, thus, to identify the cellular source of oxidative stress in the CNS of mice affected by experimental autoimmune encephalomyelitis (EAE) in the remission phase of the disease. This directly affects neuronal function in vivo, as monitored by cellular calcium levels using intravital FRET–FLIM, providing a possible mechanism of disease progression in MS. PMID:27014271

Paeoniflorin Attenuates Inflammatory Pain by Inhibiting Microglial Activation and Akt-NF-κB Signaling in the Central Nervous System

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Bo Hu

2018-05-01

Full Text Available Background/Aims: Paeoniflorin (PF is known to have anti-inflammatory and paregoric effects, but the mechanism underlying its analgesic effect remains unclear. The aim of this study was to clarify the effect of PF on Freund’s complete adjuvant (CFA-induced inflammatory pain and explore the underlying molecular mechanism. Methods: An inflammatory pain model was established by intraplantar injection of CFA in C57BL/6J mice. After intrathecal injection of PF daily for 8 consecutive days, thermal and mechanical withdrawal thresholds, the levels of inflammatory factors TNF-α, IL-1β and IL-6, microglial activity, and the expression of Akt-NF-κB signaling pathway in the spinal cord tissue were detected by animal ethological test, cell culture, enzyme-linked immunosorbent assay, immunofluorescence histochemistry, and western blot. Results: PF inhibited the spinal microglial activation in the CFA-induced pain model. The production of proinflammatory cytokines was decreased in the central nervous system after PF treatment both in vivo and in vitro. PF further displayed a remarkable effect on inhibiting the activation of Akt-NF-κB signaling pathway in vivo and in vitro. Conclusion: These results suggest that PF is a potential therapeutic agent for inflammatory pain and merits further investigation.

Endoplasmic reticulum stress response as a potential therapeutic target in multiple sclerosis

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Getts, Meghann Teague; Getts, Daniel R.; Kohm, Adam P.; Miller, Stephen D

2008-01-01

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system (CNS). Since current treatments are aimed at nonspecifically down-regulating inflammation and natural mechanisms of repair and remyelination within the CNS are inadequate for recovery of function, MS patients presently only have available treatments that delay symptom progression. The complex nature of this disease means that only multifaceted treatments hold the promise of a cure. Recent studies i...

MRI study of the cuprizone-induced mouse model of multiple sclerosis: demyelination is not found after co-treatment with polyprenols (long-chain isoprenoid alcohols)

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Khodanovich, M.; Glazacheva, V.; Pan, E.; Akulov, A.; Krutenkova, E.; Trusov, V.; Yarnykh, V.

2016-02-01

Multiple sclerosis is a neurological disorder with poorly understood pathogenic mechanisms and a lack of effective therapies. Therefore, the search for new MS treatments remains very important. This study was performed on a commonly used cuprizone animal model of multiple sclerosis. It evaluated the effect of a plant-derived substance called Ropren® (containing approximately 95% polyprenols or long-chain isoprenoid alcohols) on cuprizone- induced demyelination. The study was performed on 27 eight-week old male CD-1 mice. To induce demyelination mice were fed 0.5% cuprizone in the standard diet for 10 weeks. Ropren® was administered in one daily intraperitoneal injection (12mg/kg), beginning on the 6th week of the experiment. On the 11th week, the corpus callosum in the brain was evaluated in all animals using magnetic resonance imaging with an 11.7 T animal scanner using T2- weighted sequence. Cuprizone treatment successfully induced the model of demyelination with a significant decrease in the size of the corpus callosum compared with the control group (p<0.01). Mice treated with both cuprizone and Ropren® did not exhibit demyelination in the corpus callosum (p<0.01). This shows the positive effect of polyprenols on cuprizone-induced demyelination in mice.

Infectious and inflammatory diseases of the central nervous system-the spectrum of imaging findings and differential diagnosis.

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Rozell, Joseph M; Mtui, Edward; Pan, Yu-Ning; Li, Shan

2017-12-01

The infectious and inflammatory diseases of the central nervous system (CNS) including the brain and spine can present with a wide spectrum of clinical symptoms, locations, and appearance. The purpose of this exhibit is to review the different patterns of their presentations, to illustrate their imaging characteristics and techniques, and to discuss their clinical features and pathology so that the correct diagnosis can be made and prompt intervention can be initiated on a timely fashion.

Experimental mouse model of optic neuritis with inflammatory demyelination produced by passive transfer of neuromyelitis optica-immunoglobulin G

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2014-01-01

Background Although optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against the astrocyte water channel aquaporin-4 (AQP4). Methods Several approaches were tested to develop a robust, passive-transfer mouse model of NMO ON, including NMO-IgG and complement delivery by: (i) retrobulbar infusion; (ii) intravitreal injection; (iii) a single intracranial injection near the optic chiasm; and (iv) 3-days continuous intracranial infusion near the optic chiasm. Results Little ON or retinal pathology was seen using approaches (i) to (iii). Using approach (iv), however, optic nerves showed characteristic NMO pathology, with loss of AQP4 and glial fibrillary acidic protein immunoreactivity, granulocyte and macrophage infiltration, deposition of activated complement, demyelination and axonal injury. Even more extensive pathology was created in mice lacking complement inhibitor protein CD59, or using a genetically modified NMO-IgG with enhanced complement effector function, including significant loss of retinal ganglion cells. In control studies, optic nerve pathology was absent in treated AQP4-deficient mice, or in wild-type mice receiving control (non-NMO) IgG and complement. Conclusion Passive transfer of NMO-IgG and complement by continuous infusion near the optic chiasm in mice is sufficient to produce ON with characteristic NMO pathology. The mouse model of NMO ON should be useful in further studies of NMO pathogenesis mechanisms and therapeutics. PMID:24468108

Neuroprotective role of quercetin in locomotor activities and cholinergic neurotransmission in rats experimentally demyelinated with ethidium bromide.

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Beckmann, Diego V; Carvalho, Fabiano B; Mazzanti, Cinthia M; Dos Santos, Rosmarini P; Andrades, Amanda O; Aiello, Graciane; Rippilinger, Angel; Graça, Dominguita L; Abdalla, Fátima H; Oliveira, Lizielle S; Gutierres, Jessié M; Schetinger, Maria Rosa C; Mazzanti, Alexandre

2014-05-17

The purpose of this study was to investigate whether the flavonoid quercetin can prevent alterations in the behavioral tests and of cholinergic neurotransmission in rats submitted to the ethidium bromide (EB) experimental demyelination model during events of demyelination and remyelination. Wistar rats were randomly distributed into four groups (20 animals per group): Control (pontine saline injection and treatment with ethanol), Querc (pontine saline injection and treatment with quercetin), EB (pontine 0.1% EB injection and treatment with ethanol), and EB+Querc (pontine 0.1% EB injection and treatment with quercetin). The groups Querc and Querc+EB were treated once daily with quercetin (50mg/kg) diluted in 25% ethanol solution (1ml/kg) and the animals of the control and EB groups were treated once daily with 25% ethanol solution (1ml/kg). Two stages were observed: phase of demyelination (peak on day 7) and phase of remyelination (peak on day 21 post-injection). Behavioral tests (beam walking, foot fault and inclined plane test), acetylcholinesterase (AChE) activity and lipid peroxidation in pons, cerebellum, hippocampus, hypothalamus, striatum and cerebral cortex were measured. The quercetin promoted earlier locomotor recovery, suggesting that there was demyelination prevention or further remyelination velocity as well as it was able to prevent the inhibition of AChE activity and the increase of lipidic peroxidation, suggesting that this compound can protect cholinergic neurotransmission. These results may contribute to a better understanding of the neuroprotective role of quercetin and the importance of an antioxidant diet in humans to provide benefits in neurodegenerative diseases such as MS. Copyright © 2014. Published by Elsevier Inc.

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant.

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Binyamin, Orli; Larush, Liraz; Frid, Kati; Keller, Guy; Friedman-Levi, Yael; Ovadia, Haim; Abramsky, Oded; Magdassi, Shlomo; Gabizon, Ruth

2015-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.

Isolated Extrapontine Myelinolysis of Osmotic Demyelination Syndrome

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Ömer Yılmaz

2013-01-01

Full Text Available The osmotic demyelination syndrome (ODS has been identified as a complication of the rapid correction of hyponatremia for decades (King and Rosner, 2010. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium which cause a rapid changes in osmolality of the interstitial (extracellular compartment of the brain leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas (King and Rosner, 2010. Slow correction of the serum sodium concentration and additional administration of corticosteroids seems to be a major prevention step in ODS patients. In the current report we aimed to share a rare case which we observed in our clinic.

Central pontine myelinolysis with a hyperintense lesion in diffusion weighted MRI: overview by means of a case report

International Nuclear Information System (INIS)

Kuhn, J.; Bewermeyer, H.; Harzheim, A.

2005-01-01

Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with demyelination of other areas of the central nervous system (CNS). The etiology and pathogenesis of this disorder are still not fully understood. However, almost all cases of CPM are related to severe diseases or chronic alcoholism and occur in the setting of rapidly corrected serum hyponatremia and hypotonicity respectively. Depending on the involvement of other CNS structures, the clinical picture can vary considerably. Magnetic resonance imaging is the most sensitive investigation for the antemortem diagnosis of CPM, although the radiological findings lag behind and do not necessarily correlate with the clinical picture. Quite obviously diffusion-weighted imaging can be useful in the rapid diagnosis of CPM. This short review summarizes the current knowledge on the pathogenesis, clinical presentation, radiological findings, prognosis and therapeutic approaches of CPM. Characteristical clinical features and MR-findings including hyperintensity on diffusion-weighted images are illustrated by a typical case. (orig.)

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage.

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Romme Christensen, Jeppe; Komori, Mika; von Essen, Marina Rode; Ratzer, Rikke; Börnsen, Lars; Bielekova, Bibi; Sellebjerg, Finn

2018-05-01

Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Treatment with metallothionein prevents demyelination and axonal damage and increases oligodendrocyte precursors and tissue repair during experimental autoimmune encephalomyelitis

DEFF Research Database (Denmark)

Penkowa, Milena; Hidalgo, Juan

2003-01-01

Experimental autoimmune encephalomyelitis (EAE) is an animal model for the human demyelinating disease multiple sclerosis (MS). EAE and MS are characterized by significant inflammation, demyelination, neuroglial damage, and cell death. Metallothionein-I and -II (MT-I + II) are antiinflammatory an......)beta, neurotrophin-3 (NT-3), NT-4/5, and nerve growth factor (NGF). These beneficial effects of Zn-MT-II treatment could not be attributable to its zinc content per se. The present results support further the use of Zn-MT-II as a safe and successful therapy for multiple sclerosis....

Contribution of microglia and astrocytes to the central sensitization, inflammatory and neuropathic pain in the juvenile rat

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Ikeda Hiroshi

2012-06-01

Full Text Available Abstract Background The development of pain after peripheral nerve and tissue injury involves not only neuronal pathways but also immune cells and glia. Central sensitization is thought to be a mechanism for such persistent pain, and ATP involves in the process. We examined the contribution of glia to neuronal excitation in the juvenile rat spinal dorsal horn which is subjected to neuropathic and inflammatory pain. Results In rats subjected to neuropathic pain, immunoreactivity for the microglial marker OX42 was markedly increased. In contrast, in rats subjected to inflammatory pain, immunoreactivity for the astrocyte marker glial fibrillary acidic protein was increased slightly. Optically-recorded neuronal excitation induced by single-pulse stimulation to the dorsal root was augmented in rats subjected to neuropathic and inflammatory pain compared to control rats. The bath application of a glial inhibitor minocycline and a p38 mitogen-activated protein kinase inhibitor SB203580 inhibited the neuronal excitation in rats subjected to neuropathic pain. A specific P2X1,2,3,4 antagonist TNP-ATP largely inhibited the neuronal excitation only in rats subjected to neuropathic pain rats. In contrast, an astroglial toxin L-alpha-aminoadipate, a gap junction blocker carbenoxolone and c-Jun N-terminal kinase inhibitor SP600125 inhibited the neuronal excitation only in rats subjected to inflammatory pain. A greater number of cells in spinal cord slices from rats subjected to neuropathic pain showed Ca2+ signaling in response to puff application of ATP. This Ca2+ signaling was inhibited by minocycline and TNP-ATP. Conclusions These results directly support the notion that microglia is more involved in neuropathic pain and astrocyte in inflammatory pain.

Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial.

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Leist, Thomas P; Comi, Giancarlo; Cree, Bruce A C; Coyle, Patricia K; Freedman, Mark S; Hartung, Hans-Peter; Vermersch, Patrick; Casset-Semanaz, Florence; Scaramozza, Matthew

2014-03-01

Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS. Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985. Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, pMS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS. Merck Serono SA Geneva

Cervical spinal demyelination with ethidium bromide impairs respiratory (phrenic) activity and forelimb motor behavior in rats

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Nichols, Nicole L.; Punzo, Antonio M.; Duncan, Ian D.; Mitchell, Gordon S.; Johnson, Rebecca A.

2012-01-01

Although respiratory complications are a major cause of morbidity/mortality in many neural injuries or diseases, little is known concerning mechanisms whereby deficient myelin impairs breathing, or how patients compensate for such changes. Here, we tested the hypothesis that respiratory and forelimb motor function are impaired in a rat model of focal dorsolateral spinal demyelination (ethidium bromide, EB). Ventilation, phrenic nerve activity and horizontal ladder walking were performed 7-14 days post-C2 injection of EB or vehicle (SHAM). EB caused dorsolateral demyelination at C2-C3 followed by signficant spontaneous remyelination at 14 days post-EB. Although ventilation did not differ between groups, ipsilateral integrated phrenic nerve burst amplitude was significantly reduced versus SHAM during chemoreceptor activation at 7 days post-EB but recovered by 14 days. The ratio of ipsi- to contralateral phrenic nerve amplitude correlated with cross-sectional lesion area. This ratio was significantly reduced 7 days post-EB versus SHAM during baseline conditions, and versus SHAM and 14 day groups during chemoreceptor activation. Limb function ipsilateral to EB was impaired 7 days post-EB and partially recovered by 14 days post-EB. EB provides a reversible model of focal, spinal demyelination, and may be a useful model to study mechanisms of functional impairment and recovery via motor plasticity, or the efficacy of new therapeutic interventions to reduce severity or duration of disease. PMID:23159317

[Inflammatory spinal diseases: axial spondyloarthritis : Central importance of imaging].

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Baraliakos, X; Fruth, M; Kiltz, U; Braun, J

2017-03-01

The diagnosis of axial spondyloarthritis (axSpA) includes classical ankylosing spondylitis (AS) as well as earlier stages and abortive courses of the disease, in which structural alterations have not yet occurred. These are classified as non-radiographic axSpA (nr-axSpa). Inflammatory changes in the entire axial skeleton are characteristic for axSpA and can be visualized by magnetic resonance imaging (MRI), while in most patients structural alterations, such as new bone formation with syndesmophytes and ankylosis develop in the later course of the disease. These bony alterations can best be visualized by conventional radiography and by computed tomography. Certain MRI sequences are nowadays considered as the standard method for depiction of inflammatory changes in axSpA. The introduction of MRI has led to a paradigm shift for this disease because the inflammatory lesions characteristic for the disease can be visualized at an early stage using appropriate MRI sequences.

CCL5–Glutamate Cross-Talk in Astrocyte-Neuron Communication in Multiple Sclerosis

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Anna Pittaluga

2017-09-01

Full Text Available The immune system (IS and the central nervous system (CNS are functionally coupled, and a large number of endogenous molecules (i.e., the chemokines for the IS and the classic neurotransmitters for the CNS are shared in common between the two systems. These interactions are key elements for the elucidation of the pathogenesis of central inflammatory diseases. In recent years, evidence has been provided supporting the role of chemokines as modulators of central neurotransmission. It is the case of the chemokines CCL2 and CXCL12 that control pre- and/or post-synaptically the chemical transmission. This article aims to review the functional cross-talk linking another endogenous pro-inflammatory factor released by glial cells, i.e., the chemokine Regulated upon Activation Normal T-cell Expressed and Secreted (CCL5 and the principal neurotransmitter in CNS (i.e., glutamate in physiological and pathological conditions. In particular, the review discusses preclinical data concerning the role of CCL5 as a modulator of central glutamatergic transmission in healthy and demyelinating disorders. The CCL5-mediated control of glutamate release at chemical synapses could be relevant either to the onset of psychiatric symptoms that often accompany the development of multiple sclerosis (MS, but also it might indirectly give a rationale for the progression of inflammation and demyelination. The impact of disease-modifying therapies for the cure of MS on the endogenous availability of CCL5 in CNS will be also summarized. We apologize in advance for omission in our coverage of the existing literature.

Extra pontine osmotic demyelination syndrome.

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Zunga, Pervaiz M; Farooq, Omar; Dar, Mohd I; Dar, Ishrat H; Rashid, Samia; Rather, Abdul Q; Basu, Javid A; Ashraf, Mohammed; Bhat, Jahangeer A

2015-01-01

The osmotic demyelination syndrome (ODS) has been identified as a complication of the rapid correction of hyponatremia for decades. However, in recent years, a variety of other medical conditions have been associated with the development of ODS, independent of changes in serum sodium which cause a rapid changes in osmolality of the interstitial (extracellular) compartment of the brain leading to dehydration of energy-depleted cells with subsequent axonal damage that occurs in characteristic areas. Slow correction of the serum sodium concentration and additional administration of corticosteroids seems to be a major prevention step in ODS patients. In the current report we aimed to share a rare case which we observed in our hospital. A 65 year old female admitted as altered sensorium with history of vomiting, diarrhea was managed with intravenous fluids for 2 days at a peripheral health centre. Patient was referred to our centre with encephalopathy, evaluated and found to have hyponatremia and hypokalemia rest of biochemical parameters and septic profile were normal. Patient's electrolyte disturbances were managed as per guidelines but encephalopathy persisted. Supportive treatment was continued and patient was discharged after 2 wks of stay in hospital after gaining full sensorium and neurological functions.

Peripheral Vasculitis, Intermediate Uveitis and Interferon Use in Multiple Sclerosis

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Haluk Esgin

2016-01-01

Full Text Available Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system. A 40-year-old female patient with a 12-year history of MS was admitted to our clinic with blurred vision and floaters in her right eye for about 1 month. Here, we share the findings and the management of intermediate uveitis and retinal periphlebitis in an MS case being treated with interferon beta-1a for 7 years.

Histopathological, Ultrastructural, and Immunohistochemical Assessment of Hippocampus Structures of Rats Exposed to TCDD and High Doses of Tocopherol and Acetylsalicylic Acid

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Joanna Rosińczuk

2015-01-01

Full Text Available The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP and acetylsalicylic acid (ASA on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system.

Evaluation of the association between sexual dysfunction and demyelinating plaque location and number in female multiple sclerosis patients.

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Solmaz, Volkan; Ozlece, Hatice Kose; Him, Aydın; Güneş, Ayfer; Cordano, Christian; Aksoy, Durdane; Çelik, Yahya

2018-04-17

Purpose To investigate the frequency of sexual dysfunction (SD) in female multiple sclerosis (MS) patients and to explore its association with the location and number of demyelinating lesions. Material and Methods We evaluated 42 female patients and 41 healthy subjects. All patients underwent neurological examination and 1.5 T brain and full spinal MRI. All subjects completed the female sexual function index (FSFI), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), and Short-Form 36 Quality of Life Scale (SF-36). All participants were also evaluated for serum thyroid stimulating hormone (TSH), T4, estradiol, and total testosterone. Results No statistically significant differences between the MS and control groups were found for age, body mass index (BMI), serum TSH, T4, E2, and total testosterone level. MS patients had a statistically significantly lower FSFI and SF-36 scores and higher BDI and BAI scores compared with healthy subjects. The location and number of demyelinating lesions were not associated with SD. Conclusion In our cohort, this difference in SD appears unrelated to the location and number of demyelinating lesions. These findings highlight the importance of the assessment and treatment of psychiatric comorbidities, such as depression and anxiety, in MS patients reporting SD.

The contribution of oligodendrocytes and oligodendrocyte progenitor cells to central nervous system repair in multiple sclerosis: perspectives for remyelination therapeutic strategies

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Adriana Octaviana Dulamea

2017-01-01

Full Text Available Oligodencrocytes (OLs are the main glial cells of the central nervous system involved in myelination of axons. In multiple sclerosis (MS, there is an imbalance between demyelination and remyelination processes, the last one performed by oligodendrocyte progenitor cells (OPCs and OLs, resulting into a permanent demyelination, axonal damage and neuronal loss. In MS lesions, astrocytes and microglias play an important part in permeabilization of blood-brain barrier and initiation of OPCs proliferation. Migration and differentiation of OPCs are influenced by various factors and the process is finalized by insufficient acummulation of OLs into the MS lesion. In relation to all these processes, the author will discuss the potential targets for remyelination strategies.

Inflammatory pseudotumor of the liver: CT findings

International Nuclear Information System (INIS)

Lee, Kang Mo; Yoon, Kwon Ha; Rho, Ji Young; Park, Ki Han; Yun, Ki Jung; Kim, Chang Keun; Won, Jong Jin; Ha, Hyun Kwon; Suh, Jae Hee; Auh, Yong Ho

1998-01-01

To evaluate the CT features of inflammatory pseudotumor of the liver with histopathologic correlation. The CT features of 14 cases (ten patients) with pathologically proven inflammatory hepatic pseudotumor were retrospectively analyzed and correlated with resected and biopsy specimens. The size of lesions ranged between 2.0 and 7.0cm (mean, 3.7 cm); On unenhanced CT, the masses were seen as ill-defined hypodense lesions, while on contrast-enhanced CT they were heterogeneous and multiseptated, with enhancement of internal septa and peripheral wall (n=3D10). In four lesions, central low density and peripheral homogeneous enhancement were seen. On histopathological correlation, the central hypoattenuated area corresponded to chronic inflammatory cell infiltrates with foamy histiocytes, plasmacytes, and lymphocytes, while the hyperattenuated peripheral wall and internal septa represented dense fibrosis. In patients in whon CT shows a heterogeneous enhancing mass, inflammatory pseudotumor of the liver should be included in differential diagnosis

The Central Role of the Gut Microbiota in Chronic Inflammatory Diseases

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Caroline Marcantonio Ferreira

2014-01-01

Full Text Available The commensal microbiota is in constant interaction with the immune system, teaching immune cells to respond to antigens. Studies in mice have demonstrated that manipulation of the intestinal microbiota alters host immune cell homeostasis. Additionally, metagenomic-sequencing analysis has revealed alterations in intestinal microbiota in patients suffering from inflammatory bowel disease, asthma, and obesity. Perturbations in the microbiota composition result in a deficient immune response and impaired tolerance to commensal microorganisms. Due to altered microbiota composition which is associated to some inflammatory diseases, several strategies, such as the administration of probiotics, diet, and antibiotic usage, have been utilized to prevent or ameliorate chronic inflammatory diseases. The purpose of this review is to present and discuss recent evidence showing that the gut microbiota controls immune system function and onset, development, and resolution of some common inflammatory diseases.

Biological therapy in inflammatory bowel diseases: Access in Central and Eastern Europe

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Rencz, Fanni; Péntek, Márta; Bortlik, Martin; Zagorowicz, Edyta; Hlavaty, Tibor; Śliwczyński, Andrzej; Diculescu, Mihai M; Kupcinskas, Limas; Gecse, Krisztina B; Gulácsi, László; Lakatos, Peter L

2015-01-01

Biological drugs opened up new horizons in the management of inflammatory bowel diseases (IBD). This study focuses on access to biological therapy in IBD patients across 9 selected Central and Eastern European (CEE) countries, namely Bulgaria, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania and Slovakia. Literature data on the epidemiology and disease burden of IBD in CEE countries was systematically reviewed. Moreover, we provide an estimation on prevalence of IBD as well as biological treatment rates. In all countries with the exception of Romania, lower biological treatment rates were observed in ulcerative colitis (UC) compared to Crohn’s disease despite the higher prevalence of UC. Great heterogeneity (up to 96-fold) was found in access to biologicals across the CEE countries. Poland, Bulgaria, Romania and the Baltic States are lagging behind Hungary, Slovakia and the Czech Republic in their access to biologicals. Variations of reimbursement policy may be one of the factors explaining the differences to a certain extent in Bulgaria, Latvia, Lithuania, and Poland, but association with other possible determinants (differences in prevalence and incidence, price of biologicals, total expenditure on health, geographical access, and cost-effectiveness results) was not proven. We assume, nevertheless, that health deterioration linked to IBD might be valued differently against other systemic inflammatory conditions in distinct countries and which may contribute to the immense diversity in the utilization of biological drugs for IBD. In conclusion, access to biologicals varies widely among CEE countries and this difference cannot be explained by epidemiological factors, drug prices or total health expenditure. Changes in reimbursement policy could contribute to better access to biologicals in some countries. PMID:25684937

Sigma-1 receptor and inflammatory pain.

Science.gov (United States)

Gris, Georgia; Cobos, Enrique José; Zamanillo, Daniel; Portillo-Salido, Enrique

2015-06-01

The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain. Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary. Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

Science.gov (United States)

Matthews, Lucy; Kolind, Shannon; Brazier, Alix; Leite, Maria Isabel; Brooks, Jonathan; Traboulsee, Anthony; Jenkinson, Mark; Johansen-Berg, Heidi; Palace, Jacqueline

2015-01-01

Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

Diagnostic algorithm for relapsing acquired demyelinating syndromes in children.

Science.gov (United States)

Hacohen, Yael; Mankad, Kshitij; Chong, W K; Barkhof, Frederik; Vincent, Angela; Lim, Ming; Wassmer, Evangeline; Ciccarelli, Olga; Hemingway, Cheryl

2017-07-18

To establish whether children with relapsing acquired demyelinating syndromes (RDS) and myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) show distinctive clinical and radiologic features and to generate a diagnostic algorithm for the main RDS for clinical use. A panel reviewed the clinical characteristics, MOG-Ab and aquaporin-4 (AQP4) Ab, intrathecal oligoclonal bands, and Epstein-Barr virus serology results of 110 children with RDS. A neuroradiologist blinded to the diagnosis scored the MRI scans. Clinical, radiologic, and serologic tests results were compared. The findings showed that 56.4% of children were diagnosed with multiple sclerosis (MS), 25.4% with neuromyelitis optica spectrum disorder (NMOSD), 12.7% with multiphasic disseminated encephalomyelitis (MDEM), and 5.5% with relapsing optic neuritis (RON). Blinded analysis defined baseline MRI as typical of MS in 93.5% of children with MS. Acute disseminated encephalomyelitis presentation was seen only in the non-MS group. Of NMOSD cases, 30.7% were AQP4-Ab positive. MOG-Ab were found in 83.3% of AQP4-Ab-negative NMOSD, 100% of MDEM, and 33.3% of RON. Children with MOG-Ab were younger, were less likely to present with area postrema syndrome, and had lower disability, longer time to relapse, and more cerebellar peduncle lesions than children with AQP4-Ab NMOSD. A diagnostic algorithm applicable to any episode of CNS demyelination leads to 4 main phenotypes: MS, AQP4-Ab NMOSD, MOG-Ab-associated disease, and antibody-negative RDS. Children with MS and AQP4-Ab NMOSD showed features typical of adult cases. Because MOG-Ab-positive children showed notable and distinctive clinical and MRI features, they were grouped into a unified phenotype (MOG-Ab-associated disease), included in a new diagnostic algorithm. © 2017 American Academy of Neurology.

Purinergic signaling modulates the cerebral inflammatory response in experimentally infected fish with Streptococcus agalactiae: an attempt to improve the immune response.

Science.gov (United States)

Souza, Carine F; Baldissera, Matheus D; Bottari, Nathiele B; Moreira, Karen L S; da Rocha, Maria Izabel U M; da Veiga, Marcelo L; Santos, Roberto C V; Baldisserotto, Bernardo

2018-06-01

Appropriate control of the immune response is a critical determinant of fish health, and the purinergic cascade has an important role in the immune and inflammatory responses. This cascade regulates the levels of adenosine triphosphate (ATP), adenosine diphosphate, adenosine monophosphate and adenosine (Ado), molecules involved in physiological or pathological events as inflammatory and anti-inflammatory mediators. Thus, the aim of this study was to evaluate whether purinergic signaling, through the activities of nucleoside triphosphate diphosphohydrolase (NTPDase), 5'-nucleotidase, and adenosine deaminase (ADA), is capable of modulating the cerebral immune and inflammatory responses in silver catfish that is experimentally infected with Streptococcus agalactiae. Cerebral NTPDase (with ATP as substrate) and 5'-nucleotidase activities increased, while ADA activity decreased in silver catfish that is experimentally infected with S. agalactiae, compared to the control group. Moreover, the cerebral levels of ATP and Ado increased in infected animals compared to the uninfected control group. Brain histopathology in infected animals revealed inflammatory demyelination (the presence of occasional bubbly collections), increased cellular density in the area near to pia-mater and intercellular edema. Based on this evidence, the modulation of the purinergic cascade by the enzymes NTPDase, 5'-nucleotidase, and ADA exerts an anti-inflammatory profile due to the regulation of ATP and Ado levels. This suggests involvement of purinergic enzymes on streptococcosis pathogenesis, through regulating cerebral ATP and Ado levels, molecules known to participate in physiological or pathological events as inflammatory and anti-inflammatory mediators, respectively. In summary, the modulation of the cerebral purinergic cascade exerts an anti-inflammatory profile in an attempt to reduce inflammatory damage.

Brain white matter demyelinating lesions and amyotrophic lateral sclerosis in a patient with C9orf72 hexanucleotide repeat expansion.

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Oliveira Santos, Miguel; Caldeira, Inês; Gromicho, Marta; Pronto-Laborinho, Ana; de Carvalho, Mamede

2017-10-01

A hexanucleotide repeat expansion in the C9orf72 gene is associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. It has been described before four patients with multiple sclerosis (MS) and C9orf72-ALS. However, C9orf72 positivity is not associated with increased risk of MS. Inflammatory pathways related to NF-κB have been linked to ALS and MS, and appear to be important in C9orf72-ALS patients. A 42-year-old woman presented with progressive bulbar symptoms for 9 months. Neurological examination disclosed spastic dysarthria, atrophic tongue with fasciculations, brisk jaw and limb tendon reflexes, and bilateral Hoffman sign. Electrophysiological assessment confirmed ALS. Brain MRI revealed multiple and bilateral juxtacortical and periventricular inflammatory changes, some with gadolinium-enhancement, configuring a probable MS-like pattern. CSF evaluation was unremarkable, with no oligoclonal bands. Visual and somatosensory evoked potentials were normal. Follow-up brain MRI 6 months later showed two new lesions in two relatively characteristic locations of MS, with no gadolinium-enhancement. Genetic screening revealed a C9orf72 expansion. As patient had no clinical manifestation of MS, a diagnosis of radiologically isolated syndrome was considered. We speculate that these demyelinating lesions might facilitate expressivity of C9orf72 expansion, through NF-κB activation. This plausible association may lead to the identification of a therapeutic target in this subgroup of C9orf72-ALS patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination.

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Jasmin Nessler

Full Text Available For the treatment of patients with multiple sclerosis there are no regenerative approaches to enhance remyelination. Mesenchymal stem cells (MSC have been proposed to exert such regenerative functions. Intravenous administration of human MSC reduced the clinical severity of experimental autoimmune encephalomyelitis (EAE, an animal model mimicking some aspects of multiple sclerosis. However, it is not clear if this effect was achieved by systemic immunomodulation or if there is an active neuroregeneration in the central nervous system (CNS. In order to investigate remyelination and regeneration in the CNS we analysed the effects of intravenously and intranasally applied murine and human bone marrow-derived MSC on cuprizone induced demyelination, a toxic animal model which allows analysis of remyelination without the influence of the peripheral immune system. In contrast to EAE no effects of MSC on de- and remyelination and glial cell reactions were found. In addition, neither murine nor human MSC entered the lesions in the CNS in this toxic model. In conclusion, MSC are not directed into CNS lesions in the cuprizone model where the blood-brain-barrier is intact and thus cannot provide support for regenerative processes.

Bioluminescence Imaging of Olig2-Neural Stem Cells Reveals Improved Engraftment in a Demyelination Mouse Model

NARCIS (Netherlands)

Sher, Falak; van Dam, Go; Boddeke, Erik; Copray, Sjef

2009-01-01

A major issue in the potential application of neural stem cell (NSC)-based cell replacement therapy for demyelinating diseases is the question of the survival, functional behavior, and stability of implanted NSC-derived oligodendrocyte precursor cells (OPCs) over an extended period. To address this

MR in the diagnosis and monitoring of multiple sclerosis: An overview

International Nuclear Information System (INIS)

Rovira, Alex; Leon, Adelaida

2008-01-01

Multiple sclerosis is a chronic, persistent inflammatory-demyelinating disease of the central nervous system that typically presents as an acute clinically isolated syndrome attributable to a monofocal or multifocal demyelinating lesion, which usually affects the optic nerve, spinal cord, or brainstem and cerebellum. Although the diagnosis of multiple sclerosis is still based on clinical findings, magnetic resonance imaging is now integrated in the overall diagnostic scheme of the disease because of its unique sensitivity to demonstrate the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord. Conventional magnetic resonance imaging techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences are highly sensitive in detecting multiple sclerosis plaques and provide a quantitative assessment of inflammatory activity and lesion load. However, there is a persisting mismatch between clinical and magnetic resonance imaging efficacy of approved treatments, which underlies the fact that this technique does not suffice to explain the entire spectrum of the disease process. In recent years, great effort has been dedicated to overcoming these limitations by using non-conventional magnetic resonance-derived metrics that can selectively measure the more destructive aspects of multiple sclerosis pathology and monitor the reparative mechanisms. These metrics, which include unenhanced T1-weighted imaging, measures of central nervous system atrophy, magnetization transfer imaging, proton magnetic resonance spectroscopy, diffusion-weighted imaging, and functional magnetic resonance imaging, provide a better approximation of the pathological substrate of the multiple sclerosis plaques, have increased our understanding of the pathogenesis of the disease, and have proven useful for studying the natural history of multiple sclerosis and monitoring the effects of new treatments. Therefore, magnetic resonance imaging not only plays an

MR in the diagnosis and monitoring of multiple sclerosis: An overview

Energy Technology Data Exchange (ETDEWEB)

Rovira, Alex [Magnetic Resonance Unit (I.D.I.), Department of Radiology, Hospital Universitari Vall d' Hebron, Barcelona (Spain)], E-mail: alex.rovira@idi-cat.org; Leon, Adelaida [Magnetic Resonance Unit (I.D.I.), Department of Radiology, Hospital Universitari Vall d' Hebron, Barcelona (Spain)

2008-09-15

Multiple sclerosis is a chronic, persistent inflammatory-demyelinating disease of the central nervous system that typically presents as an acute clinically isolated syndrome attributable to a monofocal or multifocal demyelinating lesion, which usually affects the optic nerve, spinal cord, or brainstem and cerebellum. Although the diagnosis of multiple sclerosis is still based on clinical findings, magnetic resonance imaging is now integrated in the overall diagnostic scheme of the disease because of its unique sensitivity to demonstrate the spatial and temporal dissemination of demyelinating plaques in the brain and spinal cord. Conventional magnetic resonance imaging techniques, such as T2-weighted and gadolinium-enhanced T1-weighted sequences are highly sensitive in detecting multiple sclerosis plaques and provide a quantitative assessment of inflammatory activity and lesion load. However, there is a persisting mismatch between clinical and magnetic resonance imaging efficacy of approved treatments, which underlies the fact that this technique does not suffice to explain the entire spectrum of the disease process. In recent years, great effort has been dedicated to overcoming these limitations by using non-conventional magnetic resonance-derived metrics that can selectively measure the more destructive aspects of multiple sclerosis pathology and monitor the reparative mechanisms. These metrics, which include unenhanced T1-weighted imaging, measures of central nervous system atrophy, magnetization transfer imaging, proton magnetic resonance spectroscopy, diffusion-weighted imaging, and functional magnetic resonance imaging, provide a better approximation of the pathological substrate of the multiple sclerosis plaques, have increased our understanding of the pathogenesis of the disease, and have proven useful for studying the natural history of multiple sclerosis and monitoring the effects of new treatments. Therefore, magnetic resonance imaging not only plays an

Neonatal overfeeding attenuates acute central pro-inflammatory effects of short-term high fat diet

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Guohui eCai

2015-01-01

Full Text Available Neonatal obesity predisposes individuals to obesity throughout life. In rats, neonatal overfeeding also leads to early accelerated weight gain that persists into adulthood. The phenotype is associated with dysfunction in a number of systems including paraventricular nucleus of the hypothalamus (PVN responses to psychological and immune stressors. However, in many cases weight gain in neonatally overfed rats stabilizes in early adulthood so the animal does not become more obese as it ages. Here we examined if neonatal overfeeding by suckling rats in small litters predisposes them to exacerbated metabolic and central inflammatory disturbances if they are also given a high fat diet in later life. In adulthood we gave the rats normal chow, 3 days, or 3 weeks high fat diet (45% kcal from fat and measured peripheral indices of metabolic disturbance. We also investigated hypothalamic microglial changes, as an index of central inflammation, as well as PVN responses to lipopolysaccharide (LPS. Surprisingly, neonatal overfeeding did not predispose rats to the metabolic effects of a high fat diet. Weight changes and glucose metabolism were unaffected by the early life experience. However, short term (3 day high fat diet was associated with more microglia in the hypothalamus and a markedly exacerbated PVN response to LPS in control rats; effects not seen in the neonatally overfed. Our findings indicate neonatally overfed animals are not more susceptible to the adverse metabolic effects of a short-term high fat diet but may be less able to respond to the central effects.

Multiple Sclerosis: Pathogenesis and Treatment

OpenAIRE

Loma, Ingrid; Heyman, Rock

2011-01-01

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. It affects approximately 400,000 people in the United States and onset is usually during young adulthood. There are four clinical forms of MS, of which relapsing remitting type is the most common. As the etiology of MS is unknown, finding a cure will remain challenging. The main mechanism of injury appears to be inflammation and 8 agents are now FDA approved to help control MS. Th...

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

Science.gov (United States)

Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

2016-11-01

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Imaging of demyelinating and neoplastic diseases of the spinal cord; Bildgebung bei demyelinisierenden und tumoroesen Erkrankungen des Rueckenmarks

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Mueller-Mang, C. [Institut fuer CT und MRT Gaenserndorf, Gaenserndorf (Austria)

2010-12-15

The clinical symptoms of myelopathy are variable and non-specific. Demyelinating as well as neoplastic spinal cord diseases can cause paresthesia, progressive sensomotoric deficits and bowel and bladder dysfunction. Imaging of the spine, especially with magnetic resonance imaging (MRI), is an essential component in the diagnostic assessment of myelopathy and makes a substantial contribution to achieving the correct diagnosis. Although intramedullary neoplasms are far less common than demyelinating spinal cord diseases, radiologists should be familiar with the three most common entities, astrocytoma, ependymoma and hemangioblastoma, which represent over 70% of all spinal cord neoplasms. An early diagnosis and therapy is essential with neoplastic and demyelinating spinal cord diseases to hold residual neurological deficits as low as possible. (orig.) [German] Die klinische Symptomatik von Myelopathien ist aeusserst variabel und unspezifisch. Sowohl demyelinisierende als auch tumoroese Rueckenmarkerkrankungen koennen Paraesthesien, progrediente sensomotorische Ausfaelle und eine Sphinkterdysfunktion hervorrufen. Bildgebende Untersuchungen, und hier allen voran die MRT, sind ein unerlaesslicher Bestandteil zur Abklaerung von Myelopathien und tragen wesentlich zur korrekten Diagnose bei. Intramedullaere Tumoren sind zwar weitaus seltener als demyelinisierende Rueckenmarkerkrankungen, dennoch sollte der Radiologe mit den Bildmerkmalen der 3 haeufigsten Tumorarten, dem Astrozytom, Ependymom und Haemangioblastom vertraut sein, die ueber 70% aller Rueckenmarktumoren verursachen. Eine moeglichst fruehe Diagnostik und Therapie sind bei tumoroesen und demyelinisierenden Rueckenmarkerkrankungen essenziell, um bleibende neurologische Defizite moeglichst gering zu halten. (orig.)

Central pontine myelinolysis (CPM and extrapontine myelinolysis (EPM following concurrent chemoradiotherapy for nasopharyngeal carcinoma

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Chen-Hui Chong

2016-06-01

Full Text Available Central pontine myelinolysis (CPM is a disease that may present with coma, quadriplegia, or no symptoms at all. It is an iatrogenic demyelinating disease caused most frequently by overzealous correction of chronic hyponatremia and excessive swings in serum osmolality. Lesions can also occur outside the pons as extrapontine myelinolysis (EPM. Herein we have reported a case of CPM and EPM in a patient after chemoradiotherapy for recurrent nasopharyngeal carcinoma.

Pattern Recognition of the Multiple Sclerosis Syndrome

Science.gov (United States)

Stewart, Renee; Healey, Kathleen M.

2017-01-01

During recent decades, the autoimmune disease neuromyelitis optica spectrum disorder (NMOSD), once broadly classified under the umbrella of multiple sclerosis (MS), has been extended to include autoimmune inflammatory conditions of the central nervous system (CNS), which are now diagnosable with serum serological tests. These antibody-mediated inflammatory diseases of the CNS share a clinical presentation to MS. A number of practical learning points emerge in this review, which is geared toward the pattern recognition of optic neuritis, transverse myelitis, brainstem/cerebellar and hemispheric tumefactive demyelinating lesion (TDL)-associated MS, aquaporin-4-antibody and myelin oligodendrocyte glycoprotein (MOG)-antibody NMOSD, overlap syndrome, and some yet-to-be-defined/classified demyelinating disease, all unspecifically labeled under MS syndrome. The goal of this review is to increase clinicians’ awareness of the clinical nuances of the autoimmune conditions for MS and NMSOD, and to highlight highly suggestive patterns of clinical, paraclinical or imaging presentations in order to improve differentiation. With overlay in clinical manifestations between MS and NMOSD, magnetic resonance imaging (MRI) of the brain, orbits and spinal cord, serology, and most importantly, high index of suspicion based on pattern recognition, will help lead to the final diagnosis. PMID:29064441

SWI enhances vein detection using gadolinium in multiple sclerosis

International Nuclear Information System (INIS)

Maggi, Pietro; Mazzoni, Lorenzo N; Moretti, Marco; Grammatico, Matteo; Chiti, Stefano; Massacesi, Luca

2015-01-01

Susceptibility weighted imaging (SWI) combined with the FLAIR sequence provides the ability to depict in vivo the perivenous location of inflammatory demyelinating lesions – one of the most specific pathologic features of multiple sclerosis (MS). In addition, in MS white matter (WM) lesions, gadolinium-based contrast media (CM) can increase vein signal loss on SWI. This report focuses on two cases of WM inflammatory lesions enhancing on SWI images after CM injection. In these lesions in fact the CM increased the contrast between the parenchyma and the central vein allowing as well, in one of the two cases, the detection of a vein not visible on the same SWI sequence acquired before CM injection

Re-evaluating the treatment of acute optic neuritis.

Science.gov (United States)

Bennett, Jeffrey L; Nickerson, Molly; Costello, Fiona; Sergott, Robert C; Calkwood, Jonathan C; Galetta, Steven L; Balcer, Laura J; Markowitz, Clyde E; Vartanian, Timothy; Morrow, Mark; Moster, Mark L; Taylor, Andrew W; Pace, Thaddeus W W; Frohman, Teresa; Frohman, Elliot M

2015-07-01

Clinical case reports and prospective trials have demonstrated a reproducible benefit of hypothalamic-pituitary-adrenal (HPA) axis modulation on the rate of recovery from acute inflammatory central nervous system (CNS) demyelination. As a result, corticosteroid preparations and adrenocorticotrophic hormones are the current mainstays of therapy for the treatment of acute optic neuritis (AON) and acute demyelination in multiple sclerosis.Despite facilitating the pace of recovery, HPA axis modulation and corticosteroids have failed to demonstrate long-term benefit on functional recovery. After AON, patients frequently report visual problems, motion perception difficulties and abnormal depth perception despite 'normal' (20/20) vision. In light of this disparity, the efficacy of these and other therapies for acute demyelination require re-evaluation using modern, high-precision paraclinical tools capable of monitoring tissue injury.In no arena is this more amenable than AON, where a new array of tools in retinal imaging and electrophysiology has advanced our ability to measure the anatomic and functional consequences of optic nerve injury. As a result, AON provides a unique clinical model for evaluating the treatment response of the derivative elements of acute inflammatory CNS injury: demyelination, axonal injury and neuronal degeneration.In this article, we examine current thinking on the mechanisms of immune injury in AON, discuss novel technologies for the assessment of optic nerve structure and function, and assess current and future treatment modalities. The primary aim is to develop a framework for rigorously evaluating interventions in AON and to assess their ability to preserve tissue architecture, re-establish normal physiology and restore optimal neurological function. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

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Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M; Mariani, John N; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S; John, Gareth R

2015-06-01

In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an

Central nervous system immune reconstitution inflammatory syndrome in AIDS: experience of a Mexican neurological centre.

Science.gov (United States)

Guevara-Silva, Erik A; Ramírez-Crescencio, María A; Soto-Hernández, José Luís; Cárdenas, Graciela

2012-09-01

Highly active antiretroviral therapy (HAART) restores the inflammatory immune response in AIDS patients and it may unmask previous subclinical infections or paradoxically exacerbate symptoms of opportunistic infections. Up to 25% of patients receiving HAART develop immune reconstitution inflammatory syndrome (IRIS). We describe six patients with IRIS central nervous system (CNSIRIS) manifestations emphasizing the relevance of CSF cultures and neuroimaging in early diagnosis and management. Patients with CNSIRIS were identified among hospitalized HIV-infected patients that started HAART from January 2002 through December 2007 at a referral neurological center in Mexico. One-hundred and forty-two HIV-infected patients with neurological signs were hospitalized, 64 of which had received HAART, and six (9.3%) developed CNSIRIS. Five patients were male. Two cases of tuberculosis, two of cryptococcosis, one of brain toxoplasmosis, and one possible PML case were found. IRIS onset occurred within 12 weeks of HAART in five patients. Anti-infective therapy was continued. In one case, HAART was temporarily suspended. In long-term follow-up the clinical condition improved in all patients. CNSIRIS associated to opportunistic infections appeared in 9% of patients receiving HAART. Interestingly, no cases of malignancy or neoplasm IRIS-related were found. Frequent clinical assessment and neuroimaging studies supported diagnosis and treatment. Risk factors were similar to those found in other series. Copyright © 2012 Elsevier B.V. All rights reserved.

Huperzine A ameliorates experimental autoimmune encephalomyelitis via the suppression of T cell-mediated neuronal inflammation in mice.

Science.gov (United States)

Wang, Jun; Chen, Fu; Zheng, Peng; Deng, Weijuan; Yuan, Jia; Peng, Bo; Wang, Ruochen; Liu, Wenjun; Zhao, Hui; Wang, Yanqing; Wu, Gencheng

2012-07-01

Huperzine A (HupA), a sesquiterpene alkaloid and a potent and reversible inhibitor of acetylcholinesterase, possesses potential anti-inflammatory properties and is used for the treatment of certain neurodegenerative diseases such as Alzheimer's disease. However, it is still unknown whether this chemical is beneficial in the treatment of multiple sclerosis, a progressive inflammatory disease of the central nervous system. In this study, we examined the immunomodulatory properties of HupA in experimental autoimmune encephalomyelitis (EAE), a T-cell mediated murine model of multiple sclerosis. The following results were obtained: (1) intraperitoneal injections of HupA significantly attenuate the neurological severity of EAE in mice. (2) HupA decreases the accumulation of inflammatory cells, autoimmune-related demyelination and axonal injury in the spinal cords of EAE mice. (3) HupA down-regulates mRNA levels of the pro-inflammatory cytokines (IFN-γ and IL-17) and chemokines (MCP-1, RANTES, and TWEAK) while enhancing levels of anti-inflammatory cytokines (IL-4 and IL-10) in the spinal cords of EAE mice. (4) HupA inhibits MOG(35-55) stimulation-induced T-cell proliferation and IFN-γ and IL-17 secretion in cultured splenocytes. (5) HupA inhibition of T-cell proliferation is reversed by the nicotinic acetylcholinergic receptor antagonist mecamylamine. We conclude that HupA can ameliorate EAE by suppressing autoimmune responses, inflammatory reactions, subsequent demyelination and axonal injury in the spinal cord. Therefore, HupA may have a potential therapeutic value for the treatment of multiple sclerosis and as a neuroimmunomodulatory drug to control human CNS pathology. Copyright © 2012 Elsevier Inc. All rights reserved.

Anti-inflammatory effects of insulin.

Science.gov (United States)

Dandona, Paresh; Chaudhuri, Ajay; Mohanty, Priya; Ghanim, Husam

2007-07-01

This review deals with the recent observations on the pro-inflammatory effects of glucose and the anti-inflammatory actions of insulin. Apart from being novel, they are central to our understanding of why hyperglycemia is a prognosticator of bad clinical outcomes including patients with acute coronary syndromes, stroke and in patients in the intensive care unit. The pro-inflammatory effect of glucose as well as that of other macronutrients including fast food meals provides the basis of chronic oxidative stress and inflammation in the obese and their propensity to atherosclerotic disease. The anti-inflammatory action of insulin provides a neutralizing effect to balance macronutrient induced inflammation on the one hand and the possibility of using insulin as an anti-inflammatory drug on the other. The actions of macronutrients and insulin described above explain why insulin resistant states like obesity and type 2 diabetes are associated with oxidative stress, inflammation and atherosclerosis. They also suggest that insulin may be antiatherogenic.

Targeting the Redox Balance in Inflammatory Skin Conditions

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Ditte M. S. Lundvig

2013-04-01

Full Text Available Reactive oxygen species (ROS can be both beneficial and deleterious. Under normal physiological conditions, ROS production is tightly regulated, and ROS participate in both pathogen defense and cellular signaling. However, insufficient ROS detoxification or ROS overproduction generates oxidative stress, resulting in cellular damage. Oxidative stress has been linked to various inflammatory diseases. Inflammation is an essential response in the protection against injurious insults and thus important at the onset of wound healing. However, hampered resolution of inflammation can result in a chronic, exaggerated response with additional tissue damage. In the pathogenesis of several inflammatory skin conditions, e.g., sunburn and psoriasis, inflammatory-mediated tissue damage is central. The prolonged release of excess ROS in the skin can aggravate inflammatory injury and promote chronic inflammation. The cellular redox balance is therefore tightly regulated by several (enzymatic antioxidants and pro-oxidants; however, in case of chronic inflammation, the antioxidant system may be depleted, and prolonged oxidative stress occurs. Due to the central role of ROS in inflammatory pathologies, restoring the redox balance forms an innovative therapeutic target in the development of new strategies for treating inflammatory skin conditions. Nevertheless, the clinical use of antioxidant-related therapies is still in its infancy.

Extensive vascular remodeling in the spinal cord of pre-symptomatic experimental autoimmune encephalomyelitis mice; increased vessel expression of fibronectin and the α5β1 integrin

Science.gov (United States)

Boroujerdi, Amin; Welser-Alves, Jennifer V.; Milner, Richard

2013-01-01

Alterations in vascular structure and function are a central component of demyelinating disease. In addition to blood-brain barrier (BBB) breakdown, which occurs early in the course of disease, recent studies have described angiogenic remodeling, both in multiple sclerosis tissue and in the mouse demyelinating model, experimental autoimmune encephalomyelitis (EAE). As the precise timing of vascular remodeling in demyelinating disease has yet to be fully defined, the purpose of the current study was to define the time-course of these events in the MOG35-55 EAE model. Quantification of endothelial cell proliferation and vessel density revealed that a large part of angiogenic remodeling in cervical spinal cord white matter occurs during the pre-symptomatic phase of EAE. At the height of vascular remodeling, blood vessels in the cervical spinal cord showed strong transient upregulation of fibronectin and the α5β1 integrin. In vitro experiments revealed that α5 integrin inhibition reduced brain endothelial cell proliferation under inflammatory conditions. Interestingly, loss of vascular integrity was evident in all vessels during the first 4–7 days post-immunization, but after 14 days, was localized predominantly to venules. Taken together, our data demonstrate that extensive vascular remodeling occurs during the pre-symptomatic phase of EAE and point to a potential role for the fibronectin-α5β1 integrin interaction in promoting vascular remodeling during demyelinating disease. PMID:24056042

Central nervous system remyelination in culture — A tool for multiple sclerosis research

Science.gov (United States)

Zhang, Hui; Jarjour, Andrew A.; Boyd, Amanda; Williams, Anna

2011-01-01

Multiple sclerosis is a demyelinating disease of the central nervous system which only affects humans. This makes it difficult to study at a molecular level, and to develop and test potential therapies that may change the course of the disease. The development of therapies to promote remyelination in multiple sclerosis is a key research aim, to both aid restoration of electrical impulse conduction in nerves and provide neuroprotection, reducing disability in patients. Testing a remyelination therapy in the many and various in vivo models of multiple sclerosis is expensive in terms of time, animals and money. We report the development and characterisation of an ex vivo slice culture system using mouse brain and spinal cord, allowing investigation of myelination, demyelination and remyelination, which can be used as an initial reliable screen to select the most promising remyelination strategies. We have automated the quantification of myelin to provide a high content and moderately-high-throughput screen for testing therapies for remyelination both by endogenous and exogenous means and as an invaluable way of studying the biology of remyelination. PMID:21515259

Demyelinating disease in patients with myasthenia gravis Doenças desmielinizantes em pacientes com miastenia gravis

Directory of Open Access Journals (Sweden)

Denis Bernardi Bichuetti

2008-03-01

Full Text Available Myasthenia gravis (MG is an autoimmune disease characterized by fluctuating muscle weakness, caused by impaired neuromuscular transmission. Patients with MG can present other autoimmune diseases in association, commonly hypo or hyperthyroidism. The association of MG to demyelinating disease is rare and has been described before. We report on three Brazilian patients with MG that presented distinct demyelinating diseases, two monophasic and one recurrent neuromyelitis optica, several years after the diagnosis of MG, and discuss their clinical courses.Miastenia gravis (MG é doença autoimune caracterizada por episódios de fraqueza muscular alternados com melhora, causada por bloqueio da junção neuromuscular. Pacientes com MG podem apresentar outras doenças autoimunes, comumente hipo ou hipertiroidismo, e a associação de MG com doenças desmielinizantes é raramente descrita. Relatamos três pacientes brasileiros com MG que desenvolveram doenças desmielinizantes, dois monofásicos e um neuromielite óptica recorrente, vários anos após o diagnóstico de MG e discutimos seus cursos clínicos.

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis.

Directory of Open Access Journals (Sweden)

Lucy Matthews

Full Text Available Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.

Role of Demyelination Efficiency within Acellular Nerve Scaffolds during Nerve Regeneration across Peripheral Defects

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Meiqin Cai

2017-01-01

Full Text Available Hudson’s optimized chemical processing method is the most commonly used chemical method to prepare acellular nerve scaffolds for the reconstruction of large peripheral nerve defects. However, residual myelin attached to the basal laminar tube has been observed in acellular nerve scaffolds prepared using Hudson’s method. Here, we describe a novel method of producing acellular nerve scaffolds that eliminates residual myelin more effectively than Hudson’s method through the use of various detergent combinations of sulfobetaine-10, sulfobetaine-16, Triton X-200, sodium deoxycholate, and peracetic acid. In addition, the efficacy of this new scaffold in repairing a 1.5 cm defect in the sciatic nerve of rats was examined. The modified method produced a higher degree of demyelination than Hudson’s method, resulting in a minor host immune response in vivo and providing an improved environment for nerve regeneration and, consequently, better functional recovery. A morphological study showed that the number of regenerated axons in the modified group and Hudson group did not differ. However, the autograft and modified groups were more similar in myelin sheath regeneration than the autograft and Hudson groups. These results suggest that the modified method for producing a demyelinated acellular scaffold may aid functional recovery in general after nerve defects.

Innate Interferons Regulate CNS Inflammation

DEFF Research Database (Denmark)

Dieu, Ruthe; Khorooshi, Reza M. H.; Mariboe, Anne

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) whose pathology is characterised by demyelination and axonal damage. This results from interplay between CNS-resident glia, infiltrating leukocytes and a plethora of cytokines and chemokines. Currently...... potential IFN-inducing receptor that signals through NF-kB. Receptor activator of NF-kB (RANK) belongs to the TNF-receptor superfamily and has been shown to induce IFN-beta in medullary thymic epithelial cells affecting autoimmune regulatory processes and osteoclast precursor cells in association to bone...

Fluvoxamine stimulates oligodendrogenesis of cultured neural stem cells and attenuates inflammation and demyelination in an animal model of multiple sclerosis.

Science.gov (United States)

Ghareghani, Majid; Zibara, Kazem; Sadeghi, Heibatollah; Dokoohaki, Shima; Sadeghi, Hossein; Aryanpour, Roya; Ghanbari, Amir

2017-07-07

Multiple Sclerosis (MS) require medications controlling severity of the pathology and depression, affecting more than half of the patients. In this study, the effect of antidepressant drug fluvoxamine, a selective serotonin reuptake inhibitor, was investigated in vitro and in vivo. Nanomolar concentrations of fluvoxamine significantly increased cell viability and proliferation of neural stem cells (NSCs) through increasing mRNA expression of Notch1, Hes1 and Ki-67, and protein levels of NICD. Also, physiological concentrations of fluvoxamine were optimal for NSC differentiation toward oligodendrocytes, astrocytes and neurons. In addition, fluvoxamine attenuated experimental autoimmune encephalomyelitis (EAE) severity, a rat MS model, by significantly decreasing its clinical scores. Moreover, fluvoxamine treated EAE rats showed a decrease in IFN-γ serum levels and an increase in IL-4, pro- and anti-inflammatory cytokines respectively, compared to untreated EAE rats. Furthermore, immune cell infiltration and demyelination plaque significantly decreased in spinal cords of fluvoxamine-treated rats, which was accompanied by an increase in protein expression of MBP and GFAP positive cells and a decrease in lactate serum levels, a new biomarker of MS progression. In summary, besides its antidepressant activity, fluvoxamine stimulates proliferation and differentiation of NSCs particularly toward oligodendrocytes, a producer of CNS myelin.

Mitochondrial DNA double-strand breaks in oligodendrocytes cause demyelination, axonal injury, and CNS inflammation

DEFF Research Database (Denmark)

Madsen, Pernille M.; Pinto, Milena; Patel, Shreyans

2017-01-01

with time of induction. In addition, after short transient induction of mtDNA DSBs, PLP:mtPstI mice showed an exacerbated response to experimental autoimmune encephalomyelitis. Together, our data demonstrate that mtDNA damage can cause primary oligodendropathy, which in turn triggers demyelination, proving...... forms, which are not accurately reproduced in the models currently available. For this reason, the PLP: mtPstI mouse represents a unique and much needed platform for testing remyelinating therapies....

Central nervous system remyelination in culture--a tool for multiple sclerosis research.

Science.gov (United States)

Zhang, Hui; Jarjour, Andrew A; Boyd, Amanda; Williams, Anna

2011-07-01

Multiple sclerosis is a demyelinating disease of the central nervous system which only affects humans. This makes it difficult to study at a molecular level, and to develop and test potential therapies that may change the course of the disease. The development of therapies to promote remyelination in multiple sclerosis is a key research aim, to both aid restoration of electrical impulse conduction in nerves and provide neuroprotection, reducing disability in patients. Testing a remyelination therapy in the many and various in vivo models of multiple sclerosis is expensive in terms of time, animals and money. We report the development and characterisation of an ex vivo slice culture system using mouse brain and spinal cord, allowing investigation of myelination, demyelination and remyelination, which can be used as an initial reliable screen to select the most promising remyelination strategies. We have automated the quantification of myelin to provide a high content and moderately-high-throughput screen for testing therapies for remyelination both by endogenous and exogenous means and as an invaluable way of studying the biology of remyelination. Copyright © 2011 Elsevier Inc. All rights reserved.

Central pontine myelinolysis with a hyperintense lesion in diffusion weighted MRI: overview by means of a case report; Zentrale pontine Myelinolyse mit hyperintenser Laesion im diffusionsgewichteten MRT: Uebersicht anhand eines Fallberichtes

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Kuhn, J.; Bewermeyer, H. [Neurologische Klinik, Kliniken der Stadt Koeln gGmbH, Krankenhaus Merheim, Koeln (Germany); Harzheim, A. [Radiologische Klinik, Kliniken der Stadt Koeln gGmbH, Krankenhaus Merheim, Koeln (Germany)

2005-07-01

Central pontine myelinolysis (CPM) is a demyelinating disease of the pons often associated with demyelination of other areas of the central nervous system (CNS). The etiology and pathogenesis of this disorder are still not fully understood. However, almost all cases of CPM are related to severe diseases or chronic alcoholism and occur in the setting of rapidly corrected serum hyponatremia and hypotonicity respectively. Depending on the involvement of other CNS structures, the clinical picture can vary considerably. Magnetic resonance imaging is the most sensitive investigation for the antemortem diagnosis of CPM, although the radiological findings lag behind and do not necessarily correlate with the clinical picture. Quite obviously diffusion-weighted imaging can be useful in the rapid diagnosis of CPM. This short review summarizes the current knowledge on the pathogenesis, clinical presentation, radiological findings, prognosis and therapeutic approaches of CPM. Characteristical clinical features and MR-findings including hyperintensity on diffusion-weighted images are illustrated by a typical case. (orig.)

The value of qualitative and quantitative assessment of lesion to cerebral cortex signal ratio on double inversion recovery sequence in the differentiation of demyelinating plaques from non-specific T2 hyperintensities

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Hamcan, Salih; Battal, Bilal; Akgun, Veysel; Sari, Sebahattin; Tasar, Mustafa [Gulhane Military Medical School, Department of Radiology, Etlik, Ankara (Turkey); Oz, Oguzhan; Tasdemir, Serdar [Gulhane Military Medical School, Department of Neurology, Ankara (Turkey); Bozkurt, Yalcin [Golcuk Military Hospital, Department of Radiology, Kocaeli (Turkey)

2017-02-15

To assess the usefulness of the visual assessment and to determine diagnostic value of the lesion-to-cerebral cortex signal ratio (LCSR) measurement in the differentiation of demyelinating plaques and non-specific T2 hyperintensities on double inversion recovery (DIR) sequence. DIR and fluid-attenuated inversion recovery (FLAIR) sequences of 25 clinically diagnosed multiple sclerosis (MS) patients and 25 non-MS patients with non-specific T2-hyperintense lesions were evaluated visually and LCSRs were measured by two observers independently. On DIR sequence, the calculated mean LCSR ± SD for demyelinating plaques and non-specific T2-hyperintense lesions were 1.60 ± 0.26 and 0.75 ± 0.19 for observer1, and 1.61 ± 0.27 and 0.74 ± 0.19 for observer2. LCSRs of demyelinating plaques were significantly higher than other non-specific T2-hyperintense lesions on DIR sequence. By using the visual assessment demyelinating plaques were differentiated from non-specific T2-hyperintensities with 92.8 % sensitivity, 97.5 % specificity and 95.1 % accuracy for observer1 and 92.8 % sensitivity, 95 % specificity and 93.9 % accuracy for observer2. Visual assessment and LCSR measurement on DIR sequence seems to be useful for differentiating demyelinating MS plaques from supratentorial non-specific T2 hyperintensities. This feature can be used for diagnosis of MS particularly in patients with only supratentorial T2-hyperintense lesions who are categorized as radiologically possible MS. (orig.)

IFN-γ signaling to astrocytes protects from autoimmune mediated neurological disability.

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Claudia Hindinger

Full Text Available Demyelination and axonal degeneration are determinants of progressive neurological disability in patients with multiple sclerosis (MS. Cells resident within the central nervous system (CNS are active participants in development, progression and subsequent control of autoimmune disease; however, their individual contributions are not well understood. Astrocytes, the most abundant CNS cell type, are highly sensitive to environmental cues and are implicated in both detrimental and protective outcomes during autoimmune demyelination. Experimental autoimmune encephalomyelitis (EAE was induced in transgenic mice expressing signaling defective dominant-negative interferon gamma (IFN-γ receptors on astrocytes to determine the influence of inflammation on astrocyte activity. Inhibition of IFN-γ signaling to astrocytes did not influence disease incidence, onset, initial progression of symptoms, blood brain barrier (BBB integrity or the composition of the acute CNS inflammatory response. Nevertheless, increased demyelination at peak acute disease in the absence of IFN-γ signaling to astrocytes correlated with sustained clinical symptoms. Following peak disease, diminished clinical remission, increased mortality and sustained astrocyte activation within the gray matter demonstrate a critical role of IFN-γ signaling to astrocytes in neuroprotection. Diminished disease remission was associated with escalating demyelination, axonal degeneration and sustained inflammation. The CNS infiltrating leukocyte composition was not altered; however, decreased IL-10 and IL-27 correlated with sustained disease. These data indicate that astrocytes play a critical role in limiting CNS autoimmune disease dependent upon a neuroprotective signaling pathway mediated by engagement of IFN-γ receptors.

Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

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Pavlov, Valentin A.; Parrish, William R.; Rosas-Ballina, Mauricio; Ochani, Mahendar; Puerta, Margot; Ochani, Kanta; Chavan, Sangeeta; Al-Abed, Yousef; Tracey, Kevin J.

2015-01-01

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the “cholinergic anti-inflammatory pathway,” defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal- and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage. PMID:18639629

PET molecular imaging of peripheral and central inflammatory processes targeting the TSPO 18 kDa

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Bernards, Nicholas

2014-01-01

The purpose of this study was to determine the in vivo potential of the TSPO 18 kDa as a bio-marker of inflammation, with the use of its radioligand [ 18 F]DPA-714, to non-invasively quantify the inflammatory state within the scope of various pathologies. Multiple animal models of various inflammatory diseases, to include: inflammatory bowel disease, neuro-inflammation, and septic shock, were developed and put in place by adapted measures. The animals well-being and the subsequent inflammation was evaluated. The inflammatory state was measured using quantitative PET imaging with the TSPO radioligand [ 18 F]DPA-714 and correlated to the expression of conventional inflammatory markers using microscopy. Based on the observed data, we were able to distinguish control groups from treated groups when using [ 18 F]DPA-714. This TSPO radioligand permitted us to quantify the inflammatory level and to observe evolutionary changes in the inflammatory state of the disease in multiple models. The PET results, using the [ 18 F]DPA-714 signal was correlated with an increased TSPO expression at cellular level. Results indicate that [ 18 F]DPA-714 is a suitable tracer for studying inflammation of multiple diseases. [ 18 F]DPA-714 could be a good molecular probe to non-invasively evaluate the level and localization of inflammation. Moreover, in vivo imaging using this TSPO ligand is potentially a powerful tool to stage and certainly to follow the evolution and therapeutic efficiency at molecular level in inflammatory diseases. (author) [fr

Gold nanoparticles administration induced prominent inflammatory, central vein intima disruption, fatty change and Kupffer cells hyperplasia

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Abdelhalim Mohamed

2011-08-01

Full Text Available Abstract Background Advances in nanotechnology have identified promising candidates for many biological, biomedical and biomedicine applications. They are being increasingly exploited for medical uses and other industrial applications. The aim of the present study was to investigate the effects of administration of gold nanoparticles (GNPs on inflammatory cells infiltration, central vein intima disruption, fatty change, and Kupffer cells hyperplasia in the hepatic tissue in an attempt to cover and understand the toxicity and the potential threat of their therapeutic and diagnostic use. Methods A total of 70 healthy male Wistar-Kyoto rats were exposed to GNPs received 50 or 100 μl of GNPs infusion of 10, 20 and 50 nm GNPs for 3 or 7 days. Animals were randomly divided into groups, 12 GNPs-treated rats groups and one control group (NG. Groups 1, 2 and 3 received infusion of 50 μl GNPs of size 10 nm (3 or 7 days, size 20 nm (3 or 7 days and 50 nm (3 or 7 days, respectively; while groups 4, 5 and 6 received infusion of 100 μl GNPs of size 10 nm, size 20 nm and 50 nm, respectively. Results In comparison with respective control rats, exposure to GNPs doses has produced alterations in the hepatocytes, portal triads and sinusoids. The alterations in the hepatocytes were mainly vacuolar to hydropic degeneration, cytopasmic hyaline vacuolation, polymorphism, binucleation, karyopyknosis, karyolysis, karyorrhexis and necrosis. In addition, inflammatory cell infiltration, Kupffer cells hyperplasia, central veins intima disruption, hepatic strands dilatation and occasional fatty change together with a loss of normal architechiture of hepatic strands were also seen. Conclusions The alterations induced by the administration of GNPs were size-dependent with smaller ones induced more affects and related with time exposure of GNPs. These alterations might be an indication of injured hepatocytes due to GNPs toxicity that became unable to deal with the

Correlation between spinal cord MRI and clinical features in patients with demyelinating disease

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Papadopoulos, A.; Gatzonis, S.; Gouliamos, A.; Trakadas, S.; Kalovidouris, A.; Sgouropoulos, P.; Vlachos, L.; Papavasiliou, C.

1994-01-01

Localisation of spinal cord lesions by MRI was correlated with neurological symptoms and signs in 16 patients with clinical and laboratory evidence of multiple sclerosis. There was good correspondence between spinal cord lesions and motor tract signs. On the other hand, superficial or deep sensory disturbances correlated with spinal cord lesions in only about a quarter of the patients. MRI of the spinal cord appeared to explain the myelopathy in 11 patients, while in 3 there was strong clinical evidence of more extensive demyelinating lesions. In 7 of the 16 patients MRI of the brain was normal. (orig.)

Formal MRI criteria for the diagnosis of multiple sclerosis

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Harting, I.; Haehnel, S.; Meyding-Lamade, U.

2004-01-01

Multiple scloris (MS) is the most common demyelinating inflammatory disease of the central nervous system, presenting with multifocal, disseminated white matter lesions called plaques. Magnetic resonance imaging (MRI) is very sensitive in detecting white matter abnormalities. By demonstrating the spatial and temporal dissemination in patients presenting with isolated clinical findings suggestive of MS, MRI contributes to estimating the likelihood of the disease. Since MRI is highly sensitive but not specific, it is important to apply formal MRI criteria. This article describes the characteristic MRI changes of MS and the so-called McDonald criteria for an MRI-supported diagnosis of MS. (orig.) [de

The inflammatory microenvironment in colorectal neoplasia.

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McLean, Mairi H; Murray, Graeme I; Stewart, Keith N; Norrie, Gillian; Mayer, Claus; Hold, Georgina L; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N Ashley G; Drew, Janice E; El-Omar, Emad M

2011-01-07

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

The Inflammatory Microenvironment in Colorectal Neoplasia

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McLean, Mairi H.; Murray, Graeme I.; Stewart, Keith N.; Norrie, Gillian; Mayer, Claus; Hold, Georgina L.; Thomson, John; Fyfe, Nicky; Hope, Mairi; Mowat, N. Ashley G.; Drew, Janice E.; El-Omar, Emad M.

2011-01-01

Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID:21249124

The inflammatory microenvironment in colorectal neoplasia.

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Mairi H McLean

Full Text Available Colorectal cancer (CRC is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5 are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified.

Obesity, Metabolic Syndrome, and Musculoskeletal Disease: Common Inflammatory Pathways Suggest a Central Role for Loss of Muscle Integrity

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Kelsey H. Collins

2018-02-01

hypothesis that there is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities.

Obesity, Metabolic Syndrome, and Musculoskeletal Disease: Common Inflammatory Pathways Suggest a Central Role for Loss of Muscle Integrity.

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Collins, Kelsey H; Herzog, Walter; MacDonald, Graham Z; Reimer, Raylene A; Rios, Jaqueline L; Smith, Ian C; Zernicke, Ronald F; Hart, David A

2018-01-01

is a central role for muscle damage with chronic exposure to an obesity-inducing diet. The inflammatory consequence of diet and muscle dysregulation can result in dysregulated tissue repair and an imbalance toward negative adaptation, resulting in regulatory failure and other musculoskeletal tissue damage. The commonalities support the conclusion that musculoskeletal pathology with MetS should be evaluated in a comprehensive and integrated manner to understand risk for other MSK-related conditions. Implications for conservative management strategies to regulate MetS are discussed, as are future research opportunities.

Marcação imunoistoquímica da expressão astrocitária de proteína glial fibrilar ácida e de vimentina no sistema nervoso central de cães com cinomose Immunohistochemical staining of the astrocytic expression of glial fibrillary acidic protein and vimentin in the central nervous system of dogs with canine distemper

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Heloísa Orsini

2007-12-01

Full Text Available Uma vez que muitos dos aspectos envolvidos na patogenia dos processos desmielinizantes do sistema nervoso central (SNC são ainda pouco esclarecidos e que os astrócitos parecem estar envolvidos na mediação de tais processos, este estudo analisou morfologicamente a participação astrocitária na desmielinização do SNC por meio da marcação imunoistoquímica de duas proteínas dos filamentos intermediários astrocitários - a proteína glial fibrilar ácida (GFAP e a vimentina (VIM -, comparando amostras de cerebelo e de tronco encefálico de oito cães com cinomose e de dois cães normais, de diferentes raças e com idades entre um e quatro anos. Cortes histológicos dos tecidos foram submetidos à marcação pelo método indireto da avidina-biotina-peroxidase (ABC e a reatividade astrocitária, observada em microscopia de luz, foi quantificada em um sistema computacional de análise de imagens. Observou-se, na maioria dos cortes de animais doentes, a presença de lesões degenerativas compatíveis com desmielinização. A marcação para a GFAP e para a VIM foi mais intensa nos animais com cinomose do que nos animais normais, especialmente nas regiões circunventriculares e nas adjacentes às áreas de degeneração tecidual. Não houve diferença significativa entre a imunomarcação (GFAP e VIM dos animais com cinomose com e sem infiltração inflamatória da substância branca do cerebelo. O aumento da imunorreatividade dos astrócitos para a GFAP e a reexpressão de VIM nas áreas lesionais indicam o envolvimento astrocitário na resposta do tecido nervoso às lesões desmielinizantes induzidas pelo vírus da cinomose (CDV no SNC.Considering that many aspects involved in the pathogenesis of the central nervous system (CNS demyelinating diseases are still poorly understood and that astrocytes seem to mediate such processes, this study analyzed the participation of astrocytes in the demyelinating processes of CNS by using

[A young woman with central facial nerve palsy].

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Broere, Christiaan M; de Witte, B R René; Claes, J F H M Franka

2014-01-01

The distinction between central and peripheral facial nerve palsy can be difficult but is very important for the workup and treatment. A tumefactive demyelinating lesion (TDL) is a rare condition that can sometimes cause diagnostic difficulties due to its similarity to a brain tumour. We present a 20-year-old female patient who visited her GP with a discrete right-sided drooping corner of her mouth. The GP started treatment with oral glucorticoids because of presumed Bell's palsy and referred her to the neurology outpatient clinic. Repeated neurological examination showed central facial palsy on the right side of the face. An MRI study of the brain revealed a single large contrast-enhanced abnormality in the left hemisphere that was diagnosed as TDL after exclusion of other causes. In view of the limited number of clinical symptoms, an expectative policy was conducted. The patient recovered spontaneously and repeated MRI studies showed partial regression of TDL. TDL is often considered to be a first presentation of multiple sclerosis. Accurate analysis with MRI can help in making a diagnosis without the need for a biopsy.

Avaliação da atividade locomotora após indução local de desmielinização tóxica no tronco encefálico de ratos Wistar Evaluation of locomotor activity after a local induction of toxic demyelination in the brainstem of Wistar rats

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Eduardo Fernandes Bondan

2006-06-01

Full Text Available Lesões desmielinizantes induzidas pelo gliotóxico brometo de etídio (BE têm sido estudadas com o objetivo de permitir a compreensão do limitado processo de reparo mielínico no sistema nervoso central, bem como avaliar estratégias terapêuticas no sentido de acelerar a reconstrução das bainhas de mielina perdidas. Muito embora estudos eletrofisiológicos correlacionando situações de desmielinização e remielinização experimental sejam bem estabelecidos, os efeitos comportamentais não têm sido adequadamente investigados. Neste estudo, foram analisadas ultra-estruturalmente as lesões desmielinizantes e a atividade locomotora de ratos submetidos à indução focal de desmielinização pelo modelo do BE na superfície ventral do tronco encefálico, mediante observação de sua movimentação e controle motor durante a travessia de uma trave elevada de madeira (beam walking test. Foi observada a ocorrência de deficiências locomotoras até 31 dias pós-injeção de BE, constatando-se ainda que a subseqüente remielinização estava relacionada com o retorno da função perdida.Ethidium-bromide (EB - induced lesions have been used to investigate the incomplete remyelination in the central nervous system, as well as to evaluate therapeutic strategies to accelerate the reconstruction of the lost myelin sheaths. Although many electrophysiologic studies were performed in situations of experimental demyelination and remyelination, their behavioural effects have not been properly analyzed. In this study, we investigated ultrastructurally the EB - demyelinating lesions as well as the locomotor activity of rats during the beam walking test after a focal induction of demyelination using the EB model in the ventral surface of the brainstem. It was observed the occurrence of locomotor deficits until 31 days post-injection, as well as that subsequent remyelination was related to the return of the lost function.

Drug-induced liver injury due to antimicrobials, central nervous system agents, and nonsteroidal anti-inflammatory drugs.

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Devarbhavi, Harshad; Andrade, Raúl J

2014-05-01

Antimicrobial agents including antituberculosis (anti-TB) agents are the most common cause of idiosyncratic drug-induced liver injury (DILI) and drug-induced liver failure across the world. Better molecular and genetic biomarkers are acutely needed to help identify those at risk of liver injury particularly for those needing antituberculosis therapy. Some antibiotics such as amoxicillin-clavulanate and isoniazid consistently top the lists of agents in retrospective and prospective DILI databases. Central nervous system agents, particularly antiepileptics, account for the second most common class of agents implicated in DILI registries. Hepatotoxicity from older antiepileptics such as carbamazepine, phenytoin, and phenobarbital are often associated with hypersensitivity features, whereas newer antiepileptic drugs have a more favorable safety profile. Antidepressants and nonsteroidal anti-inflammatory drugs carry very low risk of significant liver injury, but their prolific use make them important causes of DILI. Early diagnosis and withdrawal of the offending agent remain the mainstays of minimizing hepatotoxicity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Spinal cord involvement in Balo's concentric sclerosis

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Kreft, Karim L.; Mellema, S. Jouke; Hintzen, Rogier Q.

2009-01-01

We present a patient with a history of myelitis, who had a steroid refractory attack of CNS inflammatory demyelinating disease that developed into cerebral concentric sclerosis of Balo after plasma exchange. The acute inflammatory disease involved the spinal cord, a phenomenon rarely demonstrated.

1H-MRS for the diagnosis of acute disseminated encephalomyelitis: insight into the acute-disease stage

International Nuclear Information System (INIS)

Ben Sira, Liat; Miller, Elka; Artzi, Moran; Fattal-Valevski, Aviva; Constantini, Shlomi; Ben Bashat, Dafna

2010-01-01

Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder of the central nervous system (CNS). Differentiating ADEM from other inflammatory disorders, such as multiple sclerosis, is not always conclusive using conventional MRI. To evaluate longitudinal magnetic resonance spectroscopy (MRS) changes that distinguish ADEM from other inflammatory disorders. MRI/MRS scans were performed in seven patients with ADEM during the acute and chronic phases of the disease. Partial recovery was detected between the acute and chronic phases in choline/creatine ratio. Major elevation of lipids and reduction in myo-inositol/creatine ratio was detected in all patients during the acute phase, followed by a reduction in lipids peak and elevation above normal in myo-inositol/creatine ratio during the chronic phase. Consistent and unique MRS changes in metabolite ratios between the acute and chronic presentations of the disease were found. To the best of our knowledge, these patterns have not been described in other inflammatory disorders and might assist in the early diagnosis of ADEM. (orig.)

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

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Binyamin O

2015-11-01

Full Text Available Orli Binyamin,1,* Liraz Larush,2,* Kati Frid,1 Guy Keller,1 Yael Friedman-Levi,1 Haim Ovadia,1 Oded Abramsky,1 Shlomo Magdassi,2 Ruth Gabizon1 1Department of Neurology, The Agnes Ginges Center of Human Neurogenetics, Hadassah University Hospital, 2Casali Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel *These authors contributed equally to this work Abstract: Multiple sclerosis (MS is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO, denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE, an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration. Keywords: nanodrops, PSO, EAE, oxidative stress, neurodegeneration

Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation.

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Bansagi, Boglarka; Phan, Vietxuan; Baker, Mark R; O'Sullivan, Julia; Jennings, Matthew J; Whittaker, Roger G; Müller, Juliane S; Duff, Jennifer; Griffin, Helen; Miller, James A L; Gorman, Grainne S; Lochmüller, Hanns; Chinnery, Patrick F; Roos, Andreas; Swan, Laura E; Horvath, Rita

2018-05-22

To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog ( PTEN ), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice. We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Will the real multiple sclerosis please stand up?

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Stys, P.K.; Zamponi, G.W.; van Minnen, J.; Geurts, J.J.G.

2012-01-01

Multiple sclerosis (MS) is considered to be an autoimmune, inflammatory disease of the CNS. In most patients, the disease follows a relapsing - remitting course and is characterized by dynamic inflammatory demyelinating lesions in the CNS. Although on the surface MS may appear consistent with a

Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model.

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Xiujuan Zhang

Full Text Available Multiple sclerosis (MS, characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE, a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression.

A bidirectional association between the gut microbiota and CNS disease in a biphasic murine model of multiple sclerosis.

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Colpitts, Sara L; Kasper, Eli J; Keever, Abigail; Liljenberg, Caleb; Kirby, Trevor; Magori, Krisztian; Kasper, Lloyd H; Ochoa-Repáraz, Javier

2017-11-02

The gut microbiome plays an important role in the development of inflammatory disease as shown using experimental models of central nervous system (CNS) demyelination. Gut microbes influence the response of regulatory immune cell populations in the gut-associated lymphoid tissue (GALT), which drive protection in acute and chronic experimental autoimmune encephalomyelitis (EAE). Recent observations suggest that communication between the host and the gut microbiome is bidirectional. We hypothesized that the gut microbiota differs between the acute inflammatory and chronic progressive stages of a murine model of secondary-progressive multiple sclerosis (SP-MS). This non-obese diabetic (NOD) model of EAE develops a biphasic pattern of disease that more closely resembles the human condition when transitioning from relapsing-remitting (RR)-MS to SP-MS. We compared the gut microbiome of NOD mice with either mild or severe disease to that of non-immunized control mice. We found that the mice which developed a severe secondary form of EAE harbored a dysbiotic gut microbiome when compared with the healthy control mice. Furthermore, we evaluated whether treatment with a cocktail of broad-spectrum antibiotics would modify the outcome of the progressive stage of EAE in the NOD model. Our results indicated reduced mortality and clinical disease severity in mice treated with antibiotics compared with untreated mice. Our findings support the hypothesis that there are reciprocal effects between experimental CNS inflammatory demyelination and modification of the microbiome providing a foundation for the establishment of early therapeutic interventions targeting the gut microbiome that could potentially limit disease progression.

Lipidomics: the function of vital lipids in embryogenesis preventing autism spectrum disorders, treating sterile inflammatory diatheses with a lymphopoietic central nervous system component.

Science.gov (United States)

Tallberg, Thomas; Dabek, Jan; Hallamaa, Raija; Atroshi, Faik

2011-01-01

The central role performed by billions of vital central nervous system (CNS) lipids "lipidomics" in medical physiology is usually overlooked. A metabolic deficiency embracing these vital lipids can form the aetiology for a variety of diseases. CNS lipids regulate embryogenesis, cell induction, mental balance by preventing autism spectrum disorders, depression, burn-out syndromes like posttraumatic stress disease PTSD, by guarding normal immunity, treating sterile inflammatory diatheses with a titanium containing lymphopoietic CNS lipid component. The propaganda driving for unphysiological fat-free diets is dangerous and can cause serious health problems for a whole generation. This article presents a broad list of various mental and motor bodily functions of which the healthy function depends on these vital CNS lipids. A rigorous fat-free diet can provoke these metabolic lipid deficiencies but they can fortunately be compensated by dietary supplementation, but not by pharmacologic treatment.

TLR3 signaling is either protective or pathogenic for the development of Theiler's virus-induced demyelinating disease depending on the time of viral infection

Directory of Open Access Journals (Sweden)

Jin Young-Hee

2011-12-01

Full Text Available Abstract Background We have previously shown that toll-like receptor 3 (TLR3-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler's murine encephalomyelitis virus (TMEV infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. Methods SJL/J and B6;129S-Tlr3tm1Flv/J (TLR3KO-B6 mice, and TLR3KO-SJL mice that TLR3KO-B6 mice were backcrossed to SJL/J mice for 6 generations were infected with Theiler's murine encephalomyelitis virus (2 × 105 PFU with or without treatment with 50 μg of poly IC. Cytokine production and immune responses in the CNS and periphery of infected mice were analyzed. Results We investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. TLR3KO-B6 mice did not develop demyelinating disease although they displayed elevated viral loads in the CNS. However, TLR3KO-SJL mice displayed increased viral loads and cellular infiltration in the CNS, accompanied by exacerbated development of demyelinating disease, compared to the normal littermate mice. Late, but not early, anti-viral CD4+ and CD8+ T cell responses in the CNS were compromised in TLR3KO-SJL mice. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas such activation after viral infection restrained disease development. Activation of TLR3 signaling prior to viral infection hindered the induction of protective IFN-γ-producing CD4+ and CD8+ T cell populations. In contrast, activation of these signals after viral infection improved the induction of IFN-γ-producing CD4+ and CD8+ T cells. In addition, poly IC-pretreated mice displayed elevated PDL-1 and

Combined treatment with ribavirin and tiazofurin attenuates response of glial cells in experimental autoimmune encephalomyelitis

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Nedeljković Nadežda

2012-01-01

Full Text Available Experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a human inflammatory and demyelinating disease. Microglia and astrocytes are glial cells of the central nervous system (CNS that play a dual role in MS and EAE pathology. The aim of this study was to examine the effect of combined treatment with two nucleoside analogues, ribavirin and tiazofurin, on microglia and astrocytes in actively induced EAE. Therapeutic treatment with a combination of these two nucleoside analogues reduced disease severity, mononuclear cell infiltration and demyelination. The obtained histological results indicate that ribavirin and tiazofurin changed activated microglia into an inactive type and attenuated astrocyte reactivity at the end of the treatment period. Since reduction of reactive microgliosis and astrogliosis correlated with EAE suppression, the present study also suggests that the obtained beneficial effect of ribavirin and tiazofurin could be a consequence of their action inside as well as outside the CNS. [Acknowledgments. This work was supported by the Serbian Ministry of Education and Science, Project No: III41014.

Human induced pluripotent stem cells differentiation into oligodendrocyte progenitors and transplantation in a rat model of optic chiasm demyelination.

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Alireza Pouya

Full Text Available BACKGROUND: This study aims to differentiate human induced pluripotent stem cells (hiPSCs into oligodendrocyte precursors and assess their recovery potential in a demyelinated optic chiasm model in rats. METHODOLOGY/PRINCIPAL FINDINGS: We generated a cell population of oligodendrocyte progenitors from hiPSCs by using embryoid body formation in a defined medium supplemented with a combination of factors, positive selection and mechanical enrichment. Real-time polymerase chain reaction and immunofluorescence analyses showed that stage-specific markers, Olig2, Sox10, NG2, PDGFRα, O4, A2B5, GalC, and MBP were expressed following the differentiation procedure, and enrichment of the oligodendrocyte lineage. These results are comparable with the expression of stage-specific markers in human embryonic stem cell-derived oligodendrocyte lineage cells. Transplantation of hiPSC-derived oligodendrocyte progenitors into the lysolecithin-induced demyelinated optic chiasm of the rat model resulted in recovery from symptoms, and integration and differentiation into oligodendrocytes were detected by immunohistofluorescence staining against PLP and MBP, and measurements of the visual evoked potentials. CONCLUSIONS/SIGNIFICANCE: These results showed that oligodendrocyte progenitors generated efficiently from hiPSCs can be used in future biomedical studies once safety issues have been overcome.

Lipidomics: The Function of Vital Lipids in Embryogenesis Preventing Autism Spectrum Disorders, Treating Sterile Inflammatory Diatheses with a Lymphopoietic Central Nervous System Component

Directory of Open Access Journals (Sweden)

Thomas Tallberg

2011-01-01

Full Text Available The central role performed by billions of vital central nervous system (CNS lipids “lipidomics” in medical physiology is usually overlooked. A metabolic deficiency embracing these vital lipids can form the aetiology for a variety of diseases. CNS lipids regulate embryogenesis, cell induction, mental balance by preventing autism spectrum disorders, depression, burn-out syndromes like posttraumatic stress disease PTSD, by guarding normal immunity, treating sterile inflammatory diatheses with a titanium containing lymphopoietic CNS lipid component. The propaganda driving for unphysiological fat-free diets is dangerous and can cause serious health problems for a whole generation. This article presents a broad list of various mental and motor bodily functions of which the healthy function depends on these vital CNS lipids. A rigorous fat-free diet can provoke these metabolic lipid deficiencies but they can fortunately be compensated by dietary supplementation, but not by pharmacologic treatment.

[Correlation between dental pulp demyelination degree and pain visual analogue scale scores data under acute and chronic pulpitis].

Science.gov (United States)

Korsantiia, N B; Davarashvili, X T; Gogiashvili, L E; Mamaladze, M T; Tsagareli, Z G; Melikadze, E B

2013-05-01

The aim of study is the analysis of pulp nerve fibers demyelination degree and its relationship with Visual Analogue Scale (VAS) score that may be measured as objective criteria. Material and methods of study. Step I: electron micrografs of dental pulp simples with special interest of myelin structural changes detected in 3 scores system, obtained from 80 patients, displays in 4 groups: 1) acute and 2) chronic pulpitis without and with accompined systemic deseases, 20 patients in each group. Dental care was realized in Kutaisi N1 Dental clinic. Step II - self-reported VAS used for describing dental pain. All data were performed by SPSS 10,0 version statistics including Spearmen-rank and Mann-Whitny coefficients for examine the validity between pulp demyelination degree and pain intensity in verbal, numbered and box scales. Researched Data were shown that damaged myelin as focal decomposition of membranes and Schwann cells hyperthrophia correspond with acute dental pain intensity as Spearman index reported in VAS numbered Scales, myelin and axoplasm degeneration as part of chronic gangrenous pulpitis disorders are in direct correlation with VAS in verbal, numbered and behavioral Rating Scales. In fact, all morphological and subjective data, including psychomotoric assessment of dental painin pulpitis may be used in dental practice for evaluation of pain syndrome considered personal story.

Demyeliniserende sygdom hos børn med akutte neurologiske symptomer

DEFF Research Database (Denmark)

Olofsson, Isa Amalie; Skov, Liselotte; Miranda, Maria Jose

2015-01-01

Demyelinating diseases in children is a broad group of illnesses, which affect the central nervous system. Demyelinating diseases can be monophasic or chronic and comprise acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, multiple sclerosis and neuromyelitis optica...

Fibronectin aggregation in multiple sclerosis lesions impairs remyelination

NARCIS (Netherlands)

Stoffels, J.M.J.; de Jonge, J.C.; Stancic, M.; Nomden, A.; van Strien, M.E.; Ma, D.; Siskova, Z.; Maier, O.; Ffrench-Constant, C.; Franklin, R.J.M.; Hoekstra, D.; Zhao, C.; Baron, W.

2013-01-01

Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of remyelination is likely mediated by many factors, including changes in the

Fibronectin aggregation in multiple sclerosis lesions impairs remyelination

NARCIS (Netherlands)

Stoffels, Josephine M. J.; de Jonge, Jenny C.; Stancic, Mirjana; Nomden, Anita; van Strien, Miriam E.; Ma, Dan; Siskova, Zuzana; Maier, Olaf; Ffrench-Constant, Charles; Franklin, Robin J. M.; Hoekstra, Dick; Zhao, Chao; Baron, Wia

Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of remyelination is likely mediated by many factors, including changes in the

Bone Morphogenetic Protein Signaling and Olig1/2 Interact to Regulate the Differentiation and Maturation of Adult Oligodendrocyte Precursor Cells

OpenAIRE

Cheng, Xiaoxin; Wang, Yaping; He, Qian; Qiu, Mengsheng; Whittemore, Scott R.; Cao, Qilin

2007-01-01

Promotion of remyelination is an important therapeutic strategy for the treatment of the demyelinating neurological disorders. Adult oligodendrocyte precursor cells (OPCs), which normally reside quiescently in the adult central nervous system (CNS), become activated and proliferative after demyelinating lesions. However, the extent of endogenous remyelination is limited because of the failure of adult OPCs to mature into myelinating oligodendrocytes (OLs) in the demyelinated CNS. Understandin...

Demyeliniserende sygdom hos børn med akutte neurologiske symptomer

DEFF Research Database (Denmark)

Olofsson, Isa Amalie; Skov, Liselotte; Miranda, Maria Jose

2015-01-01

Demyelinating diseases in children is a broad group of illnesses, which affect the central nervous system. Demyelinating diseases can be monophasic or chronic and comprise acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, multiple sclerosis and neuromyelitis optica. Demye...

High-fat diet feeding differentially affects the development of inflammation in the central nervous system.

Science.gov (United States)

Guillemot-Legris, Owein; Masquelier, Julien; Everard, Amandine; Cani, Patrice D; Alhouayek, Mireille; Muccioli, Giulio G

2016-08-26

Obesity and its associated disorders are becoming a major health issue in many countries. The resulting low-grade inflammation not only affects the periphery but also the central nervous system. We set out to study, in a time-dependent manner, the effects of a high-fat diet on different regions of the central nervous system with regard to the inflammatory tone. We used a diet-induced obesity model and compared at several time-points (1, 2, 4, 6, 8, and 16 weeks) a group of mice fed a high-fat diet with its respective control group fed a standard diet. We also performed a large-scale analysis of lipids in the central nervous system using HPLC-MS, and we then tested the lipids of interest on a primary co-culture of astrocytes and microglial cells. We measured an increase in the inflammatory tone in the cerebellum at the different time-points. However, at week 16, we evidenced that the inflammatory tone displayed significant differences in two different regions of the central nervous system, specifically an increase in the cerebellum and no modification in the cortex for high-fat diet mice when compared with chow-fed mice. Our results clearly suggest region-dependent as well as time-dependent adaptations of the central nervous system to the high-fat diet. The differences in inflammatory tone between the two regions considered seem to involve astrocytes but not microglial cells. Furthermore, a large-scale lipid screening coupled to ex vivo testing enabled us to identify three classes of lipids-phosphatidylinositols, phosphatidylethanolamines, and lysophosphatidylcholines-as well as palmitoylethanolamide, as potentially responsible for the difference in inflammatory tone. This study demonstrates that the inflammatory tone induced by a high-fat diet does not similarly affect distinct regions of the central nervous system. Moreover, the lipids identified and tested ex vivo showed interesting anti-inflammatory properties and could be further studied to better characterize

Disease: H01719 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available sease include demyelinating, inflammatory, toxic, nutritional, compressive, infiltrative, hereditary, trauma...09] Linezolid [DR:D00947] Amiodarone [DR:D00636] ... Corticosteroids Mecobalamin [DR:D03246] (for nutrition

ABCD1 dysfunction alters white matter microvascular perfusion

DEFF Research Database (Denmark)

Lauer, Arne; Da, Xiao; Hansen, Mikkel Bo

2017-01-01

Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability...... of the blood–brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic reson- ance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased...... capillary flow heterogeneity in asymptom- atic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow hetero...

Neuroprotective effect of transplanted human embryonic stem cell-derived neural precursors in an animal model of multiple sclerosis.

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Michal Aharonowiz

Full Text Available BACKGROUND: Multiple sclerosis (MS is an immune mediated demyelinating disease of the central nervous system (CNS. A potential new therapeutic approach for MS is cell transplantation which may promote remyelination and suppress the inflammatory process. METHODS: We transplanted human embryonic stem cells (hESC-derived early multipotent neural precursors (NPs into the brain ventricles of mice induced with experimental autoimmune encephalomyelitis (EAE, the animal model of MS. We studied the effect of the transplanted NPs on the functional and pathological manifestations of the disease. RESULTS: Transplanted hESC-derived NPs significantly reduced the clinical signs of EAE. Histological examination showed migration of the transplanted NPs to the host white matter, however, differentiation to mature oligodendrocytes and remyelination were negligible. Time course analysis of the evolution and progression of CNS inflammation and tissue injury showed an attenuation of the inflammatory process in transplanted animals, which was correlated with the reduction of both axonal damage and demyelination. Co-culture experiments showed that hESC-derived NPs inhibited the activation and proliferation of lymph node-derived T cells in response to nonspecific polyclonal stimuli. CONCLUSIONS: The therapeutic effect of transplantation was not related to graft or host remyelination but was mediated by an immunosuppressive neuroprotective mechanism. The attenuation of EAE by hESC-derived NPs, demonstrated here, may serve as the first step towards further developments of hESC for cell therapy in MS.

Global and 3D spatial assessment of neuroinflammation in rodent models of Multiple Sclerosis.

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Shashank Gupta

Full Text Available Multiple Sclerosis (MS is a progressive autoimmune inflammatory and demyelinating disease of the central nervous system (CNS. T cells play a key role in the progression of neuroinflammation in MS and also in the experimental autoimmune encephalomyelitis (EAE animal models for the disease. A technology for quantitative and 3 dimensional (3D spatial assessment of inflammation in this and other CNS inflammatory conditions is much needed. Here we present a procedure for 3D spatial assessment and global quantification of the development of neuroinflammation based on Optical Projection Tomography (OPT. Applying this approach to the analysis of rodent models of MS, we provide global quantitative data of the major inflammatory component as a function of the clinical course. Our data demonstrates a strong correlation between the development and progression of neuroinflammation and clinical disease in several mouse and a rat model of MS refining the information regarding the spatial dynamics of the inflammatory component in EAE. This method provides a powerful tool to investigate the effect of environmental and genetic forces and for assessing the therapeutic effects of drug therapy in animal models of MS and other neuroinflammatory/neurodegenerative disorders.

Role of Therapeutic Plasma Exchange in Treatment of Tumefactive Multiple Sclerosis-Associated Low CD4 and CD8 Levels

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Kristen Lew

2016-08-01

Full Text Available We report a 35-year-old healthy male who developed central nervous system inflammatory demyelinating disease consistent with tumefactive multiple sclerosis. About 2 weeks after onset of symptoms and prior to initiation of therapy, the patient had lymphopenia and low CD4 and CD8 levels. His lymphocyte count was 400 cells/µl (850–3,900 cells/µl, CD4 was 193 cells/µl (490–1,740 cells/µl and CD8 was 103 cells/µl (180–1,170 cells/µl. He was treated with intravenous methylprednisolone followed by therapeutic plasma exchange, the levels of CD4 and CD8 normalized, and ultimately, he recovered completely.

Magnetic resonance imaging of nerve root inflammation in the Guillain-Barre syndrome

International Nuclear Information System (INIS)

Perry, J.R.; Fung, A.; Poon, P.; Bayer, N.

1994-01-01

We report gadolinium-enhancing nerve root lesions in a 52-year-old man with typical Guillain-Barre syndrome (GBS). This enhancement correlates well with the perineurial inflammatory and demyelinating processes known to characterize GBS and other inflammatory neuropathies. MRI should enable further exploration of patterns of disease in GBS and, with further study, perhaps assist in evaluating therapy. (orig.)

Magnetic resonance imaging of nerve root inflammation in the Guillain-Barre syndrome

Energy Technology Data Exchange (ETDEWEB)

Perry, J.R. [St. Michael`s Hospital, Toronto, ON (Canada). Div. of Neurology; Fung, A. [St. Michael`s Hospital, Toronto, ON (Canada). Div. of Radiology; Poon, P. [St. Michael`s Hospital, Toronto, ON (Canada). Div. of Radiology; Bayer, N. [St. Michael`s Hospital, Toronto, ON (Canada). Div. of Neurology

1994-02-01

We report gadolinium-enhancing nerve root lesions in a 52-year-old man with typical Guillain-Barre syndrome (GBS). This enhancement correlates well with the perineurial inflammatory and demyelinating processes known to characterize GBS and other inflammatory neuropathies. MRI should enable further exploration of patterns of disease in GBS and, with further study, perhaps assist in evaluating therapy. (orig.)

The choroid plexus response to a repeated peripheral inflammatory stimulus

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Palha Joana A

2009-11-01

Full Text Available Abstract Background Chronic systemic inflammation triggers alterations in the central nervous system that may relate to the underlying inflammatory component reported in neurodegenerative disorders such as multiple sclerosis and Alzheimer's disease. However, it is far from being understood whether and how peripheral inflammation contributes to induce brain inflammatory response in such illnesses. As part of the barriers that separate the blood from the brain, the choroid plexus conveys inflammatory immune signals into the brain, largely through alterations in the composition of the cerebrospinal fluid. Results In the present study we investigated the mouse choroid plexus gene expression profile, using microarray analyses, in response to a repeated inflammatory stimulus induced by the intraperitoneal administration of lipopolysaccharide every two weeks for a period of three months; mice were sacrificed 3 and 15 days after the last lipopolysaccharide injection. The data show that the choroid plexus displays a sustained response to the repeated inflammatory stimuli by altering the expression profile of several genes. From a total of 24,000 probes, 369 are up-regulated and 167 are down-regulated 3 days after the last lipopolysaccharide injection, while at 15 days the number decreases to 98 and 128, respectively. The pathways displaying the most significant changes include those facilitating entry of cells into the cerebrospinal fluid, and those participating in the innate immune response to infection. Conclusion These observations contribute to a better understanding of the brain response to peripheral inflammation and pave the way to study their impact on the progression of several disorders of the central nervous system in which inflammation is known to be implicated.

Combination Treatment of C16 Peptide and Angiopoietin-1 Alleviates Neuromyelitis Optica in an Experimental Model

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Yuanyuan Zhang

2018-01-01

Full Text Available Neuromyelitis optica (NMO is an autoimmune inflammatory demyelinating disease that mainly affects the spinal cord and optic nerve, causing blindness and paralysis in some individuals. Moreover, NMO may cause secondary complement-dependent cytotoxicity (CDC, leading to oligodendrocyte and neuronal damage. In this study, a rodent NMO model, showing typical NMO pathogenesis, was induced with NMO-IgG from patient serum and human complement. We then tested whether the combination of C16, an αvβ3 integrin-binding peptide, and angiopoietin-1 (Ang1, a member of the endothelial growth factor family, could alleviate NMO in the model. Our results demonstrated that this combination therapy significantly decreased disease severity, inflammatory cell infiltration, secondary demyelination, and axonal loss, thus reducing neural death. In conclusion, our study suggests a possible treatment that can relieve progressive blindness and paralysis in an animal model of NMO through improvement of the inflammatory milieu.

Experimental alkylmercurial poisoning in swine. Lesions in the peripheral and central nervous systems

Energy Technology Data Exchange (ETDEWEB)

Charlton, K M

1974-01-01

The effects of alkylmercurial poisoning were studied in 16 pigs poisoned with daily oral doses of a fungicide containing methylmercury 2, 3-dihydroxy propyl mercaptide and methylmercury acetate. Clinical signs included weakness, wobbling gait, blindness, recumbency and death. Microscopic studies of the peripheral nervous system revealed Wallerian degeneration in sensory fibers and neuronal degeneration in dorsal root ganglia. In the central nervous system, there were neuronal degeneration of ischemic type, glial degeneration, gliosis and necrosis of the media of meningeal arterioles. The last mentioned lesion was not extensive. The sequential development of lesions and the absence of segmental demyelination suggest that the primary lesion in the peripheral nervous system was neuronal-axonal degeneration rather than degeneration of the Schwann cell and myelin sheath. 25 references.

Natalizumab therapy of multiple sclerosis.

LENUS (Irish Health Repository)

Hutchinson, Michael

2012-02-01

Multiple sclerosis (MS) is the commonest disabling neurological disease of young and middle-aged adults affecting 1 million persons world wide. The illness begins with a relapsing-remitting MS course in 85%-90% of patients; the other 10%-15% have a primary progressive onset MS. Our current understanding is that MS is an autoimmune disorder with an inflammatory T-cell attack on myelin or some component of the oligodendrocyte--myelin structure. Relapses of disease activity result in plaques of demyelination with destruction of myelin and, to a lesser, extent axons. Lymphocytes within the central nervous system tissue recruit more cells leading to an inflammatory cascade that causes myelin damage, axonal disruption, and neuronal death. If the plaque occurs in a vocal area of the central nervous system then symptoms relating to that area result. However, magnetic resonance imaging shows that approximately 10 times more lesions occur in asymptomatic areas of the brain. Recovery from an initial relapse may appear relatively complete but persistent inflammation results in axonal injury and residual disability results. With time and accumulated lesion load, secondary degeneration of denuded axons results in the phase of secondary progressive MS usually 15-20 years after onset.

Central control of body temperature.

Science.gov (United States)

Morrison, Shaun F

2016-01-01

Central neural circuits orchestrate the behavioral and autonomic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response and behavioral states and in response to declining energy homeostasis. This review summarizes the central nervous system circuit mechanisms controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for thermogenesis. The activation of these thermoeffectors is regulated by parallel but distinct efferent pathways within the central nervous system that share a common peripheral thermal sensory input. The model for the neural circuit mechanism underlying central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation, for elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation, and for the discovery of novel therapeutic approaches to modulating body temperature and energy homeostasis.

Optical Coherence Tomography-A New Diagnostic Tool to Evaluate Axonal Degeneration in Multiple Sclerosis: A Review

Directory of Open Access Journals (Sweden)

Nilüfer Kale

2010-09-01

Full Text Available Multiple sclerosis is an inflammatory demyelinating disorder of the central nervous system with a wide spectrum of clinical signs and symptoms. Multiple sclerosis lesions have a predilection for the optic nerves, periventricular white matter, brainstem, spinal cord, and cerebellum. The mechanisms responsible for multiple sclerosis are complex and heterogeneous across patients and disease stages. No specific markers exist for the definite diagnosis and prognosis of multiple sclerosis. The afferent visual pathway, which extends from the retina to the primary visual cortex including the optic nerve, is one of the most commonly affected sites in multiple sclerosis (94-99%. Pathology of affected optic nerves exhibits inflammation, demyelination, gliosis, axonal injury, and thinning of the retinal nerve fiber layer (RNFL. The RNFL is composed of unmyelinated axons, and measuring RNFL thickness is a viable method to monitor axonal loss reflecting disease progression. Optical coherence tomography is a noninvasive and reproducible tool in assessing the impact of multiple sclerosis on the thickness of the RNFL. Assessment of the afferent visual pathway using clinical, imaging and electrophysiological methods provides insights into the pathophysiology of multiple sclerosis and may also serve a prognostic role in multiple sclerosis

Autoantibody-induced internalization of CNS AQP4 water channel and EAAT2 glutamate transporter requires astrocytic Fc receptor.

Science.gov (United States)

Hinson, Shannon R; Clift, Ian C; Luo, Ningling; Kryzer, Thomas J; Lennon, Vanda A

2017-05-23

Aquaporin-4 (AQP4) water channel-specific IgG distinguishes neuromyelitis optica (NMO) from multiple sclerosis and causes characteristic immunopathology in which central nervous system (CNS) demyelination is secondary. Early events initiating the pathophysiological outcomes of IgG binding to astrocytic AQP4 are poorly understood. CNS lesions reflect events documented in vitro following IgG interaction with AQP4: AQP4 internalization, attenuated glutamate uptake, intramyelinic edema, interleukin-6 release, complement activation, inflammatory cell recruitment, and demyelination. Here, we demonstrate that AQP4 internalization requires AQP4-bound IgG to engage an astrocytic Fcγ receptor (FcγR). IgG-lacking Fc redistributes AQP4 within the plasma membrane and induces interleukin-6 release. However, AQP4 endocytosis requires an activating FcγR's gamma subunit and involves astrocytic membrane loss of an inhibitory FcγR, CD32B. Interaction of the IgG-AQP4 complex with FcγRs triggers coendocytosis of the excitatory amino acid transporter 2 (EAAT2). Requirement of FcγR engagement for internalization of two astrocytic membrane proteins critical to CNS homeostasis identifies a complement-independent, upstream target for potential early therapeutic intervention in NMO.

Analgesic effect of the neuropeptide cortistatin in murine models of arthritic inflammatory pain.

Science.gov (United States)

Morell, Maria; Souza-Moreira, Luciana; Caro, Marta; O'Valle, Francisco; Forte-Lago, Irene; de Lecea, Luis; Gonzalez-Rey, Elena; Delgado, Mario

2013-05-01

To investigate the role of the antiinflammatory neuropeptide cortistatin in chronic pain evoked by joint inflammation. Thermal and mechanical hyperalgesia was evoked in mouse knee joints by intraplantar injection of tumor necrosis factor α and intraarticular infusion of Freund's complete adjuvant, and the analgesic effects of cortistatin, administered centrally, peripherally, and systemically, were assessed. In addition, the effects of cortistatin on the production of nociceptive peptides and the activation of pain signaling were assayed in dorsal root ganglion cultures and in inflammatory pain models. The role of endogenous cortistatin in pain sensitization and perpetuation of chronic inflammatory states was evaluated in cortistatin-deficient mice. Finally, the effect of noxious/inflammatory stimuli in the production of cortistatin by the peripheral nociceptive system was assayed in vitro and in vivo. Expression of cortistatin was observed in peptidergic nociceptors of the peripheral nociceptive system, and endogenous cortistatin was found to participate in the tuning of pain sensitization, especially in pathologic inflammatory conditions. Results showed that cortistatin acted both peripherally and centrally to reduce the tactile allodynia and heat hyperalgesia evoked by arthritis and peripheral tissue inflammation in mice, via mechanisms that were independent of its antiinflammatory action. These mechanisms involved direct action on nociceptive neurons and regulation of central sensitization. The analgesic effects of cortistatin in murine arthritic pain were linked to binding of the neuropeptide to somatostatin and ghrelin receptors, activation of the G protein subunit Gαi , impairment of ERK signaling, and decreased production of calcitonin gene-related peptide in primary nociceptors. These findings indicate that cortistatin is an antiinflammatory factor with potent analgesic effects that may offer a new approach to pain therapy in pathologic inflammatory

Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye.

Science.gov (United States)

Lin, Hui; Li, Wei; Dong, Nuo; Chen, Wensheng; Liu, Jing; Chen, Lelei; Yuan, Hongxia; Geng, Zhixin; Liu, Zuguo

2010-01-01

To investigate the morphology, distribution, and density of inflammatory cells in the corneal epithelium of aqueous tear-deficient dry eye. Thirty-two patients with non-Sjögren's syndrome (NSS) dry eye, 14 patients with Sjögren's syndrome (SS) dry eye, and 33 healthy volunteers were studied. In vivo laser scanning confocal microscopy was used to investigate both Langerhans cell (LCs) and leukocyte distribution and density in the peripheral and central corneal epithelium. LC morphology was also evaluated. Multifactor regression analysis assessed whether there is a correlation between clinical manifestations and inflammatory cell densities. LCs were present in both central (34.9 +/- 5.7 cells/mm(2)) and peripheral (90.7 +/- 8.2 cells/mm(2)) parts of the normal corneal epithelium. Moreover, LC density increased dramatically in the central corneal epithelium in patients with NSS (89.8 +/- 10.8 cells/mm(2)) and SS (127.9 +/- 23.7 cells/mm(2)). The ratio of LCs with obvious processes was much higher in patients with dry eye than in healthy volunteers. LC density also increased in peripheral corneal epithelium in patients with SS, but not in those with NSS. Leukocyte density in normal corneal epithelium was very low, whereas it increased in the central corneal epithelium (4.6 +/- 1.0 cells/mm(2)) in NSS and in both central (49.0 +/- 12.9 cells/mm(2)) and peripheral (84.2 +/- 36.8 cells/mm(2)) corneal epithelium in SS. Densities of LCs and leukocytes showed significant correlation with the severity found in clinical evaluation. The LC and leukocyte changes in the corneal epithelium suggest their involvement in aqueous tear-deficient dry eye pathophysiology. In vivo dynamic assessment of central corneal inflammatory cell density may serve as an indicator of dry eye severity and provide new insight for dry eye treatment.

MR imaging of central diabetes insipidus: a pictorial essay

International Nuclear Information System (INIS)

Shin, Ji Hoon; Lee, Ho Kyu; Choi, Choong Gon; Suh, Dae Chul; Kim, Chang Jin; Hong, Sung Kwan; Na, Dong Gyu

2001-01-01

Central diabetes insipidus (DI) can be the outcome of a number of diseases that affect the hypothalamic-neurohypophyseal axis. The causes of the condition can be classified as traumatic, inflammatory, or neoplastic. Traumatic causes include postoperative sella or transection of the pituitary stalk, while infectious or inflammatory causes include meningitis, lymphocytic hypophysitis, and granulomatous inflammations such as sarcoidosis and Wegener's granulomatosis. Various neoplastic conditions such as germinoma, Langerhans cell histiocytosis, metastasis, leukemic infiltration, lymphoma, teratoma, pituitary adenoma, craniopharyngioma, Rathke cleft cyst, hypothalamic glioma, and meningioma are also causes of central DI. In affected patients, careful analysis of these MR imaging features and correlation with the clinical manifestations can allow a more specific diagnosis, which is essential for treatment

L-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters.

Science.gov (United States)

Xue, Jinsong; Li, Hongyan; Deng, Xueyang; Ma, Zhanqiang; Fu, Qiang; Ma, Shiping

2015-07-01

L-Menthone (MTN) is a Chinese old remedy extracted from the genus Mentha. It has been widely used as a cooling agent and a counterirritant for pain relief, although its antidepressant-like effects have not yet been reported. The present study was designed to investigate whether MTN confers an antidepressant-like effect in mice exposed to unpredictable chronic mild stress (UCMS) and to explore its potential mechanisms. The effects of MTN on mouse behavioral changes were investigated in our study. We determined the levels of the nucleotide binding, oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, inflammatory cytokines and neurotransmitters in the hippocampus of mice. Behavioral tests, including the sucrose preference test (SPT), open field test (OFT), forced swimming test (FST) and tail suspension test (TST) revealed that MTN (15 and 30mg/kg) treatments for 3weeks alleviated the depression symptoms of UCMS in mice. Mice receiving MTN treatments exhibited reduced levels of NLRP3 and caspase-1. Moreover, MTN treatments reversed the UCMS-induced alterations in the concentrations of neurotransmitter norepinephrine (NE) and serotonin (5-HT) and inhibited the expression of pro-inflammatory cytokines (PIC) interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α in the hippocampus of mice. Taken together, our findings suggested that MTN may play a potential antidepressant-like role in the UCMS mouse model by regulating the NLRP3 inflammasome and mediating inflammatory cytokines and central neurotransmitters, which together provide insight towards the development of novel therapeutic treatments for depression. Copyright © 2015 Elsevier Inc. All rights reserved.

Multiple Sclerosis and autoimmune diseases: clinical cases and review of the literature

Directory of Open Access Journals (Sweden)

A. Protti

2011-09-01

Full Text Available Multiple sclerosis (MS, the most frequent demyelinating disease in adults, is thought to be an autoimmune disease. Symptoms and signs observed in MS reflect lesions present mainly in the white matter of the central nervous system (CNS. The diagnosis remains difficult, at least concerning presenting symptoms, because of their low specificity. Diagnosis criteria are usually based on dissemination of signs in time and space, evoked potentials, findings of magnetic resonance imaging, results of cerebrospinal fluid examination, and the exclusion of other diagnosis possibly explaining the clinical signs. However, no clinical and paraclinical investigation can distinguish with certainity MS from other conditions such as autoimmune or inflammatory diseases predominantly affecting the central nervous system. These other disorders include systemic lupus erythematosus, antiphospholipid syndrome, Behcet disease, Sjogren syndrome, sarcoidosis and vasculitides. We present four clinical cases showing the difficulty in reaching a proper diagnosis...

Radionuclidr diagnosis of brain tumors, brain inflammatory and traumatic lesions

International Nuclear Information System (INIS)

Badmaev, K.N.; Mel'kishev, V.F.; Dement'ev, E.V.; Svetlova, N.L.

1982-01-01

A complex of problems of radionuclide diagnosis of central nervous system diseases including tumors, traumas, vascular lessons, inflammatory processes is considered. The principles, technique and results of radionuclide xintigraphy of a tumor, depending on its localization are given. Radioindication of brain tumours in the operation is given

Pro-inflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat

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Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua; Felder, Robert B.

2015-01-01

Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne pro-inflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating pro-inflammatory cytokines remain unclear. We hypothesized that pro-inflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of TNF-α (25 ng) or IL-1β (25 ng) into SFO increased mean blood pressure, heart rate and renal sympathetic nerve activity within 15–20 minutes, mimicking the response to systemically administered pro-inflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type 1 receptor (AT1R) blocker losartan (1 µg), angiotensin-converting enzyme (ACE) inhibitor captopril (1 µg) or cyclooxygenase (COX)-2 inhibitor NS-398 (2 µg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for ACE, AT1R, TNF-α and the p55 TNF-α receptor TNFR1, IL-1β and the IL-1R receptor, and COX-2 had increased in SFO, and mRNA for ACE, AT1R and COX-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for TNFR1 and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, co-localized with ACE, AT1R-like, COX-2 and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that pro-inflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation. PMID:25776070

Measurement of soluble CD59 in CSF in demyelinating disease: Evidence for an intrathecal source of soluble CD59.

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Zelek, Wioleta M; Watkins, Lewis M; Howell, Owain W; Evans, Rhian; Loveless, Sam; Robertson, Neil P; Beenes, Marijke; Willems, Loek; Brandwijk, Ricardo; Morgan, B Paul

2018-02-01

CD59, a broadly expressed glycosylphosphatidylinositol-anchored protein, is the principal cell inhibitor of complement membrane attack on cells. In the demyelinating disorders, multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), elevated complement protein levels, including soluble CD59 (sCD59), were reported in cerebrospinal fluid (CSF). We compared sCD59 levels in CSF and matched plasma in controls and patients with MS, NMOSD and clinically isolated syndrome (CIS) and investigated the source of CSF sCD59 and whether it was microparticle associated. sCD59 was quantified using enzyme-linked immunosorbent assay (ELISA; Hycult; HK374-02). Patient and control CSF was subjected to western blotting to characterise anti-CD59-reactive materials. CD59 was localised by immunostaining and in situ hybridisation. CSF sCD59 levels were double those in plasma (CSF, 30.2 ng/mL; plasma, 16.3 ng/mL). Plasma but not CSF sCD59 levels differentiated MS from NMOSD, MS from CIS and NMOSD/CIS from controls. Elimination of microparticles confirmed that CSF sCD59 was not membrane anchored. CSF levels of sCD59 are not a biomarker of demyelinating diseases. High levels of sCD59 in CSF relative to plasma suggest an intrathecal source; CD59 expression in brain parenchyma was low, but expression was strong on choroid plexus (CP) epithelium, immediately adjacent the CSF, suggesting that this is the likely source.

Anticarbohydrate antibodies as markers of inflammatory bowel disease in a Central European cohort.

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Malickova, Karin; Lakatos, Peter L; Bortlik, Martin; Komarek, Viktor; Janatkova, Ivana; Lukas, Milan

2010-02-01

The study discusses the role of antichitobioside carbohydrate antibody (ACCA), antilaminaribioside carbohydrate antibodies (ALCA), and antimannobioside carbohydrate antibodies (AMCA) in Central European patients with inflammatory bowel disease (IBD). Twohundred and seventy-two serum samples were used - 116 Crohn's disease (CD), 84 ulcerative colitis, and 72 healthy control samples. All samples were evaluated using enzyme-linked immunosorbent assay for the following four anticarbohydrate assays: ACCA, ALCA, AMCA, and anti-Saccharomyces cerevisiae antibodies (gASCA). gASCA antibodies showed the highest sensitivity (67%) for a CD diagnosis, followed by AMCA (31%), ACCA (27%), and ALCA (25%). Positivity of at least one of the four assays increased the overall sensitivity of antibody testing in CD up to 85.5%. Mean serum gASCA levels were significantly higher in CD patients who were younger at diagnosis and had a longer disease duration before blood sampling (PACCA, and ALCA) antibodies and CD location, behavior, age at onset, and disease duration was found; however, that sample size of some of our subgroups was probably too small to make firm conclusions on associations with all CD phenotypes. None of the assessed anticarbohydrate assays was predictive of colonic CD in patients in whom the distinction between CD and ulcerative colitis is not obvious using routine diagnostic methods. There was no relationship between the presence or concentration of anticarbohydrate antibodies and the inflammation measured by C-reactive protein levels. The use of a panel of anticarbohydrate antibodies may provide additional help in distinguishing IBD from non-IBD disease patterns. The addition of AMCA, ALCA, and ACCA assays as IBD serology markers improves the overall sensitivity of immunological examinations in IBD; however, anticarbohydrate assays are not helpful for predicting CD behavior.

MR imaging of central diabetes insipidus: a pictorial essay

Energy Technology Data Exchange (ETDEWEB)

Shin, Ji Hoon; Lee, Ho Kyu; Choi, Choong Gon; Suh, Dae Chul; Kim, Chang Jin; Hong, Sung Kwan [Ulsan University College of Medicine, Seoul (Korea, Republic of); Na, Dong Gyu [Sungkyunkwan University College of Medicine, Seoul (Korea, Republic of)

2001-12-01

Central diabetes insipidus (DI) can be the outcome of a number of diseases that affect the hypothalamic-neurohypophyseal axis. The causes of the condition can be classified as traumatic, inflammatory, or neoplastic. Traumatic causes include postoperative sella or transection of the pituitary stalk, while infectious or inflammatory causes include meningitis, lymphocytic hypophysitis, and granulomatous inflammations such as sarcoidosis and Wegener's granulomatosis. Various neoplastic conditions such as germinoma, Langerhans cell histiocytosis, metastasis, leukemic infiltration, lymphoma, teratoma, pituitary adenoma, craniopharyngioma, Rathke cleft cyst, hypothalamic glioma, and meningioma are also causes of central DI. In affected patients, careful analysis of these MR imaging features and correlation with the clinical manifestations can allow a more specific diagnosis, which is essential for treatment.

Transferability of results of cost utility analyses for biologicals in inflammatory conditions for Central and Eastern European countries.

Science.gov (United States)

Gulácsi, László; Rencz, Fanni; Péntek, Márta; Brodszky, Valentin; Lopert, Ruth; Hevér, Noémi V; Baji, Petra

2014-05-01

Several Central and Eastern European (CEE) countries require cost-utility analyses (CUAs) to support reimbursement formulary listing. However, CUAs informed by local evidence are often unavailable, and the cost-effectiveness of the several currently reimbursed biologicals is unclear. To estimate the cost-effectiveness as multiples of per capita GDP/quality adjusted life years (QALY) of four biologicals (infliximab, etanercept, adalimumab, golimumab) currently reimbursed in six CEE countries in six inflammatory rheumatoid and bowel disease conditions. Systematic literature review of published cost-utility analyses in the selected conditions, using the United Kingdom (UK) as reference country and with study selection criteria set to optimize the transfer of results to the CEEs. Prices in each CEE country were pro-rated against UK prices using purchasing power parity (PPP)-adjusted per capita GDP, and local GDP per capita/QALY ratios estimated. Central and Eastern European countries list prices were 144-333% higher than pro rata prices. Out of 85 CUAs identified by previous systematic literature reviews, 15 were selected as a convenience sample for estimating the cost-effectiveness of biologicals in the CEE countries in terms of per capita GDP/QALY. Per capita GDP/QALY values varied from 0.42 to 6.4 across countries and conditions (Bulgaria: 0.97-6.38; Czech Republic: 0.42-2.76; Hungary: 0.54-3.54; Poland: 0.59-3.90; Romania: 0.77-5.07; Slovakia: 0.55-3.61). While results must be interpreted with caution, calculating pro rata (cost-effective) prices and per capita GDP/QALY ratios based on CUAs can aid reimbursement decision-making in the absence of analyses using local data.

Painful tonic spasms and brainstem involvement in a patient with neuromyelitis optica spectrum disorder.

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Roman-Filip, Corina; Ungureanu, Aurelian; Cernuşcă-Miţaru, Mihaela

2016-01-01

Neuromyelitis optica (NMO) is an inflammatory-demyelinating disease of the central nervous system classically characterized by optic neuritis and severe myelitis. New diagnostic criteria defined neuromyelitis optica spectrum disorder as limited forms of NMO or diverse neurologic presentations in the presence of specific antiaquaporin-4 antibodies. We report the case of a 57-year-old woman admitted in our department for recurrent attacks of optic neuritis, tetraparesis with severe painful tonic spasms of the left limbs and brainstem involvement. Painful tonic spasms have been described as movement disorders associated with multiple sclerosis, but a growing number of reports describe them in cases of NMO. Copyright © 2015 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

The Urine Proteome Profile Is Different in Neuromyelitis Optica Compared to Multiple Sclerosis

DEFF Research Database (Denmark)

Nielsen, Helle H; Beck, Hans C; Kristensen, Lars P

2015-01-01

OBJECTIVES: Inflammatory demyelinating diseases of the CNS comprise a broad spectrum of diseases like neuromyelitis optica (NMO), NMO spectrum disorders (NMO-SD) and multiple sclerosis (MS). Despite clear classification criteria, differentiation can be difficult. We hypothesized that the urine...

EFNS guidelines for the use of intravenous immunoglobulin in treatment of neurological diseases: EFNS task force on the use of intravenous immunoglobulin in treatment of neurological diseases

DEFF Research Database (Denmark)

Elovaara, I.; Apostolski, S.; Doorn, P. van

2008-01-01

and consensus recommendations are given according to EFNS guidance regulations. The efficacy of IVIG has been proven in Guillain-Barre syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG...

Anti-inflammatory and antinociceptive activities of Solenostemon monostachyus aerial part extract in mice

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Jude Fiom Okokon

2016-04-01

Full Text Available Objective: Solenostemon monostachyus is used in traditional medicine for the treatment of various ailments such as ulcer, hypertension, pains and inflammatory diseases. Evaluation of anti-inflammatory and analgesic activities of S. monostachyus aerial parts was carried out to ascertain its uses in traditional medicine. Materials and Methods: The aerial parts of S. monostachyus was cold extracted by soaking the dried powdered material in ethanol. The aerial parts crude extract (75 –225 mg/kg of  S. monostachyus was investigated for analgesic and anti-inflammatory activities using various experimental models; acetic acid, formalin and thermal- induced pains models for analgesic study and carrageenin, egg albumin and xylene – induced edema models for anti-inflammatory investigation. Results: The extract caused a significant (pConclusion: The anti-inflammatory and analgesic effects of this plant may in part be mediated through the chemical constituents of the plant and the results of the analgesic action suggest central and peripheral mechanisms. The findings of this work confirm the ethno medical use of this plant to treat inflammatory conditions.

Multiple sclerosis: current immunological aspects

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Carlos Cuevas-García

2017-02-01

Full Text Available Multiple sclerosis is the most common inflammatory, chronic and degenerative condition of the central nervous system, and represents the first cause of disability in young adults. In Mexico, 11 to 20 out of every 100 000 people suffer from this disease. The causes of multiple sclerosis remain unknown, but several theories have been proposed on its origin: the interaction of environmental factors, viral infectious factors and genetic and immune susceptibility of each individual patient, which induce an autoimmune response and promote neuronal/axonal degeneration. In this review, the immune reaction main components and neurodegeneration present in multiple sclerosis are analyzed, as well as the inflammatory cascade associated with demyelination. Available treatments’ main purpose is to modulate aspects related to the adaptive immune response (B and T cells. The therapeutic challenge will be antigen-specific immune-tolerance induction, for example, with the use of tolerance protocols with peptides or DNA or nanoparticles vaccines. Future therapies should aim to control innate components (microglia, macrophages, astrocytes and to promote remyelination. To optimize the treatment, a combined therapeutic approach targeting the control of inflammatory and neurodegenerative components of the disease and monitoring of biomarkers will be necessary.

Analgesic and anti-inflammatory properties of the fruits of Vernonia anthelmintica (L Willd.

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Alok Pandey

2014-09-01

Full Text Available Objective: To evaluation of analgesic and anti-inflammatory properties of the fruits of Vernonia anthelmintica (L Willd. (V. anthelmintica. Method: Hot plate method in mice, acetic acid induced writhing response in mice, tail immersion test and carrageenan-induced paw edema in rats and cotton pellet induced granuloma in rats method were used for screening analgesic and anti-inflammatory properties of the fruit of V. anthelmintica (family: Asteraceae. Results: The result of the study showed that the ethanolic extract of V. anthelmintica (100 and 200 mg/kg body weight, p.o. fruits possed peripheral and central analgesic activity in animal model. The V. anthelmintica fruits extract showed in vivo anti-inflammatory activity on acute and chronic anti-inflammatory activity models in rats. Conclusions: On the basis of result it can be concluded that saponins, steroids, tannins and flavonoids are the major constituents that are present in the fruits of V. anthelmintica which may be responsible for its analgesic and anti-inflammatory activity.

The effect of triiodothyronine on maturation and differentiation of oligodendrocyte progenitor cells during remyelination following induced demyelination in male albino rat.

Science.gov (United States)

El-Tahry, H; Marei, H; Shams, A; El-Shahat, M; Abdelaziz, H; Abd El-Kader, M

2016-06-01

Demyelination was induced by two weeks cuprizone treatment. Rats of +ve control and triiodothyronine (T3) then received three subcutaneous injections of either saline or T3 day after day and sacrificed at the end of the third and fifth weeks. Animals in -ve control group received only standard rodent chow. After one week of cuprizone withdrawal the corpus callosum in +ve control and T3 treated rats was still demyelinated as revealed by MBP immunohistochemistry. The assay of PLP gene showed significant increase of T3 treated group compared to both the -ve control and +ve control groups. After three weeks, significant improvement in myelination was detected in T3-treated group compared to +ve control as detected by both MBP immunohistochemistry and electron microscopy. After one week of cuprizone withdrawal, PDGFRα positive cells and gene expression showed significant increase in +ve control and T3-treated groups as compared to -ve control with insignificant difference in between the former two groups. After three weeks of cuprizone withdrawal, PDGFRα positive cells in T3-treated and +ve control groups decreased to the control levels. These results suggest that T3 was effective in improving remyelination when administered during acute phase and might direct progenitor lineage toward oligodendrocytes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Uric acid in multiple sclerosis

NARCIS (Netherlands)

Koch, M; De Keyser, J

Peroxynitrite, a reactive oxidant formed by the reaction of nitric oxide with superoxide at sites of inflammation in multiple sclerosis (MS), is capable of damaging tissues and cells. Uric acid, a natural scavenger of peroxynitrite, reduces inflammatory demyelination in experimental allergic

MRA in inflammatory disorders of the central nervous system

International Nuclear Information System (INIS)

Felber, S.

2000-01-01

In this review, we discuss the diagnostic potential of time of flight (TOF) MRA and contrast enhanced (CE) MRA in inflammatory disorders of the meninges and the brain. Cerebrovascular complications are frequently observed during infectious meningoencepalitis. 3D TOF-MRA and CE-MRA are complementary for the detection of basal intracranial artery stenosis and septic cerebral vein and sinus thrombosis due to secondary vasculitis. MRA reveals stenosis and occlusion as indirect signs of vasculitis, whereas MRI shows the inflammation of the brain and meninges and occasionally the vessel wall, together with the ischemic or hemorrhagic complication. In case of septic emboli MRA can detect peripheral occlusions and 'mycotic' aneurysms. For the diagnosis of noninfectious vasculitides of the intracranial vessels, high resolution 3D TOF-MRA is superior to CE-MRA for the detection of multiloculated segmental stenoses. However, there are presently no prospective studies on the sensitivity and specificity of MRA for these indications. Therefore, only positive MRA results can directly influence clinical management. In case of normal MRA, confirmation by catheder angiography may still be required. (orig.) [de

X-ray microbeams: Tumor therapy and central nervous system research

International Nuclear Information System (INIS)

Dilmanian, F.A.; Qu, Y.; Liu, S.; Cool, C.D.; Gilbert, J.; Hainfeld, J.F.; Kruse, C.A.; Laterra, J.; Lenihan, D.; Nawrocky, M.M.; Pappas, G.; Sze, C.-I.; Yuasa, T.; Zhong, N.; Zhong, Z.; McDonald, J.W.

2005-01-01

Irradiation with parallel arrays of thin, planar slices of X-ray beams (microplanar beams, or microbeams) spares normal tissue, including the central nervous system (CNS), and preferentially damages tumors. The effects are mediated, at least in part, by the tissue's microvasculature that seems to effectively repair itself in normal tissue but fails to do so in tumors. Consequently, the therapeutic index of single-fraction unidirectional microbeam irradiations has been shown to be larger than that of single-fraction unidirectional unsegmented beams in treating the intracranial rat 9L gliosarcoma tumor model (9LGS) and the subcutaneous murine mammary carcinoma EMT-6. This paper presents results demonstrating that individual microbeams, or arrays of parallel ones, can also be used for targeted, selective cell ablation in the CNS, and also to induce demyelination. The results highlight the value of the method as a powerful tool for studying the CNS through selective cell ablation, besides its potential as a treatment modality in clinical oncology

Immune invasion of the central nervous system parenchyma and experimental allergic encephalomyelitis, but not leukocyte extravasation from blood, are prevented in macrophage-depleted mice

DEFF Research Database (Denmark)

Tran, E H; Hoekstra, K; van Rooijen, N

1998-01-01

role of peripheral macrophages in experimental allergic encephalomyelitis (EAE), a Th1-mediated demyelinating disease that serves as a an animal model for multiple sclerosis (MS), by their depletion using mannosylated liposome-encapsulated dichloromethylene diphosphonate (Cl2MDP). Here we describe....../J mice was abrogated by Cl2MDP-mnL treatment. CD4+ T cell and MHC II+ B220+ B cell extravasation from blood vessels and Th1 cytokine production were not inhibited. However, invasion of the central nervous system intraparenchymal tissues by lymphocytes, F4/80+, Mac-1+, and MOMA-1+ macrophages was almost...

Trigeminal Nerve Root Demyelination Not Seen in Six Horses Diagnosed with Trigeminal-Mediated Headshaking

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Veronica L. Roberts

2017-05-01

Full Text Available Trigeminal-mediated headshaking is an idiopathic neuropathic facial pain syndrome in horses. There are clinical similarities to trigeminal neuralgia, a neuropathic facial pain syndrome in man, which is usually caused by demyelination of trigeminal sensory fibers within either the nerve root or, less commonly, the brainstem. Our hypothesis was that the neuropathological substrate of headshaking in horses is similar to that of trigeminal neuralgia in man. Trigeminal nerves, nerve roots, ganglia, infraorbital, and caudal nasal nerves from horse abattoir specimens and from horses euthanized due to trigeminal-mediated headshaking were removed, fixed, and processed for histological assessment by a veterinary pathologist and a neuropathologist with particular experience of trigeminal neuralgia histology. No histological differences were detected between samples from horses with headshaking and those from normal horses. These results suggest that trigeminal-mediated headshaking may have a different pathological substrate from trigeminal neuralgia in man.

Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis

Science.gov (United States)

Locri, Filippo; Amato, Rosario; Marsili, Stefania; Rusciano, Dario; Bagnoli, Paola

2018-01-01

Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON) and is an initial symptom of multiple sclerosis (MS). Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC) loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG), were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM), a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro-FAG (nFAG®), a balanced mixture of fatty acids (FAs), counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role. PMID:29517994

Fatty Acids Dietary Supplements Exert Anti-Inflammatory Action and Limit Ganglion Cell Degeneration in the Retina of the EAE Mouse Model of Multiple Sclerosis

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Massimo Dal Monte

2018-03-01

Full Text Available Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON and is an initial symptom of multiple sclerosis (MS. Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG, were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM, a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro-FAG (nFAG®, a balanced mixture of fatty acids (FAs, counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role.

Implication of inflammatory signaling pathways in obesity-induced insulin resistance

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Jean-François eTANTI

2013-01-01

Full Text Available Obesity is characterized by the development of a low-grade chronic inflammatory state in different metabolic tissues including adipose tissue and liver. This inflammation develops in response to an excess of nutrient flux and is now recognized as an important link between obesity and insulin resistance. Several dietary factors like saturated fatty acids and glucose as well as changes in gut microbiota have been proposed as triggers of this metabolic inflammation through the activation of pattern-recognition receptors, including Toll-like receptors, inflammasome and NOD. The consequences are the production of pro-inflammatory cytokines and the recruitment of immune cells such as macrophages and T lymphocytes in metabolic tissues. Inflammatory cytokines activate several kinases like IKKbeta, mTOR/S6 kinase and MAP kinases as well as SOCS proteins that interfere with insulin signaling and action in adipocytes and hepatocytes. In this review, we summarize recent studies demonstrating that pattern recognition receptors and stress kinases are important integrators of metabolic and inflammatory stress signals in metabolic tissues leading to peripheral and central insulin resistance and metabolic dysfunction. We discuss recent data obtained with genetically modified mice and pharmacological approaches suggesting that these inflammatory pathways are potential novel pharmacological targets for the management of obesity-associated insulin resistance.

Multiple sclerosis and herpesvirus interaction

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Guilherme Sciascia do Olival

2013-09-01

Full Text Available Multiple sclerosis is the most common autoimmune inflammatory demyelinating disease of the central nervous system, and its etiology is believed to have both genetic and environmental components. Several viruses have already been implicated as triggers and there are several studies that implicate members of the Herpesviridae family in the pathogenesis of MS. The most important characteristic of these viruses is that they have periods of latency and exacerbations within their biological sanctuary, the central nervous system. The Epstein-Barr, cytomegalovirus, human herpesvirus 6 and human herpesvirus 7 viruses are the members that are most studied as being possible triggers of multiple sclerosis. According to evidence in the literature, the herpesvirus family is strongly involved in the pathogenesis of this disease, but it is unlikely that they are the only component responsible for its development. There are probably multiple triggers and more studies are necessary to investigate and define these interactions.

Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

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Esposito Emanuela

2011-04-01

Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

The Mitochondrial m-AAA Protease Prevents Demyelination and Hair Greying.

Science.gov (United States)

Wang, Shuaiyu; Jacquemyn, Julie; Murru, Sara; Martinelli, Paola; Barth, Esther; Langer, Thomas; Niessen, Carien M; Rugarli, Elena I

2016-12-01

The m-AAA protease preserves proteostasis of the inner mitochondrial membrane. It ensures a functional respiratory chain, by controlling the turnover of respiratory complex subunits and allowing mitochondrial translation, but other functions in mitochondria are conceivable. Mutations in genes encoding subunits of the m-AAA protease have been linked to various neurodegenerative diseases in humans, such as hereditary spastic paraplegia and spinocerebellar ataxia. While essential functions of the m-AAA protease for neuronal survival have been established, its role in adult glial cells remains enigmatic. Here, we show that deletion of the highly expressed subunit AFG3L2 in mature mouse oligodendrocytes provokes early-on mitochondrial fragmentation and swelling, as previously shown in neurons, but causes only late-onset motor defects and myelin abnormalities. In contrast, total ablation of the m-AAA protease, by deleting both Afg3l2 and its paralogue Afg3l1, triggers progressive motor dysfunction and demyelination, owing to rapid oligodendrocyte cell death. Surprisingly, the mice showed premature hair greying, caused by progressive loss of melanoblasts that share a common developmental origin with Schwann cells and are targeted in our experiments. Thus, while both neurons and glial cells are dependant on the m-AAA protease for survival in vivo, complete ablation of the complex is necessary to trigger death of oligodendrocytes, hinting to cell-autonomous thresholds of vulnerability to m-AAA protease deficiency.

Novel anti-inflammatory agents in COPD

DEFF Research Database (Denmark)

Loukides, Stelios; Bartziokas, Konstantinos; Vestbo, Jørgen

2013-01-01

Inflammation plays a central role in chronic obstructive pulmonary disease (COPD). COPD related inflammation is less responsive to inhaled steroids compared to asthma. There are three major novel anti-inflammatory approaches to the management of COPD. The first approach is phosphodiesterase...... on these strategies exist at the moment. A third potential approach involves novel agents whose mechanism of action is closely related to COPD mechanisms and pathophysiology. Such novel treatments are of great interest since they may treat both COPD and co-morbidities. Several novel agents are currently under...

Trigeminal Inflammatory Compression (TIC) injury induces chronic facial pain and susceptibility to anxiety-related behaviors.

Science.gov (United States)

Lyons, D N; Kniffin, T C; Zhang, L P; Danaher, R J; Miller, C S; Bocanegra, J L; Carlson, C R; Westlund, K N

2015-06-04

Our laboratory previously developed a novel neuropathic and inflammatory facial pain model for mice referred to as the Trigeminal Inflammatory Compression (TIC) model. Rather than inducing whole nerve ischemia and neuronal loss, this injury induces only slight peripheral nerve demyelination triggering long-term mechanical allodynia and cold hypersensitivity on the ipsilateral whisker pad. The aim of the present study is to further characterize the phenotype of the TIC injury model using specific behavioral assays (i.e. light-dark box, open field exploratory activity, and elevated plus maze) to explore pain- and anxiety-like behaviors associated with this model. Our findings determined that the TIC injury produces hypersensitivity 100% of the time after surgery that persists at least 21 weeks post injury (until the animals are euthanized). Three receptive field sensitivity pattern variations in mice with TIC injury are specified. Animals with TIC injury begin displaying anxiety-like behavior in the light-dark box preference and open field exploratory tests at week eight post injury as compared to sham and naïve animals. Panic anxiety-like behavior was shown in the elevated plus maze in mice with TIC injury if the test was preceded with acoustic startle. Thus, in addition to mechanical and cold hypersensitivity, the present study identified significant anxiety-like behaviors in mice with TIC injury resembling the clinical symptomatology and psychosocial impairments of patients with chronic facial pain. Overall, the TIC injury model's chronicity, reproducibility, and reliability in producing pain- and anxiety-like behaviors demonstrate its usefulness as a chronic neuropathic facial pain model. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

HLA-DR and -DQ phenotypes in inflammatory bowel disease: a meta-analysis

NARCIS (Netherlands)

Stokkers, P. C.; Reitsma, P. H.; Tytgat, G. N.; van Deventer, S. J.

1999-01-01

Susceptibility to inflammatory bowel disease (IBD) is partially genetically determined and the HLA class II genes are candidates for a role in genetic susceptibility to IBD, because their products play a central role in the immune response. Multiple studies have reported associations between HLA-DR

Injury-Induced Type I IFN Signaling Regulates Inflammatory Responses in the Central Nervous System

DEFF Research Database (Denmark)

Khorooshi, Reza; Owens, Trevor

2010-01-01

Innate glial response is critical for the induction of inflammatory mediators and recruitment of leukocytes to sites of the injury in the CNS. We have examined the involvement of type I IFN signaling in the mouse hippocampus following sterile injury (transection of entorhinal afferents). Type I I...

Differential diagnosis of white matter diseases in the tropics: An overview

Directory of Open Access Journals (Sweden)

Pandit Lekha

2009-01-01

Full Text Available In hospitals in the tropics, the availability of magnetic resonance imaging (MRI facilities in urban areas and especially in teaching institutions have resulted in white matter diseases being frequently reported in a variety of clinical settings. Unlike the west where multiple sclerosis (MS is the commonest white matter disease encountered, in the tropics, there are myriad causes for the same. Infectious and post infectious disorders probably account for the vast majority of these diseases. Human immunodeficiency virus (HIV infection tops the list of infective conditions. Central nervous system (CNS tuberculosis occasionally presents with patchy parenchymal lesions unaccompanied by meningeal involvement. Human T cell leukemia virus (HTLV infection and cystic inflammatory lesions such as neurocysticercosis are important causes to be considered in the differential diagnosis. Diagnosing post infectious demyelinating disorders is equally challenging since more than a third of cases seen in the tropics do not present with history of past infection or vaccinations. Metabolic and deficiency disorders such as Wernicke′s encephalopathy, osmotic demyelinating syndrome associated with extra pontine lesions and Vitamin B12 deficiency states can occassionaly cause confusion in diagnosis. This review considers a few important disorders which manifest with white matter changes on MRI and create diagnostic difficulties in a population in the tropics.

Diagnostik og behandling af neuromyelitis optica

DEFF Research Database (Denmark)

Nielsen, Helle Hvilsted; Ravnborg, Mads; Illes, Zsolt

2014-01-01

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease characterized by antibodies against aquaporin-4 in up to 80% of the cases and even less in the NMO spectrum disorders, which may be difficult to distinguish from early multiple sclerosis. While immunosuppressive therapy should...

Headache and Nausea after Treatment with High-Dose Subcutaneous versus Intravenous Immunoglobulin

DEFF Research Database (Denmark)

Markvardsen, Lars H; Christiansen, Ingelise; Andersen, Henning

2015-01-01

and could be an alternative in patients experiencing side effects. Fifty-nine patients diagnosed with neurological disorders (chronic inflammatory demyelinating polyneuropathy (CIDP), multi-focal motor neuropathy (MMN) or post-polio syndrome) were treated with IVIG, and 27 CIDP or MMN patients with SCIG...

automated (centrifugal) therapeutic plasma exchange option for ...

African Journals Online (AJOL)

Therapeutic plasma exchange (TPE) is performed frequently and effectively in developed countries, whereas the reverse is the case in developing countries. Guillain‑Barre syndrome (GBS), synonymous with acute inflammatory demyelinating polyneuropathy, is an important indication for TPE, but this is rarely administered ...

Anti-inflammatory effect by lentiviral-mediated overexpression of IL-10 or IL-1 receptor antagonist in rat glial cells and macrophages

NARCIS (Netherlands)

van Strien, N.M.; Mercier, D.; Drukarch, B.; Breve, J.J.P.; Poole, S.; Binnekade, R.; Bol, J.G.J.M.; Blits, B.; Verhaagen, J.; van Dam, A.M.W.

2010-01-01

Neuroinflammation, as defined by activation of local glial cells and production of various inflammatory mediators, is an important feature of many neurological disorders. Expression of pro-inflammatory mediators produced by glial cells in the central nervous system (CNS) is considered to contribute

Adipokine Profiling in Adult Women With Central Obesity and Hypertension

Directory of Open Access Journals (Sweden)

Rashmi Supriya

2018-03-01

Full Text Available Central obesity and hypertension are common risk factors for the metabolic syndrome, cardiovascular and renal diseases. Studies have shown that it is more difficult to control blood pressure and prevent end-organ damage in obese individuals with hypertension compared to their non-obese counterparts, especially among women. Obese females have a 6 times higher risk of developing hypertension than non-obese females while obese males are at a 1.5 times higher risk of developing hypertension, compared to their non-obese counterparts. Indeed, the inter-relationship between obesity and hypertension is unclear. Adipokines have been proposed to play a mediating role in the relationship between obesity and hypertension and are involved in the pathogenesis of metabolic diseases. Therefore, this study sought to determine the role of adipokines (adiponectin, plasminogen activator inhibitor-1, leptin, and tumor necrosis factor-α in hypertensive Hong Kong Chinese women with central obesity. A total of 387 women aged 58 ± 11 years who were examined with a 2 × 2 factorial design for central obesity (waist circumference ≥ 80 cm and hypertension (blood pressure ≥ 140/90 mmHg, were recruited from a pool of 1,492 Hong Kong Chinese adults who were previously screened for metabolic syndrome. Subjects with hyperglycemia, hypertriglyceridemia, and dyslipidemia were excluded to eliminate confounding effects. Our findings revealed that hypertensive women with central obesity had a lower anti-inflammatory status (adiponectin and a higher pro-inflammatory status (TNF-α than obese alone or hypertensive alone women. Also, women with central obesity had higher circulatory PAI-1 and leptin concentrations than their non-obese counterparts. We conclude that obesity may shift toward a more pro-inflammatory state and may become more severe in the presence of hypertension or vice versa.

Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies.

Science.gov (United States)

Langlais, David; Fodil, Nassima; Gros, Philippe

2017-04-26

Genome technologies have defined a complex genetic architecture in major infectious, inflammatory, and autoimmune disorders. High density marker arrays and Immunochips have powered genome-wide association studies (GWAS) that have mapped nearly 450 genetic risk loci in 22 major inflammatory diseases, including a core of common genes that play a central role in pathological inflammation. Whole-exome and whole-genome sequencing have identified more than 265 genes in which mutations cause primary immunodeficiencies and rare forms of severe inflammatory bowel disease. Combined analysis of inflammatory disease GWAS and primary immunodeficiencies point to shared proteins and pathways that are required for immune cell development and protection against infections and are also associated with pathological inflammation. Finally, sequencing of chromatin immunoprecipitates containing specific transcription factors, with parallel RNA sequencing, has charted epigenetic regulation of gene expression by proinflammatory transcription factors in immune cells, providing complementary information to characterize morbid genes at infectious and inflammatory disease loci.

Leukocyte extravasation as a target for anti-inflammatory therapy - Which molecule to choose?

DEFF Research Database (Denmark)

Boehncke, W-H; Schön, M P; Girolomoni, G

2005-01-01

In view of the central pathogenic importance of leukocyte extravasation in inflammatory skin diseases, therapeutic interference with this - surprisingly complex - process is clearly a promising new approach for treating these dermatoses. Despite some disappointments during the clinical use of the...

Increased mitochondrial content in remyelinated axons: implications for multiple sclerosis

Science.gov (United States)

Zambonin, Jessica L.; Zhao, Chao; Ohno, Nobuhiko; Campbell, Graham R.; Engeham, Sarah; Ziabreva, Iryna; Schwarz, Nadine; Lee, Sok Ee; Frischer, Josa M.; Turnbull, Doug M.; Trapp, Bruce D.; Lassmann, Hans; Franklin, Robin J. M.

2011-01-01

Mitochondrial content within axons increases following demyelination in the central nervous system, presumably as a response to the changes in energy needs of axons imposed by redistribution of sodium channels. Myelin sheaths can be restored in demyelinated axons and remyelination in some multiple sclerosis lesions is extensive, while in others it is incomplete or absent. The effects of remyelination on axonal mitochondrial content in multiple sclerosis, particularly whether remyelination completely reverses the mitochondrial changes that follow demyelination, are currently unknown. In this study, we analysed axonal mitochondria within demyelinated, remyelinated and myelinated axons in post-mortem tissue from patients with multiple sclerosis and controls, as well as in experimental models of demyelination and remyelination, in vivo and in vitro. Immunofluorescent labelling of mitochondria (porin, a voltage-dependent anion channel expressed on all mitochondria) and axons (neurofilament), and ultrastructural imaging showed that in both multiple sclerosis and experimental demyelination, mitochondrial content within remyelinated axons was significantly less than in acutely and chronically demyelinated axons but more numerous than in myelinated axons. The greater mitochondrial content within remyelinated, compared with myelinated, axons was due to an increase in density of porin elements whereas increase in size accounted for the change observed in demyelinated axons. The increase in mitochondrial content in remyelinated axons was associated with an increase in mitochondrial respiratory chain complex IV activity. In vitro studies showed a significant increase in the number of stationary mitochondria in remyelinated compared with myelinated and demyelinated axons. The number of mobile mitochondria in remyelinated axons did not significantly differ from myelinated axons, although significantly greater than in demyelinated axons. Our neuropathological data and findings in

Analgesic and anti-inflammatory activity of root bark of Grewia asiatica Linn. in rodents

Directory of Open Access Journals (Sweden)

Udaybhan Singh Paviaya

2013-01-01

Conclusions: The present study indicates that root bark of G. asiatica exhibits peripheral and central analgesic effect and anti-inflammatory activity, which may be attributed to the various phytochemicals present in root bark of G. asiatica.

Paranodal reorganization results in the depletion of transverse bands in the aged central nervous system

Science.gov (United States)

Shepherd, Mark N.; Pomicter, Anthony D.; Velazco, Cristine S.; Henderson, Scott C.; Dupree, Jeffrey L.

2012-01-01

Paranodal axo-glial junctional complexes anchor the myelin sheath to the axon and breakdown of these complexes presumably facilitates demyelination. Myelin deterioration is also prominent in the aging central nervous system (CNS); however, the stability of the paranodal complexes in the aged CNS has not been examined. Here, we show that transverse bands, prominent components of paranodal junctions, are significantly reduced in the aged CNS; however, the number of paired clusters of both myelin and axonal paranodal proteins is not altered. Ultrastructural analyses also reveal that thicker myelin sheaths display a “piling” of paranodal loops, the cytoplasm-containing sacs that demarcate the paranode. Loops involved in piling are observed throughout the paranode and are not limited to loops positioned in either the nodal- or juxtanodal-most regions. Here, we propose that as myelination continues, previously anchored loops lose their transverse bands and recede away from the axolemma. Newly juxtaposed loops then lose their transverse bands, move laterally to fill in the gap left by the receded loops and finally reform their transverse bands. This paranodal reorganization results in conservation of paranodal length, which may be important in maintaining ion channel spacing and axonal function. Furthermore, we propose that transverse band reformation is less efficient in the aged CNS, resulting in the significant reduction of these junctional components. Although demyelination was not observed, we propose that loss of transverse bands facilitates myelin degeneration and may predispose the aged CNS to a poorer prognosis following a secondary insult. PMID:20888080

Hypercoagulability in response to elevated body temperature and central hypovolemia

DEFF Research Database (Denmark)

Meyer, Martin; Ostrowski, Sisse R; Overgaard, Flemming Anders

2013-01-01

Coagulation abnormalities contribute to poor outcomes in critically ill patients. In trauma patients exposed to a hot environment, a systemic inflammatory response syndrome, elevated body temperature, and reduced central blood volume occur in parallel with changes in hemostasis and endothelial...... damage. The objective of this study was to evaluate whether experimentally elevated body temperature and reduced central blood volume (CBV) per se affects hemostasis and endothelial activation....

Evidence of demyelination in mild cognitive impairment and dementia using a direct and specific magnetic resonance imaging measure of myelin content.

Science.gov (United States)

Bouhrara, Mustapha; Reiter, David A; Bergeron, Christopher M; Zukley, Linda M; Ferrucci, Luigi; Resnick, Susan M; Spencer, Richard G

2018-04-18

We investigated brain demyelination in aging, mild cognitive impairment (MCI), and dementia using magnetic resonance imaging of myelin. Brains of young and old controls and old subjects with MCI, Alzheimer's disease, or vascular dementia were scanned using our recently developed myelin water fraction (MWF) mapping technique, which provides greatly improved accuracy over previous comparable methods. Maps of MWF, a direct and specific myelin measure, and relaxation times and magnetization transfer ratio, indirect and nonspecific measures, were constructed. MCI subjects showed decreased MWF compared with old controls. Demyelination was greater in Alzheimer's disease or vascular dementia. As expected, decreased MWF was accompanied by decreased magnetization transfer ratio and increased relaxation times. The young subjects showed greater myelin content than the old subjects. We believe this to be the first demonstration of myelin loss in MCI, Alzheimer's disease, and vascular dementia using a method that provides a quantitative magnetic resonance imaging-based measure of myelin. Our findings add to the emerging evidence that myelination may represent an important biomarker for the pathology of MCI and dementia. This study supports the investigation of the role of myelination in MCI and dementia through use of this quantitative magnetic resonance imaging approach in clinical studies of disease progression, relationship of functional status to myelination status, and therapeutics. Furthermore, mapping MWF may permit myelin to serve as a therapeutic target in clinical trials. Copyright © 2018. Published by Elsevier Inc.

Inflammatory bowel disease in central India: a single centre experience over five years.

Science.gov (United States)

Jain, Ajay K; Sircar, Shohini; Jain, Mayank; Adkar, Sagar; Waghmare, Chandrashekhar

2012-10-01

In this retrospective study, the records of all patients diagnosed with inflammatory bowel disease between 2005 and 2010 were analysed. Ulcerative colitis is far more common than Crohn's disease in our setting. The incidence is similar in both sexes and the age at diagnosis for both is similar. Limited left-sided ulcerative colitis is more common. Crohn's disease is difficult to diagnose and is commonly treated as tuberculosis in our setting.

Intestinal microbiota, probiotics and prebiotics in inflammatory bowel disease

Science.gov (United States)

Orel, Rok; Kamhi Trop, Tina

2014-01-01

It has been presumed that aberrant immune response to intestinal microorganisms in genetically predisposed individuals may play a major role in the pathogenesis of the inflammatory bowel disease, and there is a good deal of evidence supporting this hypothesis. Commensal enteric bacteria probably play a central role in pathogenesis, providing continuous antigenic stimulation that causes chronic intestinal injury. A strong biologic rationale supports the use of probiotics and prebiotics for inflammatory bowel disease therapy. Many probiotic strains exhibit anti-inflammatory properties through their effects on different immune cells, pro-inflammatory cytokine secretion depression, and the induction of anti-inflammatory cytokines. There is very strong evidence supporting the use of multispecies probiotic VSL#3 for the prevention or recurrence of postoperative pouchitis in patients. For treatment of active ulcerative colitis, as well as for maintenance therapy, the clinical evidence of efficacy is strongest for VSL#3 and Escherichia coli Nissle 1917. Moreover, some prebiotics, such as germinated barley foodstuff, Psyllium or oligofructose-enriched inulin, might provide some benefit in patients with active ulcerative colitis or ulcerative colitis in remission. The results of clinical trials in the treatment of active Crohn’s disease or the maintenance of its remission with probiotics and prebiotics are disappointing and do not support their use in this disease. The only exception is weak evidence of advantageous use of Saccharomyces boulardii concomitantly with medical therapy in maintenance treatment. PMID:25206258

Prevention of the Osmotic Demyelination Syndrome After Liver Transplantation: A Multidisciplinary Perspective.

Science.gov (United States)

Crismale, J F; Meliambro, K A; DeMaria, S; Bronster, D B; Florman, S; Schiano, T D

2017-10-01

The osmotic demyelination syndrome (ODS) is a serious neurologic condition that occurs in the setting of rapid correction of hyponatremia. It presents with protean manifestations, from encephalopathy to the "locked-in" syndrome. ODS can complicate liver transplantation (LT), and its incidence may increase with the inclusion of serum sodium as a factor in the Mayo End-Stage Liver Disease score. A comprehensive understanding of risk factors for the development of ODS in the setting of LT, along with recommendations to mitigate the risk of ODS, are necessary. The literature to date on ODS in the setting of LT was reviewed. Major risk factors for the development of ODS include severe pretransplant hyponatremia (serum sodium [SNa] ODS include correcting hyponatremia pretransplant via fluid restriction and/or ensuring an appropriate rate of increase from the preoperative SNa via close attention to fluid and electrolyte management both during and after surgery. Multidisciplinary management involving transplant hepatology, nephrology, neurology, surgery, and anesthesiology/critical care is key to performing LT safely in patients with hyponatremia. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

Electrodiagnostic studies in Guillain-Barre syndrome

NARCIS (Netherlands)

J. Meulstee (Jan)

1994-01-01

textabstractThe Guillain-Barre syndrome (GBS) is a monophasic (sub)acute inflammatory demyelinating predominantly motor polyradiculo-neuropathy. Clinical criteria have been proposed by Asbury (Asbury et aI., 1978; Asbury and Cornblath, 1990). GBS is a selflimiting disease, however, up to 30% of the

[A treatment of neuromyelitis optica (Devic's disease) during pregnancy].

Science.gov (United States)

Daouda, Moussa Toudou; Obenda, Norlin Samuel; Assadeck, Hamid; Camara, Diankanagbe; Djibo, Fatimata Hassane

2016-01-01

Neuromyelitis optica (Devic's disease) is an inflammatory demyelinating disease of the central nervous system that mainly affects spinal cord, optic nerve and brain regions with high aquaporin 4 antigen expression. This is a severe autoimmune disease caused by autoantibodies directed against aquaporin 4 and associated with high morbidity and mortality. Unlike other inflammatory conditions such as multiple sclerosis or rheumatoid polyarthritis, pregnancy does not seem to influence the activity of neuromyelitis optica, hence the need for a thorough treatment during pregnancy. Corticosteroid therapy is the treatment of choice for neuromyelitis optica during pregnancy. Other treatments may also be used including rituximab, some immunosuppressive agents and immunoglobulins. Immunosuppressive treatment or rituximab is recommended when the long-term corticosteroid treatment is contraindicated, in case of inefficiency or if side effects are intolerable. Immunoglobulins are administered to patients with serious outbreaks of neuromyelitis optica which do not respond to bolus methylprednisolone. Immunoglobulins alone can also be continued at a dose of 0.4 g/kg/day for 6-8 weeks until delivery. Plasmapheresis is also a good alternative to bolus methylprednisolone when outbreaks are extremely severe.

T cells in multiple sclerosis and experimental autoimmune encephalomyelitis.

LENUS (Irish Health Repository)

Fletcher, J M

2012-02-01

Multiple sclerosis (MS) is a demyelinating inflammatory disorder of the central nervous system (CNS), which involves autoimmune responses to myelin antigens. Studies in experimental autoimmune encephalomyelitis (EAE), an animal model for MS, have provided convincing evidence that T cells specific for self-antigens mediate pathology in these diseases. Until recently, T helper type 1 (Th1) cells were thought to be the main effector T cells responsible for the autoimmune inflammation. However more recent studies have highlighted an important pathogenic role for CD4(+) T cells that secrete interleukin (IL)-17, termed Th17, but also IL-17-secreting gammadelta T cells in EAE as well as other autoimmune and chronic inflammatory conditions. This has prompted intensive study of the induction, function and regulation of IL-17-producing T cells in MS and EAE. In this paper, we review the contribution of Th1, Th17, gammadelta, CD8(+) and regulatory T cells as well as the possible development of new therapeutic approaches for MS based on manipulating these T cell subtypes.

Oroal manifestations in patients with multiple sclerosis

Directory of Open Access Journals (Sweden)

Grajales González Hilda María

2014-07-01

Full Text Available Multiple sclerosis is a chronic autoimmune inflammatory disease of the central nervous system, characterized by the presence of acute focal inflammatory demyelination, axonal loss and gliosis. It affects predominantly in young adults between 20 and 40 years of age; it is infrequent in the pediatric age. A observational, retrospective and descriptive cohort research was conducted between May 1999 and January 2012 to assess demographic characteristics, and pathological manifestations in the oral cav- ity of children with this condition. Records of 17 patients, under 18 years of age, of either sex were included, who had been evaluated in the Department of Stomatology. Data recorded were age, sex, State of origin, oral and facial pathological features, focal cavity infections and ceod index. There were no patients with trigeminal neuralgia or facial paralysis; a 5.7% ceod index was identified. Most of the patients were under immunopressive treatment. A protocol for stomatological follow-up in patients with multiple sclerosis does not exist. The medical profession must be sensibilized to establish strategies for an integral follow-up in patients with this condition.

Non-steroidal anti-inflammatory drugs and antibiotics prescription trends at a central west bank hospital.

Science.gov (United States)

Tayem, Yasin I; Qubaja, Marwan M; Shraim, Riyad K; Taha, Omar B; Abu Shkheidem, Imadeddin A; Ibrahim, Murad A

2013-11-01

We aimed to reliably describe the pattern of outpatient prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics (ATBs) at a central hospital in the West Bank, Palestine. This was a retrospective, cross-sectional study investigating a cohort of 2,208 prescriptions ordered by outpatient clinics and the emergency room over one year in Beit Jala Hospital in Bethlehem, West Bank. The orders were analysed for the rate and types of NSAIDs and ATBs utilised, and the appropriateness of these drugs to the diagnosis. Of the total prescriptions, 410 contained NSAIDs (18.6%), including diclofenac (40.2%), low dose aspirin (23.9%), ibuprofen (17.8%) and indomethacin (15.1%). A minority of these prescriptions contained a combination of these agents (2.5%). Only one prescription contained cyclooxyeganse-2 inhibitors (0.2%). The appropriateness of NSAID use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). The rate of ATB use was 30.3% (669 prescriptions). The ATBs prescribed were amoxicillin (23.3%), augmentin (14.3%), quinolones (12.7%), first and second generation cephalosporins (9.4% and 12.7%, respectively) and macrolides (7.2%). ATB combinations were identified in 9.4%, with the most common being second-generation cephalopsorins and metronidazole (4.3%). Regarding the appropriateness of prescribing ATBs according to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6% and difficult to tell in 34.6% of the prescriptions. These findings revealed a relatively large number and inappropriate utilisation of ATBs and NSAIDs. An interventional programme needs to be adopted to reinforce physicians' knowledge of the rational prescription of these agents.

Inflammatory myofibroblastic tumor

Directory of Open Access Journals (Sweden)

Sangeeta Palaskar

2011-01-01

Full Text Available Inflammatory myofibroblastic tumor is an uncommon lesion of unknown cause. It encompasses a spectrum of myofibroblastic proliferation along with varying amount of inflammatory infiltrate. A number of terms have been applied to the lesion, namely, inflammatory pseudotumor, fibrous xanthoma, plasma cell granuloma, pseudosarcoma, lymphoid hamartoma, myxoid hamartoma, inflammatory myofibrohistiocytic proliferation, benign myofibroblatoma, and most recently, inflammatory myofibroblastic tumor. The diverse nomenclature is mostly descriptive and reflects the uncertainty regarding true biologic nature of these lesions. Recently, the concept of this lesion being reactive has been challenged based on the clinical demonstration of recurrences and metastasis and cytogenetic evidence of acquired clonal chromosomal abnormalities. We hereby report a case of inflammatory pseudotumor and review its inflammatory versus neoplastic behavior.

A nationwide survey of pediatric acquired demyelinating syndromes in Japan

Science.gov (United States)

Yamaguchi, Y.; Kira, R.; Ishizaki, Y.; Sakai, Y.; Sanefuji, M.; Ichiyama, T.; Oka, A.; Kishi, T.; Kimura, S.; Kubota, M.; Takanashi, J.; Takahashi, Y.; Tamai, H.; Natsume, J.; Hamano, S.; Hirabayashi, S.; Maegaki, Y.; Mizuguchi, M.; Minagawa, K.; Yoshikawa, H.; Kira, J.; Kusunoki, S.; Hara, T.

2016-01-01

Objective: To investigate the clinical and epidemiologic features of pediatric acquired demyelinating syndromes (ADS) of the CNS in Japan. Methods: We conducted a nationwide survey and collected clinical data on children with ADS aged 15 years or younger, who visited hospitals between 2005 and 2007. Results: Among 977 hospitals enrolled, 723 (74.0%) responded to our inquiries and reported a total of 439 patients as follows: 244 with acute disseminated encephalomyelitis (ADEM), 117 with multiple sclerosis (MS), 14 with neuromyelitis optica (NMO), and 64 with other ADS. We collected and analyzed detailed data from 204 cases, including those with ADEM (66), MS (58), and NMO (10). We observed the following: (1) the estimated annual incidence rate of pediatric ADEM in Japan was 0.40 per 100,000 children (95% confidence interval [CI], 0.34–0.46), with the lowest prevalence in the north; (2) the estimated prevalence rate of MS was 0.69 per 100,000 children (95% CI, 0.58–0.80), with the lowest prevalence in the south; (3) NMO in Japan was rare, with an estimated prevalence of 0.06 per 100,000 children (95% CI, 0.04–0.08); and (4) the sex ratio and mean age at onset varied by ADS type, and (5) male/female ratios correlated with ages at onset in each ADS group. Conclusions: Our results clarify the characteristic clinical features of pediatric ADS in the Japanese population. PMID:27742816

Involvement of Visceral Adipose Tissue in Immunological Modulation of Inflammatory Cascade in Preeclampsia

Directory of Open Access Journals (Sweden)

Katsuhiko Naruse

2015-01-01

Full Text Available Objectives. The pathophysiology of preeclampsia is characterized by abnormal placentation, an exaggerated inflammatory response, and generalized dysfunction of the maternal endothelium. We investigated the effects of preeclampsia serum on the expression of inflammation-related genes by adipose tissue. Materials and Methods. Visceral adipose tissue was obtained from the omentum of patients with early ovarian cancer without metastasis. Adipose tissue was incubated with sera obtained from either five women affected with severe preeclampsia or five women from control pregnant women at 37°C in a humidified incubator at 5% CO2 for 24 hours. 370 genes in total mRNA were analyzed with quantitative RT-PCR (Inflammatory Response & Autoimmunity gene set. Results. Gene expression analysis revealed changes in the expression levels of 30 genes in adipose tissue treated with preeclampsia sera. Some genes are related to immune response, oxidative stress, insulin resistance, and adipogenesis, which plays a central role in excessive systemic inflammatory response of preeclampsia. In contrast, other genes have shown beneficial effects in the regulation of Th2 predominance, antioxidative stress, and insulin sensitivity. Conclusion. In conclusion, visceral adipose tissue offers protection against inflammation, oxidative insults, and other forms of cellular stress that are central to the pathogenesis of preeclampsia.

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration.

Science.gov (United States)

Kempuraj, Duraisamy; Thangavel, Ramasamy; Selvakumar, Govindhasamy P; Zaheer, Smita; Ahmed, Mohammad E; Raikwar, Sudhanshu P; Zahoor, Haris; Saeed, Daniyal; Natteru, Prashant A; Iyer, Shankar; Zaheer, Asgar

2017-01-01

Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson's disease (PD), Alzheimer's disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1-42 (Aβ1-42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can

Role of metallothionein-III following central nervous system damage

DEFF Research Database (Denmark)

Carrasco, Javier; Penkowa, Milena; Giralt, Mercedes

2003-01-01

We evaluated the physiological relevance of metallothionein-III (MT-III) in the central nervous system following damage caused by a focal cryolesion onto the cortex by studying Mt3-null mice. In normal mice, dramatic astrogliosis and microgliosis and T-cell infiltration were observed in the area...... the inflammatory response elicited in the central nervous system by a cryoinjury, nor does it serve an important antioxidant role, but it may influence neuronal regeneration during the recovery process....

Visual outcome following optic neuritis: A 5‑year review | Pedro ...

African Journals Online (AJOL)

Background: Optic neuritis is a demyelinating inflammatory disease of the optic nerve that typically affects young adults especially females, and is usually associated with multiple sclerosis especially in Caucasians. The prognosis for visual recovery is usually good but with poor quality. Objective: The objective was to ...

Treatment-related fluctuation in Guillain-Barre syndrome

Directory of Open Access Journals (Sweden)

Thirunavukkarasu Thivakaran

2011-01-01

Full Text Available Guillain-Barre syndrome (GBS is usually a monophasic illness but relapses occur. A 55-year-old female with hypertension and vitiligo presented with acute inflammatory demyelinating polyradiculoneuropathy. She improved with immunoglobulin treatment started on day 6 of illness, but relapsed on day 14 warranting repeat immunoglobulin therapy. Thereafter recovery was complete. Her relapse was due to treatment-related fluctuation (TRF. TRF is improvement in the GBS disability scale of at least one grade after completion of immunotherapy followed by worsening of the disability scale of at least one grade within the first 2 months after disease onset. Recurrent GBS and chronic inflammatory demyelinating polyradiculoneuropathy were excluded. During the peak of the illness ANA titres were transiently high. The presence of other medical conditions, predominant proximal weakness and the absence of preceding diarrhea are predictors for TRF seen in this patient. Early treatment and evidence of ongoing immune activation have contributed toward TRF.

Inflammatory cardiovascular risk markers in obstructive sleep apnoea syndrome.

LENUS (Irish Health Repository)

Ryan, Silke

2012-02-01

Obstructive sleep apnoea syndrome (OSAS) represents a highly prevalent disease and is recognized as a major public health burden. Large-scale epidemiological studies have demonstrated an independent relationship between OSAS and various cardiovascular disorders. The pathogenesis of cardiovascular complications in OSAS is not completely understood, but given the complexity of the disorder, a multifactorial etiology is likely. Inflammatory processes have emerged as critical in the pathogenesis of atherosclerosis in general and they mediate many of the stages of atheroma formation. Circulating levels of several markers of inflammation have been associated with future cardiovascular risk. These markers include cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and selectins, cytokines such as tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), chemokines such as IL-8, and C-reactive protein (CRP). There is increasing evidence that inflammatory processes also play a central role in the cardiovascular pathophysiology of OSAS. This is supported by cell culture and animal studies identifying a preferential activation of inflammatory pathways by intermittent hypoxia (IH), the hallmark of OSAS. A number of studies have selectively examined the expression of inflammatory factors in OSAS patients with different conclusions. These different findings may have been contributed to by a number of methodological factors such as small subject numbers, inadequately matched study populations, particularly in terms of body mass index (BMI), and inclusion of patients with pre-existing cardiovascular or metabolic diseases. This review will focus on the potential role of various inflammatory markers in OSAS with a critical analysis of the current literature.

The Pro-inflammatory Effects of Glucocorticoids in the Brain

Science.gov (United States)

Duque, Erica de Almeida; Munhoz, Carolina Demarchi

2016-01-01

Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

Involvement of peripheral III nerve in multiple sclerosis patient: Report of a new case and discussion of the underlying mechanism.

Science.gov (United States)

Shor, Natalia; Amador, Maria Del Mar; Dormont, Didier; Lubetzki, Catherine; Bertrand, Anne

2017-04-01

Multiple sclerosis (MS) is a chronic disorder that affects the central nervous system myelin. However, a few radiological cases have documented an involvement of peripheral cranial nerves, within the subarachnoid space, in MS patients. We report the case of a 36-year-old female with a history of relapsing-remitting (RR) MS who consulted for a subacute complete paralysis of the right III nerve. Magnetic resonance imaging (MRI) examination showed enhancement and thickening of the cisternal right III nerve, in continuity with a linear, mesencephalic, acute demyelinating lesion. Radiological involvement of the cisternal part of III nerve has been reported only once in MS patients. Radiological involvement of the cisternal part of V nerve occurs more frequently, in almost 3% of MS patients. In both situations, the presence of a central demyelinating lesion, in continuity with the enhancement of the peripheral nerve, suggests that peripheral nerve damage is a secondary process, rather than a primary target of demyelination.

Progressive dysarthria and ataxia

Directory of Open Access Journals (Sweden)

Lynsey McAlpine

2015-02-01

Full Text Available ‘Guillain-Barre syndrome’ (GBS is a broad term used to describe a collection of clinical syndromes which manifest as acute immune-mediated demyelinating diseases or more rarely axonal diseases of the peripheral nervous system. The most commonly recognised form is ‘acute inflammatory demyelinating polyradiculoneuropathy’ (AIDP, which classically presents as a proximal and distal weakness with diminished reflexes, often involving the cranial nerves and muscles of respiration [1]. It is a neurological emergency as these patients are at risk of developing respiratory failure; one third will require admission to the Intensive Care Unit (ICU for ventilatory support, and mortality rates of 3-10% have been reported

Continued administration of ciliary neurotrophic factor protects mice from inflammatory pathology in experimental autoimmune encephalomyelitis

DEFF Research Database (Denmark)

Kuhlmann, Tanja; Remington, Leah; Cognet, Isabelle

2006-01-01

Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described as a surv......Multiple sclerosis is an inflammatory disease of the central nervous system that leads to loss of myelin and oligodendrocytes and damage to axons. We show that daily administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a neurotrophic factor that has been described...... it was withdrawn. After cessation of CNTF treatment, inflammation and symptoms returned to control levels. However, slight but significantly higher numbers of oligodendrocytes, NG2-positive cells, axons, and neurons were observed in mice that had been treated with high concentrations of CNTF. Our results show...

Shedding light on inflammatory pseudotumor in children: spotlight on inflammatory myofibroblastic tumor

Energy Technology Data Exchange (ETDEWEB)

Lai, Lillian M.; Kao, Simon C.S.; Moritani, Toshio; Clark, Eve; Ishigami, Kousei; Sato, Yutaka [University of Iowa Hospitals and Clinics, Department of Radiology, Carver College of Medicine, Iowa City, IA (United States); McCarville, M.B. [St. Jude Children' s Research Hospital, Department of Radiology, Memphis, TN (United States); Kirby, Patricia [University of Iowa Hospitals and Clinics, Department of Pathology, Carver College of Medicine, Iowa City, IA (United States); Bahrami, Armita [St. Jude Children' s Research Hospital, Department of Pathology, Memphis, TN (United States)

2015-11-15

Inflammatory pseudotumor is a generic term used to designate a heterogeneous group of inflammatory mass-forming lesions histologically characterized by myofibroblastic proliferation with chronic inflammatory infiltrate. Inflammatory pseudotumor is multifactorial in etiology and generally benign, but it is often mistaken for malignancy given its aggressive appearance. It can occur throughout the body and is seen in all age groups. Inflammatory pseudotumor has been described in the literature by many organ-specific names, resulting in confusion. Recently within this generic category of inflammatory pseudotumor, inflammatory myofibroblastic tumor has emerged as a distinct entity and is now recognized as a fibroblastic/myofibroblastic neoplasm with intermediate biological potential and occurring mostly in children. We present interesting pediatric cases of inflammatory myofibroblastic tumors given this entity's tendency to occur in children. Familiarity and knowledge of the imaging features of inflammatory pseudotumor can help in making an accurate diagnosis, thereby avoiding unnecessary radical surgery. (orig.)

Melatonin Treatment Reduces Oxidative Damage and Normalizes Plasma Pro-Inflammatory Cytokines in Patients Suffering from Charcot-Marie-Tooth Neuropathy: A Pilot Study in Three Children.

Science.gov (United States)

Chahbouni, Mariam; López, María Del Señor; Molina-Carballo, Antonio; de Haro, Tomás; Muñoz-Hoyos, Antonio; Fernández-Ortiz, Marisol; Guerra-Librero, Ana; Acuña-Castroviejo, Darío

2017-10-14

Charcot-Marie-Tooth neuropathy (CMT) is a motor and sensory neuropathy comprising a heterogeneous group of inherited diseases. The CMT1A phenotype is predominant in the 70% of CMT patients, with nerve conduction velocity reduction and hypertrophic demyelination. These patients have elevated oxidative stress and chronic inflammation. Currently, there is no effective cure for CMT; herein, we investigated whether melatonin treatment may reduce the inflammatory and oxidative damage in CMT1A patients. Three patients, aged 8-10 years, were treated with melatonin (60 mg at 21:00 h plus 10 mg at 09:00 h), and plasma levels of lipid peroxidation (LPO), nitrites (NOx), IL-1β, IL-2, IL-6, TNF-α, INF-γ, oxidized to reduced glutathione (GSSG/GSH) ratio, and the activities of superoxide dismutase (SOD), glutathione-S transferase (GST), glutathione peroxidase (GPx), and reductase (GRd), were determined in erythrocytes at 3 and 6 months of treatment. Healthy age- and sex-matched subjects were used as controls. The results showed increased activities of SOD, GST, GPx, and GRd in CMT1A patients, which were reduced at 3 and 6 months of treatment. The GSSG/GSH ratio significantly increased in the patients, returning to control values after melatonin treatment. The inflammatory process was confirmed by the elevation of all proinflammatory cytokines measured, which were also normalized by melatonin. LPO and NOx, which also were elevated in the patients, were normalized by melatonin. The results document beneficial effects of the use of melatonin in CMT1A patients to reduce the hyperoxidative and inflammatory condition, which may correlate with a reduction of the degenerative process.

Higher intake of omega-3 polyunsaturated fatty acids is associated with a decreased risk of a first clinical diagnosis of central nervous system demyelination: Results from the Ausimmune Study.

Science.gov (United States)

Hoare, Samuel; Lithander, Fiona; van der Mei, Ingrid; Ponsonby, Anne-Louise; Lucas, Robyn

2016-06-01

There is contradictory evidence for a role of dietary fat in risk of multiple sclerosis (MS). To examine the association between usual fat intake (total, saturated, monounsaturated (MUFA), polyunsaturated (PUFA), omega-3 and omega-6) and risk of a first clinical diagnosis of CNS demyelination (FCD). Multi-centre incident case-control study in four regions of Australia during 2003-2006. Cases were aged 18-59 years and had a FCD; controls were matched to a case on age, sex and location. Dietary data were collected using a validated food frequency questionnaire. In 267 cases and 517 controls with dietary data, higher intake (per g/day) of omega-3 PUFA (adjusted odds ratio, AOR=0.61 (95% CI 0.40-0.93)), and particularly that derived from fish (AOR=0.54 (95% CI 0.31-0.93)) rather than from plants (AOR=0.75 (95% CI 0.39-1.43)) was associated with a decreased risk of FCD. Total fat intake and intake of other types of fat were not associated with FCD risk. There was a significant decrease in FCD risk with higher intake of omega-3 PUFA, particularly that originating from fish. There was no evidence to indicate that the intake of other types of dietary fat or fat quantity in the previous 12 months was associated with an altered risk of FCD. © The Author(s), 2015.

Ophthalmoplegia, Dysphonia and Tetraparesis Due to Guillain ...

African Journals Online (AJOL)

Guillain-Barre's syndrome (GBS) or inflammatory/post-infectious acute polyradiculoneuropathy is due to demyelination of nerves, causing a progressive paresis or paralysis. It usually begins in the legs and sometimes goes up to the respiratory muscles and cranial nerves. The exact mechanism of GBS occurrance is still ...

2018-05-04T15:37:34Z https://www.ajol.info/index.php/all/oai oai:ojs ...

African Journals Online (AJOL)

Objective To evaluate the clinical spectrum and outcome of the neurologic manifestations in patients with HIV / AIDS over a ten year period. ... 10 (6.5%) had distal sensory polyneuropathy, 4 (2.6%) had inflammatory demyelinating polyneuropathy, and 2 (1.3%) had subacute combined degeneration of the spinal cord.

Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients

NARCIS (Netherlands)

Ketelslegers, I.A.; Modderman, P.W.; Vennegoor, A.; Killestein, J.; Hamann, D.; Hintzen, R.Q.

2011-01-01

The detection of antibodies against aquaporin-4 (AQP4) has improved the diagnosis of neuromyelitis optica (NMO). We evaluated a recently established cell-based anti-AQP4 assay in 273 patients with inflammatory CNS demyelination. The assay had a specificity of 99% and a sensitivity of 56% to detect

Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: Future therapeutic targets

NARCIS (Netherlands)

Kraneveld, A.D.; Rijnierse, A.; Nijkamp, F.P.; Garssen, J.

2008-01-01

The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory

Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome : Future therapeutic targets

NARCIS (Netherlands)

Kraneveld, A.D.|info:eu-repo/dai/nl/126612838; Rijnierse, A.|info:eu-repo/dai/nl/304830224; Nijkamp, F.P.|info:eu-repo/dai/nl/067668852; Garssen, J.|info:eu-repo/dai/nl/086369962

2008-01-01

The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory

Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages

Directory of Open Access Journals (Sweden)

Norikazu Kiguchi

2017-11-01

Full Text Available Neuropathic pain can have a major effect on quality of life but current therapies are often inadequate. Growing evidence suggests that neuropathic pain induced by nerve damage is caused by chronic inflammation. Upon nerve injury, damaged cells secrete pro-inflammatory molecules that activate cells in the surrounding tissue and recruit circulating leukocytes to the site of injury. Among these, the most abundant cell type is macrophages, which produce several key molecules involved in pain enhancement, including cytokines and chemokines. Given their central role in the regulation of peripheral sensitization, macrophage-derived cytokines and chemokines could be useful targets for the development of novel therapeutics. Inhibition of key pro-inflammatory cytokines and chemokines prevents neuroinflammation and neuropathic pain; moreover, recent studies have demonstrated the effectiveness of pharmacological inhibition of inflammatory (M1 macrophages. Nicotinic acetylcholine receptor ligands and T helper type 2 cytokines that reduce M1 macrophages are able to relieve neuropathic pain. Future translational studies in non-human primates will be crucial for determining the regulatory mechanisms underlying neuroinflammation-associated neuropathic pain. In turn, this knowledge will assist in the development of novel pharmacotherapies targeting macrophage-driven neuroinflammation for the treatment of intractable neuropathic pain.

PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing Th17-cell differentiation and regulating cytokine production.

Science.gov (United States)

Liu, Haijie; Wan, Chunxiao; Ding, Yanan; Han, Ranran; He, Yating; Xiao, Jinting; Hao, Junwei

2017-04-01

Experimental autoimmune neuritis (EAN) is a CD4 + T-cell-mediated autoimmune inflammatory demyelinating disease of the peripheral nervous system. It has been replicated in an animal model of human inflammatory demyelinating polyradiculoneuropathy, Guillain-Barré syndrome. In this study, we evaluated the therapeutic efficacy of a selective inhibitor of the immunoproteasome subunit, low-MW polypeptide 7 (PR-957) in rats with EAN. Our results showed that PR-957 significantly delayed onset day, reduced severity and shortened duration of EAN, and alleviated demyelination and inflammatory infiltration in sciatic nerves. In addition to significantly regulating expression of the cytokine profile, PR-957 treatment down-regulated the proportion of proinflammatory T-helper (T h )17 cells in sciatic nerves and spleens of rats with EAN. Data presented show the role of PR-957 in the signal transducer and activator of transcription 3 (STAT3) pathway. PR-957 not only decreased expression of IL-6 and IL-23 but also led to down-regulation of STAT3 phosphorylation in CD4 + T cells. Regulation of the STAT3 pathway led to a reduction in retinoid-related orphan nuclear receptor γ t and IL-17 production. Furthermore, reduction of STAT3 phosphorylation may have directly suppressed T h 17-cell differentiation. Therefore, our study demonstrates that PR-957 could potently alleviate inflammation in rats with EAN and that it may be a likely candidate for treating Guillain-Barré syndrome.-Liu, H., Wan, C., Ding, Y., Han, R., He, Y., Xiao, J., Hao, J. PR-957, a selective inhibitor of immunoproteasome subunit low-MW polypeptide 7, attenuates experimental autoimmune neuritis by suppressing T h 17-cell differentiation and regulating cytokine production. © FASEB.

The MR spectrum of peroxisomal disorders

International Nuclear Information System (INIS)

Knaap, M.S. van der; Valk, J.; Vrije Univ., Amsterdam

1991-01-01

In the last decade an increasing number of peroxisomal disorders has been recognized. Almost all peroxisomal disorders affect the central nervous system. Many of them lead to demyelination, some of them lead to migrational disturbances. The MR pattern of X-linked adrenoleukodystrophy is well known, but the pattern of the other peroxisomal disorders is less well known. We evaluated the gray and white matter abnormalities of 20 patients on 32 occasions. We compared the results with histological data and in this way came to the description of a number of characteristic MR patterns occurring in peroxisomal disorders: (1) Neuronal migrational disturbances in combination with hypomyelination, dysmyelination or demyelination. (2) Symmetrical demyelination of posterior limb of the internal capsule, cerebellar white matter and brain stem tracts with a variable affection of cerebral hemispheres. (3) Symmetrical demyelination, exhibiting two zones, starting in the occipital area and spreading outwards and forwards; affection of brain stem tracts. (4) Less characteristic patterns of demyelination. The patterns are illustrated and differentiation from other disorders is discussed. (orig.)

Standing postural reaction to visual and proprioceptive stimulation in chronic acquired demyelinating polyneuropathy.

Science.gov (United States)

Provost, Clement P; Tasseel-Ponche, Sophie; Lozeron, Pierre; Piccinini, Giulia; Quintaine, Victorine; Arnulf, Bertrand; Kubis, Nathalie; Yelnik, Alain P

2018-02-28

To investigate the weight of visual and proprioceptive inputs, measured indirectly in standing position control, in patients with chronic acquired demyelinating polyneuropathy (CADP). Prospective case study. Twenty-five patients with CADP and 25 healthy controls. Posture was recorded on a double force platform. Stimulations were optokinetic (60°/s) for visual input and vibration (50 Hz) for proprioceptive input. Visual stimulation involved 4 tests (upward, downward, rightward and leftward) and proprioceptive stimulation 2 tests (triceps surae and tibialis anterior). A composite score, previously published and slightly modified, was used for the recorded postural signals from the different stimulations. Despite their sensitivity deficits, patients with CADP were more sensitive to proprioceptive stimuli than were healthy controls (mean composite score 13.9 ((standard deviation; SD) 4.8) vs 18.4 (SD 4.8), p = 0.002). As expected, they were also more sensitive to visual stimuli (mean composite score 10.5 (SD 8.7) vs 22.9 (SD 7.5), p <0.0001). These results encourage balance rehabilitation of patients with CADP, aimed at promoting the use of proprioceptive information, thereby reducing too-early development of visual compensation while proprioception is still available.

Antinociceptive and anti-inflammatory activities of a pomegranate (Punica granatum L.) extract rich in ellagitannins.

Science.gov (United States)

González-Trujano, María Eva; Pellicer, Francisco; Mena, Pedro; Moreno, Diego A; García-Viguera, Cristina

2015-01-01

Pomegranate (Punica granatum L.) has been used for centuries for the treatment of inflammatory diseases. However, there is a lack of comprehensive information focused on the properties of a certain pomegranate (poly)phenolic profile to cure pain and gastric injury induced by anti-inflammatory drugs. This study investigated the systemic effects of different doses of a HPLC-characterized pomegranate extract on the formalin-induced nociceptive behavior in mice. The effect of the extract against gastric injury caused by non-steroidal anti-inflammatory drugs and ethanol was also assessed. Pomegranate reduced nociception in both phases of the formalin test, suggesting central and peripheral activities to inhibit nociception. Indomethacin-induced gastric injury was not produced in the presence of pomegranate, which also protected against ethanol-induced gastric lesions. The present results reinforce the benefits of pomegranate (poly)phenolics in the treatment of pain as well as their anti-inflammatory properties.

Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange

NARCIS (Netherlands)

van der Neut Kolfschoten, Marijn; Schuurman, Janine; Losen, Mario; Bleeker, Wim K.; Martínez-Martínez, Pilar; Vermeulen, Ellen; den Bleker, Tamara H.; Wiegman, Luus; Vink, Tom; Aarden, Lucien A.; de Baets, Marc H.; van de Winkel, Jan G. J.; Aalberse, Rob C.; Parren, Paul W. H. I.

2007-01-01

Antibodies play a central role in immunity by forming an interface with the innate immune system and, typically, mediate proinflammatory activity. We describe a novel posttranslational modification that leads to anti-inflammatory activity of antibodies of immunoglobulin G, isotype 4 (IgG4). IgG4

PET imaging of focal demyelination and remyelination in a rat model of multiple sclerosis: comparison of [{sup 11}C]MeDAS, [{sup 11}C]CIC and [{sup 11}C]PIB

Energy Technology Data Exchange (ETDEWEB)

Paula Faria, Daniele de [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen (Netherlands); University of Sao Paulo Medical School, Center of Nuclear Medicine, Sao Paulo (Brazil); Copray, Sjef [University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen (Netherlands); Sijbesma, Jurgen W.A.; Willemsen, Antoon T.M.; Dierckx, Rudi A.J.O.; Vries, Erik F.J. de [University of Groningen, University Medical Center Groningen, Department of Nuclear Medicine and Molecular Imaging, Groningen (Netherlands); Buchpiguel, Carlos A. [University of Sao Paulo Medical School, Center of Nuclear Medicine, Sao Paulo (Brazil)

2014-05-15

In this study, we compared the ability of [{sup 11}C]CIC, [{sup 11}C]MeDAS and [{sup 11}C]PIB to reveal temporal changes in myelin content in focal lesions in the lysolecithin rat model of multiple sclerosis. Pharmacokinetic modelling was performed to determine the best method to quantify tracer uptake. Sprague-Dawley rats were stereotactically injected with either 1 % lysolecithin or saline into the corpus callosum and striatum of the right brain hemisphere. Dynamic PET imaging with simultaneous arterial blood sampling was performed 7 days after saline injection (control group), 7 days after lysolecithin injection (demyelination group) and 4 weeks after lysolecithin injection (remyelination group). The kinetics of [{sup 11}C]CIC, [{sup 11}C]MeDAS and [{sup 11}C]PIB was best fitted by Logan graphical analysis, suggesting that tracer binding is reversible. Compartment modelling revealed that all tracers were fitted best with the reversible two-tissue compartment model. Tracer uptake and distribution volume in lesions were in agreement with myelin status. However, the slow kinetics and homogeneous brain uptake of [{sup 11}C]CIC make this tracer less suitable for in vivo PET imaging. [{sup 11}C]PIB showed good uptake in the white matter in the cerebrum, but [{sup 11}C]PIB uptake in the cerebellum was low, despite high myelin density in this region. [{sup 11}C]MeDAS distribution correlated well with myelin density in different brain regions. This study showed that PET imaging of demyelination and remyelination processes in focal lesions is feasible. Our comparison of three myelin tracers showed that [{sup 11}C]MeDAS has more favourable properties for quantitative PET imaging of demyelinated and remyelinated lesions throughout the CNS than [{sup 11}C]CIC and [{sup 11}C]PIB. (orig.)

Computed tomography of the central nervous system in small animals

International Nuclear Information System (INIS)

Tipold, A.; Tipold, E.

1991-01-01

With computed tomography in 44 small animals some well defined anatomical structures and pathological processes of the central nervous system are described. Computed tomography is not only necessary for the diagnosis of tumors; malformations, inflammatory, degenerative and vascular diseases and traumas are also visible

Magnetic resonance features of primary central nervous system lymphoma in the immunocompetent patient: a pictorial essay

International Nuclear Information System (INIS)

Yap, Kelvin K.; Sutherland, Tom; Liew, Elain; Tartaglia, Con J.; Trost, Nick; Pang, Mei

2012-01-01

Primary central nervous system lymphoma (PCNSL) is an uncommon but important variant of non-Hodgkin lymphoma and represents up to 6% of all primary central nervous system (CNS) malignancies. Recognition of this entity by radiologist on MRI may avoid unnecessary neurosurgical resection and redirect to biopsy. The pretreatment MRI of patients with biopsy proven PCNSL from the last 5 years at our institution was reviewed. Selected examples were used to construct a pictorial essay to illustrate some of the typical and atypical MR features of PCNSL. MRI of other CNS conditions with imaging similarities to PCNSL was included to demonstrate possible mimics. The typical features of PCNSL lymphoma are intra-axial homogenous single or multiple contrast enhancing lesions, with marked surrounding oedema and restricted diffusion, usually contacting a cerebrospinal fluid (CSF) surface. Necrosis, peripheral enhancement, haemorrhage or calcification are unusual and other diagnoses should be considered if any of these features are present. Potential mimics include high grade glioma, infarcts, metastatic disease, demyelination, abscess and secondary lymphoma. Careful assessment of the MR features and correlation with the clinical findings should enable the radiologists to raise the possibility of PCNSL and minimise the risk of unnecessary resection.

IL-12p35 Inhibits Neuroinflammation and Ameliorates Autoimmune Encephalomyelitis

Directory of Open Access Journals (Sweden)

Jin Kyeong Choi

2017-10-01

Full Text Available Multiple sclerosis (MS is an inflammatory demyelinating disease in which cytokines produced by immune cells that infiltrate the brain and spinal cord play a central role. We show here that the IL-12p35, the alpha subunit of IL-12 or IL-35 cytokine, might be an effective biologic for suppressing neuroinflammatory responses and ameliorating the pathology of experimental autoimmune encephalomyelitis (EAE, the mouse model of human MS. We further show that IL-12p35 conferred protection from neuropathy by inhibiting the expansion of pathogenic Th17 and Th1 cells and inhibiting trafficking of inflammatory cells into the brain and spinal cord. In addition, in vitro exposure of encephalitogenic cells to IL-12p35 suppressed their capacity to induce EAE by adoptive transfer. Importantly, the IL-12p35-mediated expansion of Treg and Breg cells and its amelioration of EAE correlated with inhibition of cytokine-induced activation of STAT1/STAT3 pathways. Moreover, IL-12p35 inhibited lymphocyte proliferation by suppressing the expressions of cell-cycle regulatory proteins. Taken together, these results suggest that IL-12p35 can be exploited as a novel biologic for treating central nervous system autoimmune diseases and offers the promise of ex vivo production of large amounts of Tregs and Bregs for immunotherapy.

Effects of levothyroxine on visual evoked potential impairment following local injections of lysolecithin into the rat optic chiasm

Directory of Open Access Journals (Sweden)

Cobra Payghani

2018-01-01

Full Text Available Background: Multiple sclerosis (MS is a demyelinating disease of the central nervous system which has no any known definitive treatment. Studies have shown that thyroid hormones (THs in addition to their roles in the development of the nervous system and the production of myelin have important roles in the adult's brain function. Since the only way to treat MS is the restoration of myelin, the aim of this study was to evaluate the effects of levothyroxine on visual evoked potential (VEP impairment following local injections of lysolecithin into the rat optic chiasm. Methods: To induce demyelination, lysolecithin was injected into the optic chiasm of male Wistar rats. VEP recording was used to evaluate demyelination and remyelination before and 10, 17, and 24 days after the lysolecithin injection. The rats received an intraperitoneal injection of levothyroxine with doses 20, 50, and 100 μg/kg in different experimental groups. Results: VEP latency and amplitude showed demyelination at 10 and 17 days after an induced lesion in MS group which was reversed at day 24. Levothyroxine prevented these impairments, especially in high doses. Conclusions: According to the results, lysolecithin-induced demyelination at optic chiasm and VEP impairments can be restored by administration of levothyroxine. Therefore, THs probably have positive effects in demyelinating diseases.

Therapeutic interference with leukocyte recirculation in multiple sclerosis

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Sellebjerg, F; Sørensen, P S

2015-01-01

Multiple sclerosis (MS) is an immune-mediated disease where T cells are thought to initiate an inflammatory reaction in the brain and spinal cord, resulting in demyelination and axonal pathology. Interfering with the activation and recruitment of immune cells reduces disease activity in MS. We...... review the mechanism of action and treatment effects of natalizumab and fingolimod, which interfere with the recruitment of pathogenic immune cells in MS. Fingolimod blocks the egress of activated lymphocytes from lymph nodes by binding to the sphingosine-1-phosphate (S1P) receptor 1, but may also have...... effects on S1P receptor-expressing cells within the central nervous system (CNS). Natalizumab reduces the migration of lymphocytes to the CNS by binding to the α4 integrin very late antigen 4. Fingolimod and natalizumab also have other effects, but these are less well understood. Both treatments...

Direct Pathogenic Effects of HERV-encoded Proteins

DEFF Research Database (Denmark)

Hansen, Dorte Tranberg; Møller-Larsen, Anné; Petersen, Thor

Background: Multiple sclerosis (MS) is a demyelinating, inflammatory disease of the central nervous system (CNS). MS is mediated by the immune system but the etiology of the disease remains unknown. Retroviral envelope (Env) proteins, encoded by human endogenous retroviruses (HERVs), are expressed...... in increased amounts on B cells from MS patients. Furthermore, the amount of anti-HERV antibodies in serum and cerebrospinal fluid from patients with MS is increased when compared with healthy controls. Aim: The overall aim of this project is to investigate the potential role of HERVs in the development of MS...... and the possible direct pathogenic effects of HERV-encoded Env proteins on the CNS. Methods: Construction and characterization of a panel of recombinant Env-proteins is initiated and their pathogenic potential will be investigated: Fusiogenic potential analyzed by flow cytometry and confocal microscopy. Analysis...

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, Finn; Cadavid, Diego; Steiner, Deborah

2016-01-01

progressive MS (SPMS), for which approved disease-modifying therapies are limited. In this review, we summarize the pathophysiological mechanisms involved in the development of SPMS and the rationale and clinical potential for natalizumab, which is currently approved for the treatment of relapsing forms of MS......Multiple sclerosis (MS) is a common and chronic central nervous system (CNS) demyelinating disease and a leading cause of permanent disability. Patients most often present with a relapsing-remitting disease course, typically progressing over time to a phase of relentless advancement in secondary......, to exert beneficial effects in reducing disease progression unrelated to relapses in SPMS. In both forms of MS, active brain-tissue injury is associated with inflammation; but in SPMS, the inflammatory response occurs at least partly behind the blood-brain barrier and is followed by a cascade of events...

Neuropsychology in Multiple Sclerosis: A literature review.

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Rodneys Mauricio Jiménez Morales

2011-11-01

Full Text Available Multiple sclerosis is an inflammatory disease of the central nervous system that is characterized by demyelination and degeneration. The objective of this article is to offer a review of the latest scientific discoveries in the field of neuropsychology in ME. A description is presented of the most frequent neuropsychological manifestations and their probable association with other factors such as: school level, fatigue, disability, cerebral dysfunction, time and clinical form of evolution, as well as depression and other states of mind starting from recent evidences in the scientific community. Also addressed is the development of tests and valid sensitive neuropsychological sets to evaluate cognitive functions. The use of sensitive and specific test facilitates the evaluation of neuropsychological alterations associated to ME, besides other socio-demographic and clinical-evaluative factors to contemplate in the exploration.

The impact of HSV for inflammatory arthropathy patients.

LENUS (Irish Health Repository)

O'Connor, Mortimer B

2012-02-01

Herpes simplex virus type 1 (HSV-1), also known as herpes labialis, is the etiologic agent of vesicular lesions of the oral mucosa commonly referred to as "cold sores". HSV-1 can also cause clinical disease in a wide variety of other anatomic locations including the genitalia, liver, lung, eye, and central nervous system. These infections can be severe, particularly in the setting of immunosuppression, such as inflammatory arthropathy patients on Methotrexate ± biological therapies. Here, we highlight the importance of physician awareness of HSV due to its potential impact for rheumatology patients.

Hypertensive Encephalopathy: Isolated Pons Involvement Mimicking Central Pontine Myelinolysis

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Gamanagatti, S.; Subramanian, S.

2006-01-01

MRI of the brain was performed, and it demonstrated an isolated high signal on the T2 weighted and fluid attenuated inversion recovery sequences that involved only the central pons with sparing the periphery. There was no restricted diffusion on diffusion weighted imaging. The differential diagnosis included posterior reversible syndrome and central pontine myelinolysis; however, the blood sodium on admission was normal. The pathogenesis of HE is that the auto-regulatory mechanisms that control the cerebral blood flow are exceeded, resulting in hyper-perfusion. The consequent over-distension of the cerebral vessels, the breakdown of the blood brain barrier and ultimately, the extravasation of fluid into the interstitium all cause vasogenic edema. In most cases, the changes of hypertensive encephalopathy represent reversible vasogenic edema, which can be seen on T2-weighted images, and restricted diffusion is not seen on the diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) maps. Hypertensive encephalopathy that manifests as a reversible increased signal isolated to the pons on T2-weighted images is extremely uncommon. The differential diagnosis for such pontine T2 hyperintensity includes pontine glioma, ischemic and radiation changes (generally irreversible conditions), as well as central pontine myelinolysis (CPM) and demyelinating disorders such as multiple sclerosis, acute disseminated encephalomyelitis and rhomb-encephalitis. In CPM electrolyte imbalances provide a clue for the diagnosis, where as for glioma, there will be an expansion and mass effect. In conclusion, clinical recognition of brainstem HE may be difficult. The features of a lack of correlation between the severity of the radiological abnormality and the clinical status, combined with the rapid resolution following antihypertensive treatment, should suggest the diagnosis. It is important for the radiologist to be familiar with the imaging abnormalities of this life

Hypertensive Encephalopathy: Isolated Pons Involvement Mimicking Central Pontine Myelinolysis

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Gamanagatti, S.; Subramanian, S. [India Institute of Medical Sciences, New Delhi (India)

2006-09-15

MRI of the brain was performed, and it demonstrated an isolated high signal on the T2 weighted and fluid attenuated inversion recovery sequences that involved only the central pons with sparing the periphery. There was no restricted diffusion on diffusion weighted imaging. The differential diagnosis included posterior reversible syndrome and central pontine myelinolysis; however, the blood sodium on admission was normal. The pathogenesis of HE is that the auto-regulatory mechanisms that control the cerebral blood flow are exceeded, resulting in hyper-perfusion. The consequent over-distension of the cerebral vessels, the breakdown of the blood brain barrier and ultimately, the extravasation of fluid into the interstitium all cause vasogenic edema. In most cases, the changes of hypertensive encephalopathy represent reversible vasogenic edema, which can be seen on T2-weighted images, and restricted diffusion is not seen on the diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) maps. Hypertensive encephalopathy that manifests as a reversible increased signal isolated to the pons on T2-weighted images is extremely uncommon. The differential diagnosis for such pontine T2 hyperintensity includes pontine glioma, ischemic and radiation changes (generally irreversible conditions), as well as central pontine myelinolysis (CPM) and demyelinating disorders such as multiple sclerosis, acute disseminated encephalomyelitis and rhomb-encephalitis. In CPM electrolyte imbalances provide a clue for the diagnosis, where as for glioma, there will be an expansion and mass effect. In conclusion, clinical recognition of brainstem HE may be difficult. The features of a lack of correlation between the severity of the radiological abnormality and the clinical status, combined with the rapid resolution following antihypertensive treatment, should suggest the diagnosis. It is important for the radiologist to be familiar with the imaging abnormalities of this life

Optimizing the management of neuromyelitis optica and spectrum disorders in resource poor settings: Experience from the Mangalore demyelinating disease registry

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Lekha Pandit

2013-01-01

Full Text Available Background: In resource-poor settings, the management of neuromyelitis optica (NMO and NMO spectrum (NMOS disorders is limited because of delayed diagnosis and financial constraints. Aim: To device a cost-effective strategy for the management of NMO and related disorders in India. Materials and Methods: A cost-effective and disease-specific protocol was used for evaluating the course and treatment outcome of 70 consecutive patients. Results: Forty-five patients (65% had a relapse from the onset and included NMO (n = 20, recurrent transverse myelitis (RTM; n = 10, and recurrent optic neuritis (ROPN; n = 15. In 38 (84.4% patients presenting after multiple attacks, the diagnosis was made clinically. Only 7 patients with a relapsing course were seen at the onset and included ROPN (n = 5, NMO (n = 1, and RTM (n = 1. They had a second attack after a median interval of 1 ± 0.9 years, which was captured through our dedicated review process. Twenty-five patients had isolated longitudinally extensive transverse myelitis (LETM, of which 20 (80% remained ambulant at follow-up of 3 ± 1.9 years. Twelve patients (17% with median expanded disability status scale (EDSS of 8.5 at entry had a fatal outcome. Serum NMO-IgG testing was done in selected patients, and it was positive in 7 of 18 patients (39%. Irrespective of the NMO-IgG status, the treatment compliant patients (44.4% showed significant improvement in EDSS (P ≤ 0.001. Conclusions : Early clinical diagnosis and treatment compliance were important for good outcome. Isolated LETM was most likely a post-infectious demyelinating disorder in our set-up. NMO and NMOS disorders contributed to 14.9% (45/303 of all demyelinating disorders in our registry.

Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia.

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Bozic, Iva; Savic, Danijela; Laketa, Danijela; Bjelobaba, Ivana; Milenkovic, Ivan; Pekovic, Sanja; Nedeljkovic, Nadezda; Lavrnja, Irena

2015-01-01

Microglial cells are resident immune cells of the central nervous system (CNS), recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine) derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS) and NO; cyclooxygenase-2 (COX-2), heat-shock protein 70 (Hsp70), tumor necrosis factor alpha α (TNF-α), interleukin-6 (IL-6), whereas it increased anti-inflammatory interleukin-10 (IL-10) production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK) and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the nucleus. Therefore, benfotiamine may

HOW DOES FINGOLIMOD (GILENYA® FIT IN THE TREATMENT ALGORITHM FOR HIGHLY ACTIVE RELAPSING-REMITTING MULTIPLE SCLEROSIS?

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Franz eFazekas

2013-05-01

Full Text Available Multiple sclerosis (MS is a neurological disorder characterised by inflammatory demyelination and neurodegeneration in the central nervous system (CNS. Until recently, disease modifying treatment was based on agents requiring parenteral delivery, thus limiting long-term compliance. Basic treatments such as beta-interferon provide only moderate efficacy, and although therapies for second-line treatment and highly active MS are more effective, they are associated with potentially severe side effects. Fingolimod (Gilenya® is the first oral treatment of MS and has recently been approved as single disease-modifying therapy in highly active relapsing-remitting multiple sclerosis (RRMS for adult patients with high disease activity despite basic treatment (beta-interferon and for treatment-naïve patients with rapidly evolving severe RRMS. At a scientific meeting that took place in Vienna on November 18th, 2011, experts from 10 Central and Eastern European countries discussed the clinical benefits and potential risks of fingolimod for MS, suggested how the new therapy fits within the current treatment algorithm and provided expert opinion for the selection and management of patients.

Mechanisms of action of cannabidiol in adoptively transferred experimental autoimmune encephalomyelitis.

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González-García, Coral; Torres, Irene Moreno; García-Hernández, Ruth; Campos-Ruíz, Lucía; Esparragoza, Luis Rodríguez; Coronado, María José; Grande, Aranzazu García; García-Merino, Antonio; Sánchez López, Antonio J

2017-12-01

Cannabidiol (CBD) is one of the most important compounds in Cannabis sativa, lacks psychotropic effects, and possesses a high number of therapeutic properties including the amelioration of experimental autoimmune encephalomyelitis (EAE). The aim of this study was to analyse the relative efficacy of CBD in adoptively transferred EAE (at-EAE), a model that allows better delineation of the effector phase of EAE. Splenocytes and lymph nodes from mice with actively induced EAE were cultured in the presence of MOG 35-55 and IL-12 and inoculated intraperitoneally in recipient female C57BL/6J mice. The effects of CBD were evaluated using clinical scores and magnetic resonance imaging (MRI). In the central nervous system, the extent of cell infiltration, axonal damage, demyelination, microglial activation and cannabinoid receptors expression was assessed by immunohistochemistry. Lymph cell viability, apoptosis, oxidative stress and IL-6 production were measured in vitro. Preventive intraperitoneal treatment with CBD ameliorated the clinical signs of at-EAE, and this improvement was accompanied by a reduction of the apparent diffusion coefficient in the subiculum area of the brain. Inflammatory infiltration, axonal damage, and demyelination were reduced, and cannabinoid receptor expression was modulated. Incubation with CBD decreased encephalitogenic cell viability, increasing early apoptosis and reactive oxygen species (ROS) and decreasing IL-6 production. The reduction in viability was not mediated by CB 1 , CB 2 or GPR55 receptors. CBD markedly improved the clinical signs of at-EAE and reduced infiltration, demyelination and axonal damage. The CBD-mediated decrease in the viability of encephalitogenic cells involves ROS generation, apoptosis and a decrease in IL-6 production and may contribute to the therapeutic effect of this compound. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

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Alger, Jeffry R.; Barker, Peter B.; Bartha, Robert; Bizzi, Alberto; Boesch, Chris; Bolan, Patrick J.; Brindle, Kevin M.; Cudalbu, Cristina; Dinçer, Alp; Dydak, Ulrike; Emir, Uzay E.; Frahm, Jens; González, Ramón Gilberto; Gruber, Stephan; Gruetter, Rolf; Gupta, Rakesh K.; Heerschap, Arend; Henning, Anke; Hetherington, Hoby P.; Howe, Franklyn A.; Hüppi, Petra S.; Hurd, Ralph E.; Kantarci, Kejal; Klomp, Dennis W. J.; Kreis, Roland; Kruiskamp, Marijn J.; Leach, Martin O.; Lin, Alexander P.; Luijten, Peter R.; Marjańska, Małgorzata; Maudsley, Andrew A.; Meyerhoff, Dieter J.; Mountford, Carolyn E.; Nelson, Sarah J.; Pamir, M. Necmettin; Pan, Jullie W.; Peet, Andrew C.; Poptani, Harish; Posse, Stefan; Pouwels, Petra J. W.; Ratai, Eva-Maria; Ross, Brian D.; Scheenen, Tom W. J.; Schuster, Christian; Smith, Ian C. P.; Soher, Brian J.; Tkáč, Ivan; Vigneron, Daniel B.; Kauppinen, Risto A.

2014-01-01

A large body of published work shows that proton (hydrogen 1 [1H]) magnetic resonance (MR) spectroscopy has evolved from a research tool into a clinical neuroimaging modality. Herein, the authors present a summary of brain disorders in which MR spectroscopy has an impact on patient management, together with a critical consideration of common data acquisition and processing procedures. The article documents the impact of 1H MR spectroscopy in the clinical evaluation of disorders of the central nervous system. The clinical usefulness of 1H MR spectroscopy has been established for brain neoplasms, neonatal and pediatric disorders (hypoxia-ischemia, inherited metabolic diseases, and traumatic brain injury), demyelinating disorders, and infectious brain lesions. The growing list of disorders for which 1H MR spectroscopy may contribute to patient management extends to neurodegenerative diseases, epilepsy, and stroke. To facilitate expanded clinical acceptance and standardization of MR spectroscopy methodology, guidelines are provided for data acquisition and analysis, quality assessment, and interpretation. Finally, the authors offer recommendations to expedite the use of robust MR spectroscopy methodology in the clinical setting, including incorporation of technical advances on clinical units. © RSNA, 2014 Online supplemental material is available for this article. PMID:24568703

Meningeal mast cells affect early T cell central nervous system infiltration and blood-brain barrier integrity through TNF: a role for neutrophil recruitment?

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Sayed, Blayne A; Christy, Alison L; Walker, Margaret E; Brown, Melissa A

2010-06-15

Mast cells contribute to the pathogenesis of experimental autoimmune encephalomyelitis, a rodent model of the human demyelinating disease multiple sclerosis. Yet their site and mode of action is unknown. In both diseases, myelin-specific T cells are initially activated in peripheral lymphoid organs. However, for disease to occur, these cells must enter the immunologically privileged CNS through a breach in the relatively impermeable blood-brain barrier. In this study, we demonstrate that a dense population of resident mast cells in the meninges, structures surrounding the brain and spinal cord, regulate basal CNS barrier function, facilitating initial T cell CNS entry. Through the expression of TNF, mast cells recruit an early wave of neutrophils to the CNS. We propose that neutrophils in turn promote the blood-brain barrier breach and together with T cells lead to further inflammatory cell influx and myelin damage. These findings provide specific targets for intervention in multiple sclerosis as well as other immune-mediated CNS diseases.

Chagas disease: modulation of the inflammatory response by acetylcholinesterase in hematological cells and brain tissue.

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Silva, Aniélen D; Bottari, Nathieli B; do Carmo, Guilherme M; Baldissera, Matheus D; Souza, Carine F; Machado, Vanessa S; Morsch, Vera M; Schetinger, Maria Rosa C; Mendes, Ricardo E; Monteiro, Silvia G; Da Silva, Aleksandro S

2018-01-01

Chagas disease is an acute or chronic illness that causes severe inflammatory response, and consequently, it may activate the inflammatory cholinergic pathway, which is regulated by cholinesterases, including the acetylcholinesterase. This enzyme is responsible for the regulation of acetylcholine levels, an anti-inflammatory molecule linked to the inflammatory response during parasitic diseases. Thus, the aim of this study was to investigate whether Trypanosoma cruzi infection can alter the activity of acetylcholinesterase and acetylcholine levels in mice, and whether these alterations are linked to the inflammatory cholinergic signaling pathway. Twenty-four mice were divided into two groups: uninfected (control group, n = 12) and infected by T. cruzi, Y strain (n = 12). The animals developed acute disease with a peak of parasitemia on day 7 post-infection (PI). Blood, lymphocytes, and brain were analyzed on days 6 and 12 post-infection. In the brain, acetylcholine and nitric oxide levels, myeloperoxidase activity, and histopathology were analyzed. In total blood and brain, acetylcholinesterase activity decreased at both times. On the other hand, acetylcholinesterase activity in lymphocytes increased on day 6 PI compared with the control group. Infection by T. cruzi increased acetylcholine and nitric oxide levels and histopathological damage in the brain of mice associated to increased myeloperoxidase activity. Therefore, an intense inflammatory response in mice with acute Chagas disease in the central nervous system caused an anti-inflammatory response by the activation of the cholinergic inflammatory pathway.

Transgenic inhibition of astroglial NF-κB protects from optic nerve damage and retinal ganglion cell loss in experimental optic neuritis

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Brambilla Roberta

2012-09-01

Full Text Available Abstract Background Optic neuritis is an acute, demyelinating neuropathy of the optic nerve often representing the first appreciable symptom of multiple sclerosis. Wallerian degeneration of irreversibly damaged optic nerve axons leads to death of retinal ganglion cells, which is the cause of permanent visual impairment. Although the specific mechanisms responsible for triggering these events are unknown, it has been suggested that a key pathological factor is the activation of immune-inflammatory processes secondary to leukocyte infiltration. However, to date, there is no conclusive evidence to support such a causal role for infiltrating peripheral immune cells in the etiopathology of optic neuritis. Methods To dissect the contribution of the peripheral immune-inflammatory response versus the CNS-specific inflammatory response in the development of optic neuritis, we analyzed optic nerve and retinal ganglion cells pathology in wild-type and GFAP-IκBα-dn transgenic mice, where NF-κB is selectively inactivated in astrocytes, following induction of EAE. Results We found that, in wild-type mice, axonal demyelination in the optic nerve occurred as early as 8 days post induction of EAE, prior to the earliest signs of leukocyte infiltration (20 days post induction. On the contrary, GFAP-IκBα-dn mice were significantly protected and showed a nearly complete prevention of axonal demyelination, as well as a drastic attenuation in retinal ganglion cell death. This correlated with a decrease in the expression of pro-inflammatory cytokines, chemokines, adhesion molecules, as well as a prevention of NAD(PH oxidase subunit upregulation. Conclusions Our results provide evidence that astrocytes, not infiltrating immune cells, play a key role in the development of optic neuritis and that astrocyte-mediated neurotoxicity is dependent on activation of a transcriptional program regulated by NF-κB. Hence, interventions targeting the NF-κB transcription

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-04-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Citral reduces nociceptive and inflammatory response in rodents

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Lucindo J. Quintans-Júnior

2011-06-01

Full Text Available Citral (CIT, which contains the chiral enantiomers, neral (cis and geranial (trans, is the majority monoterpene from Lippia alba and Cymbopogon citratus. The present study aimed to evaluate CIT for antinociceptive and anti-inflammatory activities in rodents. Antinociceptive and anti-inflammatory effects were studied by measuring nociception through acetic acid and formalin tests, while inflammation was verified by inducing peritonitis and paw edema with carrageenan. All tested doses of CIT had significant protection (p<0.001 against acetic acid (0.8% induced nociceptive behavior and the effects were also similar to morphine while formalin induced nociception was significantly protected (p<0.05 only at higher dose (200 mg/kg of CIT in the first phase of the test. CIT significantly reduce (p<0.001 nociceptive behavior emanating from inflammation in second phase at all the doses.The pretreatment with CIT (100 and 200 mg/kg significantly reduced the paw edema induced by carrageenan. Moreover, systemic treatment with CIT (100 and 200 mg/kg significantly reduced (p<0.001 the leukocyte migration in the carrageenan-induced migration to the peritoneal cavity. Our investigation shows that CIT possess significant central and peripheral antinociceptive effects. It was also verified an anti-inflammatory activity. All together these results suggest that CIT might represent important tool for treatment of painful conditions.

Central nervous system mast cells in peripheral inflammatory nociception

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Ellmeier Wilfried

2011-06-01

Full Text Available Abstract Background Functional aspects of mast cell-neuronal interactions remain poorly understood. Mast cell activation and degranulation can result in the release of powerful pro-inflammatory mediators such as histamine and cytokines. Cerebral dural mast cells have been proposed to modulate meningeal nociceptor activity and be involved in migraine pathophysiology. Little is known about the functional role of spinal cord dural mast cells. In this study, we examine their potential involvement in nociception and synaptic plasticity in superficial spinal dorsal horn. Changes of lower spinal cord dura mast cells and their contribution to hyperalgesia are examined in animal models of peripheral neurogenic and non-neurogenic inflammation. Results Spinal application of supernatant from activated cultured mast cells induces significant mechanical hyperalgesia and long-term potentiation (LTP at spinal synapses of C-fibers. Lumbar, thoracic and thalamic preparations are then examined for mast cell number and degranulation status after intraplantar capsaicin and carrageenan. Intradermal capsaicin induces a significant percent increase of lumbar dural mast cells at 3 hours post-administration. Peripheral carrageenan in female rats significantly increases mast cell density in the lumbar dura, but not in thoracic dura or thalamus. Intrathecal administration of the mast cell stabilizer sodium cromoglycate or the spleen tyrosine kinase (Syk inhibitor BAY-613606 reduce the increased percent degranulation and degranulated cell density of lumbar dural mast cells after capsaicin and carrageenan respectively, without affecting hyperalgesia. Conclusion The results suggest that lumbar dural mast cells may be sufficient but are not necessary for capsaicin or carrageenan-induced hyperalgesia.

Standing postural reaction to visual and proprioceptive stimulation in chronic acquired demyelinating polyneuropathy

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Clement P. Provost

2018-01-01

Full Text Available Objective: To investigate the weight of visual and proprioceptive inputs, measured indirectly in standing position control, in patients with chronic acquired demyelinating polyneuropathy (CADP. Design: Prospective case study. Subjects: Twenty-five patients with CADP and 25 healthy controls. Methods: Posture was recorded on a double force platform. Stimulations were optokinetic (60°/s for visual input and vibration (50 Hz for proprioceptive input. Visual stimulation involved 4 tests (upward, downward, rightward and leftward and proprioceptive stimulation 2 tests (triceps surae and tibialis anterior. A composite score, previously published and slightly modified, was used for the recorded postural signals from the different stimulations. Results: Despite their sensitivity deficits, patients with CADP were more sensitive to proprioceptive stimuli than were healthy controls (mean composite score 13.9 ((standard deviation; SD 4.8 vs 18.4 (SD 4.8, p = 0.002. As expected, they were also more sensitive to visual stimuli (mean composite score 10.5 (SD 8.7 vs 22.9 (SD 7.5, p< 0.0001. Conclusion: These results encourage balance rehabilitation of patients with CADP, aimed at promoting the use of proprioceptive information, thereby reducing too-early development of visual compensation while proprioception is still available.

Xanomeline suppresses excessive pro-inflammatory cytokine responses through neural signal-mediated pathways and improves survival in lethal inflammation

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Rosas-Ballina, Mauricio; Ferrer, Sergio Valdés; Dancho, Meghan; Ochani, Mahendar; Katz, David; Cheng, Kai Fan; Olofsson, Peder S.; Chavan, Sangeeta S.; Al-Abed, Yousef; Tracey, Kevin J.; Pavlov, Valentin A.

2014-01-01

Inflammatory conditions characterized by excessive immune cell activation and cytokine release, are associated with bidirectional immune system-brain communication, underlying sickness behavior and other physiological responses. The vagus nerve has an important role in this communication by conveying sensory information to the brain, and brain-derived immunoregulatory signals that suppress peripheral cytokine levels and inflammation. Brain muscarinic acetylcholine receptor (mAChR)-mediated cholinergic signaling has been implicated in this regulation. However, the possibility of controlling inflammation by peripheral administration of centrally-acting mAChR agonists is unexplored. To provide insight we used the centrally-acting M1 mAChR agonist xanomeline, previously developed in the context of Alzheimer’s disease and schizophrenia. Intraperitoneal administration of xanomeline significantly suppressed serum and splenic TNF levels, alleviated sickness behavior, and increased survival during lethal murine endotoxemia. The anti-inflammatory effects of xanomeline were brain mAChR-mediated and required intact vagus nerve and splenic nerve signaling. The anti-inflammatory efficacy of xanomeline was retained for at least 20h, associated with alterations in splenic lymphocyte, and dendritic cell proportions, and decreased splenocyte responsiveness to endotoxin. These results highlight an important role of the M1 mAChR in a neural circuitry to spleen in which brain cholinergic activation lowers peripheral pro-inflammatory cytokines to levels favoring survival. The therapeutic efficacy of xanomeline was also manifested by significantly improved survival in preclinical settings of severe sepsis. These findings are of interest for strategizing novel therapeutic approaches in inflammatory diseases. PMID:25063706

Neural control disturbances of the gastrointestinal tract and visceral pain in inflammatory bowel diseases 

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Katarzyna Ciesielczyk

2013-04-01

Full Text Available Inflammatory bowel disease (IBD is a chronic intestinal inflammatory condition, the etiology of which is composed of factors such as the environment, genetic predisposition, gut dysbiosis and inadequate immune response. The pathologic findings in Crohn’s disease and ulcerative colitis are related to dysfunction of gastrointestinal secretion and motility and also disturbed visceral sensory function, with accompanying intestinal and parenteral complications. The systemic inflammatory response affects neurological control via the gut-brain axis, which modulates the cooperation of the autonomic nervous system (ANS, enteric nervous system (ENS and gut-associated lymphoid tissue (GALT. In chronic inflammation the intestinal neuropathy disrupts peristalsis and intestinal secretion as well as causing unpleasant symptoms of the patients. Pain receptors are stimulated by inflammatory mediators, and due to the intensified activation of the nociceptive system visceral hypersensitivity through central and peripheral sensitization is generated. Chronic visceral pain negatively influences the course of disease and the quality of the patient’s life. The growing knowledge about the neurological control dysfunction of the intestine and immune system dysregulation could provide proper directives for treatment of inflammatory bowel diseases.

Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp Beta and down-regulation of G-CSF

DEFF Research Database (Denmark)

Worm, Jesper; Stenvang, Jan; Petri, Andreas

2009-01-01

microRNA-155 (miR-155) has been implicated as a central regulator of the immune system, but its function during acute inflammatory responses is still poorly understood. Here we show that exposure of cultured macrophages and mice to lipopolysaccharide (LPS) leads to up-regulation of miR-155......-stimulating factor (G-CSF), a central regulator of granulopoiesis during inflammatory responses. Consistent with these data, we show that silencing of miR-155 in LPS-treated mice by systemically administered LNA-antimiR results in derepression of the c/ebp Beta isoforms and down-regulation of G-CSF expression...

Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis

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Espejo, C; Carrasco, J; Hidalgo, J

2001-01-01

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein......-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression...

A Review of Select Centralized Pain Syndromes

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David R. Spiegel

2015-01-01

Full Text Available Pain can be broadly divided into 3 classes, including nociceptive or inflammatory pain (protective, neuropathic (pathological, occurring after damage to the nervous system, or centralized (pathological, due to abnormal function but with no damage or inflammation to the nervous system. The latter has been posited to occur when descending analgesic pathways are attenuated and/or glutamatergic transmission is facilitated. Additionally, this “pain prone phenotype” can be associated with early life trauma and a suboptimal response to opiates. This article will review the relationships between centralized pain syndromes (ie, fibromyalgia, chronic low back pain, childhood sexual abuse, and opiate misuse. Finally, treatment implications, potentially effecting primary care physicians, will be discussed.

Borneol, a Bicyclic Monoterpene Alcohol, Reduces Nociceptive Behavior and Inflammatory Response in Mice

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Jackson Roberto Guedes da Silva Almeida

2013-01-01

Full Text Available Borneol, a bicyclic monoterpene, has been evaluated for antinociceptive and anti-inflammatory activities. Antinociceptive and anti-inflammatory activities were studied by measuring nociception by acetic acid, formalin, hot plate, and grip strength tests, while inflammation was prompted by carrageenan-induced peritonitis. The rotarod test was used to evaluate motor coordination. Borneol produced a significant (P<0.01 reduction of the nociceptive behavior at the early and late phases of paw licking and reduced the writhing reflex in mice (formalin and writhing tests, resp.. When the hot plate test was conducted, borneol (in higher dose produced an inhibition (P<0.05 of the nociceptive behavior. Such results were unlikely to be provoked by motor abnormality. Additionally, borneol-treated mice reduced the carrageenan-induced leukocytes migration to the peritoneal cavity. Together, our results suggest that borneol possess significant central and peripheral antinociceptive activity; it has also anti-inflammatory activity. In addition, borneol did not impair motor coordination.

Molecular Epidemiology of Human Polyomavirus JC in the Biaka Pygmies and Bantu of Central Africa

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Sylvester C Chima

1998-09-01

Full Text Available Polyomavirus JC (JCV is ubiquitous in humans and causes a chronic demyelinating disease of the central nervous system , progressive multifocal leukoencephalopathy which is common in AIDS. JCV is excreted in urine of 30-70% of adults worldwide. Based on sequence analysis of JCV complete genomes or fragments thereof, JCV can be classified into geographically derived genotypes. Types 1 and 2 are of European and Asian origin respectively while Types 3 and 6 are African in origin. Type 4, a possible recombinant of European and African genotypes (1 and 3 is common in the USA. To delineate the JCV genotypes in an aboriginal African population, random urine samples were collected from the Biaka Pygmies and Bantu from the Central African Republic. There were 43 males and 25 females aged 4-55 years, with an average age of 26 years. After PCR amplification of JCV in urine, products were directly cycle sequenced. Five of 23 Pygmy adults (22% and four of 20 Bantu adults (20% were positive for JC viruria. DNA sequence analysis revealed JCV Type 3 (two, Type 6 (two and one Type 1 variant in Biaka Pygmies. All the Bantu strains were Type 6. Type 3 and 6 strains of JCV are the predominant strains in central Africa. The presence of multiple subtypes of JCV in Biaka Pygmies may be a result of extensive interactions of Pygmies with their African tribal neighbors during their itinerant movements in the equatorial forest.

Neuroimmune regulation of inflammatory responses in inflammatory bowel disease

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Rijnierse, Anneke

2006-01-01

The term inflammatory bowel disease (IBD) is used to describe chronic inflammatory conditions of the gastro-intestinal tract. Patients suffer from abdominal pain, diarrhea, rectal bleeding and a substantial personal burden. The etiology of IBD is gradually being unraveled but remains a complex

Mouse hepatitis virus infection upregulates genes involved in innate immune responses.

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Dhriti Chatterjee

Full Text Available Neurotropic recombinant strain of Mouse Hepatitis Virus, RSA59, induces meningo-encephalitis, myelitis and demyelination following intracranial inoculation. RSA59 induced neuropathology is partially caused by activation of CNS resident microglia, as demonstrated by changes in cellular morphology and increased expression of a microglia/macrophage specific calcium ion binding factor, Iba1. Affymetrix Microarray analysis for mRNA expression data reveals expression of inflammatory mediators that are known to be released by activated microglia. Microglia-specific cell surface molecules, including CD11b, CD74, CD52 and CD68, are significantly upregulated in contrast to CD4, CD8 and CD19. Protein analysis of spinal cord extracts taken from mice 6 days post-inoculation, the time of peak inflammation, reveals robust expression of IFN-γ, IL-12 and mKC. Data suggest that activated microglia and inflammatory mediators contribute to a local CNS microenvironment that regulates viral replication and IFN-γ production during the acute phase of infection, which in turn can cause phagolysosome maturation and phagocytosis of the myelin sheath, leading to demyelination.

Huperzine A inhibits CCL2 production in experimental autoimmune encephalomyelitis mice and in cultured astrocyte.

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Tian, G X; Zhu, X Q; Chen, Y; Wu, G C; Wang, J

2013-01-01

The active role of chemokines and inflammatory cytokines in the central nervous system (CNS) during the pathogenesis of experimental autoimmune encephalomyelitis (EAE) has been clearly established. Recent studies from our laboratory reported that Huperzine A (HupA) can attenuate the disease process in EAE by the inhibition of inflammation, demyelination, and axonal injury in the spinal cord as well as encephalomyelitic T-cell proliferation. In this study, the effects of low dose HupA on CCL2, TNF-alpha, IL-6, and IL-1beta expression were evaluated in EAE. The effect of HupA on lipopolysachharide (LPS)-induced inflammatory molecule secretion was investigated in cultured-astrocytes in vitro. In MOG35-55-induced EAE mice, intraperitoneal injections of HupA (0.1 mg/kg•d−1) significantly suppressed the expression of CCL2, IL-6, TNF-alpha, and IL-1beta in the spinal cord. HupA also repressed LPS-induced CCL2 production, but with little influence on pro-inflammatory cytokines in primary cultured astrocytes. The inhibition effect of HupA on CCL2 is PPARgamma-dependent and nicotine receptor-independent. Conditioned culture media from HupA-treated astrocyte decreased PBMC migration in vitro. Collectively, these results suggest that HupA can ameliorate EAE by inhibiting CCL2 production in astrocyte, which may consequently decrease inflammatory cell infiltration in the spinal cord. HupA may have a potential therapeutic value for the treatment of MS and other neuroinflammatory diseases.

Waist-to-Height Ratio in Indian Women: Comparison With Traditional Indices of Obesity, Association With Inflammatory Biomarkers and Lipid Profile.

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Dilip Malshe, Sharvari; Anand Udipi, Shobha

2017-07-01

We compared waist-to-height ratio (WHtR) with traditional anthropometric indices in healthy women aged 21 to 45 years from urban slums of Mumbai city, India. Lipid profile and inflammatory markers were measured in a subsample of 200 women, and their relationship with WHtR was examined. Mean WHtR was 0.50 ± 0.1, but a little more than half (51.9%) of the women had WHtR ≥0.50. WHtR could correctly identify centrally obese adult women, even when they were categorized as healthy or normal according to body mass index, waist circumference, waist to hip ratio, and percentage body fat. Also, in centrally obese women, inflammatory markers-namely, high-sensitivity C-reactive protein, interleukin-6, and interleukin-10-were significantly and positively correlated with WHtR. Thus, results of this study indicate that WHtR is a simple and effective anthropometric variable that has the potential to identify central obesity and the associated inflammation even in women with normal BMI.

Anti-inflammatory and antinociceptive activities of Phyllanthus niruri spray-dried standardized extract

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Cínthia R. C. Porto

2013-02-01

Full Text Available Phyllanthus niruri L., Euphorbiaceae, spray-dried standardized extract was studied for its anti-inflammatory and antinociceptive activities in adult albino rats and mice. The anti-inflammatory effect of spray-dried standardized extract was observed in carrageenan-induced paw edema and thioglycolate-induced leukocyte migration, while antinociceptive effects were observed using Randall & Selitto, tail flick, and hot plate tests. This study showed that intraperitoneal spray-dried standardized extract at 100, 200, 800, or 1600 mg/kg reduced the vascular response in the inflammatory process of paw edema induced by 1% carrageenan. Oral spray-dried standardized extract at 100 or 200 mg/kg inhibited leukocyte migration to the site of inflammation induced by 3% thioglycolate. In rats, at 100 and 200 mg/kg intraperitoneally, the extract exhibited a marked peripheral analgesic effect in a Randall & Selitto assay and showed significant central analgesic activity in a hot plate and tail flick assay. In conclusion, this study suggested that Phyllanthus niruri spray-dried standardized extract has potent inflammatory and antinociceptive activities and that these activities are not modified by standard drying process, making it feasible to use the dry extract standardized to obtain a phytotherapic preparation and thus validating its use for the treatment of pain and inflammation disorders.

Sulfatide levels correlate with severity of neuropathy in metachromatic leukodystrophy

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Dali, Christine I; Barton, Norman W; Farah, Mohamed H

2015-01-01

OBJECTIVE: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disorder due to deficient activity of arylsulfatase A (ASA) that causes accumulation of sulfatide and lysosulfatide. The disorder is associated with demyelination and axonal loss in the central and peripheral...... had a sensory-motor demyelinating neuropathy on electrophysiological testing, whereas two patients had normal studies. Sural nerve and CSF (lyso)sulfatide levels strongly correlated with abnormalities in electrophysiological parameters and large myelinated fiber loss in the sural nerve, but there were...

Inflammatory fatigue and sickness behaviour - lessons for the diagnosis and management of chronic fatigue syndrome.

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Arnett, S V; Clark, I A

2012-12-10

Persistent and severe fatigue is a common part of the presentation of a diverse range of disease processes. There is a growing body of evidence indicating a common inflammatory pathophysiology underlying many conditions where fatigue is a primary patient concern, including chronic fatigue syndrome. This review explores current models of how inflammatory mediators act on the central nervous system to produce fatigue and sickness behaviour, and the commonality of these processes in conditions as diverse as surgical trauma, infection, various cancers, inflammatory bowel disease, connective tissue diseases and autoimmune diseases. We also discuss evidence indicating chronic fatigue syndrome may have important pathophysiological similarities with cytokine mediated sickness behaviour, and what lessons can be applied from sickness behaviour to chronic fatigue syndrome with regards to the diagnosis and management. Copyright © 2012 Elsevier B.V. All rights reserved.

The anti-inflammatory effects of venlafaxine in the rat model of carrageenan-induced paw edema

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Valiollah Hajhashemi

2015-07-01

Full Text Available Objective(s:Recently anti-inflammatory effects of antidepressants have been demonstrated. Venlafaxine belongs to newer antidepressants with serotonin norepinephrine reuptake inhibition property. The pain alleviating properties of venlafaxine in different pain models such as neurogenic pain, diabetic neuropathy, and fibromyalgia have been demonstrated. Anti-inflammatory effects of venlafaxine and also its underlying mechanisms remain unclear. The present study was designed to evaluate the anti-inflammatory effects of venlafaxine and determine possible underlying mechanisms. Materials and Methods: We examined the anti-inflammatory effects of intraperitoneal (IP and intracerebroventricular (ICV administration of venlafaxine in the rat model of carrageenan-induced paw edema. Results: Our results showed that both IP (50 and 100 mg/kg and ICV (50 and 100 μg/rat injection of venlafaxine inhibited carrageenan-induced paw edema. Also IP and ICV administration of venlafaxine significantly decreased myeloperoxidase (MPO activity and interleukin (IL-1β and tumor necrosis factor (TNF-α production. Finally, we tried to reverse the anti-inflammatory effect of venlafaxine by yohimbine (5 mg/kg, IP, an alpha2-adrenergic antagonist. Our results showed that applied antagonist failed to change the anti-inflammatory effect of venlafaxine. Conclusion: These results demonstrated that venlafaxine has potent anti-inflammatory effect which is related to the peripheral and central effects of this drug. Also we have shown that anti-inflammatory effect of venlafaxine is mediated mostly through the inhibition of IL-1β and TNF-α production and decreases MPO activity in the site of inflammation.

Central control of body temperature [version 1; referees: 3 approved

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Shaun F. Morrison

2016-05-01

Full Text Available Central neural circuits orchestrate the behavioral and autonomic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response and behavioral states and in response to declining energy homeostasis. This review summarizes the central nervous system circuit mechanisms controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for thermogenesis. The activation of these thermoeffectors is regulated by parallel but distinct efferent pathways within the central nervous system that share a common peripheral thermal sensory input. The model for the neural circuit mechanism underlying central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation, for elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation, and for the discovery of novel therapeutic approaches to modulating body temperature and energy homeostasis.

Visfatin Triggers Anorexia and Body Weight Loss through Regulating the Inflammatory Response in the Hypothalamic Microglia

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Thai Hien Tu

2017-01-01

Full Text Available Visfatin is an adipokine that is secreted from adipose tissue, and it is involved in a variety of physiological processes. In particular, visfatin has been implicated in metabolic diseases, such as obesity and type 2 diabetes, which are directly linked to systemic inflammation. However, the potential impacts of visfatin on the hypothalamic control of energy homeostasis, which is involved in microglial inflammation, have not fully been investigated. In this study, we found that treatment with exogenous recombinant visfatin protein led to the activation of the inflammatory response in a microglial cell line. In addition, we observed that central administration of visfatin led to the activation of microglia in the hypothalamus. Finally, we found that visfatin reduced food intake and body weight through activating POMC neurons in association with microglia activation in mice. These findings indicate that elevation of central visfatin levels may be associated with homeostatic feeding behavior in response to metabolic shifts, such as increased adiposity following inflammatory processes in the hypothalamus.

Wallerian degeneration: gaining perspective on inflammatory events after peripheral nerve injury

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Popovich Phillip G

2011-08-01

Full Text Available Abstract In this review, we first provide a brief historical perspective, discussing how peripheral nerve injury (PNI may have caused World War I. We then consider the initiation, progression, and resolution of the cellular inflammatory response after PNI, before comparing the PNI inflammatory response with that induced by spinal cord injury (SCI. In contrast with central nervous system (CNS axons, those in the periphery have the remarkable ability to regenerate after injury. Nevertheless, peripheral nervous system (PNS axon regrowth is hampered by nerve gaps created by injury. In addition, the growth-supportive milieu of PNS axons is not sustained over time, precluding long-distance regeneration. Therefore, studying PNI could be instructive for both improving PNS regeneration and recovery after CNS injury. In addition to requiring a robust regenerative response from the injured neuron itself, successful axon regeneration is dependent on the coordinated efforts of non-neuronal cells which release extracellular matrix molecules, cytokines, and growth factors that support axon regrowth. The inflammatory response is initiated by axonal disintegration in the distal nerve stump: this causes blood-nerve barrier permeabilization and activates nearby Schwann cells and resident macrophages via receptors sensitive to tissue damage. Denervated Schwann cells respond to injury by shedding myelin, proliferating, phagocytosing debris, and releasing cytokines that recruit blood-borne monocytes/macrophages. Macrophages take over the bulk of phagocytosis within days of PNI, before exiting the nerve by the circulation once remyelination has occurred. The efficacy of the PNS inflammatory response (although transient stands in stark contrast with that of the CNS, where the response of nearby cells is associated with inhibitory scar formation, quiescence, and degeneration/apoptosis. Rather than efficiently removing debris before resolving the inflammatory response as

Inflammatory pathways of importance for management of inflammatory bowel disease

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Pedersen, Jannie; Coskun, Mehmet; Soendergaard, Christoffer

2014-01-01

Inflammatory bowel disease (IBD) is a group of chronic disorders of the gastrointestinal tract comprising Crohn's disease (CD) and ulcerative colitis (UC). Their etiologies are unknown, but they are characterised by an imbalanced production of pro-inflammatory mediators, e.g., tumor necrosis factor......-inflammatory cytokines, antibodies targeting integrins, and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium, reducing their infiltration into the inflamed mucosa. In this review we have elucidated the major signaling pathways of clinical importance for IBD...

Activation of voltage-gated KCNQ/Kv7 channels by anticonvulsant retigabine attenuates mechanical allodynia of inflammatory temporomandibular joint in rats

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Xu Wen

2010-08-01

Full Text Available Abstract Background Temporomandibular disorders (TMDs are characterized by persistent orofacial pain and have diverse etiologic factors that are not well understood. It is thought that central sensitization leads to neuronal hyperexcitability and contributes to hyperalgesia and spontaneous pain. Nonsteroidal anti-inflammatory drugs (NSAIDs are currently the first choice of drug to relieve TMD pain. NSAIDS were shown to exhibit anticonvulsant properties and suppress cortical neuron activities by enhancing neuronal voltage-gated potassium KCNQ/Kv7 channels (M-current, suggesting that specific activation of M-current might be beneficial for TMD pain. Results In this study, we selected a new anticonvulsant drug retigabine that specifically activates M-current, and investigated the effect of retigabine on inflammation of the temporomandibular joint (TMJ induced by complete Freund's adjuvant (CFA in rats. The results show that the head withdrawal threshold for escape from mechanical stimulation applied to facial skin over the TMJ in inflamed rats was significantly lower than that in control rats. Administration of centrally acting M-channel opener retigabine (2.5 and 7.5 mg/kg can dose-dependently raise the head withdrawal threshold of mechanical allodynia, and this analgesic effect can be reversed by the specific KCNQ channel blocker XE991 (3 mg/kg. Food intake is known to be negatively associated with TMJ inflammation. Food intake was increased significantly by the administration of retigabine (2.5 and 7.5 mg/kg, and this effect was reversed by XE991 (3 mg/kg. Furthermore, intracerebralventricular injection of retigabine further confirmed the analgesic effect of central retigabine on inflammatory TMJ. Conclusions Our findings indicate that central sensitization is involved in inflammatory TMJ pain and pharmacological intervention for controlling central hyperexcitability by activation of neuronal KCNQ/M-channels may have therapeutic potential for

Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease.

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Brown, Melissa A; Weinberg, Rebecca B

2018-01-01

Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4 + and CD8 + T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease-promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically.

Oxidative stress in a model of toxic demyelination in rat brain: the effect of piracetam and vinpocetine.

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Abdel-Salam, Omar M E; Khadrawy, Yasser A; Salem, Neveen A; Sleem, Amany A

2011-06-01

We studied the role of oxidative stress and the effect of vinpocetine (1.5, 3 or 6 mg/kg) and piracetam (150 or 300 mg/kg) in acute demyelination of the rat brain following intracerebral injection of ethidium bromide (10 μl of 0.1%). ethidium bromide caused (1) increased malondialdehyde (MDA) in cortex, hippocampus and striatum; (2) decreased total antioxidant capacity (TAC) in cortex, hippocampus and striatum; (3) decreased reduced glutathione (GSH) in cortex and hippocampus (4); increased serum nitric oxide and (5) increased striatal (but not cortical or hippocampal) acetylcholinesterase (AChE) activity. MDA decreased in striatum and cortex by the lower doses of vinpocetine or piracetam but increased in cortex and hippocampus and in cortex, hypothalamus and striatum by the higher dose of vinpocetine or piracetam, respectively along with decreased TAC. GSH increased by the higher dose of piracetam and by vinpocetine which also decreased serum nitric oxide. Vinpocetine and piracetam displayed variable effects on regional AChE activity.

Interferon-β Modulates Inflammatory Response in Cerebral Ischemia.

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Kuo, Ping-Chang; Scofield, Barbara A; Yu, I-Chen; Chang, Fen-Lei; Ganea, Doina; Yen, Jui-Hung

2016-01-08

Stroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon-β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis for more than a decade. Its anti-inflammatory properties and well-characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke. We investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4(+) T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain. Our results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti-inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Benfotiamine attenuates inflammatory response in LPS stimulated BV-2 microglia.

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Iva Bozic

Full Text Available Microglial cells are resident immune cells of the central nervous system (CNS, recognized as key elements in the regulation of neural homeostasis and the response to injury and repair. As excessive activation of microglia may lead to neurodegeneration, therapeutic strategies targeting its inhibition were shown to improve treatment of most neurodegenerative diseases. Benfotiamine is a synthetic vitamin B1 (thiamine derivate exerting potentially anti-inflammatory effects. Despite the encouraging results regarding benfotiamine potential to alleviate diabetic microangiopathy, neuropathy and other oxidative stress-induced pathological conditions, its activities and cellular mechanisms during microglial activation have yet to be elucidated. In the present study, the anti-inflammatory effects of benfotiamine were investigated in lipopolysaccharide (LPS-stimulated murine BV-2 microglia. We determined that benfotiamine remodels activated microglia to acquire the shape that is characteristic of non-stimulated BV-2 cells. In addition, benfotiamine significantly decreased production of pro-inflammatory mediators such as inducible form of nitric oxide synthase (iNOS and NO; cyclooxygenase-2 (COX-2, heat-shock protein 70 (Hsp70, tumor necrosis factor alpha α (TNF-α, interleukin-6 (IL-6, whereas it increased anti-inflammatory interleukin-10 (IL-10 production in LPS stimulated BV-2 microglia. Moreover, benfotiamine suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2, c-Jun N-terminal kinases (JNK and protein kinase B Akt/PKB. Treatment with specific inhibitors revealed that benfotiamine-mediated suppression of NO production was via JNK1/2 and Akt pathway, while the cytokine suppression includes ERK1/2, JNK1/2 and Akt pathways. Finally, the potentially protective effect is mediated by the suppression of translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB in the nucleus. Therefore

Acute Disseminated Encephalomyelitis following Vaccination against Hepatitis B in a Child: A Case Report and Literature Review

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Jun-liang Yuan

2016-01-01

Full Text Available Acute disseminated encephalomyelitis (ADEM is an inflammatory demyelinating disease of the central nervous system, which has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, and the Hog vaccine. Here, we presented a case of 12-year-old child who suffered from ADEM three weeks after hepatitis B vaccination. He was admitted to our hospital with symptoms of weakness of limbs, high fever, and alteration of consciousness. Some abnormalities were also found in CSF. Treatment with high-dose corticosteroids and intravenous immunoglobulin had significant effect, with marked improvement of the clinical symptoms and the results of CSF. The findings of MRI also detected some abnormal lesions located in both brain and spinal cord. The clinical features, the findings of CSF and MRI, and therapeutic effect may contribute to such diagnosis of ADEM.

Epidemiological, clinical and immunological aspects of neuromyelitis optica (NMO)

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Asgari, Nasrin

2013-01-01

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease (IDD) of the central nervous system (CNS) and probably the most common non-multiple sclerosis (MS) CNS IDD. Serum immunoglobulin G autoantibodies have been identified in the majority of NMO patients with the water channel aquaporin...... on either the Wingerchuk 2006 criteria or the United States National Multiple Sclerosis Society 2008 criteria could be made purely on clinical grounds in a high proportion (64%) of cases. Heterogeneity of clinical NMO manifestations including optic neuritis, longitudinal extensive transverse myelitis (LETM...... with specific clinical, immunogenetic and experimental perspectives. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 105 person-years (95% CI 0.30-0.54) and the prevalence was 4.4 per 105 (95% CI 3.1-5.7). The results indicated that NMO is more common in a Caucasian population...

Neuromyelitis optica, atypical hemophagocytic lymphohistiocytosis and heterozygous perforin A91V mutation.

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Palterer, Boaz; Brugnolo, Francesca; Sieni, Elena; Barilaro, Alessandro; Parronchi, Paola

2017-10-15

Neuromyelitis optica is an autoimmune demyelinating inflammatory disease characterized by optic neuritis and myelitis with anti-aquaporin 4 antibodies. Hemophagocytic lymphohistiocytosis is a severe systemic inflammatory syndrome that can present in a genetic primary form or secondarily to infective, neoplastic or autoimmune diseases. Our case discusses the first reported case of atypical late-onset hemophagocytic lymphohistiocytosis in a patient with neuromyelitis optica, with multiple triggering factors and carrying the common A91V hypomorphic perforin mutation, that blurs the distinction between primary and secondary forms. Copyright © 2017 Elsevier B.V. All rights reserved.

The ties that bind: Ingroup ties are linked with diminished inflammatory immune responses and fewer mental health symptoms through less rumination.

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Ysseldyk, Renate; McQuaid, Robyn J; McInnis, Opal A; Anisman, Hymie; Matheson, Kimberly

2018-01-01

The present research explored whether components of social identity, namely ingroup ties, affect, and centrality, were differentially linked to mental health and inflammatory immune responses, and whether rumination mediated those relations. Study 1 (N = 138) indicated that stronger ingroup ties were associated with fewer mental health (depressive and post-traumatic stress) symptoms; those relations were mediated by the tendency for individuals with strong ties to rely less on ruminative coping to deal with a stressful life event. Study 2 (N = 54) demonstrated that ingroup ties were negatively associated with depressive symptoms, dispositional rumination, as well as stress-linked inflammatory elements at the physiological level. Consistent associations for centrality and ingroup affect were absent, suggesting that ingroup ties may have unique health benefits.

Acute Transverse Myelitis in Children, Literature Review.

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Tavasoli, Azita; Tabrizi, Aidin

2018-01-01

Acute transverse myelitis (ATM) is a rare inflammatory demyelinating disorder characterized by relatively acute onset of motor, sensory, and autonomic dysfunction. Children comprise 20% of total cases of ATM. In this review, we described the current literature on childhood ATM, focusing on the epidemiology, pathogenesis, clinical presentation, approach to diagnosis, differential diagnosis, treatment and outcome in the pediatric population. We searched the related articles in electronic databases such as Scopus, EMBASE, Google Scholar, and PubMed. All study designs were included and the essential key words for searching were myelitis, acute transverse myelitis, childhood transverse myelitis, and acquired demyelinating syndromes. The related data focusing on the epidemiology, pathogenesis, clinical presentation, diagnostic approach and differential diagnosis, treatment and outcome of pediatric ATM were gathered and described. ATM is a heterogeneous disorder in children with a broad spectrum of clinical presentation, etiology, and outcome. It may be the first presentation of relapsing acquired demyelinating syndromes and also must be distinguished from compressive and noninflamatory myelopathies. Correct diagnosis is crucial for treatment and prognosis.

Curcumin in inflammatory diseases.

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Shehzad, Adeeb; Rehman, Gauhar; Lee, Young Sup

2013-01-01

Curcumin (diferuloylmethane), a yellow coloring agent extracted from turmeric is also used as a remedy for the treatment and prevention of inflammatory diseases. Acute and chronic inflammation is a major factor in the progression of obesity, type II diabetes, arthritis, pancreatitis, cardiovascular, neurodegenerative and metabolic diseases, as well as certain types of cancer. Turmeric has a long history of use in Ayurvedic medicine for the treatment of inflammatory disorders. Recent studies on the efficacy and therapeutic applicability of turmeric have suggested that the active ingredient of tumeric is curcumin. Further, compelling evidence has shown that curcumin has the ability to inhibit inflammatory cell proliferation, invasion, and angiogenesis through multiple molecular targets and mechanisms of action. Curcumin is safe, non-toxic, and mediates its anti-inflammatory effects through the down-regulation of inflammatory transcription factors, cytokines, redox status, protein kinases, and enzymes that all promote inflammation. In addition, curcumin induces apoptosis through mitochondrial and receptor-mediated pathways, as well as activation of caspase cascades. In the current study, the anti-inflammatory effects of curcumin were evaluated relative to various chronic inflammatory diseases. Based on the available pharmacological data obtained from in vitro and in vivo research, as well as clinical trials, an opportunity exists to translate curcumin into clinics for the prevention of inflammatory diseases in the near future. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Functional analysis of the CC chemokine receptor 5 (CCR5) on virus-specific CD8+ T cells following coronavirus infection of the central nervous system

International Nuclear Information System (INIS)

Glass, William G.; Lane, Thomas E.

2003-01-01

Intracranial infection of C57BL/6 mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by a demyelinating disease similar in pathology to the human disease multiple sclerosis (MS). T cells participate in both defense and disease progression following MHV infection. Expression of chemokine receptors on activated T cells is important in allowing these cells to traffic into and accumulate within the central nervous system (CNS) of MHV-infected mice. The present study evaluated the contributions of CCR5 to the activation and trafficking of virus-specific CD8 + T cells into the MHV-infected CNS mice. Comparable numbers of virus-specific CD8 + T cells derived from immunized CCR5 +/+ or CCR5 -/- mice were present within the CNS of MHV-infected RAG1 -/- mice following adoptive transfer, indicating that CCR5 is not required for trafficking of these cells into the CNS. RAG1 -/- recipients of CCR5 -/- -derived CD8 + T cells exhibited a modest, yet significant (P ≤ 0.05), reduction in viral burden within the brain which correlated with increased CTL activity and IFN-γ expression. Histological analysis of RAG1 -/- recipients of either CCR5 +/+ or CCR5 -/- -derived CD8 + T cells revealed only focal areas of demyelination with no significant differences in white matter destruction. These data indicate that CCR5 signaling on CD8 + T cells modulates antiviral activities but is not essential for entry into the CNS

Extensive grey matter pathology in the cerebellum in multiple sclerosis is linked to inflammation in the subarachnoid space.

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Howell, Owain W; Schulz-Trieglaff, Elena Katharina; Carassiti, Daniele; Gentleman, Steven M; Nicholas, Richard; Roncaroli, Federico; Reynolds, Richard

2015-10-01

Multiple sclerosis (MS) is a progressive inflammatory neurological disease affecting myelin, neurons and glia. Demyelination and neurodegeneration of cortical grey matter contribute to a more severe disease, and inflammation of the forebrain meninges associates with pathology of the underlying neocortical grey matter, particularly in deep sulci. We assessed the extent of meningeal inflammation of the cerebellum, another structure with a deeply folded anatomy, to better understand the association between subarachnoid inflammation and grey matter pathology in progressive MS. We examined demyelinating and neuronal pathology in the context of meningeal inflammation in cerebellar tissue blocks from a cohort of 27 progressive MS cases previously characterized on the basis of the absence/presence of lymphoid-like aggregates in the forebrain meninges, in comparison with 11 non-neurological controls. Demyelination and meningeal inflammation of the cerebellum was greatest in those cases previously characterized as harbouring lymphoid-like structures in the forebrain regions. Meningeal inflammation was mild to moderate in cerebellar tissue blocks, and no lymphoid-like structures were seen. Quantification of meningeal macrophages, CD4+, CD8+ T lymphocytes, B cells and plasma cells revealed that the density of meningeal macrophages associated with microglial activation in the grey matter, and the extent of grey matter demyelination correlated with the density of macrophages and plasma cells in the overlying meninges, and activated microglia of the parenchyma. These data suggest that chronic inflammation is widespread throughout the subarachnoid space and contributes to a more severe subpial demyelinating pathology in the cerebellum. © 2014 British Neuropathological Society.

A minimal unified model of disease trajectories captures hallmarks of multiple sclerosis

KAUST Repository

Kannan, Venkateshan; Kiani, Narsis A.; Piehl, Fredrik; Tegner, Jesper

2017-01-01

Multiple Sclerosis (MS) is an autoimmune disease targeting the central nervous system (CNS) causing demyelination and neurodegeneration leading to accumulation of neurological disability. Here we present a minimal, computational model involving

Central and peripheral nervous systems: master controllers in cancer metastasis.

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Shi, Ming; Liu, Dan; Yang, Zhengyan; Guo, Ning

2013-12-01

Central and sympathetic nervous systems govern functional activities of many organs. Solid tumors like organs are also innervated by sympathetic nerve fibers. Neurotransmitters released from sympathetic nerve fibers can modulate biological behaviors of tumor cells. Multiple physiologic processes of tumor development may be dominated by central and sympathetic nervous systems as well. Recent studies suggest that dysfunction of central and sympathetic nervous systems and disorder of the hormone network induced by psychological stress may influence malignant progression of cancer by inhibiting the functions of immune system, regulating metabolic reprogramming of tumor cells, and inducing interactions between tumor and stromal cells. Over-release of inflammatory cytokines by tumors may aggravate emotional disorder, triggering the vicious cycles in tumor microenvironment and host macroenvironment. It is reasonable to hypothesize that cancer progression may be controlled by central and sympathetic nervous systems. In this review, we will focus on the recent information about the impacts of central and sympathetic nervous systems on tumor invasion and metastasis.

Characterization of the antinociceptive and anti-inflammatory activities from Cocos nucifera L. (Palmae).

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Rinaldi, Sebastian; Silva, Davi O; Bello, Fabiana; Alviano, Celuta S; Alviano, Daniela S; Matheus, Maria Eline; Fernandes, Patricia D

2009-04-21

Cocos nucifera cultivated in Brazil is known as "coco-da-Bahia" or "coqueiro-da-India". The tea from the husk fiber is widely used to several inflammatory disorders. Crude extract and fractions obtained from Cocos nucifera "common variety" were evaluated to test the anti-inflammatory and antinociceptive activities. Crude extract (CE, 50, 100, and 150 mg/kg), fraction 1 (F1, molecular weight lesser than 1 kDa, 1, 10, and 50mg/kg), fraction 2 (F2, molecular weight higher than 1 kDa, 1, 10, and 50mg/kg), and the references drugs morphine (5mg/kg), acetilsalicilic acid (200mg/kg), prometazine (30 mg/kg), and metisergide (5mg/kg) were evaluated on models of analgesia and inflammation. CE, F1, and F2 significantly develop peripheral and central antinociceptive activity but with less effect on supra-spinal regions of the brain. Administration of the opioid antagonist, naloxone (5mg/kg) inhibited the antinociceptive effect indicating that Cocos nucifera crude extract and fractions may be acting in opioid receptors. CE and F1 also inhibited rat paw edema induced by histamine, and serotonin. results demonstrated that Cocos nucifera and its fractions have antinociceptive and anti-inflammatory activities which confirm the popular use of this plant in several inflammatory disorders.

Antioxidant and anti-inflammatory nutrient status, supplementation, and mechanisms in patients with schizophrenia.

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Mitra, Sumedha; Natarajan, Radhika; Ziedonis, Douglas; Fan, Xiaoduo

2017-08-01

Over 50 million people around the world suffer from schizophrenia, a severe mental illness characterized by misinterpretation of reality. Although the exact causes of schizophrenia are still unknown, studies have indicated that inflammation and oxidative stress may play an important role in the etiology of the disease. Pro-inflammatory cytokines are crucial for normal central nervous development and proper functioning of neural networks and neurotransmitters. Patients with schizophrenia tend to have abnormal immune activation resulting in elevated pro-inflammatory cytokine levels, ultimately leading to functional brain impairments. Patients with schizophrenia have also been found to suffer from oxidative stress, a result of an imbalance between the production of free radicals and the ability to detoxify their harmful effects. Furthermore, inflammation and oxidative stress are implicated to be related to the severity of psychotic symptoms. Several nutrients are known to have anti-inflammatory and antioxidant functions through various mechanisms in our body. The present review evaluates studies and literature that address the status and supplementation of omega-3 polyunsaturated fatty acids, vitamin D, B vitamins (B6, folate, B12), vitamin E, and carotenoids in different stages of schizophrenia. The possible anti-inflammatory and antioxidant mechanisms of action of each nutrient are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

Analgesic and anti-inflammatory activity of root bark of Grewia asiatica Linn. in rodents.

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Paviaya, Udaybhan Singh; Kumar, Parveen; Wanjari, Manish M; Thenmozhi, S; Balakrishnan, B R

2013-01-01

Grewia asiatica Linn. (Family: Tiliaceae), called Phalsa in Hindi is an Indian medicinal plant used for a variety of therapeutic and nutritional uses. The root bark of the plant is traditionally used in rheumatism (painful chronic inflammatory condition). The present study demonstrates the analgesic and anti-inflammatory activity of root bark of G. asiatica in rodents. The methanolic extract of Grewia asiatica (MEGA) and aqueous extract of Grewia asiatica (AEGA) of the bark were prepared and subjected to phytochemical tests and pharmacological screening for analgesic and anti-inflammatory effect in rodents. Analgesic effect was studied using acetic acid-induced writhing in mice and hot plate analgesia in rats while anti-inflammatory activity was investigated using carrageenan-induced paw oedema in rats. The MEGA or AEGA was administered orally in doses of 200 and 400 mg/kg/day of body weight. Data were analysed by one-way analysis of variance followed by Dunnett's test. The extracts showed a significant inhibition of writhing response and increase in hot plate reaction time and also caused a decrease in paw oedema. The effects were comparable with the standard drugs used. The present study indicates that root bark of G. asiatica exhibits peripheral and central analgesic effect and anti-inflammatory activity, which may be attributed to the various phytochemicals present in root bark of G. asiatica.

Effects of continuous positive airway pressure on hemorheology and serum inflammatory factors in patients with obstructive sleep apnea hypopnea syndrome

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Ye-Jun Liu

2016-02-01

Full Text Available Objective: To investigate the effects of continuous positive airway pressure (CPAP on hemorheology and serum inflammatory factors in patients with obstructive sleep apnea hypopnea syndrome (OSAHS. Methods: A total of 87 patients with moderate and severe OSAHS from Department of Otolaryngology-Head and Neck Surgery of South Central Hospital of Wuhan University and Qianjiang Central Hospital were selected as research objects in the treatment group, while 37 healthy individuals were chosen as objects in the control group. The changes of hemorheology indexes including hematocrit (HCT, whole blood viscosity, platelet aggregation (PAG and endothelin (ET as well as serum inflammatory factors including interleukin-6 (IL-6, IL-18 and tumor necrosis factor-α (TNF-α were measured in the control group and the treatment group, and comparisons involving these indexes were made between the two groups. Results: Before treatment, the hemorheology indexes HCT, whole blood viscosity (high, medium and low sheer rates, PAG and ET as well as the inflammatory factors IL-6, IL-18 and TNF-α levels were significantly higher than those in the control group; after CPAP treatment, all these indexed mentioned above in the treatment group were significantly decreased compared with before treatment. Conclusion: CPAP treatment has a reliable therapeutic effect on OSAHS patients, which can obviously improve the hemorheology and largely reduce the inflammatory response.

Inflammatory bowel disease: the role of inflammatory cytokine gene polymorphisms

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Joanna Balding

2004-01-01

Full Text Available THE mechanisms responsible for development of inflammatory bowel disease (IBD have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n=172 and healthy controls (n=389 for polymorphisms in genes encoding various cytokines (interleukin (IL-1β, IL-6, tumour necrosis factor (TNF, IL-10, IL-1 receptor antagonist. Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-α-308 polymorphism (p=0.0135. There was also variation in the frequency of IL-6-174 and TNF-α-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p=0.01. We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

Poly(ADP-RibosePolymerase-1 in Lung Inflammatory Disorders: A Review

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Gurupreet S. Sethi

2017-09-01

Full Text Available Asthma, acute lung injury (ALI, and chronic obstructive pulmonary disease (COPD are lung inflammatory disorders with a common outcome, that is, difficulty in breathing. Corticosteroids, a class of potent anti-inflammatory drugs, have shown less success in the treatment/management of these disorders, particularly ALI and COPD; thus, alternative therapies are needed. Poly(ADP-ribosepolymerases (PARPs are the post-translational modifying enzymes with a primary role in DNA repair. During the last two decades, several studies have reported the critical role played by PARPs in a good of inflammatory disorders. In the current review, the studies that address the role of PARPs in asthma, ALI, and COPD have been discussed. Among the different members of the family, PARP-1 emerges as a key player in the orchestration of lung inflammation in asthma and ALI. In addition, PARP activation seems to be associated with the progression of COPD. Furthermore, PARP-14 seems to play a crucial role in asthma. STAT-6 and GATA-3 are reported to be central players in PARP-1-mediated eosinophilic inflammation in asthma. Interestingly, oxidative stress–PARP-1–NF-κB axis appears to be tightly linked with inflammatory response in all three-lung diseases despite their distinct pathophysiologies. The present review sheds light on PARP-1-regulated factors, which may be common or differential players in asthma/ALI/COPD and put forward our prospective for future studies.

Chitosan drives anti-inflammatory macrophage polarisation and pro-inflammatory dendritic cell stimulation

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MI Oliveira

2012-07-01

Full Text Available Macrophages and dendritic cells (DC share the same precursor and play key roles in immunity. Modulation of their behaviour to achieve an optimal host response towards an implanted device is still a challenge. Here we compare the differentiation process and polarisation of these related cell populations and show that they exhibit different responses to chitosan (Ch, with human monocyte-derived macrophages polarising towards an anti-inflammatory phenotype while their DC counterparts display pro-inflammatory features. Macrophages and DC, whose interactions with biomaterials are frequently analysed using fully differentiated cells, were cultured directly on Ch films, rather than exposed to the polymer after complete differentiation. Ch was the sole stimulating factor and activated both macrophages and DC, without leading to significant T cell proliferation. After 10 d on Ch, macrophages significantly down-regulated expression of pro-inflammatory markers, CD86 and MHCII. Production of pro-inflammatory cytokines, particularly TNF-α, decreased with time for cells cultured on Ch, while anti-inflammatory IL-10 and TGF-β1, significantly increased. Altogether, these results suggest an M2c polarisation. Also, macrophage matrix metalloproteinase activity was augmented and cell motility was stimulated by Ch. Conversely, DC significantly enhanced CD86 expression, reduced IL-10 secretion and increased TNF-α and IL-1β levels. Our findings indicate that cells with a common precursor may display different responses, when challenged by the same biomaterial. Moreover, they help to further comprehend macrophage/DC interactions with Ch and the balance between pro- and anti-inflammatory signals associated with implant biomaterials. We propose that an overall pro-inflammatory reaction may hide the expression of anti-inflammatory cytokines, likely relevant for tissue repair/regeneration.

Treatment strategies for multiple sclerosis: When to start, when to change, when to stop?

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Gajofatto, Alberto; Benedetti, Maria Donata

2015-01-01

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system determined by a presumed autoimmune process mainly directed against myelin components but also involving axons and neurons. Acute demyelination shows as clinical relapses that may fully or partially resolve, while chronic demyelination and neuroaxonal injury lead to persistent and irreversible neurological symptoms, often progressing over time. Currently approved disease-modifying therapies are immunomodulatory or immunosuppressive drugs that significantly although variably reduce the frequency of attacks of the relapsing forms of the disease. However, they have limited efficacy in preventing the transition to the progressive phase of MS and are of no benefit after it has started. It is therefore likely that the potential advantage of a given treatment is condensed in a relatively limited window of opportunity for each patient, depending on individual characteristics and disease stage, most frequently but not necessarily in the early phase of the disease. In addition, a sizable proportion of patients with MS may have a very mild clinical course not requiring a disease-modifying therapy. Finally, individual response to existing therapies for MS varies significantly across subjects and the risk of serious adverse events remains an issue, particularly for the newest agents. The present review is aimed at critically describing current treatment strategies for MS with a particular focus on the decision of starting, switching and stopping commercially available immunomodulatory and immunosuppressive therapies. PMID:26244148

Autoimmune AQP4 channelopathies and neuromyelitis optica spectrum disorders.

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Hinson, Shannon R; Lennon, Vanda A; Pittock, Sean J

2016-01-01

Neuromyelitis optica (NMO) spectrum disorders (SD) represent an evolving group of central nervous system (CNS)-inflammatory autoimmune demyelinating diseases unified by a pathogenic autoantibody specific for the aquaporin-4 (AQP4) water channel. It was historically misdiagnosed as multiple sclerosis (MS), which lacks a distinguishing biomarker. The discovery of AQP4-IgG moved the focus of CNS demyelinating disease research from emphasis on the oligodendrocyte and myelin to the astrocyte. NMO is recognized today as a relapsing disease, extending beyond the optic nerves and spinal cord to include brain (especially in children) and skeletal muscle. Brain magnetic resonance imaging abnormalities, identifiable in 60% of patients at the second attack, are consistent with MS in 10% of cases. NMOSD-typical lesions (another 10%) occur in AQP4-enriched regions: circumventricular organs (causing intractable nausea and vomiting) and the diencephalon (causing sleep disorders, endocrinopathies, and syndrome of inappropriate antidiuresis). Advances in understanding the immunobiology of AQP4 autoimmunity have necessitated continuing revision of NMOSD clinical diagnostic criteria. Assays that selectively detect pathogenic AQP4-IgG targeting extracellular epitopes of AQP4 are promising prognostically. When referring to AQP4 autoimmunity, we suggest substituting the term "autoimmune aquaporin-4 channelopathy" for the term "NMO spectrum disorders." Randomized clinical trials are currently assessing the efficacy and safety of newer immunotherapies. Increasing therapeutic options based on understanding the molecular pathogenesis is anticipated to improve the outcome for patients with AQP4 channelopathy. © 2016 Elsevier B.V. All rights reserved.

Anti-inflammatory activities of the hydroalcoholic extracts from Erythrina velutina and E. mulungu in mice

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Silvânia M. M. Vasconcelos

2011-12-01

Full Text Available This work studied the anti-inflammatory activities of the hydroalcoholic extracts (HAEs from Erythrina velutina Willd. (Ev and E. mulungu Mart. ex Benth. (Em in the carrageenan- and dextran-induced mice hind paw edema models. These medicinal plants belonging to the Fabaceae family are used in some Brazilian communities to treat pain, inflammation, insomnia and disorders of the central nervous system. In the present work, the extracts were administered orally in male mice at the doses of 200 or 400 mg/kg. In the carrageenan-induced test, only Em showed anti-inflammatory activity, decreasing the paw edema, at the doses of 200 and 400 mg/kg. No effect was observed with Ev in this model. On the other hand, in the dextran model, Ev demonstrated anti-inflammatory effect, showing decrease of the paw edema at the 1, 2, 3, 4 and 24th h. Em (200 or 400 mg/kg presented anti-inflammatory effect at the 2, 3 and 4th h after administration of dextran, as compared to control. In conclusion, the work showed that Ev and Em present anti-edematous actions, which possibly occurs by distinct mechanisms. While Ev seems to interfere especially in inflammatory processes in which mast cells have an important role, Em exerts greater activity in the inflammatory process that depends mainly on polymorphonuclear leucocytes. However, further studies are needed to determine the exact mechanism of action of the species investigated.

Anti-inflammatory activities of the hydroalcoholic extracts from Erythrina velutina and E. mulungu in mice

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Silvânia M. M. Vasconcelos

2011-08-01

Full Text Available This work studied the anti-inflammatory activities of the hydroalcoholic extracts (HAEs from Erythrina velutina Willd. (Ev and E. mulungu Mart. ex Benth. (Em in the carrageenan- and dextran-induced mice hind paw edema models. These medicinal plants belonging to the Fabaceae family are used in some Brazilian communities to treat pain, inflammation, insomnia and disorders of the central nervous system. In the present work, the extracts were administered orally in male mice at the doses of 200 or 400 mg/kg. In the carrageenan-induced test, only Em showed anti-inflammatory activity, decreasing the paw edema, at the doses of 200 and 400 mg/kg. No effect was observed with Ev in this model. On the other hand, in the dextran model, Ev demonstrated anti-inflammatory effect, showing decrease of the paw edema at the 1, 2, 3, 4 and 24th h. Em (200 or 400 mg/kg presented anti-inflammatory effect at the 2, 3 and 4th h after administration of dextran, as compared to control. In conclusion, the work showed that Ev and Em present anti-edematous actions, which possibly occurs by distinct mechanisms. While Ev seems to interfere especially in inflammatory processes in which mast cells have an important role, Em exerts greater activity in the inflammatory process that depends mainly on polymorphonuclear leucocytes. However, further studies are needed to determine the exact mechanism of action of the species investigated.

Diabetes alters activation and repression of pro- and anti- inflammatory signalling pathways in the vasculature

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Elyse eDi Marco

2013-06-01

Full Text Available A central mechanism driving vascular disease in diabetes is immune cell-mediated inflammation. In diabetes, enhanced oxidation and glycation of macromolecules, such as lipoproteins, insults the endothelium and activates both innate and adaptive arms of the immune system by generating new antigens for presentation to adaptive immune cells. Chronic inflammation of the endothelium in diabetes leads to continuous infiltration and accumulation of leukocytes at sites of endothelial cell injury. We will describe the central role of the macrophage as a source of signalling molecules and damaging by-products which activate infiltrating lymphocytes in the tissue and contribute to the pro-oxidant and pro-inflammatory micro-environment. An important aspect to be considered is the diabetes- associated defects in the immune system, such as fewer or dysfunctional athero-protective leukocyte subsets in the diabetic lesion compared to non-diabetic lesions. This review will discuss the key pro-inflammatory signalling pathways responsible for leukocyte recruitment and activation in the injured vessel, with particular focus on pro- and anti-inflammatory pathways aberrantly activated or repressed in diabetes. We aim to describe the interaction between advanced glycation end products (AGEs and their principle receptor RAGE, Angiotensin II (Ang II and the Ang II type 1 receptor (AT1R, in addition to reactive oxygen species (ROS production by NADPH oxidase (Nox enzymes that are relevant to vascular and immune cell function in the context of diabetic vasculopathy. Furthermore, we will touch on recent advances in epigenetic medicine that have revealed high glucose-mediated changes in the transcription of genes with known pro-inflammatory downstream targets. Finally, novel anti-atherosclerosis strategies that target the vascular immune interface will be explored; such as vaccination against modified LDL and pharmacological inhibition of ROS producing enzymes.

The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.

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Callaghan, Brian C; Price, Raymond S; Chen, Kevin S; Feldman, Eva L

2015-12-01

Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking. Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important

Neck stiffness in Guillaine-Barre syndrome subsequent to cytomegalovirus infection

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İbrahim Etem Pişkin

2011-03-01

Full Text Available Guillain-Barre syndrome is an acute inflammatory demyelinating polyradiculoneuropathy that can be seen at any age. The classic symptoms such as flaccid paralysis and areflexia are not always predominant in children. In this study, we presented a 3-year-old girl with Guillain-Barre syndrome associated with cytomegalovirus infection who referred with showed atypical symptoms including neck stiffness.

Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis.

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Koch, Marcus W; Zabad, Rana; Giuliani, Fabrizio; Hader, Walter; Lewkonia, Ray; Metz, Luanne; Wee Yong, V

2015-11-15

Microglial activation is thought to be a key pathophysiological mechanism underlying disease activity in all forms of MS. Hydroxychloroquine (HCQ) is an antimalarial drug with immunomodulatory properties that is widely used in the treatment of rheumatological diseases. In this series of experiments, we explore the effect of HCQ on human microglial activation in vitro and on the development of experimental autoimmune encephalitis (EAE) in vivo. We activated human microglia with lipopolysaccharide (LPS), and measured concentrations of several pro- and anti-inflammatory cytokines in untreated and HCQ pretreated cultures. We investigated the effect of HCQ pretreatment at two doses on the development of EAE and spinal cord histology. HCQ pretreatment reduced the production of pro-inflammatory (TNF-alpha, IL-6, and IL-12) and anti-inflammatory (IL-10 and IL-1 receptor antagonist) cytokines in LPS-stimulated human microglia. HCQ pretreatment delayed the onset of EAE, and reduced the number of Iba-1 positive microglia/macrophages and signs of demyelination in the spinal cords of HCQ treated animals. HCQ treatment reduces the activation of human microglia in vitro, delays the onset of EAE, and decreases the representation of activated macrophages/microglia and demyelination in the spinal cord of treated mice. HCQ is a plausible candidate for further clinical studies in MS. Copyright © 2015 Elsevier B.V. All rights reserved.

Remyelination of the injured spinal cord

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Sasaki, Masanori; Li, Bingcang; Lankford, Karen L.; Radtke, Christine; Kocsis, Jeffery D.

2008-01-01

Contusive spinal cord injury (SCI) can result in necrosis of the spinal cord, but often long white matter tracts outside of the central necrotic core are demyelinated. One experimental strategy to improve functional outcome following SCI is to transplant myelin-forming cells to remyelinate these axons and improve conduction. This review focuses on transplantation studies using olfactory ensheathing cell (OEC) to improve functional outcome in experimental models of SCI and demyelination. The biology of the OEC, and recent experimental research and clinical studies using OECs as a potential cell therapy candidate are discussed. PMID:17618995

Coexistence of multiple sclerosis and ankylosing spondylitis: Report of four cases from Russia and review of the literature.

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Fominykh, Vera; Shevtsova, Tatyana; Arzumanian, Narine; Brylev, Lev

2017-10-01

Multiple sclerosis is a chronic demyelinating disorder of the central nervous system. There are many cases of multiple sclerosis - like syndrome and demyelinating disorders in systemic lupus erythematosus, Sjogren disease, Behcet disease and other autoimmune conditions. Coexistence of ankylosing spondylitis and multiple sclerosis usually is rare but in this article we report 4 Russian patients with concomitant multiple sclerosis and ankylosing spondylitis diseases. None of these patients received anti-tumor necrosis factor alpha therapy prior to diagnosis of multiple sclerosis. Pathogenesis, diagnostic and treatment challenges are discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Toll-Like Receptor 2 mediates in vivo pro- and anti-inflammatory effects of Mycobacterium tuberculosis and modulates autoimmune encephalomyelitis

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Alessia ePiermattei

2016-05-01

Full Text Available Mycobacteria display pro- and anti-inflammatory effects in human and experimental pathology. We show here that both effects are mediated by Toll like receptor 2 (Tlr2, by exploiting a previously characterized Tlr2 variant (Met82Ile. Tlr2 82ile promoted self-specific pro-inflammatory polarization as well as expansion of ag-specific FoxP3+ Tregs, while Tlr2 82met impairs the expansion of Tregs and reduces the production of IFN-γ and IL-17 pro-inflammatory cytokines. Preferential dimerization with Tlr1 or Tlr6 could not explain these differences. In silico, we showed that Tlr2 variant Met82Ile modified the binding pocket for peptidoglycans and participate directly to a putative binding pocket for sugars and Cadherins. The distinct pro- and anti-inflammatory actions impacted on severity, extent of remission and distribution of the lesions within the Central Nervous System of Experimental Autoimmune Encephalomyelitis. Thus, Tlr2 has a janus function in vivo as mediator of the role of bacterial products in balancing pro- and anti-inflammatory immune responses.

Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation*

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Hao, Wu; Tashiro, Syoichi; Hasegawa, Tomoka; Sato, Yuiko; Kobayashi, Tami; Tando, Toshimi; Katsuyama, Eri; Fujie, Atsuhiro; Watanabe, Ryuichi; Morita, Mayu; Miyamoto, Kana; Morioka, Hideo; Nakamura, Masaya; Matsumoto, Morio; Amizuka, Norio; Toyama, Yoshiaki; Miyamoto, Takeshi

2015-01-01

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition. PMID:25998127

Inflammatory Arthritis, Sacroiliitis, and Morphea: Evidence of a Systemic Inflammatory Disease

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Omair, Mohammed A.; Johnson, Sindhu R.

2013-01-01

Morphea is a skin disease characterized by local skin inflammation and fibrosis. Extracutaneous manifestations have been described with this disease including inflammatory arthritis. We describe a case of morphea who developed inflammatory polyarthritis and sacroiliitis coincident with new skin lesions.

Therapeutic potential of flavonoids in inflammatory bowel disease: A comprehensive review.

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Salaritabar, Ali; Darvishi, Behrad; Hadjiakhoondi, Farzaneh; Manayi, Azadeh; Sureda, Antoni; Nabavi, Seyed Fazel; Fitzpatrick, Leo R; Nabavi, Seyed Mohammad; Bishayee, Anupam

2017-07-28

The inflammatory process plays a central role in the development and progression of numerous pathological situations, such as inflammatory bowel disease (IBD), autoimmune and neurodegenerative diseases, metabolic syndrome, and cardiovascular disorders. IBDs involve inflammation of the gastrointestinal area and mainly comprise Crohn's disease (CD) and ulcerative colitis (UC). Both pathological situations usually involve recurring or bloody diarrhea, pain, fatigue and weight loss. There is at present no pharmacological cure for CD or UC. However, surgery may be curative for UC patients. The prescribed treatment aims to ameliorate the symptoms and prevent and/or delay new painful episodes. Flavonoid compounds are a large family of hydroxylated polyphenolic molecules abundant in plants, including vegetables and fruits which are the major dietary sources of these compounds for humans, together with wine and tea. Flavonoids are becoming very popular because they have many health-promoting and disease-preventive effects. Most interest has been directed towards the antioxidant activity of flavonoids, evidencing a remarkable free-radical scavenging capacity. However, accumulating evidence suggests that flavonoids have many other biological properties, including anti-inflammatory, antiviral, anticancer, and neuroprotective activities through different mechanisms of action. The present review analyzes the available data about the different types of flavonoids and their potential effectiveness as adjuvant therapy of IBDs.

Reverse Engineering the Inflammatory "Clock": From Computational Modeling to Rational Resetting.

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Vodovotz, Yoram

2016-01-01

Properly-regulated inflammation is central to homeostasis. Traumatic injury, hemorrhagic shock, septic shock, and other injury-related processes such as wound healing are associated with dysregulated inflammation. Like many biological processes, inflammation is a dynamic, complex system whose function, like that of an analog clock, cannot be discerned simply from a laundry list of its parts (data). The advent of multiplexed platforms for gathering biological data, while providing an unprecedented level of detailed information about the inflammatory response, has paradoxically also proven to be overwhelming. This problem is especially acute when the datasets involve time courses, since typical statistical analyses and data-driven modeling are geared towards single time points. Various groups have addressed this problem using dynamic approaches to data-driven and mechanistic computational modeling. These modeling tools can be thought of as the "gears" and "hands" of the "clock," and have led to insights regarding principal drivers, dynamic networks, feedbacks, and regulatory switches that characterize and perhaps regulate the inflammatory response. In parallel, mechanistic computational models have given an abstracted sense of how the inflammatory "clock" works, leading to in silico models of critically ill individuals and populations. Integrating data-driven and mechanistic modeling may point the way to a rational "resetting" of inflammation via model-driven precision medicine.

Altered blood-brain barrier transport in neuro-inflammatory disorders.

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Schenk, Geert J; de Vries, Helga E

2016-06-01

During neurodegenerative and neuroinflammatory disorders of the central nervous system (CNS), such as Alzheimer's disease (AD) and multiple sclerosis (MS), the protective function of the blood-brain barrier (BBB) may be severely impaired. The general neuro-inflammatory response, ranging from activation of glial cells to immune cell infiltration that is frequently associated with such brain diseases may underlie the loss of the integrity and function of the BBB. Consequentially, the delivery and disposition of drugs to the brain will be altered and may influence the treatment efficiency of such diseases. Altered BBB transport of drugs into the CNS during diseases may be the result of changes in both specific transport and non-specific transport pathways. Potential alterations in transport routes like adsorptive mediated endocytosis and receptor-mediated endocytosis may affect drug delivery to the brain. As such, drugs that normally are unable to traverse the BBB may reach their target in the diseased brain due to increased permeability. In contrast, the delivery of (targeted) drugs could be hampered during inflammatory conditions due to disturbed transport mechanisms. Therefore, the inventory of the neuro-inflammatory status of the neurovasculature (or recovery thereof) is of utmost importance in choosing and designing an adequate drug targeting strategy under disease conditions. Within this review we will briefly discuss how the function of the BBB can be affected during disease and how this may influence the delivery of drugs into the diseased CNS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases.

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Nakayama, Hiroyuki; Otsu, Kinya

2018-03-06

Mitochondria play a central role in multiple cellular functions, including energy production, calcium homeostasis, and cell death. Currently, growing evidence indicates the vital roles of mitochondria in triggering and maintaining inflammation. Chronic inflammation without microbial infection - termed sterile inflammation - is strongly involved in the development of heart failure. Sterile inflammation is triggered by the activation of pattern recognition receptors (PRRs) that sense endogenous ligands called damage-associated molecular patterns (DAMPs). Mitochondria release multiple DAMPs including mitochondrial DNA, peptides, and lipids, which induce inflammation via the stimulation of multiple PRRs. Among the mitochondrial DAMPs, mitochondrial DNA (mtDNA) is currently highlighted as the DAMP that mediates the activation of multiple PRRs, including Toll-like receptor 9, Nod-like receptors, and cyclic GMP-AMP synthetase/stimulator of interferon gene pathways. These PRR signalling pathways, in turn, lead to the activation of nuclear factor-κB and interferon regulatory factor, which enhances the transcriptional activity of inflammatory cytokines and interferons, and induces the recruitment of inflammatory cells. As the heart is an organ comprising abundant mitochondria for its ATP consumption (needed to maintain constant cyclic contraction and relaxation), the generation of massive amounts of mitochondrial radical oxygen species and mitochondrial DAMPs are predicted to occur and promote cardiac inflammation. Here, we will focus on the role of mtDNA in cardiac inflammation and review the mechanism and pathological significance of mtDNA-induced inflammatory responses in cardiac diseases. © 2018 The Author(s).

Inflammatory Arthritis, Sacroiliitis, and Morphea: Evidence of a Systemic Inflammatory Disease

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Mohammed A. Omair

2013-01-01

Full Text Available Morphea is a skin disease characterized by local skin inflammation and fibrosis. Extracutaneous manifestations have been described with this disease including inflammatory arthritis. We describe a case of morphea who developed inflammatory polyarthritis and sacroiliitis coincident with new skin lesions.

Erupção acneiforme aguda induzida por interferon beta-1b durante tratamento para esclerose múltipla Acute acneiform eruption induced by interferon beta-1b during treatment for multiple sclerosis

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Dário Júnior de Freitas Rosa

2011-04-01

Full Text Available Esclerose múltipla é uma doença inflamatória desmielinizante, com presumida origem autoimune, que afeta o sistema nervoso central. A principal modalidade terapêutica é baseada no uso de imunomoduladores, como o interferon beta, que são geralmente bem tolerados. As manifestações cutâneas secundárias ao interferon beta-1b são representadas, na maioria das vezes, por reações no local de sua aplicação subcutânea. Descrevemos o caso de uma paciente do sexo feminino que desenvolveu um quadro de erupção acneiforme pelo interferon beta-1b.Multiple sclerosis is an inflammatory demyelinating disease of presumed autoimmune origin that affects the central nervous system. The main form of therapy is based on the use of immunomodulators such as interferon beta, which are usually well tolerated. Skin manifestations resulting from treatment with interferon beta-1b consist principally of reactions at the site of subcutaneous application of the drug. The present case report describes a female patient who developed an acneiform eruption resulting from treatment with interferon beta-1b.

Anti-inflammatory Effect of Sodium Valproate on Carrageenan-Induced Paw Edema in Male Rat

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mj Khoshnood

2008-12-01

Full Text Available ABESTRACT: Introduction & objective: Inflammation is a body defensive response to the endogenous and exogenous stimulators such as chemical, radiation, trauma and invasive microorganism, which result pain and tissue necrosis. There are many natural and synthetic drugs for treatment of inflammation and lot of them are under investigation. Sodium valporate is an antiepileptic drug used particularly in the treatment of primary generalized seizure notably absence, myocolonic seizure, acute manic phase of bipolar disorder and prophylaxis of migraine. The previous observations showed sodium valporate increases level of gamma amino butyric acid (GABA in the central and peripheral nervous system. In acute inflammation, GABA showed a significant attenuation of paw edema and nociception. The aim of this study was evaluation of anti-inflammatory effect of sodium valporate. Materials & Methods: In order to evaluated the anti-inflammatory and antiexudative of sodium valporate doses of 200,400 and 600 mg/kg were investigated on rat paw edema that induced by carrageenan. In addition, the plasma leakage in the inflamed tissue was evaluated by application of trypan blue as intravenous injection. Dexamethason was used as positive control. Results: Results showed sodium valporate doses of 400 and 600 mg/kg decreased inflammatory and exudative effect as compared to control group. Conclusion: Although the anti-inflammatory mechanisms of this drug were not evident but we can say sodium valporate in addition to already proved effects has anti-inflammatory effect.