Gilli, Francesca; Li, Libin; Royce, Darlene B; DiSano, Krista D; Pachner, Andrew R
Teriflunomide is an oral therapy approved for the treatment of relapsing remitting multiple sclerosis (MS), showing both anti-inflammatory and antiviral properties. Currently, it is uncertain whether one or both of these properties may explain teriflunomide's beneficial effect in MS. Thus, to learn more about its mechanisms of action, we evaluated the effect of teriflunomide in the Theiler's encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) model, which is both a viral infection and an excellent model of the progressive disability of MS. We assessed the effects of the treatment on central nervous system (CNS) viral load, intrathecal immune response, and progressive neurological disability in mice intracranially infected with TMEV. In the TMEV-IDD model, we showed that teriflunomide has both anti-inflammatory and antiviral properties, but there seemed to be no impact on disability progression and intrathecal antibody production. Notably, benefits in TMEV-IDD were mostly mediated by effects on various cytokines produced in the CNS. Perhaps the most interesting result of the study has been teriflunomide's antiviral activity in the CNS, indicating it may have a role as an antiviral prophylactic and therapeutic compound for CNS viral infections.
Howard, Laurence M.; Neville, Katherine L.; Haynes, Lia M.; Dal Canto, Mauro C.; Miller, Stephen D
Transient CD154 blockade at the onset of Theiler's murine encephalomyelitis virus-induced demyelinating disease ameliorated disease progression for 80 days, reduced immune cell infiltration, and transiently increased viral loads in the central nervous system. Peripheral antiviral and autoimmune T-cell responses were normal, and disease severity returned to control levels by day 120.
McCarthy, Derrick P; Richards, Maureen H; Miller, Stephen D
Experimental autoimmune encephalomyelitis (EAE) and Theiler's Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV.
Bowen, Jenna L; Olson, Julie K
Theiler's murine encephalomyelitis virus (TMEV) induces a demyelinating disease in susceptible SJL mice that has similarities to multiple sclerosis in humans. TMEV infection of susceptible mice leads to a persistent virus infection of the central nervous system (CNS), which promotes the development of demyelinating disease associated with an inflammatory immune response in the CNS. TMEV infection of resistant C57BL6 mice results in viral clearance without development of demyelinating disease. Interestingly, TMEV infection of resistant mice deficient in IFNγ leads to a persistent virus infection in the CNS and development of demyelinating disease. We have previously shown that the innate immune response affects development of TMEV- induced demyelinating disease, thus we wanted to determine the role of IFNγ during the innate immune response. TMEV-infected IFNγ-deficient mice had an altered innate immune response, including reduced expression of innate immune cytokines, especially type I interferons. Administration of type I interferons, IFNα and IFNß, to TMEV-infected IFNγ-deficient mice during the innate immune response restored the expression of innate immune cytokines. Most importantly, administration of type I interferons to IFNγ-deficient mice during the innate immune response decreased the virus load in the CNS and decreased development of demyelinating disease. Microglia are the CNS resident immune cells that express innate immune receptors. In TMEV-infected IFNγ-deficient mice, microglia had reduced expression of innate immune cytokines, and administration of type I interferons to these mice restored the innate immune response by microglia. In the absence of IFNγ, microglia from TMEV-infected mice had reduced expression of some innate immune receptors and signaling molecules, especially IRF1. These results suggest that IFNγ plays an important role in the innate immune response to TMEV by enhancing the expression of innate immune cytokines
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 inhibitory cytokines and
Kim, Byung S; Jin, Young-Hee; Meng, Liping; Hou, Wanqiu; Kang, Hyun Seok; Park, Hey Suk; Koh, Chang-Sung
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. 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. 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. 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 inhibitory cytokines and regulatory molecules. Therefore, the balance of
Jin, Young-Hee; Kim, Seung Jae; So, Eui Young; Meng, Liping; Colonna, Marco
Infection of dendritic and glial cells with Theiler's murine encephalomyelitis virus (TMEV) induces various cytokines via Toll-like receptor- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways. However, the involvement and role of MDA5 in cytokine gene activation and the pathogenesis of TMEV-induced demyelinating disease are largely unknown. In this study, we demonstrate that MDA5 plays a critical role in the production of TMEV-induced alpha interferon (IFN-α) during early viral infection and in protection against the development of virus-induced demyelinating disease. Our results indicate that MDA5-deficient 129SvJ mice display significantly higher viral loads and apparent demyelinating lesions in the central nerve system (CNS) accompanied by clinical symptoms compared with wild-type 129SvJ mice. During acute viral infection, MDA5-deficient mice produced elevated levels of chemokines, consistent with increased cellular infiltration, but reduced levels of IFN-α, known to control T cell responses and cellular infiltration. Additional studies with isolated CNS glial cells from these mice suggest that cells from MDA5-deficient mice are severely compromised in the production of IFN-α upon viral infection, which results in increased cellular infiltration and viral loads in the CNS. Despite inadequate stimulation, the overall T cell responses to the viral determinants were significantly elevated in MDA5-deficient mice, reflecting the increased cellular infiltration. Therefore, the lack of MDA5-mediated IFN-α production may facilitate a massive viral load and elevated cellular infiltration in the CNS during early viral infection, leading to the pathogenesis of demyelinating disease. PMID:22090123
McCarthy, Derrick P.; Richards, Maureen H.; Miller, Stephen D.
Experimental autoimmune encephalomyelitis (EAE) and Theiler’s Murine Encephalitis Virus-Induced Demyelinating Disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS). Like MS, both are characterized by mononuclear cell infiltration into the CNS and demyelination. EAE is induced by either the administration of myelin protein or peptide in adjuvant or by the adoptive transfer of encephalitogenic T cell blasts into naïve recipients. The relative merits of each of these protocols are compared. Depending on the type of question being asked, different mouse strains and peptides are used. Different disease courses are observed with different strains and different peptides in active EAE. These variations are also addressed. Additionally, issues relevant to clinical grading of EAE in mice are discussed. In addition to EAE induction, useful references for other disease indicators such as DTH, in vitro proliferation, and immunohistochemistry are provided. TMEV-IDD is a useful model for understanding the possible viral etiology of MS. This section provides detailed information on the preparation of viral stocks and subsequent intracerebral infection of mice. Additionally, virus plaque assay and clinical disease assessment are discussed. Recently, recombinant TMEV strains have been created for the study of molecular mimicry which incorporate various 30 amino acid myelin epitopes within the leader region of TMEV. PMID:22933080
Kobayashi, Kunitoshi; Tomiki, Hiroki; Inaba, Yuji; Ichikawa, Motoki; Kim, Byung S; Koh, Chang-Sung
Dimethyl fumarate (DMF) is a modifier of the nuclear factor (erythroid-derived 2)-2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. DMF treatment in the effector phase significantly suppressed the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) both clinically and histologically. DMF treatment leads to an enhanced Nrf2 antioxidant response in TMEV-IDD mice. DMF treatment in the effector phase significantly suppressed the level of IL-17A mRNA. DMF is known to inhibit differentiation of T helper 17 (Th17) cells via suppressing NF-κB. Taken together, our data suggest that DMF treatment in the effector phase may suppress TMEV-IDD not only via enhancing the antioxidant response but also via suppressing IL-17A. © The Japanese Society for Immunology. 2015. All rights reserved. For permissions, please e-mail: email@example.com.
Kaneyama, Tomoki; Tomiki, Hiroki; Tsugane, Sayaka; Inaba, Yuji; Ichikawa, Motoki; Akiba, Hisaya; Yagita, Hideo; Kim, Byung S; Koh, Chang-Sung
Infection by Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-γ and IL-10 by CD4(+) T cells and IFN-γ by CD8(+) T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4(+) T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Olson, Julie K.; Miller, Stephen D
Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler’s murine encephalomyelitis virus (TMEV)- induced demyelinating disease serves as a relevant mouse model for MS. TMEV- infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days post infection which is associated with development of myelin- specific, PLP139–151, CD4+ T c...
Tomiki, Hiroki; Kaneyama, Tomoki; Kobayashi, Kunitoshi; Inaba, Yuji; Ichikawa, Motoki; Yagita, Hideo; Kim, Byung S; Koh, Chang-Sung
We examined the regulatory role of αv integrins in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a model of multiple sclerosis (MS). Blockade of αv integrins by anti-αv integrin monoclonal antibody (mAb) in the effector phase significantly suppressed the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells (MNCs) in the CNS was significantly decreased in mice treated with anti-αv integrin mAb. Flow cytometric analysis of cytokine staining revealed that absolute numbers of IFN-γ- and IL-17-producing CD4+ and IFN-γ-producing CD8+ T cells were significantly decreased in the CNS of mice treated with anti-αv integrin mAb. These data suggest that αv integrins may play important roles in the development of TMEV-IDD. Copyright © 2014 Elsevier B.V. All rights reserved.
Jayasri Das Sarma
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.
Olson, Julie K; Miller, Stephen D
Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant mouse model for MS. TMEV-infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days after infection, which is associated with development of myelin-specific, PLP(139-151), CD4(+) T cell responses. Viruses have been suggested to initiate autoimmune disease through bystander activation of immune cells or through bystander damage to tissue during infection. We examined the effect of the innate immune response on development of autoimmune demyelinating disease by altering the innate immune response through administration of innate immune cytokines, IFN-alpha or IFN-beta, or antiserum against the type I IFNs during the innate immune response to TMEV. Administration of IFN-beta, but not IFN-alpha, to TMEV- infected mice led to reduced myelin-specific CD4(+) T cell responses and reduced demyelinating disease, which was associated with decreased immune cell infiltration into the CNS and increased expression of IL-10 in the CNS. Conversely, administration of antiserum to IFN-beta led to a more severe demyelinating disease. In addition, administration of poly(I:C), which is an innate immune agonist, to TMEV-infected mice during the innate immune response resulted in decreased myelin-specific CD4(+) T cell responses and reduced demyelinating disease. These results demonstrate that activating or enhancing the innate immune response can reduce the subsequent initiation and progression of the autoimmune response and demyelinating disease.
Olson, Julie K.; Miller, Stephen D.
Multiple sclerosis (MS) is a human CNS autoimmune demyelinating disease. Epidemiological evidence has suggested a role for virus infection in the initiation and/or exacerbation of MS. Theiler’s murine encephalomyelitis virus (TMEV)- induced demyelinating disease serves as a relevant mouse model for MS. TMEV- infected mice develop a demyelinating disease with clinical symptoms beginning around 35 days post infection which is associated with development of myelin- specific, PLP139–151, CD4+ T cell responses. Viruses have been suggested to initiate autoimmune disease through bystander activation of immune cells or through bystander damage to tissue during infection. We examined the effect of the innate immune response on development of autoimmune demyelinating disease by altering the innate immune response through administration of innate immune cytokines, IFNα or IFNβ, or antiserum against the type I interferons during the innate immune response to TMEV. Administration of IFNβ, but not IFNα, to TMEV- infected mice led to reduced myelin-specific CD4+ T cell responses and reduced demyelinating disease which was associated with decreased immune cell infiltration into the CNS and increased expression of IL-10 in the CNS. Conversely, administration of antiserum to IFNβ led to a more severe demyelinating disease. In addition, administration of polyI:C, which is an innate immune agonist, to TMEV- infected mice during the innate immune response resulted in decreased myelin-specific CD4+ T cell responses and reduced demyelinating disease. These results demonstrate that activating or enhancing the innate immune response can reduce the subsequent initiation and progression of the autoimmune response and demyelinating disease. PMID:19380818
Olson, Julie K
Theiler's murine encephalomyelitis virus (TMEV) infection of susceptible mice leads to the development of demyelinating disease in the central nervous system (CNS) associated with an inflammatory immune response. The demyelinating disease in mice has similarities to multiple sclerosis in humans and is used as an experimental model for the human disease. The innate immune response initiates the immune response to TMEV through innate immune receptors on cells that recognize components of the virus and activate intracellular signaling that leads to the expression of innate immune cytokines, chemokines, and effector molecules. The innate immune response directly affects the development of the adaptive immune response, especially the T cell response, which mediates viral clearance. However, infection of Swiss Jim Laboratory (SJL) mice with TMEV leads to a persistent virus infection of the microglia/macrophage in the CNS which contributes to the development of demyelinating disease. Susceptibility to demyelinating disease has been linked to the T cell response against the virus. However, the current studies will examine the role of the innate immune response to TMEV and the affect it has on the adaptive immune response and development of demyelinating disease following TMEV infection. The innate immune cytokines, chemokines, and effector molecules as well as the innate immune cells, both CNS resident and infiltrating peripheral cells, all contribute to the innate immune response following TMEV and may affect susceptibility to demyelinating disease.
Gilli, Francesca; Li, Libin; Pachner, Andrew R
Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is an important model of the progressive disability caused by irreversible CNS tissue injury, and provides an example of how a CNS pathogen can cause inflammation, demyelination, and neuronal damage. We were interested in which molecules, especially inflammatory mediators, might be upregulated in the CNS throughout TMEV-IDD. We quantitated by a real-time RT-PCR multi-gene system the expression of a pathway-focused panel of genes at 30 and 165 days post infection, characterizing both the early inflammatory and the late neurodegenerative stages of TMEV-IDD. Also, we measured 32 cytokines/chemokines by multiplex Luminex analysis in CSF specimens from early and late TMEV-IDD as well as sham-treated mice. Results indicate that, in the later stage of TMEV-IDD, activation of the innate immune response is most prominent: TLRs, type I IFN response genes, and innate immunity-associated cytokines were highly expressed in late TMEV-IDD compared to sham (p ≤ 0.0001) and early TMEV-IDD (p disease to different extents. CSF provides an optimal source of biomarkers of CNS neuroinflammation.
Turrin Nicolas P
Full Text Available Abstract Background In immunopathological diseases, such as multiple sclerosis (MS, genetic and environmental factors that contribute to the initiation and progression of the disease are often discussed. The Theiler murine encephalomyelitis virus-induced demyelination disease (TMEV-IDD model used to study MS reflects this: genetically susceptible mice infected intra-cerebrally with TMEV develop a chronic demyelination disease. TMEV-IDD can be induced in resistant mouse strains by inducing innate immunity with lipopolysaccharide (LPS. Interestingly, Toll-like receptor 4 (TLR4 is the cognate receptor for LPS and its activation can induces up-regulation of other TLRs, such as TLR7 (the receptor for TMEV and 9, known to be involved in autoimmunity. Up-regulation of TLRs could be involved in precipitating an autoimmune susceptible state. Consequently, we looked at TLR expression in the susceptible (SJL/J and resistant (C57BL/6 strains of mice infected with TMEV. The resistant mice were induced to develop TMEV-IDD by two LPS injections following TMEV infection. Results Both strains were found to up-regulate multiple TLRs (TLR2, 7 and 9 following the TMEV infection. Expression of these TLRs and of viral mRNA was significantly greater in infected SJL/J mice. The susceptible SJL/J mice showed up-regulation of TLR3, 6 and 8, which was not seen in C57BL/6 mice. Conclusion Expression of TLRs by susceptible mice and the up-regulation of the TLRs in resistant mice could participate in priming the mice toward an autoimmune state and develop TMEV-IDD. This could have implications on therapies that target TLRs to prevent the emergence of conditions such as MS in patients at risk for the disease.
Takizawa, Sho; Kaneyama, Tomoki; Tsugane, Sayaka; Takeichi, Naoya; Yanagisawa, Satoshi; Ichikawa, Motoki; Yagita, Hideo; Kim, Byung S; Koh, Chang-Sung
Programmed death-1 (PD-1) belongs to the CD28 family of co-stimulatory and co-inhibitory molecules and regulates adaptive immunity. This molecule induces the development of regulatory T cells, T cell tolerance, or apoptosis. We examined the role of PD-1 pathway in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) mice. Up-regulation of PD-1 and PD-1 ligand-1 (PD-L1) mRNA expression in bone marrow-derived dendritic cells were induced by TMEV infection in vitro. Furthermore, PD-1 and PD-L1 mRNA expression was increased in the spinal cords of the TMEV-infected mice in vivo. Treatment with a blocking monoclonal antibody (mAb) against PD-1, especially during the effector phase, resulted in significant deterioration of the TMEV-IDD both clinically and histologically. Flow cytometric analysis revealed a dramatically increase of CD4(+) T cells producing Th1 cytokines such as IFN-γ and TNF-α in the spinal cord of anti-PD-1 mAb-treated mice. These results indicate that the PD-1 pathway plays a pivotal regulatory role in the development of TMEV-IDD. Copyright © 2014 Elsevier B.V. All rights reserved.
Bowen, Jenna L; Olson, Julie K
Multiple sclerosis is a demyelinating disease associated with an inflammatory immune response in the CNS. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease is a relevant mouse model for the study of multiple sclerosis. TMEV infection of susceptible mice leads to a persistent virus infection of the CNS which contributes to development of demyelinating disease. We have previously shown that the innate immune response can affect the development and progression of demyelinating disease. In the current studies, we determined that the predominant infiltrating cells during the innate immune response are CD11b(+)Ly6C(+) cells. CD11b(+)Ly6C(+) cells are immature myeloid cells that have exited the bone marrow without maturing and have been shown to suppress CD4(+) and CD8(+) T cell responses. Therefore, we wanted to determine what role these cells play in development and progression of demyelinating disease. TMEV-infected mice depleted of CD11b(+)Ly6C(+) cells during the innate immune response developed a reduced demyelinating disease which was associated with a decreased myelin-specific CD4(+) T cell response and a decreased inflammatory immune response in the CNS. TMEV-infected mice depleted of CD11b(+)Ly6C(+) cells had increased virus-specific CD4(+) and CD8(+) T cell responses during early virus infection associated with increased expression of IFN-gamma and IL-17 and decreased expression of IL-10 in the CNS. These results suggest that CD11b(+)Ly6C(+) cells which infiltrate into the CNS during the innate immune response are myeloid-derived suppressor cells that suppress virus-specific T cell responses and contribute to the development of demyelinating disease.
Jin, Young-Hee; Kaneyama, Tomoki; Kang, Min Hyung; Kang, Hyun Seok; Koh, Chang-Sung; Kim, Byung S
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. 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. 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 regulatory FoxP3+ CD4+ T cells in the CNS, while
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 regulatory FoxP3+ CD4+ T
Jin, Young Hee; Kang, Hyun Seok; Hou, Wanqiu; Meng, Liping; Kim, Byung S
Intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carry H-2(s) MHC genes instead of H-2(b) MHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1- and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response. In vitro studies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases. This study indicates that innate immune cytokines produced in antigen-presenting cells stimulating the T cell immune responses during early viral infection play a critical role in determining the susceptibility of mice to the development of demyelinating disease. The level of innate immune cytokines
Jin, Young Hee; Kang, Hyun Seok; Hou, Wanqiu; Meng, Liping
ABSTRACT Intracerebral infection with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in susceptible SJL/J mice but not in resistant C57BL/6 mice. Previous studies have indicated that the major histocompatibility complex (MHC) genes play the most prominent role in the development of TMEV-induced demyelinating disease. In this study, we used C57BL/6.S (B6.S) congenic mice, which carry H-2s MHC genes instead of H-2b MHC genes in conjunction with the C57BL/6 (B6) background genes. Our data show that virus-infected B6.S mice are free from disease and have significantly lower viral loads than susceptible SJL mice, particularly in the spinal cord. A strong protective Th1-type T helper response with virtually no pathogenic Th17 response was detected in B6.S mice, in contrast to the reduced Th1- and robust Th17-type responses in SJL mice. Notably, lower levels of viral infectivity in B6.S antigen-presenting cells (APCs) correlated with the disease resistance and T-cell-type response. In vitro studies using APCs from B6.S and SJL mice show that TLR2, -3, -4, and -7, but not TLR9, signaling can replace viral infection and augment the effect of viral infection in the differentiation of the pathogenic Th17 cell type. Taken together, these results strongly suggest that the viral replication levels in APCs critically affect the induction of protective versus pathogenic Th cell types via the signaling of pattern recognition receptors for innate immune responses. Our current findings further imply that the levels of viral infectivity/replication and TLR-mediated signaling play critical roles in the pathogenesis of chronic viral diseases. IMPORTANCE This study indicates that innate immune cytokines produced in antigen-presenting cells stimulating the T cell immune responses during early viral infection play a critical role in determining the susceptibility of mice to the development of demyelinating disease. The level of innate immune
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
D'Anne S Duncan
Full Text Available The CNS is a unique organ due to its limited capacity for immune surveillance. As macrophages of the CNS, microglia represent a population originally known for the ability to assist neuronal stability, are now appreciated for their role in initiating and regulating immune responses in the brain. Theiler's murine encephalomyelitis virus (TMEV-induced demyelinating disease is a mouse model of multiple sclerosis (MS. In response to TMEV infection in vitro, microglia produce high levels of inflammatory cytokines and chemokines, and are efficient antigen-presenting cells (APCs for activating CD4(+ T cells. However, the regulatory function of microglia and other CNS-infiltrating APCs in response to TMEV in vivo remains unclear. Here we demonstrate that microglia increase expression of proliferating cell nuclear antigen (PCNA, and phenotypically express high levels of major histocompatibility complex (MHC-Class I and II in response to acute infection with TMEV in SJL/J mice. Microglia increase expression of the inhibitory co-stimulatory molecule, B7-H1 as early as day 5 post-infection, while CNS-infiltrating CD11b(+CD11c(-CD45(HIGH monocytes/macrophages and CD11b(+CD11c(+CD45(HIGH dendritic cells upregulate expression of B7-H1 by day 3 post-infection. Utilizing a neutralizing antibody, we demonstrate that B7-H1 negatively regulates TMEV-specific ex vivo production of interferon (IFN-γ, interleukin (IL-17, IL-10, and IL-2 from CD4(+ and CD8(+ T cells. In vivo blockade of B7-H1 in SJL/J mice significantly exacerbates clinical disease symptoms during the chronic autoimmune stage of TMEV-IDD, but only has minimal effects on viral clearance. Collectively, these results suggest that CNS expression of B7-H1 regulates activation of TMEV-specific T cells, which affects protection against TMEV-IDD.
Rahmlow, Megan R.; Kantarci, Orhun
Fulminant demyelinating disease is a heading that covers acute disseminated encephalomyelitis and its variant acute hemorrhagic leukoencephalitis (Hurst disease), severe relapses of multiple sclerosis (MS), variants of MS (tumefactive MS, Marburg variant, Balo concentric sclerosis, myelinoclastic diffuse sclerosis), and neuromyelitis optica-spectrum disorders associated with aquaporin autoimmunity. These categories of inflammatory demyelinating disease often prompt hospital admission and many necessitate intensive care monitoring due to the aggressive nature of the illness and associated neurologic morbidity. In this review, we highlight the discriminating clinical, radiographic, and pathologic features of these disorders. Acute management is often accomplished with use of high-dose intravenous steroids and plasma exchange. Aggressive disease may respond to immunosuppression. Prognosis for recovery varies among the disorders but most patients improve. Factors influencing outcome are also discussed. PMID:23983890
Central nervous system inflammatory demyelinating disease can affect patients across the life span. Consensus definitions and criteria of all of the different acquired demyelinating diseases that fall on this spectrum have magnetic resonance imaging criteria. The advances of both neuroimaging techniques and important discoveries in immunology have produced an improved understanding of these conditions and classification. Neuroimaging plays a central role in the accurate diagnosis, prognosis, disease monitoring and research efforts that are being undertaken in this disease. This review focuses on the imaging spectrum of acquired demyelinating disease. PMID:23858328
Tillema, Jan-Mendelt; Pirko, Istvan
Central nervous system inflammatory demyelinating disease can affect patients across the life span. Consensus definitions and criteria of all of the different acquired demyelinating diseases that fall on this spectrum have magnetic resonance imaging criteria. The advances of both neuroimaging techniques and important discoveries in immunology have produced an improved understanding of these conditions and classification. Neuroimaging plays a central role in the accurate diagnosis, prognosis, disease monitoring and research efforts that are being undertaken in this disease. This review focuses on the imaging spectrum of acquired demyelinating disease.
Tillema, Jan-Mendelt; Pirko, Istvan
Central nervous system inflammatory demyelinating disease can affect patients across the life span. Consensus definitions and criteria of all of the different acquired demyelinating diseases that fall on this spectrum have magnetic resonance imaging criteria. The advances of both neuroimaging techniques and important discoveries in immunology have produced an improved understanding of these conditions and classification. Neuroimaging plays a central role in the accurate diagnosis, prognosis, ...
Mayo, Lior; Quintana, Francisco J.; Weiner, Howard L
Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, nat...
Mayo, Lior; Quintana, Francisco J; Weiner, Howard L
Demyelinating diseases such as multiple sclerosis are chronic inflammatory autoimmune diseases with a heterogeneous clinical presentation and course. Both the adaptive and the innate immune systems have been suggested to contribute to their pathogenesis and recovery. In this review, we discuss the role of the innate immune system in mediating demyelinating diseases. In particular, we provide an overview of the anti-inflammatory or pro-inflammatory functions of dendritic cells, mast cells, natural killer (NK) cells, NK-T cells, γδ T cells, microglial cells, and astrocytes. We emphasize the interaction of astroctyes with the immune system and how this interaction relates to the demyelinating pathologies. Given the pivotal role of the innate immune system, it is possible that targeting these cells may provide an effective therapeutic approach for demyelinating diseases. © 2012 John Wiley & Sons A/S.
Full Text Available Abstract Background There is evidence that at least 5% of Multiple sclerosis (MS cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. Methods/Design The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA, allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS is an epidemiological surveillance study that already received ethical approvals, and started on the 1st
Absoud, Michael; Cummins, Carole; Chong, Wui K; De Goede, Christian; Foster, Katharine; Gunny, Roxanna; Hemingway, Cheryl; Jardine, Philip; Kneen, Rachel; Likeman, Marcus; Lim, Ming J; Pike, Mike; Sibtain, Naomi; Whitehouse, William P; Wassmer, Evangeline
There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient
Segal, Benjamin Matthew
Recently published studies in multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) have demonstrated an association between the development of demyelinating plaques and the accumulation of Th17 cells in the central nervous system and periphery. However, a causal relationship has been difficult to establish. In fact, in reports published thus far, interleukin (IL)-17A deficiency or neutralization in vivo attenuates, but does not completely abrogate, EAE. There is growing evidence that clinically similar forms of autoimmune demyelinating disease can be driven by myelin-specific T cells of distinct lineages with different degrees of dependence on IL-17A production to achieve their pathological effects. While such observations cast doubts about the potential therapeutic efficacy of Th17 blocking agents in MS, the collective data suggest that IL-17A expression in peripheral blood mononuclear cells could serve as a surrogate biomarker of neuroinflammation and plaque formation and be a useful outcome measure for future clinical trials.
Beres, Shannon J; Graves, Jennifer; Waubant, Emmanuelle
Rituximab is a B-cell therapy used off-label to reduce relapses in adult demyelinating diseases. There is limited knowledge of its clinical use in pediatric neuromyelitis optica and multiple sclerosis. Demyelinating diseases in children can have high morbidity, and B-cell therapies hold promise for those with a severe course. Our study investigates the clinical experience of safety and efficacy with rituximab in children with demyelinating diseases of the central nervous system. This is a retrospective case series of 11 patients with pediatric neuromyelitis optica and multiple sclerosis who received at least one rituximab infusion at the Pediatric Multiple Sclerosis Clinic, University of California, San Francisco. Each patient was infused up to 1000 mg twice 2 weeks apart. Patients were monitored prospectively, and relapse events, laboratories, and adverse reactions were recorded. Eight children with neuromyelitis optica, two with relapsing-remitting multiple sclerosis and one with secondary-progressive multiple sclerosis received rituximab treatment. The median number of cycles was 3. Most patients (82%, n = 9) experienced reduction of relapses after initiating rituximab. There were no serious infections. Infusion reactions were reported in three patients and managed successfully in subsequent infusions with increased pretreatment (dexamethasone and diphenhydramine) and use of slower infusion rates. Rituximab was not discontinued in any child because of side effects; two switched treatment therapy after 4.5 and 11 months because of relapses. The use of rituximab in our pediatric neuromyelitis optica and multiple sclerosis cohort was overall safe and effective. Larger studies should confirm our observations. Copyright © 2014 Elsevier Inc. All rights reserved.
DeLuca, Gabriele C; Joseph, Albert; George, Jithin; Yates, Richard L; Hamard, Marie; Hofer, Monika; Esiri, Margaret M
Olfactory dysfunction is common in multiple sclerosis (MS). Olfactory bulb and tract pathology in MS and other demyelinating diseases remain unexplored. A human autopsy cohort of pathologically confirmed cases encompassing the spectrum of demyelinating disease (MS; n = 17), neuromyelitis optica [(NMO); n = 3] and acute disseminated encephalomyelitis [(ADEM); n = 7] was compared to neuroinflammatory [herpes simplex virus encephalitis (HSE); n = 3], neurodegenerative [Alzheimer's disease (AD); n = 4] and non-neurologic (n = 8) controls. For each case, olfactory bulbs and/or tracts were stained for myelin, axons and inflammation. Inferior frontal cortex and hippocampus were stained for myelin in a subset of MS and ADEM cases. Olfactory bulb/tract demyelination was frequent in all demyelinating diseases [MS 12/17 (70.6%); ADEM 3/7 (42.9%); NMO 2/3 (66.7%)] but was absent in HSE, AD and non-neurologic controls. Inflammation was greater in the demyelinating diseases compared to non-neurologic controls. Olfactory bulb/tract axonal loss was most severe in MS where it correlated significantly with the extent of demyelination (r = 0.610, P = 0.009) and parenchymal inflammation (r = 0.681, P = 0.003). The extent of olfactory bulb/tract demyelination correlated with that found in the adjacent inferior frontal cortex but not hippocampus. We provide unequivocal evidence that olfactory bulb/tract demyelination is frequent, can occur early and is highly inflammatory, and is specific to demyelinating disease. © 2014 International Society of Neuropathology.
Siffrin, Volker; Müller-Forell, Wibke; von Pein, Harald; Zipp, Frauke
Glioma-like inflammatory demyelinating lesions can be found in patients with pre-diagnosed multiple sclerosis, but they have also been described as an isolated disease entity. The initial diagnostic work-up usually includes a biopsy for histopathological analysis. However, even after unambiguous histopathologic classification, tumefactive lesions pose a therapeutic challenge. Until now, there have been no guidelines on how to treat patients with these rare and extreme lesion phenotypes. Here we report a patient with a relapsing unifocal tumefactive demyelinating lesion. The patient initially showed a good response to steroid treatment, with full clinical recovery. However, after relapse of the same lesion, recovery was incomplete. Although immunosuppression was initiated, the patient presented with subsequent further deterioration. Only maximal escalation of immunosuppression was able to stop the inflammatory activity. Due to the length of time of the step-wise escalation treatment however, the lengthy lesion activity led to irreversible tissue destruction and residual non-remitting disability. Early aggressive treatment with an induction therapy regimen might be more appropriate for these rare and often strongly disabling lesion subtypes.
Kim, Seung Jae; Jin, Young-Hee; Kim, Byung S
Infection of various cells with Theiler's murine encephalomyelitis virus (TMEV) activates the TLR- and melanoma differentiation-associated gene 5 (MDA5)-dependent pathways, resulting in the production of IL-1β via the activation of caspase-1 upon assembly of the node-like receptor protein 3 (NLRP3) inflammasome. The role of IL-1β in the pathogenesis of TMEV-induced demyelinating disease was previously investigated. However, the signaling effects of prostaglandin E2 (PGE2) downstream of the NLRP3 inflammasome on the immune responses to viral determinants and the pathogenesis of demyelinating disease are unknown. In this study, we investigated the levels of intermediate molecules leading to PGE2 signaling and the effects of blocking PGE2 signaling on the immune response to TMEV infection, viral persistence and the development of demyelinating disease. We demonstrate here that TMEV infection activates the NLRP3 inflammasome and PGE2 signaling much more vigorously in dendritic cells (DCs) and CD11b+ cells from susceptible SJL mice than in cells from resistant B6 mice. Inhibition of virus-induced PGE2 signaling using AH23848 resulted in decreased pathogenesis of demyelinating disease and viral loads in the central nervous system (CNS). In addition, AH23848 treatment caused the elevation of protective early IFN-γ-producing CD4+ and CD8+ T cell responses. Because the levels of IFN-β were lower in AH23848-treated mice but the level of IL-6 was similar, over-production of pathogenic IFN-β was modulated and the generation of IFN-γ-producing T cell responses was enhanced by the inhibition of PGE2 signaling. These results strongly suggest that excessive activation of the NLRP3 inflammasome and downstream PGE2 signaling contribute to the pathogenesis of TMEV-induced demyelinating disease.
Albulaihe, Hana; Alabdali, Majed; Alsulaiman, Abdulla; Abraham, Alon; Breiner, Ari; Barnett, Carolina; Katzberg, Hans D; Lovblom, Leif E; Perkins, Bruce A; Bril, Vera
Evaluation of disease status in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is often done by a combination of clinical evaluation and electrodiagnostic studies. A CIDP disease activity status (CDAS) was developed to standardize outcomes in CIDP patients. We aimed to determine if the CDAS was concordant with classical evaluation and whether CDAS enables benchmarking of CIDP. We performed a retrospective chart review of 305 CIDP patients and identified 206 patients with >1 visit and applied the CDAS to this cohort. We examined relationships between the CDAS and classical evaluation as to outcomes and compared our cohort to other CIDP cohorts who had CDAS. We found that the CDAS mirrored disease severity as measured by electrophysiology and vibration perception thresholds in that CDAS class 5 had more severe neuropathy. Our results are similar to other cohorts in the middle CDAS strata with the exception of fewer subjects in CDAS 1 and more in CDAS 5. The only demographic factor predicting CDAS 5 in our cohort was age, and the overall treatment response rate using the CDAS classification was 79.3%. CDAS appears to have sufficient face-validity as a grading system to assess disease activity in relation to treatment status. The use of CDAS appears to allow benchmarking of patients with CIDP that may be useful in subject selection for clinical trials and also to highlight differences in practice. Copyright © 2016 Elsevier B.V. All rights reserved.
O'Mahony, Julia; Bar-Or, Amit; Arnold, Douglas L; Sadovnick, A Dessa; Marrie, Ruth Ann; Banwell, Brenda
The diagnosis of acquired demyelinating syndromes of the central nervous system in children requires exclusion of other acute central nervous system disorders. In a 23-site national demyelinating disease study, standardized clinical, laboratory, and magnetic resonance imaging (MRI) data were obtained prospectively from onset, and serially at 3, 6, and 12 months and annually. Twenty of 332 (6%) participants (mean [SD] age, 10.21 [4.32] years; 12 (60%) female) were ultimately diagnosed with vascular disorders (primary or secondary central nervous system vasculitis, vasculopathy, stroke, or migraine, n = 11 children), central nervous system malignancy (n = 3), mitochondrial disease (n = 2), or central nervous system symptoms in the accompaniment of confirmed infection (n = 4). Red flags that may serve to distinguish disorders in the differential of acquired demyelination are described.
Höftberger, Romana; Lassmann, Hans
Inflammatory demyelinating diseases are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. The pathologic hallmark of multiple sclerosis (MS) is the presence of focal demyelinated lesions with partial axonal preservation and reactive astrogliosis. Demyelinated plaques are present in the white as well as gray matter, such as the cerebral or cerebellar cortex and brainstem nuclei. Activity of the disease process is reflected by the presence of lesions with ongoing myelin destruction. Axonal and neuronal destruction in the lesions is a major substrate for permanent neurologic deficit in MS patients. The MS pathology is qualitatively similar in different disease stages, such as relapsing remitting MS or secondary or primary progressive MS, but the prevalence of different lesion types differs quantitatively. Acute MS and Balo's type of concentric sclerosis appear to be variants of classic MS. In contrast, neuromyelitis optica (NMO) and spectrum disorders (NMOSD) are inflammatory diseases with primary injury of astrocytes, mediated by aquaporin-4 antibodies. Finally, we discuss the histopathology of other inflammatory demyelinating diseases such as acute disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated demyelination. Knowledge of the heterogenous immunopathology in demyelinating diseases is important, to understand the clinical presentation and disease course and to find the optimal treatment for an individual patient. Copyright © 2017 Elsevier B.V. All rights reserved.
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.
Full Text Available Multiple sclerosis (MS is an autoimmune mediated neurodegenerative disease characterized by demyelination and oligodendrocyte (OL loss in the central nervous system and accompanied by local inflammation and infiltration of peripheral immune cells. Although many risk factors and symptoms have been identified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inflammation or whether the local inflammation is the cause of OL death and demyelination. This review briefly discusses several models that have been developed to specifically ablate oligodendrocytes in an effort to separate the effects of demyelination from inflammation.
Gong, Xiaoming; Xie, Zuoping; Zuo, Huancong
Demyelinating disease is pathologically characterized by the death of mature oligodendrocytes that normally synthesize myelin to perform insulating functions. Moreover, demyelinating disease also results in the failure of remyelination process in which oligodendrocyte progenitor cells reactivate and differentiate into new oligodendrocytes. Thus, this disease reflects decreased nerve conduction velocity and eventually dysfunction of the nervous system. A notable fact in the clinic is that demyelination is one of the most common diabetes-induced complications, implying that demyelinating disease may be relevant to insulin deficiency in vivo. However, the explicit pathological relationship between demyelination and diabetes remains unclear. Mainstream theories posit that demyelinating disease is an autoimmune disease arising from abnormal immunological reactions, but this perspective is limited when applied to the clinic. Olig1 is a vital transcription factor involved in oligodendrogenesis and is essential for the survival and maturation of oligodendrocyte progenitor cells. Furthermore, Olig1 is required for the onset of remyelination in adults. In the present study, we serendipitously found by means of protein immunoblot that the expression of nuclear Olig1 was inhibited when mouse oligodendrocyte progenitor cells were cultured in the absence of insulin. Combining this finding with the clinical relevance of demyelination and diabetes, we hypothesize that in vivo insulin deficiency impairs the reactivation and differentiation of oligodendrocyte progenitor cells through downregulation of nuclear Olig1 expression and therefore hinders the remyelination, which is an important process required for functional recovery in demyelinating disease. This hypothesis implies that in vivo insulin deficiency may be a novel etiological cause of demyelinating disease and thus contribute to improved the clinical therapies for remyelination repair. We suggest that sustaining normal
Magro Checa, César; Cohen, Danielle; Bollen, Eduard L E M; van Buchem, Mark A; Huizinga, Tom W J; Steup-Beekman, Gerda M
Among the 12 systemic lupus erythematosus (SLE)-related central nervous system (CNS) syndromes defined by the American College of Rheumatology (ACR), demyelinating syndrome and myelopathy are two of the less prevalent and more poorly understood ones. One important issue concerning demyelinating disease in SLE is that it can be easily misdiagnosed with other central nervous system demyelinating disorders such as multiple sclerosis (MS). A clinically isolated neurological syndrome can be the presenting feature before other concomitant symptoms of SLE appear or definite MS is diagnosed. Although challenging, some diagnostic tests used in clinical practice and research may help to differentiate between these entities. These tests have improved the understanding of the pathogenesis in these diseases, but some points, such as the role of antiphospholipid antibodies in SLE-associated transverse myelitis, remain unclear and are a matter of ongoing debate. This review discusses clinical, pathophysiological, radiological and therapeutic concepts of demyelinating disease of the CNS in SLE, focussing on its differentiation from MS and its relation with other CNS demyelinating processes, such as transverse myelitis, optic neuritis and neuromyelitis optica. Copyright © 2013 Elsevier Ltd. All rights reserved.
Talwar, D; Smith, S A
CAMFAK syndrome is an inherited disease characterized by congenital cataracts, microcephaly, failure to thrive, and kyphoscoliosis with onset in early infancy. Its pathogenesis has not been clearly defined. We report on a patient with this syndrome and present evidence that it is a neurologic disease characterized by peripheral and central demyelination similar to that seen in Cockayne syndrome.
Brenton, J Nicholas; Koenig, Scott; Goldman, Myla D
To evaluate the prevalence of and associated factors impacting vitamin D insufficiency and deficiency in childhood versus adult-onset demyelinating disease. We conducted a retrospective, cross-sectional, chart-review, cohort study on geographically-similar pediatric, young adult, and adult patients with a diagnosis of demyelinating disease identified at the University of Virginia from 2008 to 2013. Group prevalence of vitamin D insufficiency and deficiency as well as relevant factors associated with vitamin D status was analyzed and compared. We identified 24 childhood-onset (CO), 33 young adult-onset (Y-AO), and 59 adult-onset (AO) cases. There was no difference in the prevalence of vitamin D insufficiency or deficiency between the cohorts. Non-Caucasian race and elevated body mass index were significantly associated with low vitamin D levels, regardless of age of onset. In regression models, race and obesity were independent predictors of vitamin D status. The prevalence of obesity was significantly higher in the childhood-onset cohort (CO=58.5%; Y-AO=31%; AO=34%; p=0.02). Our findings demonstrate no difference in the prevalence of vitamin D insufficiency/deficiency between childhood and adult-onset demyelinating disease, suggesting age at disease onset is irrelevant to vitamin D status in demyelinating disease. Both race and obesity are independent factors associated with vitamin D insufficiency/deficiency, regardless of age of disease onset. Obesity, independent of gender, is significantly higher in children compared to adult patients diagnosed with multiple sclerosis and may have a role in the development of childhood-onset demyelinating disease. Copyright © 2014 Elsevier B.V. All rights reserved.
Sips, G. J.; Chesik, D.; Glazenburg, L.; Wilschut, J.; De Keyser, J.; Wilczak, N.
Two members of the morbillivirus genus of the family Paramyxoviridae, canine distemper virus (CDV) and measles virus (MV), are well-known for their ability to cause a chronic demyelinating disease of the CNS in their natural hosts, dogs and humans, respectively. Both viruses have been studied for
J Gordon Millichap
Full Text Available A case of familial hemophagocytic lymphohistiocytosis type 3 (FHLH3 presenting in a 3-year-old boy with fulminant demyelinating neurological disease is reported by researchers at Kravis Children’s Hospital at Mount Sinai Medical Center, New York.
Casserly, Courtney S; Nantes, Julia C; Whittaker Hawkins, Ryder F; Vallières, Luc
Neutrophils are essential to a healthy life, yet pose a threat if improperly controlled. Neutrophil perversion is well documented in a variety of inflammatory disorders (e.g. arthritis, lupus, psoriasis), but is only beginning to be demystified in autoimmune demyelination, the most common cause of neurological disability in young adults. Using the animal model experimental autoimmune encephalomyelitis (EAE), several molecules that help neutrophils invade the central nervous system (CNS) have been identified. Mechanisms by which neutrophils may contribute to demyelination have also been proposed (e.g. secretion of endothelial/leukocytic modulators, antigen presentation to T cells, myelin degradation and phagocytosis). In human, neutrophils are seen in the CNS of people with neuromyelitis optica spectrum disorder and other severe variants of autoimmune demyelinating diseases. At the time of autopsy for multiple sclerosis (MS) - often many years after its onset - neutrophils appear to have escaped the scene of the crime. However, new clues implicate neutrophils in MS relapses and progression. This warrants further investigating 1) the differential importance of neutrophils among demyelinating diseases, 2) the largely unknown effects of current MS therapies on neutrophils, and 3) the potential of neutrophil proteins as clinical biomarkers or therapeutic targets. Copyright © 2017 Elsevier B.V. All rights reserved.
Saberio Lo Presti MD
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.
Weinshenker, Brian G
Whether or not recurrent tumefactive demyelinating lesions are a unique form of CNS demyelinating disease or part of the continuum of multiple sclerosis is a question raised by the case report on which this commentary is based. Detailed review and immunopathologic study of biopsy material may not only confirm or refute a diagnosis of demyelinating disease, but potentially uncover unique features that may assist in understanding pathophysiology and nosology of rare cases with recurrent tumefactive demyelination. © The Author(s), 2015.
Greer, Judith M; Broadley, Simon; Pender, Michael P
Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with coexistent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with coexisting CNS demyelinating disease and AITD were identified and their clinical and radiological features were record...
Full Text Available Myelin oligodendrocyte glycoprotein (MOG, a member of the immunoglobulin (Ig superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS. Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs, as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients’ samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM, aquaporin-4 (AQP4 seronegative neuromyelitis optica spectrum disorders (NMOSD, monophasic or recurrent isolated optic neuritis (ON, or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic
Sandro Luiz de Andrade Matas
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.
Peschl, Patrick; Bradl, Monika; Höftberger, Romana; Berger, Thomas; Reindl, Markus
Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS). Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs), as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients’ samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD), monophasic or recurrent isolated optic neuritis (ON), or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic. This article
Stimmer, Lev; Fovet, Claire-Maëlle; Serguera, Ché
Human idiopathic inflammatory demyelinating diseases (IIDD) are a heterogeneous group of autoimmune inflammatory and demyelinating disorders of the central nervous system (CNS). These include multiple sclerosis (MS), the most common chronic IIDD, but also rarer disorders such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO). Great efforts have been made to understand the pathophysiology of MS, leading to the development of a few effective treatments. Nonetheless, IIDD still require a better understanding of the causes and underlying mechanisms to implement more effective therapies and diagnostic methods. Experimental autoimmune encephalomyelitis (EAE) is a commonly used animal model to study the pathophysiology of IIDD. EAE is principally induced through immunization with myelin antigens combined with immune-activating adjuvants. Nonhuman primates (NHP), the phylogenetically closest relatives of humans, challenged by similar microorganisms as other primates may recapitulate comparable immune responses to that of humans. In this review, the authors describe EAE models in 3 NHP species: rhesus macaques ( Macaca mulatta), cynomolgus macaques ( Macaca fascicularis), and common marmosets ( Callithrix jacchus), evaluating their respective contribution to the understanding of human IIDD. EAE in NHP is a heterogeneous disease, including acute monophasic and chronic polyphasic forms. This diversity makes it a versatile model to use in translational research. This clinical variability also creates an opportunity to explore multiple facets of immune-mediated mechanisms of neuro-inflammation and demyelination as well as intrinsic protective mechanisms. Here, the authors review current insights into the pathogenesis and immunopathological mechanisms implicated in the development of EAE in NHP.
Behan, Peter O; Chaudhuri, Abhijit
Experimental allergic encephalomyelitis (EAE) is the commonest, readily induced, organspecific, autoimmune disorder of laboratory animals of its kind. It is an artificial disorder brought about by the immunisation of susceptible animals with brain antigens in complete Freund׳s adjuvant (CFA). Variations can be induced by altering the nature of the antigen and the conditions involving immunisation. Whilst it is often described as a demyelinating disease, in strict terms it is not, since the primary pathologic process is not demyelination but rather an encephalomyelitis that is immunologically induced. Rather, the prototype demyelinating disease is multiple sclerosis and its variants. In this paper, the central question we ask is whether the data gleaned from the EAE model contributes to our understanding of the pathological events in MS. Towards answering this, we describe the historical development of EAE and its hyperacute form, and discuss the findings studied extensively in the non-human primate which show that ordinary EAE is an exact model for ADEM in the human, and that the hyperacute form of EAE is represented by AHLE in the human. Additionally, we shall comment on the latest research on new variants of EAE, and explain our opinion regarding the use of EAE models in research aiming to understand the pathogenesis of multiple sclerosis. Copyright © 2014 Elsevier B.V. All rights reserved.
Chastain, Emily M L; Miller, Stephen D
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that affects about 0.1% of the worldwide population. This deleterious disease is marked by infiltration of myelin-specific T cells that attack the protective myelin sheath that surrounds CNS nerve axons. Upon demyelination, saltatory nerve conduction is disrupted, and patients experience neurologic deficiencies. The exact cause for MS remains unknown, although most evidence supports the hypothesis that both genetic and environmental factors contribute to disease development. Epidemiologic evidence supports a role for environmental pathogens, such as viruses, as potentially key contributors to MS induction. Pathogens can induce autoimmunity via several well-studied mechanisms with the most postulated being molecular mimicry. Molecular mimicry occurs when T cells specific for peptide epitopes derived from pathogens cross-react with self-epitopes, leading to autoimmune tissue destruction. In this review, we discuss an in vivo virus-induced mouse model of MS developed in our laboratory, which has contributed greatly to our understanding of the mechanisms underlying molecular mimicry-induced CNS autoimmunity. © 2011 John Wiley & Sons A/S.
Amorim,Ana Luiza M.; Cabral, Nadia C.; Osaku, Fabiane M.; Claudio A. Len; Oliveira, Enedina M.L.; Terreri, Maria Teresa
ABSTRACT Introduction: Multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating diseases of the central nervous system. Autoimmunity in patients with demyelinating disease and in their families has been broadly investigated and discussed. Recent studies show a higher incidence of rheumatic autoimmune diseases among adult patients with MS or NMO and their families, but there are no studies in the pediatric population. Objective: To evaluate an association of MS and NMO with a...
Hu, Xianzhen; Wohler, Jillian E.; Dugger, Kari J.; Barnum, Scott R.
Experimental autoimmune encephalomyelitis as a model for demyelinating disease challenges the mindset that β2-integrins are redundant in function and potential therapeutic targets for multiple sclerosis.
Kim, Jee-Eun; Park, Kang M; Kim, Yerim; Yoon, Dae Y; Bae, Jong S
To identify and analyze the characteristics of the most influential articles about central nervous system (CNS) inflammatory demyelinating disease. The Institute for Scientific Information (ISI) Web of Science database and the 2014 Journal Citation Reports Science Edition were used to retrieve the top 100 cited articles on CNS inflammatory demyelinating disease. The citation numbers, journals, years of publication, authorships, article types, subjects and main issues were analyzed. For neuromyelitis optica (NMO), articles that were cited more than 100 times were regarded as a citation classic and described separately. The top 100 cited articles were published between 1972 and 2011 in 13 journals. The highest number of articles (n = 24) was published in Brain, followed by The New England Journal of Medicine (n = 21). The average number of citations was 664 (range 330-3,897), and 64% of the articles were from the United States and the United Kingdom. The majority of the top 100 cited articles were related to multiple sclerosis (n = 87), and only a few articles reported on other topics such as NMO (n = 9), acute disseminated encephalomyelitis (n = 2) and optic neuritis (n = 2). Among the top 100 cited articles, 77% were original articles. Forty-one citation classics were found for NMO. Our study provides a historical perspective on the research progress on CNS inflammatory demyelinating disease and may serve as a guide for important advances and trends in the field for associated researchers.
Murphy, Natalia A; Franklin, Robin J M
Demyelinating diseases, such as multiple sclerosis (MS), are responsible for a significant portion of the neurological disability burden worldwide, especially in young adults. Demyelination can be followed by a spontaneous regenerative process called remyelination, in which new myelin sheaths are restored to denuded axons. However, in chronic demyelinating disease such as MS, this process becomes progressively less efficient. This chapter reviews the biology of remyelination and the rationale and strategies by which it can be enhanced therapeutically in acquired demyelinating disease. © 2017 Elsevier B.V. All rights reserved.
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
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.
Nakasu, Yoko; Suda, Kinya; Handa, Jyoji; Hazama, Fumitada (Shiga Univ. of Medical Science, Otsu (Japan))
Demyelinating diseases of the brain may show mass effects and/or contrast enhancement on CT scans, simulating the appearance of infiltrating glioma. A 36-year-old male, had suffered from gait disturbance and convulsive attacks involving the right lower limb since the age of 30. He had gradually developed character changes and urine incontinence. Six months prior to admission he experienced several attacks of generalized convulsions. On admission, he showed a mild hemiparesis, bilateral Babinski signs, and ataxic gait. He was disoriented and had memory disturbance and moria. CT scan showed low density areas in the bilateral frontal lobes Fand corpus callosum associated with a mild mass effect. Contrast study revealed irregular enhancement along the edge of the low density area and another small enhancing lesion in the left temporal lobe. This CT finding was interpreted as that of ''butterfly'' glioma. Craniotomy and right frontal lobectomy were performed. Histological study, however, demonstrated demyelination in the white matter associated with perivascular proliferation of lymphocytes. The final diagnosis was the 'transitional sclerosis' of Poser.
Lawrence Charles Kenyon
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.
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.
Katsenos, Chrysostomos; Androulaki, Despoina; Lyra, Stavroula; Tsoutsouras, Theodoros; Mandragos, Costas
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. 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. 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.
Aspli, Klaus Thanke; Flaten, Trond Peder; Roos, Per M; Holmøy, Trygve; Skogholt, Jon H; Aaseth, Jan
The pathophysiological mechanisms of progressive demyelinating disorders including multiple sclerosis are incompletely understood. Increasing evidence indicates a role for trace metals in the progression of several neurodegenerative disorders. The study of Skogholt disease, a recently discovered demyelinating disease affecting both the central and peripheral nervous system, might shed some light on the mechanisms underlying demyelination. Cerebrospinal fluid iron and copper concentrations are about four times higher in Skogholt patients than in controls. The transit into cerebrospinal fluid of these elements from blood probably occurs in protein bound form. We hypothesize that exchangeable fractions of iron and copper are further transferred from cerebrospinal fluid into myelin, thereby contributing to the pathogenesis of demyelination. Free or weakly bound iron and copper ions may exert their toxic action on myelin by catalyzing production of oxygen radicals. Similarities to demyelinating processes in multiple sclerosis and other myelinopathies are discussed. Copyright © 2014 Elsevier GmbH. All rights reserved.
Miyaji, Kazuki; Paul, Friedemann; Shahrizaila, Nortina; Umapathi, Thirugnanam; Yuki, Nobuhiro
Tetraspanin family proteins, CD9, CD81 and CD82 are expressed in the oligodendrocytes and Schwann cells. We investigated autoantibodies to tetraspanin proteins in patients with demyelinating diseases. Sera were collected from 119 multiple sclerosis patients, 19 neuromyelitis optica, 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy and 13 acute motor axonal neuropathy as well as 55 healthy controls. Few multiple sclerosis and acute inflammatory demyelinating polyneuropathy patients had autoantibodies that were weakly reactive to CD9 or CD81 but the significance is unclear. It is unlikely that these autoantibodies are pathogenic or serve as potential biomarkers in demyelinating diseases. Copyright © 2015 Elsevier B.V. All rights reserved.
Lee, Samuel M; Chin, Lih-Shen; Li, Lian
Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.
Akiyama, Yukinori; Suzuki, Hime; Mikuni, Nobuhiro
Cases of intracranial germinoma with granulomatous reaction are rare, so a pathological diagnosis of this disease is difficult. In this report, we describe the case of a 13-year-old boy with a bilateral thalamic germinoma which initially mimicked tumefactive demyelinating disease with inflammation, based on the clinical symptoms, imaging results and histology of a biopsy specimen obtained endoscopically. Upon examination of the cerebrospinal fluid, oligoclonal bands were detected. Although his symptoms and radiological findings improved following steroid pulse treatment, they worsened dramatically almost 1 year after the first surgery and even after an additional steroid pulse treatment. Prompted by the clinical course, a second biopsy was performed, and a pathological examination of the specimen showed a two-cell pattern. The diagnosis was changed to intracranial germinoma. After chemotherapeutic treatment with etoposide and cisplatin, the patient's symptoms and radiological findings dramatically improved. We conclude that it is very challenging to distinguish germinomas with a granulomatous reaction due to other inflammatory diseases, especially when only small specimens can be obtained. Stereotactic or endoscopic biopsies should be performed using samples from several different points even if the lesions are associated with eloquent brain regions. © 2016 S. Karger AG, Basel.
Spalice, Alberto; Parisi, Pasquale; Papetti, Laura; Nicita, Francesco; Ursitti, Fabiana; Del Balzo, Francesca; Properzi, Enrico; Verrotti, Alberto; Ruggieri, Martino; Iannetti, Paola
Inflammatory demyelinating diseases comprise a spectrum of disorders affecting the myelin of the central and peripheral nervous system. These diseases can usually be differentiated on the basis of clinical, radiological, laboratory and pathological findings. Recent studies have contributed to current awareness that inflammatory demyelinating diseases are not restricted to the adult age group, but are more common in pediatric age than previously believed. Some of pediatric inflammatory demyelinating diseases carry an unfavorable long-term prognosis but appropriate treatments can improve the outcome. The possibility of physical and cognitive disability resulting from these diseases, highlights the urgent need for therapeutic strategies for neurorehabilitation, neuroregeneration, and neurorepair. This review discusses characteristics of primary demyelinating diseases more frequently observed in childhood, focusing on epidemiology, clinical aspects and treatments. PMID:21119885
Vega-Riquer, Jose M; Mendez-Victoriano, Gerardo; Morales-Luckie, Raul A; Gonzalez-Perez, Oscar
Multiple sclerosis, Guillain-Barré syndrome, peripheral nerve polyneuropathy and others comprise a group of demyelinating diseases characterized by progressive (and eventually irreversible) loss of oligodendrocytes and myelin sheaths in the white matter of the brain. To date, the etiology of these disorders is not well known and no effective treatments are currently available. Therefore, further research is needed to gain a better understand and treat these patients. To accomplish this goal, it is necessary to have appropriate animal models that closely resemble the pathophysiology of these diseases. Herein, we describe the model of toxic demyelination induced by cuprizone, a copper chelator that reduces the cytochrome and monoamine oxidase activity into the brain, produces mitochondrial stress and triggers local immunological responses. These biochemical and cellular changes ultimately result in selective loss of oligodendrocytes, extensive areas of demyelination and reactive gliosis in the corpus callosum, superior cerebellar peduncles and cerebral cortex. Remarkably, some aspects of the histological pattern induced by cuprizone are similar to those found in multiple sclerosis. Cuprizone exposure also provokes behavioral changes, impairs motor skills and affects mood as that observed in several demyelinating diseases. Upon cuprizone removal, the pathological and histological changes gradually revert. Therefore, the cuprizone model allows to partially mimic the disease relapses of some demyelinating diseases. In summary, the model of cuprizone-induced demyelination is a good experimental approach to study demyelinating diseases that has maintained its validity, and is a suitable pharmacological model for reproducing some key features of demyelinating diseases, including multiple sclerosis. Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.
Rovira Canellas, A. [Vall d' Hebron University Hospital, Magnetic Resonance Unit (I.D.I.), Department of Radiology, Barcelona (Spain); Rovira Gols, A. [Parc Tauli University Institute - UAB, UDIAT, Diagnostic Centre, Sabadell (Spain); Rio Izquierdo, J.; Tintore Subirana, M.; Montalban Gairin, X. [Vall d' Hebron University Hospital, Neuroimmunology Unit, Department of Neurology, Barcelona (Spain)
Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. The relapsing-remitting and secondary progressive forms of multiple sclerosis (MS) are the most common IIDDs. Other MS phenotypes include those with a progressive course from onset (primary progressive and progressive relapsing) or with a benign course continuing for years after onset (benign MS). Uncommon forms of IIDDs can be classified clinically into: (1) fulminant or acute IIDDs, such as the Marburg variant of MS, Balo's concentric sclerosis, Schilder's disease, and acute disseminated encephalomyelitis; (2) monosymptomatic IIDDs, such as those involving the spinal cord (transverse myelitis), optic nerve (optic neuritis) or brainstem and cerebellum; and (3) IIDDs with a restricted topographical distribution, including Devic's neuromyelitis optica, recurrent optic neuritis and relapsing transverse myelitis. Other forms of IIDD, which are classified clinically and radiologically as pseudotumoral, can have different forms of presentation and clinical courses. Although some of these uncommon IIDDs are variants of MS, others probably correspond to different entities. MR imaging of the brain and spine is the imaging technique of choice for diagnosing these disorders, and together with the clinical and laboratory findings can accurately classify them. Precise classification of these disorders may have relevant prognostic and treatment implications, and might be helpful in distinguishing them from tumoral or infectious lesions, avoiding unnecessary aggressive diagnostic or therapeutic procedures. (orig.)
Wang, Hongfen; Chen, Zhaohui; Ling, Li; Shang, Aijia; Qiao, Guangyu; Cui, Fang; Yang, Fei; Huang, Xusheng
To investigate the value of needle electromyography (EMG) in differentiating intramedullary tumor from inflammatory demyelinating disease of cervical region. Patients hospitalized in the Chinese PLA General Hospital from March 2008 to June 2013 with abnormalities on MRI of cervical vertebra and preliminary diagnosed as intramedullary tumor or inflammatory demyelinating disease of cervical region were enrolled in the study. Electrophysiological examination was performed before any treatment. Pathological findings were analyzed and prognosis was evaluated in all the subjects. A total of fifty-five patients were enrolled in the study with 33 cases of inflammatory demyelinating disease and 22 cases of intramedullary tumor defined by the postoperative pathological findings. In all the 33 cases with demyelinating disease, only one case (3.03%) presented as neurogenic damage by needle EMG. While in all the 22 cases with intramedullary tumor, needle EMG revealed neurogenic damage in 15 cases (68.18%) and the spinal segments of muscles with neurogenic damage were all within the spinal lesions demonstrated by MRI. The diagnostic sensitivity of EMG for intramedullary tumor was 68.18% and the diagnostic specificity was 96.97%, while the diagnostic sensitivity and specificity for intramedullary tumor by the medical history, symptoms and signs were 59.09% and 75.76% respectively. Needle EMG might play an important role in distinguishing intramedullary tumor from inflammatory demyelinating disease of cervical spinal cord.
Amorim, Ana Luiza M; Cabral, Nadia C; Osaku, Fabiane M; Len, Claudio A; Oliveira, Enedina M L; Terreri, Maria Teresa
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating diseases of the central nervous system. Autoimmunity in patients with demyelinating disease and in their families has been broadly investigated and discussed. Recent studies show a higher incidence of rheumatic autoimmune diseases among adult patients with MS or NMO and their families, but there are no studies in the pediatric population. To evaluate an association of MS and NMO with autoimmune rheumatic diseases in pediatric patients. 22 patients younger than 21 years old with MS or NMO diagnosed before the age of 18 years were evaluated regarding epidemiological data, clinical presentation, association with autoimmune diseases, family history of autoimmune diseases, laboratory findings, imaging studies and presence of auto-antibodies. Among the patients studied, there was a prevalence of females (68.1%). The mean age of symptoms onset was 8 years and 9 months and the mean current age was 16 years and 4 months. Two patients (9%) had a history of associated autoimmune rheumatic disease: one case of juvenile dermatomyositis in a patient with NMO and another of systemic lupus erythematosus in a patient with MS. Three patients (13%) had a family history of autoimmunity in first-degree relatives. Antinuclear antibody was found positive in 80% of patients with NMO and 52% of patients with MS. About 15% of antinuclear antibody-positive patients were diagnosed with rheumatologic autoimmune diseases. Among patients with demyelinating diseases diagnosed in childhood included in this study there was a high frequency of antinuclear antibody positivity but a lower association with rheumatologic autoimmune diseases than that observed in studies conducted in adults. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.
Full Text Available The aquaporin 4 (AQP4 plays an important role in the maintenance of transmembrane water transfer, blood-brain barrier (BBB integrity and homeostasis of central nervous system, and its highly specific autoantibody NMO-IgG has been used as a specific biomarker of neuromyelitis optica. However, in recent years, several studies have found that the positive rate in patients with neuromyelitis optica is not 100%, and it even can be detected in some other demyelinating diseases of central nervous system. This paper aims to make a review of the diagnostic value of NMO-IgG in demyelinating diseases of central nervous system, in order to deepen the understanding of this antibody and guide the clinical diagnosis and differential diagnosis on demyelinating diseases of central nervous system. DOI: 10.3969/j.issn.1672-6731.2016.09.006
Shindler, Kenneth S.; Kenyon, Lawrence C.; Dutt, Mahasweta; Hingley, Susan T.; Sarma, Jayasri Das
Optic neuritis (ON), an inflammatory demyelinating optic nerve disease, occurs in multiple sclerosis (MS). Pathological mechanisms and potential treatments for ON have been studied via experimental autoimmune MS models. However, evidence suggests that virus-induced inflammation is a likely etiology triggering MS and ON; experimental virus-induced ON models are therefore required. We demonstrate that MHV-A59, a mouse hepatitis virus (MHV) strain that causes brain and spinal cord inflammation and demyelination, induces ON by promoting mixed inflammatory cell infiltration. In contrast, MHV-2, a nondemyelinating MHV strain, does not induce ON. Results reveal a reproducible virus-induced ON model important for the evaluation of novel therapies. PMID:18579591
Barakat, Nadia; Gorman, Mark P; Benson, Leslie; Becerra, Lino; Borsook, David
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.
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.
Huang, Yangyang; Dreyfus, Cheryl F.
A variety of growth factors are being explored as therapeutic agents relevant to the axonal and oligodendroglial deficits that occur as a result of demyelinating lesions. This review focuses on five such proteins that are present in the lesion site and impact oligodendrocyte regeneration. It then presents approaches that are being exploited to manipulate the lesion environment affiliated with multiple neurodegenerative diseases and suggests that the utility of these approaches can extend to demyelination. Challenges are to further understand the roles of specific growth factors on a cellular and tissue level. Emerging technologies can then be employed to optimize the use of growth factors to ameliorate the deficits associated with demyelinating degenerative diseases. PMID:27016070
Huang, Yangyang; Dreyfus, Cheryl F
A variety of growth factors are being explored as therapeutic agents relevant to the axonal and oligodendroglial deficits that occur as a result of demyelinating lesions such as are evident in Multiple Sclerosis (MS). This review focuses on five such proteins that are present in the lesion site and impact oligodendrocyte regeneration. It then presents approaches that are being exploited to manipulate the lesion environment affiliated with multiple neurodegenerative diseases and suggests that the utility of these approaches can extend to demyelination. Challenges are to further understand the roles of specific growth factors on a cellular and tissue level. Emerging technologies can then be employed to optimize the use of growth factors to ameliorate the deficits associated with demyelinating degenerative diseases. Copyright © 2016 Elsevier Inc. All rights reserved.
Brenton, J Nicholas; Banwell, Brenda L
Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination.
Shaw, Maureen A; Gao, Zhen; McElhinney, Kathryn E; Thornton, Sherry; Flick, Matthew J; Lane, Adam; Degen, Jay L; Ryu, Jae Kyu; Akassoglou, Katerina; Mullins, Eric S
Multiple sclerosis (MS) is a neuroinflammatory, demyelinating disease of the CNS. Fibrinogen deposition at sites of blood-brain barrier breakdown is a prominent feature of neuroinflammatory disease and contributes to disease severity. Plasminogen, the primary fibrinolytic enzyme, also modifies inflammatory processes. We used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to evaluate the hypothesis that the loss of plasminogen would exacerbate neuroinflammatory disease. However, contrary to initial expectations, EAE-challenged plasminogen-deficient (Plg-) mice developed significantly delayed disease onset and reduced disease severity compared with wild-type (Plg+) mice. Similarly, pharmacologic inhibition of plasmin activation with tranexamic acid also delayed disease onset. The T-cell response to immunization was similar between genotypes, suggesting that the contribution of plasminogen was downstream of the T-cell response. Spinal cords from EAE-challenged Plg- mice demonstrated significantly decreased demyelination and microglial/macrophage accumulation compared with Plg+ mice. Although fibrinogen-deficient mice or mice with combined deficiencies of plasminogen and fibrinogen had decreased EAE severity, they did not exhibit the delay in EAE disease onset, as seen in mice with plasminogen deficiency alone. Together, these data suggest that plasminogen and plasmin-mediated fibrinolysis is a key modifier of the onset of neuroinflammatory demyelination.SIGNIFICANCE STATEMENT Multiple sclerosis is a severe, chronic, demyelinating disease. Understanding the pathobiology related to the autoreactive T-cell and microglial/macrophage demyelinating response is critical to effectively target therapeutics. We describe for the first time that deficiency of plasminogen, the key fibrinolytic enzyme, delays disease onset and protects from the development of the paralysis associated with a murine model of multiple sclerosis, experimental autoimmune
Biswas, Kaushiki; Chatterjee, Dhriti; Addya, Sankar; Khan, Reas S; Kenyon, Lawrence C; Choe, Alexander; Cohrs, Randall J; Shindler, Kenneth S; Das Sarma, Jayasri
The presence of immunoglobulin oligoclonal bands in the cerebrospinal fluid of Multiple Sclerosis (MS) patients supports the hypothesis of an infectious etiology, although the antigenic targets remain elusive. Neurotropic mouse hepatitis virus (MHV) infection in mice provides a useful tool for studying mechanisms of demyelination in a virus-induced experimental model of MS. This study uses Affymetrix microarray analysis to compare differential spinal cord mRNA levels between mice infected with demyelinating and non-demyelinating strains of MHV to identify host immune genes expressed in this demyelinating disease model. The study reveals that during the acute stage of infection, both strains induce inflammatory innate immune response genes, whereas upregulation of several immunoglobulin genes during chronic stage infection is unique to infection with the demyelinating strain. Results suggest that the demyelinating strain induced an innate-immune response during acute infection that may promote switching of Ig isotype genes during chronic infection, potentially playing a role in antibody-mediated progressive demyelination even after viral clearance. Copyright © 2016 Elsevier Inc. All rights reserved.
Robinson, Andrew P; Rodgers, Jane M; Goings, Gwendolyn E; Miller, Stephen D
Characterizing and enumerating cells of the oligodendrocyte lineage (OLCs) is crucial for understanding demyelination and therapeutic benefit in models of demyelinating disease in the central nervous system. Here we describe a novel method for the rapid, unbiased analysis of mouse OLCs using flow cytometry. The assay was optimized to maximize viable yield of OLCs and maintain OLC antigen integrity. Panels of antibodies were assembled for simultaneous analysis of seven antigens on individual cells allowing for characterization of oligodendroglial cells throughout the lineage. We verified the utility of the assay with cultured OLCs and through a time course of developmental myelination. Next we employed the assay to characterize OLC populations in two well-characterized models of demyelination: cuprizone-induced demyelination and experimental autoimmune encephalomyelitis (EAE). In EAE we observed a dramatic loss of mature oligodendrocytes coincident with a dramatic expansion of oligodendrocyte progenitors cells (OPCs) at the onset of disease suggesting an attempt of the host to repair myelin. This expanded OPC pool was maintained through remission and relapse suggesting an arrest in differentiation in the face of the chronic autoimmune T cell-mediated inflammatory response. These robust, reproducible changes in OLCs through disease provide a rapid quantitative global analysis of myelin-producing cells in the adult mouse brain and important information regarding effects of disease on oligodendroglial proliferation/differentiation which is useful for defining the pathogenesis and therapy of MS.
Full Text Available Inflammatory demyelinating diseases in children and adolescents are sufficient problem of modern medicine. Its topicality is conditioned by as traditionally high prevalence of acute demyelinating conditions (acute disseminated encephalomyelitis as increase of morbidity with chronic demyelinating forms of pathology (disseminated sclerosis in children. The absence of clear diagnostic algorithm presents difficulties for the determination of tactics of treatment and prognosis on early stages of their development, e.g. at the time of maximal effectiveness of immunomodulatory medications. Besides, the list of medications for the prolonged immunomodulatory treatment of demyelinating diseases, registered in Russia, includes such drugs as interferon beta 1a for the subcutaneous injection, officially annotated for the use from 12-year old age.Key words: children, inflammatory demyelinating diseases, diagnostics, treatment.(Voprosy sovremennoi pediatrii — Current Pediatrics. 2009;8(6:139-145
Burton, Jodie M; Costello, Fiona E
The role of vitamin D as both a risk factor and a disease modifier in multiple sclerosis (MS) has a storied history with ongoing accumulation of supportive convergent evidence from animal data, clinical studies and trials, and biomarkers of disease. A detailed review of the published literature ranging from in vivo immune studies to human clinical studies of epidemiology, physiology, immunology, clinical, and radiological markers was undertaken. There is compelling evidence that vitamin D is not only a risk factor for central nervous system (CNS) demyelinating disease (namely MS) but also seems to modify both the inflammatory and neurodegenerative elements of the disease, with large-scale treatment trials underway. The authors also address questions of interest that remain unanswered. Vitamin D is an important contributor and modifiable risk factor in CNS demyelinating disease. Further work will determine whether it is also neuroprotective and if such benefits will apply to other inflammatory and degenerative neurological diseases.
Khan, Reas S; Dine, Kimberly; Das Sarma, Jayasri; Shindler, Kenneth S
Multiple sclerosis (MS) is characterized by central nervous system inflammation and demyelination, and increasing evidence demonstrates significant neuronal damage also occurs and is associated with permanent functional impairment. Current MS therapies have limited ability to prevent neuronal damage, suggesting additional neuroprotective therapies are needed. Compounds that activate the NAD+-dependent SIRT1 deacetylase prevent neuronal loss in an autoimmune-mediated MS model, but the mechanism of this effect is unknown, and it is unclear whether SIRT1 activating compounds exert similar effects in demyelinating disease induced by other etiologies. We measured neuronal loss in C57BL/6 mice inoculated with a neurotropic strain of mouse hepatitis virus, MHV-A59, that induces an MS-like disease. Oral treatment with the SIRT1 activating compound SRTAW04 significantly increased SIRT1 activity within optic nerves and prevented neuronal loss during optic neuritis, an inflammatory demyelinating optic nerve lesion that occurs in MS and its animal models. MHV-A59 induced neuronal loss was associated with reactive oxygen species (ROS) accumulation, and SRTAW04 treatment significantly reduced ROS levels while promoting increased expression of enzymes involved in mitochondrial function and reduction of ROS. SRTAW04 exerted similar protective effects in EAE spinal cords, with decreased demyelination. Results demonstrate that SIRT1 activating compounds prevent neuronal loss in viral-induced demyelinating disease similar to their effects in autoimmune-mediated disease. One mechanism of this neuroprotective effect involves increasing mitochondrial biogenesis with reduction of oxidative stress. SIRT1 activators represent a potential neuroprotective therapy for MS. Understanding common mechanisms of these effects in distinct disease models will help identify targets for more specific therapies.
Pakpoor, Julia; Goldacre, Raph; Schmierer, Klaus; Giovannoni, Gavin; Waubant, Emmanuelle; Goldacre, Michael J
The profile of psychiatric disorders associated with multiple sclerosis (MS) may differ in children. We aimed to assess the risk of psychiatric disorders in children with MS and other demyelinating diseases, and vice versa. We analyzed linked English Hospital Episode Statistics, and mortality data, 1999-2011. Cohorts were constructed of children admitted with MS and other central nervous system (CNS) demyelinating diseases. We searched for any subsequent episode of care with psychiatric disorders in these cohorts and compared to a reference cohort. Children with CNS demyelinating diseases had an increased rate of psychotic disorders (rate ratio (RR) = 5.77 (95% confidence interval (CI) = 2.48-11.41)); anxiety, stress-related, and somatoform disorders (RR = 2.38 (1.39-3.81)); intellectual disability (RR = 6.56 (3.66-10.84)); and other behavioral disorders (RR = 8.99 (5.13-14.62)). In analysis of the pediatric MS cohort as the exposure, there were elevated rates of psychotic disorders (RR = 10.76 (2.93-27.63)), mood disorders (RR = 2.57 (1.03-5.31)), and intellectual disability (RR = 6.08 (1.25-17.80)). In reverse analyses, there were elevated rates of a recorded hospital episode with CNS demyelinating disease after a previous recorded episode with anxiety, stress-related, and somatoform disorders; attention-deficit hyperactivity disorder (ADHD); autism; intellectual disability; and other behavioral disorders. This analysis of a national diagnostic database provides strong evidence for an association between pediatric CNS demyelinating diseases and psychiatric disorders, and highlights a need for early involvement of mental health professionals.
Greer, Judith M; Broadley, Simon; Pender, Michael P
Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with coexistent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with coexisting CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with coexisting AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients.
Morgan-Followell, Bethanie; Aylward, Shawn C
The authors aimed to compare the opening pressures of children with demyelinating disease to children with primary intracranial hypertension. Medical records were reviewed for a primary diagnosis of demyelinating disease, or primary intracranial hypertension. Diagnosis of demyelinating disease was made according to either the 2007 or 2012 International Pediatric Multiple Sclerosis Study Group criteria. Primary intracranial hypertension diagnosis was confirmed by presence of elevated opening pressure, normal cerebrospinal fluid composition and neuroimaging. The authors compared 14 children with demyelinating disease to children with primary intracranial hypertension in 1:1 and 1:2 fashions. There was a statistically significant higher BMI in the primary intracranial hypertension group compared to the demyelinating group ( P = .0203). The mean cerebrospinal fluid white blood cell count was higher in the demyelinating disease group compared to primary intracranial hypertension ( P = .0002). Among both comparisons, the cerebrospinal fluid opening pressure, glucose, protein and red blood cell counts in children with demyelinating disease were comparable to age- and sex-matched controls with primary intracranial hypertension.
Romanova, E V; Karlova, I Z; Shapiro, A L; Shamshinova, A M
Visual system channels were examined in 25 patients with multiple sclerosis. A new complex of symptoms was detected, reflecting the acute stage and the chronic demyelinizing process, which includes disorders of contrast, color, and spatial contrast sensitivity and stereoscopic vision. This can be useful in differential diagnosis of optic nerve diseases and evaluation of the visual system function in multiple sclerosis and prediction of the disease course.
Hayashi, Makiko; Abe, Akiko; Murakami, Tatsufumi; Yamao, Satoshi; Arai, Hidee; Hattori, Hideji; Iai, Mizue; Watanabe, Kyoko; Oka, Nobuyuki; Chida, Keiji; Kishikawa, Yumiko; Hayasaka, Kiyoshi
Charcot-Marie-Tooth disease (CMT), the most common hereditary neuropathy, has been classified into two types, demyelinating and axonal types. We previously analyzed the genes causing dominant demyelinating CMT in 227 Japanese patients to identify the genetic background, but could not find any mutations in 110 patients. To investigate the frequency of patients with autosomal recessive demyelinating CMT (CMT4) mutations, we analyzed the coding sequence of known causative genes of CMT4 in 103 demyelinating CMT patients, excluding seven patients owing to lack of specimens. We found one patient with a GDAP1 mutation, one patient with an MTMR2 mutation, two patients with SH3TC2/KIAA1985 mutations and three patients with FGD4 mutations. Twelve patients, including five previously detected patients with PRX mutations, were diagnosed as CMT4, accounting for 5.5% of demyelinating CMT. In the patient with GDAP1 mutation, only one mutation inherited from his mother was detected by genomic sequencing. Analysis by reverse transcription polymerase chain reaction using messenger RNA (mRNA) from the patient's leukocytes revealed the absence of transcription from the allele inherited from his father, suggesting the existence of one more mutation leading to a lack or destabilization of mRNA. Most patients carrying CMT4 gene mutations present with early-onset and slowly progressive symptoms, which may be associated with the function of mutants. We could not identify the disease-causing gene in 96 patients (about 45%). Further studies including studies with next-generation sequencers will be required to identify the causative gene in Japanese CMT.
Yamamoto, Shinji; Yamashina, Kota; Ishikawa, Masaki; Gotoh, Mari; Yagishita, Sosuke; Iwasa, Kensuke; Maruyama, Kei; Murakami-Murofushi, Kimiko; Yoshikawa, Keisuke
Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. We demonstrated that 2ccPA suppressed the CoCl2-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE
Weil, Marie-Theres; Möbius, Wiebke; Winkler, Anne; Ruhwedel, Torben; Wrzos, Claudia; Romanelli, Elisa; Bennett, Jeffrey L; Enz, Lukas; Goebels, Norbert; Nave, Klaus-Armin; Kerschensteiner, Martin; Schaeren-Wiemers, Nicole; Stadelmann, Christine; Simons, Mikael
Breakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat model of neuromyelitis optica (NMO), to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP), which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca(2+) levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
Full Text Available Breakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat model of neuromyelitis optica (NMO, to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP, which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca2+ levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases.
Full Text Available Introduction. Syringomyelia is a cavitary extension inside the spinal cord which can be either symptomatic or congenitally-idiopathic. Syringomyelia during the course of the disease in patients presenting with clinically definite multiple sclerosis was described earlier. Syringomyelia in patients presenting with a clinically isolated syndrome suggestive of multiple sclerosis is unusual. Case Outline. We present two patients presenting with demy-elinating disease of the central nervous system with syringomyelia in the cervical and thoracic spinal cord. We did not find classical clinical signs of syringomyelia in our patients, but we disclosed syringomyelia incidentally during magnetic resonance exploration. Magnetic resonance exploration using the gadolinium contrast revealed the signs of active demyelinating lesions in the spinal cord in one patient but not in the other. Conclusion. Syringomyelia in demyelinating disease of the central nervous system opens the question whether it is a coincidental finding or a part of clinical features of the disease. Differentiation of the significance of syringomyelia finding in these patients plays a role in the choice of treatment concept in such patients.
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.
Berer, Kerstin; Boziki, Marina; Krishnamoorthy, Gurumoorthy
...), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively...
Narula, Sona; Liu, Grant T; Avery, Robert A; Banwell, Brenda; Waldman, Amy T
Cerebrospinal fluid opening pressure is elevated with central nervous system infection and vasculitis, but has not been studied in inflammatory demyelinating disease. This retrospective study sought to determine whether children with demyelinating disease demonstrate elevated cerebrospinal fluid opening pressure, and to explore possible clinical and radiologic correlates. Pediatric patients with acute disseminated encephalomyelitis, multiple sclerosis, or a clinically isolated syndrome (including optic neuritis and transverse myelitis) who had a lumbar puncture within 1 month of presentation were eligible for inclusion, and were compared with a reference cohort of healthy children from the same institution. Regression analyses were used to determine the association of variables collected with opening pressure. Opening pressure was elevated in 15 of 53 (28%) children, which was significantly higher than the reference cohort (P = 0.001). There was no relationship between elevated opening pressure and any of the clinical or radiologic variables collected. Although almost one third of children with inflammatory demyelinating disease have an elevated cerebrospinal fluid opening pressure, the clinical and radiologic variables evaluated in this study did not explain this finding, and further understanding may require assessment of cerebrospinal fluid flow dynamics. Copyright © 2015 Elsevier Inc. All rights reserved.
Castillo, D.; Samaniego, René; Jiménez, Y.; Cuenca, L.; Vivanco, O.; Rodríguez-Álvarez, M. J.
This work presents the advance to development of an algorithm for automatic detection of demyelinating lesions and cerebral ischemia through magnetic resonance images, which have contributed in paramount importance in the diagnosis of brain diseases. The sequences of images to be used are T1, T2, and FLAIR. Brain demyelination lesions occur due to damage of the myelin layer of nerve fibers; and therefore this deterioration is the cause of serious pathologies such as multiple sclerosis (MS), leukodystrophy, disseminated acute encephalomyelitis. Cerebral or cerebrovascular ischemia is the interruption of the blood supply to the brain, thus interrupting; the flow of oxygen and nutrients needed to maintain the functioning of brain cells. The algorithm allows the differentiation between these lesions.
Waubant, Emmanuelle; Ponsonby, Anne-Louise; Pugliatti, Maura; Hanwell, Heather; Mowry, Ellen M; Hintzen, Rogier Q
The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501 In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS. The role of vitamin D remains to be confirmed in this age category. Finally, although very likely critical in disease processes, few gene-environment interactions and epigenetic changes have been reported for adult and pediatric MS susceptibility. Of interest, some of the risk factors for MS have also been associated with disease course modification, such as low 25(OH) vitamin D serum levels in pediatric and adult MS. Age is also a clear disease modifier of clinical, CSF, and MRI phenotype in children with the disease. Finally, although much has yet to be unraveled regarding molecular processes at play in MS, there is a larger gap in our knowledge of genetic and environmental risk factors for pediatric neuromyelitis optica spectrum disorders and acute disseminated encephalomyelitis and only collaborative studies will answer those questions. © 2016 American Academy of Neurology.
Weiss, Hanne A; Millward, Jason M; Owens, Trevor
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...
Self, Mariella M; Fobian, Aaron; Cutitta, Katherine; Wallace, Arianne; Lotze, Timothy E
Decreased health-related quality of life (HRQOL) in pediatric patients with multiple sclerosis is established, but little research has examined HRQOL in the broader pediatric demyelinating disease population, and predictors of reduced HRQOL are largely unexplored. We sought to (1) compare generic HRQOL and fatigue of pediatric patients with relapsing (i.e., multiple sclerosis and neuromyelitis optica) versus monophasic demyelinating diseases (i.e., acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, clinically isolated syndrome) and (2) examine the extent to which disability, relapsing disease, and fatigue predict HRQOL. Child and/or parent-proxy reports of generic and fatigue-related HRQOL were collected for 64 pediatric patients with demyelinating diseases. HRQOL of the sample was compared with published healthy child norms. Independent samples t -tests compared HRQOL and fatigue for children with monophasic versus relapsing diseases. Regression analyses examined disability, disease presentation, and fatigue as potential predictors of HRQOL. Compared with healthy child norms, generic HRQOL was significantly lower for the demyelinating disorder group, for both child and parent reports across multiple domains. As hypothesized, the relapsing disease group reported lower overall HRQOL and more fatigue than the monophasic group. Disability and relapsing disease predicted lower HRQOL for both parents and children, whereas fatigue was only predictive per the child perspective. Children with demyelinating diseases evidence significantly lower HRQOL than healthy peers, supporting need for intervention. Those with relapsing disease appear particularly at risk; targeting disability and fatigue may be fruitful areas for intervention.
Full Text Available The preclinical Alzheimer's disease (AD - amnestic mild cognitive impairment (MCI - is manifested by phenotypes classified into exclusively memory (single-domain MCI (sMCI and multiple-domain MCI (mMCI. We suggest that typical MCI-to-AD progression occurs through the sMCI-to-mMCI sequence as a result of the extension of initial pathological processes. To support this hypothesis, we assess myelin content with a Magnetization Transfer Ratio (MTR in 21 sMCI and 21 mMCI patients and in 42 age-, sex-, and education-matched controls. A conjunction analysis revealed MTR reduction shared by sMCI and mMCI groups in the medial temporal lobe and posterior structures including white matter (WM: splenium, posterior corona radiata and gray matter (GM: hippocampus; parahippocampal and lingual gyri. A disjunction analysis showed the spread of demyelination to prefrontal WM and insula GM in executive mMCI. Our findings suggest that demyelination starts in the structures affected by neurofibrillary pathology; its presence correlates with the clinical picture and indicates the method of MCI-to-AD progression. In vivo staging of preclinical AD can be developed in terms of WM/GM demyelination.
Benzinger, Tammie L. S.; Cross, Anne H.; Xu, Junqian; Naismith, Robert; Sun, Shu-Wei; Song, Sheng-Kwei
Directional diffusivities derived from diffusion tensor magnetic resonance imaging (DTI) measurements describe water movement parallel to (λ ||, axial diffusivity) and perpendicular to (λ⊥radial diffusivity) axonal tracts. λ || and λ⊥ have been shown to differentially detect axon and myelin abnormalities in several mouse models of central nervous system white matter pathology in our laboratory. These models include experimental autoimmune encephalomyelitis (EAE), (1) myelin basic protein mutant mice with dysmyelination and intact axons, (2) cuprizone-induced demyelination, and remyelination, with reversible axon injury (2, 3) and a model of retinal ischemia in which retinal ganglion cell death is followed by Wallerian degeneration of optic nerve, with axonal injury preceding demyelination. (4) Decreased λ|| correlates with acute axonal injury and increased λ⊥ indicates myelin damage. (4) More recently, we have translated this approach to human MR, investigating acute and chronic optic neuritis in adults with multiple sclerosis, brain lesions in adults with multiple sclerosis, and acute disseminated encephalomyelitis (ADEM) in children. We are also investigating the use of this technique to probe the underlying structural change of the cervical spinal cord in acute and chronic T2- hyperintense lesions in spinal stenosis, trauma, and transverse myelitis. In each of these demyelinating diseases, the discrimination between axonal and myelin injury which we can achieve has important prognostic and therapeutic implications. For those patients with myelin injury but intact axons, early, directed drug therapy has the potential to prevent progression to axonal loss and permanent disability.
Onu, Mihaela; Aroceanu, Adina; Ferastraoaru, Victor; Bajenaru, Ovidiu
Recent MR studies have shown that, in multiple sclerosis, selective regional, but not global gray matter atrophy occurs in multiple sclerosis. Our aim was to identify specific areas of gray matter volume changes and explore the relationship between atrophy and clinical motor outcomes. Nine patients with relapsing remitting MS and 9 matched healthy controls were recruited. The Multiple Sclerosis Functional Composite was administered. For MR acquisitions, a GE- Genesis- Signa, 1.5T MR system, was used. A voxel-based morphometry (VBM), subcortical structures segmentation (FIRST) and volumetric (SIENAx) FSL tools were used in the study. Group comparison showed atrophy for several gray matter regions. The most important volume reductions were found for subcortical deep gray matter areas. Correlations with clinical scores were checked and specific gray matter areas showed significant volume reductions associated with motor scores (9-hole peg time and 25-feet walk time) and EDSS (Expanded Disability Status Scale). We performed a voxelwise analysis of gray matter changes in MS and found a more prominent atrophy for the subcortical structures than for cortical gray matter. Using an additional analysis (FIRST and SIENAx segmentation/volumetry) we were able to confirm the VBM results and to quantify the degree of atrophy in specific structures. Specific gray matter regions which volume reductions correlate with 25-feet walk, 9-hole peg times and EDSS suggest that 25-feet walk time is the best predictor of disease progression in terms of gray matter reduction.
Onu, Mihaela; Roceanu, Adina; Sboto-Frankenstein, Uta; Bendic, Robert; Tarta, Eugen; Preoteasa, Florentin; Bajenaru, Ovidiu
Magnetic resonance imaging (MRI) has been explored as a noninvasive tool to assess pathology in multiple sclerosis (MS) patients. However, the correlation between classical MRI measures and physical disability is modest in MS. The diffusion tensor imaging (DTI) MRI technique holds particular promise in this regard. The present study shows brain regions where FA and individual diffusivities abnormalities are present and check their correlations with physical disability clinical scores. Eight patients and 12 matched healthy controls were recruited. The Multiple Sclerosis Functional Composite was administered. For MR-DTI acquisitions, a Genesis Signa 1.5 T MR system, an EP/SE scanning sequence, 25 gradient directions were used. Tract Based Spatial Statistics (TBSS) group comparisons showed reduced FA and increased individual diffusivities in several brain regions in patients. Significant correlations were found between FA and: EDSS, 9-HPT(NON)DOM and 25 FW score; between λ2 and: P100 (r&l), 9-HPT(NON)DOM and 25 FW; between λ3 and: 9-HPT(NON)DOM and 25 FW score. Fractional anisotropy and individual radial diffusivities proved to be important markers of motor disabilities in MS patients when the disease duration mean and the disability scores values range are relatively high. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
Joseph, Albert; DeLuca, Gabriele C
Olfactory dysfunction is recognised across an ever broadening spectrum of neuropsychiatric conditions including central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS) and neuromyelitis optica (NMO). In this review, we unravel the striking evidence highlighting how olfactory loss is a common clinical feature in MS and NMO. We provide an overview of the supportive psychophysical, electrophysiological, radiological and pathological data that point to the anatomical substrate of olfactory deficits in these diseases. The pattern of underlying pathology affecting the olfactory system is shown to be complex, involving multiple structures that are affected in different ways throughout the course of the disease. This review is the first to synthesise the expanding body of literature on the topic, provides novel insight into the way in which the olfactory system is affected in CNS demyelinating diseases, and raises intriguing questions about the role of this system in the pathogenesis of these diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Siva, A; Saip, S; Altintas, A; Jacob, A; Keegan, B M; Kantarci, O H
Natural history of patients with incidentally discovered lesions that fulfill magnetic resonance imaging (MRI) criteria for multiple sclerosis (MS) in the absence of objective clinical symptoms suggestive of central nervous system (CNS) inflammatory-demyelinating disease is not well defined. We evaluated the risk of developing symptomatic MS in patients with radiologically uncovered asymptomatic possible inflammatory-demyelinating disease (RAPIDD). We identified and longitudinally followed a cohort of 22 patients from two tertiary care MS centers: Istanbul University, Cerrahpasa School of Medicine, Istanbul, Turkey, and Mayo Clinic, Rochester, Minnesota, after an initial MRI study fulfilling the Barkhof-Tintore MRI criteria completed for other reasons unrelated to MS. Eight of 22 patients developed an objective clinical symptom consistent with a CNS inflammatory-demyelinating syndrome and fulfilled dissemination in space and time criteria for definite MS. Median age at the time of diagnosis of MS was 44.8 years (range 28.3-71.4 years). Time taken for the development of definite MS was studied by survival analysis. Cumulative event rates were; 12 months: 9%, 24 months: 15%, 36 months: 30.4%, and 60 months: 44.6%. Six of 22 patients were followed beyond 60 months. Two of these six patients developed MS later (at 66 and 112 months, respectively). Three patients remained asymptomatic despite follow-up of 10 years. with RAPIDD develop MS at a similar rate to treated patients (and less frequently than placebo groups) with clinically isolated syndromes from prior randomized controlled studies. Some patients with RAPIDD continue to have radiological evolution of subclinical disease without MS symptoms despite long follow-up periods.
Scheller, Nikolai Madrid; Svanström, Henrik; Pasternak, Björn; Arnheim-Dahlström, Lisen; Sundström, Karin; Fink, Katharina; Hviid, Anders
Case reports have suggested a link between human papillomavirus (HPV) vaccination and development of multiple sclerosis and other demyelinating diseases. To investigate if quadrivalent HPV (qHPV) vaccination is associated with an increased risk of multiple sclerosis and other demyelinating diseases. Using nationwide registers we identified a cohort of all females aged 10 years to 44 years in Denmark and Sweden, followed up from 2006 to 2013, information on qHPV vaccination, and data on incident diagnoses of multiple sclerosis and other demyelinating diseases. The primary analysis used a cohort design including vaccinated and unvaccinated study participants. A secondary analysis used a self-controlled case-series design including only cases. Both analyses used a 2-year risk period following vaccination. Information on qHPV vaccination was obtained through the national vaccination and prescription registers. The primary outcomes were multiple sclerosis and a composite end point of other demyelinating diseases. Incidence rate ratios were estimated using Poisson regression, comparing rates of events in the 2-year risk periods following vaccination and in unvaccinated time periods. The study included 3,983,824 females, among whom 789,082 received a total of 1,927,581 qHPV vaccine doses. During follow-up, 4322 multiple sclerosis cases and 3300 cases of other demyelinating diseases were identified, of which 73 and 90, respectively, occurred within the risk period. In the cohort analysis, there was no increased risk of multiple sclerosis (crude incidence rates, 6.12 events/100,000 person-years [95% CI, 4.86-7.69] and 21.54 events/100,000 person-years [95% CI, 20.90-22.20] for the vaccinated and unvaccinated periods; adjusted rate ratio, 0.90 [95% CI, 0.70-1.15]) or other demyelinating diseases (crude incidence rates, 7.54 events/100,000 person-years [95% CI, 6.13-9.27] and 16.14 events/100,000 person-years [95% CI, 15.58-16.71]; adjusted rate ratio, 1.00 [95% CI, 0
Cruz Fernández-Espartero, María; Pérez-Zafrilla, Beatriz; Naranjo, Antonio; Esteban, Carmen; Ortiz, Ana M; Gómez-Reino, Juan J; Carmona, Loreto
To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95% CI). In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF-antagonists in BIOBADASER was 0.65 per 1000 patient-years (95% CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95% CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA (n = 19) and in the literature (n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries. Copyright © 2011. Published by Elsevier Inc.
Hirano, Yuta; Kobayashi, Kunitoshi; Tomiki, Hiroki; Inaba, Yuhji; Ichikawa, Motoki; Kim, Byung S; Koh, Chang-Sung
Natalizumab, which is an antibody against α4 integrin, has been used for the treatment of multiple sclerosis. In the present study, we investigated both the role of α4 integrin and the therapeutic effect of HCA3551, a newly synthesized orally active small molecule α4 integrin antagonist, in the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). The mRNA levels of α4 integrins were significantly up-regulated in the central nervous system (CNS) of mice with TMEV-IDD as compared with naive mice (*P < 0.05). HCA3551 treatment in the effector phase significantly suppressed both the clinical and histological development of TMEV-IDD. The number of infiltrating mononuclear inflammatory cells in the CNS was significantly decreased in the mice treated with HCA3551 (**P < 0.01). The labeling indices for CD68 antigen and the absolute cell numbers of TNF-α-producing CD4(+) T cells and IFN-γ-producing CD8(+) T cells were significantly decreased in the CNS of mice treated with HCA3551 (*P < 0.05). HCA3551 treatment in the effector phase might inhibit the binding of α4 integrin to vascular cell adhesion molecule-1, thereby decreasing the number of mononuclear cells in the CNS. © The Japanese Society for Immunology. 2016. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Jay S. Coggan
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.
Coggan, Jay S.; Bittner, Stefan; Stiefel, Klaus M.; Meuth, Sven G.; Prescott, Steven A.
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. PMID:26370960
Coggan, Jay S; Bittner, Stefan; Stiefel, Klaus M; Meuth, Sven G; Prescott, Steven A
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.
Delios, Anna Maria; Rosenblum, Marc; Jakubowski, Ann A; DeAngelis, Lisa M
Immune mediated demyelinating disease (IMDD) after allogeneic hemopoietic stem cell transplant (HSCT) is rare and its etiology unclear. In this retrospective study, we identified patients who underwent HSCT between January 1992 and December 2010 and had IMDD post transplant. A total of 1,484 patients received HSCT and 7 (0.5 %) suffered from IMDD; five were men, and the median age was 54 years (range, 29-64 years). HSCT treated acute myeloid leukemia (n = 5), myelodysplastic syndrome (n = 1), and Waldenström macroglobulinemia (n = 1). All received an HLA matched donor graft, related (6), unrelated (1); from the bone marrow (1), peripheral blood stem cell (6); and T-cell depleted, ex vivo (6) or in vivo (1). The median time from transplant to neurologic symptoms was 120 days (range, 60-390 days). Three had acute demyelinating encephalomyelitis (ADEM), three acute inflammatory demyelinating polyradiculopathy (AIDP) and one autonomic neuropathy. Four of six patients tested had hemopoietic mixed chimerism prior to neurologic symptoms and low CD4(+) T-cell counts, median 76 (15-500 cells/μL). Two patients had simultaneous systemic graft versus host disease (GVHD). Two patients with ADEM had a spinal cord or brain biopsy which revealed demyelination. No patients had a viral etiology identified in the cerebrospinal fluid. Patients were treated with IV immunoglobulin, high dose steroids and/or rituximab. Five patients had a significant recovery. Response to immune modulators suggests an immune-based etiology. The incidence of de novo autoimmune disease after HSCT for hematological diseases is rare and may be difficult to differentiate from GVHD.
Dagher, A.P. [Thomas Jefferson Univ. Hospital, Philadelphia, PA (United States). Div. of Neuroradiology; Smirniotopoulos, J. [Thomas Jefferson Univ. Hospital, Philadelphia, PA (United States). Div. of Neuroradiology]|[Armed Forces Inst. of Pathology, Washington, DC (United States). Dept. of Radiological Pathology
We studied 21 cases of pathologically confirmed tumefactive demyelinating lesions and reviewed the spectrum of tumefactive demyelinating lesions in the literature. Radiological features and clinical data were reviewed to characterize the lesions as consistent with a known demyelinating disease, most notably multiple sclerosis. Atypical clinical or radiological features (other than tumefaction) were noted. Most lesions were part of a clinical and/or radiological picture consistent with multiple sclerosis. No case strongly suggestive of variants or related diseases, such as Schilder`s disease or Balo`s concentric sclerosis, were found. There was one case suggestive of acute disseminated encephalomyelitis. Features which help distinguish the lesions from tumour are discussed. (orig.)
Nashold, Faye E; Nelson, Corwin D; Brown, Lauren M; Hayes, Colleen E
Multiple sclerosis (MS) is an incurable inflammatory demyelinating disease. We investigated one calcitriol dose plus vitamin D3 (calcitriol/+D) as a demyelinating disease treatment in experimental autoimmune encephalomyelitis (EAE). Evidence that calcitriol-vitamin D receptor pathway deficits may promote MS, and data showing calcitriol enhancement of autoimmune T cell apoptosis provided the rationale. Whereas vitamin D3 alone was ineffective, calcitriol/+D transiently increased central nervous system (CNS) Helios(+)FoxP3(+) T cells and sustainably decreased CNS T cells, pathology, and neurological deficits in mice with EAE. Calcitriol/+D, which was more effective than methylprednisolone, has potential for reversing inflammatory demyelinating disease safely and cost-effectively. © 2013.
Kim, Suji; Kang, Seok-Jae; Oh, Ki-Wook; Ahn, Byung Kyu; Lee, Hang Lak; Han, Dong Soo; Jang, Kiseok; Kim, Young Seo
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare complication of Crohn's disease (CD), and it is uncertain whether it is associated with CD itself or with its treatment. We describe a case of CIDP-like neuropathy as an initial symptom of CD. The neurologic symptoms of the patient which responded partially to intravenous immunoglobulin (IVIG) recovered after resection of the appendiceal CD. A 17-year-old male had experienced three separate attacks of motor weakness and paresthesia of all four extremities over a period of 7 months. The electrophysiologic findings revealed a demyelinating sensory-motor polyneuropathy which was compatible with CIDP. However, repeated intravenous IVIG (2 g/kg) treatment gave only a partial response. Four days after the last discharge, he was diagnosed as appendiceal CD after surgical resection of a periappendiceal abscess. His neurologic symptoms and electrophysiologic findings recovered without any maintenance therapy. CIDP-like neuropathy can be an initial presentation of CD, and recovery of the CIDP symptoms may result from resection of the CD. Clinicians should be aware of the possibility of CD in patients with intractable CIDP symptoms.
Ikeguchi, Ryotaro; Shimizu, Yuko; Shimizu, Satoru; Kitagawa, Kazuo
It is often difficult to diagnose central nervous system (CNS) inflammatory demyelinating diseases (IDDs) because they are similar to CNS lymphoma and glioma. To evaluate whether cerebrospinal fluid (CSF) analysis can differentiate CNS IDDs from CNS lymphoma and glioma. We measured CSF cell counts; concentrations of proteins, glucose, interleukin (IL)-6, IL-10, soluble IL-2 receptor (sIL-2R), and myelin basic protein; and IgG index in patients with multiple sclerosis (MS, n = 64), neuromyelitis optica spectrum disorder (NMOSD, n = 35), tumefactive demyelinating lesion (TDL, n = 17), CNS lymphoma ( n = 12), or glioma ( n = 10). We detected diagnostic markers using logistic regression and receiver operating characteristic (ROC) analyses. Median CSF IL-10 and sIL-2R levels were higher in CNS lymphoma patients than in MS, NMOSD, or TDL patients. Logistic regression revealed that CSF sIL-2R levels predicted CNS lymphoma. In the ROC analysis of CSF sIL-2R levels, the area under the curve was 0.867, and the sensitivity and specificity were 83.3% and 90.0%, respectively. CSF sIL-2R levels can be used to differentiate CNS lymphoma from CNS IDDs. Further studies may identify other applications of CSF as a diagnostic biomarker.
Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy.
Sugimoto, Takamichi; Ochi, Kazuhide; Hosomi, Naohisa; Takahashi, Tetsuya; Ueno, Hiroki; Nakamura, Takeshi; Nagano, Yoshito; Maruyama, Hirofumi; Kohriyama, Tatsuo; Matsumoto, Masayasu
Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p disease. When we evaluated ESN of four selected sites for screening from the intermediate region, the sensitivity and specificity to distinguish between demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP.
Ling, Zongxin; Liu, Xia; Cheng, Yiwen; Jiang, Xiawei; Jiang, Haiyin; Wang, Yuezhu; Li, Lanjuan
Increasing evidence suggests that altered gut microbiota is implicated in the pathogenesis of hepatitis B virus-induced chronic liver disease (HBV-CLD). However, the structure and composition of the oral microbiota of patients with HBV-CLD remains unclear. High-throughput pyrosequencing showed that decreased oral bacterial diversity was found in patients with HBV-CLD. The Firmicutes/Bacteroidetes ratio was increased significantly, which indicated that dysbiosis of the oral microbiota participated in the process of HBV-CLD development. However, the changing patterns of the oral microbiota in patients with HBV-induced liver cirrhosis (LC) were almost similar to patients with chronic hepatitis B (CHB). HBV infection resulted in an increase in potential H2S- and CH3SH-producing phylotypes such as Fusobacterium, Filifactor, Eubacterium, Parvimonas and Treponema, which might contribute to the increased oral malodor. These key oral-derived phylotypes might invade into the gut as opportunistic pathogens and contribute to altering the composition of the gut microbiota. This study provided important clues that dysbiosis of the oral microbiota might be involved in the development of HBV-CLD. Greater understanding of the relationships between the dysbiosis of oral microbiota and the development of HBV-CLD might facilitate the development of non-invasive differential diagnostic procedures and targeted treatments of HBV-CLD patients harbouring specific oral phylotypes. PMID:26606973
Theibich, Ali; Dreyer, Lene; Magyari, Melinda
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...... patients who developed neurological symptoms during this time period. We found six patients with signs of demyelinizing neurological disorders: four resembling MS, one MS-like condition, and one multifocal motor neuropathy. During a relatively short time period, we found a remarkably high number...
Shimizu, Takahiro; Wisessmith, Wilaiwan; Li, Jiayi; Abe, Manabu; Sakimura, Kenji; Chetsawang, Banthit; Sahara, Yoshinori; Tohyama, Koujiro; Tanaka, Kenji F; Ikenaka, Kazuhiro
In demyelinating diseases such as multiple sclerosis (MS), an imbalance between the demyelination and remyelination rates underlies the degenerative processes. Microglial activation is observed in demyelinating lesions; however, the molecular mechanism responsible for the homeostatic/environmental change remains elusive. We previously found that cystatin F (CysF), a cysteine protease inhibitor, is selectively expressed in microglia only in actively demyelinating/remyelinating lesions but ceases expression in chronic lesions, suggesting its role in remyelination. Here, we report the effects of manipulating the expression of CysF and cathepsin C (CatC), a key target of CysF, in a murine model of transgenic demyelinating disease, Plp(4e/-) . During the active remyelinating phase, both CysF knockdown (CysFKD) and microglial-selective CatC overexpression (CatCOE) showed a worsening of the demyelination in Plp(4e/-) transgenic mice. Conversely, during the chronic demyelinating phase, CatC knockdown (CatCKD) ameliorated the demyelination. Our results suggest that the balance between CatC and CysF expression controls the demyelination and remyelination process. © 2017 Wiley Periodicals, Inc.
Torre-Fuentes, L; Moreno-Jiménez, L; Pytel, V; Matías-Guiu, J A; Gómez-Pinedo, U; Matías-Guiu, J
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.
Stefanou, M I; Bischof, F
We aimed to evaluate clinical and diagnostic features of central and peripheral immune-mediated demyelinating disease (CPID) in allogeneic hematopoietic stem cell transplantation (aHSCT) recipients. CPID refers to the late-onset, immune-mediated neurological complications following aHSCT, when other frequent differential diagnoses have been ruled out, and when symptoms and signs of systemic GvHD manifestations are absent. Case records at the University of Tuebingen, between 2001 and 2015, were screened to identify patients with CPID after aHSCT. Seven patients who developed CPID after aHSCT were identified. The average time interval from aHSCT until onset of CPID was 2.6 (±2.8) years (mean±SD). The most prevalent manifestations of CPID were optic neuritis and/or myelitis and polyneuropathy. Cerebrospinal fluid analyses involved elevated protein concentration and lymphocytic pleocytosis, while oligoclonal bands in CSF, but not in serum, were detected in 28% of cases. Aquaporin-4-antibodies were consistently absent. MRI studies showed features suggestive of demyelination processes, with cerebral and/or spinal cord white-matter involvement, and features compatible with cerebral vasculitis. Corticosteroids, Immunoglobulins, Cyclophosphamide, Rituximab and Interferon beta-1a showed marginal treatment responses, whereas plasma exchange resulted in marked clinical improvement in two treated patients. A chronic disease-course with persisting neurological deficits was prevalent. CPID may comprise a rare complication of aHSCT, which manifests as optic neuritis and/or myelitis and is accompanied by sensorimotor polyneuropathy. A concomitant systemic manifestation of GvHD is not mandatory for CPID diagnosis. Usually, CPID exhibits a chronic, persisting disease course. Thus, clinical awareness is required, as early diagnosis and aggressive treatment may be prognostically advantageous. Copyright © 2017 Elsevier B.V. All rights reserved.
Rajabally, Y A; Cassereau, J; Robbe, A; Nicolas, G
Chronic inflammatory demyelinating polyneuropathy (CIDP) may have variable evolution profiles, which have not been compared between cohorts. The relationship of disease status with motor strength, function and electrophysiology is uncertain. Disease status was studied with a simplified proposed scale in two patient cohorts totalling 72 subjects from Leicester, U.K., and Angers, France. Clinical and electrophysiological records were analysed. Independent ascertainment of disease status in each cohort revealed similar rates of remission (P = 0.23), stable/improving disease (P = 0.34) and unstable/active disease (P = 1). No correlation was ascertained with strength or function. Median nerve compound muscle action potential was the only independent electrophysiological predictor of disease status ascertained (P = 0.046). Disease status distribution may represent an important comparative indicator for management of CIDP cohorts and could be useful for benchmarking service and treatment provision. Degree of upper limb motor axonal loss may represent a useful electrophysiological marker of disease status in CIDP. © 2015 EAN.
Full Text Available Patients with systemic lupus erythematosus (SLE and Sjögren's syndrome (SS display increased levels of type I IFN-induced genes. Plasmacytoid dendritic cells (PDCs are natural interferon producing cells and considered to be a primary source of IFN-α in these two diseases. Differential expression patterns of type I IFN inducible transcripts can be found in different immune cell subsets and in patients with both active and inactive autoimmune disease. A type I IFN gene signature generally consists of three groups of IFN-induced genes - those regulated in response to virus-induced type I IFN, those regulated by the IFN-induced mitogen-activated protein kinase/extracellular-regulated kinase (MAPK/ERK pathway, and those by the IFN-induced phosphoinositide-3 kinase (PI-3K pathway. These three groups of type I IFN-regulated genes control important cellular processes such as apoptosis, survival, adhesion, and chemotaxis, that when dysregulated, contribute to autoimmunity. With the recent generation of large datasets in the public domain from next-generation sequencing and DNA microarray experiments, one can perform detailed analyses of cell type-specific gene signatures as well as identify distinct transcription factors that differentially regulate these gene signatures. We have performed bioinformatics analysis of data in the public domain and experimental data from our lab to gain insight into the regulation of type I IFN gene expression. We have found that the genetic landscape of the IFNA and IFNB genes are occupied by transcription factors, such as insulators CTCF and cohesin, that negatively regulate transcription, as well as IRF5 and IRF7, that positively and distinctly regulate IFNA subtypes. A detailed understanding of the factors controlling type I IFN gene transcription will significantly aid in the identification and development of new therapeutic strategies targeting the IFN pathway in autoimmune disease.
Brisebois, Marcel; Zehntner, Simone P.; Estrada, José
Transgenic (Tg) mice that overexpress the costimulatory ligand B7.2/CD86 on microglia spontaneously develop a T cell-mediated demyelinating disease. Characterization of the inflammatory infiltrates in the nervous tissue revealed a predominance of CD8+ T cells, suggesting a prominent role of this T...
Feliú, Ana; Bonilla Del Río, Itziar; Carrillo-Salinas, Francisco Javier; Hernández-Torres, Gloria; Mestre, Leyre; Puente, Nagore; Ortega-Gutiérrez, Silvia; López-Rodríguez, Maria L; Grandes, Pedro; Mecha, Miriam; Guaza, Carmen
The failure to undergo remyelination is a critical impediment to recovery in multiple sclerosis. Chondroitin sulfate proteoglycans (CSPGs) accumulate at demyelinating lesions creating a nonpermissive environment that impairs axon regeneration and remyelination. Here, we reveal a new role for 2-arachidonoylglycerol (2-AG), the major CNS endocannabinoid, in the modulation of CSPGs deposition in a progressive model of multiple sclerosis, the Theiler's murine encephalomyelitis virus-induced demyelinating disease. Treatment with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-AG degradation in the mouse CNS, modulates neuroinflammation and reduces CSPGs accumulation and astrogliosis around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. Inhibition of 2-AG hydrolysis augments the number of mature oligodendrocytes and increases MBP, leading to remyelination and functional recovery of mice. Our findings establish a mechanism for 2-AG promotion of remyelination with implications in axonal repair in CNS demyelinating pathologies.SIGNIFICANCE STATEMENT The deposition of chondroitin sulfate proteoglycans contributes to the failure in remyelination associated with multiple sclerosis. Here we unveil a new role for 2-arachidonoylglycerol, the major CNS endocannabinoid, in the modulation of chondroitin sulfate proteoglycan accumulation in Theiler's murine encephalomyelitis virus-induced demyelinating disease. The treatment during the chronic phase with a potent reversible inhibitor of the enzyme monoacylglycerol lipase, which accounts for 85% of the 2-arachidonoylglycerol degradation in the mouse CNS, modulates neuroinflammation and reduces chondroitin sulfate proteoglycan deposition around demyelinated lesions in the spinal cord of Theiler's murine encephalomyelitis virus-infected mice. The increased 2-arachidonoylglycerol tone promotes remyelination in a model of progressive
Waschbisch, Anne; Kallmünzer, Bernd; Schwab, Stefan; Gölitz, Philipp; Vincent, Angela; Lee, De-Hyung; Linker, Ralf A
Anti-N-methyl-D-aspartate receptor immunoglobulin G antibodies directed against the GluN1 subunit are considered highly specific for anti-N-methyl-D-aspartate receptor encephalitis, a severe clinical syndrome characterized by seizures, psychiatric symptoms, orofacial dyskinesia and autonomic dysfunction. Here we report a 33 year old Caucasian male patient with clinically definite multiple sclerosis who was found to be positive for anti-N-methyl-D-aspartate receptor antibodies. Rituximab therapy was initiated. On the 18 months follow-up visit the patient was found to be clinically stable, without typical signs of anti-N-methyl-D-aspartate receptor encephalitis. Our findings add to the growing evidence for a possible association between anti-N-methyl-D-aspartate receptor encephalitis and demyelinating diseases.
Zepp, Jarod; Wu, Ling; Li, Xiaoxia
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is widely used to dissect molecular mechanisms of MS and to develop new therapeutic strategies. The T helper 17 (Th17) subset of CD4 T cells plays a crucial role in the development of EAE. IL-17, a cytokine produced by Th17 cells, participates in EAE pathogenesis through induction of inflammatory gene expression in target cells. Recent work has shown that Act1, a U-box E3 ubiquitin ligase, is recruited to IL-17 receptor (IL-17R) upon IL-17 stimulation and is required for IL-17-mediated signaling. Here, we review the molecular and cellular mechanisms by which IL-17 and Act1-mediated signaling contribute to EAE. Copyright © 2011 Elsevier Ltd. All rights reserved.
Dubois-Dalcq, Monique; Williams, Anna; Stadelmann, Christine; Stankoff, Bruno; Zalc, Bernard; Lubetzki, Catherine
In the central nervous system (CNS) of man, evolutionary pressure has preserved some capability for remyelination while axonal regeneration is very limited. In contrast, two efficient programmes of regeneration exist in the adult fish CNS, neurite regrowth and remyelination. The rapidity of CNS remyelination is critical since it not only restores fast conduction of nerve impulses but also maintains axon integrity. If myelin repair fails, axons degenerate, leading to increased disability. In the human CNS demyelinating disease multiple sclerosis (MS), remyelination often takes place in the midst of inflammation. Here, we discuss recent studies that address the innate repair capabilities of the axon-glia unit from fish to man. We propose that expansion of this research field will help find ways to maintain or enhance spontaneous remyelination in man.
Ulrich, Reiner; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang
Theiler's murine encephalomyelitis is an experimentally virus-induced inflammatory demyelinating disease of the spinal cord, displaying clinical and pathological similarities to chronic progressive multiple sclerosis. The aim of this study was to identify pathways associated with chronic demyelination using an assumption-free combined microarray and immunohistology approach. Movement control as determined by rotarod assay significantly worsened in Theiler's murine encephalomyelitis -virus-infected SJL/J mice from 42 to 196 days after infection (dpi). In the spinal cords, inflammatory changes were detected 14 to 196 dpi, and demyelination progressively increased from 42 to 196 dpi. Microarray analysis revealed 1001 differentially expressed genes over the study period. The dominating changes as revealed by k-means and functional annotation clustering included up-regulations related to intrathecal antibody production and antigen processing and presentation via major histocompatibility class II molecules. A random forest machine learning algorithm revealed that down-regulated lipid and cholesterol biosynthesis, differentially expressed neurite morphogenesis and up-regulated toll-like receptor-4-induced pathways were intimately associated with demyelination as measured by immunohistology. Conclusively, although transcriptional changes were dominated by the adaptive immune response, the main pathways associated with demyelination included up-regulation of toll-like receptor 4 and down-regulation of cholesterol biosynthesis. Cholesterol biosynthesis is a rate limiting step of myelination and its down-regulation is suggested to be involved in chronic demyelination by an inhibition of remyelination.
Kim, Sung-Min; Waters, Patrick; Woodhall, Mark; Yang, Ji Won; Yang, Hyeran; Kim, Jee-Eun; Sung, Jung-Joon; Park, Kyung Seok; Lee, Kwang-Woo
The relative frequencies of demyelinating diseases among Korean patients with idiopathic inflammatory demyelinating disease of the central nervous system (IIDD) have not been sufficiently studied. We therefore describe a cohort of 203 patients with IIDD from three centers in Korea whose syndromes were identified precisely according to international clinical criteria and autoantibody to aquaporin 4 (AQP4-Ab) status. In total, 260 consecutive patients were screened and 203 were included from three hospitals in Korea. All were tested for AQP4-Ab by using a cell-based assay. Patients who met the criteria for definite neuromyelitis optica (NMO) or had a positive AQP4-Ab test result were defined as the NMO group. Among the others, patients were assessed if they had acute disseminated encephalomyelitis, multiple sclerosis (MS), acute transverse myelitis, optic neuritis, or other demyelinating disease as a clinically isolated syndrome of the brain. Eighteen percent of patients were classified as the NMO group, 2% as acute disseminated encephalomyelitis, 18% as MS, 41% as acute transverse myelitis, 11% as optic neuritis, and 8% as other clinically isolated syndrome of the brain. AQP4-Ab was positive in 18% of patients and the relative frequency of NMO to MS (NMO/MS ratio) was 1.06. The mean duration of follow up in our patients was 64 months. Among Korean patients with idiopathic inflammatory demyelinating diseases, the incidence of NMO may be similar to that of MS, and the overall positivity of AQP4-Ab could be lower than previously reported. In addition, acute transverse myelitis that is not associated with MS or NMO can be relatively common in these patients. Further population-based studies with AQP4-Ab are needed to determine the exact incidence of NMO and other idiopathic inflammatory demyelinating diseases in Korea.
Kristina S. Burrack
Full Text Available When an antiviral immune response is generated, a balance must be reached between two opposing pathways: the production of proinflammatory and cytotoxic effectors that drive a robust antiviral immune response to control the infection and regulators that function to limit or blunt an excessive immune response to minimize immune-mediated pathology and repair tissue damage. Myeloid cells, including monocytes and macrophages, play an important role in this balance, particularly through the activities of the arginine-hydrolyzing enzymes nitric oxide synthase 2 (Nos2; iNOS and arginase 1 (Arg1. Nitric oxide (NO production by iNOS is an important proinflammatory mediator, whereas Arg1-expressing macrophages contribute to the resolution of inflammation and wound repair. In the context of viral infections, expression of these enzymes can result in a variety of outcomes for the host. NO has direct antiviral properties against some viruses, whereas during other virus infections NO can mediate immunopathology and/or inhibit the antiviral immune response to promote chronic infection. Arg1 activity has important wound healing functions but can also inhibit the antiviral immune response during some viral infections. Thus, depending on the specific virus and the tissue(s involved, the activity of both of these arginine-hydrolyzing enzymes can either exacerbate or limit the severity of virus-induced disease. In this review, we will discuss a variety of viral infections, including HIV, SARS-CoV, LCMV, HCV, RSV, and others, where myeloid cells influence the control and clearance of the virus from the host, as well as the severity and resolution of tissue damage, via the activities of iNOS and/or Arg1. Clearly, monocyte/macrophage activation and arginine metabolism will continue to be important areas of investigation in the context of viral infections.
Matthew F Cusick
Full Text Available In patients with multiple sclerosis (MS and in mice with experimental autoimmune encephalomyelitis (EAE, proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK, a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.
Cusick, Matthew F; Libbey, Jane E; Trede, Nikolaus S; Fujinami, Robert S
In patients with multiple sclerosis (MS) and in mice with experimental autoimmune encephalomyelitis (EAE), proliferating autoreactive T cells play an important role in the pathogenesis of the disease. Due to the importance of these myelin-specific T cells, these cells have been therapeutic targets in a variety of treatments. Previously we found that Lenaldekar (LDK), a novel small molecule, could inhibit exacerbations in a preclinical model of MS when given at the start of an EAE exacerbation. In those studies, we found that LDK could inhibit human T cell recall responses and murine myelin responses in vitro. In these new studies, we found that LDK could inhibit myelin specific T cell responses through the insulin-like growth factor-1 receptor (IGF-1R) pathway. Alteration of this pathway led to marked reduction in T cell proliferation and expansion. Blocking this pathway could account for the observed decreases in clinical signs and inflammatory demyelinating disease, which was accompanied by axonal preservation. Our data indicate that IGF-1R could be a potential target for new therapies for the treatment of autoimmune diseases where autoreactive T cell expansion is a requisite for disease.
Kersh, Anna E; Edwards, Lindsay J; Evavold, Brian D
In this study, we investigate the basis of T cell recognition of myelin that governs the progression from acute symptoms into disease remission, relapse, and chronic progression in a secondary progressive model of demyelinating disease. Until now, the frequency and affinity of myelin-reactive CD4 T cells that elicit relapsing-remitting disease have not been quantified. The micropipette adhesion frequency assay was used to obtain a sensitive and physiologically relevant two-dimensional measurement of frequency and TCR affinity for myelin, as the inherent low affinity does not allow the use of specific peptide:MHC-II tetramers for this purpose. We found the highest affinity and frequency of polyclonal myelin oligodendrocyte glycoprotein-reactive cells infiltrate the CNS during acute disease, whereas affinities during remission, relapse, and chronic disease are not significantly different from each other. Frequency analysis revealed that the vast majority of CNS-infiltrating CD4 T cells are myelin oligodendrocyte glycoprotein reactive at all time points, demonstrating epitope spread is not a predominant factor for disease progression. Furthermore, time points at which mice were symptomatic were characterized by an infiltration of Th17 cells in the CNS, whereas symptom remission showed an enrichment of cells producing IFN-γ. Also, the ratio of regulatory T cells to Foxp3(-) CD4 T cells was significantly higher in the CNS at remission than during acute disease. The results of this study indicate that a high frequency of T cells specific for a single myelin Ag, rather than increased TCR affinity or epitope spread, governs the transition from acute symptoms through remission, relapse, and chronic disease states. Copyright © 2014 by The American Association of Immunologists, Inc.
Fujisawa, Miwako; Sano, Yasuteru; Omoto, Masatoshi; Ogasawara, Jyun-Ichi; Koga, Michiaki; Takashima, Hiroshi; Kanda, Takashi
We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.
Kraus, Verena; Srivastava, Rajneesh; Kalluri, Sudhakar Reddy; Seidel, Ulrich; Schuelke, Markus; Schimmel, Mareike; Rostasy, Kevin; Leiz, Steffen; Hosie, Stuart; Grummel, Verena; Hemmer, Bernhard
A serum antibody against the inward rectifying potassium channel KIR4.1 (KIR4.1-IgG) was recently discovered, which is found in almost half of adult patients with multiple sclerosis. We investigated the prevalence of KIR4.1-IgG in children with acquired demyelinating disease (ADD) of the CNS. We also compared antibody responses to KIR4.1 and myelin oligodendrocyte glycoproteins (MOGs), another potential autoantigen in childhood ADDs. We measured KIR4.1-IgG by ELISA in children with ADD (n = 47), other neurologic disease (n = 22), and autoimmune disease (n = 22), and in healthy controls (HCs) (n = 18). One hundred six samples were also measured by capture ELISA. Binding of KIR4.1-IgG human subcortical white matter was analyzed by immunofluorescence. Anti-MOG antibodies were measured using a cell-based assay. KIR4.1-IgG titers were significantly higher in children with ADD compared with all control groups by ELISA and capture ELISA (p disease or autoimmune disease or the HCs (0%) were KIR4.1-IgG antibody positive by ELISA. Sera containing KIR4.1-IgG stained glial cells in brain tissue sections. No correlation among KIR4.1-IgG, age, or MOG-IgG was observed in the ADD group. Serum antibodies to KIR4.1 are found in the majority of children with ADD but not in children with other diseases or in HCs. These findings suggest that KIR4.1 is an important target of autoantibodies in childhood ADD.
Karandikar, Nitin J.
The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8+ T cell responses that can potentially suppress pathogenic CD4+ T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8+ T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8+ T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4+ regulatory T cells in an antigen-independent manner, required CD8+ T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8+ T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent. PMID:23805274
Tyler, Andrew F; Mendoza, Jason P; Firan, Mihail; Karandikar, Nitin J
The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.
Beyene, Getu; Chauhan, Raj Deepika; Taylor, Nigel J
Cassava mosaic disease (CMD) is a major constraint to cassava production in sub-Saharan Africa. Under field conditions, evaluation for resistance to CMD takes 12-18 months, often conducted across multiple years and locations under pressure from whitefly-mediated transmission. Under greenhouse or laboratory settings, evaluation for resistance or susceptibility to CMD involves transmission of the causal viruses from an infected source to healthy plants through grafting, or by using Agrobacterium-mediated or biolistic delivery of infectious clones. Following inoculation, visual assessment for CMD symptom development and recovery requires 12-22 weeks. Here we report a rapid screening system for determining resistance and susceptibility to CMD based on virus-induced gene silencing (VIGS) of an endogenous cassava gene. A VIGS vector was developed based on an infectious clone of the virulent strain of East African cassava mosaic virus (EACMV-K201). A sequence from the cassava (Manihot esculenta) ortholog of Arabidopsis SPINDLY (SPY) was cloned into the CP position of the DNA-A genomic component and used to inoculate cassava plants by Helios® Gene Gun microparticle bombardment. Silencing of Manihot esculenta SPY (MeSPY) using MeSPY1-VIGS resulted in shoot-tip necrosis followed by death of the whole plant in CMD susceptible cassava plants within 2-4 weeks. CMD resistant cultivars were not affected and remained healthy after challenge with MeSPY1-VIGS. Significantly higher virus titers were detected in CMD-susceptible cassava lines compared to resistant controls and were correlated with a concomitant reduction in MeSPY expression in susceptible plants. A rapid VIGS-based screening system was developed for assessing resistance and susceptibility to CMD. The method is space and resource efficient, reducing the time required to perform CMD screening to as little as 2-4 weeks. It can be employed as a high throughput rapid screening system to assess new cassava cultivars and for
Mueller-Mang, C. [Institut fuer CT und MRT Gaenserndorf, Gaenserndorf (Austria)
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.)
Zehntner, Simone P; Brisebois, Marcel; Tran, Elise
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...
Ziehn, Marina O; Avedisian, Andrea A; Dervin, Shannon M; Umeda, Elizabeth A; O'Dell, Thomas J; Voskuhl, Rhonda R
Over 50% of multiple sclerosis (MS) patients experience cognitive deficits, and hippocampal-dependent memory impairment has been reported in >30% of these patients. While postmortem pathology studies and in vivo magnetic resonance imaging demonstrate that the hippocampus is targeted in MS, the neuropathology underlying hippocampal dysfunction remains unknown. Furthermore, there are no treatments available to date to effectively prevent neurodegeneration and associated cognitive dysfunction in MS. We have recently demonstrated that the hippocampus is also targeted in experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of MS. The objective of this study was to assess whether a candidate treatment (testosterone) could prevent hippocampal synaptic dysfunction and underlying pathology when administered in either a preventative or a therapeutic (postdisease induction) manner. Electrophysiological studies revealed impairments in basal excitatory synaptic transmission that involved both AMPA receptor-mediated changes in synaptic currents, and faster decay rates of NMDA receptor-mediated currents in mice with EAE. Neuropathology revealed atrophy of the pyramidal and dendritic layers of hippocampal CA1, decreased presynaptic (Synapsin-1) and postsynaptic (postsynaptic density 95; PSD-95) staining, diffuse demyelination, and microglial activation. Testosterone treatment administered either before or after disease induction restores excitatory synaptic transmission as well as presynaptic and postsynaptic protein levels within the hippocampus. Furthermore, cross-modality correlations demonstrate that fluctuations in EPSPs are significantly correlated to changes in postsynaptic protein levels and suggest that PSD-95 is a neuropathological substrate to impaired synaptic transmission in the hippocampus during EAE. This is the first report demonstrating that testosterone is a viable therapeutic treatment option that can restore both hippocampal
Yao, Jiarui; Huang, Dehui; Gui, Qiuping; Chen, Xiaolei; Lou, Xin; Wu, Lei; Cheng, Chen; Li, Jie; Wu, Weiping
Tumefactive demyelinating disease is a rare inflammatory demyelinating disease (IDD) of the central nervous system (CNS). The literature lacks a clear and consistent description of the clinical and radiological spectrum of this disorder, and few Chinese cases have been studied. Here we report 17 Chinese patients, with pathology confirmed CNS IDD, who had distinct clinical and imaging features from those in previous reports. Median age at onset was 47 years, with a female to male ratio of 1.1:1. Multifocal lesions were present in nine cases (53%) on their pre-biopsy magnetic resonance imagings (MRIs), with locations predominantly involving periventricular white matter (41%), subcortical white matter (41%), juxtacortical regions (41%), and cortical gray matter (35%). Moderate to severe perilesional edema and/or mass effect were present in 35% of cases. A variety of enhancement patterns were observed; most were heterogeneous, including ring-like, patchy, venular-like, nodular, punctate, and diffuse in a decreased frequency. Perilesional restriction on diffusion-weighted images (DWI) were evident in 70% cases. Clinical course prior to biopsy was a first neurological event in 82% cases. During a median follow-up of 4.1 years, 76% of cases remained as isolated demyelinating syndrome, and 70% experienced a total or near-total recovery regardless of whether they received immunotherapy. Further studies are needed, especially concerning series with pathological confirmation and long-term follow-up information. Copyright © 2014 Elsevier B.V. All rights reserved.
Young, Erin E.; Sieve, Amy N.; Vichaya, Elisabeth G.; Carcoba, Luis M.; Young, Colin R.; Ambrus, Andrew; Storts, Ralph; Welsh, C. Jane R.; Meagher, Mary W.
Theiler’s murine encephalomyelitis virus (TMEV) infection is a well-characterized model of multiple sclerosis (MS). Previous research has shown that chronic restraint stress (RS) during early TMEV infection exacerbates behavioral signs of disease. The present data suggest RS-induced increases in CNS inflammation, demyelination, and axonal degeneration may underlie this exacerbation. In addition, we report that males exhibit greater CNS inflammation and higher numbers of demyelinating lesions while females show greater susceptibility to RS-induced exacerbation. These findings indicate RS during early TMEV infection increases CNS lesion formation during the late phase and suggest the effects of RS are sex-dependent. PMID:20167380
Fredrick Hogan; Melhem Solh
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 (...
De Felice, K M; Novotna, M; Enders, F T; Faubion, W A; Tremaine, W J; Kantarci, O H; Raffals, L E
Anti-TNFα biologics induce and maintain remission in inflammatory bowel disease (IBD). Also, they have been reported to induce or unmask idiopathic inflammatory demyelinating disease of the central nervous system (IIDD). To determine if anti-TNFα biologics increased the risk of IIDD in a large cohort of patients with IBD. We retrospectively identified adult patients referred to the Mayo Clinic, Rochester, MN for management of IBD from a five state capture area (Minnesota, Wisconsin, North Dakota, South Dakota and Iowa) between 1996 and 2010. IIDDs were identified in both Crohn's disease (CD) and ulcerative colitis (UC) patients with and without anti-TNFα exposure using the 2010 McDonald MRI criteria. The risk of IIDDs in patients with and without anti-TNFα exposure was estimated for IBD; CD and UC groups separately. A total of 9095 patients with IBD were identified (4342 CD and 4753 UC). Four patients with CD with exposure to anti-TNFα agents (4/2054) and five patients with CD without anti-TNFα exposure (5/2288) developed a confirmed IIDD. One patient with UC with exposure to anti-TNFα agents (1/1371) and five patients with UC without anti-TNFα agents developed a confirmed IIDD (5/3382). The per cent of IIDDs in patients with and without anti-TNFα exposure was; IBD: 0.15% and 0.18% (RR = 0.83, 95% CI: 0.28-2.42; P = 0.729); CD: 0.19% and 0.22% (RR = 0.89, 95% CI: 0.24-3.31; P = 0.863); UC: 0.07% and 0.15% (RR = 0.49, 95% CI: 0.06-4.22; P = 0.510). Anti-TNFα biologics do not appear to impact the risk of developing clinical idiopathic inflammatory demyelinating disease in patients with inflammatory bowel disease. © 2014 John Wiley & Sons Ltd.
Denis Bernardi Bichuetti
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.
García-Merino, A; Fernández, O; Montalbán, X; de Andrés, C; Oreja-Guevara, C; Rodríguez-Antigüedad, A; Arbizu, T
Treatments for multiple sclerosis therapy are rapidly evolving. It is believed that new drugs will be approved in the near future, thereby changing current indications for treatment. In this context, the Spanish Society of Neurology's study group on demyelinating diseases, which evaluates medication use in MS, has decided to draw up a consensus statement on the current indications and guidelines for multiple sclerosis treatment. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.
London, Frédéric; Hadhoum, Nawal; Zéphir, Hélène; Vermersch, Patrick; Outteryck, Olivier
Facial myokymia (FM) is an uncommon involuntary movement, disorder of the musculature supplied by the facial nerve and, characterized by spontaneous undulating, vermicular movements beneath the, skin. It has rarely been described as a form of presentation of multiple, sclerosis. We describe a 31-year-old man presenting with continuous, unilateral facial myokymia as the revealing symptom of a demyelinating, disorder of central nervous system. Brain magnetic resonance imaging, showed an ipsilateral pontine T2/FLAIR hyperintensity close to the, postgenu course of facial nerve, suggestive of a segmental demyelination, of facial nerve causing facial nuclear hyperactivity and resulting in FM., Facial myokymia must raise the possibility of MS in adults under the age, of 40. Copyright © 2016 Elsevier B.V. All rights reserved.
Park, Soo Jin; Jeong, In Hye; Kong, Byung Soo; Lee, Jung-Eun; Kim, Kyoung Heon; Lee, Do Yup; Kim, Ho Jin
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.
Díaz-San Segundo, Fayna; Weiss, Marcelo; Pérez-Martín, Eva; Dias, Camila C.; Grubman, Marvin J.; de los Santos, Teresa
Foot-and-mouth disease virus (FMDV) leader proteinase (Lpro) cleaves itself from the viral polyprotein and cleaves the translation initiation factor eIF4G. As a result, host cell translation is inhibited, affecting the host innate immune response. We have demonstrated that Lpro is also associated with degradation of nuclear factor κB (NF-κB), a process that requires Lpro nuclear localization. Additionally, we reported that disruption of a conserved protein domain within the Lpro coding sequen...
Zhou, Lei; Huang, Yongheng; Li, Haiqing; Fan, Jie; Zhangbao, Jingzi; Yu, Hai; Li, Yuxin; Lu, Jiahong; Zhao, Chongbo; Lu, Chuanzhen; Wang, Min; Quan, Chao
We aim to evaluate the clinical relevance of MOG-ab in a cohort of Chinese Han adults with CNS inflammatory demyelinating diseases (IDDs). MOG-ab and AQP4-ab were examined through a fixed cell based indirect immune-fluorescence assay in 86 patients with CNS-IDDs. MOG-ab was positive in 12 patients, while AQP4-ab was positive in 31 patients; none double positives. Optic neuritis (ON) was the most frequent symptom at onset (75.0%) or during the whole disease course (83.3%) of MOG-ab associated IDDs (MOG-IDDs); 79.5% of the episodes involved only the optic nerve in MOG-IDDs. MOG-ab related ON (MOG-ON) usually caused severe visual impairment, longitudinally extensive optic nerve lesion with anterior enhancement and perineural soft tissue enhancement, responded well to steroid, but still could leave remarkable thinning of retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC). MOG-IDDs had less spinal cord involvement compared to AQP4-ab mediated NMO/SD. Heterogeneous brain lesions existed in 66.7% of the patients with MOG-IDDs. Large, edematous white matter lesions were observed with the pathological feature of obvious demyelination yet preservation of astrocyte and axon, fundamentally different from the astrocytopathy typically seen in NMO/SD. Our investigations suggest that MOG-ab mediates a distinct disease entity separate from NMO/SD. Copyright © 2017 Elsevier B.V. All rights reserved.
Sadnicka, Anna; Reilly, Mary M; Mummery, Cath; Brandner, Sebastian; Hirsch, Nicholas; Lunn, Michael P T
A 76-year-old man with a pre-existing diagnosis of myasthenia gravis was admitted to an intensive care unit with pneumonia and type II respiratory failure. In addition, muscle weakness, widespread myokymia, neuropsychiatric disturbance and autonomic disturbance were present. Antivoltage gated potassium channel antibodies, antistriated muscle antibodies and antiacetylcholine receptor antibodies were positive. Nerve-conduction studies demonstrated findings consistent with patchy demyelination. Electromyography confirmed widespread myokymia, and there was evidence of diffuse encephalopathy on electroencephalography. Diagnoses of Morvan syndrome and chronic inflammatory demyelinating polyradiculopathy (CIDP) were made. Treatment with intravenous immunoglobulin, plasma exchange and high-dose steroids were ineffective, and the patient remained dependent on mechanical ventilation. The coexistence of possibly three humorally mediated autoimmune diseases led to treatment with rituximab. Rituximab treatment was followed by an improvement in muscle strength, allowing successful weaning from mechanical ventilation, diminution in myokymia and improved cognition. At follow-up, there was reversal of the neuropsychiatric manifestations and normal muscle strength. This case suggests that rituximab may be useful in the treatment of autoimmune neurological disease refractory to other immunosuppressant therapies. Specifically, it adds further evidence for the use of rituximab in CIDP. As indications for rituximab in humorally mediated disease continue to expand, international multicentre randomised controlled trials are required to prove the effectiveness of this important emerging biological agent.
Full Text Available Tangier disease is an autosomal recessive disorder characterized by an abnormal accumulation of cholesterol esters in various organs secondary to adenotriphosphate binding cassette transporter A-1 (ABCA-1 transporter deficiency and disrupted reverse cholesterol transport. It causes neuropathy in half of the affected individuals. We present the clinical, electrophysiological, and histopathological findings in a middle aged gentleman of Tangier disease who was initially misdiagnosed leprosy and treated with antileprosy drugs. The presence of a demyelinating neuropathy on electrophysiology in a patient with predominant upper limb involvement and facial diplegia should raise the suspicion of Tangier disease. The characteristic lipid profile of Tangier disease was noted in this patient viz. extremely low high density lipoprotein (HDL, elevated triglyceride (TG, and reduced apolipoprotein A1. Estimation of serum lipids should form a part of routine evaluation in order to avoid misdiagnosis.
Park, Tae-Joon; Kim, Jeong-Hyun; Kim, Ho Jin; Bae, Joon Seol; Cheong, Hyun Sub; Park, Byung Lae; Shin, Hyoung Doo
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are demyelinating autoimmune inflammatory diseases that affect the central nervous system (CNS). Previous genome-wide or candidate gene studies have suggested that genetic variants might be associated with the risk of MS or NMO. Aquaporin 4 (AQP4) is a commonly distributed water channel in astrocytes of the CNS, and its expression is decreased in NMO lesions due to astrocyte cytotoxicity. Previous studies have suggested the associations of AQP4 single nucleotide polymorphisms (SNPs) with MS and/or NMO. However, there have been few replication studies in various ethnic populations. This study, as the first of its kind performed in an Asian population, investigated associations of AQP4 SNPs with the risk of inflammatory demyelinating disease (IDD), including MS and NMO, in a Korean population. A total of seven common AQP4 SNPs were selected based on status of linkage disequilibrium (LD), and then genotyped in 178 IDD cases (79 MS and 99 NMO patients) and 237 normal controls. Statistical analyses showed no significant associations between AQP4 SNPs/haplotypes and development of IDD, including MS and NMO (P>0.05). Further replications in larger cohorts and other ethnic groups are needed. Copyright © 2013 Elsevier B.V. All rights reserved.
Nygårdas, Michaela; Paavilainen, Henrik; Müther, Nadine; Nagel, Claus-Henning; Röyttä, Matias; Sodeik, Beate; Hukkanen, Veijo
Herpes simplex virus type 1 (HSV-1) has properties that can be exploited for the development of gene therapy vectors. The neurotropism of HSV enables delivery of therapeutic genes to the nervous system. Using a bacterial artificial chromosome (BAC), we constructed an HSV-1(17(+))-based replicative vector deleted of the neurovirulence gene γ134.5, and expressing leukemia inhibitory factor (LIF) as a transgene for treatment of experimental autoimmune encephalomyelitis (EAE). EAE is an inducible T-cell mediated autoimmune disease of the central nervous system (CNS) and is used as an animal model for multiple sclerosis. Demyelination and inflammation are hallmarks of both diseases. LIF is a cytokine that has the potential to limit demyelination and oligodendrocyte loss in CNS autoimmune diseases and to affect the T-cell mediated autoimmune response. In this study SJL/J mice, induced for EAE, were treated with a HSV-LIF vector intracranially and the subsequent changes in disease parameters and immune responses during the acute disease were investigated. Replicating HSV-LIF and its DNA were detected in the CNS during the acute infection, and the vector spread to the spinal cord but was non-virulent. The HSV-LIF significantly ameliorated the EAE and contributed to a higher number of oligodendrocytes in the brains when compared to untreated mice. The HSV-LIF therapy also induced favorable changes in the expression of immunoregulatory cytokines and T-cell population markers in the CNS during the acute disease. These data suggest that BAC-derived HSV vectors are suitable for gene therapy of CNS disease and can be used to test the therapeutic potential of immunomodulatory factors for treatment of EAE.
Papadopoulos, A. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.; Gatzonis, S. [Univ. of Athens Medical School, Eginition Hospital (Greece). Neurology Dept.; Gouliamos, A. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.; Trakadas, S. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.; Kalovidouris, A. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.; Sgouropoulos, P. [Univ. of Athens Medical School, Eginition Hospital (Greece). Neurology Dept.; Vlachos, L. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.; Papavasiliou, C. [Areteion Hospital, Athens (Greece). CT and MRI Unit, X-ray Dept.
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.)
Melzer, N; Meuth, S G
Multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent chronic, autoimmune demyelinating disorders of the central and peripheral nervous system. Although both disorders share some fundamental pathogenic elements, treatments do not provide uniform effects across both disorders. We aim at providing an overview of current and future disease-modifying strategies in these disorders to demonstrate communalities and distinctions. Intravenous immunoglobulins (IVIG) have demonstrated short- and long-term beneficial effects in CIDP but are not effective in MS. Dimethyl fumarate (BG-12), teriflunomide and laquinimod are orally administered immunomodulatory drugs that are already approved or likely to be approved in the near future for the basic therapy of patients with relapsing-remitting MS (RRMS) due to positive results in Phase III clinical trials. However, clinical trials with these drugs in CIDP have not (yet) been initiated. Natalizumab and fingolimod are approved for the treatment of RRMS, and trials to evaluate their safety and efficacy in CIDP are now planned. Alemtuzumab, ocrelizumab and daclizumab respresent monoclonal antibodies in advanced stages of clinical development for their use in RRMS patients. Attempts to study the safety and efficacy of alemtuzumab and B cell-depleting anti-CD20 antibodies, i.e. rituximab, ocrelizumab or ofatumumab, in CIDP patients are currently under way. We provide an overview of the mechanism of action and clinical data available on disease-modifying immunotherapy options for MS and CIDP. Enhanced understanding of the relative effects of therapies in these two disorders may aid rational treatment selection and the development of innovative treatment approaches in the future. © 2013 British Society for Immunology.
Ju A. Shim
Full Text Available The T cell immunoglobulin mucin (TIM proteins regulate T cell activation and tolerance. TIM-1 plays an important role in the regulation of immune responses and the development of autoimmune diseases. TIM-4 is a natural ligand of TIM-1, and the interaction of TIM-1 and TIM-4 is involved in the regulation of T helper (Th cell responses and modulation of the Th1/Th2 cytokine balance. Behçet’s disease (BD is a chronic, multisystemic inflammatory disorder with arthritic, intestinal, mucocutaneous, ocular, vascular, and central nervous system involvement. Tim-1 expression was lower in a herpes simplex virus-induced BD mouse model compared to that in asymptomatic BD normal (BDN mice. Tim-4 expression was higher in BD mice than that in BDN mice. In this study, we investigated the Tim expression in a BD mouse model with BD-like symptoms. Tim-1 and Tim-4 expression was regulated by an expression vector or siRNA injected into the BD mouse model. The Tim-1 vector injected into BD mice resulted in changes in BD-like symptoms and decreased the severity score. Treatment with Tim-4 siRNA also improved BD-like symptoms and decreased the severity score accompanied by upregulation of regulatory T cells. We showed that regulating Tim-1 or Tim-4 affected BD-like symptoms in mice.
Kip, E; Nazé, F; Suin, V; Vanden Berghe, T; Francart, A; Lamoral, S; Vandenabeele, P; Beyaert, R; Van Gucht, S; Kalai, M
Rabies virus is a highly neurovirulent RNA virus, which causes about 59000 deaths in humans each year. Previously, we described macrophage cytotoxicity upon infection with rabies virus. Here we examined the type of cell death and the role of specific caspases in cell death and disease development upon infection with two laboratory strains of rabies virus: Challenge Virus Standard strain-11 (CVS-11) is highly neurotropic and lethal for mice, while the attenuated Evelyn–Rotnycki–Abelseth (ERA) strain has a broader cell tropism, is non-lethal and has been used as an oral vaccine for animals. Infection of Mf4/4 macrophages with both strains led to caspase-1 activation and IL-1β and IL-18 production, as well as activation of caspases-3, -7, -8, and -9. Moreover, absence of caspase-3, but not of caspase-1 and -11 or -7, partially inhibited virus-induced cell death of bone marrow-derived macrophages. Intranasal inoculation with CVS-11 of mice deficient for either caspase-1 and -11 or -7 or both IL-1β and IL-18 led to general brain infection and lethal disease similar to wild-type mice. Deficiency of caspase-3, on the other hand, significantly delayed the onset of disease, but did not prevent final lethal outcome. Interestingly, deficiency of caspase-1/11, the key executioner of pyroptosis, aggravated disease severity caused by ERA virus, whereas wild-type mice or mice deficient for either caspase-3, -7, or both IL-1β and IL-18 presented the typical mild symptoms associated with ERA virus. In conclusion, rabies virus infection of macrophages induces caspase-1- and caspase-3-dependent cell death. In vivo caspase-1/11 and caspase-3 differently affect disease development in response to infection with the attenuated ERA strain or the virulent CVS-11 strain, respectively. Inflammatory caspases seem to control attenuated rabies virus infection, while caspase-3 aggravates virulent rabies virus infection. PMID:28280602
Background: Newcastle disease (ND), caused by Newcastle disease virus (NDV), is a devastating disease of poultry and wild birds. ND is prevented by rigorous biocontainment and vaccination. One potential approach to prevent spread of the virus is production of birds that show innate resistance to NDV...
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.
Berer, Kerstin; Boziki, Marina; Krishnamoorthy, Gurumoorthy
Myelin-specific, pro-inflammatory TH17 cells are widely regarded as the drivers of experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple sclerosis (MS). The factors, responsible for the generation and maintenance of TH17 cells as well as their participation in the pathogenic cascade leading to the demyelinating disease, have been studied extensively. However, how these harmful autoreactive cells are controlled in vivo remains unclear. By comparing TCR transgenic mice on a disease susceptible and a disease resistant genetic background, we show here that pathogenic TH17 cells are sequestered within the intestine of spontaneous EAE resistant B10.S mice. Disease resistant B10.S mice harbored higher frequencies of TH17 cells in the intestine compared to EAE susceptible SJL/J mice. Moreover, transferred TH17 cells selectively migrated to intestinal lymphoid organs of B10.S mice. The sequestration of TH17 cells in the gut was partially dependent on the gut homing receptor α4β7-mediated adhesion to the intestine. Administration of α4β7 blocking-antibodies increased the peripheral availability of TH17 cells, resulting in increased EAE severity after immunization in B10.S mice. Together, these results support the concept that the intestine is a check-point for controlling pathogenic, organ-specific T cells.
Kang, Y; Cai, Y
Hepatitis B is one of the most common infectious diseases globally. It has been estimated that there are 350 million chronic hepatitis B virus (HBV) carriers worldwide. The liver is connected to the small intestine by the bile duct, which carries bile formed in the liver to the intestine. Nearly all of the blood that leaves the stomach and intestines must pass through the liver. Human intestines contain a wide diversity of microbes, collectively termed the 'gut microbiota'. Gut microbiota play a significant role in host metabolic processes and host immune modulation, and influence host development and physiology (organ development). Altered gut microbiota is a common complication in liver disease. Changes in intestinal microbiota seem to play an important role in induction and promotion of HBV-induced chronic liver disease progression, and specific species among the intestinal commensal bacteria may play either a pathogenic or a protective role in the development of HBV-induced chronic liver disease. Thus, the gut microbiome may represent fertile targets for prevention or management of HBV-induced chronic liver disease. Faecal microbiota transplantation (FMT) may be a useful therapy for HBV-related disease in the future. However, the data available in this field remain limited, and relevant scientific work has only just commenced. New technologies have enabled systematic studies of gut microbiota, and provided more realistic information about its composition and pathological variance. This review summarizes the cutting edge of research into the relationship between gut microbiota and HBV-induced chronic liver disease, and the future prospects of FMT therapy. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.
Torres, J M; Ramírez, M A; Morales, M; Bárcena, J; Vázquez, B; Espuña, E; Pagès-Manté, A; Sánchez-Vizcaíno, J M
We have recently developed a transmissible vaccine to immunize rabbits against myxomatosis and rabbit haemorrhagic disease based on a recombinant myxoma virus (MV) expressing the rabbit haemorrhagic disease virus (RHDV) capsid protein [Bárcena et al. Horizontal transmissible protection against myxomatosis and rabbit haemorragic disease using a recombinant myxoma virus. J. Virol. 2000;74:1114-23]. Administration of the recombinant virus protects rabbits against lethal RHDV and MV challenges. Furthermore, the recombinant virus is capable of horizontal spreading promoting protection of contact animals, thus providing the opportunity to immunize wild rabbit populations. However, potential risks must be extensively evaluated before considering its field use. In this study several safety issues concerning the proposed vaccine have been evaluated under laboratory conditions. Results indicated that vaccine administration is safe even at a 100-fold overdose. No undesirable effects were detected upon administration to immunosuppressed or pregnant rabbits. The recombinant virus maintained its attenuated phenotype after 10 passages in vivo.
Full Text Available Abstract Background Respiratory syncytial virus (RSV is the leading respiratory viral pathogen in young children worldwide. RSV disease is associated with acute airway obstruction (AO, long-term airway hyperresponsiveness (AHR, and chronic lung inflammation. Using two different mouse strains, this study was designed to determine whether RSV disease patterns are host-dependent. C57BL/6 and BALB/c mice were inoculated with RSV and followed for 77 days. RSV loads were measured by plaque assay and polymerase chain reaction (PCR in bronchoalveolar lavage (BAL and whole lung samples; cytokines were measured in BAL samples. Lung inflammation was evaluated with a histopathologic score (HPS, and AO and AHR were determined by plethysmography. Results Viral load dynamics, histopathologic score (HPS, cytokine concentrations, AO and long-term AHR were similar in both strains of RSV-infected mice, although RSV-infected C57BL/6 mice developed significantly greater AO compared with RSV-infected BALB/c mice on day 5. PCR detected RSV RNA in BAL samples of RSV infected mice until day 42, and in whole lung samples through day 77. BAL concentrations of cytokines TNF-α, IFN-γ, and chemokines MIG, RANTES and MIP-1α were significantly elevated in both strains of RSV-infected mice compared with their respective controls. Viral load measured by PCR significantly correlated with disease severity on days 14 and 21. Conclusion RSV-induced acute and chronic airway disease is independent of genetic background.
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.
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.
Hogan, Fredrick; Solh, Melhem
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.
Horellou, Philippe; Wang, Min; Keo, Vixra; Chrétien, Pascale; Serguera, Ché; Waters, Patrick; Deiva, Kumaran
Acquired demyelinating syndromes (ADS) in children evolve either as a monophasic disease diagnosed as acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) or optic neuritis (ON), or a multiphasic one with several relapses most often leading to the diagnosis of multiple sclerosis (MS) or neuromyelitis optica (NMO). These neuroinflammatory disorders are increasingly associated with autoantibodies against proteins such as aquaporin-4 in rare instances, and more frequently against myelin oligodendrocyte glycoprotein (MOG). Recently, in adult NMO patients, C5a levels were shown to be elevated in cerebrospinal fluid (CSF) during acute exacerbation. We investigated the CSF levels of anaphylatoxins and pro-inflammatory cytokines, and plasma MOG antibodies in onset samples from children with ADS. Thirty four children presenting with a first episode of ADS, 17 with monophasic ADS (9 with ADEM, 4 with TM and 4 with ON) and 17 with MS, who had paired blood and CSF samples at onset were included and compared to 12 patients with other non-inflammatory neurological disorders (OND). Cytokines and anaphylatoxins in CSF were measured by Cytometric Bead Array immunoassay. MOG antibody titers in plasma were tested by flow cytometry using a stable cell line expressing full-length human MOG. We found a significant increase in C5a levels in the CSF of patients with monophasic ADS (n=17) compared to OND (n=12, p=0.0036) and to MS (n=17, p=0.0371). The C5a levels in MS were higher than in OND without reaching significance (p=0.2). CSF IL-6 levels were significantly increased in monophasic ADS compared to OND (p=0.0027) and to MS (p=0.0046). MOG antibody plasma levels were significantly higher in monophasic ADS (p<0.0001) and, to a lesser extent, in MS compared to OND (p=0.0023). Plasma MOG antibodies and CSF IL-6 levels were significantly correlated (r=0.51, p=0.018). CSF C5a and IL-6 levels are increased in monophasic ADS but not in MS when compared to OND, suggesting
Cossu, Davide; Yokoyama, Kazumasa; Tomizawa, Yuji; Momotani, Eiichi; Hattori, Nobutaka
Mycobacterium avium subsp. paratuberculosis (MAP) and Mycobacterium bovis (BCG) have been associated to several human autoimmune diseases such as multiple sclerosis (MS), but there are conflicting evidence on the issue. The objective of this study is to evaluate their role in Japanese patients affected by inflammatory demyelinating disorders of the central nervous system (IDDs). A total of 97 IDDs subjects including 51 MS and 46 neuromyelitis optica spectrum disorder (NMOSD) patients, and 34 healthy controls (HCs) were tested for the detection of IgG, IgM and IgA against mycobacterial antigens by indirect ELISA. The levels of anti-MAP IgG were higher in MS patients compared to NMOSD patients (AUC = 0.59, p = 0.02) and HCs (AUC = 0.67, p = 0.01), and the anti-MAP antibodies were more prevalent in MS patients treated with interferon-beta (OR = 11.9; p = 0.004). Anti-BCG IgG antibodies were detected in 8% of MS, 32% of NMOSD and 18% of HCs, the difference between MS and NMOSD groups was statistically significant (AUC = 0.66, p = 0.005). Competition experiments showed that nonspecific IgM were elicited by common mycobacterial antigens. Our study provided further evidence for a possible association between MAP and MS, while BCG vaccination seemed to be inversely related to the risk of developing MS.
Dimachkie, Mazen M; Saperstein, David S
Acquired immune demyelinating neuropathies refer to a group of disorders that share overlapping sensory, motor, and autonomic clinical, laboratory, and electrodiagnostic features. It is important to recognize acquired immune demyelinating neuropathies as they are generally responsive to immunosuppressive or immunomodulatory therapies. This article reviews recently developed early prognostic tools in Guillain-Barré syndrome and discusses the evolving understanding of chronic demyelinating phenotypes with differing treatment responsiveness. While weakness and numbness progress over 2 to 4 weeks in Guillain-Barré syndrome, they continue to evolve beyond 8 weeks in chronic inflammatory demyelinating polyradiculoneuropathy and over 4 to 8 weeks in subacute inflammatory demyelinating polyradiculoneuropathy. Acquired immune demyelinating neuropathies present uncommonly as variants with predominance of ocular, bulbar, sensory, autonomic, or motor manifestations in addition to regional variants, such as paraparetic acquired immune demyelinating neuropathies. Establishing the correct diagnosis is important as these immune disorders differ in response to corticosteroids and other immunosuppressive therapies.
Olson, Julie K; Ludovic Croxford, J; Miller, Stephen D
Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.
Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE), whereas Th2 cells contribute to recovery from disease. A maj or determinant in the development of Th1 and Th2 cells is the type of
Murthy, J. M.
Four cases of acute inflammatory demyelinating polyradiculoneuropathy following varicella are described. The role of immunosuppression as a contributing factor in triggering an autoimmune disease of the peripheral nervous system following viral infection is discussed.
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
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.
Miller, Patrick G; Bonn, Michael B; Franklin, Craig L; Ericsson, Aaron C; McKarns, Susan C
TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein-specific 2D2 TCR transgenic mice. Disease in TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein-specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to TNFR2(-/-) 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders. Copyright © 2015 by The American Association of Immunologists, Inc.
Full Text Available Evidence is accumulating that Th1 cells play an important role in the development of multiple sclerosis (MS and experimental allergic encephalomyelitis (EAE, whereas Th2 cells contribute to recovery from disease. A major determinant in the development of Th1 and Th2 cells is the type of antigen-presenting cell (APC involved and its functional characteristics, e.g., the production of interleukin-12. Therefore, modulation of APC might interfere with the development of Th1 type responses and as such be beneficial for MS and EAE. The potential of cytokines, in particular interleukin-10, and glucocorticoids to exert a selective effect on APC, and as a consequence to affect the Th1-Th2 balance in EAE, is discussed
Mansour, A M; Chan, C-C; Crawford, M A; Tabbarah, Z A; Shen, D; Haddad, W F; Salti, I; Ghazi, N G
To investigate a viral etiology in certain chalazia. A prospective study over 7.5 years of all newly presenting chalazia associated with diffuse follicular conjunctivitis but without any other aetiological factors. Patients were investigated for ocular or systemic infections by history, physical exam, slit-lamp exam, and/or histology of conjunctival biopsy (including transmission electron microscopy). A total of 27 patients developed follicular conjunctivitis without meibomian gland dysfunction, blepharitis, or sexually transmitted diseases. Evidence for a viral aetiology included: recent systemic viral illness (15/27), recent contact with subjects with chalazia or follicular conjunctivitis (5/27), preauricular lymphadenopathy (4/27), viral corneal disease (4/27), or viral particles by ultrastructure (4/4). Chalazia may be associated with viral conjunctivitis. Intralesional corticosteroids should be considered with great caution for viral-induced chalazia.
Zaidman, Craig M; Pestronk, Alan
Nerves are often enlarged in chronic inflammatory demyelinating polyneuropathy (CIDP). In this investigation we studied changes with treatment over time. We retrospectively compared serial ultrasound measurements of median and ulnar nerve size with clinical and electrodiagnostic evaluations in 23 CIDP subjects. We defined remission as stable clinical improvement on low or decreasing amounts of medication. Nerves were normal at last follow-up more often in subjects who achieved remission than in those who did not (10 of 13 vs. 0 of 10, P = 0.0001). Nerves were normal or smaller (>30% reduction) more often in subjects whose grip strength improved or remained strong compared those whose grip strength weakened (12 of 16 vs. 0 of 3, P = 0.04), and in subjects whose demyelinating electrodiagnostic features resolved compared with those whose demyelination persisted (7 of 7 vs. 6 of 12, P = 0.04). Over time, nerve size decreased more in subjects with baseline nerve enlargement who achieved remission than in those who did not (-41% vs. 7%, P = 0.04). In CIDP, enlarged nerves normalized or decreased with remission. © 2014 Wiley Periodicals, Inc.
Tripathi, Richa B; Rivers, Leanne E; Young, Kaylene M; Jamen, Francoise; Richardson, William D
The adult mammalian brain and spinal cord contain glial precursors that express platelet-derived growth factor receptor α subunit (PDGFRA) and the NG2 proteoglycan. These "NG2 cells" descend from oligodendrocyte precursors in the perinatal CNS and continue to generate myelinating oligodendrocytes in the gray and white matter of the postnatal brain. It has been proposed that NG2 cells can also generate reactive astrocytes at sites of CNS injury or demyelination. To test this we examined the fates of PDGFRA/NG2 cells in the mouse spinal cord during experimental autoimmune encephalomyelitis (EAE)--a demyelinating condition that models some aspects of multiple sclerosis in humans. We administered tamoxifen to Pdgfra-CreER(T2):Rosa26R-YFP mice to induce yellow fluorescent protein (YFP) expression in PDGFRA/NG2 cells and their differentiated progeny. We subsequently induced EAE and observed a large (>4-fold) increase in the local density of YFP(+) cells, >90% of which were oligodendrocyte lineage cells. Many of these became CC1-positive, NG2-negative differentiated oligodendrocytes that expressed myelin markers CNP and Tmem10/Opalin. PDGFRA/NG2 cells generated very few GFAP(+)-reactive astrocytes (1-2% of all YFP(+) cells) or NeuN(+) neurons (demyelinated spinal cord.
Le Moan, Natacha; Baeten, Kim M; Rafalski, Victoria A; Ryu, Jae Kyu; Rios Coronado, Pamela E; Bedard, Catherine; Syme, Catriona; Davalos, Dimitrios; Akassoglou, Katerina
Hypoxia-like tissue alterations, characterized by the upregulation of hypoxia-inducible factor-1α (HIF-1α), have been described in the normal appearing white matter and pre-demyelinating lesions of multiple sclerosis (MS) patients. As HIF-1α regulates the transcription of a wide set of genes involved in neuroprotection and neuroinflammation, HIF-1α expression may contribute to the pathogenesis of inflammatory demyelination. To test this hypothesis, we analyzed the effect of cell-specific genetic ablation or overexpression of HIF-1α on the onset and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. HIF-1α was mainly expressed in astrocytes and microglia/macrophages in the mouse spinal cord at the peak of EAE. However, genetic ablation of HIF-1α in astrocytes and/or myeloid cells did not ameliorate clinical symptoms. Furthermore, conditional knock-out of Von Hippel Lindau, a negative regulator of HIF-1α stabilization, failed to exacerbate the clinical course of EAE. In accordance with clinical symptoms, genetic ablation or overexpression of HIF-1α did not change the extent of spinal cord inflammation and demyelination. Overall, our data indicate that despite dramatic upregulation of HIF-1α in astrocytes and myeloid cells in EAE, HIF-1α expression in these two cell types is not required for the development of inflammatory demyelination. Despite numerous reports indicating HIF-1α expression in glia, neurons, and inflammatory cells in the CNS of MS patients, the cell-specific contribution of HIF-1α to disease pathogenesis remains unclear. Here we show that although HIF-1α is dramatically upregulated in astrocytes and myeloid cells in EAE, cell-specific depletion of HIF-1α in these two cell types surprisingly does not affect the development of neuroinflammatory disease. Together with two recently published studies showing a role for oligodendrocyte-specific HIF-1α in myelination and T-cell-specific HIF-1α in EAE, our
Zhou, Xiuming; Wang, Xiang; Zhang, Xiejun; Wu, Qiang; Huang, Guodong; Li, Weiping
Demyelinating lesions were recognized as a kind of rare central nervous system demyelinating lesion. The diagnosis and differential diagnosis of demyelinating lesions is difficult. Once the diagnosis was delayed or incorrect, it will make a great impact on patients.Demyelinating lesions often involved in young and middle-aged, but this patient was the aged, which is rare.
[Autopsy case of a patient with Charcot-Marie-Tooth disease type 1A and suspected chronic inflammatory demyelinating polyradiculoneuropathy, which was later diagnosed as amyotrophic lateral sclerosis].
Higuchi, Yujiro; Sakiyama, Yusuke; Nishihira, Yasushi; Endo, Kazuhiro; Suwazono, Shugo; Suehara, Masahito
We report an autopsy case of a 74-year-old man with late onset Charcot-Marie-Tooth disease type 1A (CMT1A) diagnosed by genetic screening, later associated with amyotrophic lateral sclerosis (ALS). At the age of 70 years, the patient was admitted to our hospital because of progressive weakness and dysesthesia in the right upper limb. In the early stages of the illness, he was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and transient improvement was achieved with intravenous immunoglobulin. However, the symptoms progressively worsened and became refractory. Gene analysis revealed PMP22 gene duplication, which confirmed CMT1A. On sural nerve biopsy, severe demyelinating neuropathy and abundant onion-bulb formations with endoneurial infiltration of inflammatory cells were observed. Thereafter, pseudo-bulbar palsy and respiratory muscle weakness developed insidiously and progressed rapidly along with muscle weakness in the limbs and trunk. The patient died about four years after the onset of this disease. Postmortem examination showed moderate neuronal cell loss, Bunina bodies, and TDP-43-positive inclusions in the anterior horn cells. The spinal cord revealed axonal loss and extensive macrophage permeation in the corticospinal tracts. On the basis of these findings, the final neuropathological diagnosis was ALS. This is the first report of an autopsy case of CMT1A complicated with ALS. We here discuss the significant clinical and neuropathological findings of this case.
Said, Gérard; Krarup, Christian
Chronic inflammatory demyelinative polyneuropathy (CIDP) is an acquired polyneuropathy presumably of immunological origin. It is characterized by a progressive or a relapsing course with predominant motor deficit. The diagnosis rests on the association of non-length-dependent predominantly motor ...
Blanchfield, Lori; Sabatino, Joseph J; Lawrence, Laurel; Evavold, Brian D
Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4(+) T cells due to cross-recognition of multiple self-epitopes such as has been suggested for myelin oligodendrocyte glycoprotein epitope 35-55 (MOG35-55) and neurofilament medium protein epitope 15-35 (NFM15-35). NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic Ag. Despite reported cross-reactivity with MOG-specific T cells, the polyclonal response to NFM15-35 did not expand threshold numbers of MOG38-49 tetramer-positive T cells. Furthermore, NFM lacked functional synergy with MOG to promote experimental autoimmune encephalomyelitis because NFM-deficient synonymous with knockout mice developed an identical disease course to wild-type mice after challenge with MOG35-55 Single-cell analysis of encephalitogenic T cells using the peptide:MHC monomer-based two-dimensional micropipette adhesion frequency assay confirmed that NFM was not a critical Ag driving demyelinating disease because NFM18-30-specific T cells in the CNS were predominantly reactive to MOG38-49 The absence of NFM contribution to disease allowed mapping of the amino acids required for encephalitogenicity and expansion of high-affinity, MOG-specific T cells that defined the polyclonal response. Alterations of N-terminal residues outside of the NFM15-35 core nonamer promoted expansion of high-affinity, MOG38-49 tetramer-positive T cells and promoted consistent experimental autoimmune encephalomyelitis induction, unlike mice challenged with NFM15-35 Although NFM15-35 is immunogenic and cross-reactive with MOG at the polyclonal level, it fails to expand a threshold level of encephalitogenic, high-affinity MOG-specific T cells. Copyright © 2017 by The American Association of Immunologists, Inc.
Piscosquito, Giuseppe; Saveri, Paola; Magri, Stefania; Ciano, Claudia; Gandioli, Claudia; Morbin, Michela; Bella, Daniela D; Moroni, Isabella; Taroni, Franco; Pareyson, Davide
Charcot-Marie-Tooth disease type 4C (CMT4C) is an autosomal recessive (AR) demyelinating neuropathy associated to SH3TC2 mutations, characterized by early onset, spine deformities, and cranial nerve involvement. We screened 43 CMT4 patients (36 index cases) with AR inheritance, demyelinating nerve conductions, and negative testing for PMP22 duplication, GJB1 and MPZ mutations, for SH3TC2 mutations. Twelve patients (11 index cases) had CMT4C as they carried homozygous or compound heterozygous mutations in SH3TC2. We found six mutations: three nonsense (p.R1109*, p.R954*, p.Q892*), one splice site (c.805+2T>C), one synonymous variant (p.K93K) predicting altered splicing, and one frameshift (p.F491Lfs*32) mutation. The splice site and the frameshift mutations are novel. Mean onset age was 7 years (range: 1-14). Neuropathy was moderate-to-severe. Scoliosis was present in 11 patients (severe in 4), and cranial nerve deficits in 9 (hearing loss in 7). Scoliosis and cranial nerve involvement are frequent features of this CMT4 subtype, and their presence should prompt the clinician to look for SH3TC2 gene mutations. In our series of undiagnosed CMT4 patients, SH3TC2 mutation frequency is 30%, confirming that CMT4C may be the most common AR-CMT type. © 2016 Peripheral Nerve Society.
Bramow, Stephan; Frischer, Josa M; Lassmann, Hans
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...
Tsukagoshi, Hiroyuki; Ishioka, Taisei; Noda, Masahiro; Kozawa, Kunihisa; Kimura, Hirokazu
Acute respiratory illness (ARI) due to various viruses is not only the most common cause of upper respiratory infection in humans but is also a major cause of morbidity and mortality, leading to diseases such as bronchiolitis and pneumonia. Previous studies have shown that respiratory syncytial virus (RSV), human rhinovirus (HRV), human metapneumovirus (HMPV), human parainfluenza virus (HPIV), and human enterovirus infections may be associated with virus-induced asthma. For example, it has been suggested that HRV infection is detected in the acute exacerbation of asthma and infection is prolonged. Thus it is believed that the main etiological cause of asthma is ARI viruses. Furthermore, the number of asthma patients in most industrial countries has greatly increased, resulting in a morbidity rate of around 10-15% of the population. However, the relationships between viral infections, host immune response, and host factors in the pathophysiology of asthma remain unclear. To gain a better understanding of the epidemiology of virus-induced asthma, it is important to assess both the characteristics of the viruses and the host defense mechanisms. Molecular epidemiology enables us to understand the pathogenesis of microorganisms by identifying specific pathways, molecules, and genes that influence the risk of developing a disease. However, the epidemiology of various respiratory viruses associated with virus-induced asthma is not fully understood. Therefore, in this article, we review molecular epidemiological studies of RSV, HRV, HPIV, and HMPV infection associated with virus-induced asthma.
Full Text Available Acute respiratory illness (ARI due to various viruses is not only the most common cause of upper respiratory infection in humans but is also a major cause of morbidity and mortality, leading to diseases such as bronchiolitis and pneumonia. Previous studies have shown that respiratory syncytial virus (RSV, human rhinovirus (HRV, human metapneumovirus (HMPV, human parainfluenza virus (HPIV, and human enterovirus (HEV infections may be associated with virus-induced asthma. For example, it has been suggested that HRV infection is detected in the acute exacerbation of asthma and infection is prolonged. Thus it is believed that the main etiological cause of asthma is ARI viruses. Furthermore, the number of asthma patients in most industrial countries has greatly increased, resulting in a morbidity rate of around 10-15% of the population. However, the relationships between viral infections, host immune response, and host factors in the pathophysiology of asthma remain unclear. To gain a better understanding of the epidemiology of virus-induced asthma, it is important to assess both the characteristics of the viruses and the host defense mechanisms. Molecular epidemiology enables us to understand the pathogenesis of microorganisms by identifying specific pathways, molecules, and genes that influence the risk of developing a disease. However, the epidemiology of various respiratory viruses associated with virus-induced asthma is not fully understood. Therefore, in this article, we review molecular epidemiological studies of RSV, HRV, HPIV, and HMPV infection associated with virus-induced asthma.
Shimizu, T. (Takeshi); M.J.M. Smits (Ron); Ikenaka, K. (Kazuhiro)
textabstractOligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not
Falah, Nadia; Posey, Jennifer E; Thorson, Willa; Benke, Paul; Tekin, Mustafa; Tarshish, Brocha; Lupski, James R; Harel, Tamar
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.
Read, Scott A; Douglas, Mark W
Chronic inflammation as a result of viral infection significantly increases the likelihood of cancer development. A handful of diverse viruses have confirmed roles in cancer development and progression, but the list of suspected oncogenic viruses is continually growing. Viruses induce cancer directly and indirectly, by activating inflammatory signalling pathways and cytokines, stimulating growth of infected cells and inhibiting apoptosis. Although oncogenic viruses induce inflammation by various mechanisms, it is generally mediated by the MAPK, NFκB and STAT3 signalling pathways. This review will explore the unique mechanisms by which different oncogenic viruses induce inflammation to promote cancer initiation and progression. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Full Text Available Epidemiological studies of neuromyelitis optica (NMO in Jamaica are lacking. Here we reviewed the clinical records of 700 patients undergoing neurological evaluation at the Kingston Public Hospital, the largest tertiary institution in Jamaica over a 4 month period. We investigated the diagnostic utility of Aquaporin-4 ImmuneglobulinG (AQP4-IgG testing in 36 consecutive patients with a diagnosis of an inflammatory demyelinating disorder (IDD of the central nervous system (CNS. Patients were classified into 3 categories: i NMO, n=10; ii multiple sclerosis (MS, n=14 and iii unclassified IDD (n=12. All sera were tested for AQP-IgG status by cell binding assay (Euroimmun. No MS cases were positive. Ninety per cent of NMO cases were positive. Four of 12 patients with unclassified IDD tested positive for AQP4-IgG. AQP4-IgG seropositivity was associated with a lower socioeconomic status, higher EDSS (P=0.04 and lower pulmonary function than the seronegative cases (P=0.007. Aquaporin-4 autoimmunity may account for a significant proportion of Jamaican CNS IDDs.
King, Irah L; Dickendesher, Travis L; Segal, Benjamin M
Mature myeloid cells (macrophages and CD11b(+) dendritic cells) form a prominent component of neuroinflammatory infiltrates in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). The mechanism by which these cells are replenished during relapsing and chronic neuroinflammation is poorly understood. Here we demonstrate that CD11b(+)CD62L(+)Ly6C(hi) monocytes with colony-forming potential are mobilized into the bloodstream by a granulocyte-macrophage colony-stimulating factor-dependent pathway immediately before EAE relapses. Circulating Ly6C(hi) monocytes traffic across the blood-brain barrier, up-regulate proinflammatory molecules, and differentiate into central nervous system dendritic cells and macrophages. Enrichment of Ly6C(hi) monocytes in the circulating pool is associated with an earlier onset and increased severity of clinical EAE. Our studies indicate that granulocyte-macrophage colony-stimulating factor-driven release of Ly6C(hi) precursors from the bone marrow prevents exhaustion of central nervous system myeloid populations during relapsing or chronic autoimmune demyelination, suggesting a novel pathway for therapeutic targeting.
I.A. Ketelslegers (Immy)
markdownabstract__Abstract__ Acquired inflammatory demyelinating diseases of the central nervous system (CNS) cause damage to myelin sheaths and typically result in white matter lesions due to inflammation, myelin loss and axonal pathology. Clinically, this may result in transient, relapsing or
Sung, Jia-Ying; Tani, Jowy; Park, Susanna B; Kiernan, Matthew C; Lin, Cindy Shin-Yi
Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P demyelinating polyneuropathy and acute-onset chronic inflammatory demyelinating polyneuropathy could be clearly separated into two non-overlapping groups. Studies of nerve excitability may be able to differentiate acute from acute
Al-Radaideh, Ali M; Wharton, Samuel J; Lim, Su-Yin; Tench, Christopher R; Morgan, Paul S; Bowtell, Richard W; Constantinescu, Cris S; Gowland, Penny A
To determine, using ultra-high field magnetic resonance imaging (MRI), whether changes in iron content occur in the earliest phases of demyelinating disease, by quantifying the magnetic susceptibility of deep grey matter structures in patients with Clinically Isolated Syndrome (CIS) that is suggestive of multiple sclerosis (MS), as compared with age-matched healthy subjects. We compared 19 CIS patients to 20 age-matched, healthy controls. Scanning of the study subjects was performed on a 7T Philips Achieva system, using a 3-dimensional, T2*-weighted gradient echo acquisition. Phase data were first high-pass filtered, using a dipole fitting method, and then inverted to produce magnetic susceptibility maps. Region of interest (ROI) analysis was used to estimate magnetic susceptibility values for deep grey matter structures (caudate nucleus, putamen, globus pallidus, the thalamus and its pulvinar). Significantly increased relative susceptibilities were found in the CIS group, compared with controls, for the caudate nucleus (p = 0.05). In CIS patients, the time elapsed since the clinical event and the Expanded Disability Status Scale (EDSS) scores were not correlated with iron levels in any ROI (r(2) 0.05); however, a moderate correlation (r(2) = 0.3; p disease.
Lee, Samuel M.
Peripheral neuropathies such as Charcot-Marie-Tooth disease (CMT) are a group of neurological disorders that affect the peripheral nervous system. Although demyelinating CMT is the most prevalent hereditary peripheral neuropathy, there are currently no effective treatments for patients suffering from this disease. Recent studies by our group and others have provided a link between protein misfolding and demyelinating CMT and indicate that impairment of the proteasome and aggresome-autophagy pathways may contribute to CMT pathogenesis. These studies suggest that targeting protein quality control systems involved in cytoprotection against CMT-associated misfolded proteins could have therapeutic benefits for treating demyelinating CMT. PMID:22482025
Mannie, Mark D; Blanchfield, J Lori; Islam, S M Touhidul; Abbott, Derek J
Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS). Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE) in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen) fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre-treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was as follows: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL-13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS.
Mark D. Mannie
Full Text Available Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS. Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre-treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific-cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II (MHCII glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS.
Ning, Xianbin; Zhao, Changfu; Wang, Caiqin; Zhang, Duo; Luo, Qi
Demyelinating pseudotumor is a rare inflammatory demyelinating disease of the central nervous system (CNS) that has a similar clinical presentation and computed tomography (CT) and magnetic resonance imaging (MRI) imaging findings as brain tumors or abscesses. Unlike brain tumors, demyelinating pseudotumors respond well to steroid hormones. There are only a few reported cases of intracranial demyelinating pseudotumors in the literature. In this case report, we present the diagnosis and treatment of demyelinating pseudotumor in a patient whose condition was initially misdiagnosed as an astrocytoma. Based on the literature and our case, we formulated an outline for the differential diagnosis of demyelinating pseudotumor and astrocytoma. A timely and correct diagnosis of demyelinating pseudotumor would avoid blind surgery, radiotherapy and chemotherapy, which are used to treat brain tumors.
Di Prisco, Silvia; Merega, Elisa; Bonfiglio, Tommaso; Olivero, Guendalina; Cervetto, Chiara; Grilli, Massimo; Usai, Cesare; Marchi, Mario; Pittaluga, Anna
Presynaptic, release-regulating metabotropic glutamate 2 and 3 (mGlu2/3) autoreceptors exist in the CNS. They represent suitable targets for therapeutic approaches to central diseases that are typified by hyperglutamatergicity. The availability of specific ligands able to differentiate between mGlu2 and mGlu3 subunits allows us to further characterize these autoreceptors. In this study we investigated the pharmacological profile of mGlu2/3 receptors in selected CNS regions and evaluated their functions in mice with experimental autoimmune encephalomyelitis (EAE). The comparative analysis of presynaptic mGlu2/3 autoreceptors was performed by determining the effect of selective mGlu2/3 receptor agonist(s) and antagonist(s) on the release of [(3)H]-D-aspartate from cortical and spinal cord synaptosomes in superfusion. In EAE mice, mGlu2/3 autoreceptor-mediated release functions were investigated and effects of in vivo LY379268 administration on impaired glutamate release examined ex vivo. Western blot analysis and confocal microscopy confirmed the presence of presynaptic mGlu2/3 receptor proteins. Cortical synaptosomes possessed LY541850-sensitive, NAAG-insensitive autoreceptors having low affinity for LY379268, while LY541850-insensitive, NAAG-sensitive autoreceptors with high affinity for LY379268 existed in spinal cord terminals. In EAE mice, mGlu2/3 autoreceptors completely lost their inhibitory activity in cortical, but not in spinal cord synaptosomes. In vivo LY379268 administration restored the glutamate exocytosis capability in spinal cord but not in cortical terminals in EAE mice. We propose the existence of mGlu2-preferring and mGlu3-preferring autoreceptors in mouse cortex and spinal cord respectively. The mGlu3 -preferring autoreceptors could represent a target for new pharmacological approaches for treating demyelinating diseases. © 2016 The British Pharmacological Society.
Bright, Richard J; Wilkinson, Jenny; Coventry, Brendon J
Chronic inflammatory demyelinating polyradiculoneuropathy is a rare acquired immune-mediated progressive or relapsing disorder causing peripheral neuropathic disease of duration more than two months. Many individuals with chronic inflammatory demyelinating polyradiculoneuropathy fail to make a long-term recovery with current treatment regimes. The aim of this study was to prospectively review the literature to determine the effectiveness of therapies for chronic inflammatory demyelinating polyradiculoneuropathy. Articles published from January 1990 to December 2012 were searched for studies to treat adults with chronic inflammatory demyelinating polyradiculoneuropathy. Peer-reviewed full-text articles published in English were included. Nine placebo-controlled double-blinded randomised trials were reviewed to treat subjects with chronic inflammatory demyelinating polyradiculoneuropathy exhibiting various degrees of effectiveness. The most effect treatments were; three randomised controlled trials using intravenous immunoglobulin, a study comparing pulsed dexamethasone and short term prednisolone and rituximab all showed promising results and were well tolerated. IVIg and corticosteroids remain first line treatments for CIDP. Therapies using monoclonal antibodies, such as Rituximab and Natalizumab offer the most promise for treatment of Chronic inflammatory demyelinating polyradiculoneuropathy however they also need further research, as does the use of stem cell therapy for treating Chronic inflammatory demyelinating polyradiculoneuropathy. Large randomised controlled trials and better patient selection are required to address responsiveness of CIDP patients to conventional treatments to elucidate mechanisms of action and future directions for therapeutic improvement.
Nguyen, Thi Hiep; Maltby, Steven; Simpson, Jodie L; Eyers, Fiona; Baines, Katherine J; Gibson, Peter G; Foster, Paul S; Yang, Ming
Viral respiratory infections trigger severe exacerbations of asthma, worsen disease symptoms, and impair lung function. To investigate the mechanisms underlying viral exacerbation, we established a mouse model of respiratory syncytial virus (RSV)-induced exacerbation after allergen sensitization and challenge. RSV infection of OVA-sensitized/challenged BALB/c mice resulted in significantly increased airway hyperresponsiveness (AHR) and macrophage and neutrophil lung infiltration. Exacerbation was accompanied by increased levels of inflammatory cytokines (including TNF-α, MCP-1, and keratinocyte-derived protein chemokine [KC]) compared with uninfected OVA-treated mice or OVA-treated mice exposed to UV-inactivated RSV. Dexamethasone treatment completely inhibited all features of allergic disease, including AHR and eosinophil infiltration, in uninfected OVA-sensitized/challenged mice. Conversely, dexamethasone treatment following RSV-induced exacerbation only partially suppressed AHR and failed to dampen macrophage and neutrophil infiltration or inflammatory cytokine production (TNF-α, MCP-1, and KC). This mimics clinical observations in patients with exacerbations, which is associated with increased neutrophils and often poorly responds to corticosteroid therapy. Interestingly, we also observed increased TNF-α levels in sputum samples from patients with neutrophilic asthma. Although RSV-induced exacerbation was resistant to steroid treatment, inhibition of TNF-α and MCP-1 function or depletion of macrophages suppressed features of disease, including AHR and macrophage and neutrophil infiltration. Our findings highlight critical roles for macrophages and inflammatory cytokines (including TNF-α and MCP-1) in viral-induced exacerbation of asthma and suggest examination of these pathways as novel therapeutic approaches for disease management. Copyright © 2016 by The American Association of Immunologists, Inc.
Mennini, Francesco Saverio; Marcellusi, Andrea; Andreoni, Massimo; Gasbarrini, Antonio; Salomone, Salvatore; Craxì, Antonio
At present, there are no specific nationwide epidemiological studies representing the whole Italian population. This study is aimed at describing the epidemiological and economic burden that HCV will generate in the next few years in Italy. Furthermore, the impact that future anti-HCV treatments may have on the burden of disease was considered. This analysis was developed for the period 2012-2030 from the perspective of the Italian National Health Service (NHS). A published system dynamic model was adapted for Italy in order to quantify the HCV-infected population in terms of disease progression and the associated costs from 1950 to 2030. The model structure was based on transition probabilities reflecting the natural history of the disease. In order to estimate the efficacy of current anti-HCV treatment strategies for genotypes 1 and 4, the sustained virological response (SVR) rate in registration clinical trials for both boceprevir and telaprevir was estimated. It was assumed that the efficacy for patients treated with peginterferon + ribavirin was equal to the placebo arm of a randomized clinical trial (RCT) relating to boceprevir and telaprevir. For genotypes 2/3 patients it was assumed that treatment efficacy with dual therapy was equal to a SVR rate from the literature. According to the aim of this study, only direct health care costs (hospital admissions, drugs, treatment, and care of patients) incurred by the Italian NHS have been included in the model. Costs have been extrapolated using the published scientific literature available in Italy and actualized with the 2012 ISTAT (Istituto Nazionale di Statistica) Price Index system for monetary revaluation. Three different scenarios were assumed in order to evaluate the impact of future anti-HCV treatments on the burden of disease. Overall, in Italy, 1.2 million infected subjects were estimated in 2012. Of these, about 211,000 patients were diagnosed, while only about 11,800 subjects were actually being
Li, Chuntian; Zhu, Zixiang; Du, Xiaoli; Cao, Weijun; Yang, Fan; Zhang, Xiangle; Feng, Huanhuan; Li, Dan; Zhang, Keshan; Liu, Xiangtao; Zheng, Haixue
The interferon-induced double-strand RNA activated protein kinase (PKR) plays important roles in host defense against viral infection. Here we demonstrate the significant antiviral role of PKR against foot-and-mouth disease virus (FMDV) and report that FMDV infection inhibits PKR expression and activation in porcine kidney (PK-15) cells. The viral nonstructural protein 3C proteinase (3Cpro) is identified to be responsible for this inhibition. However, it is independent of the well-known proteinase activity of 3Cpro or 3Cpro-induced shutoff of host protein synthesis. We show that 3Cpro induces PKR degradation by lysosomal pathway and no interaction is determined between 3Cpro and PKR. Together, our results indicate that PKR acts an important antiviral factor during FMDV infection, and FMDV has evolved a strategy to overcome PKR-mediated antiviral role by downregulation of PKR protein. Copyright © 2017 Elsevier Inc. All rights reserved.
Du, Sienmi; Sandoval, Francisco; Trinh, Pauline; Umeda, Elizabeth; Voskuhl, Rhonda
Estrogens act upon nuclear estrogen receptors (ER) to ameliorate cell-mediated autoimmune disease. As most immunomodulatory effects of estrogens in EAE have been attributed to the function of ER-α, we previously demonstrated that ER-β ligand treatment reduced disease severity without affecting peripheral cytokine production or levels of CNS inflammation, suggesting a direct neuroprotective effect; however, the effect of ER-β treatment on the function of immune cells within the target organ remained unknown. Here, we used adoptive transfer studies to show that ER-β ligand treatment was protective in the effector, but not the induction phase of EAE, as shown by decreased clinical disease severity with the preservation of axons and myelin in spinal cords. The analysis of the immune cell infiltrates in the CNS revealed that while ER-β ligand treatment did not reduce overall levels of CNS inflammation, there was a decrease in the DC percentage, and these CNS DC had decreased TNF-α production. Finally, experiments using DC deficient in ER-β revealed that the expression of ER-β on DC was essential for protective effects of ER-β ligand treatment in EAE. Our results demonstrate for the first time an effect of ER-β ligand treatment in vivo on DC in the target organ of a prototypic cell-mediated autoimmune disease. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Nakazawa, Atsuko; Nakano, Natsuko; Fukuda, Akinari; Sakamoto, Seisuke; Imadome, Ken-Ichi; Kudo, Toyoichiro; Matsuoka, Kentaro; Kasahara, Mureo
The decision to perform liver transplantation (LT) in patients with Epstein-Barr virus (EBV)-induced fulminant hepatic failure (FHF) relies on a precise assessment of laboratory and pathological findings. In this study, we analyzed clinical and laboratory data as well as the pathological features of the liver in order to evaluate the pathogenesis and the need for LT in 5 patients with EBV-induced FHF. According to the King's College criteria, the Acute Liver Failure Early Dynamic (ALFED) model, and the Japanese criteria (from the Acute Liver Failure Study Group of Japan), only 1 patient was considered to be a candidate for LT. However, explanted liver tissues in 3 cases exhibited massive hepatocellular necrosis together with diffuse CD8-positive T cell infiltration in both the portal area and the sinusoid. EBV was detected in the liver, plasma, and peripheral blood mononuclear cells (PBMNCs). In 2 cases indicated to be at moderate risk by the ALFED model, liver biopsy showed CD8-positive and EBV-encoded RNA signal-positive lymphocytic infiltration predominantly in the portal area, but massive hepatocellular necrosis was not observed. These patients were treated with immunosuppressants and etoposide under the diagnosis of EBV-induced hemophagocytic lymphohistiocytosis or systemic EBV-positive T cell lymphoproliferative disease of childhood. EBV DNA was detected at a high level in PBMNCs, although it was negative in plasma. On the basis of the pathological analysis of the explanted liver tissues, LT was proposed for the restoration of liver function and the removal of the EBV-infected lymphocytes concentrated in the liver. Detecting EBV DNA by a quantitative polymerase chain reaction in plasma and PBMNCs was informative. An accurate evaluation of the underlying pathogenesis is essential for developing a treatment strategy in patients with EBV-induced FHF. © 2015 American Association for the Study of Liver Diseases.
Sartore, M.; Semeraro, A.; Fortina, P. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others
LHON is a mitochondrial genetic disease characterized by maternal inheritance and late onset of blindness caused by bilateral retinal degeneration. A number of molecular defects are known affecting expression of seven mitochondrial genes encoding subunits of respiratory chain complex I, III and IV. We screened genomic DNA from Italian patients for seven of the known point mutations in the ND-1, ND-4 and ND-6 subunits of complex I by PCR followed by SSCP and restriction enzyme digestion. Most of the patients had nonfamilial bilateral visual loss with partial or no recovery and normal neurological examination. Fundoscopic examination revealed that none of the patients had features typical of LHON. Nine of 21 patients (43%) showed multifocal CNS demyelination on MRI. Our results show aberrant SSCP patterns for a PCR product from the ND-4 subunit in one affected child and his mother. Sfa NI and Mae III digestions suggested the absence of a previously defined LHON mutation, and automated DNA sequence analysis revealed two A to G neutral sequence polymorphisms in the third position of codons 351 and 353. In addition, PCR products from the same two samples and an unrelated one showed abnormal SSCP patterns for the ND-1 subunit region of complex I due to the presence of a T to C change at nt 4,216 which was demonstrated after Nla III digestion of PCR products and further confirmed by DNA sequence analysis. Our results indicate that additional defects are present in the Italian population, and identification of abnormal SSCP patterns followed by targeted automated DNA sequence analysis is a reasonable strategy for delineation of new LHON mutations.
Wu, Jianxiang; Yu, Lian; Li, Long; Hu, Jinqiang; Zhou, Jiyong; Zhou, Xueping
The expression of infectious bursal disease virus (IBDV) host-protective immunogen VP2 protein in rice seeds, its immunogenicity and protective capability in chickens were investigated. The VP2 cDNA of IBDV strain ZJ2000 was cloned downstream of the Gt1 promoter of the rice glutelin GluA-2 gene in the binary expression vector, pCambia1301-Gt1. Agrobacterium tumefaciens containing the recombinant vector was used to transform rice embryogenic calli, and 121 transgenic lines were obtained and grown to maturity in a greenhouse. The expression level of VP2 protein in transgenic rice seeds varied from 0.678% to 4.521% microg/mg of the total soluble seed protein. Specific pathogen-free chickens orally vaccinated with transgenic rice seeds expressing VP2 protein produced neutralizing antibodies against IBDV and were protected when challenged with a highly virulent IBDV strain, BC6/85. These results demonstrate that transgenic rice seeds expressing IBDV VP2 can be used as an effective, safe and inexpensive vaccine against IBDV.
Full Text Available Francesco Saverio Mennini,1,2 Andrea Marcellusi,1,3 Massimo Andreoni,4 Antonio Gasbarrini,5 Salvatore Salomone,6 Antonio Craxì71Centre for Economic and International Studies (CEIS – Economic Evaluation and HTA (EEHTA Faculty of Economics, University of Rome Tor Vergata, Rome, Italy; 2Institute of Leadership and Management in Health, Kingston University, London, UK; 3Department of Demography, University of Rome La Sapienza, Rome, Italy; 4Department of Public Health and Cell Biology, School of Medicine, University of Rome Tor Vergata, Rome, Italy; 5Gastroenterology Division, Catholic University of the Sacred Heart of Rome, School of Medicine, Rome, Italy; 6Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania, Catania, Italy; 7Gastroenterology Division, University of Palermo, Palermo, ItalyBackground: At present, there are no specific nationwide epidemiological studies representing the whole Italian population. This study is aimed at describing the epidemiological and economic burden that HCV will generate in the next few years in Italy. Furthermore, the impact that future anti-HCV treatments may have on the burden of disease was considered. This analysis was developed for the period 2012–2030 from the perspective of the Italian National Health Service (NHS. Methods: A published system dynamic model was adapted for Italy in order to quantify the HCV-infected population in terms of disease progression and the associated costs from 1950 to 2030. The model structure was based on transition probabilities reflecting the natural history of the disease. In order to estimate the efficacy of current anti-HCV treatment strategies for genotypes 1 and 4, the sustained virological response (SVR rate in registration clinical trials for both boceprevir and telaprevir was estimated. It was assumed that the efficacy for patients treated with peginterferon + ribavirin was equal to the placebo arm of a
Setsuda, Joyce; Teruya-Feldstein, Julie; Harris, Nancy L.; Ferry, Judith A.; Sorbara, Lynn; Gupta, Ghanshyam; Jaffe, Elaine S.; Tosato, Giovanna
T cell immunodeficiency plays an important role in the pathogenesis of posttransplant lymphoproliferative disease (PTLD) by permitting the unbridled expansion of Epstein-Barr virus (EBV)-infected B lymphocytes. However, factors other than T cell function may contribute to PTLD pathogenesis because PTLD infrequently develops even in the context of severe T cell immunodeficiency, and athymic mice that are T-cell-immunodeficient can reject EBV-immortalized cells. Here we report that PTLD tissues express significantly lower levels of IL-18, interferon-γ (IFN-γ), Mig, and RANTES compared to lymphoid tissues diagnosed with acute EBV-induced infectious mononucleosis, as assessed by semiquantitative RT-PCR analysis. Other cytokines and chemokines are expressed at similar levels. Immunohistochemistry confirmed that PTLD tissues contain less IL-18 and Mig protein than tissues with infectious mononucleosis. IL-18, primarily a monocyte product, promotes the secretion of IFN-γ, which stimulates Mig and RANTES expression. Both IL-18 and Mig display antitumor activity in mice involving inhibition of angiogenesis. These results document greater expression of IL-18, IFN-γ, Mig, and RANTES in lymphoid tissues with acute EBV-induced infectious mononucleosis compared to tissues with PTLD and raise the possibility that these mediators participate in critical host responses to EBV infection. PMID:10393857
Full Text Available The best therapeutic strategy in virus-induced vasculitides should take into account the etiology of the disease and be adapted to the pathogenesis. The combination of antiviral treatments and plasma exchanges has been proven effective in polyarteritis nodosa (PAN. In human immunodeficiency virus (HIV-related vasculitis this strategy is also effective and does not jeopardize, like cytotoxic agents, the outcome of AIDS. In vasculitis related to HCV-associated cryoglobulinemia, plasma exchanges improve the outcome but the poor effectiveness of antiviral drugs is not able to favor, usually, a definite recovery of the patients and relapses are frequent.
Full Text Available Abstract Background Cisplatin resistance is a serious problem in cancer treatment. To overcome it, alternative approaches including virotherapy are being pursued. One of the candidates for anticancer virotherapy is the Newcastle disease virus (NDV. Even though NDV's oncolytic properties in various cancer cells have been widely reported, information regarding its effects on cisplatin resistant cancer cells is still limited. Therefore, we tested the oncolytic efficacy of a strain of NDV, designated as AF2240, in a cisplatin-resistant breast cancer cell line. Methods Cisplatin-resistant cell line (MCF7-CR was developed from the MCF7 human breast adenocarcinoma cell line by performing a seven-cyclic exposure to cisplatin. Following NDV infection, fluorescence-activated cell sorting (FACS analysis and immunoblotting were used to measure cell viability and viral protein expression, respectively. Production of virus progeny was then assessed by using the plaque assay technique. Results Infection of a mass population of the MCF7-CR with NDV resulted in 50% killing in the first 12 hours post-infection (hpi, comparable to the parental MCF7. From 12 hpi onwards, the remaining MCF7-CR became less susceptible to NDV killing. This reduced susceptibility led to increased viral protein synthesis and virus progeny production. The reduction was also associated with a prolonged cell survival via stabilization of the survivin protein. Conclusions Our findings showed for the first time, the involvement of survivin in the reduction of NDV-induced oncolysis in a subpopulation of cisplatin-resistant cells. This information will be important towards improving the efficacy of NDV as an anticancer agent in drug resistant cancers.
Bhopale, Mahendra K; Hilliard, Brendan; Constantinescu, Cris S; Phillips, S Michael; Rostami, Abdolmohamad
We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4(+) cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis. The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice. The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry. C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DAB389IL-2 treatment reduced CD3(+)CD4(+), CD3(+)CD8(+), CD4(+)CD8(+), CD3(+)IL-2(+), CD3(+)IFN-γ(+) and CD3(+)TNF-α(+) T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19(+) B-cells positive for IL-2 or CD11b(+) in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3(+)CD8(+), CD4(+)CD8(+), CD3(+)CD25(+) populations on day 16, and lymph node CD3(+)IL-10(+) and peripheral blood CD3(+)CD25(+) populations on day 24. Our study demonstrates that DAB389IL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development.
Sun, Li; Weng, Huan; Li, Zhenxin
Idiopathic optic neuritis (ION) is an inflammation of the optic nerve that may result in a complete or partial loss of vision. ION is usually due to the immune attack of the myelin sheath covering the optic nerve. ION acts frequently as the first symptoms of multiple sclerosis (MS) and neuromyelitis optica (NMO), or other inflammatory demyelinating disorders. The pathogenic progression of ION remains unclear. Experimental autoimmune encephalitis (EAE) is a commonly used model of idiopathic inflammatory demyelinating disorders (IIDDs); the optic nerve is affected in EAE as well. The specific mediators of demyelination in optic neuritis are unknown. Recent studies have indicated what T-cell activation in peripheral blood is associated with optic neuritis pathogenesis. The object of the present study was to determine whether certain cytokines (IL-6, IL-17A, and IL-23) and AQP4 contribute to the demyelinating process using EAE model. We have found that IL-6R, AQP4 and IL-23R are significantly increased in mRNA and protein levels in optic nerves in EAE mice compared to control mice; serum AQP4, IL-6, IL-17A, IL-23 are increased whereas transforming growth factor beta (TGF-β) is decreased in EAE mice. These results suggest that AQP4 and selective cytokines in serum are associated with ION pathogenesis in the animal model, and these results shine light for future clinical diagnosis as potential biomarkers in ION patients.
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)
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.)
Hood, Jennifer D; Zarnitsyna, Veronika I; Zhu, Cheng; Evavold, Brian D
Having regulatory T cells (Tregs) with the same Ag specificity as the responding conventional T cells is thought to be important in maintaining peripheral tolerance. It has been demonstrated that during experimental autoimmune encephalomyelitis there are myelin oligodendrocyte glycoprotein (MOG)--specific Tregs that infiltrate into the CNS. However, the affinity of naturally occurring polyclonal Tregs for any self-antigen, let alone MOG, has not been analyzed in the periphery or at the site of autoimmune disease. Utilizing the highly sensitive micropipette adhesion frequency assay, which allows one to determine on a single-cell basis the affinity and frequency of polyclonal Ag-specific T cells directly ex vivo, we demonstrate that at peak disease MOG-specific Tregs were progressively enriched in the draining cervical lymph nodes and CNS as compared with spleen. These frequencies were greater than the frequencies measured by tetramer analysis, indicative of the large fraction of lower affinity T cells that comprise the MOG-specific conventional T cell (Tconv) and Treg response. Of interest, the self-reactive CD4(+) Tconvs and Tregs displayed overlapping affinities for MOG in the periphery, yet in the CNS, the site of neuroinflammation, Tconvs skew toward higher affinities. Most of the MOG-specific Tregs in the CNS possessed the methylation signature associated with thymic-derived Tregs. These findings indicate that thymic-derived Treg affinity range matches that of their Tconvs in the periphery and suggest a change in TCR affinity as a potential mechanism for autoimmune progression and escape from immune regulation. Copyright © 2015 by The American Association of Immunologists, Inc.
Jani-Acsadi, Agnes; Lewis, Richard A
Demyelinating neuropathies are typically characterized by physiological slowing of conduction velocity and pathologically by segmental loss of myelin and in some instances, evidence of remyelination. Clinically, patients with demyelinating neuropathy can be seen with inherited disorders (Charcot-Marie-Tooth disease) or acquired disorders, typically immune-mediated or inflammatory. The acquired disorders can be either acute or subacute as seen in the acute inflammatory demyelinating polyneuropathy (AIDP) form of Guillain-Barré syndrome or chronic progressive or relapsing disorders such as chronic inflammatory demyelinating polyneuropathy. It is important to develop a logical approach to diagnosing these disorders. This requires an understanding of the clinical, genetic, physiological, and pathological features of these neuropathies. Clinically, important features to consider are the temporal progression, degree of symmetry, and involvement of proximal as well as distal muscles. Genetically, recognizing the different inheritance patterns and age of onset allow for a coordinated approach to determining a specific genotype. Physiologically, besides nerve conduction slowing, other physiological hallmarks of demyelination include temporal dispersion of compound motor action potentials (CMAP) on proximal stimulation, conduction block, and distal CMAP duration prolongation with certain patterns of involvement pointing to specific disorders. This chapter focuses on these various aspects of the evaluation of patients with chronic acquired demyelinating neuropathies to develop a comprehensive and thoughtful diagnostic concept. Copyright © 2013 Elsevier B.V. All rights reserved.
Virus-induced Gene Silencing-based Functional Analyses Revealed the Involvement of Several Putative Trehalose-6-Phosphate Synthase/Phosphatase Genes in Disease Resistance against Botrytis cinerea and Pseudomonas syringae pv. tomato DC3000 in Tomato
Full Text Available Trehalose and its metabolism have been demonstrated to play important roles in control of plant growth, development and stress responses. However, direct genetic evidence supporting the functions of trehalose and its metabolism in defense response against pathogens is lacking. In the present study, genome-wide characterization of putative trehalose-related genes identified 11 SlTPSs for trehalose-6-phosphate synthase, 8 SlTPPs for trehalose-6-phosphate phosphatase and one SlTRE1 for trehalase in tomato genome. Nine SlTPSs, 4 SlTPPs and SlTRE1 were selected for functional analyses to explore their involvement in tomato disease resistance. Some selected SlTPSs, SlTPPs and SlTRE1 responded with distinct expression induction patterns to Botrytis cinerea and Pseudomonas syringae pv. tomato (Pst DC3000 as well as to defense signaling hormones (e.g. salicylic acid, jasmonic acid and a precursor of ethylene. Virus-induced gene silencing-mediated silencing of SlTPS3, SlTPS4 or SlTPS7 led to deregulation of ROS accumulation and attenuated the expression of defense-related genes upon pathogen infection and thus deteriorated the resistance against B. cinerea or Pst DC3000. By contrast, silencing of SlTPS5 or SlTPP2 led to an increased expression of the defense-related genes upon pathogen infection and conferred an increased resistance against Pst DC3000. Silencing of SlTPS3, SlTPS4, SlTPS5, SlTPS7 or SlTPP2 affected trehalose level in tomato plants with or without infection of B. cinerea or Pst DC3000. These results demonstrate that SlTPS3, SlTPS4, SlTPS5, SlTPS7 and SlTPP2 play roles in resistance against B. cinerea and Pst DC3000, implying the importance of trehalose and tis metabolism in regulation of defense response against pathogens in tomato.
Haliloğlu, Göknur; Yüksel, Deniz; Temoçin, Cağri Mesut; Topaloğlu, Haluk
Chronic inflammatory demyelinating neuropathy, a treatable immune-mediated disease of the peripheral nervous system is less common in childhood compared to adults. Despite different sets of diagnostic criteria, lack of a reliable biologic marker leads to challenges in diagnosis, follow-up and treatment. Our first aim was to review clinical presentation, course, response to treatment, and prognosis in our childhood patients. We also aimed to document diagnostic and therapeutic pitfalls and challenges at the bedside. Our original cohort consisted of 23 pediatric patients who were referred to us with a clinical diagnosis of chronic inflammatory demyelinating neuropathy. Seven patients reaching to an alternative diagnosis were excluded. In the remaining patients, diagnostic, treatment and follow-up data were compared in typical patients who satisfied both clinical and electrodiagnostic criteria and atypical patients who failed to meet minimal research chronic inflammatory demyelinating neuropathy electrodiagnostic requirements. Eight of 16 patients (50%) met the minimal chronic inflammatory demyelinating neuropathy research diagnostic requirements. There was only a statistically significant difference (p = 0.010) in terms of European Neuromuscular Centre childhood chronic inflammatory diagnostic mandatory clinical criteria between the two groups. Misdiagnosis due to errors in electrophysiological interpretation (100%, n = 8), cerebrospinal fluid cytoalbuminologic dissociation (100%, n = 4 and/or subjective improvement on any immunotherapy modality (80 ± 19.27%)) was frequent. Pediatric CIDP is challenging in terms of diagnostic and therapeutic pitfalls at the bedside. Diagnostic errors due to electrophysiological interpretation, cerebrospinal fluid cytoalbuminologic dissociation, and/or subjective improvement on immunotherapy should be considered. Copyright © 2016 Elsevier B.V. All rights reserved.
Olut, Ali Ilgin; Ozünlü, Haluk; Tan, Ersin; Kocagöz, Tanal
Infectious etiology of the demyelinating diseases is an intensive matter of research. Among the suspected pathogens, herpesviruses had attracted particular attention because of their capacity to remain latent in nervous tissues, axonal transportation of some members within neurons, relapsing-remitting characteristic of the infections, and capability of inducing demyelination both in human host and animal models. Human herpesvirus-8 (HHV-8) is the least studied of this group even some of the HHV-8 related disorders such as HIV associated Castleman's disease, some lymphomas, monoclonal gammopathy of uncertain significance (MGUS), may be seen in patients with demyelinating conditions. The aim of this study was the investigation of a probable relationship between HHV-8 infection and certain demyelinating diseases. For this purpose, the presence of HHV-8 DNA has been investigated by polymerase chain reaction in the blood samples of 14 multiple sclerosis (MS), six chronic inflammatory demyelinizing polyneuropathy (CIDP), three Guillain-Barre syndrome (GBS), and one Miller-Fisher syndrome patients, together with 24 age- and sex-matched healthy subjects as control. As a result, one of MS, two of CIDP and all of the GBS patients were found HHV-8 DNA positive, whereas all the subjects in control group were negative. Although the interpretation of the results of this study does not seem to be possible owing to the limited number of patients, it emphasizes the need for larger scale, detailed studies on this subject since no other report dealing with this matter has been encountered in the literature.
Izadi, Sadegh; Karamimagham, Sina; Poursadeghfard, Maryam
Chronic Inflammatory Demyelinating Polyneuropathy is an autoimmune disease with progressive and relapsing courses. The main clinical presentations are diffuse deep tendon hyporeflexia or areflexia and symmetric proximal-distal muscles weakness. Myasthenia gravis is also an immune mediated disease with fluctuating ocular and bulbar symptoms and sometimes weakness. Although both myasthenia gravis and chronic inflammatory demyelinating polyneuropathy are immune mediated disorders, clinical presentations are obviously different in the two diseases. Herein, we will report a case of chronic inflammatory demyelinating polyneuropathy who presented with isolated unilateral ptosis. Initially, the patient was managed as ocular type of myasthenia gravis, but after progression to general limb weakness and areflexia, the diagnosis of chronic inflammatory demyelinating polyneuropathy was made. Although unilateral ptosis is a typical feature of myasthenia gravis, it may be seen as the first presentation of chronic inflammatory demyelinating polyneuropathy as well which mimics myasthenia gravis disease.
Olson, Julie K; Eagar, Todd N; Miller, Stephen D
Molecular mimicry is the process by which T cells activated in response to determinants on an infecting microorganism cross-react with self epitopes, leading to an autoimmune disease. Normally, infection of SJL/J mice with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) results in a persistent CNS infection, leading to a chronic progressive, CD4(+) T cell-mediated demyelinating disease. Myelin damage is initiated by T cell responses to virus persisting in CNS APCs, and progressive demyelinating disease (50 days postinfection) is perpetuated by myelin epitope-specific CD4(+) T cells activated by epitope spreading. We developed an infectious model of molecular mimicry by inserting a sequence encompassing the immunodominant myelin epitope, proteolipid protein (PLP) 139-151, into the coding region of a nonpathogenic TMEV variant. PLP139-TMEV-infected mice developed a rapid onset paralytic inflammatory, demyelinating disease paralleled by the activation of PLP139-151-specific CD4(+) Th1 responses within 10-14 days postinfection. The current studies demonstrate that the early onset demyelinating disease induced by PLP139-TMEV is the direct result of autoreactive PLP139-151-specific CD4(+) T cell responses. PLP139-151-specific CD4(+) T cells from PLP139-TMEV-infected mice transferred demyelinating disease to naive recipients and PLP139-151-specific tolerance before infection prevented clinical disease. Finally, infection with the mimic virus at sites peripheral to the CNS induced early demyelinating disease, suggesting that the PLP139-151-specific CD4(+) T cells could be activated in the periphery and traffic to the CNS. Collectively, infection with PLP139-151 mimic encoding TMEV serves as an excellent model for molecular mimicry by inducing pathologic myelin-specific CD4(+) T cells via a natural virus infection.
Zhu, Tian Hao; Nakamura, Mio; Abrouk, Michael; Farahnik, Benjamin; Koo, John; Bhutani, Tina
Tumor necrosis factor-α inhibitors (TNFi) are the most widely used systemic treatments for patients with psoriasis and psoriatic arthritis. There currently exists a U.S. Food and Drug Administration issued warning label on all TNFi for "rare cases of new onset or exacerbation of central nervous system demyelinating disorders." The aim of this review was to update the incidence of TNFi-induced demyelinating diseases. Pubmed database was searched for safety data regarding demyelinating disease secondary to TNFi therapy prescribed for psoriasis. In clinical trials: 6990 patients had received treatment with etanercept with one reported case of multiple sclerosis; 5204 patients were treated with adalimumab with no cases identified and 2322 patients were treated with infliximab with one case of demyelinating polyneuropathy. Outside of clinical trials: 19 individual cases of demyelinating disorders from TNFi treatment have been reported. Although there is potential for TNF blockade to lead to demyelination of the central and peripheral nervous systems, the results of the present review suggest that demyelinating diseases associated with TNFi are extremely rare. TNFi are not recommended for use in patients with a personal history of demyelinating disease. However, with clinical vigilance and individualized treatment regimen, TNFi may be safe for use in other patients.
Franssen, Hessel; Straver, Dirk C G
In the second part of this review we deal with the clinical aspects of immune-mediated demyelinating neuropathies. We describe the relationship between pathophysiology and symptoms and discuss the pathophysiology of specific disease entities, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, anti-myelin-associated glycoprotein neuropathy, and POEMS syndrome. Copyright © 2013 Wiley Periodicals, Inc.
de Maar, E. F.; Kas-Deelen, DM; de Jager, AEJ; The, T. Hauw; Tegzess, Adam M.; van Son, WJ
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disease with a prevalence of approximately 1/100 000 in the general population . The pathogenesis of the demyelination is thought to be immune mediated but the mechanism is uncertain . Antecedent infections are reported in 35%
Barohn, Richard J.; Katz, Jonathan
Chronic acquired demyelinating neuropathies (CADP) are an important group of immune neuromuscular disorders affecting myelin. These are distinct from chronic inflammatory demyelinating polyneuropathy (CIDP). Classically, CIDP is characterized by proximal and distal weakness, large fiber sensory loss, elevated cerebrospinal fluid (CSF) protein content, demyelinating changes nerve conduction studies or nerve biopsy, and response to immunomodulating treatment. In this chapter we discuss CADP with emphasis on multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), distal acquired demyelinating symmetric (DADS) neuropathy and conclude with less common variants. While each of these entities has distinctive laboratory and electrodiagnostic features that aid in their diagnosis, clinical characteristics are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies. Unlike CIDP, MMN is typically asymmetric and affects only the motor nerve fibers. MMN is a rare disease that presents chronically, over several years of progression affecting the arms are more commonly than the legs. Men are more likely than women to develop MMN. MADSAM should be suspected in patients who have weakness and loss of sensation in primarily one arm or leg which progresses slowly over several months to years. It is important in patient with multifocal demyelinating clinical presentation to distinguish MMN from MADSAM since corticosteroids are not effective in MMN where the mainstay of therapy is intravenous gammaglobulin (IVIg). DADS can be subdivided into DADS-M (associated woth M-protein) and DADS-I which is idioapthic. While DADS-I patients respond somewhat to immunotherapy, DADS-M patients present with distal predominant sensorimotor demyelinating neuropathy phenotype and are notoriously refractory to immunotherapies regardless of antibodies to myelin-associated glycoprotein (MAG). Our knowledge
Karussis, Dimitrios; Petrou, Panayiota
A wide variety of inflammatory diseases temporally associated with the administration of various vaccines, has been reported in the literature. A PubMed search from 1979 to 2013 revealed seventy one (71) documented cases. The most commonly reported vaccinations that were associated with CNS demyelinating diseases included influenza (21 cases), human papilloma virus (HPV) (9 cases), hepatitis A or B (8 cases), rabies (5 cases), measles (5 cases), rubella (5 cases), yellow fever (3 cases), anthrax (2 cases),meningococcus (2 cases) and tetanus (2 cases). The vast majority of post-vaccination CNS demyelinating syndromes, are related to influenza vaccination and this could be attributed to the high percentage of the population that received the vaccine during the HI1N1 epidemia from 2009 to 2012. Usually the symptoms of the CNS demyelinating syndrome appear few days following the immunization (mean: 14.2 days) but there are cases where the clinical presentation was delayed (more than 3 weeks or even up to 5 months post-vaccination) (approximately a third of all the reported cases). In terms of the clinical presentation and the affected CNS areas, there is a great diversity among the reported cases of post-vaccination acute demyelinating syndromes. Optic neuritis was the prominent clinical presentation in 38 cases, multifocal disseminated demyelination in 30, myelitis in 24 and encephalitis in 17. Interestingly in a rather high proportion of the patients (and especially following influenza and human papiloma virus vaccination-HPV) the dominant localizations of demyelination were the optic nerves and the myelon, presenting as optic neuritis and myelitis (with or without additional manifestations of ADEM), reminiscent to neuromyelitic optica (or, more generally, the NMO-spectrum of diseases). Seven patients suffered an NMO-like disease following HPV and we had two similar cases in our Center. One patient with post-vaccination ADEM, subsequently developed NMO. Overall, the
Knopp, M; Leese, R J; Martin-Lamb, D; Rajabally, Y A
The involvement of optic and auditory pathways has rarely been studied in demyelinating polyneuropathies. We here aimed to study this further in a cohort of patients with acquired and gentic demyelinating neuropathy. We studied eight patients with hereditary neuropathy with liability to pressure palsies (HNPP), six with Charcot-Marie-Tooth disease type 1A (CMT1A), ten with chronic inflammatory demyelinating polyneuropathy (CIDP) and seven with antimyelin-associated glycoprotein (MAG) neuropathy using visual evoked potentials and brainstem auditory evoked potentials. Optic pathway dysfunction was detected in 6/7 anti-MAG neuropathy patients, about half of those with CIDP and HNPP, but only in 1/6 patients with CMT1A. Peripheral auditory nerve dysfunction appeared common in all groups except HNPP. Brainstem involvement was exceptional in all groups. We conclude optic nerve involvement may be frequent in all demyelinating polyneuropathies, particularly anti-MAG neuropathy, except in CMT1A. Peripheral auditory nerves may be spared in HNPP possibly due to absence of local compression. Evidence for central brainstem pathology appeared infrequent in all four studied neuropathies. This study suggests that acquired and genetic demyelinating polyneuropathies may be associated with optic and auditory nerve involvement, which may contribute to neurological disability, and require greater awareness. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Ware, Tyson L; Kornberg, Andrew J; Rodriguez-Casero, M Victoria; Ryan, Monique M
Chronic inflammatory demyelinating polyneuropathy is a rare condition in children. In this article, we report our experience in the management of 10 cases of childhood chronic inflammatory demyelinating polyneuropathy in a single center, in the era of contrast-enhanced magnetic resonance imaging (MRI), genetic microarray, and chronic inflammatory demyelinating polyneuropathy disease activity status. Robust neurophysiologic abnormalities were present in all cases and both MRI and lumbar puncture were useful adjuncts in diagnosis. Genetic microarray is a simple technique useful in excluding the most common hereditary demyelinating neuropathy. Intravenous immunoglobulin was an effective first-line therapy in most cases, with refractory cases responding to corticosteroids and rituximab. We found the chronic inflammatory demyelinating polyneuropathy disease activity status useful for assessing outcome at final follow-up, whereas the modified Rankin score was better for assessing peak motor disability.
Das, H. K.; Das, D.; Doley, R.; Sahu, P. P.
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.
Cereda, C W; Zecca, C; Mazzucchelli, L; Valci, L; Staedler, C; Bassetti, C L; Gobbi, C
Tumor necrosis factor alpha (TNF-α) is a pro-inflammatory and immunoregulatory cytokine involved in the pathogenesis of several autoimmune disorders. Etanercept, a TNF-α antagonist (anti-TNF-α) acting as a soluble TNF-α receptor, has been associated with neurological demyelinating disorders. This paper aims to report an unusual case showing tumefactive central nervous system (CNS) inflammatory demyelination in a patient in the course of TNF -α antagonist therapy, requiring decompressive hemicraniectomy. This report is based on magnetic resonance imaging (MRI) findings and histology. A biopsy confirmed the inflammatory demyelinating nature of the lesions. The clinical presentation is unusual due to the severity of the disease process, requiring decompressive hemicraniotomy with a clinically favorable outcome.
Wang, Ying; Wang, Min; Liang, Hui; Yu, Quntao; Yan, Zhihui; Kong, Min
Inflammatory demyelinating pseudotumor usually occurs in the brain and rarely occurs in the spinal cord. On imaging, inflammatory demyelinating pseudotumor appears very similar to intramedullary tumors such as gliomas. It is often misdiagnosed as intramedullary tumor and surgically resected. In view of this, the clinical and magnetic resonance imaging manifestations and the pathological fea-tures of 36 cases of inflammatory demyelinating pseudotumor in the spinal cord were retrospec-tively analyzed and summarized. Most of these cases suffered from acute or subacute onset and exhibited a sensorimotor disorder. Among them, six cases were misdiagnosed as having intra-dullary gliomas, and inflammatory demyelinating pseudotumor was only identified and pathologi-cally confirmed after surgical resection. Lesions in the cervical and thoracic spinal cord were com-mon. Magnetic resonance imaging revealed edema and space-occupying lesions to varying grees at the cervical-thoracic junction, with a predominant feature of non-closed rosette-like forcement (open-loop sign). Pathological examination showed perivascular cuffing of predominantly dense lymphocytes, and demyelination was observed in six of the misdiagnosed cases. These re-sults suggest that tumor-like inflammatory demyelinating disease in the spinal cord is a kind of special demyelinating disease that can be categorized as inflammatory pseudotumor. These solitary lesions are easily confused with intramedullary neoplasms. Patchy or non-closed reinforcement (open-ring sign) on magnetic resonance imaging is the predominant property of inflammatory myelinating pseudotumor, and inflammatory cell infiltration and demyelination are additional pa-logical properties.
L. Visser (Lizette); L.A. Boven (Leonie); B.A. 't Hart (Bert); J.D. Laman (Jon); M.J. Melief (Marie-José); D.A.J. van Riel (Debby); M. van Meurs (Marjan); E.A. Sick (Ella); N. Inamura (Naoko); J.J. Bajramovic (Jeffrey); S. Amor (Sandra); R.Q. Hintzen (Rogier)
textabstractRecent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is
Full Text Available The spectrum of chronic dysimmune neuropathies has widened well beyond chronic demyelinating polyradiculoneuropathy (CIDP. Pure motor (multifocal motor neuropathy, sensorimotor with asymmetrical involvement (multifocal acquired demylinating sensory and motor neuropathy, exclusively distal sensory (distal acquired demyelinating sensory neuropathy and very proximal sensory (chronic immune sensory polyradiculopathy constitute the variants of CIDP. Correct diagnosis of these entities is of importance in terms of initiation of appropriate therapy as well as prognostication of these patients. The rates of detection of immune-mediated neuropathies with monoclonal cell proliferation (monoclonal gammopathy of unknown significance, multiple myeloma, etc. have been facilitated as better diagnostic tools such as serum immunofixation electrophoresis are being used more often. Immune neuropathies associated with malignancies and systemic vasculitic disorders are being defined further and treated early with better understanding of the disease processes. As this field of dysimmune neuropathies will evolve in the future, some of the curious aspects of the clinical presentations and response patterns to different immunosuppressants or immunomodulators will be further elucidated. This review also discusses representative case studies.
Wallner-Blazek, Mirja; Rovira, Alex; Fillipp, Massimo
Atypical lesions of a presumably idiopathic inflammatory demyelinating origin present quite variably and may pose diagnostic problems. The subsequent clinical course is also uncertain. We, therefore, wanted to clarify if atypical idiopathic inflammatory demyelinating lesions (AIIDLs) can...... and magnetic resonance imaging data and obtained follow-up (FU) information on 77 of these patients over a mean duration of 4 years. The AIIDLs presented as a single lesion in 72 (80 %) patients and exhibited an infiltrative (n = 35), megacystic (n = 16), Baló (n = 10) or ring-like (n = 16) lesion appearance...... in 77 (86 %) patients. Additional multiple sclerosis (MS)-typical lesions existed in 48 (53 %) patients. During FU, a further clinical attack occurred rarely (23-35 % of patients) except for patients with ring-like AIIDLs (62 %). Further attacks were also significantly more often in patients...
Kagiava, Alexia; Sargiannidou, Irene; Theophilidis, George; Karaiskos, Christos; Richter, Jan; Bashiardes, Stavros; Schiza, Natasa; Nearchou, Marianna; Christodoulou, Christina; Scherer, Steven S; Kleopa, Kleopas A
Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot-Marie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.
Ghezzi, Silvia; Cooper, Lynsay; Rubio, Alicia; Pagani, Isabel; Capobianchi, Maria Rosaria; Ippolito, Giuseppe; Pelletier, Julien; Meneghetti, Maria Cecilia Z; Lima, Marcelo A; Skidmore, Mark A; Broccoli, Vania; Yates, Edwin A; Vicenzi, Elisa
The recent Zika virus (ZIKV) outbreak, which mainly affected Brazil and neighbouring states, demonstrated the paucity of information concerning the epidemiology of several flaviruses, but also highlighted the lack of available agents with which to treat such emerging diseases. Here, we show that heparin, a widely used anticoagulant, while exerting a modest inhibitory effect on Zika Virus replication, fully prevents virus-induced cell death of human neural progenitor cells (NPCs). Copyright © 2017 Elsevier B.V. All rights reserved.
Yiu, Eppie M; Laughlin, Suzanne; Verhey, Leonard H; Banwell, Brenda L
Tumefactive demyelinating lesions can be difficult to distinguish from tumors. Clinical and magnetic resonance imaging features of children with tumefactive demyelination and supratentorial brain tumors were compared. Patients were identified through a 23-site national demyelinating disease study, and from a single-site neuroradiology database. For inclusion, lesions met at least 1 of 3 criteria: maximal cross-sectional diameter >20 mm, local or global cerebral mass effect, or presence of perilesional edema. Thirty-one children with tumefactive demyelination (5 with solitary lesions) were identified: 27 of 189 (14.3%) from the demyelinating disease study and 4 from the database. Thirty-three children with tumors were identified. Children with tumefactive demyelination were more likely to have an abnormal neurologic examination and polyfocal neurologic deficits compared to children with tumors. Tumefactive demyelination was distinguished from tumor by the presence of multiple lesions, absence of cortical involvement, and decrease in lesion size or detection of new lesions on serial imaging.
Lagumersindez-Denis, Nielsen; Wrzos, Claudia; Mack, Matthias; Winkler, Anne; van der Meer, Franziska; Reinert, Marie C; Hollasch, Heiko; Flach, Anne; Brühl, Hilke; Cullen, Eilish; Schlumbohm, Christina; Fuchs, Eberhard; Linington, Christopher; Barrantes-Freer, Alonso; Metz, Imke; Wegner, Christiane; Liebetanz, David; Prinz, Marco; Brück, Wolfgang; Stadelmann, Christine; Nessler, Stefan
Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2 + monocytes are required for both. Depleting CCR2 + monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2 + monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.
Anbarasan, Deepti; Campion, Gabriel; Campion, Paul; Howard, Jonathan
Not all patients referred for evaluation of multiple sclerosis (MS) meet criteria required for MS or related entities. Identification of markers to exclude demyelinating disease may help detect patients whose presenting symptoms are inconsistent with MS. In this study, we evaluate whether patients who present a self-prepared list of symptoms during an initial visit are less likely to have demyelinating disease and whether this action, which we term the "list sign," may help exclude demyelinating disease. Using chart review, 300 consecutive new patients who presented for evaluation to a neurologist at a tertiary MS referral center were identified retrospectively. Patients were defined as having demyelinating disease if diagnosed with MS or a related demyelinating condition. Of the 233 enrolled subjects, 157 were diagnosed with demyelinating disease and 74 did not meet criteria for demyelinating disease. Fifteen (8.4%) subjects had a positive list sign, of which 1 patient had demyelinating disease. The 15 subjects described a mean of 12.07 symptoms, and 8 of these patients met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for somatic symptom disorder. The specificity and positive predictive value of the list sign for non-demyelinating disease were 0.99 (95% confidence interval (CI) 0.96-0.99) and 0.93 (95% CI 0.66-0.99), respectively. A positive list sign may be useful to exclude demyelinating disease and to guide diagnostic evaluations for other conditions. Patients with a positive list sign also have a high incidence of somatic symptom disorder.
Full Text Available Objective : This is a retrospective chart review of consecutive children with acquired demyelinating disorders presenting to a north Indian tertiary care hospital over 4 years. The aim of this review is to describe all the patients (with single event as well as those with recurrences with detailed description of those who recurred. Materials and Methods: Overall 35 cases were reviewed and their clinical presentations, diagnosis, management, and follow-up are being presented. Results : Out of 35 cases, 24 did not show any recurrences (seven acute disseminated encephalomyelitis (ADEM and 17 clinically isolated syndromes. Amongst the 11 patients with recurrent demyelination, majority were multiple sclerosis (8/11, 72.7% followed by neuromyelitis optica (NMO; 2/11, and multiphasic ADEM (1/11. The median disease duration and follow-up since onset for those with recurrent episodes is 4 years (2.5-4.5 years. Steroids caused significant improvement in acute episodes of demyelination. However, recurrent demyelinating disorders like multiple sclerosis and NMO required long-term immunomodulation. Azathioprine currently is the most favored long-term immunomodulator used in NMO. Interferon-β and glatiramer acetate are currently recommended for multiple sclerosis. However, azathioprine may be a suitable alternative in a resource-limited setting. Conclusion : The consensus definitions for these groups of disorders need further validation in the pediatric age group. Studies with larger population size are required to characterize features that predict future recurrences.
Le Goffic, Ronan; Arshad, Muhammad Imran; Rauch, Michel; L'Helgoualc'h, Annie; Delmas, Bernard; Piquet-Pellorce, Claire; Samson, Michel
IL-33, a novel IL-1 family member, is crucially expressed and involved in pulmonary diseases, but its regulation in viral diseases such as influenza A virus (IAV) remains unclear. This study aimed to characterize the expression and release of IL-33 in lungs of IAV-infected mice in vivo and in murine respiratory epithelial cells (MLE-15) in vitro. Our results provide evidence of up-regulation of IL-33 mRNA in IAV-infected murine lungs, compared with noninfected control mice. The overexpression of IL-33 was positively correlated with a significant increase in mRNA encoding the proinflammatory cytokines TNF-α, IFN-γ, IL-1β, and IL-6, and was also associated with an increase in IFN-β mRNA. A profound overexpression of IL-33 protein was evident in IAV-infected murine lungs and bronchoalveolar lavages of influenza-infected mice, compared with low concentrations in naive lungs in vivo. Immunolocalization highlighted the cellular expression of IL-33 in alveolar epithelial and endothelial cells, along with increased infiltrate cells in virus-infected lungs. Further in vitro experiments showed an induction of IL-33 transcript-in MLE-15 cells and human epithelial cells (A549) infected with different strains of IAV in comparison with noninfected cells. In conclusion, our findings evidenced a profound expression of IL-33 in lungs during both in vivo and in vitro IAV infections, suggesting a role for IL-33 in virus-induced lung infections.
Full Text Available Chronic obstructive pulmonary disease (COPD is characterized by chronic airway inflammation and/or airflow limitation due to pulmonary emphysema. Chronic bronchitis, pulmonary emphysema, and bronchial asthma may all be associated with airflow limitation; therefore, exacerbation of asthma may be associated with the pathophysiology of COPD. Furthermore, recent studies have suggested that the exacerbation of asthma, namely virus-induced asthma, may be associated with a wide variety of respiratory viruses.COPD and asthma have different underlying pathophysiological processes and thus require individual therapies. Exacerbation of both COPD and asthma, which are basically defined and diagnosed by clinical symptoms, is associated with a rapid decline in lung function and increased mortality. Similar pathogens, including human rhinovirus, respiratory syncytial virus, influenza virus, parainfluenza virus and coronavirus, are also frequently detected during exacerbation of asthma and/or COPD. Immune response to respiratory viral infections, which may be related to the severity of exacerbation in each disease, varies in patients with both COPD and asthma. In this regard, it is crucial to recognize and understand both the similarities and differences of clinical features in patients with COPD and/or asthma associated with respiratory viral infections, especially in the exacerbative stage.In relation to definition, epidemiology, and pathophysiology, this review aims to summarize current knowledge concerning exacerbation of both COPD and asthma by focusing on the clinical significance of associated respiratory virus infections.
Wanscher, B.; Sørensen, P. S.; Juhler, M.
Experimental allergic encephalomyelitis, demyelination, inflammation, immunology, neuropathology......Experimental allergic encephalomyelitis, demyelination, inflammation, immunology, neuropathology...
Penkowa, Milena; Hidalgo, Juan
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...
Berg, Carsten Tue; Khorooshi, Reza; Asgari, Nasrin; Owens, Trevor
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. 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. Purified IgG2a monoclonal anti-MOG antibody and mouse complement were stereotactically injected into the corpus callosum of wild-type and type I IFN receptor deficient mice (IFNAR1-KO) with and without pre-established experimental autoimmune encephalomyelitis (EAE). Anti-MOG induced complement-dependent demyelination in the corpus callosum of wild-type mice and did not occur in mice that received control IgG2a. Deposition of activated complement coincided with demyelination, and this was significantly reduced in IFNAR1-KO mice. Co-injection of anti-MOG and complement at onset of symptoms of EAE induced similar levels of callosal demyelination in wild-type and IFNAR1-KO mice. 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.
Agildere, A.M.; Coskun, M.; Boyvat, F. [Baskent University Medical School Hospital, Radiology Department, Ankara (Turkey); Benli, S. [Baskent University Medical School Hospital, Neurology Department, Ankara (Turkey); Erten, Y.; Oezdemir, N. [Baskent University Medical School Hospital, Nephrology Department, Ankara (Turkey)
Neurological disorders may be seen in end-stage renal disease patients due to uraemia or to complications of dialysis. A dysequilibrium syndrome may be seen, usually soon after or towards the end of haemodialysis. This group of patients has no particular findings on MRI. On the other hand, the osmotic demyelination syndrome has definitive MRI findings, not to date reported with the dysequilibrium syndrome. We report a patient with end-stage renal disease and the dysequilibrium syndrome who showed findings of osmotic demyelination on MRI. The patient had a convulsion after a first haemodialysis, with quadriparesis and hyperactive deep tendon reflexes and bilateral Babinski signs. The upper motor neurone signs lasted for a week. Meanwhile, he was also dysarthric and had dysphagia. He recovered neurologically without any residuum following appropriate treatment and there was improvement on MRI. (orig.) With 3 figs., 11 refs.
T. E. Popova
Full Text Available Current article provides an overview of the results of epidemiological studies of chronic inflammatory demyelinating polyneuropathy (CIDP in Russia and abroad. It is shown that the prevalence of CIDP is different in countries, due to the use of different diagnostic criteria. It should be noted that the reliability of epidemiological prevalence and incidence is affected by difficulties of diagnosis of atypical forms of the disease.
Jeong, In Hye; Kim, Su-Hyun; Hyun, Jae-Won; Joung, AeRan; Cho, Hyo-Jin; Kim, Ho Jin
Tumefactive demyelinating lesions (TDLs) are associated with a variety of demyelinating diseases in the central nervous system (CNS). However, there are no current guidelines describing how to classify and treat patients with this rare phenotype. Thus, the present study aimed to determine the long-term evolution and disease course of patients initially presenting with TDLs and to describe their clinical and radiographic characteristics. From the National Cancer Center registry of inflammatory diseases of the CNS, 31 patients initially presenting with TDLs with follow-up for at least 12 months were enrolled and their demographic, clinical, and radiographic characteristics were evaluated. The median follow-up duration was 37.6 months, during which time 11 patients were diagnosed with neuromyelitis optica spectrum disorder (NMOSD), seven with multiple sclerosis (MS), and 11 remained idiopathic; six did not experience any further clinical events (isolated demyelinating syndrome), and five patients experienced recurrent demyelinating events that were not consistent with either MS or NMOSD. Of the remaining two patients, one was diagnosed with hyperthyroidism-associated demyelination and one with tacrolimus-induced demyelination. The majority of TDLs evolve into MS or NMOSD. However, despite extensive diagnostic work-ups and long-term follow-ups, the etiology of TDLs was unknown for some patients. Copyright © 2015 Elsevier B.V. All rights reserved.
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.
Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F; Cahalan, Michael D; Lane, Thomas E
Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. While a broad range of therapeutics effectively reduce the incidence of focal white matter inflammation and plaque formation for patients with relapse-remitting forms of MS, a challenge within the field is to develop therapies that allow for axonal protection and remyelination. In the last decade, growing interest has focused on utilizing neural precursor cells (NPCs) to promote remyelination. To understand how NPCs function in chronic demyelinating environments, several excellent pre-clinical mouse models have been developed. One well accepted model is infection of susceptible mice with neurotropic variants of mouse hepatitis virus (MHV) that undergo chronic demyelination exhibiting clinical and histopathologic similarities to MS patients. Combined with the possibility that an environmental agent such as a virus could trigger MS, the MHV model of demyelination presents a relevant mouse model to assess the therapeutic potential of NPCs transplanted into an environment in which inflammatory-mediated demyelination is established.
Sanvito, Lara; Constantinescu, Cris S; Gran, Bruno
Multiple Sclerosis (MS) is the most common autoimmune demyelinating disorder in Western countries and can lead to permanent disability. Over the past decades remarkable progress has been made in providing new therapeutic strategies to tackle the burden of the disease. Oral drugs and monoclonal antibodies are the main innovative approaches that have been tested in advanced stage clinical trials. Several new drugs have been shown to be superior to traditional disease modifying treatments (DMTs), in terms of both clinical and imaging outcome measures. Oral drugs have the advantage of offering a convenient route of administration. Recently fingolimod has received approval for the treatment of relapsing remitting (RR)-MS in several countries, becoming the first oral drug available to patients. Whilst the majority of the current studies focus on RR-MS, some trials investigate the primary or secondary progressive subtypes as well as the early forms of the disease aiming at delaying the conversion to clinically definite MS. Overall the future of the treatment options looks promising, although the occurrence of significant adverse events in some instances points to cautious evaluation of risks and benefits. Extension studies for most of the new drugs are under way and will provide evidence on the efficacy and long term effects of the new treatment strategies.
Algahtani, Hussein; Shirah, Bader; Alassiri, Ali
Tumefactive multiple sclerosis or tumefactive demyelinating lesion (TDL) is one of the rare variants of multiple sclerosis (MS) posing a diagnostic challenge and a therapeutic enigma since it is difficult to distinguish from a true central nervous system (CNS) neoplasm or other CNS lesions on magnetic resonance imaging (MRI). The prevalence of TDL is estimated to be 1-3/1000 cases of MS with an annual incidence of 0.3/100,000. This could be an underestimate due to unavailability of a global MS registry and under-reporting of this condition. TDL may occur at any age with the ages between the 20s and 30s being more frequently affected. The pathogenesis of TDL remains unknown, but some speculations have been made. These include the autoimmune theory based on the close relationship between TDLs and MS, Fingolimod use, Fingolimod cessation, and Natalizumab use. The clinical presentation of patients with TDL is variable and atypical for demyelinating disease due to the differences in size and location of the lesion. In this article, we aim to explore TDL comprehensively and provide an evidence-based approach for diagnosis and treatment. This will result in recommendations that may improve the diagnostic accuracy and treatment outcomes. Detailed history, physical examination, and several MRI imaging can spare patients the need for a brain biopsy. Treatment of acute lesions includes corticosteroids and plasma exchange therapy. When a diagnosis of relapsing-remitting MS is fulfilled, conventional first line MS disease modifying therapy should be used. Available recently published data suggests that Fingolimod should not be used in TDL patients, mainly due to the possibility of more than just a chance association between TDLs and initiation of Fingolimod. The use of several new MS disease modifying therapy for the management of TDL remains to be studied. Further well-conducted research including multi-center trials is needed to explain several ambiguous aspects related to
Ayyappan, Sujith; Day, Timothy; Kiers, Lynette
Paraneoplastic neuropathies are well recognized as a remote effect of cancer, and subacute sensory neuronopathy is a recognized syndrome. Demyelinating neuropathies are relatively rare. Distal acquired demyelinating symmetric (DADS) neuropathy associated with lymphoproliferative disease has been reported previously. We present the association of DADS neuropathy with solid tumor. We report the clinical presentation, electrophysiology, and progress of DADS neuropathy in a patient later found to have colorectal adenocarcinoma. A patient presented with subacute onset of symmetric distal sensory and motor symptoms. Electrophysiology was typical of DADS neuropathy. Anti-MAG antibodies were initially positive at low titer, and indirect immunofluorescence analysis for anti-nuclear antibodies revealed autoantibodies to centromere nuclear protein-F (CENP-F). There was clinical and electrophysiologic resolution after tumor resection. This case describes the presentation of DADS neuropathy as a paraneoplastic syndrome in a patient later found to have colorectal adenocarcinoma. © 2014 Wiley Periodicals, Inc.
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
Miyaji, Kazuki; Paul, Friedemann; Shahrizaila, Nortina; Umapathi, Thirugnanam; Yuki, Nobuhiro
Given their localization and important role in regulating complement, complement regulatory proteins may act as target antigens and their antibodies as biomarkers in demyelinating neuropathies. We investigated the binding of autoantibodies to complement regulatory proteins (CD46, 55 and 59) in demyelinating diseases. In 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy, 13 acute motor axonal neuropathy, 71 multiple sclerosis, and 19 neuromyelitis optica patients as well as 55 healthy controls, we were unable to detect significant titers of antibodies to CD46, CD55 and CD59. These autoantibodies are unlikely to be biomarkers in acute and chronic inflammatory demyelinating polyneuropathies. Copyright © 2014 Elsevier B.V. All rights reserved.
Stadelmann, Christine; Wegner, Christiane; Brück, Wolfgang
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system which responds to anti-inflammatory treatments in the early disease phase. However, the pathogenesis of the progressive disease phase is less well understood, and inflammatory as well as neurodegenerative mechanisms of tissue damage are currently being discussed. This review summarizes current knowledge on the interrelation between inflammation, demyelination, and neurodegeneration derived from the study of human autopsy and biopsy brain tissue and experimental models of MS. 2010 Elsevier B.V. All rights reserved.
Eftimov, Filip; Winer, John B.; Vermeulen, Marinus; de Haan, Rob; van Schaik, Ivo N.
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, developing over at least two months. Uncontrolled studies suggest that intravenous immunoglobulin (IVIg) helps. This review was first published in 2002 and has since
Eftimov, Filip; Winer, John B.; Vermeulen, Marinus; de Haan, Rob; van Schaik, Ivo N.
Background Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) causes progressive or relapsing weakness and numbness of the limbs, developing over at least two months. Uncontrolled studies suggest that intravenous immunoglobulin (IVIg) helps. Objectives To review systematically the
Grimm, Alexander; Heiling, Bianka; Schumacher, Ulrike; Witte, Otto W; Axer, Hubertus
Ultrasound can be used to visualize peripheral nerve abnormality. Our objective in this study was to prove whether nerve ultrasound can differentiate between axonal and demyelinating polyneuropathies (PNPs). Systematic ultrasound measurements of peripheral nerves were performed in 53 patients (25 with demyelinating, 20 with axonal, 8 with mixed neuropathy) and 8 healthy controls. Nerve conduction studies of corresponding nerves were undertaken. Analysis of variance revealed significant differences between the groups with regard to motor conduction velocity, compound muscle action potential amplitude, and cross-sectional area (CSA) of different nerves at different locations. Receiver operating characteristic curve analysis revealed CSA measurements to be well suited for detection of demyelinating neuropathies, and boundary values of peripheral nerve CSA could be defined. Systematic ultrasound CSA measurement in different nerves helped detect demyelination, which is an additional cue in the etiological diagnosis of PNP, along with nerve conduction studies and nerve biopsy. © 2014 Wiley Periodicals, Inc.
Full Text Available Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm.A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs. Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+ migrated away from this area as a function of time.Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis.
Itani, Farah R; Sinha, Sushmita; Brate, Ashley A; Pewe, Lecia L; Gibson-Corley, Katherine N; Harty, John T; Karandikar, Nitin J
CD8 T-cells predominate in CNS lesions of MS patients and display oligoclonal expansion. However, the role of myelin-specific CD8 T-cells in disease remains unclear, with studies showing protective and pathogenic roles in EAE. We demonstrated a disease-suppressive function for CNS-specific CD8 T-cells in a model where the antigen is exogenously administered in vivo and used for in vitro activation. To probe the nature of the CD8 response elicited by endogenously presented myelin antigens in vivo, we developed a novel approach utilizing infection with Listeria monocytogenes (LM) encoding proteolipid protein peptide (PLP) amino acids 178-191 (LM-PLP). LM-PLP infection preferentially induced PLP-specific CD8 T-cell responses. Despite the induction of PLP-specific CD8 T-cells, LM-PLP infection did not result in disease. In fact, LM-PLP infection resulted in significant amelioration of PLP178-191-induced EAE. Disease suppression was not observed in mice deficient in CD8 T-cells, IFN-γ or perforin. DTH responses and CNS infiltration were reduced in protected mice, and their CD4 T-cells had reduced capacity to induce tissue inflammation. Importantly, infection with LM-PLP ameliorated established disease. Our studies indicate that CD8 T-cells induced by endogenous presentation of PLP178-191 attenuate CNS autoimmunity in models of EAE, implicating the potential of this approach as a novel immunotherapeutic strategy.
Haider, Lukas; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang
Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645
Nutrigenomics is a relatively new branch of nutrition science, which aim is to study the impact of the foods we eat on the function of our genes. Hepatosteatosis is strongly associated with hepatitis C virus infection, which is known to increase the risk of the disease progression and reduce the likelihood of responding to anti- virus treatment. It is well documented that hepatitis C virus can directly alter host cell lipid metabolism through nuclear transcription factors. To date, only a limited number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis C virus -induced hepatosteatosis. Three nutrients, selected among 46 different nutrients: β-carotene, vitamin D2, and linoleic acid were found in a cell culture system to inhibit hepatitis C virus RNA replication. In addition, polyunsaturated fatty acids (PUFAs) especially arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) have been demonstrated to inhibit hepatitis C virus RNA replication. These PUFAs, in particular the highly unsaturated n-3 fatty acids change the gene expression of PPARa and SREBP, suppress the expression of mRNAs encoding key metabolic enzymes and hereby suppress hepatic lipogenesis and triglyceride synthesis, as well as secretion and accumulation in tissues. A recent prospective clinical trial of 1,084 chronic hepatitis C patients compared to 2,326 healthy subjects suggests that chronic hepatitis C patients may benefit from strict dietary instructions. Increasing evidence suggest that some crucial nuclear transcription factors related to hepatitis C virus -associated hepatosteatosis and hepatitis C virus RNA itself can be controlled by specific anti- hepatitis C virus nutrition. It seems important that these findings are taken into account and specific nutritional supplements developed to be used in combination with interferon as adjunctive therapy with the aim to improve both the early as well as the sustained
Liu, Qing; Bengmark, Stig; Qu, Shen
Nutrigenomics is a relatively new branch of nutrition science, which aim is to study the impact of the foods we eat on the function of our genes. Hepatosteatosis is strongly associated with hepatitis C virus infection, which is known to increase the risk of the disease progression and reduce the likelihood of responding to anti- virus treatment. It is well documented that hepatitis C virus can directly alter host cell lipid metabolism through nuclear transcription factors. To date, only a limited number of studies have been on the effect of human foods on the nuclear transcription factors of hepatitis C virus -induced hepatosteatosis.Three nutrients, selected among 46 different nutrients: beta-carotene, vitamin D2, and linoleic acid were found in a cell culture system to inhibit hepatitis C virus RNA replication. In addition, polyunsaturated fatty acids (PUFAs) especially arachidonic acid (AA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) have been demonstrated to inhibit hepatitis C virus RNA replication. These PUFAs, in particular the highly unsaturated n-3 fatty acids change the gene expression of PPARa and SREBP, suppress the expression of mRNAs encoding key metabolic enzymes and hereby suppress hepatic lipogenesis and triglyceride synthesis, as well as secretion and accumulation in tissues. A recent prospective clinical trial of 1,084 chronic hepatitis C patients compared to 2,326 healthy subjects suggests that chronic hepatitis C patients may benefit from strict dietary instructions.Increasing evidence suggest that some crucial nuclear transcription factors related to hepatitis C virus -associated hepatosteatosis and hepatitis C virus RNA itself can be controlled by specific anti- hepatitis C virus nutrition. It seems important that these findings are taken into account and specific nutritional supplements developed to be used in combination with interferon as adjunctive therapy with the aim to improve both the early as well as the sustained
Dong, Chaoling; Greathouse, Kelsey M; Beacham, Rebecca L; Palladino, Steven P; Helton, E Scott; Ubogu, Eroboghene E
The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2mg/kg FNCS1 peptide for 5days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25μM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of
Waldman, Amy T.; Gorman, Mark P.; Rensel, Mary R.; Austin, Tracy E.; Hertz, Deborah P.; Kuntz, Nancy L.
Demyelinating diseases are a group of autoimmune inflammatory disorders affecting the central nervous system in adults and children; however, the diagnosis, evaluation, and treatment of these disorders are primarily based on adult data. The purpose of this study was to assess the practice patterns of US physicians who specialize in treating acquired central nervous system demyelinating diseases in children and adolescents. The Delphi technique was used to identify areas of consensus in management and treatment. Forty-two experts in the field participated in the process. Intravenous methylprednisolone was the first-line treatment of choice for acute episodes of all forms of demyelinating disease; however, consensus was lacking regarding specific dose, treatment duration, and use of an oral taper. First-line disease-modifying therapies for pediatric multiple sclerosis were interferons and glatiramer acetate, chosen based on perceived efficacy and tolerability, respectively. Areas lacking agreement among the expert panel and requiring further research are identified. PMID:21518802
Waldman, Amy T; Gorman, Mark P; Rensel, Mary R; Austin, Tracy E; Hertz, Deborah P; Kuntz, Nancy L
Demyelinating diseases are a group of autoimmune inflammatory disorders affecting the central nervous system in adults and children; however, the diagnosis, evaluation, and treatment of these disorders are primarily based on adult data. The purpose of this study was to assess the practice patterns of US physicians who specialize in treating acquired central nervous system demyelinating diseases in children and adolescents. The Delphi technique was used to identify areas of consensus in management and treatment. Forty-two experts in the field participated in the process. Intravenous methylprednisolone was the first-line treatment of choice for acute episodes of all forms of demyelinating disease; however, consensus was lacking regarding specific dose, treatment duration, and use of an oral taper. First-line disease-modifying therapies for pediatric multiple sclerosis were interferons and glatiramer acetate, chosen based on perceived efficacy and tolerability, respectively. Areas lacking agreement among the expert panel and requiring further research are identified.
Várallyay, Eva; Giczey, Gábor; Burgyán, József
Powdery mildew is one of the most important cereal diseases worldwide. Genetic analysis has revealed that mutant alleles of the Mlo gene cause broad-spectrum resistance against this pathogen in barley. In this study, the possibility of inducing broad-spectrum powdery mildew resistance against this pathogen by RNAi of the barley Mlo ortholog in wheat was examined using virus-induced gene silencing (VIGS). A clear correlation was found between resistance and accumulation of Mlo-specific siRNAs, raising the possibility of designing powdery mildew resistance in wheat by RNA silencing using both transgenic and non-transgenic approaches.
Okazaki, Rentaro; Doi, Toru; Hayakawa, Kentaro; Morioka, Kazuhito; Imamura, Osamu; Takishima, Kunio; Hamanoue, Makoto; Sawada, Yasuhiro; Nagao, Motoshi; Tanaka, Sakae; Ogata, Toru
Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of
Elliott, Ruth; Li, Fan; Dragomir, Isabelle; Chua, Ming Ming W.; Gregory, Brian D.; Weiss, Susan R.
Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV-induced demyelination. Here, we detail the genes and pathways associated with MHV-induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection. PMID:24058676
Full Text Available Abstract Background Although neuropathic pain is frequently observed in demyelinating diseases such as Guillain-Barré syndrome and multiple sclerosis, the molecular basis for the relationship between demyelination and neuropathic pain behaviors is poorly understood. Previously, we found that lysophosphatidic acid receptor (LPA1 signaling initiates sciatic nerve injury-induced neuropathic pain and demyelination. Results In the present study, we have demonstrated that sciatic nerve injury induces marked demyelination accompanied by myelin-associated glycoprotein (MAG down-regulation and damage of Schwann cell partitioning of C-fiber-containing Remak bundles in the sciatic nerve and dorsal root, but not in the spinal nerve. Demyelination, MAG down-regulation and Remak bundle damage in the dorsal root were abolished in LPA1 receptor-deficient (Lpar1-/- mice, but these alterations were not observed in sciatic nerve. However, LPA-induced demyelination in ex vivo experiments was observed in the sciatic nerve, spinal nerve and dorsal root, all which express LPA1 transcript and protein. Nerve injury-induced dorsal root demyelination was markedly attenuated in mice heterozygous for autotaxin (atx+/-, which converts lysophosphatidylcholine (LPC to LPA. Although the addition of LPC to ex vivo cultures of dorsal root fibers in the presence of recombinant ATX caused potent demyelination, it had no significant effect in the absence of ATX. On the other hand, intrathecal injection of LPC caused potent dorsal root demyelination, which was markedly attenuated or abolished in atx+/- or Lpar1-/- mice. Conclusions These results suggest that LPA, which is converted from LPC by ATX, activates LPA1 receptors and induces dorsal root demyelination following nerve injury, which causes neuropathic pain.
Marques, Wilson; Funayama, Carolina A R; Secchin, Juliana B; Lourenço, Charles M; Gouvêa, Silmara P; Marques, Vanessa D; Bastos, Patricia G; Barreira, Amilton A
We report an 18-month-old Charcot-Marie-Tooth type 1A (CMT1A) patient who developed a rapid-onset neuropathy, with proximal and distal weakness, and non-uniform nerve conduction studies. The neuropathy responded well to immunomodulation, confirming the coexistence of an inherited and an inflammatory neuropathy. Unexpected clinical and/or electrophysiological manifestations in CMT1A patients should alert clinicians to concomitant inflammatory neuropathy. In addition, this association raises reflections about disease mechanism in CMT1A.
Graham, Kareem L; Zabel, Brian A; Loghavi, Sanam; Zuniga, Luis A; Ho, Peggy P; Sobel, Raymond A; Butcher, Eugene C
We examined the involvement of chemokine-like receptor-1 (CMKLR1) in experimental autoimmune encephalomyelitis (EAE), a model of human multiple sclerosis. Upon EAE induction by active immunization with myelin oligodendrocyte glycoprotein amino acids 35-55 (MOG(35-55)), microglial cells and CNS-infiltrating myeloid dendritic cells expressed CMKLR1, as determined by flow cytometric analysis. In addition, chemerin, a natural ligand for CMKLR1, was up-regulated in the CNS of mice with EAE. We found that CMKLR1-deficient (CMKLR1 knockout (KO)) mice develop less severe clinical and histologic disease than their wild-type (WT) counterparts. CMKLR1 KO lymphocytes proliferate and produce proinflammatory cytokines in vitro, yet MOG(35-55)-reactive CMKLR1 KO lymphocytes are deficient in their ability to induce EAE by adoptive transfer to WT or CMKLR1 KO recipients. Moreover, CMKLR1 KO recipients fail to fully support EAE induction by transferred MOG-reactive WT lymphocytes. The results imply involvement of CMKLR1 in both the induction and effector phases of disease. We conclude that CMKLR1 participates in the inflammatory mechanisms of EAE and represents a potential therapeutic target in multiple sclerosis.
Wu, Qian; Chen, Bo; Liu, Na; Hu, Yang; Pan, Chao; Zhang, Ping; Tang, Zhou-Ping; Bu, Bi-Tao
Inflammatory demyelinating disease of central nervous system (CNS) is an inflammatory disease characterized by a high childbearing female predominance. Labor-related alterations for postpartum demyelinating attacks are not entirely clear. This study aimed to summarize clinical features of female patients of reproductive age with initial CNS inflammatory demyelinating attacks during puerperium. Fourteen female patients with initial demyelinating events during puerperium between January 2013 and December 2016 were retrospectively studied. Records of clinical features, neuroimaging, serum antibodies, cerebrospinal fluid (CSF) findings, annualized relapse rate (ARR), and treatment were analyzed. Among 14 patients, 5 patients were diagnosed with multiple sclerosis (MS), four as neuromyelitis optica (NMO), two as longitudinal extensive transverse myelitis, two as clinical isolated syndrome (CIS), and one as acute brainstem syndrome. All the 14 puerperal female patients presented with more than one manifestation of hemiplegia, paraplegia, uroschesis, visual loss or dysarthria, and with mild to moderate abnormalities of CSF. Attacks occurred during the first trimester postpartum and cesarean section was the main delivery way (n = 10). Median Expanded Disability Status Scale (EDSS) scores were 5.0 (range: 2.0-9.0) at the onset and 2.5 (range: 0-7.0) at the end of follow-ups. Patients with MS and CIS had a significantly lower EDSS scores than patients with NMO spectrum disorders (P demyelinating diseases of central nervous system.
Kollar, Jozsef E-mail: email@example.com; Peter, Mozes; Fuelesdi, Bela; Sikula, Judit
Neuroimaging of a 75-year-old lady demonstrated the characteristic pathological features of the Marchiafava-Bignami disease (MBD), which develops usually in chronic alcoholics. The onset of the neurological symptoms and signs were abrupt and similar to those seen in common ischemic vascular lesions. Our patient denied that she had consumed alcoholic beverage during her life. Laboratory results showed her liver enzymes were not elevated and a subsequent abdominal ultrasound examination revealed no liver pathology. The attack responded fairly well to anti-ischemic therapy and a complete recovery was observed within a week. In this sense, her pathology cannot be considered as a true MBD in spite of the presence of the CT and MRI findings of MBD. Our case seems to show that the CT and MRI findings in MBD are not specific because new imaging procedures reveal edematous, necrotic lesions that may have the appearance of MBD.
Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P
To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.
Spanier, Justin A; Nashold, Faye E; Mayne, Christopher G; Nelson, Corwin D; Hayes, Colleen E
Multiple sclerosis (MS) is a neurodegenerative disease resulting from an autoimmune attack on the axon-myelin unit. A female MS bias becomes evident after puberty and female incidence has tripled in the last half-century, implicating a female sex hormone interacting with a modifiable environmental factor. These aspects of MS suggest that many female MS cases may be preventable. Mechanistic knowledge of this hormone-environment interaction is needed to devise strategies to reduce female MS risk. We previously demonstrated that vitamin D3 (D3) deficiency increases and D3 supplementation decreases experimental autoimmune encephalomyelitis (EAE) risk in a female-biased manner. We also showed that D3 acts in an estrogen (E2)-dependent manner, since ovariectomy eliminated and E2 restored D3-mediated EAE protection. Here we probed the hypothesis that E2 and D3 interact synergistically within CD4(+) T cells to control T cell fate and prevent demyelinating disease. The E2 increased EAE resistance in wild-type (WT) but not T-Vdr(0) mice lacking Vdr gene function in CD4(+) T cells, so E2 action depended entirely on Vdr(+)CD4(+) T cells. The E2 levels were higher in WT than T-Vdr(0) mice, suggesting the Vdr(+)CD4(+) T cells produced E2 or stimulated its production. The E2 decreased Cyp24a1 and increased Vdr transcripts in T cells, prolonging the calcitriol half-life and increasing calcitriol responsiveness. The E2 also increased CD4(+)Helios(+)FoxP3(+) T regulatory (Treg) cells in a Vdr-dependent manner. Thus, CD4(+) T cells have a cooperative amplification loop involving E2 and calcitriol that promotes CD4(+)Helios(+)FoxP3(+) Treg cell development and is disrupted when the D3 pathway is impaired. The global decline in population D3 status may be undermining a similar cooperative E2-D3 interaction controlling Treg cell differentiation in women, causing a breakdown in T cell self tolerance and a rise in MS incidence. Copyright © 2015 Elsevier B.V. All rights reserved.
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
Chamberlain, Kelly A; Chapey, Kristen S; Nanescu, Sonia E; Huang, Jeffrey K
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
Full Text Available Chronic hepatitis C is characterized by metabolic disorders and a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that lead in the long term to hepatocellular carcinoma. Many lines of evidence suggest that mitochondrial dysfunctions, including modification of metabolic fluxes, generation and elimination of oxidative stress, Ca2+ signaling and apoptosis, play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV proteins localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory, probably due to the use of artificial expression and replication systems. In vivo studies are hampered by the fact that innate and adaptive immune responses will overlay mitochondrial dysfunctions induced directly in the hepatocyte by HCV. Thus, the molecular aspects underlying HCV-induced mitochondrial dysfunctions and their roles in viral replication and the associated pathology need yet to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems.
Tanaka, Tatsuhide; Murakami, Koichi; Bando, Yoshio; Yoshida, Shigetaka
Remyelination is disrupted in demyelinating diseases such as multiple sclerosis, but the underlying pathogenetic mechanisms are unclear. In this study, we employed the murine cuprizone model of demyelination, in which remyelination occurs after removal of the toxin from the diet, to examine the cellular and molecular changes during demyelination and remyelination. Microglia accumulated in the corpus callosum during weeks 2-4 of the cuprizone diet, and these cells remained activated 2 weeks after the change to the normal diet. To examine the role of microglia in remyelination, mice were treated with minocycline to inactivate these cells after cuprizone-induced demyelination. Minocycline treatment reduced the number of CC1-positive oligodendrocytes, as well as levels of myelin basic protein (MBP) and CNPase in the remyelination phase. The expression of CNTF mRNA in the corpus callosum increased after 4 weeks on the cuprizone diet and remained high 2 weeks after the change to the normal diet. Minocycline suppressed CNTF expression during the remyelination phase on the normal diet. Primary culture experiments showed that CNTF was produced by microglia in addition to astrocytes. In vitro, CNTF directly affected the differentiation of oligodendrocytic cells. These findings suggest that minocycline reduces remyelination by suppressing CNTF expression by microglia after cuprizone-induced demyelination. © 2013 International Society for Neurochemistry.
Smits, Ron; Ikenaka, Kazuhiro
Oligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) demyelinating-mouse model of MS, inflammatory microglia produce cytokines, including interleukin-1β (IL-1β). Since microglia and noncanonical Wnt signaling components in neurons, such as the coreceptor Ror2, were observed in the spinal cords of mice with EAE (EAE mice), we postulated that the interplay between activated microglia and spinal neurons under EAE conditions is mediated through noncanonical Wnt signaling. EAE treatment upregulated in vivo expression of noncanonical Wnt signaling components in spinal neurons through microglial activation. In accordance with the neuronal degeneration detected in the EAE spinal cord in vivo, coculture of spinal neurons with microglia or the application of recombinant IL-1β upregulated noncanonical Wnt signaling and induced neuron death, which was suppressed by the inhibition of the Wnt-Ror2 pathway. Ectopic noncanonical Wnt signaling aggravated the demyelinating pathology in another MS mouse model due to Wnt5a-induced neurodegeneration. The linkage between activated microglia and neuronal Wnt-Ror2 signaling may provide a candidate target for therapeutic approaches to demyelinating disorders. PMID:27550808
Shimizu, Takeshi; Smits, Ron; Ikenaka, Kazuhiro
Oligodendrocytes are myelinating cells of the central nervous system. Multiple sclerosis (MS) is a demyelinating disease characterized by both myelin loss and neuronal degeneration. However, the molecular mechanisms underlying neuronal degeneration in demyelinating disorders are not fully understood. In the experimental autoimmune encephalomyelitis (EAE) demyelinating mouse model of MS, inflammatory microglia produce cytokines including interleukin-1β (IL-1β). Since microglia and non-canonical Wnt signaling components in neurons, such as the co-receptor Ror2, were observed in the spinal cord of EAE mice, we postulated that the interplay between activated microglia and spinal neurons under EAE conditions is mediated through non-canonical Wnt signaling. EAE treatment up-regulated in vivo expression of non-canonical Wnt signaling components in spinal neurons through microglial activation. In accordance with the neuronal degeneration detected in the EAE spinal cord in vivo, co-culture of spinal neurons with microglia or the application of recombinant IL-1β up-regulated non-canonical Wnt signaling, and induced neuronal cell death, which was suppressed by the inhibition of the Wnt-Ror2 pathway. Ectopic non-canonical Wnt signaling aggravated the demyelinating pathology in another MS mouse model due to Wnt5a-induced neurodegeneration. The linkage between activated microglia and neuronal Wnt-Ror2 signaling may provide a possible candidate target for therapeutic approaches to demyelinating disorders. Copyright © 2016, American Society for Microbiology. All Rights Reserved.
Full Text Available Differentiating hereditary motor sensory neuropathy (HMSN from chronic inflammatory demyelinating polyneuropathy (CIDP is often difficult especially when the disease starts at an early age and has protracted course. This study compares the clinical, electro, physiological and histopathological features of hereditary and acquired chronic demyelinating neuropathies. Records of 26 patients of chronic demyelinating neuropathy who underwent sural nerve biopsy were reviewed; HMSN 9, CIDP 13, chronic relapsing demyelinating polyneuropathy (CRDP-4, Salient features of the HMSN group were: Consanguineous parentage-4, onset in first decade-9, skeletal markers-7, absence of positive sensory symptoms- 7 and clinically thickened nerves-6. None of the patients with acquired neuropathy had skeletal markers, 11 had positive sensory symptoms and only 4 had nerve thickening. Electrophysiological evaluation in 22 motor nerves in the HMSN group revealed: inexcitable nerves -13, prolonged distal latency - 6, slow conduction velocity-8 and prolonged f wave latency-3. The 44 motor nerves in patients with acquired neuropathy showed: inexcitable nerves- 7, prolonged distal latency-35, slow conduction velocity-34, f wave prolongation-30 and conduction block 9. Elevated CSF protein was noticed only in acquired group (77%. Pathologically in HMSN the fibre loss was always diffuse and onion bulb formation was frequent while endoneural edema and inflammatory infiltration were absent in this group. Selection of patients with chronic demyelinating neuropathies for therapeutic modulation needs comprehensive clinical and laboratory evaluation.
Neuropathol Exp Neurol 65:245-256. Arnett HA, Fancy SP, Alberta JA, Zhao C, Plant SR, Kaing S, Raine CS, Rowitch DH, Franklin RJ, Stiles CD (2004...multiple sclerosis (MS) and control cases. Chapter 3 – Figure 1 – Detection of hPDGF-A trangene in cuprizone demyelinated corpus callosum. 109 Chapter
Gilhuis, H.J.; Schelhaas, H.J.; Cruysberg, J.R.M.; Zwarts, M.J.
We report a patient with Leber hereditary optic neuropathy (G11778A mtDNA) and a severe demyelinating neuropathy, for which no other cause except his mitochondrial disorder could be found. The involvement of the peripheral nervous system of patients with LHON, in particular with a 11778 mtDNA, is
Ketelslegers, I A; Catsman-Berrevoets, C E; Neuteboom, R F; Boon, M; van Dijk, K G J; Eikelenboom, M J; Gooskens, R H J M; Niks, E H; Overweg-Plandsoen, W C G; Peeters, E A J; Peeters-Scholte, C M P C D; Poll-The, B T; de Rijk-van Andel, J F; Samijn, J P A; Snoeck, I N; Stroink, H; Vermeulen, R J; Verrips, A; Vles, J S H; Willemsen, M A A P; Rodrigues Pereira, R; Hintzen, R Q
Acquired demyelinating syndromes (ADS) can be a first presentation of multiple sclerosis (MS) in children. The incidence of these disorders in Europe is currently unknown. Children (autoimmune diseases were reported in 23%, more often in patients with relapsing disease than monophasic disease (46 vs. 15%, p = 0.002) and occurring most often in the maternal family (84%, p disease onset of ADS was most common.
Armstrong, R.; Friedrich, V.L. Jr.; Holmes, K.V.; Dubois-Dalcq, M. (National Institute of Neurological Disorders and Stroke, Bethesda, MD (USA))
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.
of Guillain -Barr6 syndrome , absence of BZLF1 transcription. The absence of both 450 acute demyelinating encephalitis, transverse myelitis, and and...43 W 1,904 nd CVID/IVIG GCV Improved 28 Guillain -Barr1 M 55 W 2,000 nd A NONE ACV Stable EBV = Epstein- Barr virus; CSF = cerebrospinal fluid; CNSL... Guillain -Barr6 syndrome , acute demy- 6 - elinating encephalitis, polyradiculomyelitis, or trans- verse myelitis (see Table). T -CSF examinations showed
Sher, Falak; van Dam, Go; Boddeke, Erik; Copray, Sjef
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
K. Kuitwaard (Krista); P.A. van Doorn (Pieter); M. Vermeulen (Marinus); L.H. van den Berg (Leonard); E. Brusse (Esther); A.J. Kooj (Anneke); W.L. van der Pol (Ludo); I.N. van Schaik (Ivo); N.C. Notermans (Nicolette); A.P. Tio-Gillen (Anne); W. van Rijs (Wouter); T. van Gelder (Teun); B.C. Jacobs (Bart)
textabstractObjective: To determine the variability of serum IgG in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: All 25 CIDP patients had active but stable disease and were treated with individually optimised fixed dose IVIg regimens. IgG was measured by
MacNeill, A L; Moldenhauer, T; Doty, R; Mann, T
There is growing interest in utilizing replicating oncolytic viruses as cancer therapeutics agents. The effectiveness of myxoma virus-induced oncolysis was evaluated in two feline cancer cell cultures. Although myxoma virus is a rabbit-specific pathogen, protein expression driven by myxoma virus and production of infectious viral particles were detected. Cell death occurred in primary feline cancer cells within 48 h of inoculation with myxoma virus. Future studies to determine if other feline neoplasms are susceptible to myxoma virus infection are warranted. Copyright © 2011 Elsevier Ltd. All rights reserved.
Full Text Available Chronic inflammatory demyelinating polyneuropathy (CIDP in children is a rare autoimmune disease of the peripheral nervous system. The article analyzes current international diagnostic criteria and clinical presentation features of the disease in childhood. The article discusses general principles of CIDP treatment and focuses on the pathogenetic therapies: intravenous immunotherapy using a standard human immunoglobulin (IVIG with the content of IgG > 95%, prescription of large doses of glucocorticoids and plasmapheresis. It analyzes the recommendations for prioritizing the use of different types of treatment when initiating the therapy and describes the main drug prescription protocols and recommended doses. Two clinical cases of CIDP in children are described. It is shown that the use of adequate doses of IVIG, glucocorticoids and long-term maintenance treatment can completely reverse the symptoms of peripheral lesion, prevent repeated exacerbations of the disease and significantly improve the quality of life.
Abdoli, Mohammad; Freedman, Mark S
Tumefactive demyelinating lesions (TDLs) are not an uncommon manifestation of demyelinating disease but can pose diagnostic challenges in patients without a pre-existing diagnosis of multiple sclerosis (MS) as well as in known MS patients. Brain tumours can also arise in MS patients and can be seen in chronic MS patients as co-morbidities. Delayed diagnosis or unnecessary intervention or treatment will affect the ultimate prognosis of these patients. In this article, we will review some typical cases illustrating the dilemma and review the information that helps to differentiate the two conditions. The intention is not to present an extensive differential diagnosis of both entities, but to examine some typical examples when the decision arises to decide between the two. We take a somewhat different approach, by presenting the cases in "real time", allowing the readers to consider in their own minds which diagnosis they favour, discussing in detail some of the pertinent literature, then revealing later the actual diagnosis. We would urge readers to consider re-visiting their first thoughts about each case after reading the discussion, before reading the follow-up of each case. The overall objective is to highlight the real possibility of being forced to decide between these two entities in clinical practise, present a reasonable approach to help differentiate them and especially to focus on the possibility of TDLs in order to avoid unnecessary biopsy. Copyright © 2015 Elsevier B.V. All rights reserved.
Dalakas, Marinos C
The main chronic autoimmune neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and anti-myelin-associated glycoprotein (MAG) demyelinating neuropathy. On the basis of randomized controlled studies, corticosteroids, intravenous immunoglobulin (IVIg), and plasmapheresis provide short-term benefits in CIDP. MMN responds only to IVIg. Because in MMN and CIDP, IVIg infusions are required every 3-6 weeks to sustain benefits or long-term remissions, there is a need for "IVIg-sparing" agents. In CIDP, immunosuppressive drugs, such as azathioprine, cyclosporine, methotrexate, mycophenolate, and cyclophosphamide, are used, but controlled trials have not shown that they are effective. Controlled trials have also not shown benefit to any agents in anti-MAG neuropathy. However, clinicians use many immunosuppressive drugs in both settings, but all have potentially serious side effects and are only effective in some patients. Thus, there is a need for new therapies in the inflammatory and paraproteinemic neuropathies. New agents targeting T cells, B cells, and transmigration and transduction molecules are discussed as potential treatment options for new trials. The need for biomarkers that predict therapeutic responses or identify patients with active disease is emphasized, and the search for better scoring tools that capture meaningful changes after response to therapies is highlighted. © 2012 Peripheral Nerve Society.
Chronic inflammatory demyelinating polyradiculoneuropathy in chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation: case report Polirradiculoneuropatia desmielinizante inflamatória crônica na doença do enxerto contra o hospedeiro após transplante de células hematopoiéticas alogênicas: relato de caso
Paulo José Lorenzoni
Full Text Available The chronic inflammatory demyelinating polyradiculoneuropathy (CIDP is an unusual but important complication of hematopoietic stem cell transplantation (HSCT rarely reported to date. We describe a 17-year-old woman with a diagnosis of acute myeloid leukemia due to Fanconi's anemia who was submitted to allogeneic HSCT and developed CIDP as part of graft-versus-host disease. Investigation showed high cerebrospinal fluid protein; electrophysiological studies revealed sensory-motor demyelinating polyradiculoneuropathy; muscle and nerve biopsy were compatible with CIDP.A polirradiculoneuropatia desmielinizante inflamatória crônica (CIDP é uma incomum, porém, importante complicação do transplante de células hematopoiéticas (HSCT raramente relatada até a data. Nós descrevemos uma mulher de 17 anos com diagnóstico de leucemia mielóide aguda por anemia de Fanconi que foi submetida à HSCT e desenvolveu CIDP como parte da doença do enxerto contra o hospedeiro. A investigação mostrou elevação na proteína no líquor; estudo eletrofisiológico revelando polirradiculoneuropatia desmielinizante sensitivo-motora; e biópsia de músculo e nervo compatível com CIDP.
Zaidman, Craig M.; Harms, Matthew B.; Pestronk, Alan
Introduction We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. Methods We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited (Charcot-Marie Tooth-1 (CMT-1) (n=35)) and acquired (Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (n=55), Guillaine-Barre Syndrome (GBS) (n=21) and Multifocal Motor Neuropathy (MMN) (n=17)) demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none- no enlargement; mild-nerves enlarged but never more than twice normal; regional- nerves normal at at least one region and enlarged more than twice normal at atleast one region; diffuse- nerves enlarged at all four regions with atleast one region more than twice normal size. Results Nerve enlargement was commonly diffuse (89%) and generally more than twice normal size in CMT-1, but not (pdemyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. PMID:24101129
Full Text Available Demyelinating diseases consist of a variety of autoimmune conditions in which the myelin sheath is damaged due to genetic and/or environmental factors. During clinical treatment, some patients undergo partial remyelination, especially during the early disease stages. However, the mechanisms that regulate demyelination remain unclear. The myelin structure, myelin formation and myelin-related gene expression are highly conserved between mammals and zebrafish. Therefore, the zebrafish is an ideal model organism to study myelination. In this study, we generated a transgenic zebrafish Tg(mbp:nfsB-egfp expressing a fusion protein composed of enhanced green fluorescent protein (EGFP and NTR from the myelin basic protein (mbp promoter. Tg(mbp:nfsB-egfp expressed NTR-EGFP reproducibly and hereditarily in oligodendrocytes along the spinal cord. Treatment of zebrafish larvae Tg(mbp:nfsB-egfp with metronidazole (Mtz resulted in the selective ablation of oligodendrocytes and led to demyelination, accompanied by behavioral changes, including decreased total movement distance, velocity, total movement time and fast movement time. After withdrawal of Mtz for a seven day recovery period, the expression of EGFP and MBP protein was observed again which indicates remyelination. Additionally, locomotor capacity was restored. Collectively, Tg(mbp:nfsB-egfp, a heritable and stable transgenic line, provides a novel, powerful tool to study the mechanisms of demyelination and remyelination.
de Sèze, J; Kremer, L; Alves do Rego, C; Taleb, O; Lam, D; Beiano, W; Mensah-Nyagan, G; Trifilieff, E; Brun, S
Animal models are fundamental to advance knowledge of disease pathogenesis and to test/develop new therapeutic strategies. Most of the current knowledge about the pathogenic mechanisms underpinning autoimmune demyelination processes implicating autoantigens has been obtained using the Experimental Autoimmune Neuritis (EAN) animal model. The most widely used EAN model is obtained by active immunization of Lewis rats using a peptide, P0 (180-199), issuing from the major peripheral nervous system myelin protein. But this model mimics only the classical monophasic acute form of demyelinating polyradiculoneuropathy, i.e. Guillain-Barré syndrome (GBS). We developed a new model by immunizing Lewis rats using the same immunodominant neuritogenic peptide P0 (180-199) but this time with its S-palmitoyl derivative, S-palm P0 (180-199). All of the animals immunized with the S-palm P0 (180-199) peptide developed a chronic relapsing-remitting form of the disease corresponding to the electrophysiological criteria of demyelination (slow sensory nerve conduction velocity, prolonged motor nerve latency, partial motor nerve conduction blocks) with axon degeneration. These findings were confirmed by immunohistopathology study and thus, appear to mimic human chronic inflammatory demyelinating polyradiculopathy (CIDP). This new model opens up new avenues of research for testing new anti-inflammatory and neuroprotective therapeutic strategies. Copyright Â© 2016 Elsevier Masson SAS. All rights reserved.
Stathopoulos, Panos; Alexopoulos, Harry; Dalakas, Marinos C
Mounting evidence suggests that autoantibodies contribute to the pathogenesis of demyelination in the PNS and CNS. Rapid reversal of electrophysiological blockade after plasmapheresis or intravenous immunoglobulin treatment for acute or chronic inflammatory demyelinating polyneuropathy is more likely to result from removal or neutralization of an antibody that impairs saltatory conduction than from remyelination. Although up to 30% of patients with acute or chronic inflammatory demyelinating polyneuropathy harbour autoantibodies, specific antigens have been identified in no more than 13% of cases. To date, autoantigens identified at the node of Ranvier include neurofascin 186, gliomedin and possibly moesin in the nodal domain, and contactin-1, Caspr1 and neurofascin 155 in the paranodal domain. In some patients with multiple sclerosis, paranodal CNPase and juxtaparanodal contactin-2 trigger a humoral response. This Review explores the molecular anatomy of the node of Ranvier, focusing on proteins with extracellular domains that could serve as antigens. The clinical implications of node-specific antibody responses are addressed, and the best approaches to identify antibodies that target nodal proteins are highlighted. Also discussed are the roles of these antibodies as either secondary, disease-exacerbating responses, or as a primary effector mechanism that defines demyelination or axonal degeneration at the node, identifies disease subtypes or determines response to treatments.
Koshihara, Hiroshi; Oguchi, Kenya; Takei, Yo-ichi; Kitazawa, Kazuo; Higuchi, Kayoko; Ohara, Shinji
Acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) are both CNS inflammatory demyelinating diseases with overlapping clinical features. A case is reported of a 51-year-old female who presented with headache, progressive aphasia and hemiparesis without preceding infection or vaccination. Brain MRI revealed multiple, often confluent, subcortical white matter lesions without enhancement, affecting predominantly the left cerebral hemisphere. CSF examination failed to reveal oligoclonal bands. Brain biopsy revealed both pathological features of ADEM and findings are consistent with the early stage of MS, including meningeal B and T lymphocytic infiltration, perivenular demyelination, subpial demyelination and discrete confluent plaque-like foci of demyelination. Steroid treatment resulted in remarkable clinical and radiological improvement and there has been no recurrence in six years of follow-up. This case highlights the difficulties in differentiating between ADEM and the first attack of MS and further suggests that ADEM and the early stage of MS, and its tumefactive variant, may have a common underlying pathologic mechanism, which may have a therapeutic implication in treating these diseases. Copyright © 2014 Elsevier B.V. All rights reserved.
Increased severity of experimental autoimmune encephalomyelitis, chronic macrophage/microglial reactivity, and demyelination in transgenic mice producing tumor necrosis factor-alpha in the central nervous system
Taupin, V; Renno, T; Bourbonnière, L
Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine implicated in a number of autoimmune diseases. Apoptotic cell death is induced by TNF-alpha in vitro, and has been suggested as one cause of autoimmune pathology, including autoimmune demyelinating diseases where oligodendrocytes...... and showed no spontaneous pathology, but they developed experimental autoimmune encephalomyelitis (EAE) with greater severity than nontransgenic controls when immunized with MBP in adjuvant. Unlike nontransgenic controls, EAE then progressed to a nonabating demyelinating disease. Macrophage....../microglial reactivity was evident in demyelinating lesions in spinal cord, but T cells were not detected during chronic disease. The participation of TNF-alpha in the demyelinating process is thus more probably due to the perpetuation of macrophage/microglial activation than to direct cytotoxicity of myelin...
... autosomal recessive Genetic Testing Registry: Charcot-Marie-Tooth disease, demyelinating, type 1b Genetic Testing Registry: Charcot-Marie-Tooth disease, demyelinating, type 1d Genetic Testing Registry: Charcot-Marie-Tooth ...
Saroja, Aralikatte O; Naik, Karkal R; Mali, Rajendra V; Kunam, Sanjeeva R
Osmotic demyelination syndrome resulting from postpartum hypernatremia is a recently described entity wherein young women present with hypernatremic encephalopathy and white matter hyperintensities...
Facchini, Maria Cristina; O'Dowd, Colin; Danovaro, Roberto
The processes that link phytoplankton biomass and productivity to the organic matter enrichment in sea spray aerosol are far from being understood and modelling predictions remain highly uncertain at the moment. While some studies have asserted that the enrichment of OM in sea spray aerosol is independent on marine productivity, others, on the contrary, have shown significant correlation with phytoplankton biomass and productivity (Chl-a retrieved by satellites). Here we show that viral infection of prokaryotes and phytoplankton, by inducing the release of large quantities of surfaceactive organic matter (cell debris, exudates and other colloidal gel-forming material), in part due to cell lysis and plankton defence reactions, and in part from rapid virus multiplication, triggers the organic matter (OM) enrichment in the sea-spray particles during blooms. We show that virus-induced bloom dynamics may explain the contrasting results present in literature on the link between primary productivity and OM sea spray enrichment.
Vanderver, Adeline; Hussey, Heather; Schmidt, Johanna L; Pastor, William; Hoffman, Heather J
Epidemiologic frequencies of pediatric white matter disorders as a class have not been well defined. This is particularly true of genetic disorders of the white matter of the brain. In this study, ICD-9 codes were used to estimate relative incidence rates and descriptive statistics of leukodystrophies, other genetic leukoencephalopathies and acquired demyelinating disease among children residing in the Washington, D.C. metropolitan area. Children being treated at US children's hospitals between January 1, 2004, and December 31, 2009, for acquired demyelinating disease or genetic white matter disorders were captured using the Pediatric Health Information System and the Physician Practice Management system and validated with local electronic medical records. Comparisons were made between genetic white matter disorders and acquired demyelinating disorders, to determine differences in incidence, age, gender, ethnicity, and mortality. Genetic causes of white matter disease identified with ICD-9 codes had an estimated incidence of 1.2/100,000 children in the Washington, DC area. What was of interest was nearly 5 out of 10 cases of pediatric white matter disease of any etiology were attributable to genetic causes. When only progressive white matter diseases were considered, 7 out of 10 cases were attributable to genetic causes, and only 3 out of 10 to progressive acquired demyelinating disease such as multiple sclerosis. These findings signify the important contribution of heritable white matter disorders to pediatric neurologic disease in the Washington, DC, metro area as well as throughout the United States. Continued research of these understudied disorders should compare disease incidence and determinants to validate these findings in different populations. Published by Elsevier Inc.
Hamada, Mustafa S; Popovic, Marko A; Kole, Maarten H P
In cortical pyramidal neurons the presynaptic terminals controlling transmitter release are located along unmyelinated axon collaterals, far from the original action potential (AP) initiation site, the axon initial segment (AIS). Once initiated, APs will need to reliably propagate over long distances and regions of geometrical inhomogeneity like branch points (BPs) to rapidly depolarize the presynaptic terminals and confer temporally precise synaptic transmission. While axon pathologies such as demyelinating diseases are well established to impede the fidelity of AP propagation along internodes, to which extent myelin loss affects propagation along BPs and axon collaterals is not well understood. Here, using the cuprizone demyelination model, we performed optical voltage-sensitive dye (VSD) imaging from control and demyelinated layer 5 pyramidal neuron axons. In the main axon, we find that myelin loss switches the modality of AP propagation from rapid saltation towards a slow continuous wave. The duration of single AP waveforms at BPs or nodes was, however, only slightly briefer. In contrast, by using two-photon microscopy-guided loose-seal patch recordings from axon collaterals we revealed a presynaptic AP broadening in combination with a reduced velocity and frequency-dependent failure. Finally, internodal myelin loss was also associated with de novo sprouting of axon collaterals starting from the primary (demyelinated) axon. Thus, the loss of oligodendrocytes and myelin sheaths bears functional consequences beyond the main axon, impeding the temporal fidelity of presynaptic APs and affecting the functional and structural organization of synaptic connectivity within the neocortex.
Stephanova, D I; Krustev, S M; Daskalova, M
To expand our studies on the mechanisms underlying the clinical decline of the nerve excitability properties in patients with hereditary demyelinating neuropathies, the contribution of myelin sheath aqueous layers on multiple membrane properties of simulated fiber demyelinations is investigated. Three progressively greater degrees of internodal systematic demyelinations (two mild and one severe termed as ISD1, ISD2 and ISD3, respectively) without/with aqueous layers are simulated using our previous multi-layered model of human motor nerve fiber. The calculated multiple membrane excitability properties are as follows: potentials (intracellular action, electrotonic), strength-duration time constants, rheobasic currents and recovery cycles. They reflect the propagating, accommodative and adaptive processes in the fibers. The results show that all membrane properties, except for the strength-duration time constants and refractoriness, worsen when the myelin lamellae and their corresponding aqueous layers are uniformly reduced along the fiber length. The effect of the aqueous layers is significantly higher on the accommodative and adaptive processes than on the propagating processes in the fibers. Our multi-layered model better approximated some of the functional deficits documented for axons of patients with Charcot-Marie-Tooth disease type 1A. The study provides new and important information on the mechanisms underlying the pathophysiology of hereditary demyelinating neuropathies. © Imperial College Press
Shah, Akshay; Rison, Richard A; Beydoun, Said R
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive demyelinating neuropathy, which typically presents with proximal and distal neuropathic symptoms and is typically responsive to immunomodulatory therapies. Many variants have been subsequently described in the literature and have similarly shown to be responsive to immunotherapy. We present a case of a 43-year-old Middle Eastern/Arabic man presenting with symptoms of mixed sensorimotor neuropathy most evident at entrapment sites mimicking hereditary neuropathy with liability to pressure palsies. His electrodiagnostic study revealed features of acquired demyelinating neuropathy and a negative genetic workup. Alternative diagnosis of CIDP was considered in the context of symptomatic disease progression, negative genetic workup, and electrodiagnosis leading to initiation of immunotherapy with intravenous immunoglobulins. His neuropathy responded confirming our diagnosis of an inflammatory demyelinating polyneuropathy. We describe a previously unknown variant of CIDP with phenotypic characteristics of hereditary neuropathy with liability to pressure palsies and its potential for successful treatment with intravenous immunoglobulins. This case illustrates an unusual presentation of CIDP mimicking hereditary neuropathy with liability to pressure palsies.
Full Text Available Collagenous colitis (CC is a form of microscopic colitis characterized by the presence of inflammatory infiltrate and subepithelial deposition of collagen in the colon and it is a rare condition with a predominant prevalence in the adult population. Only few cases have been reported in children. We report two children with the CC with concomitant neurological manifestations. Both cases demonstrated variable neurological symptoms clinically and significant cerebral demyelination. In both patients, the gastrointestinal manifestations drastically improved with a short course of prednisolone. However, the neurological symptoms were persistent and progressive. To the best of our knowledge, similar association has not been reported in children.
Full Text Available Multiple Sclerosis (MS is a demyelinating autoimmune disease of the central nervous system (CNS with a presumed autoimmune etiology. Approved treatments for MS are immunoregulatory and are able to reduce the inflammatory components of the disease. However, these treatments do not suppress progressive clinical disability. Approaches that directly protect myelin-producing oligodendrocytes and enhance remyelination are likely to improve long-term outcomes and reduce the rate of axonal damage. Galanin (GAL is a bioactive neuropeptide that is widely distributed throughout the nervous system and has diverse neuromodulatory effects. In this study, using the cuprizone (CPZ demyelination model of MS, we demonstrate that GAL has pronounced neuroprotective effects with respect to demyelination and remyelination. Using our GAL transgenic mouse (GAL-Tg, we identified a novel attenuation of OLs against CPZ induced demyelination, which was exerted independently of progenitor cells. Alleviation of myelin breakdown in the GAL-Tg mice was observed to be significant. Furthermore, we observed changes in the expression of the GAL receptor GalR1 during the demyelination and remyelination processes. Our data strongly indicate that GAL has the capacity to influence the outcome of primary insults that directly target OLs, as opposed to cases where immune activation is the primary pathogenic event. Taken together, these results suggest that GAL is a promising next-generation target for the treatment of MS.
Valenzise, Mariella; Meloni, Antonella; Betterle, Corrado; Giometto, Bruno; Autunno, Massimo; Mazzeo, Anna; Cao, Antonio; De Luca, Filippo
We describe two unrelated boys with autoimmune poly-endocrine-candidiasis-ectodermal dystrophy syndrome (APECED) who, in addition to manifesting the most common symptoms (chronic mucocutaneous candidiasis, hypoparathyroidism and Addison's disease), developed progressive muscular weakness in both the proximal and distal limbs, sensory loss and absent tendon reflexes. Electrophysiological studies disclosed a reduction of nerve conduction velocity in both patients that was consistent with the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP).This diagnosis was supported by histological demyelination in nerve biopsy specimens with patchy CD4, CD8 and CD68-positive cell infiltration in the first patient and increased protein content in the cerebrospinal fluid in the second patient. Our cases represent the first report of an association between APECED and CIDP, in which peripheral nerve demyelination may represent a novel disease component in APECED. Our findings highlight the need to explore apparently rare manifestations in patients with APECED.
Shakhbazau, Antos; Schenk, Geert J; Hay, Curtis; Kawasoe, Jean; Klaver, Roel; Yong, V Wee; Geurts, Jeroen J G; van Minnen, Jan
Glial cells were previously proven capable of trafficking polyribosomes to injured axons. However, the occurrence of such transfer in the general pathological context, such as demyelination-related diseases, needs further evidence. Since this may be a yet unidentified universal contributor to axonal survival, we study putative glia-axonal ribosome transport in response to demyelination in animal models and patients in both peripheral and central nervous system. In the PNS we investigate whether demyelination in a rodent model has the potential to induce ribosome transfer. We also probe the glia-axonal ribosome supply by implantation of transgenic Schwann cells engineered to produce fluorescent ribosomes in the same demyelination model. We furthermore examine the presence of axonal ribosomes in mouse experimental autoimmune encephalomyelitis (EAE), a well-established model for multiple sclerosis (MS), and in human MS autopsy brain material. We provide evidence for increased axonal ribosome content in a pharmacologically demyelinated sciatic nerve, and demonstrate that at least part of these ribosomes originate in the transgenic Schwann cells. In the CNS one of the hallmarks of MS is demyelination, which is associated with severe disruption of oligodendrocyte-axon interaction. Here, we provide evidence that axons from spinal cords of EAE mice, and in the MS human brain contain an elevated amount of axonal ribosomes compared to controls. Our data provide evidence that increased axonal ribosome content in pathological axons is at least partly due to glia-to-axon transfer of ribosomes, and that demyelination in the PNS and in the CNS is one of the triggers capable to initiate this process.
Piñeyro, Pablo; Sponenberg, D Philip; Pancotto, Theresa; King, Rosalind H M; Jortner, Bernard S
Chronic inflammatory demyelinating polyradiculoneuropathy occurred in an 11-year-old Labrador Retriever dog. Spinal cord compression resulted from massive radiculitis with prominent cholesterol granulomas. Cholesterol deposition and associated granuloma formation is unique in chronic inflammatory demyelinating polyradiculoneuropathy, in both its human and canine expressions. © 2015 The Author(s).
Remington, Leah T; Babcock, Alicia A; Zehntner, Simone P
antigen-presenting cells in vitro. T cells were recruited to the demyelinated corpus callosum but did not appear to be activated. Our study highlights the role of microglia as a heterogeneous population of cells in primary demyelination, with the capacity to present antigen, proliferate, and migrate...
Kanbayashi, Takamichi; Sonoo, Masahiro
Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by an insidious onset showing progression over two months. However, up to 16% of CIDP patients may show acute presentation similar to Guillain-Barré syndrome (GBS). Such cases are termed acute-onset CIDP (A-CIDP). Distinguishing A-CIDP from GBS, especially the acute inflammatory demyelinating polyneuropathy (AIDP) subtype, is critical because therapeutic strategies and outcomes may differ between the two syndromes. Regarding clinical features, A-CIDP is less likely to have autonomic nervous system involvement, facial weakness, a preceding infectious illness, or the need for mechanical ventilation, in comparison with AIDP. Electrophysiological features are usually quite similar between the two, although follow-up studies may elucidate key differences. Around 8%-16% of GBS patients may show clinical deterioration shortly after improvement or stabilization following initial immunological therapy. Such a situation is termed treatment-related fluctuation (TRF; GBS-TRF). The distinction between GBS-TRF and A-CIDP is an important clinical issue because maintenance treatment is often required in CIDP. The diagnosis of A-CIDP should be considered when the condition of a patient with GBS deteriorates after nine weeks from onset, or when deterioration occurs three times or more.
Thawani, Sujata P; Tanji, Kurenai; De Sousa, Eduardo A; Weimer, Louis H; Brannagan, Thomas H
Bortezomib is a proteasome inhibitor that is frequently used for multiple myeloma and lymphoma. A sensory predominant axonal neuropathy is associated with bortezomib treatment but a demyelinating neuropathy is also described primarily based on electrodiagnostic findings. We report a series of patients treated with bortezomib who developed peripheral neuropathy and were found to have demyelinating features on electrodiagnostic testing. Four patients who developed a bortezomib-induced peripheral neuropathy underwent electrophysiological testing, and 1 patient had a nerve biopsy. The four patients with bortezomib-induced peripheral neuropathy had demyelinating features on their electrophysiological testing. The nerve biopsy performed in 1 patient demonstrated a demyelinating component in a background of axonal degeneration. Although most toxic neuropathies are symmetrical axonal neuropathies, bortezomib is part of a small list of agents that may cause a demyelinating polyneuropathy and axonal degeneration. These findings have been confirmed by nerve biopsy.
Lombardo, M C; Barresi, R; Bilotta, E; Gargano, F; Pantano, P; Sammartino, M
In this paper we derive a reaction-diffusion-chemotaxis model for the dynamics of multiple sclerosis. We focus on the early inflammatory phase of the disease characterized by activated local microglia, with the recruitment of a systemically activated immune response, and by oligodendrocyte apoptosis. The model consists of three equations describing the evolution of macrophages, cytokine and apoptotic oligodendrocytes. The main driving mechanism is the chemotactic motion of macrophages in response to a chemical gradient provided by the cytokines. Our model generalizes the system proposed by Calvez and Khonsari (Math Comput Model 47(7-8):726-742, 2008) and Khonsari and Calvez (PLos ONE 2(1):e150, 2007) to describe Baló's sclerosis, a rare and aggressive form of multiple sclerosis. We use a combination of analytical and numerical approaches to show the formation of different demyelinating patterns. In particular, a Turing instability analysis demonstrates the existence of a threshold value for the chemotactic coefficient above which stationary structures develop. In the case of subcritical transition to the patterned state, the numerical investigations performed on a 1-dimensional domain show the existence, far from the bifurcation, of complex spatio-temporal dynamics coexisting with the Turing pattern. On a 2-dimensional domain the proposed model supports the emergence of different demyelination patterns: localized areas of apoptotic oligodendrocytes, which closely fit existing MRI findings on the active MS lesion during acute relapses; concentric rings, typical of Baló's sclerosis; small clusters of activated microglia in absence of oligodendrocytes apoptosis, observed in the pathology of preactive lesions.
Meng, Lan-Huan; Wang, Rui-Heng; Zhu, Ben-Zhong; Zhu, Hong-Liang; Luo, Yun-Bo; Fu, Da-Qi
Solanum rostratum is a “super weed” that grows fast, is widespread, and produces the toxin solanine, which is harmful to both humans and other animals. To our knowledge, no study has focused on its molecular biology owing to the lack of available transgenic methods and sequence information for S. rostratum. Virus-induced gene silencing (VIGS) is a powerful tool for the study of gene function in plants; therefore, in the present study, we aimed to establish tobacco rattle virus (TRV)-derived VIGS in S. rostratum. The genes for phytoene desaturase (PDS) and Chlorophyll H subunit (ChlH) of magnesium protoporphyrin chelatase were cloned from S. rostratum and used as reporters of gene silencing. It was shown that high-efficiency VIGS can be achieved in the leaves, flowers, and fruit of S. rostratum. Moreover, based on our comparison of three different types of infection methods, true leaf infection was found to be more efficient than cotyledon and sprout infiltration in long-term VIGS in multiple plant organs. In conclusion, the VIGS technology and tomato genomic sequences can be used in the future to study gene function in S. rostratum. PMID:27258320
Full Text Available Solanum rostratum is a "super weed" that grows fast, is widespread, and produces the toxin solanine, which is harmful to both humans and other animals. To our knowledge, no study has focused on its molecular biology owing to the lack of available transgenic methods and sequence information for S. rostratum. Virus-induced gene silencing (VIGS is a powerful tool for the study of gene function in plants; therefore, in the present study, we aimed to establish tobacco rattle virus (TRV-derived VIGS in S. rostratum. The genes for phytoene desaturase (PDS and Chlorophyll H subunit (ChlH of magnesium protoporphyrin chelatase were cloned from S. rostratum and used as reporters of gene silencing. It was shown that high-efficiency VIGS can be achieved in the leaves, flowers, and fruit of S. rostratum. Moreover, based on our comparison of three different types of infection methods, true leaf infection was found to be more efficient than cotyledon and sprout infiltration in long-term VIGS in multiple plant organs. In conclusion, the VIGS technology and tomato genomic sequences can be used in the future to study gene function in S. rostratum.
Lebrun, Christine; Cohen, Mikael; Pignolet, Beatrice; Seitz-Polski, Barbara; Bucciarelli, Florence; Benzaken, Sylvia; Kantarci, Orhun; Siva, Aksel; Okuda, Darin; Pelletier, Daniel; Brassat, David
Radiologically isolated syndrome (RIS) is a sub clinical demyelinating neurological disorder and to date no biomarker that triggers the seminal event has been identified. As for multiple sclerosis (MS), disease activity and clinical course are unpredictable. In MS, exploratory studies reported increased IL-17 levels in CSF but results in detecting IL-17 in serum at different stage of the disease are controversial. We investigate levels of IL-17 in serum and CSF in patients diagnosed at different stages of demyelinating diseases (RIS, CIS, relapsing remitting (RR) or active multiple sclerosis patients:AMS) as a marker of inflammatory condition. 1417 sera has been tested for IL-17A (1177 from active MS, 80 RRMS, 35 RIS, 35 CIS, 10 IIH: idiopathic intracranial hypertension, and 80 controls) and 240 CSF from RIS, CIS, IIH and controls. No difference has been found between RIS who early clinically converted and CIS patients who rapidly evolve in McDonald or clinically definite MS, nor active MS. No correlation was found with usual MRI or CSF criteria. Our results do not confirm that IL-17 can be considerate as a reliable marker of inflammation in the demyelinating spectrum disorders, either in blood or CSF. Copyright © 2016 Elsevier B.V. All rights reserved.
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)
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.
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.
Cao, Yiming; Menon, Parvathi; Ching-Fen Chang, Florence; Mahant, Neil; Geevasinga, Nimeshan; Fung, Victor S C; Vucic, Steve
Chronic inflammatory demyelinating polyneuropathy (CIDP) typically presents with a combination of sensory and motor impairments. Tremor is recognized as a common and debilitating feature in CIDP, although the underlying mechanisms are unclear. Clinical tremor severity and disability scores were collected prospectively in 25 CIDP patients and compared with 22 neuromuscular controls. Postural and kinetic tremor were significantly more frequent in CIDP patients (80%) than in neuromuscular controls (35%; P Tremor severity and tremor-related disability were also significantly greater in CIDP patients than in controls. Accelerometry data confirmed the presence of a 5.5 Hz postural tremor and a 5 Hz kinetic tremor. Tremor appears to be a common clinical feature of CIDP that results in significant disability. Sensory and motor impairment may be associated with development of tremor in CIDP. Muscle Nerve 55: 338-343, 2017. © 2016 Wiley Periodicals, Inc.
Sherafat, Mohammad Amin; Javan, Mohammad; Mozafari, Sabah; Mirnajafi-Zadeh, Javad; Motamedi, Fereshteh
Multiple sclerosis (MS) is a demyelinating disease that affects the central nervous system. MS is the most common neurological disorder in young adults with a greater incidence among females. Male gonadal hormones have a protective effect on neural system development and myelin maturation. In this study, we investigate the effect of castration on lysolecithin-induced demyelination and remyelination processes using visual evoked potentials, in addition to measuring the expressions of Olig2, MBP, Nogo-A and GFAP mRNAs as oligodendrocyte or astrocyte markers; and histological assessments by myelin-specific staining. We observed more expanded demyelination with delayed repair process in castrated rats. Expression levels of the aforementioned marker genes confirmed histological and electrophysiological observations. Our results showed a pivotal role for endogenous male hormones in the context of demyelinating insults. It may also account for the different prognosis of MS between male and female genders and provide new insights for therapeutic treatments.
Cerina, Manuela; Narayanan, Venu; Göbel, Kerstin; Bittner, Stefan; Ruck, Tobias; Meuth, Patrick; Herrmann, Alexander M; Stangel, Martin; Gudi, Viktoria; Skripuletz, Thomas; Daldrup, Thiemo; Wiendl, Heinz; Seidenbecher, Thomas; Ehling, Petra; Kleinschnitz, Christoph; Pape, Hans-Christian; Budde, Thomas; Meuth, Sven G
Myelin loss is a severe pathological hallmark common to a number of neurodegenerative diseases, including multiple sclerosis (MS). Demyelination in the central nervous system appears in the form of lesions affecting both white and gray matter structures. The functional consequences of demyelination on neuronal network and brain function are not well understood. Current therapeutic strategies for ameliorating the course of such diseases usually focus on promoting remyelination, but the effectiveness of these approaches strongly depends on the timing in relation to the disease state. In this study, we sought to characterize the time course of sensory and behavioral alterations induced by de- and remyelination to establish a rational for the use of remyelination strategies. By taking advantage of animal models of general and focal demyelination, we tested the consequences of myelin loss on the functionality of the auditory thalamocortical system: a well-studied neuronal network consisting of both white and gray matter regions. We found that general demyelination was associated with a permanent loss of the tonotopic cortical organization in vivo, and the inability to induce tone-frequency-dependent conditioned behaviors, a status persisting after remyelination. Targeted, focal lysolecithin-induced lesions in the white matter fiber tract, but not in the gray matter regions of cortex, were fully reversible at the morphological, functional and behavioral level. These findings indicate that remyelination of white and gray matter lesions have a different functional regeneration potential, with the white matter being able to regain full functionality while cortical gray matter lesions suffer from permanently altered network function. Therefore therapeutic interventions aiming for remyelination have to consider both region- and time-dependent strategies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Full Text Available Demyelinating pseudotumors are rare, benign, solitary intracranial space occupying lesions which masquerade cerebral neoplasms. Contrast MRI shows open ring enhancement which is fairly specific for this entity. Advanced MRI techniques like MR spectroscopy and magnetizing transfer techniques can help differentiating these lesions. NAA/Cr ratio is significantly elevated in central regions of demyelinating pseudotumors than in gliomas and other lesions. Presence of abundant foamy macrophages, lymphoid inflammatory infiltrates around blood vessels, sheets of gemistocytic astrocytes with well-developed processes, well defined border of the lesion absence of neovascularity and necrosis should help us diagnose demyelinating pseudotumor fairly confidently on histopathology.
Low, Choon Kuang, E-mail: firstname.lastname@example.org [Singapore General Hospital, Department of Diagnostic Radiology, Outram Road, Singapore 169608 (Singapore); Lim, Winston E.H.; Rumpel, Helmut [Singapore General Hospital, Department of Diagnostic Radiology, Outram Road, Singapore 169608 (Singapore)
Background: A tumefactive demyelinating lesion (TDL) often masquerades as a brain tumour and poses a diagnostic dilemma which may result in unnecessary surgery in some rare cases. This case emphasizes the need for caution when confronted with a patient whose differential diagnosis is between TDL and neoplasm. Summary of report: A 31-year-old woman was diagnosed as having a brain neoplasm. She was referred to our institution for further diagnostic imaging and treatment. Structural and physiologic scan were performed and these findings suggested a TDL rather than a neoplasm. Stereotactic biopsy of the lesion showed findings in keeping with demyelinating disease. The patient received steroid treatment, and showed improvement. Conclusion: The utility of the physiologic technique with structural scan may lead to an increased accuracy in differentiating TDL from neoplasm.
Full Text Available Asthma inception is associated with respiratory viral infection, especially infection with respiratory syncytial virus (RSV and/or human rhinovirus (HRV, in the vast majority of cases. However, the reason why RSV and HRV induce the majority of bronchiolitis cases during early childhood and why only a small percentage of children with RSV- and HRV-induced bronchiolitis later develop asthma remains unclear. A genetic association study has revealed the important interaction between viral illness and genetic variants in patients with asthma. Severe RSV- and HRV-induced bronchiolitis may be associated with a deficiency in the innate immune response to RSV and HRV. RSV and HRV infections in infants with deficient innate immune response and the dysfunction of regulatory T cells are considered to be a risk factor for the development of asthma. Sensitization to aeroallergens, beginning in the first year of life, consistently predisposes children to HRV-induced wheezing illnesses, but the converse is not true. Some evidence of virus specificity exists, in that allergic sensitization specifically increased the risk of wheezing in individuals infected with HRV, but not RSV. Administration of Palivizumab, a humanized monoclonal antibody that targets the A antigenic site of the Fusion-protein of RSV, decreases the risk of hospitalization in high-risk infants and the risk of recurrent of wheezing. However, palivizumab did not have any effect on subsequent recurrent wheezing in children with a family history of atopy. These findings suggest that infection with RSV and infection with HRV might predispose individuals to recurrent wheezing through an atopy-independent and an atopy-dependent mechanism, respectively. Respiratory virus-induced wheezing illnesses may encompass multiple sub-phenotypes that relate to asthma in different ways.
Zhang, Jing; Zhang, Zheng Gang; Li, Yi; Lu, Mei; Zhang, Yi; Elias, Stanton B; Chopp, Michael
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). No effective remyelination therapies are in use. We hypothesized that thymosin beta4 (Tβ4) is an effective remyelination treatment by promoting differentiation of oligodendrocyte progenitor cells (OPCs), and that the epidermal growth factor receptor (EGFR) signaling pathway contributes to this process. Two demyelination animal models were employed in this study: 1) experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE mice were treated daily for 30days, with Tβ4 or saline treatment initiated on the day of EAE onset; and 2) cuprizone diet model, a non-inflammatory demyelination model. The mice were treated daily for 4weeks with Tβ4 or saline after fed a cuprizone diet for 5weeks. Immunofluorescent staining and Western blot were performed to measure the differentiation of OPCs, myelin and axons, respectively. To obtain insight into mechanisms of action, the expression and activation of the EGFR pathway was measured. AG1478, an EGFR inhibitor, was employed in a loss-of-function study. Data revealed that animals in both demyelination models exhibited significant reduction of myelin basic protein (MBP(+)) levels and CNPase(+) oligodendrocytes. Treatment of EAE mice with Tβ4 significantly improved neurological outcome. Double immunofluorescent staining showed that Tβ4 significantly increased the number of newly generated oligodendrocytes identified by BrdU(+)/CNPase(+) cells and MBP(+) mature oligodendrocytes, and reduced axonal damage in the EAE mice compared with the saline treatment. The newly generated mature oligodendrocytes remyelinated axons, and the increased mature oligodendrocytes significantly correlated with functional improvement (r=0.73, pdemyelination model, Tβ4 treatment was confirmed that significantly increased OPC differentiation and remyelination, and increased the expression of EGFR and activated the EGFR pathway in the demyelinating
Full Text Available Tangier disease is a rare metabolic disorder that causes neuropathy in half of the affected individuals. We present the clinical, electrophysiological, and histopathological findings in a middle-aged gentleman of Tangier disease who was initially diagnosed as leprosy and treated with antileprosy drugs. The presence of a demyelinating electrophysiology in a patient with predominant upper limb involvement and facial diplegia should raise the suspicion of Tangier disease. Estimation of serum lipids should form a part of routine evaluation in order to avoid misdiagnosis.
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.
Wouda, W; van Nes, J J
A clinicopathological study of a neurologic disease in Rottweiler dogs was conducted. Clinical data were available on 16 dogs, 11 of which were examined pathologically. All dogs had a history of progressive gait abnormalities, which had commenced insidiously at an age varying from 1.5 to 3.5 years. In most dogs the fore limbs were affected prior to the hind limbs. At neurologic examination ataxia of all 4 limbs was seen, in some instances accompanied by an apparent paresis. Proprioceptive positioning was delayed whereas spinal reflexes were often hyperactive. Plain and contrast radiographs of the spine did not reveal any compressive lesions in 5 dogs examined. Cerebrospinal fluid analysis in 4 dogs was normal. Electrodiagnostic testing in 3 dogs revealed no abnormalities. At pathologic examination demyelinating lesions were found in the central nervous system. These were largely confined to the cervical spinal cord and brain stem and had a rather characteristic more or less symmetric distribution. Pedigree data suggested that the disease is transmitted genetically.
Mathey, Emily K; Park, Susanna B; Hughes, Richard A C; Pollard, John D; Armati, Patricia J; Barnett, Michael H; Taylor, Bruce V; Dyck, P James B; Kiernan, Matthew C; Lin, Cindy S-Y
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. PMID:25677463
Peltier, Amanda C.; Donofrio, Peter D.
Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is the most common treatable chronic autoimmune neuropathy. Multiple diagnostic criteria have been established, with the primary goal of identifying neurophysiologic hallmarks of acquired demyelination. Treatment modalities have expanded to include numerous immuno-modulatory therapies, although the best evidence continues to be for corticosteroids, plasma exchange, and intravenous immunoglobulins (IVIg). This review describes the pathology, epidemiology, pathogenesis, diagnosis, and treatment of CIDP. PMID:23117943
Somani S K
Full Text Available We report a case of Acute inflammatory demyelinating polyradiculo neuropathy (AIDP, following infectious mononucleosis. A 12 year old girl presented with acute flaccid quadriplegia with bilateral cervical lymphadenopathy and enlarged tonsils six weeks after a febrile illness. Cerebrospinal fluid revealed albuminocytological dissociation and electrophysiology showed evidence of axonal-demyelinating polyradiculoneuropathy. Heterophile antibody test was positive and lymph node biopsy showed non -specific reactive hyperplasia. She was managed conservatively with good outcome.
Ressonância magnética e características clínicas em adultos com doenças desmielinizantes monofásicas: encefalomielite aguda disseminada ou uma variante da esclerose múltipla? Magnetic resonance imaging and clinical features in adults with monophasic demyelinating diseases: acute disseminated encephalomyelitis or a variant of multiple sclerosis?
Full Text Available A encefalomielite aguda disseminada (ADEM é doença monofásica inflamatória difusa do sistema nervoso central, que geralmente ocorre após infecção ou vacinação. Neste estudo, apresentamos a análise da ressonância magnética (RM, líquor e aspectos clínicos de quatro pacientes com diagnóstico presuntivo inicial de ADEM. O achado de lesões desmielinizantes na RM foi importante, mas não por si só suficiente para o diagnóstico definitivo. O seguimento clínico e realização de RM de controle, para excluir o aparecimento de novas lesões e reavaliar as anteriores, assim como as análises liquóricas, foram importantes para o diagnóstico diferencial com outras doenças desmielinizantes, particularmente a esclerose múltipla. Além disso, mostramos que a introdução precoce de metilprednisolona foi eficaz tanto para a melhora do quadro clínico quanto para redução ou desaparecimento das lesões na RM.Acute disseminated encephalomyelitis (ADEM is a widespread monophasic inflamatory disease affecting the central nervous system, that usually follows an infection or vaccination. In this study, we present an analysis of magnetic resonance imaging (MRI, cerebrospinal fluid (CSF and clinical aspects in four patients with clinical diagnosis of ADEM. The presence of MRI demyelinating lesions was crucial, but not in itself sufficient for definitive diagnosis. Clinical and MRI follow up, in order to exclude new lesions and to reevaluate the former ones, as well as CSF, were important for the differential diagnosis with other demyelinating diseases, particularly multiple sclerosis. In addition, we have shown that early treatment with methylprednisolone after the initial symptoms was effective for improving clinical manifestations as well as for reducing MRI lesions.
Lopergolo, Diego; Isak, Baris; Gabriele, Maria; Onesti, Emanuela; Ceccanti, Marco; Capua, Gelsomina; Fionda, Laura; Biasiotta, Antonella; Di Stefano, Giulia; La Cesa, Silvia; Frasca, Vittorio; Inghilleri, Maurizio
To investigate the cutaneous silent period (CSP), a spinal inhibitory reflex mainly mediated by A-delta fibres, in demyelinating and axonal polyneuropathy (PNP) and evaluate whether CSP parameters differ between patients with and without neuropathic pain. Eighty-four patients with demyelinating PNP, 178 patients with axonal PNP and 265 controls underwent clinical examination, DN4 questionnaire, standard nerve conduction study, motor-root stimulation and CSP recordings from abductor digiti minimi. We calculated the afferent conduction time of CSP (a-CSP time) with the formula: CSP latency-root motor evoked potential latency. In the demyelinating PNP group the a-CSP time was significantly longer; in the axonal PNP group, CSP duration was shorter than the demyelinating group (p=0.010) and controls (p=0.001). CSP parameters were not different between patients with and without neuropathic pain. The abnormality of a-CSP time in the demyelinating PNP group suggests the crucial role of A-delta fibres in the mechanism of CSP; the shorter CSP duration in the axonal PNP group supports the strong influence of the number of axons on this parameter. Our study suggests that neuropathic pain could be related to pathophysiological mechanisms differing from mere A-delta fibre loss. CSP evaluation is effective in detecting A-delta fibre dysfunction in axonal as well as demyelinating PNP. Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Mariotto, Sara; Ferrari, Sergio; Monaco, Salvatore
Chronic infection with hepatitis C virus (HCV) is associated with a large spectrum of extrahepatic manifestations (EHMs), mostly immunologic/rheumatologic in nature owing to B-cell proliferation and clonal expansion. Neurological complications are thought to be immune-mediated or secondary to invasion of neural tissues by HCV, as postulated in transverse myelitis and encephalopathic forms. Primarily axonal neuropathies, including sensorimotor polyneuropathy, large or small fiber sensory neuropathy, motor polyneuropathy, mononeuritis, mononeuritis multiplex, or overlapping syndrome, represent the most common neurological complications of chronic HCV infection. In addition, a number of peripheral demyelinating disorders are encountered, such as chronic inflammatory demyelinating polyneuropathy, the Lewis-Sumner syndrome, and cryoglobulin-associated polyneuropathy with demyelinating features. The spectrum of demyelinating forms also includes rare cases of iatrogenic central and peripheral nervous system disorders, occurring during treatment with pegylated interferon. Herein, we review HCV-related demyelinating conditions, and disclose the novel observation on the significantly increased frequency of chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibodies in a cohort of 59 consecutive patients recruited at our institution. We also report a second case of neuromyelitis optica with serum IgG autoantibody against the water channel aquaporin-4. The prompt recognition of these atypical and underestimated complications of HCV infection is of crucial importance in deciding which treatment option a patient should be offered.
Mariotto, Sara; Ferrari, Sergio; Monaco, Salvatore
Chronic infection with hepatitis C virus (HCV) is associated with a large spectrum of extrahepatic manifestations (EHMs), mostly immunologic/rheumatologic in nature owing to B-cell proliferation and clonal expansion. Neurological complications are thought to be immune-mediated or secondary to invasion of neural tissues by HCV, as postulated in transverse myelitis and encephalopathic forms. Primarily axonal neuropathies, including sensorimotor polyneuropathy, large or small fiber sensory neuropathy, motor polyneuropathy, mononeuritis, mononeuritis multiplex, or overlapping syndrome, represent the most common neurological complications of chronic HCV infection. In addition, a number of peripheral demyelinating disorders are encountered, such as chronic inflammatory demyelinating polyneuropathy, the Lewis-Sumner syndrome, and cryoglobulin-associated polyneuropathy with demyelinating features. The spectrum of demyelinating forms also includes rare cases of iatrogenic central and peripheral nervous system disorders, occurring during treatment with pegylated interferon. Herein, we review HCV-related demyelinating conditions, and disclose the novel observation on the significantly increased frequency of chronic demyelinating neuropathy with anti-myelin-associated glycoprotein antibodies in a cohort of 59 consecutive patients recruited at our institution. We also report a second case of neuromyelitis optica with serum IgG autoantibody against the water channel aquaporin-4. The prompt recognition of these atypical and underestimated complications of HCV infection is of crucial importance in deciding which treatment option a patient should be offered. PMID:25198705
Full Text Available Multiple sclerosis is a disease caused by demyelination of nerve fibers. In order to determine the loss of signal with the percentage of demyelination, we need to develop models that can simulate this effect. Existing time-based models does not provide a method to determine the influences of demyelination based on simulation results. Our goal is to develop a system identification approach to generate a transfer function in the frequency domain. The idea is to create a unified modeling approach for neural action potential propagation along the length of an axon containing number of Nodes of Ranvier (N. A system identification approach has been used to identify a transfer function of the classical Hodgkin-Huxley equations for membrane voltage potential. Using this approach, we model cable properties and signal propagation along the length of the axon with N node myelination. MATLAB/ Simulink platform is used to analyze an N node-myelinated neuronal axon. The ability to transfer function in the frequency domain will help reduce effort and will give a much more realistic feel when compared to the classical time-based approach. Once a transfer function is identified, the conduction as a cascade of each linear time invariant system-based transfer function can be modeled. Using this approach, future studies can model the loss of myelin in various parts of nervous system.
Totaro, Rocco; Di Carmine, C; Splendiani, A; Torlone, S; Patriarca, L; Carrocci, C; Sciamanna, S; Marini, C; Carolei, A
Although tumefactive multiple sclerosis is a well recognized variant of multiple sclerosis, prognostic uncertainty still exists about long term prognosis. The aim of this study was to estimate the occurrence and long term outcome of tumefactive demyelinating lesions (TDLs) in a cohort of multiple sclerosis patients. We reviewed brain MRI of 443 patients referred to our MS clinic. All patients meeting the McDonald criteria for multiple sclerosis and showing at least one TDL were included. Kaplan-Meier estimates of disease-free survival in patient cohort were compared with control group without TDLs using a log-rank test. Seven cases with TDLs were identified (occurrence 1.58 %). Tumefactive demyelinating lesion recurrence was 16.6 %. Cumulative proportion of patients free from clinical relapse and from new T2 lesions was lower in the control group although not reaching statistical significance (30 vs 50 %; P = 0.666 and 21.7 vs 33.3 %; P = 0.761, respectively). Disability progression analysis showed a not significant trend towards lower probability of remaining progression free for TDL patients (50 vs 61 %; P = 0.295). Occurrence of tumefactive demyelinating lesions in our cohort was higher than those reported in other studies. Overall, TDLs were not predictive of poor outcome in terms of disability progression.
Haines, Jeffery D.; Herbin, Olivier; de la Hera, Belén; Vidaurre, Oscar G.; Moy, Gregory A.; Sun, Qingxiang; Fung, Ho Yee Joyce; Albrecht, Stephanie; Alexandropoulos, Konstantina; McCauley, Dilara; Chook, Yuh Min; Kuhlmann, Tanja; Kidd, Grahame J.; Shacham, Sharon; Casaccia, Patrizia
Axonal damage has been associated with aberrant protein trafficking. This study characterizes a novel class of compounds targeting nucleo-cytoplasmic shuttling, by binding to the catalytic groove of the nuclear export protein XPO1/CRM1 (chromosome region maintenance protein1). Oral administration of novel reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but observed also in other mouse models of axonal damage (i.e. kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding for CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection. PMID:25706475
Haines, Jeffery D; Herbin, Olivier; de la Hera, Belén; Vidaurre, Oscar G; Moy, Gregory A; Sun, Qingxiang; Fung, Ho Yee Joyce; Albrecht, Stefanie; Alexandropoulos, Konstantina; McCauley, Dilara; Chook, Yuh Min; Kuhlmann, Tanja; Kidd, Grahame J; Shacham, Sharon; Casaccia, Patrizia
Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection.
Gonzalez, Ginez A.; Hofer, Matthias P.; Syed, Yasir A.; Amaral, Ana I.; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R. N.
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models. PMID:27554391
Full Text Available Abstract Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications – decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that lysophosphatidic acid receptor activation initiates neuropathic pain, as well as possible peripheral mechanims of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Aβ- and noxious C- or Aδ-fibers to influence the molecular mechanisms of allodynia.
Nelis, E; Erdem, S; Van Den Bergh, P Y K; Belpaire-Dethiou, M-C; Ceuterick, C; Van Gerwen, V; Cuesta, A; Pedrola, L; Palau, F; Gabreëls-Festen, A A W M; Verellen, C; Tan, E; Demirci, M; Van Broeckhoven, C; De Jonghe, P; Topaloglu, H; Timmerman, V
Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot-Marie-Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
Miura, Yumako; Devaux, Jérôme J; Fukami, Yuki; Manso, Constance; Belghazi, Maya; Wong, Anna Hiu Yi; Yuki, Nobuhiro
A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: email@example.com.
Gonzalez, Ginez A; Hofer, Matthias P; Syed, Yasir A; Amaral, Ana I; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R N
Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models.
Longoni, Giulia; Brown, Robert A; MomayyezSiahkal, Parya; Elliott, Colm; Narayanan, Sridar; Bar-Or, Amit; Marrie, Ruth Ann; Yeh, E Ann; Filippi, Massimo; Banwell, Brenda; Arnold, Douglas L
See Hacohen et al. (doi:10.1093/awx075) for a scientific commentary on this article. Most children who experience an acquired demyelinating syndrome of the central nervous system will have a monophasic disease course, with no further clinical or radiological symptoms. A subset will be diagnosed with multiple sclerosis, a life-long disorder. Using linear mixed effects models we examined longitudinal diffusion properties of normal-appearing white matter in 505 serial scans of 132 paediatric participants with acquired demyelinating syndromes followed for a median of 4.4 years, many from first clinical presentation, and 106 scans of 80 healthy paediatric participants. Fifty-three participants with demyelinating syndromes eventually received a diagnosis of paediatric-onset multiple sclerosis. Diffusion tensor imaging measures properties of water diffusion through tissue, which normally becomes increasingly restricted and anisotropic in the brain during childhood and adolescence, as fibre bundles develop and myelinate. In the healthy paediatric participants, our data demonstrate the expected trajectory of more restricted and anisotropic white matter diffusivity with increasing age. However, in participants with multiple sclerosis, fractional anisotropy decreased and mean diffusivity of non-lesional, normal-appearing white matter progressively increased after clinical presentation, suggesting not only a failure of age-expected white matter development but also a progressive loss of tissue integrity. Surprisingly, patients with monophasic disease failed to show age-expected changes in diffusion parameters in normal-appearing white matter, although they did not show progressive loss of integrity over time. Further analysis demonstrated that participants with monophasic disease experienced different post-onset trajectories in normal-appearing white matter depending on their presenting phenotype: those with acute disseminated encephalomyelitis demonstrated abnormal
Münzel, Eva Jolanda; Becker, Catherina G; Becker, Thomas; Williams, Anna
In the human demyelinating central nervous system (CNS) disease multiple sclerosis, remyelination promotes recovery and limits neurodegeneration, but this is inefficient and always ultimately fails. Furthermore, these regenerated myelin sheaths are thinner and shorter than the original, leaving the underlying axons potentially vulnerable. In rodent models, CNS remyelination is more efficient, so that in young animals (but not old) the number of myelinated axons is efficiently restored to normal, but in both young and old rodents, regenerated myelin sheaths are still short and thin. The reasons for these differences in remyelination efficiency, the thinner remyelinated myelin sheaths compared to developmental myelin and the subsequent effect on the underlying axon are unclear. We studied CNS remyelination in the highly regenerative adult zebrafish (Danio rerio), to better understand mechanisms of what we hypothesised would be highly efficient remyelination, and to identify differences to mammalian CNS remyelination, as larval zebrafish are increasingly used for high throughput screens to identify potential drug targets to improve myelination and remyelination. We developed a novel method to induce a focal demyelinating lesion in adult zebrafish optic nerve with no discernible axonal damage, and describe the cellular changes over time. Remyelination is indeed efficient in both young and old adult zebrafish optic nerves, and at 4 weeks after demyelination, the number of myelinated axons is restored to normal, but internode lengths are short. However, unlike in rodents or in humans, in young zebrafish these regenerated myelin sheaths were of normal thickness, whereas in aged zebrafish, they were thin, and remained so even 3 months later. This inability to restore normal myelin thickness in remyelination with age was associated with a reduced macrophage/microglial response. Zebrafish are able to efficiently restore normal thickness myelin around optic nerve axons after
Full Text Available Vitamin D is emerging as a probably important environmental risk factor in multiple sclerosis, affecting both susceptibility and disease progression. It is not known to what extent this effect is due to a modulation of peripheral lymphocyte function, or to intrathecal effects of vitamin D. We investigated the effect of dietary vitamin D3 content on de/remyelination in the cuprizone model, which is a well established toxic model of demyelination, with no associated lymphocyte infiltration. The mice received diets either deficient of (<50 IU/kg, or supplemented with low (500 IU/kg, high (6200 IU/kg or very high (12500 IU/kg amounts of vit D3. Cuprizone (0.2% was added to the diet for six weeks, starting two weeks after onset of the experimental diets. Mouse brain tissue was histopathologically evaluated for myelin and oligodendrocyte loss, microglia/macrophage activation, and lymphocyte infiltration after six weeks of cuprizone exposure, and two weeks after discontinuation of cuprizone exposure. High and very high doses of vitamin D3 significantly reduced the extent of white matter demyelination (p = 0.004 and attenuated microglia activation (p = 0.001. No differences in the density of oligodendrocytes were observed between the diet groups. Two weeks after discontinuation of cuprizone exposure, remyelination was only detectable in the white matter of mice receiving diets deficient of or with low vitamin D3 content. In conclusion, high dietary doses of vitamin D3 reduce the extent of demyelination, and attenuate microglia activation and macrophage infiltration in a toxic model of demyelination, independent of lymphocyte infiltration.
European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision
van den Bergh, P. Y. K.; Hadden, R. D. M.; Bouche, P.; Cornblath, D. R.; Hahn, A.; Illa, I.; Koski, C. L.; Léger, J.-M.; Nobile-Orazio, E.; Pollard, J.; Sommer, C.; van Doorn, P. A.; van Schaik, I. N.
Consensus guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been previously published in European Journal of Neurology and Journal of the Peripheral Nervous System. To revise these guidelines. Disease experts,
Gajofatto, A; Bongianni, M; Zanusso, G; Bianchi, M R; Turatti, M; Benedetti, M D; Monaco, S
Initial demyelinating event (IDE) diagnosis and prognosis are not straightforward. To identify potential diagnostic markers and outcome predictors of IDEs suggestive of multiple sclerosis (MS), that is, clinically isolated syndromes (CISs). Clinically isolated syndrome cases (i.e., subjects with an IDE compatible with MS onset and no alternative explanation) with at least 1.5 years' follow-up were retrospectively identified. All cases underwent clinical, neurophysiological, MRI, and cerebrospinal fluid (CSF) assessment, including exploratory tau, 14-3-3, and cystatin C testing. CIS recovery, conversion to MS, and long-term neurological disability were used as outcome measures. Patients with neuromyelitis optica spectrum disorders, idiopathic acute transverse myelitis (IATM), Creutzfeldt-Jacob disease, and non-inflammatory/non-neurodegenerative disorders served as controls for CSF analysis. Forty-six CIS cases were included. Severe presentation was associated with incomplete recovery, while presence of at least 3 periventricular lesions on baseline MRI correlated with MS conversion. Initial pyramidal tract involvement, incomplete CIS recovery, and number of relapses predicted neurological disability. CSF tau, 14-3-3, and cystatin C did not correlate with any outcome measure. CIS cases had significantly lower tau and cystatin C levels compared to IATM. An extensive diagnostic evaluation of patients with an IDE is worthwhile to make prognostic predictions. More robust molecular biomarkers are needed. © 2013 John Wiley & Sons A/S.
Titulaer, Maarten J.; Höftberger, Romana; Iizuka, Takahiro; Leypoldt, Frank; McCracken, Lindsey; Cellucci, Tania; Benson, Leslie A.; Shu, Huidy; Irioka, Takashi; Hirano, Makito; Singh, Gagandeep; Calvo, Alvaro Cobo; Kaida, Kenichi; Morales, Pamela S.; Wirtz, Paul W.; Yamamoto, Tomotaka; Reindl, Markus; Rosenfeld, Myrna R.; Graus, Francesc; Saiz, Albert; Dalmau, Josep
Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent MRI and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of NMO-spectrum disorder (5 cases, 4 anti-AQP4-positive), or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG-positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4-positive, 2 MOG-positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis: NMDAR-antibodies were detected only in the 50 anti-NMDAR patients, MOG-antibodies in 3/50 anti-NMDAR and 1/56 NMO patients, and AQP4-antibodies in 48/56 NMO and 1/50 anti-NMDAR patients (pdemyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1/23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18/50 anti-NMDAR controls (p=0.011) Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (e.g., dyskinesias, psychosis) may have anti-NMDAR encephalitis. PMID:24700511
Young, Nathan P; Weinshenker, Brian G; Parisi, Joseph E; Scheithauer, B; Giannini, C; Roemer, Shanu F; Thomsen, Kristine M; Mandrekar, Jayawant N; Erickson, Bradley J; Lucchinetti, Claudia F
Distinction between acute disseminated encephalomyelitis and acute multiple sclerosis is often clinically difficult. Perivenous demyelination is the pathological hallmark of acute disseminated encephalomyelitis, whereas confluent demyelination is the hallmark of acute multiple sclerosis. We investigated whether perivenous demyelination versus confluent demyelination distinguishes acute disseminated encephalomyelitis from multiple sclerosis. Patients with perivenous demyelination (n = 13; median age 43 years, range 5-67) on brain biopsy and/or autopsy, ascertained retrospectively, were compared with a cohort with confluent demyelination only (n = 91; 84% multiple sclerosis, 16% isolated syndrome at follow-up; median age 39 years, range 10-69). Clinical presentation, course and the International Paediatric Multiple Sclerosis Study Group clinical criteria for acute disseminated encephalomyelitis were assessed in both cohorts. Among the perivenous demyelination cohort, 10 patients had only perivenous demyelination and three also had confluent demyelination. All but one patient with perivenous demyelination only had a monophasic course, whereas two of three with both types had a relapsing course. The perivenous demyelination cohort was more likely than the confluent demyelination cohort to present with encephalopathy (P acute disseminated encephalomyelitis (perivenous demyelination), but misdiagnosed acute disseminated encephalomyelitis among 9% of patients with confluent demyelination and multiple sclerosis diagnosis at last follow-up. Perivenous demyelination is associated with meningoencephalopathic presentations and a monophasic course. Depressed level of consciousness is a more specific clinical criterion for pathologically confirmed acute disseminated encephalomyelitis than encephalopathy, which over-diagnosed acute disseminated encephalomyelitis among multiple sclerosis patients. A distinct pattern of cortical microglial activation without cortical demyelination
Lim, Jia Pei; Devaux, Jérôme; Yuki, Nobuhiro
Guillain-Barré syndrome is classified into acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. Whereas autoantibodies to GM1 or GD1a induce the development of acute motor axonal neuropathy, pathogenic autoantibodies have yet to be identified in acute inflammatory demyelinating polyneuropathy and chronic inflammatory demyelinating polyneuropathy. This review highlights the importance of autoantibodies to peripheral nerve proteins in the physiopathology of acute and chronic inflammatory demyelinating polyneuropathies. Moreover, we listed up other potential antigens, which may become helpful biomarkers for acquired, dysimmune demyelinating neuropathies based on their critical functions during myelination and their implications in hereditary demyelinating neuropathies. Copyright © 2014 Elsevier B.V. All rights reserved.
Kallewaard, Nicole L; Zhang, Lili; Chen, Jin-Wen; Guttenberg, Marta; Sanchez, Melissa D; Bergelson, Jeffrey M
In cultured cells, infection by group B coxsackievirus (CVB) is mediated by the coxsackievirus and adenovirus receptor (CAR), but the importance of this molecule in CVB-induced disease has not been determined. We generated mice with tissue-specific ablation of CAR within each of two major CVB target organs, the pancreas and heart. In the pancreas, deletion of CAR resulted in a significant reduction in both virus titers and virus-induced tissue damage. Similarly, cardiomyocyte-specific CAR deletion resulted in a marked reduction in virus titer, infection-associated cytokine production, and histopathology within the heart. Consistent with the in vivo phenotype, CAR-deficient cardiomyocytes resisted infection in vitro. These results demonstrate a critical function for CAR in the pathogenesis of CVB infection in vivo and in virus tropism for the heart and pancreas.
Kallewaard, Nicole L.; Zhang, Lili; Chen, Jin-Wen; Guttenberg, Marta; Sanchez, Melissa D.; Bergelson, Jeffrey M.
SUMMARY In cultured cells, infection by Group B coxsackieviruses (CVB) is mediated by the coxsackievirus and adenovirus receptor (CAR), but the importance of this molecule in CVB disease has not been determined. We used tissue-specific CAR gene deletion to generate mice that lacked CAR within each of two major CVB target organs, the pancreas and heart. Deletion of CAR from the pancreas resulted in a 1000-fold reduction in virus titers within the pancreas during infection, and a significant reduction in virus-induced tissue damage and inflammation. Similarly, cardiomyocyte-specific CAR deletion resulted in a 100-fold reduction in virus titer within the heart, and a marked reduction in cytokine production and histopathology. Although primary cardiomyocytes from control animals were susceptible to virus infection, CAR-deficient cardiomyocytes resisted infection in vitro. These results demonstrate a critical function for CAR in the pathogenesis of CVB infection in vivo, and in virus tropism for the heart and pancreas. PMID:19616768
You, Yu; Zhao, Yaqun; Bai, Hui; Liu, Zhiliang; Meng, Fanxin; Zhang, Hua; Xu, Ruxiang
Glatiramer acetate (GA) is a clinically prescribed immunomodulator drug used to treat demyelinating disease like multiple sclerosis (MS). Persistent down-regulation in the expression of myelin sheath proteins has been observed in both rats with pentylenetetrazol (PTZ) induced chronic epilepsy and some clinical epilepsy patients. Hypothetically, protection of myelin sheath by pharmaceutical means in the process of epilepsy might, to some extent, be helpful to control epileptic seizures. Therefore, we tried to use GA to treat PTZ-induced epilepsy rats. GA treatment successfully protected rats' myelin sheath from demyelination in the process of PTZ-induced epileptic seizures. Notably, electroencephalogram (EEG) monitoring demonstrated that GA-treated epilepsy rats showed significantly lowered epileptiform discharges. Correspondingly, behavioral recording showed reduced frequency of seizures in GA-treated epilepsy rats. The results indicate that epilepsy associated demyelination may be a contributing factor in seizures behavior, and early intervention with anti-demyelination drugs may be beneficial to reduce the severity of seizures behavior. Copyright © 2013 Elsevier B.V. All rights reserved.
Aldrete Cortez, V R; Duriez-Sotelo, E; Carrillo-Mora, P; Pérez-Zuno, J A
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.
Justin D Glenn
Full Text Available Mesenchymal stem cells (MSCs are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS, which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1 and IL-17A-producing (TH17 effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.
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)
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.)
Hainz, Nadine; Becker, Philipp; Rapp, Daniel; Wagenpfeil, Stefan; Wonnenberg, Bodo; Beisswenger, Christoph; Tschernig, Thomas; Meier, Carola
Recent experiments showed that a pannexin-1 inhibitor, probenecid, reduced clinical symptoms in the murine experimental autoimmune encephalomyelitis when applied during the initial phase of neuronal inflammation. An inflammatory component is also present in a toxically induced inflammation and demyelination using cuprizone diet. Probenecid is a pannexin-1 antagonist and a probenecid therapy was investigated. Mice were fed for 10days with a cuprizone diet. In the following, the diet was continued but combined with a daily injection of a low dose of probenecid or solvent for 10days. Electron microscopy revealed demyelination in the optic nerve. The demyelination as measured by the axonal diameter was significantly reduced in the animals treated with 100mg per kg body weight probenecid. In comparison to controls, the number of leukocytes and lymphocytes in the peripheral blood was reduced in all cuprizone groups including the treatment group. In conclusion, early demyelination in the optic nerve was moderately reduced by 10days treatment with a low dose probenecid. This is a hint for the involvement of pannexin-1 modulated inflammation in cuprizone feeding induced toxic demyelination. Thus, probenecid is a candidate for the treatment of neuro-inflammation and multiple sclerosis. Copyright © 2017 Elsevier B.V. All rights reserved.
Chronic neuropathies are operationally classified as primarily demyelinating or axonal, on the basis of electrodiagnostic or pathological criteria. Demyelinating neuropathies are further classified as hereditary or acquired-this distinction is important, because the acquired neuropathies are immune-mediated and, thus, amenable to treatment. The acquired chronic demyelinating neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein (MAG; anti-MAG neuropathy), multifocal motor neuropathy (MMN), and POEMS syndrome. They have characteristic--though overlapping--clinical presentations, are mediated by distinct immune mechanisms, and respond to different therapies. CIDP is the default diagnosis if the neuropathy is demyelinating and no other cause is found. Anti-MAG neuropathy is diagnosed on the basis of the presence of anti-MAG antibodies, MMN is characterized by multifocal weakness and motor conduction blocks, and POEMS syndrome is associated with IgG or IgA λ-type monoclonal gammopathy and osteosclerotic myeloma. The correct diagnosis, however, can be difficult to make in patients with atypical or overlapping presentations, or nondefinitive laboratory studies. First-line treatments include intravenous immunoglobulin (IVIg), corticosteroids or plasmapheresis for CIDP; IVIg for MMN; rituximab for anti-MAG neuropathy; and irradiation or chemotherapy for POEMS syndrome. A correct diagnosis is required for choosing the appropriate treatment, with the aim of preventing progressive neuropathy.
Braun, Monika; Björkström, Niklas K; Gupta, Shawon; Sundström, Karin; Ahlm, Clas; Klingström, Jonas; Ljunggren, Hans-Gustaf
Clinical infection with hantaviruses cause two severe acute diseases, hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). These diseases are characterized by strong immune activation, increased vascular permeability, and up to 50% case-fatality rates. One prominent feature observed in clinical hantavirus infection is rapid expansion of natural killer (NK) cells in peripheral blood of affected individuals. We here describe an unusually high state of activation of such expanding NK cells in the acute phase of clinical Puumala hantavirus infection. Expanding NK cells expressed markedly increased levels of activating NK cell receptors and cytotoxic effector molecules. In search for possible mechanisms behind this NK cell activation, we observed virus-induced IL-15 and IL-15Rα on infected endothelial and epithelial cells. Hantavirus-infected cells were shown to strongly activate NK cells in a cell-cell contact-dependent way, and this response was blocked with anti-IL-15 antibodies. Surprisingly, the strength of the IL-15-dependent NK cell response was such that it led to killing of uninfected endothelial cells despite expression of normal levels of HLA class I. In contrast, hantavirus-infected cells were resistant to NK cell lysis, due to a combination of virus-induced increase in HLA class I expression levels and hantavirus-mediated inhibition of apoptosis induction. In summary, we here describe a possible mechanism explaining the massive NK cell activation and proliferation observed in HFRS patients caused by Puumala hantavirus infection. The results add further insights into mechanisms behind the immunopathogenesis of hantavirus infections in humans and identify new possible targets for intervention.
Murata, Ken-ya; Ishiguchi, Hiroshi; Ando, Ryuki; Miwa, Hideto; Kondo, Tomoyoshi
We report a patient with chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis (PBC). Except for minimal biochemical abnormalities, clinical symptoms of PBC were not observed, and we diagnosed our patient with asymptomatic PBC from the results of a liver biopsy. Although the patient noticed little muscle weakness, an electrophysiological study demonstrated slow conduction velocities and prolonged distal latencies, with definite conduction blocks in the median, ulnar, and tibial nerves. The disturbed sensory pattern was asymmetrical, and sensory nerve action potentials were not evoked. From these observations, we diagnosed this patient with chronic inflammatory demyelinating polyneuropathy. Neuropathy associated with PBC is very rare. We must differentiate demyelinating neuropathy with PBC in patients with asymmetrical sensory dominant neuropathy with high immunoglobulin M titers, and investigate for the presence of anti-mitochondrial antibodies to rule out a complication of asymptomatic PBC. Copyright © 2013 Elsevier Ltd. All rights reserved.
Oh, Shin J
Multifocal sensory demyelinating neuropathy has not been adequately reported in the literature. A 42-year-old man with numbness of the left hand for 3 years and of the right hand for 6 months had a pure multifocal sensory neuropathy involving both hands, most prominently affecting 2-point discrimination, number writing, and object recognition of the left hand. Near-nerve needle sensory and mixed nerve conduction studies were performed on the left ulnar nerve. Studies of the left ulnar nerve documented a demyelinating neuropathy characterized by temporal dispersion and marked decrease in the amplitudes of the sensory and mixed compound nerve potentials in the above-elbow-axilla segment. With intravenous immunoglobulin treatment, there was improvement in his neuropathic condition. In this study I describe a case of multifocal sensory demyelinating neuropathy as a counterpart of multifocal motor neuropathy. Muscle Nerve 56: 825-828, 2017. © 2016 Wiley Periodicals, Inc.
Kueker, W.; Mehnert, F.; Mader, I.; Naegele, T. [Department of Neuroradiology, University of Tuebingen Medical School, Hoppe-Seyler-Str. 3, 72076, Tuebingen (Germany); Ruff, J. [Siemens Medical Solutions, Erlangen (Germany); Gaertner, S. [Department of Neurology, University of Tuebingen Medical School, Tuebingen (Germany)
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.)
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.
Benned-Jensen, Tau; Smethurst, Christopher; Holst, Peter Johannes
The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven-transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we...
Vries, de Maaike; Bedke, Nicole; Smithers, Natalie P.; Loxham, Matthew; Howarth, Peter H.; Nawijn, Martijn C.; Davies, Donna E.
Therapeutic options to treat virus-induced asthma exacerbations are limited and urgently needed. Therefore, we tested Pim1 kinase as potential therapeutic target in human rhinovirus (HRV) infections. We hypothesised that inhibition of Pim1 kinase reduces HRV replication by augmenting the
Full Text Available 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.
Seehusen, Frauke; Al-Azreg, Seham A.; Raddatz, Barbara B.; Haist, Verena; Puff, Christina; Spitzbarth, Ingo; Ulrich, Reiner; Baumgärtner, Wolfgang
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. PMID:27441688
Marro, Brett S; Grist, Jonathan J; Lane, Thomas E
The functional role of the ELR(+) chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain, and spinal cord that correlated with increased frequency of Ly6G(+)CD11b(+) neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells, and there was no difference in control of JHMV replication compared with control mice, indicating that T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1-transgenic mice reduced the severity of demyelination in mice, arguing for a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and that neutrophils can contribute to this process in a model of viral-induced neurologic disease. Copyright © 2016 by The American Association of Immunologists, Inc.
Full Text Available Multiple sclerosis (MS is an autoimmune disease of the central nervous system (CNS characterized by inflammation, demyelination and axonal pathology. Myelin basic protein/proteolipid protein (MBP-PLP fusion protein MP4 is capable of inducing chronic experimental autoimmune encephalomyelitis (EAE in susceptible mouse strains mirroring diverse histopathological and immunological hallmarks of MS. Lack of human tissue underscores the importance of animal models to study the pathology of MS.Twenty-two female C57BL/6 (B6 mice were immunized with MP4 and the clinical development of experimental autoimmune encephalomyelitis (EAE was observed. Methylene blue-stained semi-thin and ultra-thin sections of the lumbar spinal cord were assessed at the peak of acute EAE, three months (chronic EAE and six months after onset of EAE (long-term EAE. The extent of lesional area and inflammation were analyzed in semi-thin sections on a light microscopic level. The magnitude of demyelination and axonal damage were determined using electron microscopy. Emphasis was put on the ventrolateral tract (VLT of the spinal cord.B6 mice demonstrated increasing demyelination and severe axonal pathology in the course of MP4-induced EAE. Additionally, mitochondrial swelling and a decrease in the nearest neighbor neurofilament distance (NNND as early signs of axonal damage were evident with the onset of EAE. In semi-thin sections we observed the maximum of lesional area in the chronic state of EAE while inflammation was found to a similar extent in acute and chronic EAE. In contrast to the well-established myelin oligodendrocyte glycoprotein (MOG model, disease stages of MP4-induced EAE could not be distinguished by assessing the extent of parenchymal edema or the grade of inflammation.Our results complement our previous ultrastructural studies of B6 EAE models and suggest that B6 mice immunized with different antigens constitute useful instruments to study the diverse
Short, K.R.; Diavatopoulos, D.A.; Thornton, R.; Pedersen, J.; Strugnell, R.A.; Wise, A.K.; Reading, P.C.; Wijburg, O.L.
Otitis media (OM) is one of the most common childhood diseases. OM can arise when a viral infection enables bacteria to disseminate from the nasopharynx to the middle ear. Here, we provide the first infant murine model for disease. Mice coinfected with Streptococcus pneumoniae and influenza virus
P.A. van Doorn (Pieter)
textabstractPatients with a chronic inflammatory demyelinating polyneuropathy (CIDP) may respond to treatment with corticosteroids and to plasmapheresis, which was demonstrated in controlled clinical studies. In an uncontrolled study it was found that 13/17 CIDP patients had a rapid and
Kıztanır, Hikmet; Bektaş, Gonca; Yıldız, Edibe Pembegül; Uzunhan, Tuğçe Aksu; Tatlı, Burak; Aydınlı, Nur; Çalışkan, Mine; Özmen, Meral
To determine the incidence and clinical relevance of neuronal autoantibodies in children with demyelinating syndromes. We conducted a prospective study including 31 consecutive children with demyelinating syndromes. Four patients with N-Methyl-D-aspartate receptor (NMDAR) encephalitis, 32 patients with Guillain-Barre syndrome, 13 children with benign childhood epilepsy, and 28 healthy children were used as controls. Prior to initiating immunomodulatory therapy, serum samples were tested for antibodies against NMDAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) 1, AMPAR2, leucine-rich glioma-activated protein 1, contactin-associated protein 2, gamma-aminobutyric acid B receptors, paraneoplastic ma antigen 2 (PNMA2/Ta), Yo, Ri, Hu, CV2, amphiphysin, and aquaporin-4 by indirect immunofluorescence assays. Three anti-neuronal antibodies were detected; NMDAR antibody in one with multiple sclerosis, PNMA2/Ta antibody in one with multiple sclerosis, and Yo antibody in one with clinically isolated syndrome. The positivity rate of neuronal autoantibodies in demyelinating syndrome was 10%. All seropositive patients were found to be negative for tumor screening. None of these patients exhibited symptoms of encephalitis. Children with demyelinating syndromes without symptoms of encephalitis can be positive for anti-neuronal antibodies. Copyright © 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Kuwabara, S; Ogawara, K; Misawa, S; Koga, M; Mori, M; Hiraga, A; Kanesaka, T; Hattori, T; Yuki, N
Campylobacter jejuni enteritis is the most common antecedent infection in Guillain-Barré syndrome (GBS). C. jejuni-related GBS is usually acute motor axonal neuropathy (AMAN), but previous reports described many cases of the demyelinating subtype of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) after C. jejuni infection. To investigate whether C. jejuni infection elicits AIDP. In 159 consecutive patients with GBS, antibodies against C. jejuni were measured using ELISA. Antecedent C. jejuni infection was determined by the strict criteria of positive C. jejuni serology and a history of a diarrheal illness within the previous 3 weeks. Electrodiagnostic studies were performed weekly for the first 4 weeks, and sequential findings were analyzed. There was evidence of recent C. jejuni infection in 22 (14%) patients. By electrodiagnostic criteria, these patients were classified with AMAN (n = 16; 73%) or AIDP (n = 5; 23%) or as unclassified (n = 1) in the first studies. The five C. jejuni-positive patients with the AIDP pattern showed prolonged motor distal latencies in two or more nerves and had their rapid normalization within 2 weeks, eventually all showing the AMAN pattern. In contrast, patients with cytomegalovirus- or Epstein-Barr virus-related AIDP (n = 13) showed progressive increases in distal latencies in the 8 weeks after onset. Patients with C. jejuni-related Guillain-Barré syndrome can show transient slowing of nerve conduction, mimicking demyelination, but C. jejuni infection does not appear to elicit acute inflammatory demyelinating polyneuropathy.
J Gordon Millichap
Full Text Available Initial MRI factors predictive of a second attack and disability following a first episode of acute CNS inflammatory demyelination in a cohort of 116 children seen between 1990 and 2002 were studied at the Hopital Cochin-Saint-Vincent de Paul, Paris; Hopital Bicetre, Lille; Hopital Neurologique, Lyon, France; and McGill University, Montreal, Canada.
Short, Kirsty R.; Diavatopoulos, Dimitri A.; Thornton, Ruth; Pedersen, John; Richard A. Strugnell; Wise, Andrew K.; Reading, Patrick C.; Wijburg, Odilia L.
Otitis media (OM) is one of the most common childhood diseases. OM can arise when a viral infection enables bacteria to disseminate from the nasopharynx to the middle ear. Here, we provide the first infant murine model for disease. Mice coinfected with Streptococcus pneumoniae and influenza virus had high bacterial load in the middle ear, middle ear inflammation, and hearing loss. In contrast, mice colonized with S. pneumoniae alone had significantly less bacteria in the ear, minimal hearing ...
Hussain, Rashad; Ghoumari, Abdel M; Bielecki, Bartosz; Steibel, Jérôme; Boehm, Nelly; Liere, Philippe; Macklin, Wendy B; Kumar, Narender; Habert, René; Mhaouty-Kodja, Sakina; Tronche, François; Sitruk-Ware, Regine; Schumacher, Michael; Ghandour, M Said
Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic
Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas
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.
Ketelslegers, Immy A; Van Pelt, Daniëlle E; Bryde, Susanne; Neuteboom, Rinze F; Catsman-Berrevoets, Coriene E; Hamann, Dörte; Hintzen, Rogier Q
Acquired demyelinating syndromes (ADS) in children are a group of distinct first immune-mediated demyelinating events of the central nervous system (CNS). Predictive biomarkers for future diagnosis are lacking. A putative target antigen is myelin oligodendrocyte glycoprotein (MOG). We analyzed the presence of MOG antibodies in a cohort of ADS patients in The Netherlands. Using a cell-based assay, we analyzed 117 children with ADS from a nationwide cohort, whom were divided into five groups: optic neuritis (ON; n = 20), transverse myelitis (TM; n = 7), other monofocal ADS (n = 22), polyfocal ADS without encephalopathy (n = 44) and polyfocal ADS with encephalopathy (n = 24). Additionally, we tested children with other neurological diseases (OND; n = 13), healthy children (n = 31) and adult polyfocal ADS plus encephalopathy (ADEM) patients (n = 29). We found that 21 of the 117 children with ADS tested anti-MOG seropositive (18%). The group of patients with ADEM had the highest prevalence of anti-MOG seropositivity (42% versus 18% in the non-encephalopathic polyfocal ADS patients). Although 47 ADS children had a final diagnosis of multiple sclerosis (MS), in only one of them were MOG antibodies detected (2%), with only borderline positivity. Only 1 out of the 29 adult ADEM patients tested anti-MOG seropositive. MOG antibodies are strongly skewed towards ADS children that present with an ADEM-like disease onset. The presence of such antibodies pleads against a future diagnosis of MS. © The Author(s), 2015.
and anorexia; the adenopathy persisted. The week after this she developed vasculitic lesions on the palms and soles, arthritis of the right knee and moderate hypertension. Urinary dipstick testing showed proteinuria + + and haematuria + +. A screen for auto-immune diseases revealed that antinuclear antibodies were ...
Valerio, L; de Balanzó, X; Jiménez, O; Pedro-Bolet, M L
Dengue fever, a viral infectious disease characteristic of tropical climates, is considered to be a re-emergent pathology responsible for several serious outbreaks in the last decade. Some factors have been involved in the spread of the virus and its vectorial mosquito carrier: human alteration of the ecosystems, improvement and speed in the transit of goods and people and climate changes. As a reflection of this, an increase in imported cases is probable, especially in tourists coming from endemic areas, considering its short period of incubation (7-10 days). The recognition of personal antecedents of journeys, the main symptoms of the disease and the potential presence of complications (haemorrhagic dengue) should be included in the examination of fever of unknown origin or feverish exanthema. The case of a patient is presented whose clinical picture of classic dengue fever was worsened by self-treatment with acetylsalicylic acid.
in other disease models, such as cardiac hypertrophy and ischemia-reperfusion injury, as well as rheumathoid arthritis (20, 43). HDAC1 and 2 activity...model we will determine by established clinical-like parameters and pathophysiologic endpoints of airway dysfunction the effect of such pharmacologic...synthesis. There are no studies investigating the role of H2S generation in pathophysiology of viral infections or the use of H2S donors as
Peschl, Patrick; Schanda, Kathrin; Zeka, Bleranda; Given, Katherine; Böhm, Denise; Ruprecht, Klemens; Saiz, Albert; Lutterotti, Andreas; Rostásy, Kevin; Höftberger, Romana; Berger, Thomas; Macklin, Wendy; Lassmann, Hans; Bradl, Monika; Bennett, Jeffrey L; Reindl, Markus
Antibodies to the myelin oligodendrocyte glycoprotein (MOG) are associated with a subset of inflammatory demyelinating diseases of the central nervous system such as acute disseminated encephalomyelitis and neuromyelitis optica spectrum disorders. However, whether human MOG antibodies are pathogenic or an epiphenomenon is still not completely clear. Although MOG is highly conserved within mammals, previous findings showed that not all human MOG antibodies bind to rodent MOG. We therefore hypothesized that human MOG antibody-mediated pathology in animal models may only be evident using species-specific MOG antibodies. We screened 80 human MOG antibody-positive samples for their reactivity to mouse and rat MOG using either a live cell-based assay or immunohistochemistry on murine, rat, and human brain tissue. Selected samples reactive to either human MOG or rodent MOG were subsequently tested for their ability to induce complement-mediated damage in murine organotypic brain slices or enhance demyelination in an experimental autoimmune encephalitis (EAE) model in Lewis rats. The MOG monoclonal antibody 8-18-C5 was used as a positive control. Overall, we found that only a subset of human MOG antibodies are reactive to mouse (48/80, 60%) or rat (14/80, 18%) MOG. Purified serum antibodies from 10 human MOG antibody-positive patients (8/10 reactive to mouse MOG, 6/10 reactive to rat MOG), 3 human MOG-negative patients, and 3 healthy controls were tested on murine organotypic brain slices. Purified IgG from one patient with high titers of anti-human, mouse, and rat MOG antibodies and robust binding to myelin tissue produced significant, complement-mediated myelin loss in organotypic brain slices, but not in the EAE model. Monoclonal 8-18-C5 MOG antibody caused complement-mediated demyelination in both the organotypic brain slice model and in EAE. This study shows that a subset of human MOG antibodies can induce complement-dependent pathogenic effects in a murine ex vivo
Kedra, Joanna; Foltz, Violaine; Viala, Karine; Tan, Sivy; Fautrel, Bruno
Chronic inflammatory demyelinating polyradiculoneuropathies are a group of autoimmune neuropathies with a chronic course. Lewis-Sumner syndrome is a variant of this disease, characterized by an asymmetrical distal and mostly motor involvement, predominating at upper limb. We report the case of a patient who developed almost currently rheumatoid arthritis and Lewis-Sumner syndrome, which raised the problem of therapeutic intensification for his rheumatism when methotrexate proved to be ineffective. Finally, rituximab had been introduced by common consent with neurologists, and the patient noticed an improvement fifteen days after the first infusion. Even if it is striking that both dysimmune diseases had declared within a few months, the association between chronic inflammatory demyelinating polyradiculoneuropathies and rheumatoid arthritis is exceptional, since the only cases reported in the literature are secondary to TNF-alpha inhibitors. Given the potential demyelinating impact of some biologics, rituximab and perhaps abatacept seem to be the best therapeutic options when DMARDs had proven insufficient to control the rheumatism activity. Copyright © 2017. Published by Elsevier SAS.
Full Text Available The disruption of myelin causes severe neurological diseases. An understanding of the mechanism of myelination and remyelination is essential for the development of therapeutic strategies for demyelination diseases. Our previous findings indicated that the FcRγ/Fyn cascade is a potential therapeutic target for remyelination caused by the Chinese/Japanese traditional herbal (Kampo medicine ninjin’youeito (Ninjin-youei-to, NYT, which is a hot-water extract made from 12 medicinal herbs. To identify which constituents of NYT are involved in the reversal of demyelination and to examine the potential therapeutic effect, we tested several of the chemical constituents of NYT. Here, we report that Chinpi, a constituent of NYT, upregulates the FcRγ/Fyn signaling cascade resulting in a potentially therapeutic effect against age-induced demyelination. In addition, we observed that phosphorylated (activated FcRγ/Fyn upregulated the expression of the 21.5 kDa isoform of myelin basic protein, inducing rapid morphological differentiation, when oligodendrocyte precursor cells (OPCs were cultured in the presence of hesperidin and/or narirutin (the major active constituents of Chinpi. These results suggest that hesperidin and narirutin participate in the FcRγ/Fyn signaling pathway in OPCs causing these cells to differentiate into myelinating oligodendrocytes.
Ripellino, Paolo; Fleetwood, Thomas; Cantello, Roberto; Comi, Cristoforo
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, in which both cellular and humoral immune responses are involved. The disease is clinically heterogeneous with some patients displaying pure motor form and others also showing a variable degree of sensory dysfunction; disease evolution may also differ from patient to patient, since monophasic, progressive, and relapsing forms are reported. Underlying such clinical variability there is probably a broad spectrum of molecular dysfunctions that are and will be the target of therapeutic strategies. In this review we first explore the biological bases of current treatments and subsequently we focus on the practical management that must also take into account pharmacoeconomic issues. PMID:24527207
Full Text Available Unlike stereotypical neurotropic viruses, influenza A viruses have been detected in the brain tissues of human and animal models. To investigate the interaction between neurons and influenza A viruses, mouse cortical neurons were isolated, infected with human H1N1 influenza virus, and then examined for the production of various inflammatory molecules involved in immune response. We found that replication of the influenza virus in neurons was limited, although early viral transcription was not affected. Virus-induced neuron viability decreased at 6 h postinfection (p.i. but increased at 24 h p.i. depending upon the viral strain. Virus-induced apoptosis and cytopathy in primary cortical neurons were not apparent at 24 h p.i. The mRNA levels of inflammatory cytokines, chemokines, and type I interferons were upregulated at 6 h and 24 h p.i. These results indicate that the influenza virus induces inflammatory response in mouse primary cortical neurons with limited viral replication. The cytokines released in viral infection-induced neuroinflammation might play critical roles in influenza encephalopathy, rather than in viral replication-induced cytopathy.
Arikkatt, Jaisy; Ullah, Md Ashik; Short, Kirsty Renfree; Zhang, Vivan; Gan, Wan Jun; Loh, Zhixuan; Werder, Rhiannon B; Simpson, Jennifer; Sly, Peter D; Mazzone, Stuart B; Spann, Kirsten M; Ferreira, Manuel Ar; Upham, John W; Sukkar, Maria B; Phipps, Simon
Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target.
Arikkatt, Jaisy; Ullah, Md Ashik; Short, Kirsty Renfree; Zhang, Vivan; Gan, Wan Jun; Loh, Zhixuan; Werder, Rhiannon B; Simpson, Jennifer; Sly, Peter D; Mazzone, Stuart B; Spann, Kirsten M; Ferreira, Manuel AR; Upham, John W; Sukkar, Maria B; Phipps, Simon
Asthma is a chronic inflammatory disease. Although many patients with asthma develop type-2 dominated eosinophilic inflammation, a number of individuals develop paucigranulocytic asthma, which occurs in the absence of eosinophilia or neutrophilia. The aetiology of paucigranulocytic asthma is unknown. However, both respiratory syncytial virus (RSV) infection and mutations in the receptor for advanced glycation endproducts (RAGE) are risk factors for asthma development. Here, we show that RAGE deficiency impairs anti-viral immunity during an early-life infection with pneumonia virus of mice (PVM; a murine analogue of RSV). The elevated viral load was associated with the release of high mobility group box-1 (HMGB1) which triggered airway smooth muscle remodelling in early-life. Re-infection with PVM in later-life induced many of the cardinal features of asthma in the absence of eosinophilic or neutrophilic inflammation. Anti-HMGB1 mitigated both early-life viral disease and asthma-like features, highlighting HMGB1 as a possible novel therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.21199.001 PMID:28099113
Salem, Neveen A; Assaf, Naglaa; Ismail, Manal F; Khadrawy, Yasser A; Samy, Mohga
Multiple sclerosis, an autoimmune inflammatory disease of the central nervous system, is characterized by excessive demyelination. The study aimed to investigate the possible protective effect of ozone (O3) therapy in ethidium bromide (EB)-induced demyelination in rats either alone or in combination with corticosteroids in order to decrease the dose of steroid therapy. Rats were divided into Group (1) normal control rats received saline, Group (2) Sham-operated rats received saline, Group (3) Sham-operated rats received vehicle (oxygen), Group (4) EB-treated rats received EB, Group (5) EB-treated rats received O3, Group (6) EB-treated rats received methylprednisolone (MP), and Group (7) EB-treated rats received half the dose of MP concomitant with O3. EB-treated rats showed a significant increase in the number of footfalls in the grid walk test, decreased brain GSH, and paraoxonase-1 enzyme activity, whereas brain MDA, TNF-α, IL-1β, INF-γ, Cox-2 immunoreactivity, and p53 protein levels were increased. A significant decline in brain serotonin, dopamine, norepinephrine, and MBP immunoreactivity was also reported. Significant improvement of the above-mentioned parameters was demonstrated with the administration of either MP or O3, whereas best amelioration was achieved by combining half the dose of MP with ozone.
Lucke, Ilse M; Peric, Stojan; van Lieverloo, Gwen G A; Wieske, Luuk; Verhamme, Camiel; van Schaik, Ivo N; Basta, Ivana; Eftimov, Filip
Cerebrospinal fluid (CSF) examination is often part of the diagnostic work-up of a patient suspected of having chronic inflammatory demyelinating polyneuropathy (CIDP). According to the European Federation of Neurological Societies and the Peripheral Nerve Society (EFNS/PNS) criteria, an elevated protein level without pleocytosis (leukocytes leukocytes are compatible with the diagnosis CIDP and how extensive the diagnostic work-up should be in patients with a demyelinating neuropathy and pleocytosis. We performed a retrospective study at two tertiary neuromuscular referral clinics and identified 14 out of 273 (6%) patients with CIDP with elevated CSF leukocytes (≥10 cells/µl). All these patients met the EFNS/PNS criteria for definite or probable CIDP. Eight patients (57%) presented with a subacute onset and four patients with an antecedent infection. Most patients responded well to therapy, and eight patients are currently in remission. In four patients, lumbar puncture was repeated. A spontaneous decrease in leukocytes before start of treatment was found in three patients. Our data indicate that a mild to moderate pleocytosis in CSF does not exclude the diagnosis of CIDP, especially in patients with a subacute onset of disease. © 2018 Peripheral Nerve Society.
Young Bin Hong
Full Text Available Charcot-Marie-Tooth disease (CMT is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV. Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy.
Codeluppi, Luca; Bigliardi, Guido; Chiari, Annalisa; Meletti, Stefano
Paroxysmal dysarthria is an unusual condition characterised by brief episodes of dysarthria with the sudden onset and frequent recurrence. It has been mainly reported in multiple sclerosis and an association with midbrain lesions has been claimed; however, most of the reported patients had multiple brain alterations so it was difficult to associate this symptom with a specific lesion site. We illustrate the cases of two patients with an isolated demyelinating midbrain lesion presenting paroxysmal dysarthria as the only symptom; both participants had oligoclonal bands in the cerebrospinal fluid and an unremarkable follow-up. Both patients had benefit from carbamazepine treatment, similarly to previously reported cases. Our report confirms that a demyelinating midbrain lesion is sufficient to provoke paroxysmal dysarthria. It is noteworthy that an erroneous diagnosis of psychogenic disorders was initially made in both cases, highlighting the importance not to underestimate isolated paroxysmal symptoms in clinical practice.
van der Linde, Karina; Kastner, Christine; Kumlehn, Jochen; Kahmann, Regine; Doehlemann, Gunther
Infection of maize (Zea mays) plants with the corn smut fungus Ustilago maydis leads to the formation of large tumors on the stem, leaves and inflorescences. In this biotrophic interaction, plant defense responses are actively suppressed by the pathogen, and previous transcriptome analyses of infected maize plants showed massive and stage-specific changes in host gene expression during disease progression. To identify maize genes that are functionally involved in the interaction with U. maydis, we adapted a virus-induced gene silencing (VIGS) system based on the brome mosaic virus (BMV) for maize. Conditions were established that allowed successful U. maydis infection of BMV-preinfected maize plants. This set-up enabled quantification of VIGS and its impact on U. maydis infection using a quantitative real-time PCR (qRT-PCR)-based readout. In proof-of-principle experiments, an U. maydis-induced terpene synthase was shown to negatively regulate disease development while a protein involved in cell death inhibition was required for full virulence of U. maydis. The results suggest that this system is a versatile tool for the rapid identification of maize genes that determine compatibility with U. maydis. © (2010) Max Planck Society. Journal compilation © New Phytologist Trust (2010).
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune mediated disorder of the peripheral nervous system with clinical features that include weakness, sensory loss, imbalance, pain and impaired ambulation which may lead to substantial disability. This review highlights current treatment strategies for CIDP, how best to utilize proven therapies such as intravenous immunoglobulin, oral prednisone, pulse dexamethasone, and plasma exchange, and when and how to use alternative immunosuppressive agents when first-line therapies are ineffective or poorly tolerated. PMID:23139706
Full Text Available Objective To study the clinical manifestations, imaging and pathological features, treatment and prognosis of 5 patients diagnosed as demyelinating pseudotumor (DPT by pathology. Methods The data of clinical features, radiological and histological examination of 5 patients with DPT were retrospectively analyzed, and relevant literatures were reviewed. Results All patients were male. Main symptoms included limb weakness in 3 cases, dizziness and impaired memory in 2 cases, seizures in one case. Head MRI examination revealed space-occupying lesions with hypointense signal on T1WI, hyperintense signal on T2WI and FLAIR. Enhanced MRI showed obvious enhancement of lesions (open-ring enhancement in 3 cases. The lesion were totally (4 cases or partially (one case removed, and postoperative histological examination showed inflammatory demyelination. One case died after twice relapse, and others had favorable prognosis. Conclusions DPT is an inflammatory demyelination with mass effect. It should be differentiated from central nervous system tumors in order to avoid unnecessary resection or radiotherapy. DOI: 10.3969/j.issn.1672-6731.2017.03.010
This review describes the progress made in preparing Cochrane systematic reviews of randomized controlled trials for Guillain–Barré syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), multifocal motor neuropathy (MMN) and the demyelinating neuropathies associated with paraproteins. The discovery of antibodies against myelin andaxolemmal glycolipids and proteins has not yet replaced the clinicopathological classificationon which treatment trials have been based. Systematic reviews have endorsed the equivalence of plasma exchange (PE) and intravenous immunoglobulin (IVIg) and the lack of efficacy of steroids in GBS. Systematic reviews have also endorsed the value of steroids, PE and IVIg in CIDP butrandomized controlled trials have only shown benefit from IVIg in MMN. There is a paucity of evidence concerning the efficacy of treatments in paraproteinaemic demyelinating neuropathy apartment from small trials showing short-term benefit from PE or IVIg. There is a lack of good quality controlled trials of immunosuppressive agents in any of these conditions. As the numberof treatment trials increases, Cochrane systematic reviews will be an increasingly valuable resource for summarizing the evidence from randomised controlled trials on which to base clinical practice. They already demonstrate major deficiencies in the existing evidence base. PMID:12090400
Mortenson, Andrew R; Sprung, Juraj; Watson, James C; Dyck, P James B; Weingarten, Toby N
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired autoimmune demyelinating polyneuropathy characterized by symmetrical diffuse weakness that also can rarely affect bulbar and respiratory muscles. The study objective was to describe perioperative outcomes of patients with CIDP who received general anesthesia. This retrospective observational study evaluated patients with active (diagnosed or treated within the previous year) CIDP who underwent general anesthesia at our institution between January 1, 2010, and December 31, 2015. Medical records were reviewed for perioperative outcomes with emphasis on respiratory complications or unexpected reactions to muscle relaxants. Seventeen patients with CIDP underwent general anesthesia, of whom 16 had muscle weakness. Succinylcholine was used in 5 cases (29.4%) and nondepolarizing muscle relaxants in 11 cases (64.7%). Two patients required postoperative mechanical ventilation; one was critically ill and the other had open heart surgery. One patient had aspiration on the second postoperative day and required endotracheal intubation and mechanical ventilation for 3 days. Three patients had worsening CIDP symptoms: 1 acutely after surgery; 1 several months later; and 1 who died in the hospital. The patient who died underwent lengthy abdominal exploration, had acute worsening of neurologic symptoms, and died after 46 days of malnutrition. Anesthetic concerns of patients with CIDP include frailty, bulbar dysfunction, and the effects of immunosuppressive therapy. Although our patients tolerated neuromuscular drugs, substantial theoretical concerns with these medications in patients with demyelinating neuropathies preclude safety in this population without further study.
Full Text Available Neurotropin® (NTP, a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases.
Koutlidis, R M; Ayrignac, X; Pradat, P-F; Le Forestier, N; Léger, J-M; Salachas, F; Maisonobe, T; Fournier, E; Viala, K
Somatosensory-evoked potentials with segmental recordings were performed with the aim of distinguishing chronic inflammatory demyelinating polyneuropathy from other sensory neuropathies. Four groups of 20 subjects each corresponded to patients with (1) possible sensory chronic inflammatory demyelinating polyneuropathy, (2) patients with sensory polyneuropathy of unknown origin, (3) patients with amyotrophic lateral sclerosis and (4) normal subjects. The patients selected for this study had preserved sensory potentials on electroneuromyogram and all waves were recordable in evoked potentials. Somatosensory-evoked potentials evaluations were carried out by stimulation of the posterior tibial nerve at the ankle, recording peripheral nerve potential in the popliteal fossa, radicular potential and spinal potential at the L4-L5 and T12 levels, and cortical at C'z, with determination of distal conduction time, proximal and radicular conduction time and central conduction time. In the group of chronic inflammatory demyelinating polyneuropathy, 80% of patients had abnormal conduction in the N8-N22 segment and 95% had abnormal N18-N22 conduction time. In the group of neuropathies, distal conduction was abnormal in most cases, whereas 60% of patients had no proximal abnormality. None of the patients in the group of amyotrophic lateral sclerosis had an abnormal N18-N22 conduction time. Somatosensory-evoked potentials with segmental recording can be used to distinguish between atypical sensory chronic inflammatory demyelinating polyneuropathy and other sensory neuropathies, at the early stage of the disease. Graphical representation of segmental conduction times provides a rapid and accurate visualization of the profile of each patient. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Full Text Available H01717 Optic neuritis Optic neuritis is a demyelinating inflammatory disease of th...feron or glatiramer acetate is recommended. Nervous system disease ... Methylprednisolone [DR:D00751] Inter
Grønlund, Mette; Olsen, Anne; Johansen, Elisabeth
Virus-induced gene silencing (VIGS) is an alternative reverse genetics tool for silencing of genes in some plants, which are difficult to transform. The pea early-browning virus (PEBV) has been developed as a VIGS vector and used in pea for functional analysis of several genes. However......, the available PEBV-VIGS protocols are inadequate for studying genes involved in the symbiosis with arbuscular mycorrhizal fungi (AMF). Here we describe a PEBV-VIGS protocol suitable for reverse genetics studies in pea of genes involved in the symbiosis with AMF and show its effectiveness in silencing genes...
Furusho, Miki; Roulois, Aude J; Franklin, Robin J M; Bansal, Rashmi
Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of proregenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease. © 2015 Wiley Periodicals, Inc.
Hellmann, M A; Lev, N; Lotan, I; Mosberg-Galili, R; Inbar, E; Luckman, J; Fichman-Horn, S; Yakimov, M; Steiner, I
Finglimod, a sphingosine 1-phosphate receptor modulator, is the first orally administered therapy approved for prophylaxis in multiple sclerosis (MS). Several reports in the last two years suggested that it might be associated with severe augmentation of disease activity upon initiation or discontinuation of therapy. We present an MS patient who developed a giant cavitating brain lesion under fingolimod and in whom cessation of therapy was associated with a very active course. Brain biopsy revealed the lesion to be due to an active demyelinating inflammatory process. With the current wave of immunosuppressive treatments for MS, there is a need to be vigilant to side effects and risks not identified in large multicenter trials, collect the data and set guidelines and precautions for present and future medications. Copyright © 2014 Elsevier B.V. All rights reserved.
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.
Teige, Ingrid; Treschow, Alexandra; Teige, Anna
Since the basic mechanisms behind the beneficial effects of IFN-beta in multiple sclerosis (MS) patients are still obscure, here we have investigated the effects of IFN-beta gene disruption on the commonly used animal model for MS, experimental autoimmune encephalomyelitis (EAE). We show that IFN......-beta knockout (KO) mice are more susceptible to EAE than their wild-type (wt) littermates; they develop more severe and chronic neurological symptoms with more extensive CNS inflammation and demyelination. However, there was no discrepancy observed between wt and KO mice regarding the capacity of T cells...... to proliferate or produce IFN-gamma in response to recall Ag. Consequently, we addressed the effect of IFN-beta on encephalitogenic T cell development and the disease initiation phase by passive transfer of autoreactive T cells from KO or wt littermates to both groups of mice. Interestingly, IFN-beta KO mice...
Bril, Vera; Blanchette, Christopher M.; Noone, Joshua M.; Runken, M. Chris; Gelinas, Deborah; Russell, James W.
Purpose We reviewed the literature on chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetes mellitus (DM) and explored real-world data on the prevalence and treatment of CIDP within DM. Methods: A literature search of Scopus was performed for the terms chronic inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, and prevalence, incidence, epidemiology, or diabetes; peripheral neuropathy and prevalence or diabetes. We also searched through the reference lists of the resulting publications for additional findings that may have been missed. Additional publications on guidelines for the diagnosis of CIDP and diabetic neuropathy were also included. A descriptive analysis of the 2009–2013 PharMetrics Plus™ Database was performed to estimate the prevalence and treatment of CIDP within the DM population. Results There is an increasing body of literature suggesting that the prevalence of CIDP tends to be higher in diabetic patients, especially in those of older age. Our real-world data seem to support published findings from the literature. For the total cohort (N = 101,321,694), the percent prevalence of CIDP (n = 8,173) was 0.008%; DM (n = 4,026,740) was 4%. The percent prevalence of CIDP without DM (n = 5,986) was 0.006%; CIDP with DM (n = 2,187) was 9-fold higher at 0.054%. For patients >50 years old, there was a significantly higher percentage of CIDP with DM than CIDP without DM. Approximately 50% of CIDP patients were treated with IVIg, 23%–24% with steroids, 1%–2% with PE, and 20%–23% received no treatment. Conclusions In addition to the growing evidence of higher prevalence of CIDP in DM, our findings reinforce the need for heightened awareness of the association of CIDP and DM. PMID:27389526
Marsh, E A
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.
Seki, Scott M; Stevenson, Max; Rosen, Abagail M; Arandjelovic, Sanja; Gemta, Lelisa; Bullock, Timothy N J; Gaultier, Alban
Multiple sclerosis (MS) is a disease that is characterized by immune-mediated destruction of CNS myelin. Current MS therapies aim to block peripheral immune cells from entering the CNS. Although these treatments limit new inflammatory activity in the CNS, no treatment effectively prevents long-term disease progression and disability accumulation in MS patients. One explanation for this paradox is that current therapies are ineffective at targeting immune responses already present in the CNS. To this end, we sought to understand the metabolic properties of T cells that mediate ongoing inflammation in the demyelinating CNS. Using experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a well-studied model of MS, we showed that the CD4(+) and CD8(+) T cells that invade the EAE CNS are highly glycolytic. Elevated glycolytic rates in T cells isolated from the EAE CNS correlate with upregulated expression of glycolytic machinery and is essential for inflammatory responses to myelin. Surprisingly, we found that an inhibitor of GAPDH, 3-bromopyruvic acid (3-BrPa), blocks IFN-γ, but not IL-17A, production in immune cells isolated from the EAE CNS. Indeed, in vitro studies confirmed that the production of IFN-γ by differentiated Th1 cells is more sensitive to 3-BrPa than is the production of IL-17A by Th17 cells. Finally, in transfer models of EAE, 3-BrPa robustly attenuates the encephalitogenic potential of EAE-driving immune cells. To our knowledge, these data are among the first to demonstrate the metabolic properties of T cells in the demyelinating CNS in vivo. Copyright © 2017 by The American Association of Immunologists, Inc.
Karma, A; Pirttilä, T A; Viljanen, M K; Lähde, Y E; Raitta, C M
A 15-year-old girl developed retinitis pigmentosa-like fundus changes in the left eye and optic neuropathy in the right eye as well as cerebral demyelination as a result of late Lyme borreliosis (LB). The diagnosis was confirmed by polymerase chain reaction, which detected a Borrelia burgdorferi specific segment of a gene coding for 41 kD endoflagellin, both in the vitreous and the cerebrospinal fluid. The diagnosis was delayed because testing for Borrelia antibodies in serum and cerebrospinal fluid yielded negative results. However, later on, another laboratory reported the antibodies of the patient's pretreatment serum to be positive for LB. Images PMID:8435413
Saini, Jitender; Chatterjee, Somenath; Thomas, Bejoy; Kesavadas, Chandrasekharan (Dept. of Imaging Sciences and Interventional Radiology, Sree Chitra Thirunal Inst. for Medical Sciences and Technology, Trivandrum (India)), email: firstname.lastname@example.org
Background. Tumefactive demyelination (TD) is a relatively uncommon entity which mimics other focal intracranial lesions. Conventional radiological findings in tumefactive demyelination have been well described. However, DTI and MRS findings in TD have not been studied in detail. Purpose. To evaluate the usefulness of conventional magnetic resonance imaging (MRI), multivoxel 1H spectroscopy (MRS) and diffusion tensor imaging (DTI) in diagnosis and follow-up of TD of the brain. Material and Methods. Clinical and imaging findings of 18 patients were reviewed. MR imaging data which included conventional imaging as well as MRS and DTI were reviewed. At TE 135ms MRS various metabolite ratios were calculated at different depths of the demyelinating lesions. At TE 30 ms, glutamate-glutamine (GLX-2.1-2.5 ppm) was compared in the lesion to the contralateral normal side. DTI data were available for 15 patients and Dav (mean diffusivity) and trace values were recorded from central and peripheral layers of the index lesion. Histopathological (9 patients) and therapeutic response (9 patients) on follow-up imaging were taken as the diagnostic criterion. In addition, the follow-up MRI scans available were also reviewed. Results. Characteristic peripheral 'broken ring' type of contrast enhancement was noted in 12 cases. Two or three concentric distinct zones were noted on imaging with distinct metabolic and structural signature in most cases. On TE 135ms, the central part showed variable Choline (Cho) and significantly low N-Acetyl Aspartate (NAA). DTI demonstrated high Dav and very low trace value in this zone. The intermediate area showed higher Cho and lower NAA compared to contralateral normal side. The outermost layer, which corresponded to the contrast enhancing areas on MRI, showed high Cho, lower NAA, and restricted diffusion on DTI. The GLX increase was noted in tumefactive lesions. Lactate was observed in all patients and it appeared higher at the center
Beppu, Minako; Sawai, Setsu; Satoh, Mamoru; Mori, Masahiro; Kazami, Takahiro; Misawa, Sonoko; Shibuya, Kazumoto; Ishibashi, Masumi; Sogawa, Kazuyuki; Kado, Sayaka; Kodera, Yoshio; Nomura, Fumio; Kuwabara, Satoshi
To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of "typical" CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients. Copyright © 2015 Elsevier B.V. All rights reserved.
Full Text Available Epidemiologic and clinical evidence suggests that virus infection plays an important role in human type 1 diabetes pathogenesis. We used the virus-inducible BioBreeding Diabetes Resistant (BBDR rat to investigate the ability of sodium salicylate, a non-steroidal anti-inflammatory drug (NSAID, to modulate development of type 1 diabetes. BBDR rats treated with Kilham rat virus (KRV and polyinosinic:polycytidylic acid (pIC, a TLR3 agonist develop diabetes at nearly 100% incidence by ~2 weeks. We found distinct temporal profiles of the proinflammatory serum cytokines, IL-1β, IL-6, IFN-γ, IL-12, and haptoglobin (an acute phase protein in KRV+pIC treated rats. Significant elevations of IL-1β and IL-12, coupled with sustained elevations of haptoglobin, were specific to KRV+pIC and not found in rats co-treated with pIC and H1, a non-diabetogenic virus. Salicylate administered concurrently with KRV+pIC inhibited the elevations in IL-1β, IL-6, IFN-γ and haptoglobin almost completely, and reduced IL-12 levels significantly. Salicylate prevented diabetes in a dose-dependent manner, and diabetes-free animals had no evidence of insulitis. Our data support an important role for innate immunity in virus-induced type 1 diabetes pathogenesis. The ability of salicylate to prevent diabetes in this robust animal model demonstrates its potential use to prevent or attenuate human autoimmune diabetes.
Dong, Zhan-Qi; Chen, Ting-Ting; Zhang, Jun; Hu, Nan; Cao, Ming-Ya; Dong, Fei-Fan; Jiang, Ya-Ming; Chen, Peng; Lu, Cheng; Pan, Min-Hui
Although current antiviral strategies can inhibit baculovirus infection and decrease viral DNA replication to a certain extent, novel tools are required for specific and accurate elimination of baculovirus genomes from infected insects. Using the newly developed clustered regularly interspaced short palindromic repeats/associated protein 9 nuclease (CRISPR/Cas9) technology, we disrupted a viral genome in infected insect cells in vitro as a defense against viral infection. We optimized the CRISPR/Cas9 system to edit foreign and viral genome in insect cells. Using Bombyx mori nucleopolyhedrovirus (BmNPV) as a model, we found that the CRISPR/Cas9 system was capable of cleaving the replication key factor ie-1 in BmNPV thus effectively inhibiting virus proliferation. Furthermore, we constructed a virus-inducible CRISPR/Cas9 editing system, which minimized the probability of off-target effects and was rapidly activated after viral infection. This is the first report describing the application of the CRISPR/Cas9 system in insect antiviral research. Establishment of a highly efficient virus-inducible CRISPR/Cas9 system in insect cells provides insights to produce virus-resistant transgenic strains for future. Copyright © 2016 Elsevier B.V. All rights reserved.
Full Text Available Converging lines of clinical and epidemiological evidence suggest that viral infections in early developmental stages may be a causal factor in neuropsychiatric disorders such as schizophrenia, bipolar disorder, and autism-spectrum disorders. This etiological link, however, remains controversial in view of the lack of consistent and reproducible associations between viruses and mental illness. Animal models of virus-induced neurobehavioral disturbances afford powerful tools to test etiological hypotheses and explore pathophysiological mechanisms. Prenatal or neonatal inoculations of neurotropic agents (such as herpes-, influenza-, and retroviruses in rodents result in a broad spectrum of long-term alterations reminiscent of psychiatric abnormalities. Nevertheless, the complexity of these sequelae often poses methodological and interpretational challenges and thwarts their characterization. The recent conceptual advancements in psychiatric nosology and behavioral science may help determine new heuristic criteria to enhance the translational value of these models. A particularly critical issue is the identification of intermediate phenotypes, defined as quantifiable factors representing single neurochemical, neuropsychological, or neuroanatomical aspects of a diagnostic category. In this paper, we examine how the employment of these novel concepts may lead to new methodological refinements in the study of virus-induced neurobehavioral sequelae through animal models.
E.D. van Pelt - Gravesteijn (Daniëlle)
markdownabstractAcquired demyelinating syndromes (ADS) cover a broad spectrum of central nervous system (CNS) inflammatory demyelinating syndromes, of which multiple sclerosis (MS) is the most common subtype. This thesis focuses on two relatively rare clinical subtypes of ADS: neuromyelitis optica
Stephanova, D I; Krustev, S M; Negrev, N; Daskalova, M
Recently, patients with chronic demyelinating neuropathies have demonstrated significant abnormalities in their multiple nerve excitability properties measured by a non-invasive threshold tracking technique. In order to expand our studies on the possible mechanisms underlying these abnormalities, which are not yet well understood, we investigate the contributions of the aqueous layers within the myelin sheath on multiple membrane properties of simulated fibre demyelinations. Four degrees of systematic paranodal demyelinations (two mild demyelinations termed PSD1 and PSD2, without/with aqueous layers respectively, and two severe demyelinations termed PSD3 and PSD4, with/without aqueous layers, respectively) are simulated using our previous multi-layered model of human motor nerve fibre. We studied the following parameters of myelinated axonal function: potentials (intracellular action, electrotonic-reflecting the propagating and accommodative fibre processes, respectively) and strength-duration time constants, rheobases, recovery cycles (reflecting the adaptive fibre processes). The results show that each excitability parameter is markedly potentiated when the aqueous layers within their paranodally demyelinated sheaths are taken into account. The effect of the aqueous layers is significantly higher on the propagating processes than on the accommodative and adaptive processes in the fibres. The aqueous layers restore the action potential propagation, which is initially blocked when they are not taken into account. The study provides new and important information on the mechanisms of chronic demyelinating neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP). © Imperial College Press
Dunham, Jordon; van de Vis, Reinofke; Bauer, Jan; Wubben, Jacqueline; van Driel, Nikki; Laman, Jon D; 't Hart, Bert A; Kap, Yolanda S
Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders
Anadani, Mohammad; Katirji, Bashar
Acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is an increasingly recognized CIDP subtype. Differentiating A-CIDP from Guillain-Barré syndrome (GBS) is challenging but important, because there are different treatment outcomes. We report 3 patients with A-CIDP who were initially diagnosed with severe GBS but were later confirmed to have CIDP based on their clinical course and electrodiagnostic (EDx) studies. We also report on the long-term treatment of these patients and review the literature on EDx studies in this syndrome. Three patients were initially diagnosed with GBS and responded to treatment. However, all 3 had arrest in improvement or deterioration during their rehabilitation phases. EDx studies showed prominent demyelinating changes many months after the initial presentation. All responded very well to immunotherapy. Although several features may suggest the diagnosis of A-CIDP at initial presentation, close follow-up of GBS patients during the recovery phase is also needed for accurate diagnosis. EDx studies may distinguish patients with A-CIDP from GBS patients. © 2015 Wiley Periodicals, Inc.
Bjerregaard, Asger; Laing, Ingrid A; Poulsen, Nadia
BACKGROUND: In experimental studies viral infections have been shown to induce type 2 inflammation in asthmatics, but whether this is a feature of naturally occurring virus-induced asthma exacerbations is unknown. Thymic stromal lymphopoietin (TSLP) released from the airway epithelium in response...... occurring virus-induced exacerbations of asthma and whether TSLP is associated with this type 2 inflammation. METHODS: Patients presenting to hospital with acute asthma were examined during the exacerbation, and after 4 weeks recovery. The assessments included spirometry, FeNO and induced sputum...
Berg, Carsten Tue; Khorooshi, Reza M. H.; Asgari, Nasrin
-MOG antibody and mouse complement were stereotactically injected into the corpus callosum of wild-type and type I IFN receptor deficient mice (IFNAR1-KO) with and without pre-established experimental autoimmune encephalomyelitis (EAE). Results Anti-MOG induced complement-dependent demyelination in the corpus...... callosum of wild-type mice and did not occur in mice that received control IgG2a. Deposition of activated complement coincided with demyelination, and this was significantly reduced in IFNAR1-KO mice. Co-injection of anti-MOG and complement at onset of symptoms of EAE induced similar levels of callosal...... 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....
Popescu, Bogdan F.G.; Guo, Yong; Jentoft, Mark E.; Parisi, Joseph E.; Lennon, Vanda A.; Pittock, Sean J.; Weinshenker, Brian G.; Wingerchuk, Dean M.; Giannini, Caterina; Metz, Imke; Brück, Wolfgang; Shuster, Elizabeth A.; Carter, Jonathan; Boyd, Clara D.; Clardy, Stacey Lynn; Cohen, Bruce A.
Objective: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4–immunoglobulin G (IgG) serologic testing. Methods: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. Results: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)–positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. Conclusions: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS. PMID:25503621
Full Text Available Abstract Introduction Granulomatous lesions are commonly encountered abnormalities in pulmonary pathology, and often pose a diagnostic challenge. We report an unusual case of granulomatous lung disease with uncommon characteristics, which developed following Epstein-Barr-virus-induced mononucleosis and new-onset systemic lupus erythematosus. We aim to highlight a diagnostic approach for the condition and to raise awareness of the possibility of it being related to the immunological reaction caused by Epstein-Barr virus infection. Case presentation A 36-year-old Japanese man, who had been diagnosed with Epstein-Barr-virus-induced infectious mononucleosis, new-onset systemic lupus erythematosus, and secondary Sjögren’s syndrome three weeks previously, presented to our facility with fever and diffuse pulmonary infiltrates. A computed tomography scan of the chest revealed multiple small nodules in both lungs. Fiberoptic bronchoscopy with bronchoalveolar lavage revealed lymphocytosis with predominance of T lymphocytes. A histological examination of a lung biopsy taken during video-assisted thoracic surgery showed randomly distributed tiny granulomatous lesions with infiltration of eosinophils. The differential diagnoses included hypersensitivity pneumonitis, sarcoidosis, and pulmonary involvement of Crohn’s disease, systemic lupus erythematosus, and Sjögren’s syndrome, but the clinical and pathological findings were not consistent with any of these. Our patient’s condition did not improve; therefore, prednisolone therapy was started because of the possibility of specific immunological reactions associated with Epstein-Barr virus infection. After steroid treatment, our patient showed radiological and clinical improvement. Conclusions To the best of our knowledge, this is the first case of a patient developing randomly distributed multiple granulomatous lung lesions with eosinophilic infiltrates after Epstein-Barr virus infection and systemic
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
Full Text Available Multiple sclerosis (MS is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS. Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1 have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB. The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS.
Wijnands, José M A; Kingwell, Elaine; Zhu, Feng; Zhao, Yinshan; Högg, Tanja; Stadnyk, Karen; Ekuma, Okechukwu; Lu, Xinya; Evans, Charity; Fisk, John D; Marrie, Ruth Ann; Tremlett, Helen
Degenerative processes in neurodegenerative diseases can start years before clinical manifestation. We aimed to establish whether a multiple sclerosis prodromal period exists by examining patterns of health-care use before a first demyelinating event. In this matched cohort study, we used data from linked health administrative and clinical databases from four Canadian provinces (British Columbia, Saskatchewan, Manitoba, and Nova Scotia) to compare hospital, physician, and prescription use data from people with multiple sclerosis and matched general population controls in the 5 years before the first demyelinating disease claim (health administrative index date) or clinically reported symptom onset (clinical index date). Rate ratios (RRs) were estimated using negative binomial regression and combined across provinces using random effect models. The primary outcome was all-cause use of health care during each of the 5 years before the health administrative or clinical index date. The health administrative cohort included 14 428 multiple sclerosis cases and 72 059 matched controls for whom data were available between April, 1984, and April, 2014. Annual health-care use increased steadily between 5 years and 1 year before the first demyelinating disease claim in people with multiple sclerosis compared with controls (from RR 1·26 [95% CI 1·16-1·36] to 1·78 [1·50-2·10] for hospital admissions; from 1·24 [1·16-1·32] to 1·88 [1·72-2·07] for physician claims; and from 1·23 [1·06-1·41] to 1·49 [1·41-1·59] for prescriptions, assessed as drug classes). Similar patterns for physician claims and prescriptions were observed in the cohort with available clinical symptom onset (3202 individuals with multiple sclerosis and 16 006 controls), although the differences in use in each of the 5 years mostly did not reach statistical significance. More frequent use of health care in patients with multiple sclerosis than in controls in the 5 years before a first
Meulstee, J.; van der Meché, F G
Since the development of effective but expensive therapeutic strategies for the treatment of Guillain-Barré syndrome, early confirmation of the diagnosis has become very important. Electrodiagnostic criteria were developed for the discrimination of polyneuropathy and in particular for demyelination. The sensitivity and specificity of these criteria were determined in 135 patients with Guillain-Barré syndrome in an early stage of the disease, along with 45 healthy volunteers. The algorithms us...
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.
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...
Full Text Available erized by compressive focal neuropathies and an underlying sensorimotor demyelinative polyneuropathy. HNPP i...d in Charcot-Marie-Tooth disease type 1A (CMT1A). The other identified underlying genetic defects in HNPP ar
Bruun-Rasmussen, Marianne; Madsen, Christian Toft; Jessing, Stine
Virus-induced gene silencing (VIGS) can be used as a powerful tool for functional genomics studies in plants. With this approach, it is possible to target most genes and downregulate the messenger (m)RNA in a sequence-specific manner. Barley stripe mosaic virus (BSMV) is an established VIGS vector...... for barley and wheat; however, silencing using this vector is generally transient, with efficient silencing often being confined to the first two or three systemically infected leaves. To investigate this further, part of the barley Phytoene desaturase (PDS) gene was inserted into BSMV and the resulting...... photobleaching in infected barley plants was used as a reporter for silencing. In addition, downregulation of PDS mRNA was measured by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Using fragments of PDS ranging from 128 to 584 nucleotides in BSMV, we observed that insert length...
Mankgopo Magdeline Kgatle
Full Text Available Approximately 20% of human cancers is attributable to DNA oncogenic viruses such as human papillomavirus (HPV, hepatitis B virus (HBV, and Epstein-Barr virus (EBV. Unrepaired DNA damage is the most common and overlapping feature of these DNA oncogenic viruses and a source of genomic instability and tumour development. Sustained DNA damage results from unceasing production of reactive oxygen species and activation of inflammasome cascades that trigger genomic changes and increased propensity of epigenetic alterations. Accumulation of epigenetic alterations may interfere with genome-wide cellular signalling machineries and promote malignant transformation leading to cancer development. Untangling and understanding the underlying mechanisms that promote these detrimental effects remain the major objectives for ongoing research and hope for effective virus-induced cancer therapy. Here, we review current literature with an emphasis on how DNA damage influences HPV, HVB, and EBV replication and epigenetic alterations that are associated with carcinogenesis.
Mei, Yu; Whitham, Steven A
Virus-induced gene silencing (VIGS) is a powerful technology for rapidly and transiently knocking down the expression of plant genes to study their functions. A VIGS vector for maize derived from Foxtail mosaic virus (FoMV), a positive-sense single-stranded RNA virus, was recently developed. A cloning site created near the 3' end of the FoMV genome enables insertion of 200-400 nucleotide fragments of maize genes targeted for silencing. The recombinant FoMV clones are inoculated into leaves of maize seedlings by biolistic particle delivery, and silencing is typically observed within 2 weeks after inoculation. This chapter provides a protocol for constructing FoMV VIGS clones and inoculating them into maize seedlings.
Castro, Marcelo A.; Thomasson, David; Avila, Nilo A.; Hufton, Jennifer; Senseney, Justin; Johnson, Reed F.; Dyall, Julie
Monkeypox virus is an emerging zoonotic pathogen that results in up to 10% mortality in humans. Knowledge of clinical manifestations and temporal progression of monkeypox disease is limited to data collected from rare outbreaks in remote regions of Central and West Africa. Clinical observations show that monkeypox infection resembles variola infection. Given the limited capability to study monkeypox disease in humans, characterization of the disease in animal models is required. A previous work focused on the identification of inflammatory patterns using PET/CT image modality in two non-human primates previously inoculated with the virus. In this work we extended techniques used in computer-aided detection of lung tumors to identify inflammatory lesions from monkeypox virus infection and their progression using CT images. Accurate estimation of partial volumes of lung lesions via segmentation is difficult because of poor discrimination between blood vessels, diseased regions, and outer structures. We used hard C-means algorithm in conjunction with landmark based registration to estimate the extent of monkeypox virus induced disease before inoculation and after disease progression. Automated estimation is in close agreement with manual segmentation.
Christensen, Jeanette Erbo; Simonsen, Stine; Fenger, Christina
Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30...
Benned-Jensen, Tau; Madsen, Christian M; Arfelt, Kristine N
The Epstein-Barr virus induced gene 2 (EBI2) was recently identified as the first oxysterol-activated 7TM receptor. EBI2 is essential for B cell trafficking within lymphoid tissues and thus the humoral immune response in general. Here we characterize the antagonism of the non-peptide molecule GSK...
Benned-Jensen, Tau; Norn, Christoffer; Laurent, Stephane
, the family of G protein-coupled seven transmembrane-spanning receptors (7TM receptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2 or GPR183) was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol (7α,25-OHC). Nothing is known about...
Christensen, Jeanette E; Simonsen, Stine; Fenger, Christina
Intracerebral inoculation of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) normally results in fatal CD8+ T cell mediated meningoencephalitis. However, in CXCL10-deficient mice, the virus-induced CD8+ T cell accumulation in the neural parenchyma is impaired, and only 30-50% ...
Virus-induced gene silencing (VIGS) is a widely used tool for gene function studies in many plant species, though its use in monocots has been limited. Using a Brome mosaic virus (BMV) vector designed to silence the maize phytoene desaturase gene, a genetically diverse set of maize inbred lines was ...
Grønlund, Mette; Kjær, Gabriela Didina Constantin; Piednoir, Elodie
Virus-induced gene silencing (VIGS) has become an important reverse genetics tool for functional genomics. VIGS vectors based on Pea early browning virus (PEBV, genus Tobravirus) and Bean pod mottle virus (genus Comovirus) are available for the legume species Pisum sativum and Glycine max...
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.
Markvardsen, L H; Harbo, T; Sindrup, S H
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...... 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...... remained unchanged. CONCLUSION: SCIG preserves muscle strength and functional ability in patients with CIDP who previously responded to IVIG. SCIG should be considered as an alternative in long-term treatment of CIDP patients....
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)
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.)
Tugal-Tutkun, Ilknur; Cimino, Luca; Akova, Yonca Aydin
Varicella zoster virus (VZV)-induced anterior uveitis (AU) may complicate the course of primary varicella infection typically seen in children. In adults, especially with advanced age, VZV AU is more commonly associated with herpes zoster ophthalmicus (HZO) with or without skin rash affecting the distribution of the ophthalmic nerve due to reactivation of the latent VZV in the trigeminal ganglion. While it is typically a mild self-limiting AU in primary infection, HZO AU is often accompanied by keratitis, may have a chronic recurrent course, and lead to sectoral iris atrophy, pupillary distortion, and ocular hypertension. Diagnosis is often clinical and proven by analysis of aqueous humor for viral genome or antiviral antibodies. Systemic antiviral agents and topical steroids are the mainstay of treatment. Visual prognosis is favorable with timely diagnosis and appropriate treatment.
Moalem-Taylor, Gila; Allbutt, Haydn N; Iordanova, Mihaela D; Tracey, David J
Experimental autoimmune neuritis (EAN) is a T cell mediated autoimmune disease of the peripheral nervous system that serves as an animal model of the acute inflammatory demyelinating polyradiculoneuropathy in Guillain-Barre syndrome (GBS). Although pain is a common symptom of GBS occurring in 55-85% of cases, it is often overlooked and the underlying mechanisms are poorly understood. Here we examined whether animals with EAN exhibit signs of neuropathic pain including hyperalgesia and allodynia, and assessed their peripheral nerve autoimmune inflammation. We immunized Lewis rats with peripheral myelin P2 peptide (amino acids 57-81) emulsified with complete Freund's adjuvant, or with adjuvant only as control. P2-immunized rats developed mild to modest monophasic EAN with disease onset at day 8, peak at days 15-17, and full recovery by day 28 following immunization. Rats with EAN showed a significant decrease in withdrawal latency to thermal stimuli and withdrawal threshold to mechanical stimuli, in both hindpaws and forepaws, during the course of the disease. We observed a significant infiltration of T cells bearing alphabeta receptors, and a significant increase in antigen-presenting cells expressing MHC class II as well as macrophages, in EAN-affected rats. Our results demonstrate that animals with active EAN develop significant thermal hyperalgesia and mechanical allodynia, accompanied by pronounced autoimmune inflammation in peripheral nerves. These findings suggest that EAN is a useful model for the pain seen in many GBS patients, and may facilitate study of neuroimmune mechanisms underlying pain in autoimmune neuropathies.
Following 4000 rad of x-irradiation and transplantation of sciatic nerve over the dorsal columns, extensive partial demyelination occurred in some animals. This dose of radiation inhibits remyelination so this phenomenon could be studied knowing that remyelination was absent. Partial demyelination was characterized by translocation of myelin to form large myelin ovoids which remained associated with the remaining thinned myelin sheath; nodal widening, involvement of one paranode only, transition from thin to thick myelin along an internode, enlargement and disorientated oligodendrocyte tongues were also features of this change. It is concluded that partial demyelination results when oligodendrocytes have to function in a sub-optimal environment.
Kamel, M H
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.
Krutenkova, E., E-mail: email@example.com; Pan, E.; Khodanovich, M., E-mail: firstname.lastname@example.org [National Research Tomsk State University, Lenina pr., 36, Tomsk (Russian Federation)
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.
Esposito, Susanna; Di Pietro, Giada Maria; Madini, Barbara; Mastrolia, Maria Vincenza; Rigante, Donato
Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that involves multifocal areas of the white matter, rarely the gray matter and spinal cord, mainly affecting children and mostly occurring 1-2weeks after infections or more rarely after vaccinations. Though a specific etiologic agent is not constantly identified, to evaluate carefully patient's clinical history and obtain adequate samples for the search of a potential ADEM causal agent is crucial. In the case of a prompt diagnosis and adequate treatment, most children with ADEM have a favorable outcome with full recovery, but in the case of diagnostic delays or inappropriate treatment some patients might display neurological sequelae and persistent deficits or even show an evolution to multiple sclerosis. The suspicion of ADEM rises on a clinical basis and derives from systemic and neurologic signs combined with magnetic resonance imaging of the central nervous system. Other advanced imaging techniques may help an appropriate differential diagnosis and definition of exact disease extension. Although there is no standardized protocol or management for ADEM, corticosteroids, intravenous immunoglobulin, and plasmapheresis have been successfully used. There is no marker that permits to identify the subset of children with worse prognosis and future studies should try to detect any biological clue for prevision of neurologic damage as well as should optimize treatment strategies using an approach based on the effective risk of negative evolution. Copyright © 2015 Elsevier B.V. All rights reserved.
Full Text Available The authors report a 24-year-old man with Hansen′s disease in Type 1 reaction, developing a demyelinating disorder affecting the central and peripheral nervous system. He responded well to plasma exchange and intravenous methyl prednisolone. The neural damage could have been due to cross-reacting epitopes causing molecular mimicry and resultant demyelinating disorder.
Jagessar, S Anwar; Kap, Yolanda S; Heijmans, Nicole; van Driel, Nikki; van Straalen, Linda; Bajramovic, Jeffrey J; Brok, Herbert P M; Blezer, Erwin L A; Bauer, Jan; Laman, Jon D; 't Hart, Bert A
Experimental autoimmune encephalomyelitis in the neotropical primate common marmoset (Callithrix jacchus) is a relevant autoimmune animal model of multiple sclerosis. T cells specific for peptide 34 to 56 of myelin/oligodendrocyte glycoprotein (MOG34-56) have a central pathogenic role in this model. The aim of this study was to assess the requirement for innate immune stimulation for activation of this core pathogenic autoimmune mechanism. Marmoset monkeys were sensitized against synthetic MOG34-56 peptide alone or in combination with the nonencephalitogenic peptide MOG74-96 formulated in incomplete Freund adjuvant, which lacks microbial components. Experimental autoimmune encephalomyelitis development was recorded by monitoring neurological signs, brain magnetic resonance imaging, and longitudinal profiling of cellular and humoral immune parameters. All monkeys developed autoimmune inflammatory/demyelinating central nervous system disease characterized by massive brain and spinal cord demyelinating white matter lesions with activated macrophages and CD3+ T cells. Immune profiling ex vivo demonstrated the activation of mainly CD3+CD4+/8+CD56+ T cells against MOG34-56. Upon ex vivo stimulation, these T cells produced more interleukin 17A compared with TH1 cytokines (e.g. interferon-gamma) and displayed peptide-specific cytolytic activity. These results indicate that the full spectrum of marmoset experimental autoimmune encephalomyelitis can be induced by sensitization against a single MOG peptide in incomplete Freund adjuvant lacking microbial compounds for innate immune activation and by eliciting antigen-specific T-cell cytolytic activity.
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.
Daneshdoust, Danyal; Khalili-Fomeshi, Mohsen; Ghasemi-Kasman, Maryam; Ghorbanian, Davoud; Hashemian, Mona; Gholami, Mohammad; Moghadamnia, Aliakbar; Shojaei, Amir
Multiple sclerosis (MS) is an autoimmune disease in which more than 70% of patients experience visual disturbance as the earliest symptoms. Lysolecithin (LPC)-induced focal demyelination model has been developed to evaluate the effects of different therapies on myelin repair improvement. In this study, the effects of pregabalin administration on myelin repair and glial activation were investigated. Local demyelination was induced by administration of LPC (1%, 2μL) into the rat optic chiasm. Rats underwent daily injection of pregabalin (30mg/kg, i.p) or vehicle. Visual-evoked potentials (VEPs) recordings were performed for evaluating the function of optic pathway on days 3, 7, 14 and 28 post lesions. Myelin specific staining and immunostaining against GFAP and Iba1 were also carried out for assessment of myelination and glial activation respectively. Electrophysiological data indicated that pregabalin administration could significantly reduce the P1-N1 latency and increase the amplitude of VEPs waves compared to saline group. Luxol fast blue staining and immunostaining against PLP, as mature myelin marker, showed that myelin repair was improved in animals received pregabalin treatment. In addition, pregabalin effectively reduced the expression of GFAP and Iba1 as activated glial markers in optic chiasm. The present study indicates that pregabalin administration enhances myelin repair and ameliorates glial activation of optic chiasm following local injection of LPC. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.
Dai, Peihong; Cao, Hua; Merghoub, Taha; Avogadri, Francesca; Wang, Weiyi; Parikh, Tanvi; Fang, Chee-Mun; Pitha, Paula M.; Fitzgerald, Katherine A.; Rahman, Masmudur M.; McFadden, Grant; Hu, Xiaoyu; Houghton, Alan N.; Shuman, Stewart; Deng, Liang
Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-α, IFN-β, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs. PMID:21835795
Dai, Peihong; Cao, Hua; Merghoub, Taha; Avogadri, Francesca; Wang, Weiyi; Parikh, Tanvi; Fang, Chee-Mun; Pitha, Paula M; Fitzgerald, Katherine A; Rahman, Masmudur M; McFadden, Grant; Hu, Xiaoyu; Houghton, Alan N; Shuman, Stewart; Deng, Liang
Poxviruses are large DNA viruses that replicate in the cytoplasm of infected cells. Myxoma virus is a rabbit poxvirus that belongs to the Leporipoxvirus genus. It causes a lethal disease called myxomatosis in European rabbits but cannot sustain any detectable infection in nonlagomorphs. Vaccinia virus is a prototypal orthopoxvirus that was used as a vaccine to eradicate smallpox. Myxoma virus is nonpathogenic in mice, whereas systemic infection with vaccinia virus can be lethal even in immunocompetent mice. Plasmacytoid dendritic cells (pDCs) are potent type I interferon (IFN)-producing cells that play important roles in antiviral innate immunity. How poxviruses are sensed by pDCs to induce type I IFN production is not well understood. Here we report that infection of primary murine pDCs with myxoma virus, but not with vaccinia virus, induces IFN-α, IFN-β, tumor necrosis factor (TNF), and interleukin-12p70 (IL-12p70) production. Using pDCs derived from genetic knockout mice, we show that the myxoma virus-induced innate immune response requires the endosomal DNA sensor TLR9 and its adaptor MyD88, transcription factors IRF5 and IRF7, and the type I IFN positive-feedback loop mediated by IFNAR1. It is independent of the cytoplasmic RNA sensing pathway mediated by the mitochondrial adaptor molecule MAVS, the TLR3 adaptor TRIF, or the transcription factor IRF3. Using pharmacological inhibitors, we demonstrate that myxoma virus-induced type I IFN and IL-12p70 production in murine pDCs is also dependent on phosphatidylinositol 3-kinase (PI3K) and Akt. Furthermore, our results reveal that the N-terminal Z-DNA/RNA binding domain of vaccinia virulence factor E3, which is missing in the orthologous M029 protein expressed by myxoma virus, plays an inhibitory role in poxvirus sensing and innate cytokine production by murine pDCs.
Gitiaux, Cyril; Blin-Rochemaure, Nathalie; Hully, Marie; Echaniz-Laguna, Andoni; Calmels, Nadège; Bahi-Buisson, Nadia; Desguerre, Isabelle; Dabaj, Ivana; Wehbi, Samer; Quijano-Roy, Susana; Laugel, Vincent
Cockayne syndrome (CS) is characterized by postnatal growth failure and progressive multi-organ dysfunctions. CSA and CSB gene mutations account for the majority of cases and three degrees of severity are delineated. A peripheral neuropathy is known to be associated with CS but the type, severity and correlation of the nerve involvement with CS subtypes remain unknown in genetically identified patients. Clinical and nerve conduction studies (NCS) in 25 CS patients with CSA (n=13) CSB (n=12) mutations. NCS show a widespread decrease in motor and sensory conduction velocities (CV) in all severe and classical form of CS. In one patient, CV were normal at age 8months but severe slowing was detected at 2years. Conduction block and/or temporal dispersion were observed in 68% of patients. CS is associated with a progressive sensory and motor neuropathy. Signs of segmental demyelination, including conduction blocks, may not be obvious before the age of 2years. CV slowing is correlated with the CS clinical sev