Sample records for acrylamide-induced axonal neuropathy

  1. Neuroprotective Effect of Calpeptin on Acrylamide-Induced Neuropathy in Rats. (United States)

    Wei, Xiaomin; Yan, Fengfeng; E, Meng; Zhang, Cuili; Li, Guozhen; Yang, Xiwei; Zhang, Fengmei; Wang, Shue; Yu, Sufang


    Acrylamide (ACR) is a vinyl monomer with established human neurotoxic effects, which is characterized by the accumulation of neurofilaments (NFs) in the distal swellings of large axons in peripheral and central nervous systems. However, the mechanisms of neurotoxicity remain unclear. The objective is to investigate the neuroprotective effect of calpeptin (CP) on ACR-induced neuropathy and its mechanism. Female adult Wistar rats were randomly divided into four groups (control, CP, ACR, and ACR + CP group). Control group received 0.9 % saline, ACR and ACR + CP groups received 30 mg/kg ACR by intraperitoneal injection. In addition, CP and ACR + CP groups also received 200 µg/kg CP. Gait analysis and hind limb splay were measured weekly to analyze neurobehavioral changes. The calpain activity and the changes of NFs protein levels in spinal cord are determined. Compared with control group, body weight of rats in ACR group decreased by 11.3 % (P < 0.01), while in ACR + CP group body weight increased significantly by 8.3 % (P < 0.01) compared with ACR group by the end of the 4th week; gait score of rats in both ACR and ACR + CP groups increased significantly by 167 % and 100 % (P < 0.01) compared with control group, while it decreased significantly by 25.1 % (P < 0.01) in ACR + CP group compared with ACR group; the distance of hind limb splay in both ACR and ACR + CP groups increased by 76.7 % and 49.5 % (P < 0.01) compared with control group, while it decreased by 15.4 % (P < 0.01) in ACR + CP group compared with ACR group; calpain activity of spinal cord at ACR and ACR + CP groups increased significantly by 14.9 % and 10.0 % (P < 0.01) compared with control group, while it decreased 4.2 % (P < 0.01) in ACR + CP group compared with ACR group; compared with control group, the levels of light NF (NF-L), medium NF (NF-M) and heavy NF (NF-H) subunits increased by 81.2 %, 263.6 % and 22.6 % (P < 0.01) in the supernatant of ACR group in spinal cord tissue and increased by 28

  2. Genetics Home Reference: giant axonal neuropathy (United States)

    ... R. Proteomic analysis in giant axonal neuropathy: new insights into disease mechanisms. Muscle Nerve. 2012 Aug;46( ... healthcare professional . About Genetics Home Reference Site Map Customer Support Selection Criteria for Links Copyright ...

  3. Giant Axonal Neuropathy Among Two Siblings - A Case Report

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    John Jhon. K


    Full Text Available Giant axonal neuropathy is a rate disorder with an autosomal recessive inheritance. It should be differentiated from toxic neuropathies, and hereditary degenerative disorders of nervous system like Friedreich′s ataxia and HMSN. Thick curly hair, though may not be present always is a useful clinical clue to identify cases. Prognosis is generally poor though course of the illness is variable. We report here a clinically and hisopathologically characteristic familial case of giant axonal neuropathy, which occurred in a 17-year-old boy, and his 21-year-old sister.

  4. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy. (United States)

    Sung, Jia-Ying; Tani, Jowy; Chang, Tsui-San; Lin, Cindy Shin-Yi


    This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (Pmotor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (Pdevelopment of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches.

  5. Sodium Channels, Mitochondria, and Axonal Degeneration in Peripheral Neuropathy. (United States)

    Persson, Anna-Karin; Hoeijmakers, Janneke G J; Estacion, Mark; Black, Joel A; Waxman, Stephen G


    Peripheral neuropathy results from damage to peripheral nerves and is often accompanied by pain in affected limbs. Treatment represents an unmet medical need and a thorough understanding of the mechanisms underlying axonal injury is needed. Longer nerve fibers tend to degenerate first (length-dependence), and patients carrying pathogenic mutations throughout life usually become symptomatic in mid- or late-life (time-dependence). The activity of voltage-gated sodium channels can contribute to axonal injury and sodium channel gain-of-function mutations have been linked to peripheral neuropathy. Recent studies have implicated sodium channel activity, mitochondrial compromise, and reverse-mode Na(+)/Ca(2+) exchange in time- and length-dependent axonal injury. Elucidation of molecular mechanisms underlying axonal injury in peripheral neuropathy may provide new therapeutic strategies for this painful and debilitating condition.

  6. Uncovering sensory axonal dysfunction in asymptomatic type 2 diabetic neuropathy (United States)

    Sung, Jia-Ying; Tani, Jowy; Chang, Tsui-San; Lin, Cindy Shin-Yi


    This study investigated sensory and motor nerve excitability properties to elucidate the development of diabetic neuropathy. A total of 109 type 2 diabetes patients were recruited, and 106 were analyzed. According to neuropathy severity, patients were categorized into G0, G1, and G2+3 groups using the total neuropathy score-reduced (TNSr). Patients in the G0 group were asymptomatic and had a TNSr score of 0. Sensory and motor nerve excitability data from diabetic patients were compared with data from 33 healthy controls. Clinical assessment, nerve conduction studies, and sensory and motor nerve excitability testing data were analyzed to determine axonal dysfunction in diabetic neuropathy. In the G0 group, sensory excitability testing revealed increased stimulus for the 50% sensory nerve action potential (P<0.05), shortened strength-duration time constant (P<0.01), increased superexcitability (P<0.01), decreased subexcitability (P<0.05), decreased accommodation to depolarizing current (P<0.01), and a trend of decreased accommodation to hyperpolarizing current in threshold electrotonus. All the changes progressed into G1 (TNSr 1–8) and G2+3 (TNSr 9–24) groups. In contrast, motor excitability only had significantly increased stimulus for the 50% compound motor nerve action potential (P<0.01) in the G0 group. This study revealed that the development of axonal dysfunction in sensory axons occurred prior to and in a different fashion from motor axons. Additionally, sensory nerve excitability tests can detect axonal dysfunction even in asymptomatic patients. These insights further our understanding of diabetic neuropathy and enable the early detection of sensory axonal abnormalities, which may provide a basis for neuroprotective therapeutic approaches. PMID:28182728

  7. Antiretroviral Therapy-Associated Acute Motor and Sensory Axonal Neuropathy

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    Kimberly N. Capers


    Full Text Available Guillain-Barré syndrome (GBS has been reported in HIV-infected patients in association with the immune reconstitution syndrome whose symptoms can be mimicked by highly active antiretroviral therapy (HAART-mediated mitochondrial toxicity. We report a case of a 17-year-old, HIV-infected patient on HAART with a normal CD4 count and undetectable viral load, presenting with acute lower extremity weakness associated with lactatemia. Electromyography/nerve conduction studies revealed absent sensory potentials and decreased compound muscle action potentials, consistent with a diagnosis of acute motor and sensory axonal neuropathy. Lactatemia resolved following cessation of HAART; however, neurological deficits minimally improved over several months in spite of immune modulatory therapy. This case highlights the potential association between HAART, mitochondrial toxicity and acute axonal neuropathies in HIV-infected patients, distinct from the immune reconstitution syndrome.

  8. Pili canaliculi as manifestation of giant axonal neuropathy* (United States)

    de Almeida Jr., Hiram Larangeira; Garcias, Gilberto; Silva, Ricardo Marques e; Batista, Stela Laner; Pasetto, Fernanda


    Giant axonal neuropathy is a rare autosomal recessive neurodegenerative disease. The condition is characterized by neurons with abnormally large axons due to intracellular filament accumulation. The swollen axons affect both the peripheral and central nervous system. A 6-year old female patient had been referred to a geneticist reporting problems with walking and hypotonia. At the age of 10, she became wheelchair dependent. Scanning electron microscopy of a curly hair classified it as pili canaliculi. GAN gene sequencing demonstrated mutation c.1456G>A (p.GLU486LYS). At the age of 12, the patient died due to respiratory complications. Dermatologists should be aware of this entity since hair changes are considered suggestive of GAN.

  9. Pyridoxine neuropathy in rats: specific degeneration of sensory axons. (United States)

    Windebank, A J; Low, P A; Blexrud, M D; Schmelzer, J D; Schaumburg, H H


    When rats received pyridoxine in doses large enough to cause neuropathy in humans, the animals developed gait ataxia that subsided after the toxin was withdrawn. By using quantitative histologic techniques, we found axonal degeneration of sensory system fibers and that the fibers derived from the ventral root were spared. Although the degeneration approached the dorsal root ganglion, neurons in the ganglion did not degenerate. We found no early decrease in oxygen consumption of nerve, suggesting that impaired oxidative metabolism was not the primary event.

  10. New form of autosomal-recessive axonal hereditary sensory motor neuropathy. (United States)

    Eckhardt, S M; Hicks, E M; Herron, B; Morrison, P J; Aicardi, J


    Two siblings, a male and a female, had severe axonal neuropathy and sideroblastic anemia. Despite a distinct clinical picture with areflexia, ataxia, hypotonia, optic atrophy, and progressive sensory neural hearing loss, no definite diagnosis could be reached and the older sibling died at 6 years of age of respiratory failure. It is proposed that the two affected siblings have a new form of autosomal-recessive axonal hereditary sensory motor neuropathy.

  11. Truncated HSPB1 causes axonal neuropathy and impairs tolerance to unfolded protein stress

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    Emil Ylikallio


    General significance: sHSPs have important roles in prevention of protein aggregates that induce toxicity. We showed that C-terminal part of HSPB1 is critical for tolerance of unfolded protein stress, and when lacking causes axonal neuropathy in patients.

  12. Pure motor axonal neuropathy triggered by antituberculous therapy in an undiagnosed case of acute intermittent porphyria. (United States)

    Babar, Masood Uz Zaman; Hakeem, Haris; Khan, Sara


    A man aged 22 years misdiagnosed as suffering from recurrent abdominal tuberculosis, in view of recurrent abdominal pain was treated for abdominal tuberculosis in the past. The patient was prescribed antituberculous therapy. 2 months after starting treatment, he developed progressive weakness of all 4 limbs. Electrodiagnostic examination revealed an acute severe motor axonal neuropathy. Further workup revealed elevated porphyrin precursors in urine.

  13. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. (United States)

    Viader, Andreu; Sasaki, Yo; Kim, Sungsu; Strickland, Amy; Workman, Cayce S; Yang, Kui; Gross, Richard W; Milbrandt, Jeffrey


    Mitochondrial dysfunction is a common cause of peripheral neuropathy. Much effort has been devoted to examining the role played by neuronal/axonal mitochondria, but how mitochondrial deficits in peripheral nerve glia (Schwann cells [SCs]) contribute to peripheral nerve diseases remains unclear. Here, we investigate a mouse model of peripheral neuropathy secondary to SC mitochondrial dysfunction (Tfam-SCKOs). We show that disruption of SC mitochondria activates a maladaptive integrated stress response (ISR) through the actions of heme-regulated inhibitor (HRI) kinase, and causes a shift in lipid metabolism away from fatty acid synthesis toward oxidation. These alterations in SC lipid metabolism result in depletion of important myelin lipid components as well as in accumulation of acylcarnitines (ACs), an intermediate of fatty acid β-oxidation. Importantly, we show that ACs are released from SCs and induce axonal degeneration. A maladaptive ISR as well as altered SC lipid metabolism are thus underlying pathological mechanisms in mitochondria-related peripheral neuropathies.

  14. Mitochondrial biogenesis and fission in axons in cell culture and animal models of diabetic neuropathy. (United States)

    Vincent, Andrea M; Edwards, James L; McLean, Lisa L; Hong, Yu; Cerri, Federica; Lopez, Ignazio; Quattrini, Angelo; Feldman, Eva L


    Mitochondrial-mediated oxidative stress in response to high glucose is proposed as a primary cause of dorsal root ganglia (DRG) neuron injury in the pathogenesis of diabetic neuropathy. In the present study, we report a greater number of mitochondria in both myelinated and unmyelinated dorsal root axons in a well-established model of murine diabetic neuropathy. No similar changes were seen in younger diabetic animals without neuropathy or in the ventral motor roots of any diabetic animals. These findings led us to examine mitochondrial biogenesis and fission in response to hyperglycemia in the neurites of cultured DRG neurons. We demonstrate overall mitochondrial biogenesis via increases in mitochondrial transcription factors and increases in mitochondrial DNA in both DRG neurons and axons. However, this process occurs over a longer time period than a rapidly observed increase in the number of mitochondria in DRG neurites that appears to result, at least in part, from mitochondrial fission. We conclude that during acute hyperglycemia, mitochondrial fission is a prominent response, and excessive mitochondrial fission may result in dysregulation of energy production, activation of caspase 3, and subsequent DRG neuron injury. During more prolonged hyperglycemia, there is evidence of compensatory mitochondrial biogenesis in axons. Our data suggest that an imbalance between mitochondrial biogenesis and fission may play a role in the pathogenesis of diabetic neuropathy.

  15. Severe acute axonal neuropathy following treatment with arsenic trioxide for acute promyelocytic leukemia: a case report

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    Marcus Kuhn


    Full Text Available Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences. We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up. Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide.

  16. Asymmetric Acute Motor Axonal Neuropathy With Unilateral Tongue Swelling Mimicking Stroke. (United States)

    Chi, Man Sum; Ng, Shi Hon; Chan, Lok Yiu


    A 60-year-old man presented with acute onset of left hemiparesis and left hypoglossal nerve palsy with ipsilateral tongue swelling. He then progressed to tetraparesis in a few days. Cerebrospinal fluid showed cell protein dissociation. A nerve conduction study showed motor axonal neuropathy with sensory sparing. A subsequent blood test revealed anti-GD1b IgG antibody positivity. He was diagnosed to have acute motor axonal neuropathy (AMAN) and treated with a course of intravenous immunoglobulin with slow improvement. This is probably the first AMAN with asymmetrical presentation mimicking stroke reported in the literature in detail. The anti-GD1b IgG antibody is also not commonly associated with AMAN.

  17. DNA Single-Strand Break Repair and Spinocerebellar Ataxia with Axonal Neuropathy-1


    Caldecott, K. W.


    DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiester...

  18. DNA single-strand break repair and spinocerebellar ataxia with axonal neuropathy-1


    El-Khamisy, S.F.; Caldecott, K. W.


    DNA single-strand breaks (SSBs) are the commonest DNA lesions arising spontaneously in cells, and if not repaired may block transcription or may be converted into potentially lethal/clastogenic DNA double-strand breaks (DSBs). Recently, evidence has emerged that defects in the rapid repair of SSBs preferentially impact the nervous system. In particular, spinocerebellar ataxia with axonal neuropathy (SCAN1) is a human disease that is associated with mutation of TDP1 (tyrosyl DNA phosphodiester...

  19. A Case of Acute Motor Axonal Neuropathy Mimicking Brain Death and Review of the Literature. (United States)

    Ravikumar, Sandhya; Poysophon, Poysophon; Poblete, Roy; Kim-Tenser, May


    We describe a case report of fulminant Guillain-Barré syndrome (GBS) mimicking brain death. A previously healthy 60-year-old male was admitted to the neurointensive care unit after developing rapidly progressive weakness and respiratory failure. On presentation, the patient was found to have absent brainstem and spinal cord reflexes resembling that of brain death. Acute motor axonal neuropathy, a subtype of GBS, was diagnosed by cerebrospinal fluid and nerve conduction velocity testing. An electroencephalogram showed that the patient had normal, appropriately reactive brain function. Transcranial Doppler (TCD) ultrasound showed appropriate blood flow to the brain. GBS rarely presents with weakness so severe as to mimic brain death. This article provides a review of similar literature. This case demonstrates the importance of performing a proper brain death examination, which includes evaluation for irreversible cerebral injury, exclusion of any confounding conditions, and performance of tests such as electroencephalography and TCDs when uncertainty exists about the reliability of the clinical exam.

  20. Recent advances in the genetics of hereditary axonal sensory-motor neuropathies type 2. (United States)

    Ajroud-Driss, Senda; Deng, Han-Xiang; Siddique, Teepu


    Hereditary axonal motor and sensory neuropathies or Charcot-Marie-Tooth disease type 2 (CMT2) are characterized clinically by distal muscle weakness and atrophy, sensory loss, and foot deformities. Conduction velocities are usually in the normal range or mildly slowed. The majority of CMT2 are autosomal-dominant but autosomal-recessive forms have been described. The number of genes associated with CMT2 have significantly increased in the past decade, with the gene causing CMT2C/SPSMA being the last one discovered. More than 10 genes are now associated with different subtypes of CMT2, which are classified from CMT2A to CMT2N. These genes have distinct functions, but some appear to be involved in common biological pathways, therefore, providing important clues for understanding the pathogenic mechanism of these heterogeneous disorders.

  1. Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat. (United States)

    Xiao, W H; Zheng, H; Zheng, F Y; Nuydens, R; Meert, T F; Bennett, G J


    The dose-limiting side effect of the anti-neoplastic agent, paclitaxel, is a chronic distal symmetrical peripheral neuropathy that produces sensory dysfunction (hypoesthesia and neuropathic pain) but little or no distal motor dysfunction. Similar peripheral neuropathies are seen with chemotherapeutics in the vinca alkaloid, platinum-complex, and proteasome inhibitor classes. Studies in rats suggest that the cause is a mitotoxic effect on axonal mitochondria. If so, then the absence of motor dysfunction may be due to mitotoxicity that affects sensory axons but spares motor axons. To investigate this, paclitaxel exposure levels in the dorsal root, ventral root, dorsal root ganglion, peripheral nerve, and spinal cord were measured, and the ultrastructure and the respiratory function of mitochondria in dorsal roots and ventral roots were compared. Sensory and motor axons in the roots and nerve had comparably low exposure to paclitaxel and exposure in the spinal cord was negligible. However, sensory neurons in the dorsal root ganglion had a very high and remarkably persistent (up to 10 days or more after the last injection) exposure to paclitaxel. Paclitaxel evoked a significant increase in the incidence of swollen and vacuolated mitochondria in the myelinated and unmyelinated sensory axons of the dorsal root (as seen previously in the peripheral nerve) but not in the motor axons of the ventral root. Stimulated mitochondrial respiration in the dorsal root was significantly depressed in paclitaxel-treated animals examined 2-4 weeks after the last injection, whereas respiration in the ventral root was normal. We conclude that the absence of motor dysfunction in paclitaxel-evoked peripheral neuropathy may be due to the absence of a mitotoxic effect in motor neuron axons, whereas the sensory dysfunction may be due to a mitotoxic effect resulting from the primary afferent neuron's cell body being exposed to high and persistent levels of paclitaxel.

  2. Sensory neuropathy in progressive motor neuronopathy (pmn) mice is associated with defects in microtubule polymerization and axonal transport. (United States)

    Schäfer, Michael K; Bellouze, Sarah; Jacquier, Arnaud; Schaller, Sébastien; Richard, Laurence; Mathis, Stéphane; Vallat, Jean-Michel; Haase, Georg


    Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) are now recognized as multi-system disorders also involving various non-motor neuronal cell types. The precise extent and mechanistic basis of non-motor neuron damage in human ALS and ALS animal models remain however unclear. To address this, we here studied progressive motor neuronopathy (pmn) mice carrying a missense loss-of-function mutation in tubulin binding cofactor E (TBCE). These mice manifest a particularly aggressive form of motor axon dying back and display a microtubule loss, similar to that induced by human ALS-linked TUBA4A mutations. Using whole nerve confocal imaging of pmn × thy1.2-YFP16 fluorescent reporter mice and electron microscopy, we demonstrate axonal discontinuities, bead-like spheroids and ovoids in pmn suralis nerves indicating prominent sensory neuropathy. The axonal alterations qualitatively resemble those in phrenic motor nerves but do not culminate in the loss of myelinated fibers. We further show that the pmn mutation decreases the level of TBCE, impedes microtubule polymerization in dorsal root ganglion (DRG) neurons and causes progressive loss of microtubules in large and small caliber suralis axons. Live imaging of axonal transport using GFP-tagged tetanus toxin C-fragment (GFP-TTC) demonstrates defects in microtubule-based transport in pmn DRG neurons, providing a potential explanation for the axonal alterations in sensory nerves. This study unravels sensory neuropathy as a pathological feature of mouse pmn, and discusses the potential contribution of cytoskeletal defects to sensory neuropathy in human motor neuron disease.

  3. A review of gigaxonin mutations in giant axonal neuropathy (GAN) and cancer. (United States)

    Kang, James J; Liu, Isabelle Y; Wang, Marilene B; Srivatsan, Eri S


    Gigaxonin, the product of GAN gene localized to chromosome 16, is associated with the early onset neuronal degeneration disease giant axonal neuropathy (GAN). Gigaxonin is an E3 ubiquitin ligase adaptor protein involved in intermediate filament processing in neural cells, and vimentin filaments in fibroblasts. Mutations of the gene cause pre-neural filaments to accumulate and form giant axons resulting in the inhibition of neural cell signaling. Analysis of the catalog of somatic mutations in cancer, driver DB and IDGC data portal databases containing 21,000 tumor genomic sequences has identified GAN patient mutations in cancer cell lines and primary tumors. The database search has also shown the presence of identical missense and nonsense gigaxonin mutations in GAN and colon cancer. These mutations frequently occur in the domains associated with protein homodimerization and substrate interaction such as Broad-Complex, Tramtrack and Bric a brac (BTB), BTB associated C-terminal KELCH (BACK), and KELCH repeats. Analysis of the International HapMap Project database containing 1200 normal genomic sequences has identified a single nucleotide polymorphism (SNP), rs2608555, in exon 8 of the gigaxonin sequence. While this SNP is present in >40 % of Caucasian population, it is present in less than 10 % of Japanese and Chinese populations. Although the role of gigaxonin polymorphism is not yet known, CFTR and MDR1 gene studies have shown that silent mutations play a role in the instability and aberrant splicing and folding of mRNAs. We believe that molecular and functional investigation of gigaxonin mutations including the exon 8 polymorphism could lead to an improved understanding of the relationship between GAN and cancer.

  4. Axonal loss and blood flow disturbances in the natural course of indirect traumatic optic neuropathy

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    SHI Wei; WANG Huai-zhou; SONG Wei-xian; YANG Wen-li; LI Wei-ye; WANG Ning-li


    Background Indirect traumatic optic neuropathy (TON) is an acute injury of the optic nerve associated with severe visual dysfunction,which may be a result of secondary mechanical injury and vascular disorder of the optic nerve due to trauma.We analyzed the natural course of axonal loss and blood flow disturbances in patients with indirect TON to find a possible therapeutic window.Methods A cohort of 54 patients with indirect TON recruited between October 2008 and October 2010 at Beijing Tongren Hospital was retrospectively analyzed.The patients were divided into no light perception group (NLP) and better than NLP (btNLP) group.Specifically,the thickness of the retinal nerve fiber layer (RNFL) measured by spectral domain optical coherence tomography (SD-OCT),and hemodynamic parameters of the ophthalmic artery (OA),central retinal artery (CRA) and posterior ciliary artery (PCA) were determined.Results Two weeks after injury,there was a statistically significant decrease in the thickness of RNFL in the btNLP group as compared with the fellow control eyes (P <0.05).In contrast,in the NLP group,RNFL thickness slightly increased for 2 weeks following injury,then overtly reduced after 4 weeks (P <0.05).Peak systolic velocity (PSV) of CRA was significantly decreased 4 weeks after injury (P <0.05) in both the NLP group and btNLP group (P <0.05).The thickness of RNFL in the NLP group was negatively correlated with PSV of CRA after 1 week of injury (P <0.05,r=-0.962).Conclusions SD-OCT is a useful supplement in detecting the axonal loss in TON.The dynamic change of the thickness of RNFL appears to correlate with the hemodynamic disturbances in the natural course of TON.The first 2 weeks following an injury is critical and should be considered as the therapeutic window for TON patients.

  5. Ischemic optic neuropathy as a model of neurodegenerative disorder: A review of pathogenic mechanism of axonal degeneration and the role of neuroprotection. (United States)

    Khalilpour, Saba; Latifi, Shahrzad; Behnammanesh, Ghazaleh; Majid, Amin Malik Shah Abdul; Majid, Aman Shah Abdul; Tamayol, Ali


    Optic neuropathy is a neurodegenerative disease which involves optic nerve injury. It is caused by acute or intermittent insults leading to visual dysfunction. There are number of factors, responsible for optic neuropathy, and the optic nerve axon is affected in all type which causes the loss of retinal ganglion cells. In this review we will highlight various mechanisms involved in the cell loss cascades during axonal degeneration as well as ischemic optic neuropathy. These mechanisms include oxidative stress, excitotoxicity, angiogenesis, neuroinflammation and apoptosis following retinal ischemia. We will also discuss the effect of neuroprotective agents in attenuation of the negative effect of factors involve in the disease occurrence and progression.

  6. Abnormal intermediate filament organization alters mitochondrial motility in giant axonal neuropathy fibroblasts. (United States)

    Lowery, Jason; Jain, Nikhil; Kuczmarski, Edward R; Mahammad, Saleemulla; Goldman, Anne; Gelfand, Vladimir I; Opal, Puneet; Goldman, Robert D


    Giant axonal neuropathy (GAN) is a rare disease caused by mutations in the GAN gene, which encodes gigaxonin, an E3 ligase adapter that targets intermediate filament (IF) proteins for degradation in numerous cell types, including neurons and fibroblasts. The cellular hallmark of GAN pathology is the formation of large aggregates and bundles of IFs. In this study, we show that both the distribution and motility of mitochondria are altered in GAN fibroblasts and this is attributable to their association with vimentin IF aggregates and bundles. Transient expression of wild-type gigaxonin in GAN fibroblasts reduces the number of IF aggregates and bundles, restoring mitochondrial motility. Conversely, silencing the expression of gigaxonin in control fibroblasts leads to changes in IF organization similar to that of GAN patient fibroblasts and a coincident loss of mitochondrial motility. The inhibition of mitochondrial motility in GAN fibroblasts is not due to a global inhibition of organelle translocation, as lysosome motility is normal. Our findings demonstrate that it is the pathological changes in IF organization that cause the loss of mitochondrial motility.

  7. Cryptic Amyloidogenic Elements in the 3′ UTRs of Neurofilament Genes Trigger Axonal Neuropathy (United States)

    Rebelo, Adriana P.; Abrams, Alexander J.; Cottenie, Ellen; Horga, Alejandro; Gonzalez, Michael; Bis, Dana M.; Sanchez-Mejias, Avencia; Pinto, Milena; Buglo, Elena; Markel, Kasey; Prince, Jeffrey; Laura, Matilde; Houlden, Henry; Blake, Julian; Woodward, Cathy; Sweeney, Mary G.; Holton, Janice L.; Hanna, Michael; Dallman, Julia E.; Auer-Grumbach, Michaela; Reilly, Mary M.; Zuchner, Stephan


    Abnormal protein aggregation is observed in an expanding number of neurodegenerative diseases. Here, we describe a mechanism for intracellular toxic protein aggregation induced by an unusual mutation event in families affected by axonal neuropathy. These families carry distinct frameshift variants in NEFH (neurofilament heavy), leading to a loss of the terminating codon and translation of the 3′ UTR into an extra 40 amino acids. In silico aggregation prediction suggested the terminal 20 residues of the altered NEFH to be amyloidogenic, which we confirmed experimentally by serial deletion analysis. The presence of this amyloidogenic motif fused to NEFH caused prominent and toxic protein aggregates in transfected cells and disrupted motor neurons in zebrafish. We identified a similar aggregation-inducing mechanism in NEFL (neurofilament light) and FUS (fused in sarcoma), in which mutations are known to cause aggregation in Charcot-Marie-Tooth disease and amyotrophic lateral sclerosis, respectively. In summary, we present a protein-aggregation-triggering mechanism that should be taken into consideration during the evaluation of stop-loss variants. PMID:27040688

  8. A Case of Acute Motor Axonal Neuropathy Mimicking Brain Death and Review of the Literature

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    Sandhya eRavikumar


    Full Text Available We describe a case report of fulminant Guillain-Barré syndrome mimicking brain death. A previously healthy 60-year-old male was admitted to the neurointensive care unit after developing rapidly progressive weakness and respiratory failure. On presentation, the patient was found to have absent brainstem and spinal cord reflexes resembling that of brain death. Acute motor axonal neuropathy (AMAN, a subtype of Guillain-Barré syndrome, was diagnosed by cerebrospinal fluid and nerve conduction velocity testing. An electroencephalogram showed that the patient had normal, appropriately reactive brain function. Transcranial Doppler ultrasound showed appropriate blood flow to the brain. Guillain-Barré syndrome rarely presents with weakness so severe as to mimic brain death. This article provides a review of similar literature. This case demonstrates the importance of performing a proper brain death examination, which includes evaluation for irreversible cerebral injury, exclusion of any confounding conditions, and performance of tests such as electroencephalography and transcranial dopplers when uncertainty exists about the reliability of the clinical exam.

  9. GRS defective axonal distribution as a potential contributor to distal spinal muscular atrophy type V pathogenesis in a new model of GRS-associated neuropathy. (United States)

    Seo, Ah Jung; Park, Byung Sun; Jung, Junyang


    Distal spinal muscular atrophy type V (dSMA-V), a hereditary axonal neuropathy, is a glycyl-tRNA synthetase (GRS)-associated neuropathy caused by a mutation in GRS. In this study, using an adenovirus vector system equipped with a neuron-specific promoter, we constructed a new GRS-associated neuropathy mouse model. We found that wild-type GRS (WT) is distributed in peripheral axons, dorsal root ganglion (DRG) cell bodies, central axon terminals and motor neuron cell bodies in the mouse model. In contrast, the L129P mutant GRS was localized in DRG and motor neuron cell bodies. Thus, we propose that the disease-causing L129P mutant is linked to a distribution defect in peripheral nerves in vivo.

  10. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2

    NARCIS (Netherlands)

    S. Zuchner; P. de Jonghe; A. Jordanova; K.G. Claeys; V. Guergueltcheva; S. Cherninkova; S.R. Hamilton; G. van Stavern; K.M. Krajewski; J. Stajich; I. Tournev; K. Verhoeven; C.T. Langerhorst; M. de Visser; F. Baas; T. Bird; V. Timmerman; M. Shy; J.M. Vance


    Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has

  11. Clinical pathological and genetic analysis of 2 cases of mitochondrial myopathy presented as acute motor axonal neuropathy

    Directory of Open Access Journals (Sweden)

    Hou-min YIN


    Full Text Available Background The main clinical manifestations of mitochondrial myopathy are chronic limb weakness and muscular soreness. Subclinical peripheral nerve injury is also reported, but acute axonal syndrome concurrent with lactic acidosis is rare. In this paper the clinical features of 2 patients presenting as acute lactic acidosis and sudden muscle weakness were analyzed. Pathological changes and genetic mutations were detected.  Methods Electromyography (EMG and muscle biopsy were performed. Modified Gomori trichrome (MGT and succinodehydrogenase (SDH staining were used to identify pathological changes. Changes of ultra microstructure of muscular tissue were observed under electron microscope. Mitochondrial DNA (mtDNA full length sequencing was performed using 24 pairs of partially overlapping primers.  Results EMG showed a coexistence of neurogenic and myogenic changes. Dramatic decrease of motor nerve amplitude and moderately reduced sensory nerve amplitude were observed but nerve conduction velocity was normal in both patients. Impressive ragged red fibers were seen on MGT staining. Electron microscope showed dramatic mitochondrial abnormalities in Case 1 and paracrystaline inclusions in Case 2. mtDNA sequencing showed 3243A > G mutation in Case 1 and 8344A > G mutation in Case 2. Conclusions Mitochondrial myopathy can present as metabolic crisis like acute lactic acidosis, dyspnea and acute motor axonal syndrome. It is a life.threatening phenotype that needs more attention. doi: 10.3969/j.issn.1672-6731.2014.06.007

  12. 4-Hydroxy-2-nonenal induces mitochondrial dysfunction and aberrant axonal outgrowth in adult sensory neurons that mimics features of diabetic neuropathy. (United States)

    Akude, Eli; Zherebitskaya, Elena; Roy Chowdhury, Subir K; Girling, Kimberly; Fernyhough, Paul


    Modification of proteins by 4-hydroxy-2-nonenal (4-HNE) has been proposed to cause neurotoxicity in a number of neurodegenerative diseases, including distal axonopathy in diabetic sensory neuropathy. We tested the hypothesis that exposure of cultured adult rat sensory neurons to 4-HNE would result in the formation of amino acid adducts on mitochondrial proteins and that this process would be associated with impaired mitochondrial function and axonal regeneration. In addition, we compared 4-HNE-induced axon pathology with that exhibited by neurons isolated from diabetic rats. Cultured adult rat dorsal root ganglion (DRG) sensory neurons were incubated with varying concentrations of 4-HNE. Cell survival, axonal morphology, and level of axon outgrowth were assessed. In addition, video microscopy of live cells, western blot, and immunofluorescent staining were utilized to detect protein adduct formation by 4-HNE and to localize actively respiring mitochondria. 4-HNE induced formation of protein adducts on cytoskeletal and mitochondrial proteins, and impaired axon regeneration by approximately 50% at 3 microM while having no effect on neuronal survival. 4-HNE initiated formation of aberrant axonal structures and caused the accumulation of mitochondria in these dystrophic structures. Neurons treated with 4-HNE exhibited a distal loss of active mitochondria. Finally, the distal axonopathy and the associated aberrant axonal structures generated by 4-HNE treatment mimicked axon pathology observed in DRG sensory neurons isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic sensory neuropathy.

  13. Vasculitic neuropathy. (United States)

    Sampaio, Luzia; Silva, Lã Gia; Terroso, Georgina; Nadais, Goreti; Mariz, Eva; Ventura, Francisco


    Vasculitic neuropathy corresponds to the occurrence of vasculitis at the level of vasa nervorum, resulting in ischemic damage of the peripheral nerve and axonal degeneration. Vasculitic neuropathy commonly occurs in association with systemic diseases and may be the initial manifestation or arise in the course of established disease. Although rare, vasculitis can be confined to the peripheral nervous system - non-systemic vasculitic neuropathy. This paper aims to review the classification, diagnosis and treatment of vasculitic neuropathy.

  14. Peripheral neuropathy in the Twitcher mouse involves the activation of axonal caspase 3

    Directory of Open Access Journals (Sweden)

    Ernesto R Bongarzone


    Full Text Available Infantile Krabbe disease results in the accumulation of lipid-raft-associated galactosylsphingosine (psychosine, demyelination, neurodegeneration and premature death. Recently, axonopathy has been depicted as a contributing factor in the progression of neurodegeneration in the Twitcher mouse, a bona fide mouse model of Krabbe disease. Analysis of the temporal-expression profile of MBP (myelin basic protein isoforms showed unexpected increases of the 14, 17 and 18.5 kDa isoforms in the sciatic nerve of 1-week-old Twitcher mice, suggesting an abnormal regulation of the myelination process during early postnatal life in this mutant. Our studies showed an elevated activation of the pro-apoptotic protease caspase 3 in sciatic nerves of 15- and 30-day-old Twitcher mice, in parallel with increasing demyelination. Interestingly, while active caspase 3 was clearly contained in peripheral axons at all ages, we found no evidence of caspase accumulation in the soma of corresponding mutant spinal cord motor neurons. Furthermore, active caspase 3 was found not only in unmyelinated axons, but also in myelinated axons of the mutant sciatic nerve. These results suggest that axonal caspase activation occurs before demyelination and following a dying-back pattern. Finally, we showed that psychosine was sufficient to activate caspase 3 in motor neuronal cells in vitro in the absence of myelinating glia. Taken together, these findings indicate that degenerating mechanisms actively and specifically mediate axonal dysfunction in Krabbe disease and support the idea that psychosine is a pathogenic sphingolipid sufficient to cause axonal defects independently of demyelination.

  15. Peripheral Neuropathy in the Twitcher Mouse Involves the Activation of Axonal Caspase 3

    Directory of Open Access Journals (Sweden)

    Benjamin Smith


    Full Text Available Infantile Krabbe disease results in the accumulation of lipid-raft-associated galactosylsphingosine (psychosine, demyelination, neurodegeneration and premature death. Recently, axonopathy has been depicted as a contributing factor in the progression of neurodegeneration in the Twitcher mouse, a bona fide mouse model of Krabbe disease. Analysis of the temporal-expression profile of MBP (myelin basic protein isoforms showed unexpected increases of the 14, 17 and 18.5 kDa isoforms in the sciatic nerve of 1-week-old Twitcher mice, suggesting an abnormal regulation of the myelination process during early postnatal life in this mutant. Our studies showed an elevated activation of the pro-apoptotic protease caspase 3 in sciatic nerves of 15- and 30-day-old Twitcher mice, in parallel with increasing demyelination. Interestingly, while active caspase 3 was clearly contained in peripheral axons at all ages, we found no evidence of caspase accumulation in the soma of corresponding mutant spinal cord motor neurons. Furthermore, active caspase 3 was found not only in unmyelinated axons, but also in myelinated axons of the mutant sciatic nerve. These results suggest that axonal caspase activation occurs before demyelination and following a dying-back pattern. Finally, we showed that psychosine was sufficient to activate caspase 3 in motor neuronal cells in vitro in the absence of myelinating glia. Taken together, these findings indicate that degenerating mechanisms actively and specifically mediate axonal dysfunction in Krabbe disease and support the idea that psychosine is a pathogenic sphingolipid sufficient to cause axonal defects independently of demyelination.

  16. Acquired inflammatory demyelinating neuropathies. (United States)

    Ensrud, E R; Krivickas, L S


    The acquired demyelinating neuropathies can be divided into those with an acute onset and course and those with a more chronic course. The acute neuropathies present as Guillain-Barré syndrome and include acute inflammatory demyelinating polyradiculoneuropathy (AIDP), Miller Fisher syndrome, acute motor axonal neuropathy (AMAN), acute motor and sensory axonal neuropathy (AMSAN), and acute pandysautonomia. The chronic neuropathies are collectively known as chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and include MADSAM (multifocal acquired demyelinating sensory and motor neuropathy, also know as Lewis-Sumner syndrome) and DADS (distal acquired demyelinating symmetric neuropathy) as variants. The clinical features, pathology, pathogenesis, diagnosis, treatment, rehabilitation, and prognosis of these neuropathies are discussed.

  17. Disulfiram neuropathy.



    Disulfiram (Antabuse) can produce neuropathy in daily doses of less than the usually recommended 500 mg. The four recent cases reported in this paper emphasize the need for greater recognition of this condition. Nerve biopsies showed axonal degeneration. The neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drug's use is st...

  18. HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation. (United States)

    Kim, Ji-Yon; Woo, So-Youn; Hong, Young Bin; Choi, Heesun; Kim, Jisoo; Choi, Hyunjung; Mook-Jung, Inhee; Ha, Nina; Kyung, Jangbeen; Koo, Soo Kyung; Jung, Sung-Chul; Choi, Byung-Ok


    The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

  19. HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation

    Directory of Open Access Journals (Sweden)

    Ji-Yon Kim


    Full Text Available The Charcot-Marie-Tooth disease 2F (CMT2F and distal hereditary motor neuropathy 2B (dHMN2B are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1 gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

  20. Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy [v1; ref status: indexed,

    Directory of Open Access Journals (Sweden)

    Lori Sames


    Full Text Available Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF, Hannah's Hope Fund (HHF, The Neuropathy Association (TNA and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies

  1. Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy [v2; ref status: indexed,

    Directory of Open Access Journals (Sweden)

    Lori Sames


    Full Text Available Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF, Hannah's Hope Fund (HHF, The Neuropathy Association (TNA and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies

  2. Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich’s ataxia

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    Belén Mollá


    Full Text Available Frataxin (FXN deficiency causes Friedreich’s ataxia (FRDA, a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG, sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence.

  3. Research progress of acute motor axonal neuropathy%急性运动轴索性神经病的研究进展

    Institute of Scientific and Technical Information of China (English)

    张刚; 秦新月


    急性运动轴索性神经病(AMAN)是吉兰-巴雷综合征(GBS)的主要亚型之一,与GBS主要亚型急性炎症性脱髓鞘性多发性神经病(AIDP)在临床表现、免疫病理生理机制、神经电生理检查、血清学抗体等方面均有不同。本文就AMAN相关研究进展做一综述。%Acute motor axonal neuropathy (AMAN) is one of the main subtypes of Guillain-Barré syndrome (GBS), which presents with acute ascending flaccid paralysis like acute inflammatory demyelinating polyneuropathy (AIDP). But AMAN can be different with AIDP in clinical manifestation, immunopathogenesis, electrophysiology, serum antibody, prognosis, et al. This review focused on the research progress of AMAN.

  4. Mitochondrial dynamics and peripheral neuropathy. (United States)

    Baloh, Robert H


    Peripheral neuropathy is perhaps the archetypal disease of axonal degeneration, characteristically involving degeneration of the longest axons in the body. Evidence from both inherited and acquired forms of peripheral neuropathy strongly supports that the primary pathology is in the axons themselves and points to disruption of axonal transport as an important disease mechanism. Recent studies in human genetics have further identified abnormalities in mitochondrial dynamics--the fusion, fission, and movement of mitochondria--as a player in the pathogenesis of inherited peripheral neuropathy. This review provides an update on the mechanisms of mitochondrial trafficking in axons and the emerging relationship between the disruption of mitochondrial dynamics and axonal degeneration. Evidence suggests mitochondria are a "critical cargo" whose transport is necessary for proper axonal and synaptic function. Importantly, understanding the regulation of mitochondrial movement and the consequences of decreased axonal mitochondrial function may define new paths for therapeutic agents in peripheral neuropathy and other neurodegenerative diseases.

  5. Poor efficacy of the phosphorylated high-molecular-weight neurofilament heavy subunit serum level, a biomarker of axonal damage, as a marker of chemotherapy-induced peripheral neuropathy (United States)



    The phosphorylated form of the high-molecular-weight neurofilament heavy subunit (pNF-H) is a major structural protein in axons. The pNF-H level is elevated in the serum of certain patients with central nervous disorders, including chemotherapy-induced cognitive impairment. The present study was conducted to elucidate the potential role of pNF-H as a marker of chemotherapy-induced peripheral neuropathy (CIPN). A total of 71 patients with early breast cancer in various stages of treatment (following 1, 3 or 7 cycles of chemotherapy, or a previous history of breast cancer chemotherapy) were assessed with a self-administered PainDETECT questionnaire [pain location, pain intensity on an 11-point numeric rating scale (NRS), and various pain qualities] and a single serum pNF-H measurement. Patients were divided into two groups based on the presence or absence of bilateral symmetric pain in the distal portions of the extremities [CIPN(+) or CIPN(−)]. The χ2 and Mann-Whitney tests were used for statistical analyses. Among the participants, only 8 patients complained of CIPN. Their pain intensity was 3.5±1.9 (mean ± standard deviation) compared with 1.5±1.8 in the CIPN(−) group (P<0.01). The NRS of numbness in the CIPN(+) group was significantly higher (2.4±1.4) than that of the CIPN(−) group (1.0±1.0). Increased pNF-H levels were observed in 37.5% of the CIPN(+) patients and in 23.8% of CIPN(−) patients (P=0.40). In conclusion, CIPN is observed in the most distal portions of the peripheral nerves that are composed of dendrites but not axons. Although serum pNF-H is a biomarker of axonal damage, it is not useful as a marker of CIPN. PMID:27284419

  6. Comparison of Nerve Excitability Testing, Nerve Conduction Velocity, and Behavioral Observations for Acrylamide Induced Peripheral Neuropathy (United States)

    Nerve excitability (NE) testing is a sensitive method to test for peripheral neurotoxicity in humans,and may be more sensitive than compound nerve action potential (CNAP) or nerve conduction velocity (NCV).We used acrylamide to compare the NE and CNAP/NCV methods. Behavioral test...

  7. Acrylamide induces locomotor defects and degeneration of dopamine neurons in Caenorhabditis elegans. (United States)

    Li, Jia; Li, Dan; Yang, Yongsheng; Xu, Tiantian; Li, Ping; He, Defu


    Acrylamide can form in foods during the cooking process and cause multiple adverse effects. However, the neurotoxicity and mechanisms of acrylamide have not been fully elucidated. In Caenorhabditis elegans, we showed that 48 h exposure to 10-625 mg l(-1) acrylamide resulted in a significant decline in locomotor frequency of body bending, head thrashing and pharynx pumping. In addition, acrylamide exposure reduced crawling speeds and changed angles of body bending. It indicates that acrylamide induces locomotor defects, along with parkinsonian-like movement impairment, including bradykinesia and hypokinesia. Acrylamide also affected chemotaxis plasticity and reduced learning ability. Using transgenic nematodes, we found that acrylamide induced downexpression of P(dat-1) and led to the degeneration of dopaminergic neurons. Moreover, the enhanced expression of unc-54, encoding a subunit of α-synuclein was found. It illustrates that acrylamide is efficient in inducing crucial parkinsonian pathology, including dopaminergic damage and α-synuclein aggregation. These findings suggest the acrylamide-induced locomotor defects and neurotoxicity are associated with Parkinson's disease.

  8. Electrodiagnosis of peripheral neuropathy. (United States)

    Ross, Mark A


    Electrodiagnostic studies are an important component of the evaluation of patients with suspected peripheral nerve disorders. The pattern of findings and the features that are seen on the motor and sensory nerve conduction studies and needle electromyography can help to identify the type of neuropathy, define the underlying pathophysiology (axonal or demyelinating), and ultimately help to narrow the list of possible causes. This article reviews the electrodiagnostic approach to and interpretation of findings in patients with peripheral neuropathies.

  9. [Developments in hereditary neuropathies]. (United States)

    Dubourg, O


    Hereditary sensorimotor neuropathies, or Charcot-Marie-Tooth disease (CMT) comprise a group of diseases with heterogeneous clinical, electrophysiological and genetic expression. They are classified by the mode of inheritance (autosomal dominant, X-linked dominant, autosomal recessive) and their electrophysiological characteristics taking into account the speed of motor conduction of the median nerve (demyelinating, intermediary and axonal forms). Certain purely motor forms are called spinal CMT or hereditary distal motor neuropathy, or distal spinal amyotrophy. CMT involving an important sensorial component, trophic disorders, or signs of dysautonomia are included in the classification of hereditary sensory and autonomic neuropathies.

  10. De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy

    NARCIS (Netherlands)

    Lee, Jae Ran; Srour, Myriam; Kim, Doyoun; Hamdan, Fadi F.; Lim, So Hee; Brunel-Guitton, Catherine; Décarie, Jean Claude; Rossignol, Elsa; Mitchell, Grant A.; Schreiber, Allison; Moran, Rocio; Van Haren, Keith; Richardson, Randal; Nicolai, Joost; Oberndorff, Karin M E J; Wagner, Justin D.; Boycott, Kym M.; Rahikkala, Elisa; Junna, Nella; Tyynismaa, Henna; Cuppen, Inge; Verbeek, Nienke E.; Stumpel, Connie T R M; Willemsen, Michel A.; de Munnik, Sonja A.; Rouleau, Guy A.; Kim, Eunjoon; Kamsteeg, Erik Jan; Kleefstra, Tjitske; Michaud, Jacques L.


    KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p

  11. Thalidomide neuropathy in childhood. (United States)

    Fleming, Fiona J; Vytopil, Michal; Chaitow, Jeffrey; Jones, H Royden; Darras, Basil T; Ryan, Monique M


    Thalidomide was withdrawn from world markets in 1961 following recognition of its teratogenic effects. More recently, however, thalidomide treatment has been reintroduced to adult and paediatric practice for a variety of dermatologic, immunologic, rheumatologic and neoplastic disorders. Neuropathy is a significant side effect of thalidomide therapy, which may limit its clinical use. We report four cases of sensorimotor axonal neuropathy in children aged 10-15 years, treated with thalidomide for myxopapillary ependymoma, Crohn's disease and recurrent giant aphthous ulceration. Thalidomide neuropathy is often associated with proximal weakness and may progress even after discontinuation of treatment, in the phenomenon of 'coasting'. Children treated with thalidomide should undergo regular neurophysiologic studies in order to detect presymptomatic or progressive peripheral neuropathy.

  12. Olive oil abrogates acrylamide induced nephrotoxicity by modulating biochemical and histological changes in rats. (United States)

    Ghorbel, Imen; Elwej, Awatef; Fendri, Nesrine; Mnif, Héla; Jamoussi, Kamel; Boudawara, Tahia; Grati Kamoun, Naziha; Zeghal, Najiba


    Acrylamide (ACR) is one of the most important contaminants occurring in foods heated at high temperatures. The aim of this study is to investigate the protective efficacy of extra virgin olive oil (EVOO), a main component of the Mediterranean diet, against nephrotoxicity induced by ACR. Rats have received by gavage during 21 days either ACR (40 mg/kg body weight) or ACR-associated with EVOO (300 μl) or only EVOO (300 μl). Acrylamide induced nephrotoxicity as evidenced by an increase in malondialdehyde (MDA), hydrogen peroxide (H2O2), protein carbonyls (PCOs) and a decrease in glutathione, non-protein thiols (NPSHs), and vitamin C levels. Activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) were also decreased. Lactate dehydrogenase (LDH) activity, creatinine, urea, and uric acid, urinary volume and creatinine clearance levels were modified. EVOO supplementation improved all the parameters indicated above. Kidney histoarchitecture confirmed the biochemical parameters and the beneficial role of EVOO. EVOO, when added to the diet, may have a beneficial role against kidney injury by scavenging free radicals and by its potent antioxidant power.

  13. Curcumin and (-)-epigallocatechin-3-gallate attenuate acrylamide-induced proliferation in HepG2 cells. (United States)

    Shan, Xiaoyun; Li, Yuan; Meng, Xulian; Wang, Pengqi; Jiang, Pan; Feng, Qing


    Acrylamide, a proven rodent carcinogen, is present in carbohydrate-rich food heated at high temperatures. It can be metabolized into glycidamide mainly by cytochrome P450 2E1 (CYP2E1). The fact that acrylamide is a potential carcinogen to human-beings draws public attention recently. This study aimed to elucidate the effect of acrylamide at low doses on proliferation of HepG2 cells, and to test whether the two well-studied chemopreventive agents, curcumin and (-)-epigallocatechin-3-gallate (EGCG), would have antagonistic effects against acrylamide. The results showed that lower concentration of acrylamide (⩽100μM) significantly increased the proliferation of HepG2 cells, but not of the other cancer cells (MDA-231, HeLa, A549, and PC-3). Only in HepG2 cells, low concentration of acrylamide was able to induce CYP2E1 expression significantly. Knockdown of CYP2E1 restrained acrylamide to increase viability of HepG2 cells. In addition, acrylamide raised expression of epidermal growth factor receptor (EGFR), cyclin D1 and nuclear factor-κB (NF-κB), which contributed to cell proliferation. Both curcumin and EGCG effectively reduced acrylamide-induced proliferation, as well as protein expression of CYP2E1, EGFR, cyclin D1 and NF-κB. All these results suggest that low concentration of acrylamide may contribute to progression of hepatocellular carcinoma (HCC). Curcumin or EGCG could prevent acrylamide triggering this effect.

  14. [Diabetic neuropathy]. (United States)

    Lechleitner, Monika; Abrahamian, Heidemarie; Francesconi, Claudia; Kofler, Markus


    These are the guidelines for diagnosis and treatment of diabetic neuropathy. This diabetic late complication comprises a number of mono- and polyneuropathies, plexopathies, radiculopathies and autonomic neuropathy. The position statement summarizes characteristic clinical symptoms and techniques for diagnostic assessment of diabetic neuropathy. Recommendations for the therapeutic management of diabetic neuropathy, especially for the control of pain in sensorimotor neuropathy, are provided.

  15. Restoration of optic neuropathy

    Directory of Open Access Journals (Sweden)

    You SW


    Full Text Available Si-Wei You,1 Ming-Mei Wu,2 Fang Kuang,2 Kin-Sang Cho,3 Kwok-Fai So4,5 1Department of Ophthalmology, Xijing Hospital, 2Institute of Neurosciences, The Fourth Military Medical University, Xi’an, China; 3Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; 4GHM Institute of CNS Regeneration, Key Laboratory of Brain Function and Diseases, Jinan University, Guangzhou, 5Department of Ophthalmology, The State Key laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong SAR, China Abstract: Optic neuropathy refers to disorders involving the optic nerve (ON. Any damage to ON or ON-deriving neurons, the retinal ganglion cells (RGCs, may lead to the breakdown of the optical signal transmission from the eye to the brain, thus resulting in a partial or complete vision loss. The causes of optic neuropathy include trauma, ischemia, inflammation, compression, infiltration, and mitochondrial damages. ON injuries include primary and secondary injuries. During these injury phases, various factors orchestrate injured axons to die back and become unable to regenerate, and these factors could be divided into two categories: extrinsic and intrinsic. Extrinsic inhibitory factors refer to the environmental conditions that influence the regeneration of injured axons. The presence of myelin inhibitors and glial scar, lack of neurotrophic factors, and inflammation mediated by injury are regarded as these extrinsic factors. Extrinsic factors need to trigger the intracellular signals to exert inhibitory effect. Proper regulation of these intracellular signals has been shown to be beneficial to ON regeneration. Intrinsic factors of RGCs are the pivotal reasons that inhibit ON regeneration and are closely linked with extrinsic factors. Intracellular cyclic adenosine monophosphate (cAMP and calcium levels affect axon guidance and growth cone response to guidance molecules

  16. Diabetic neuropathy part 1: overview and symmetric phenotypes. (United States)

    Pasnoor, Mamatha; Dimachkie, Mazen M; Kluding, Patricia; Barohn, Richard J


    Diabetes is the most common cause of neuropathy in United States and neuropathies are the most common complication of diabetes mellitus, affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Symptoms usually include numbness, tingling, pain, and weakness. Dizziness with postural changes can be seen with autonomic neuropathy. Metabolic, vascular, and immune theories have been proposed for the pathogenesis of diabetic neuropathy. Axonal damage and segmental demyelination can be seen with diabetic neuropathies. Management of diabetic neuropathy should begin at the initial diagnosis of diabetes and mainly requires tight and stable glycemic control.

  17. [Hereditary peripheral neuropathies]. (United States)

    Vallat, Jean-Michel; Tazir, Mériem; Calvo, Judith; Funalot, Benoît


    Currently more than 30 genes are known to be responsible for genetically determined neuropathies. Charcot-Marie-Tooth (CMT) disease is the most frequent of these hereditary neuropathies, with a prevalence of 4.7 to 36 per 100 000. In its demyelinating forms (CMT1), approximately 70% of cases are associated with a duplication of the PMP22gene. In its axonal forms (CMT2), 10-20% of the cases may be associated with a mutation of the MFN2gene. For North African patients with recessive transmission, a mutation of the LMNA gene must be sought. It is essential to stress the great variability of the phenotype--clinical, electrophysiological, and histologic--between and within families. A detailed analysis of these criteria, together with consideration of ethnic origin, may guide the search for the causal mutation. Whether the case involves certainly hereditary transmission or a sporadic form, it is desirable to be able to examine the maximum number of the patient's kin, both clinically and electrophysiologically. The forms with recessive transmission usually have a very early onset and are more serious than the dominant forms. The early- and very early-onset forms of CMT are increasingly better distinguished: congenital hypomyelination neuropathy (mutations of PMP22, MPZ or EGR2), or more axonal forms, including SMARD1 (Spinal muscle atrophy with respiratory distress; mutations of IGHMBP2) and EOHMSN (Early-onset hereditary motor and sensory neuropathy; mutations of MFN2). The prevention of cutaneous (ulcerations), bone, and amputation complications is very important in patients with hereditary sensory and autonomic neuropathies, because of the severity of the sensory disorders.

  18. Peripheral Neuropathy (United States)

    ... can be associated with peripheral neuropathy. Metabolic and endocrine disorders impair the body’s ability to transform nutrients into ... to neuropathies as a result of chemical imbalances. Endocrine disorders that lead to hormonal imbalances can disturb normal ...

  19. Diagnostic approach to peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Misra Usha


    Full Text Available Peripheral neuropathy refers to disorders of the peripheral nervous system. They have numerous causes and diverse presentations; hence, a systematic and logical approach is needed for cost-effective diagnosis, especially of treatable neuropathies. A detailed history of symptoms, family and occupational history should be obtained. General and systemic examinations provide valuable clues. Neurological examinations investigating sensory, motor and autonomic signs help to define the topography and nature of neuropathy. Large fiber neuropathy manifests with the loss of joint position and vibration sense and sensory ataxia, whereas small fiber neuropathy manifests with the impairment of pain, temperature and autonomic functions. Electrodiagnostic (EDx tests include sensory, motor nerve conduction, F response, H reflex and needle electromyography (EMG. EDx helps in documenting the extent of sensory motor deficits, categorizing demyelinating (prolonged terminal latency, slowing of nerve conduction velocity, dispersion and conduction block and axonal (marginal slowing of nerve conduction and small compound muscle or sensory action potential and dennervation on EMG. Uniform demyelinating features are suggestive of hereditary demyelination, whereas difference between nerves and segments of the same nerve favor acquired demyelination. Finally, neuropathy is classified into mononeuropathy commonly due to entrapment or trauma; mononeuropathy multiplex commonly due to leprosy and vasculitis; and polyneuropathy due to systemic, metabolic or toxic etiology. Laboratory investigations are carried out as indicated and specialized tests such as biochemical, immunological, genetic studies, cerebrospinal fluid (CSF examination and nerve biopsy are carried out in selected patients. Approximately 20% patients with neuropathy remain undiagnosed but the prognosis is not bad in them.

  20. [Autonomic peripheral neuropathy]. (United States)

    Adams, David; Cauquil, Cecile; Lozeron, Pierre


    The mechanisms of dysautonomic disturbances are varied and mostly acquired. They can result from lesions of sympathetic or parasympathetic vegetative fibers located in the peripheral contingent, or in the somatic contingent by demyelination or axonal loss; or more rarely by cellular bodies in the sympathetic or parasympathetic ganglia. Several chronic peripheral neuropathies can be associated with dysautonomia. Only some causes need to be known because they can be clinically significant. Dysautonomia may be seen during chronic acquired neuropathies but also acute or subacute ones. The most frequent cause in the world is the dysautonomia of the diabetes; it affects all the systems; the cardiovascular dysfunction has an impact on the prognosis for survival when it is severe. Hereditary autonomic neuropathies are rare; they can declare themselves very early during the Riley-Day syndrome or very late during amyloid polyneuropathies due to transthyretin gene mutation. The diagnosis can be confirmed by molecular biology. The dysautonomia is frequent and often severe. These neuropathies justify symptomatic treatment to improve quality of life. For some of them, a specific treatment can be proposed to treat the causal affection to try to stop the progression of the disease.

  1. Vasculitic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Mona Amini


    Full Text Available Primary systemic vasculitis in pre-capillary arteries is associated with peripheral neuropathy. In some types of systematic vasculitis about 60 % of patients have peripheral nervous system (PNS involvement. In vasculitic peripheral neuropathies (VPN a necrotizing and inflammatory process leads to narrowing of vasa nervorum lumen and eventually the appearance of ischemic lesions in peripheral nerves. Some features might be suggestive of VPN, like: axonal nerve degeneration, wallerian-like degeneration, and diameter irregularity of nerve. Peripheral nervous system (PNS destruction during systemic vasculitides should be considered, due to its frequency and early occurrence in vasculitis progression. The first line treatment of non systematic VPNs is corticosteroid agents, but these drugs might worsen the VPNs or systemic vasculitis.

  2. Purple pigments: the pathophysiology of acute porphyric neuropathy. (United States)

    Lin, Cindy S-Y; Lee, Ming-Jen; Park, Susanna B; Kiernan, Matthew C


    The porphyrias are inherited metabolic disorders arising from disturbance in the haem biosynthesis pathway. The neuropathy associated with acute intermittent porphyria (AIP) occurs due to mutation involving the enzyme porphobilinogen deaminase (PBGD) and is characterised by motor-predominant features. Definitive diagnosis often encompasses a combination of biochemical, enzyme analysis and genetic testing, with clinical neurophysiological findings of a predominantly motor axonal neuropathy. Symptomatic and supportive treatment are the mainstays during an acute attack. If administered early, intravenous haemin may prevent progression of neuropathy. While the pathophysiology of AIP neuropathy remains unclear, axonal dysfunction appears intrinsically linked to the effects of neural energy deficits acquired through haem deficiency coupled to the neurotoxic effects of porphyrin precursors. The present review will provide an overview of AIP neuropathy, including discussion of recent advances in understanding developed through neurophysiological approaches that have further delineated the pathophysiology of axonal degeneration.

  3. Autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J


    In order to elucidate the physiological significance of autonomic neuropathy in juvenile diabetics, cardiovascular, hormonal and metabolic functions have been investigated in three groups of juvenile diabetics: One group had no signs of neuropathy, one group had presumably slight autonomic...... neuropathy (reduced beat-to-beat variation in heart rate during hyperventilation) and one group had clinically severe autonomic neuropathy, defined by presence of orthostatic hypotension. In all three experimental situations we found sympathetic dysfunction causing cardiovascular and/or hormonal...... maladjustments in patients with autonomic neuropathy. Regarding metabolic functions we found normal responses to graded exercise and insulin-induced hypoglycemia in patients with autonomic neuropathy in spite of blunted catecholamine responses, suggesting increased sensitivity of glycogen stores and adipose...

  4. Inflammatory neuropathies. (United States)

    Whitesell, Jackie


    Inflammatory neuropathies are acquired disorders of peripheral nerves and occasionally of the central nervous system that can affect individuals at any age. The course can be monophasic, relapsing, or progressive. Inflammatory neuropathies are classified as acute or chronic. The acute form reaches a nadir by 4 weeks and the chronic form over 8 weeks or greater. The most common example of an acute inflammatory neuropathy is acute inflammatory demyelinating polyradiculoneuropathy (AIDP), which is part of the Guillain-Barré syndrome (GBS). The most common chronic inflammatory neuropathy is chronic inflammatory demyelinating polyradiculopathy (CIDP). Other chronic inflammatory neuropathies are multifocal motor neuropathy (MMN) and the Lewis-Sumner syndrome. The Fisher syndrome and Bickerstaff brainstem encephalitis occur acutely and have clinical overlap with AIDP.

  5. [Autonomic neuropathies]. (United States)

    Siepmann, T; Penzlin, A I; Illigens, B M W


    Autonomic neuropathies are a heterogeneous group of diseases that involve damage of small peripheral autonomic Aδ- and C-fibers. Causes of autonomic nerve fiber damage are disorders such as diabetes mellitus and HIV-infection. Predominant symptoms of autonomic neuropathy are orthostatic hypotension, gastro-intestinal problems, urogenital dysfunction, and cardiac arrhythmia, which can severely impair the quality of life in affected patients. Furthermore, autonomic neuropathies can be induced by autoimmune diseases such as acute inflammatory demyelinating polyneuropathy, hereditary disorders such as the lysosomal storage disorder Fabry disease and hereditary sensory and autonomic neuropathies, as well as certain toxins and drugs.

  6. 27. Molecular spectra of acrylamide-induced mutation at hprt locus in human promyelocytic leukemia HL-60 and NB4. cell lines

    Institute of Scientific and Technical Information of China (English)

    刘胜学; 曹佳; 杨梦苏; 方志俊; 安辉


    The genotoxicity of acrylamide was investigated by methods of single cell clone culturing, two-way screening count, multiplex PCR amplification and electrophoresis technique. Acrylamide only showed clear mutagenesis until dose raised 700 mg*L-1 in HL-60 cells. The most frequent spontaneous mutation were point mutation (≥90.0%) and acrylamide-induced mutation mainly included partial deletion and point mutation (respectively 40.0%~66.7%/33.3%~60.0%). Total gene deletion wasn't discovered in both of cells. There were deletion mutation in all exons of hprt gene(except 7/8 exon), and toward the 3' end of the hprt gene. The most frequent acrylamide-induced mutation were point mutation and single exon deletion (93.3%/86.1%). There were not clear difference in both of cells. The results suggest that the spectra of spontaneous and acrylamide-induced mutants were different. and the smaller changes in genetic structure have something to do with mechanism.

  7. Trigonella foenum-graecum ameliorates acrylamide-induced toxicity in rats: Roles of oxidative stress, proinflammatory cytokines, and DNA damage. (United States)

    Abdel-Daim, Mohamed M; Abd Eldaim, Mabrouk A; Hassan, Abeer G A


    Acrylamide is a hazardous substance inducing oxidative stress. Based on some evidence on the antioxidant properties of fenugreek, Trigonella foenum-graecum, this study was conducted to investigate the protective effect of fenugreek seed oil against acrylamide toxicity. Thirty-two male Wistar rats were randomly assigned into four groups. The control group was given normal saline. The second group was administered acrylamide (20 mg/kg bw orally). The third and fourth groups were administered acrylamide (20 mg/kg bw) and supplemented with 2.5% and 5% fenugreek seed oil in their diets, respectively. Acrylamide intoxication significantly increased serum levels of LDH, AST, ALT, APL, γ-GT, cholesterol, uric acid, urea, creatinine, 8-oxo-2'-deoxyguanosine, interleukin 1 beta, interleukin 6, and tumor necrosis factor α. Moreover, it increased hepatic, renal, and brain lipid peroxidation, while it impaired the activities and concentrations of the antioxidant biomarkers. Fenugreek oil supplementation normalized the altered serum parameters, prevented lipid peroxidation, and enhanced the antioxidant biomarker concentrations and activities in the hepatic, renal, and brain tissues of acrylamide-intoxicated rats in a dose-dependent manner. Thus, these results indicate that Trigonella foenum-graecum oil has a protective effect against acrylamide-induced toxicity through its free radical scavenging and potent antioxidant activities.

  8. [Diabetic neuropathy]. (United States)

    Chudzik, Wiesław; Kaczorowska, Beata; Przybyła, Monika; Chudzik, Bartosz; Gałka, Małgorzata


    Diabetic neuropathy is most common chronic complication of diabetes mellitus. It is responsible for substantial morbidity, increased mortality and impaired quality of life. Patogenesis of diabetic neuropathy is complex. Chronic hyperglycemia is a major factor induces nerve fibers injury. High level of glucose stimulate the polyol pathway causing osmotic stress and enhance reactive oxygen species generation, as well as it play an important role in diabetic angiopathy development. Distal symmetric polineuropathy is most common type of diabetic neuropathy. Many patient may develop combinations of neuropathies concerning somatic and autonomic system. Early diagnosis and administered suitable treatment are necessary to reduce severe complication of diabetic neuropathy as well as strict glycemic control and risk factor increased.

  9. [Hereditary neuropathies]. (United States)

    Vallat, Jean-Michel; Calvo, Judith; Ghorab, Karima; Tazir, Meriem


    Although there are many human hereditary neuropathies, most of them with the exception of Charcot-Marie-Tooth disease or hereditary sensorimotor neuropathy, are rare. Irrespective of their type, the mode of transmission may be autosomal dominant or recessive, or X-linked. The most difficult to diagnose, however, are the sporadic forms. It is customary to distinguish the cases in which the neuropathy is the sole clinical expression from multisystemic diseases where neuropathy is one component of multi-organ involvement. The complexity and the multiplicity of genes involved and the lack of understanding of their exact functions hinder logical presentation of these hereditary neuropathies. For understandable technical reasons, the stage of specific treatment, namely the repair of the mutated gene, has yet to be attained.

  10. Peripheral neuropathy associated with mitochondrial disease in children. (United States)

    Menezes, Manoj P; Ouvrier, Robert A


    Mitochondrial diseases in children are often associated with a peripheral neuropathy but the presence of the neuropathy is under-recognized because of the overwhelming involvement of the central nervous system (CNS). These mitochondrial neuropathies are heterogeneous in their clinical, neurophysiological, and histopathological characteristics. In this article, we provide a comprehensive review of childhood mitochondrial neuropathy. Early recognition of neuropathy may help with the identification of the mitochondrial syndrome. While it is not definite that the characteristics of the neuropathy would help in directing genetic testing without the requirement for invasive skin, muscle or liver biopsies, there appears to be some evidence for this hypothesis in Leigh syndrome, in which nuclear SURF1 mutations cause a demyelinating neuropathy and mitochondrial DNA MTATP6 mutations cause an axonal neuropathy. POLG1 mutations, especially when associated with late-onset phenotypes, appear to cause a predominantly sensory neuropathy with prominent ataxia. The identification of the peripheral neuropathy also helps to target genetic testing in the mitochondrial optic neuropathies. Although often subclinical, the peripheral neuropathy may occasionally be symptomatic and cause significant disability. Where it is symptomatic, recognition of the neuropathy will help the early institution of rehabilitative therapy. We therefore suggest that nerve conduction studies should be a part of the early evaluation of children with suspected mitochondrial disease.

  11. Peripheral Neuropathy in Rats Exposed to Dichloroacetate (United States)

    Calcutt, Nigel A.; Lopez, Veronica L.; Bautista, Arjel D.; Mizisin, Leah M.; Torres, Brenda R.; Shroads, Albert L.; Mizisin, Andrew P.; Stacpoole, Peter W.


    The use of dichloroacetate (DCA) for treating patients with mitochondrial diseases is limited by the induction of peripheral neuropathy. The mechanisms of DCA-induced neuropathy are not known. Oral DCA treatment (50–500 mg/kg/day for up to 16 weeks) induced tactile allodynia in both juvenile and adult rats; concurrent thermal hypoalgesia developed at higher doses. Both juvenile and adult rats treated with DCA developed nerve conduction slowing that was more pronounced in adult rats. No overt axonal or glial cell abnormalities were identified in peripheral nerves or spinal cord of any DCA-treated rats but morphometric analysis identified a reduction of mean axonal caliber of peripheral nerve myelinated fibers. DCA treatment also caused accumulation of oxidative stress markers in the nerves. These data indicate that behavioral, functional and structural indices of peripheral neuropathy may be induced in both juvenile and adult rats treated with DCA at doses similar to those in clinical use. DCA-induced peripheral neuropathy primarily afflicts axons and involves both metabolic and structural disorders. The DCA-treated rat may provide insight into the pathogenesis of peripheral neuropathy and facilitate development of adjuvant therapeutics to prevent this disorder that currently restricts the clinical use of DCA. PMID:19680144

  12. Autonomic Neuropathy (United States)

    ... harm. Alpha-lipoic acid Preliminary research suggests this antioxidant may be helpful in slowing or even reversing ... electrical waves transmitted through electrodes placed on the skin, may help ease pain associated with diabetic neuropathy. ...

  13. Pyridoxine neuropathy. (United States)

    Waterston, J A; Gilligan, B S


    A case of sensory neuropathy in a young woman due to long-term ingestion of pyridoxine, with subsequent recovery, is described. Pyridoxine neuropathy may occur after the long-term ingestion of doses as low as 200 mg a day. Because of its widespread use in the community, both the general public and the medical community need to be aware of this recently described complication of megavitamin therapy.

  14. [Chronic inflammatory demyelinating neuropathies and their variants (United States)

    Vallat, J.-M.; Tabaraud, F.; Magy, L.; Macian, F.


    The Chronic Inflammatory Demyelinating Polyradiculoneuropathies (CIDP) constitute a syndrome whose incidence is difficult to evaluate, and is probably underestimated. In the course of this presentation, we deliberately restricted discussion to issues raised in recent years concerning the extent of this syndrome. We discuss diagnostic criteria, especially electrophysiological ones. As the criteria proposed by the ad hoc committee of the American Academy of Neurology in 1991 have been questioned due to lack of sensitivity, new ones have been proposed recently. We briefly discuss the different types of chronic dysimmune demyelinating neuropathy: not only the CIDP, but also the Lewis and Sumner syndrome or multifocal inflammatory demyelinating neuropathy and the multiple conduction block neuropathies. At last, we point out the consistent finding of axonal involvement in the course of a chronic demyelinating neuropathy; over time, it can become predominant, which may make diagnosis difficult by suggesting a chronic axonal neuropathy that may be assumed to be primary. Consideration of these points may help clinicians recognize more chronic dysimmune neuropathies, for which immunosuppressive therapy has been found to be effective.

  15. Critical illness neuropathy

    Directory of Open Access Journals (Sweden)

    Vijayan J


    Full Text Available The neuromuscular syndrome of acute limb and respiratory weakness that commonly accompanies patients with multi-organ failure and sepsis constitutes critical illness polyneuropathy. It is a major cause of difficulty in weaning off the patient from the ventilator after respiratory and cardiac causes have been excluded. It is usually an axonal motor-sensory polyneuropathy, and is usually associated with or accompanied with a coma producing septic encephalopathy. The neuropathy is usually not apparent until the patient′s encephalopathy has peaked, and may be noted only when the brain dysfunction is resolving. Patients usually have a protracted hospital course complicated by multi-organ failure and the systemic inflammatory response syndrome. Elevated serum glucose levels and reduced albumin are risk factors for nerve dysfunction, as is prolonged intensive care unit stay. Polyneuropathy may develop after only one week of the systemic inflammatory response syndrome, but the frequency tends to correlate with the duration of the severe illness.

  16. Acquired versus familial demyelinative neuropathies in children. (United States)

    Miller, R G; Gutmann, L; Lewis, R A; Sumner, A J


    The electrophysiologic differences between chronic acquired demyelinative neuropathy and the demyelinative form of Charcot-Marie-Tooth disease have recently been reported. The present report extends these observations to include the genetically determined demyelinating neuropathies seen in metachromatic leukodystrophy, Krabbe's leukodystrophy, and Cockayne's syndrome. The electrophysiologic features of metachromatic leukodystrophy (five patients), Krabbe's (four patients), and Cockayne's syndrome (three patients) were all similar. There was uniform slowing of conduction (both in different nerves and in different nerve segments), and conduction block was not seen. These findings are consistent with a uniform degree of demyelination in multiple nerves and throughout the entire length of individual axons. Thus, uniform slowing of nerve conduction constitutes strong evidence for a familial demyelinative neuropathy, as opposed to the multifocal slowing seen in acute and chronic acquired demyelinative neuropathy.

  17. L-cysteine, N-acetyl-L-cysteine, and glutathione protect Xenopus laevis embryos against acrylamide-induced malformations and mortality in the frog embryo teratogenesis assay. (United States)

    Rayburn, James R; Friedman, Mendel


    Dietary acrylamide is largely derived from heat-induced reactions between the amino group of the free amino acid asparagine and carbonyl groups of glucose and fructose during heat processing (baking, frying) of plant-derived foods such as potato fries and cereals. After consumption, acrylamide is absorbed into the circulation and is then distributed to various organs, where it can react with DNA, neurons, hemoglobin, and essential enzymes. In the present study, we explored the potential of L-cysteine (CySH), N-acetyl-L-cysteine (NAC), reduced glutathione (GSH), and the amino acid glycine (Gly) to protect frog embryos against acrylamide-induced developmental toxicity in the frog embryo teratogenesis assay - Xenopus (FETAX). To test the antiteratogenic potential, based on concentration-response study ranging from 0.07 to 4.22 mM acrylamide in FETAX solution (pH 8.1), we selected concentrations of acrylamide that induced 100% malformations and mortality. At the end of 96 h, we counted survivors and malformed embryos and measured embryo length. The data show that CySH, NAC, and GSH protected the embryos against acrylamide induced malformations and mortality to different degrees. CySH and GSH protected the embryos against both malformations and mortality, whereas NAC protected only against mortality. Gly had no protective effect. Possible mechanisms of the protective effects and the dietary significance of the results of this and related studies for food safety and human health are discussed.

  18. Treatment of immune-mediated, dysimmune neuropathies. (United States)

    Finsterer, J


    This review focuses on the actual status and recent advances in the treatment of immune-mediated neuropathies, including: Guillain-Barre syndrome (GBS) with its subtypes acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy, acute motor and sensory axonal neuropathy, Miller Fisher syndrome, and acute pandysautonomia; chronic inflammatory demyelinating polyneuropathy (CIDP) with its subtypes classical CIDP, CIDP with diabetes, CIDP/monoclonal gammopathy of undetermined significance (MGUS), sensory CIDP, multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy or Lewis-Sumner syndrome, multifocal acquired sensory and motor neuropathy, and distal acquired demyelinating sensory neuropathy; IgM monoclonal gammopathies with its subtypes Waldenstrom's macroglobulinemia, myelin-associated glycoprotein-associated gammopathy, polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes syndrome, mixed cryoglobulinemia, gait ataxia, late-onset polyneuropathy syndrome, and MGUS. Concerning the treatment of GBS, there is no significant difference between intravenous immunoglobulins (IVIG), plasma exchange or plasma exchange followed by IVIG. Because of convenience and absent invasiveness, IVIG are usually preferred. In treating CIDP corticosteroids, IVIG, or plasma exchange are equally effective. Despite the high costs and relative lack of availability, IVIG are preferentially used. For the one-third of patients, who does not respond, other immunosuppressive options are available. In MMN IVIG are the treatment of choice. Inadequate response in 20% of the patients requires adjunctive immunosuppressive therapies. Neuropathies with IgM monoclonal gammopathy may respond to various chemotherapeutic agents, although the long-term effects are unknown. In addition, such treatment may be associated with serious side effects. Recent data support the use of rituximab, a monoclonal antibody against the B

  19. Peripheral neuropathy and antiretroviral drugs. (United States)

    Dalakas, M C


    Patients treated with nucleoside analogue reverse transcriptase inhibitors (NRTIs) develop a varying degree of myopathy or neuropathy after long-term therapy. Zidovudine (AZT) causes myopathy; zalcitabine (ddC), didanosine (ddl) and lamuvidine (3TC) cause neuropathy; stavudine (d4T) and fialuridine (FIAU) cause neuropathy or myopathy and lactic acidosis. The tissue distribution of phosphorylases responsible for phosphorylation of NRTIs relates to their selective tissue toxicity. The myopathy is characterized by muscle wasting, myalgia, fatigue, weakness and elevation of CK. The neuropathy is painful, sensory and axonal. In vitro, NRTIs inhibit the gamma-DNA polymerase, responsible for replication of mtDNA, and cause mtDNA dysfunction. In vivo, patients treated with AZT, the best studied NRTI, develop a mitochondrial myopathy with mtDNA depletion, deficiency of COX (complex IV), intracellular fat accumulation, high lactate production and marked phosphocreatine depletion, as determined with in vivo MRS spectroscopy, due to impaired oxidative phosphorylation. Animals or cultured cells treated with NRTIs develop neuropathy, myopathy, or cell destruction with similar changes in the mitochondria. There is evidence that the NRTI-related neuropathy is also due to mitochondrial toxicity. The NRTIs (AZT, ddC, ddl, d4T, 3TC) contain azido groups that compete with natural thymidine triphosphate as substrates of DNA pol-gamma and terminate mtDNA synthesis. In contrast, FIAU that contains 3'-OH groups serves as an alternate substrate for thymidine triphosphate with DNA pol-gamma and is incorporated into the DNA causing permanent mtDNA dysfunction. The NRTI-induced mitochondrial dysfunction has an influence on the clinical application of these agents, especially at high doses and when combined. They have produced in humans a new category of acquired mitochondrial toxins that cause clinical manifestations resembling the genetic mitochondrial disorders.

  20. [Diagnosis of immune-mediated neuropathies]. (United States)

    Diószeghy, Péter


    Separate discussion of immune-mediated neuropathies from other neuropathies is justified by the serious consequences of the natural course of these diseases, like disability and sometimes even life threatening conditions. On the other hand nowadays effective treatments already exist, and with timely and correct diagnosis an appropriately chosen treatment may result in significant improvement of quality of life, occasionally even complete recovery. These are rare diseases, and the increasing number of different variants makes it more difficult to recognize them. Their diagnosis is based on the precise knowledge of clinical signs and symptoms, and it is verified by the help of neurophysiologic and laboratory, first of all CSF examinations. Description of clinical features of the classic acute immune-mediated neuropathy, characterized by ascending paresis and demyelination is followed by a summary of characteristics of newly recognized axonal, regional and functional variants. Chronic immune-mediated demyelinating polyneuropathies are not diagnosed in due number even today. This paper does not only present the classic form but it also introduces the ever increasing special variants, like distal acquired demyelinating sensory neuropathy, Lewis-Sumner syndrome, multifocal motor neuropathy and paraproteinemic neuropathies. Vasculitic neuropathies can be divided into two groups: systemic and non-systemic ones. The first sign of a vasculitic neuropathy is a progressive, painful mononeuropathy; the classic clinical presentation is the mononeuritis multiplex. It is characterized by general signs like fever, loss of weight, fatigue. In systemic vasculitis organ specific symptoms are also present. From the paraneoplastic diseases the subacute sensory neuropathy and the sensory neuronopathy are members of the immune-mediated neuropathies, being most frequently associated with small cell lung cancer.

  1. Early onset (childhood) monogenic neuropathies. (United States)

    Landrieu, Pierre; Baets, Jonathan


    Hereditary neuropathies (HN) with onset in childhood are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission and, in selected cases, pathological findings. Especially relevant to pediatrics are the items "secondary" versus "primary" neuropathy, "syndromic versus nonsyndromic," and "period of life." Different combinations of these parameters frequently point toward specific monogenic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first concern in pediatrics. As a rule, metabolic diseases include additional, orienting symptoms or signs, and their biochemical diagnosis is based on logical algorithms. Primary, motor sensory are the most frequent HN and are dominated by demyelinating autosomal dominant (AD) forms (CMT1). Other forms include demyelinating autosomal recessive (AR) forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Peripheral motor neuron disorders are dominated by AR SMN-linked spinal muscular atrophies. (Distal) hereditary motor neuropathies represent 40 genes with various biological functions have been found to be responsible for primary HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait, and some for various types of transmission.

  2. Autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J


    The diagnosis of autonomic neuropathy is often difficult to establish, since clinical symptoms generally appear late in the course of the disease, and may be non-specific. A number of recently developed quantifiable and reproducible autonomic nerve function tests are reviewed, with emphasis on th...


    Directory of Open Access Journals (Sweden)

    Venkata Chalam


    Full Text Available A 5 year old girl having hereditary sensory neuropathy, type II manifesting as congenital absence of pain sensation and trophic changes in the skin is reported. This child presented with presented with multiple ulcers over hands and feet since 2 years of age. The ulcers were non - healing type with serosanguineous discharge. There is abnormal gait and weakness in upper and lower limbs. On examination there are deep ulcers measuring 5x7x2cms over left feet. Fingers of both hands and feet were mutilated with loss of phalanges, sensations to fine touch, pain and temperature are decreased bilaterally below the mid arm and feet, vibration sensations were normal, proprioception could not be tested due to deformities. Sensory and motor nerve conduction studies showed evidence of sensorimotor axonal neuropathy.

  4. Abnormal calcium homeostasis in peripheral neuropathies. (United States)

    Fernyhough, Paul; Calcutt, Nigel A


    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neurone function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation in both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies.

  5. Histopathological heterogeneity of neuropathy in insulin-dependent and non-insulin-dependent diabetes, and demonstration of axo-glial dysjunction in human diabetic neuropathy.


    Sima, A A; Nathaniel, V; Bril, V; McEwen, T A; Greene, D A


    Altered sorbitol and myo-inositol metabolism, (Na,K)-ATPase function, electrochemical sodium gradients, axonal swelling, and distortion and disruption of the node of Ranvier ("axo-glial dysjunction") directly implicate hyperglycemia in the pathogenesis of neuropathy in diabetic rats, but the relevance of this sequence to clinical neuropathy in heterogeneous groups of diabetic patients remains to be established. Fascicular sural nerve morphometry in 11 patients with neuropathy complicating ins...

  6. Genes for hereditary sensory and autonomic neuropathies : a genotype-phenotype correlation

    NARCIS (Netherlands)

    Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent


    Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven g

  7. Axonopathy in peripheral neuropathies: Mechanisms and therapeutic approaches for regeneration. (United States)

    Landowski, Lila M; Dyck, P James B; Engelstad, JaNean; Taylor, Bruce V


    Peripheral neuropathies (PNs) are injuries or diseases of the nerves which arise from varied aetiology, including metabolic disease, trauma and drug toxicity. The clinical presentation depends on the type of neuropathy, and may include the loss of motor, sensory and autonomic functions, or development of debilitating neuropathic pain distal to the injury site. It can be challenging to identify the aetiology of PNs, as the clinical syndromes are often indistinct. However, the mechanisms that underlie pathological changes in peripheral neuropathy are fundamentally different, depending on the trigger. This review focuses on the axonopathy observed in two frequently encountered forms of peripheral neuropathy, diabetic neuropathy and chemotherapy-induced neuropathy. A key manifestation of axonopathy in PN is the degeneration of terminal arbors of peripheral nerves, resulting in a loss of epidermal nerve fibres and inappropriate termination of nerve endings. Many symptoms of PN arise from aberrant termination of nerve endings, and the underlying axonopathy may be non-reversible, as nerve regeneration after injury and disease is often poor, absent, or aberrant. Directed guidance of terminal arbors back into the epidermis is therefore a suggested approach to treat peripheral neuropathy. This review will outline potential strategies to enhance and guide axonal regeneration and reinnervation in the skin. Using diabetic neuropathy and chemotherapy-induced neuropathy as specific examples, this review examines the setbacks encountered with the translation of growth factors into therapeutics for human neuropathy, and suggests a number of approaches for topical drug delivery.

  8. Lyme borreliosis neuropathy. A case report. (United States)

    Deltombe, T; Hanson, P; Boutsen, Y; Laloux, P; Clerin, M


    Lyme borreliosis is responsible for a large variety of peripheral neurologic manifestations including axonal polyneuropathy, radiculopathy, and facial nerve palsy. The prevalence of the disease must draw our attention on the possible responsibility of Borrelia burgdorferi in the pathogenesis of such symptomatology. Electrophysiologic studies demonstrate a proximal and distal axonal involvement, whereas neuropathologic studies suggest that vasculitis might be one of the primary pathophysiologic mechanisms. Electromyography provides a useful diagnostic tool and an important measure of response to treatment. Although peripheral neuropathy usually improves, our case report confirms the fact that chronic neurologic manifestations may not consistently resolve with appropriate treatment.

  9. Upregulation of inward rectifying currents and Fabry disease neuropathy. (United States)

    Geevasinga, Nimeshan; Tchan, Michel; Sillence, David; Vucic, Steve


    Peripheral neuropathy and neuropathic pain are common clinical manifestations of Fabry disease (FD). Although the mechanisms underlying the development of sensory neuropathy remain to be fully elucidated, a chronic ischemic process was proposed. Consequently, this study utilized axonal excitability techniques to gain further insights into the pathophysiological mechanisms underlying the development of FD neuropathy. Median motor and sensory axonal excitability studies were undertaken in 13 FD patients and results were compared to 19 healthy subjects. A "fanning-in" of threshold electrotonus, suggestive of membrane depolarization, was evident only in motor axons in FD patients. In contrast, the sensory axons exhibited a lower threshold in FD (p < 0.05) and a significantly increased hyperpolarizing current/threshold (I/V) gradient (FD 0.48 ± 0.03; controls, 0.31 ± 0.02, p < 0.001), which correlated with clinical scores of disease severity (Rho = 0.65, p < 0.05), neuropathy (Rho = 0.54, p < 0.05) and neuropathic pain (Rho = 0.56, p < 0.05). These findings indicate that upregulation of I(h) , rather than ischemia, may underlie the sensory symptoms and possibly development of neuropathy in FD. Modulation of sensory I(h) may prove therapeutically useful in Fabry disease.

  10. [Inflammatory neuropathies and multineuritis]. (United States)

    Kuntzer, Thierry; Chofflon, Michel


    Inflammatory neuropathies include those neuropathies in which the diagnosis, outcome and type of treatment are badly known, the reason of this review. They are expressed as diffuse (such as CIDP and ganglionopathies), multifocal (vasculitic neuropathy) or focal (MMN; plexopathies; immune reconstitution inflammatory syndrome). These forms of neuropathies are important to be known because the beneficial therapeutic possibilities of immunosuppression.

  11. The distal hereditary motor neuropathies. (United States)

    Rossor, Alexander M; Kalmar, Bernadett; Greensmith, Linda; Reilly, Mary M


    The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.

  12. Diabetic autonomic neuropathy. (United States)

    Freeman, Roy


    Diabetes mellitus is the commonest cause of an autonomic neuropathy in the developed world. Diabetic autonomic neuropathy causes a constellation of symptoms and signs affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems. Several discrete syndromes associated with diabetes cause autonomic dysfunction. The most prevalent of these are: generalized diabetic autonomic neuropathy, autonomic neuropathy associated with the prediabetic state, treatment-induced painful and autonomic neuropathy, and transient hypoglycemia-associated autonomic neuropathy. These autonomic manifestations of diabetes are responsible for the most troublesome and disabling features of diabetic peripheral neuropathy and result in a significant proportion of the mortality and morbidity associated with the disease.

  13. Cranial nerves palsy as an initial feature of an early onset distal hereditary motor neuropathy--a new distal hereditary motor neuropathy phenotype. (United States)

    Haberlová, J; Claeys, K G; De Jonghe, P; Seeman, P


    Distal hereditary motor neuropathy is a heterogeneous group of disorders characterised by a pure motor axonal neuropathy. It is occasionally associated with additional signs such as facial weakness, vocal cord paralysis, weakness of the diaphragm, and pyramidal signs. Although predominantly the inheritance is autosomal dominant, all types of inheritance have been described. Here we report a Czech family with cranial nerves palsy as an initial feature of a non progressive infantile onset dominant distal hereditary motor neuropathy. This family may represent a new subtype of distal hereditary motor neuropathy.

  14. Management of Diabetic Neuropathy


    Ali, Raymond Azman


    Diabetes mellitus is the commonest cause of neuropathy worldwide. Diabetic neuropathy (DN) develops in about 4–10% of diabetic patients after 5 years and in 15% after 20 years. Four main mechanisms have been postulated to underlie the pathogenesis of DN. Diabetic neuropathy can be divided into symmetrical and asymmetrical neuropathies. Diabetic Autonomic Neuropathy (DAN) parallels the severity of DSN, and affects primarily the cardiovascular, gastrointestinal, genitourinary and integumentary ...

  15. Pathogenesis of immune-mediated neuropathies. (United States)

    Dalakas, Marinos C


    Autoimmune neuropathies occur when immunologic tolerance to myelin or axonal antigens is lost. Even though the triggering factors and the underling immunopathology have not been fully elucidated in all neuropathy subsets, immunological studies on the patients' nerves, transfer experiments with the patients' serum or intraneural injections, and molecular fingerprinting on circulating autoantibodies or autoreactive T cells, indicate that cellular and humoral factors, either independently or in concert with each other, play a fundamental role in their cause. The review is focused on the main subtypes of autoimmune neuropathies, mainly the Guillain-Barré syndrome(s), the Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), the Multifocal Motor Neuropathy (MMN), and the IgM anti-MAG-antibody mediated neuropathy. It addresses the factors associated with breaking tolerance, examines the T cell activation process including co-stimulatory molecules and key cytokines, and discusses the role of antibodies against peripheral nerve glycolipids or glycoproteins. Special attention is given to the newly identified proteins in the nodal, paranodal and juxtaparanodal regions as potential antigenic targets that could best explain conduction failure and rapid recovery. New biological agents against T cells, cytokines, B cells, transmigration and transduction molecules involved in their immunopathologic network, are discussed as future therapeutic options in difficult cases. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.

  16. Anatomy of the optic nerve head and glaucomatous optic neuropathy. (United States)

    Radius, R L


    The mechanism of axon damage in eyes with glaucomatous optic neuropathy remains undefined. Interestingly, it has been observed that, although the entire nerve cross-section may be involved by the nerve damage, in many instances, the superior and inferior axon bundles are preferentially affected by the pressure insult. Thus, recent studies by many investigators have stressed a re-examination of the optic nerve head anatomy, including the nerve head microcirculation, the glial and connective tissue elements within the nerve head, and the morphology of the axons themselves. Any correlation between regional differences in this anatomy and the preferential involvement by specific axon bundles within the nerve head by the pressure insult may suggest some further insight into the mechanisms underlying the pressure-induced axon loss in glaucomatous eyes.

  17. Peripheral neuropathy in Whipples disease: a case report. (United States)

    Rusina, R; Keller, O; Síma, R; Zámečník, J


    Whipples disease is a chronic multisystem inflammatory disease with predominantly gastrointestinal manifestations due to Tropheryma whipplei infection. Typical neurological abnormalities include dementia, eye movement abnormalities, hypothalamic dysfunction and oculomasticatory myorhythmias. The literature on peripheral neuropathy in Whipples disease is sparse and the involvement of peripheral nerves in Whipples disease has not been documented convincingly so far. We present a case of Whipples disease presenting by axonal peripheral neuropathy without gastrointestinal involvement. The diagnosis was confirmed by a sural nerve biopsy and consequent PCR of the sample. All clinical signs disappeared progressively during the antibiotic therapy. Two years after the T. whipplei infection, the patient developed dopa-sensitive Parkinson's disease, although these two events seem to be unrelated. This case illustrates the value of peripheral nerve biopsy in cases of axonal neuropathy of unexplained origin and extends the clinical spectrum of Whipples disease to a new modality.

  18. Computing along the axon

    Institute of Scientific and Technical Information of China (English)

    Chen Haiming; Tseren-Onolt Ishdorj; Gheorghe Pǎun


    A special form of spiking neural P systems, called axon P systems, corresponding to the activity of Ranvier nodes of neuron axon, is considered and a class of SN-like P systems where the computation is done along the axon is introduced and their language generative power is investigated.

  19. [Multifocal-motor neuropathy and motor neuropathy with multifocal conduction block (Lewis-Sumner syndrome)]. (United States)

    Finsterer, J; Mamoli, B


    Multifocal motor neuropathy, which mimics lower motor neuron disease, is a rare and curious demyelinating neuropathy characterised by slowly progressive, asymmetric limb weakness within the distribution of individual peripheral nerves, wasting, cramps, fasciculations and rare sensory involvement, but without upper motor neuron signs. The cardinal feature and primary pathophysiological basis for the weakness is the multifocal motor conduction block which remains stable for years at the same site and is confined to motor axons. It is defined as > 50% reduction in both the CMAP and the negative peak area on proximal stimulation, as compared with the distal stimulus response without any change in the negative peak duration. Nerves at the site of the conduction block show demyelination, endoneural edema, rudimentary onion bulbs and lymphocytic inflammation. Sensory nerves may show mild demyelination, axon loss and lymphocytic inflammation. The majority of patients shows elevated titers of anti-glycolipid antibodies, which may block the Na+ channels, produce demyelination or interfere with remyelination. However, their role in the pathogenesis of multifocal motor neuropathy remains uncertain. Multifocal motor neuropathy is regarded as the predominantly motor variant of chronic inflammatory demyelinating polyneuropathy and can be treated best with immunoglobulins and cyclophosphamide.

  20. Histological, Scanning And Transmission Electron Microscopic Studies On The Possible Protective Role Of Ginger Extract Against AcrylamideInduced Intestinal Damage In Mice

    Directory of Open Access Journals (Sweden)

    Hala Galal El-Tantawi


    Full Text Available Objective: This study was carried out to evaluate the protective effect of ginger Zingeber officinale extract (ZOE against the acrylamide (AC which is an industrial chemical used in water treatment and it is synthesized during cooking of starch food at high temperature. Method: Thirty adult male albino mice, each weighs 20-25 g were divided into three groups (10 mice/group: (Icontrol group. (IIacrylamide treated group. (III acrylamide & ginger group. Acrylamide was given to experimental animals in the drinking water at a non-lethal dose of 200 p.p.m for 10 weeks (3 days/week. Ginger extract was orally administrated at 50 mg/L (~5 ml/day for 10 weeks (3 days/week. The ileum samples were collected for light microscope study and for scanning and transmission electron microscope examination. Results: This study revealed that acrylamide induces pathological changes of the ileum of the treated mice specially the absorptive epithelial cells. The scanning electron microscopic study revealed damage of the ileal villi, some red blood corpuscles appeared at the site of damage. The transmission electron microscopic examination clearly demonstrated degeneration of most cell organelles as mitochondria, deterioration and degranulation of the rough endoplasmic reticulum, dilatation of Golgi apparatus. Conclusion: The administration of ginger extract decreased the histological alterations and ensuring the anti-inflammatory, and antitoxic effects of ZOE at its chosen dosage level

  1. Clinicopathological study of vasculitic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Rong-fang DONG


    Full Text Available Objective To summarize the clinical features and neuropathological characteristics in patients with vasculitic peripheral neuropathy (VPN. Methods Clinical manifestations, laboratory examination and neuromuscular biopsy characteristics of 11 patients with VPN were retrospectively analyzed. The lesion of nerve, muscle and skin was observed under optical and electron microscope. Immunohistochemical analyses were carried out to detect neurofilament (NF, myelin basic protein (MBP, peripheral myelin protein 22 (PMP22 and S-100 protein (S-100 and further observing the neuropathy of neuraxon, myelin sheath and Schwann cells, and to detect human leukocyte antigen DR (HLA-DR, CD68, CD3 and CD20 to observe inflammatory cell infiltration. Immunofluorescent staining was used to detect the deposition of IgA, IgM, IgG and addiment C3 on vascular wall. The staining of periodic acid-Schiff (PAS, NADH-tetrazolium reductase (NADH-TR and modified Gomori trichrome (MGT were used to judge the myopathy. Results 1 Angiopathies were mainly manifested by small vessels of epineurium and perineurium, and infiltrated inflammatory cells were mainly CD3 + T cells. Three patients had active vasculitis, and 8 patients had non-active vasculitis. Among these 8 patients, 4 patients mainly presented fibrous obliteration of blood vessel, with slight inflammatroy cell infiltration, and the other 4 patients mainly showed perivascular inflammation. 2 Neuropathy: 6 patients had axon degeneration, and 5 patients had axon degeneration associated with demyelination. All of them demonstrated a reduction in myelinated fibers, mainly large diameter myelinated fibers, even on end-stage. 3 Muscle biopsy showed neurogenic atrophy. 4 Clinicopathologic diagnosis: among these 11 patients, 8 patients were diagnosed as systemic vasculitic peripheral neuropathy (SVPN, among whom 5 patients were diagnosed as primary systemic vasculitis [including 1 patient as Churg-Strauss syndrome (CSS, 2 patients as

  2. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease.

    LENUS (Irish Health Repository)

    Pitceathly, Robert D S


    Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).

  3. Molecular genetics of distal hereditary motor neuropathies. (United States)

    Irobi, Joy; De Jonghe, Peter; Timmerman, Vincent


    Inherited peripheral neuropathies comprise a wide variety of diseases primarily affecting the peripheral nervous system. The best-known peripheral neuropathy is Charcot-Marie-Tooth disease (CMT) described in 1886 by J.-M. Charcot, P. Marie and H.H. Tooth. In 1980, A.E. Harding and P.K. Thomas showed that in a large group of individuals with CMT, several only had motor abnormalities on clinical and electrophysiological examination, whereas sensory abnormalities were absent. This exclusively motor variant of CMT was designated as spinal CMT or hereditary distal spinal muscular atrophy, and included in the distal hereditary motor neuropathies (distal HMN). The distal HMN are clinically and genetically heterogeneous and are subdivided according to the mode of inheritance, age at onset and clinical evolution. Since the introduction of positional cloning, 12 chromosomal loci and seven disease-causing genes have been identified for autosomal dominant and recessive distal HMN. Most of the genes involved have housekeeping functions, as in RNA processing, translation synthesis, glycosylation, stress response, apoptosis, but also axonal trafficking and editing. Functional characterization of the mutations will help to unravel the cellular processes that underlie the specificity of motor neuropathies leading to neurogenic muscular atrophy of distal limb muscles. Here we review the recent progress of the molecular genetics of distal HMN and discuss the genes implicated.

  4. Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon. (United States)

    Ma, Marek


    Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed.

  5. [Genetics of neuropathies]. (United States)

    Gess, B; Schirmacher, A; Young, P


    Hereditary neuropathies belong to the most common neurogenetic disorders. They appear mostly as sensory and motor neuropathies but there are also pure sensory, pure motor as well as sensory and autonomic hereditary neuropathies. In clinical practice, knowledge of hereditary neuropathies is important in order to recognize them among polyneuropathies and achieve a successful genetic diagnosis. The molecular genetics of hereditary neuropathies are very heterogeneous with currently more than 40 known disease-causing genes. The 4 most common genes account for almost 90% of the genetically diagnosed hereditary neuropathies. In this review article we provide an overview of the currently known genes and propose a rational genetic work-up protocol of the most common genes.

  6. Use of pyridoxine and pyridostigmine in children with vincristine-induced neuropathy. (United States)

    Akbayram, Sinan; Akgun, Cihangir; Doğan, Murat; Sayin, Refah; Caksen, Huseyin; Oner, Ahmet Faik


    Four children with vincristine (VCR)-induced neuropathy are being reported. All cases were followed with the diagnosis of acute lymphoblastic leukemia. Two were boys aged between 2 and 13 year. Electromyographic examination consisted of sensoriomotor polyneuropathy with axonal involvement in three patients. In another patient, it consisted of motor axonal polyneuropathy. In all patients, pyridoxine and pyridostigmine were successfully used in the treatment of VCR-induced neuropathy. They recovered completely with this drug combination. Recovering period of symptoms was between 1-2 week.

  7. Axonal GABAA receptors. (United States)

    Trigo, Federico F; Marty, Alain; Stell, Brandon M


    Type A GABA receptors (GABA(A)Rs) are well established as the main inhibitory receptors in the mature mammalian forebrain. In recent years, evidence has accumulated showing that GABA(A)Rs are prevalent not only in the somatodendritic compartment of CNS neurons, but also in their axonal compartment. Evidence for axonal GABA(A)Rs includes new immunohistochemical and immunogold data: direct recording from single axonal terminals; and effects of local applications of GABA(A)R modulators on action potential generation, on axonal calcium signalling, and on neurotransmitter release. Strikingly, whereas presynaptic GABA(A)Rs have long been considered inhibitory, the new studies in the mammalian brain mostly indicate an excitatory action. Depending on the neuron that is under study, axonal GABA(A)Rs can be activated by ambient GABA, by GABA spillover, or by an autocrine action, to increase either action potential firing and/or transmitter release. In certain neurons, the excitatory effects of axonal GABA(A)Rs persist into adulthood. Altogether, axonal GABA(A)Rs appear as potent neuronal modulators of the mammalian CNS.

  8. Morphologic Changes in Autonomic Nerves in Diabetic Autonomic Neuropathy

    Directory of Open Access Journals (Sweden)

    Heung Yong Jin


    Full Text Available Diabetic neuropathy is one of the major complications of diabetes, and it increases morbidity and mortality in patients with both type 1 diabetes mellitus (T1DM and type 2 diabetes mellitus (T2DM. Because the autonomic nervous system, for example, parasympathetic axons, has a diffuse and wide distribution, we do not know the morphological changes that occur in autonomic neural control and their exact mechanisms in diabetic patients with diabetic autonomic neuropathy (DAN. Although the prevalence of sympathetic and parasympathetic neuropathy is similar in T1DM versus T2DM patients, sympathetic nerve function correlates with parasympathetic neuropathy only in T1DM patients. The explanation for these discrepancies might be that parasympathetic nerve function was more severely affected among T2DM patients. As parasympathetic nerve damage seems to be more advanced than sympathetic nerve damage, it might be that parasympathetic neuropathy precedes sympathetic neuropathy in T2DM, which was Ewing's concept. This could be explained by the intrinsic morphologic difference. Therefore, the morphological changes in the sympathetic and parasympathetic nerves of involved organs in T1DM and T2DM patients who have DAN should be evaluated. In this review, evaluation methods for morphological changes in the epidermal nerves of skin, and the intrinsic nerves of the stomach will be discussed.

  9. Anterior ischemic optic neuropathy precipitated by acute primary angle closure

    Directory of Open Access Journals (Sweden)

    Choudhari Nikhil


    Full Text Available A 59-year-old man with a history of longstanding systemic hypotension developed asymmetric non-arteritic anterior ischemic optic neuropathy (NAION apparently precipitated by bilateral sequential acute primary angle closure. NAION is very rarely reported in association with raised intraocular pressure. In contrast to optical coherence tomography, the failure of scanning laser polarimetry to detect axonal swelling was another interesting finding. Possible reasoning for these observations is discussed.

  10. Severe peripheral neuropathy following gastric bypass surgery for morbid obesity.


    Maryniak, O.


    Severe weakness in the limbs developed in a young woman 3 1/2 months after successful gastric bypass surgery for morbid obesity. Electromyography confirmed the clinical impression of generalized axonal polyneuropathy. Vitamin B replacement therapy was started. The gastric bypass was not reversed, and the patient continued to lose weight while undergoing rehabilitation. After 10 months she had almost fully recovered. Her total weight loss was 76 kg. Neuropathy is an uncommon but serious compli...

  11. [Review of the recent literature on hereditary neuropathies]. (United States)

    Birouk, N


    The recent literature included interesting reports on the pathogenic mechanisms of hereditary neuropathies. The axonal traffic and its abnormalities in some forms of Charcot-Marie-Tooth (CMT) disease were particularly reviewed by Bucci et al. Many genes related to CMT disease code for proteins that are involved directly or not in intracellular traffic. KIF1B controls vesicle motility on microtubules. MTMR2, MTMR13 and FIG4 regulate the metabolism of phosphoinositide at the level of endosomes. The HSPs are involved in the proteasomal degradation. GDAP1 and MFN2 regulate the mitochondrial fission and fusion respectively and the mitochondial transport within the axon. Pareyson et al. reported a review on peripheral neuropathies in mitochondrial disorders. They used the term of "mitochondrial CMT" for the forms of CMT with abnormal mitochondrial dynamic or structure. Among the new entities, we can draw the attention to a proximal form of hereditary motor and sensory neuropathy with autosomal dominant inheritance, which is characterized by motor deficit with cramps and fasciculations predominating in proximal muscles. Distal sensory deficit can be present. The gene TFG on chromosome 3 has been recently identified to be responsible for this form. Another rare form of axonal autosomal recessive neuropathy due to HNT1 gene mutation is characterized by the presence of hands myotonia that appears later than neuropathy but constitute an interesting clinical hallmark to orientate the diagnosis of this form. In terms of differential diagnosis, CMT4J due to FIG4 mutation can present with a rapidly progressive and asymmetric weakness that resembles CIDP. Bouhy et al. made an interesting review on the therapeutic trials, animal models and the future therapeutic strategies to be developed in CMT disease.

  12. Painful Traumatic Trigeminal Neuropathy. (United States)

    Rafael, Benoliel; Sorin, Teich; Eli, Eliav


    This article discusses neuropathic pain of traumatic origin affecting the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy by the International Headache Society and replaces atypical odontalgia, deafferentation pain, traumatic neuropathy, and phantom toothache. The discussion emphasizes the diagnosis and the early and late management of injuries to the trigeminal nerve and subsequent painful conditions.

  13. Genetically determined optic neuropathies

    DEFF Research Database (Denmark)

    Milea, Dan; Amati-Bonneau, Patrizia; Reynier, Pascal


    The present review focuses on recent advances in the knowledge of hereditary optic neuropathies resulting from retinal ganglion cell degeneration, mostly due to mitochondrial dysfunctions.......The present review focuses on recent advances in the knowledge of hereditary optic neuropathies resulting from retinal ganglion cell degeneration, mostly due to mitochondrial dysfunctions....

  14. HIV Associated Sensory Neuropathy


    G, Amruth; S, Praveen-kumar; B, Nataraju; BS, Nagaraja


    Background: In the era of highly active antiretroviral therapy, sensory neuropathies have increased in prevalence. We have documented the frequency and profile of the two most common forms of sensory neuropathies associated with Human Immunodeficiency Virus (HIV) infection and looked into clinicoelectrophysiological correlates to differentiate the two entities.

  15. Propylthiouracil and peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Valentina Van Boekel


    Full Text Available Peripheral neuropathy is a rare manifestation in hyperthyroidism. We describe the neurological manifestations of a 38 year old female with Graves' disease who developed peripheral neuropathy in the course of her treatment with propylthiouracil. After the drug was tapered off, the neurological signs disappeared. Therefore, we call attention for a possible toxic effect on peripheral nervous system caused by this drug.

  16. Organophosphate Related Alterations in Myelin and Axonal Transport in the Living Mammalian Brain (United States)


    and tri-o-cresyl phosphate (i.e., compounds associated with OP-induced delayed neuropathies -OPIDN) inhibited fast anterograde axonal transport in an ex...other deleterious effects of OPs that may be additive (or unrelated) to AChE inhibition and include oxidative stress, impairments of mitochondrial

  17. Reproducibility of axon reflex-related vasodilation assessed by dynamic thermal imaging in healthy subjects

    NARCIS (Netherlands)

    M.D. Nieuwenhoff (Mariska D.); Y. Wu; F.J.P.M. Huygen (Frank); A.C. Schouten (A.); F.C.T. van der Helm (Frans); S.P. Niehof (Sjoerd)


    textabstractIntroduction Small nerve fiber dysfunction is an early feature of diabetic neuropathy. There is a strong clinical need for a non-invasive method to assess small nerve fiber function. Small nerve fibers mediate axon reflex-related vasodilation and play an important role in thermoregulati

  18. Reproducibility of axon reflex-related vasodilation assessed by dynamic thermal imaging in healthy subjects

    NARCIS (Netherlands)

    M.D. Nieuwenhoff (Mariska D.); Wu, Y.; F.J.P.M. Huygen (Frank); A.C. Schouten (A.); F.C.T. van der Helm (Frans C.); S.P. Niehof (Sjoerd)


    textabstractIntroduction: Small nerve fiber dysfunction is an early feature of diabetic neuropathy. There is a strong clinical need for a non-invasive method to assess small nerve fiber function. Small nerve fibers mediate axon reflex-related vasodilation and play an important role in thermoregulati

  19. Axons take a dive (United States)

    Tong, Cheuk Ka; Cebrián-Silla, Arantxa; Paredes, Mercedes F; Huang, Eric J; García-Verdugo, Jose Manuel; Alvarez-Buylla, Arturo


    In the walls of the lateral ventricles of the adult mammalian brain, neural stem cells (NSCs) and ependymal (E1) cells share the apical surface of the ventricular–subventricular zone (V–SVZ). In a recent article, we show that supraependymal serotonergic (5HT) axons originating from the raphe nuclei in mice form an extensive plexus on the walls of the lateral ventricles where they contact E1 cells and NSCs. Here we further characterize the contacts between 5HT supraependymal axons and E1 cells in mice, and show that suprependymal axons tightly associated to E1 cells are also present in the walls of the human lateral ventricles. These observations raise interesting questions about the function of supraependymal axons in the regulation of E1 cells. PMID:26413556

  20. Disease mechanisms in hereditary sensory and autonomic neuropathies. (United States)

    Verpoorten, Nathalie; De Jonghe, Peter; Timmerman, Vincent


    Inherited peripheral neuropathies are common monogenically inherited diseases of the peripheral nervous system. In the most common variant, i.e., the hereditary motor and sensory neuropathies, both motor and sensory nerves are affected. In contrast, sensory abnormalities predominate or are exclusively present in hereditary sensory and autonomic neuropathies (HSAN). HSAN are clinically and genetically heterogeneous and are subdivided according to mode of inheritance, age of onset and clinical evolution. In recent years, 6 disease-causing genes have been identified for autosomal dominant and recessive HSAN. However, vesicular transport and axonal trafficking seem important common pathways leading to degeneration of sensory and autonomic neurons. This review discusses the HSAN-related genes and their biological role in the disease mechanisms leading to HSAN.

  1. Pyridoxine induced neuropathy by subcutaneous administration in dogs. (United States)

    Chung, Jin-Young; Choi, Jung-Hoon; Hwang, Cheol-Yong; Youn, Hwa-Young


    To construct a sensory neuropathy model, excess pyridoxine (150 mg/kg s.i.d.) was injected subcutaneously in dogs over a period of 7 days. During the administrations period, the dogs experienced body weight reduction and proprioceptive loss involving the hindquarters. After pyridoxine administration was completed, electrophysiological recordings showed that the M wave remained at a normal state, but the H-reflex of the treated dogs disappeared at 7 days. The dorsal funiculus of L(4) was disrupted irregularly in the axons and myelin with vacuolation. The dorsal root ganglia of L(4), and sciatic and tibial nerves showed degenerative changes and vacuolation. However, the lateral and ventral funiculi of L(4) showed a normal histopathologic pattern. Although this subcutaneous administration method did not cause systemic toxicity and effectively induced sensory neuropathy, this study confirmed the possibility of producing a pyridoxine-induced sensory neuropathy model in dogs with short-term administration.

  2. Etiologic spectrum of biopsy-proven peripheral neuropathies in childhood from a resource-poor setting. (United States)

    Krishnan, Pramod; Mahadevan, Anita; Bindu, Parayil Sankaran; Chickabasaviah, Yasha T; Taly, Arun B


    There are only a few studies describing the etiologic spectrum of biopsy-proven peripheral neuropathies in children. This study reviewed the clinical, electrophysiological, and pathologic profile of 239 children (≤18 years of age) who have undergone nerve biopsy in a tertiary care centre for neurologic disorders and analyzed the etiologic spectrum and utility of nerve biopsy. The clinical profile, neuropathologic findings, and other investigations were combined to infer the final diagnosis. Neuropathy was detected in 199 biopsies; axonal pathology in 43%; demyelination in 41%; mixed pattern in 8%; and nonspecific findings in 8%. The major diagnostic categories included hereditary neuropathies (48%), heredodegenerative and metabolic disorders (27%), and inflammatory neuropathies (12%). Nerve biopsy proved most helpful in diagnosis of demyelinating and inflammatory neuropathies, reiterating its usefulness in specific situations.

  3. Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy. (United States)

    Perry, Tracy Ann; Weerasuriya, Ananda; Mouton, Peter R; Holloway, Harold W; Greig, Nigel H


    Excess ingestion of pyridoxine (vitamin B6) causes a severe sensory neuropathy in humans. The mechanism of action has not been fully elucidated, and studies of pyridoxine neuropathy in experimental animals have yielded disparate results. Pyridoxine intoxication appears to produce a neuropathy characterized by necrosis of dorsal root ganglion (DRG) sensory neurons and degeneration of peripheral and central sensory projections, with large diameter neurons being particularly affected. The major determinants affecting the severity of the pyridoxine neuropathy appear to be duration and dose of pyridoxine administration, differential neuronal vulnerability, and species susceptibility. The present study used design-based stereological techniques in conjunction with electrophysiological measures to quantify the morphological and physiological changes that occur in the DRG and the distal myelinated axons of the sciatic nerve following pyridoxine intoxication. This combined stereological and electrophysiological method demonstrates a general approach that could be used for assessing the correlation between pathophysiological and functional parameters in animal models of toxic neuropathy.

  4. Axonal bleb recording

    Institute of Scientific and Technical Information of China (English)

    Wenqin Hu; Yousheng Shu


    Patch-clamp recording requires direct accessibility of the cell membrane to patch pipettes and allows the investigation of ion channel properties and functions in specific cellular compartments.The cell body and relatively thick dendrites are the most accessible compartments of a neuron,due to their large diameters and therefore great membrane surface areas.However,axons are normally inaccessible to patch pipettes because of their thin structure; thus studies of axon physiology have long been hampered by the lack of axon recording methods.Recently,a new method of patchclamp recording has been developed,enabling direct and tight-seal recording from cortical axons.These recordings are performed at the enlarged structure (axonal bleb) formed at the cut end of an axon after slicing procedures.This method has facilitated studies of the mechanisms underlying the generation and propagation of the main output signal,the action potential,and led to the finding that cortical neurons communicate not only in action potential-mediated digital mode but also in membrane potential-dependent analog mode.

  5. Medical management of hereditary optic neuropathies

    Directory of Open Access Journals (Sweden)

    Chiara eLa Morgia


    Full Text Available Hereditary optic neuropathies are diseases of the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e. the maternally inherited Leber’s Hereditary Optic Neuropathy (LHON and Dominant Optic Atrophy (DOA. They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1 and 14484/ND6 for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone. Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising venue that still needs to be validated.

  6. Medical management of hereditary optic neuropathies. (United States)

    La Morgia, Chiara; Carbonelli, Michele; Barboni, Piero; Sadun, Alfredo Arrigo; Carelli, Valerio


    Hereditary optic neuropathies are diseases affecting the optic nerve. The most common are mitochondrial hereditary optic neuropathies, i.e., the maternally inherited Leber's hereditary optic neuropathy (LHON) and dominant optic atrophy (DOA). They both share a mitochondrial pathogenesis that leads to the selective loss of retinal ganglion cells and axons, in particular of the papillo-macular bundle. Typically, LHON is characterized by an acute/subacute loss of central vision associated with impairment of color vision and swelling of retinal nerve fibers followed by optic atrophy. DOA, instead, is characterized by a childhood-onset and slowly progressive loss of central vision, worsening over the years, leading to optic atrophy. The diagnostic workup includes neuro-ophthalmologic evaluation and genetic testing of the three most common mitochondrial DNA mutations affecting complex I (11778/ND4, 3460/ND1, and 14484/ND6) for LHON and sequencing of the nuclear gene OPA1 for DOA. Therapeutic strategies are still limited including agents that bypass the complex I defect and exert an antioxidant effect (idebenone). Further strategies are aimed at stimulating compensatory mitochondrial biogenesis. Gene therapy is also a promising avenue that still needs to be validated.

  7. [Hereditary optic neuropathies]. (United States)

    Milea, D; Verny, C


    Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy and autosomal dominant optic atrophy) are very different in their clinical presentation and their genetic transmission, leading however to a common, non-specific optic nerve atrophy. Beyond the optic atrophy-related visual loss, which is the clinical hallmark of this group of diseases, other associated neurological signs are increasingly recognized.

  8. Genes for Hereditary Sensory and Autonomic Neuropathies: A Genotype-Phenotype Correlation (United States)

    Rotthier, Annelies; Baets, Jonathan; De Vriendt, Els; Jacobs, An; Auer-Grumbach, Michaela; Levy, Nicolas; Bonello-Palot, Nathalie; Kilic, Sara Sebnem; Weis, Joachim; Nascimento, Andres; Swinkels, Marielle; Kruyt, Moyo C.; Jordanova, Albena; De Jonghe, Peter; Timmerman, Vincent


    Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant ("SPTLC1"…

  9. Nerve Damage (Diabetic Neuropathies) (United States)

    ... normally. A woman may have difficulty with arousal, lubrication, or orgasm. Sweat Glands Autonomic neuropathy can affect ... performed in people with diabetes. Comprehensive foot care programs can reduce amputation rates by 45 to 85 ...

  10. Clinical and electrophysiological characteristics of neuropathy associated with Tangier disease. (United States)

    Zyss, Julie; Béhin, Anthony; Couvert, Philippe; Bouhour, Françoise; Sassolas, Agnès; Kolev, Ivan; Denys, Violaine; Vial, Christophe; Lacour, A; Carrié, Alain; Stojkovic, Tanya


    Tangier disease (TD) (OMIM#205400) is a rare autosomal recessive disorder resulting from mutations in the ABCA1 gene, leading to decreased levels of plasma high-density lipoproteins (HDL). Peripheral neuropathy is a common finding in this disease, and may present as relapsing/remitting mono/polyneuropathies or as syringomyelia-like neuropathy. We retrospectively analyzed four patients, and report here their clinical, biological, electrophysiological, imaging, and genetic findings. Three patients had a typical pseudosyringomyelic neuropathy including facial diplegia, but asymmetrical onset was observed in one patient who had first been misdiagnosed with Lewis-Sumner syndrome. Electrophysiological pattern was heterogeneous, showing both signs of demyelination and axonal degeneration. Truncating mutations of the ABCA1 gene, including two previously undescribed mutations, were constantly found. Atypical symptom onset and demyelinating features on electrophysiological examination can be misleading in case of pseudosyringomyelic neuropathy. These reports illustrate two different neurological phenotypes in TD, namely the pseudosyringomyelic type and the Lewis-Sumner-like type, and advocate for a systematic assessment of lipid profile including HDL cholesterol in demyelinating neuropathies.

  11. Diabetic neuropathy in children. (United States)

    Mah, Jean K; Pacaud, Danièle


    The worldwide burden of diabetes and its complications in children continues to increase due to the rise in type 1 and type 2 diabetes. Although overt diabetic neuropathy is rarely present in children and adolescents with diabetes, subclinical diabetic neuropathy has been estimated to occur in approximately half of all children with type 1 diabetes with a duration of 5 years or longer and up to 25% of pediatric patients with newly diagnosed diabetes have abnormal findings on nerve conduction studies. The present review on the state of pediatric diabetic neuropathy covers the definition, prevalence, pathogenesis, diagnosis, risk factors, and possible treatment approaches specific to children and adolescents with diabetes. It also highlights the many unknowns in this field. Nonetheless, new emerging interventions that can either prevent or delay the progression of diabetic microvascular and macrovascular complications may become available in the near future. Until specific interventions for diabetic neuropathy are available for use in children, it will be hard to justify screening for neuropathy other than through clinical assessment. Meanwhile, the search for quicker, easily administered, and quantifiable tests for diabetic neuropathy and efforts to establish valid pediatric norms for well-established measures used in adults will need to continue.

  12. Glia to axon RNA transfer. (United States)

    Sotelo, José Roberto; Canclini, Lucía; Kun, Alejandra; Sotelo-Silveira, José Roberto; Calliari, Aldo; Cal, Karina; Bresque, Mariana; Dipaolo, Andrés; Farias, Joaquina; Mercer, John A


    The existence of RNA in axons has been a matter of dispute for decades. Evidence for RNA and ribosomes has now accumulated to a point at which it is difficult to question, much of the disputes turned to the origin of these axonal RNAs. In this review, we focus on studies addressing the origin of axonal RNAs and ribosomes. The neuronal soma as the source of most axonal RNAs has been demonstrated and is indisputable. However, the surrounding glial cells may be a supplemental source of axonal RNAs, a matter scarcely investigated in the literature. Here, we review the few papers that have demonstrated that glial-to-axon RNA transfer is not only feasible, but likely. We describe this process in both invertebrate axons and vertebrate axons. Schwann cell to axon ribosomes transfer was conclusively demonstrated (Court et al. [2008]: J. Neurosci 28:11024-11029; Court et al. [2011]: Glia 59:1529-1539). However, mRNA transfer still remains to be demonstrated in a conclusive way. The intercellular transport of mRNA has interesting implications, particularly with respect to the integration of glial and axonal function. This evolving field is likely to impact our understanding of the cell biology of the axon in both normal and pathological conditions. Most importantly, if the synthesis of proteins in the axon can be controlled by interacting glia, the possibilities for clinical interventions in injury and neurodegeneration are greatly increased.

  13. Peripheral neuropathies in Sjögren's syndrome: a critical update on clinical features and pathogenetic mechanisms. (United States)

    Pavlakis, P P; Alexopoulos, H; Kosmidis, M L; Mamali, I; Moutsopoulos, H M; Tzioufas, A G; Dalakas, M C


    Sjögren's syndrome is a systemic autoimmune disease that, apart from exocrine glands, may affect every organ or system. Involvement of different sections of the peripheral nervous system results in a wide spectrum of neuropathic manifestations. Based on distinct clinical, electrophysiological and histological criteria, the types of neuropathies seen in Sjögren's syndrome include: a) pure sensory which presents with distal symmetric sensory loss due to axonal degeneration of sensory fibers; sensory ataxia due to loss of proprioceptive large fibers (ganglionopathy); or with painful dysethesias (small fiber sensory neuropathy) due to degeneration of cutaneous axons. The latter appears to be the most common neuropathy in Sjögren's syndrome and requires skin biopsy for diagnosis to document loss or reduction of nerve fiber density; b) sensorimotor polyneuropathy affecting sensory and motor axons, often associated with severe systemic or pro-lymhomatous manifestations, such as palpable purpura and cryoglobulinemia, and c) rare types that include autoimmune demyelinating neuropathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. In this review, the frequency, prevalence and diagnostic criteria for each neuropathy subset are discussed and possible pathogenetic mechanisms are outlined.

  14. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy



    Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuro...

  15. The mitochondrial connection in auditory neuropathy. (United States)

    Cacace, Anthony T; Pinheiro, Joaquim M B


    'Auditory neuropathy' (AN), the term used to codify a primary degeneration of the auditory nerve, can be linked directly or indirectly to mitochondrial dysfunction. These observations are based on the expression of AN in known mitochondrial-based neurological diseases (Friedreich's ataxia, Mohr-Tranebjærg syndrome), in conditions where defects in axonal transport, protein trafficking, and fusion processes perturb and/or disrupt mitochondrial dynamics (Charcot-Marie-Tooth disease, autosomal dominant optic atrophy), in a common neonatal condition known to be toxic to mitochondria (hyperbilirubinemia), and where respiratory chain deficiencies produce reductions in oxidative phosphorylation that adversely affect peripheral auditory mechanisms. This body of evidence is solidified by data derived from temporal bone and genetic studies, biochemical, molecular biologic, behavioral, electroacoustic, and electrophysiological investigations.

  16. Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited. (United States)

    Kulkantrakorn, Kongkiat


    High dose pyridoxine is neurotoxic. Previous case reports were sparse and little is known about the clinical and electrodiagnostic findings. Three patients with pyridoxine-induced sensory ataxic neuropathy were studied and a review of the involved literature was performed. Three patients, aged 80, 83 and 83 years old, presented with sensory ataxia for 3-8 months. Examination showed signs of polyneuropathy and sensory ataxia. Six hundred milligrams of pyridoxine was consumed each day for 3-10 years, in the form of vitamin B1-6-12 combination tablet. Investigations for other causes of neuropathy were unremarkable. Blood levels of vitamin B6 were markedly elevated at 104.6, 81.4 and 66.9 times of upper normal limits. Electrodiagnostic tests showed symmetric axonal sensory polyneuropathy in two patients. Two years after vitamin discontinuation, all patients showed no significant improvement in the neuropathy and gait. In conclusion, consumption of high dose pyridoxine can cause sensory neuronopathy and axonal sensorimotor polyneuropathy, leading to sensory ataxia which may not be reversible.

  17. Entrapment neuropathies in sports medicine



    The more frequent entrapment neuropathies related to sport are described: thoracic outlet syndrome in aquatic athletes and pitchers, long thoracic neuropathy in tennis players, suprascapular neuropathy in volleyball and tennis players, ulnar nerve entrapment at the elbow in pitchers and at the wrist in cyclists, Morton's syndrome in runners and dancers. Peer reviewed

  18. Current issues in peripheral neuropathy. (United States)

    Brannagan, Thomas H


    Twenty million people in the United States are estimated to have peripheral neuropathy. However, many patients are not aware of their diagnosis, are not given the diagnosis or being treated, or the diagnosis is delayed. Currently, the only treatments available for neuropathy are aimed at treating the underlying medical conditions that cause the neuropathy or treating symptoms such as pain. Neither treats the actual nerve fiber dysfunction or fiber loss, or helps nerve fibers regenerate. Idiopathic neuropathy, that is neuropathy for which a cause is not identified, is common, accounting in referral series for 25% in all neuropathy patients and 50% or more of patients with small fiber neuropathy. Currently, there is only one FDA-approved medication for a specific neuropathy (chronic inflammatory demyelinating polyneuropathy) while there are two FDA approved medications for diabetic neuropathy pain and four that are approved for post-herpetic neuralgia pain. For many patients with painful neuropathy, these medications are ineffective or not tolerated. Continued research into the underlying mechanisms of neuropathy and an increased understanding of nerve regeneration and neuropathic pain are needed to address this unmet medical need among patients with neuropathy.

  19. Hypertension-induced peripheral neuropathy and the combined effects of hypertension and diabetes on nerve structure and function in rats. (United States)

    Gregory, Joshua A; Jolivalt, Corinne G; Goor, Jared; Mizisin, Andrew P; Calcutt, Nigel A


    Diabetic neuropathy includes damage to neurons, Schwann cells and blood vessels. Rodent models of diabetes do not adequately replicate all pathological features of diabetic neuropathy, particularly Schwann cell damage. We, therefore, tested the hypothesis that combining hypertension, a risk factor for neuropathy in diabetic patients, with insulin-deficient diabetes produces a more pertinent model of peripheral neuropathy. Behavioral, physiological and structural indices of neuropathy were measured for up to 6 months in spontaneously hypertensive and age-matched normotensive rats with or without concurrent streptozotocin-induced diabetes. Hypertensive rats developed nerve ischemia, thermal hyperalgesia, nerve conduction slowing and axonal atrophy. Thinly myelinated fibers with supernumerary Schwann cells indicative of cycles of demyelination and remyelination were also identified along with reduced nerve levels of myelin basic protein. Similar disorders were noted in streptozotocin-diabetic rats, except that thinly myelinated fibers were not observed and expression of myelin basic protein was normal. Superimposing diabetes on hypertension compounded disorders of nerve blood flow, conduction slowing and axonal atrophy and increased the incidence of thinly myelinated fibers. Rats with combined insulinopenia, hyperglycemia and hypertension provide a model for diabetic neuropathy that offers an opportunity to study mechanisms of Schwann cell pathology and suggests that hypertension may contribute to the etiology of diabetic neuropathy.

  20. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. (United States)

    Zheng, Huaien; Xiao, Wen Hua; Bennett, Gary J


    Cancer chemotherapeutics like paclitaxel and oxaliplatin produce a dose-limiting chronic sensory peripheral neuropathy that is often accompanied by neuropathic pain. The cause of the neuropathy and pain is unknown. In animal models, paclitaxel-evoked and oxaliplatin-evoked painful peripheral neuropathies are accompanied by an increase in the incidence of swollen and vacuolated mitochondria in peripheral nerve axons. It has been proposed that mitochondrial swelling and vacuolation are indicative of a functional impairment and that this results in a chronic axonal energy deficiency that is the cause of the neuropathy's symptoms. However, the significance of mitochondrial swelling and vacuolation is ambiguous and a test of the hypothesis requires a direct assessment of the effects of chemotherapy on mitochondrial function. The results of such an assessment are reported here. Mitochondrial respiration and ATP production were measured in rat sciatic nerve samples taken 1-2 days after and 3-4 weeks after induction of painful peripheral neuropathy with paclitaxel and oxaliplatin. Significant deficits in Complex I-mediated and Complex II-mediated respiration and significant deficits in ATP production were found for both drugs at both time points. In addition, prophylactic treatment with acetyl-l-carnitine, which inhibited the development of paclitaxel-evoked and oxaliplatin-evoked neuropathy, prevented the deficits in mitochondrial function. These results implicate mitotoxicity as a possible cause of chemotherapy-evoked chronic sensory peripheral neuropathy.

  1. Mechanisms of diabetic neuropathy: Schwann cells. (United States)

    Mizisin, Andrew P


    As ensheathing and secretory cells, Schwann cells are a ubiquitous and vital component of the endoneurial microenvironment of peripheral nerves. The interdependence of axons and their ensheathing Schwann cells predisposes each to the impact of injury in the other. Further, the dependence of the blood-nerve interface on trophic support from Schwann cells during development, adulthood, and after injury suggests these glial cells promote the structural and functional integrity of nerve trunks. Here, the developmental origin, injury-induced changes, and mature myelinating and nonmyelinating phenotypes of Schwann cells are reviewed prior to a description of nerve fiber pathology and consideration of pathogenic mechanisms in human and experimental diabetic neuropathy. A fundamental role for aldose-reductase-containing Schwann cells in the pathogenesis of diabetic neuropathy, as well as the interrelationship of pathogenic mechanisms, is indicated by the sensitivity of hyperglycemia-induced biochemical alterations, such as polyol pathway flux, formation of reactive oxygen species, generation of advanced glycosylation end products (AGEs) and deficient neurotrophic support, to blocking polyol pathway flux.

  2. Painful neuropathies: the emerging role of sodium channelopathies. (United States)

    Brouwer, Brigitte A; Merkies, Ingemar S J; Gerrits, Monique M; Waxman, Stephen G; Hoeijmakers, Janneke G J; Faber, Catharina G


    Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.

  3. Inherited focal, episodic neuropathies: hereditary neuropathy with liability to pressure palsies and hereditary neuralgic amyotrophy. (United States)

    Chance, Phillip F


    Hereditary neuropathy with liability to pressure palsies (HNPP; also called tomaculous neuropathy) is an autosomal-dominant disorder that produces a painless episodic, recurrent, focal demyelinating neuropathy. HNPP generally develops during adolescence, and may cause attacks of numbness, muscular weakness, and atrophy. Peroneal palsies, carpal tunnel syndrome, and other entrapment neuropathies may be frequent manifestations of HNPP. Motor and sensory nerve conduction velocities may be reduced in clinically affected patients, as well as in asymptomatic gene carriers. The histopathological changes observed in peripheral nerves of HNPP patients include segmental demyelination and tomaculous or "sausage-like" formations. Mild overlap of clinical features with Charcot-Marie-Tooth (CMT) disease type 1 (CMT1) may lead patients with HNPP to be misdiagnosed as having CMT1. HNPP and CMT1 are both demyelinating neuropathies, however, their clinical, pathological, and electrophysiological features are quite distinct. HNPP is most frequently associated with a 1.4-Mb pair deletion on chromosome 17p12. A duplication of the identical region leads to CMT1A. Both HNPP and CMT1A result from a dosage effect of the PMP22 gene, which is contained within the deleted/duplicated region. This is reflected in reduced mRNA and protein levels in sural nerve biopsy samples from HNPP patients. Treatment for HNPP consists of preventative and symptom-easing measures. Hereditary neuralgic amyotrophy (HNA; also called familial brachial plexus neuropathy) is an autosomal-dominant disorder causing episodes of paralysis and muscle weakness initiated by severe pain. Individuals with HNA may suffer repeated episodes of intense pain, paralysis, and sensory disturbances in an affected limb. The onset of HNA is at birth or later in childhood with prognosis for recovery usually favorable; however, persons with HNA may have permanent residual neurological dysfunction following attack(s). Episodes are often

  4. Depletion of Mitofusin-2 Causes Mitochondrial Damage in Cisplatin-Induced Neuropathy. (United States)

    Bobylev, Ilja; Joshi, Abhijeet R; Barham, Mohammed; Neiss, Wolfram F; Lehmann, Helmar C


    Sensory neuropathy is a relevant side effect of the antineoplastic agent cisplatin. Mitochondrial damage is assumed to play a critical role in cisplatin-induced peripheral neuropathy, but the pathomechanisms underlying cisplatin-induced mitotoxicity and neurodegeneration are incompletely understood. In an animal model of cisplatin-induced neuropathy, we determined in detail the extent and spatial distribution of mitochondrial damage during cisplatin treatment. Changes in the total number of axonal mitochondria during cisplatin treatment were assessed in intercostal nerves from transgenic mice that express cyan fluorescent protein. Further, we explored the impact of cisplatin on the expression of nuclear encoded molecules of mitochondrial fusion and fission, including mitofusin-2 (MFN2), optic atrophy 1 (OPA1), and dynamin-related protein 1 (DRP1). Cisplatin treatment resulted in a loss of total mitochondrial mass in axons and in an abnormal mitochondrial morphology including atypical enlargement, increased vacuolization, and loss of cristae. These changes were observed in distal and proximal nerve segments and were more prominent in axons than in Schwann cells. Transcripts of fusion and fission proteins were reduced in distal nerve segments. Significant reduced expression levels of the fusion protein MFN2 was detected in nerves of cisplatin-exposed animals. In summary, we provide for the first time an evidence that cisplatin alters mitochondrial dynamics in peripheral nerves. Loss of MFN2, previously implicated in the pathogenesis of other neurodegenerative diseases, also contributes to the pathogenesis in cisplatin-induced neuropathy.


    Directory of Open Access Journals (Sweden)

    Vijay Kumar


    Full Text Available A need still exists to determine the clinical and neurophysiological characteristics of leprosy neuropathy at distinct times of the disease by different methods that measure the various nerve fiber functions. A prospective clinical study was performed 100 patients of clinically proven Hansen’s will take in study and given diagnosis is made by dermatologist and neurologist. For Study of Clinical, Neuropathological , Neurophysiological Pattern of leprous neuropathy and results shows that Peripheral neuropath y is common neurological disorder, although population based studies are scarce. It is a diverse group of disorder with varying etiologies. Many of these are amenable to treatment while others are not. It affects all age groups are different etiologies in various age groups. Disorder is more common in males. Leprosy is still most common cause of peripheral neuropathy in this part of world. GBS is commonest cause in acutely presenting patients of peripheral neuropathy. Vacuities is also common especially in undiagnosed peripheral neuropathy patients and revealed by nerve biopsy. Tingling and numbness are two most common sensory complains. On objective sensory examination impairment of pain/temperature was most common. Evidence of large fiber dysfunction was less common. Almost half of leprous neuropathy had impaired joint position and vibration. Anesthetic patches and thickened nerve are two commonest indicators of leprous neuropathy. Among DTRs ankle jerk was most commonly affected. Almost half of GBS patie nts had history of preceding illness. Overall sensorimotor polyneuropathy was most common type of pattern after clinical - electrophysiological evaluation. Multiple mononeuropathy was most common in leprous neuropathy. Most patients had axonal type of invo lvement. In GBS patients predominantly motor neuropathy was found Skin smear examination is readily available and easy test to diagnosed leprosy, if done carefully. Sural nerve biopsy

  6. [Pathophysiology of sensory ataxic neuropathy]. (United States)

    Sobue, G


    The main lesions of sensory ataxic neuropathy such as chronic idiopathic sensory ataxic neuropathy, (ISAN), carcinomatous neuropathy, Sjögren syndrome-associated neuropathy and acute autonomic and sensory neuropathy (AASN) are the large-diameter sensory neurons and dosal column of the spinal cord and the large myelinated fibers in the peripheral nerve trunks. In addition, afferent fibers to the Clarke's nuclei are also severely involved, suggesting Ia fibers being involved in these neuropathies. In NT-3 knockout mouse, an animal model of sensory ataxia, large-sized la neurons as well as muscle spindle and Golgi tendon organs are depleted, and are causative for sensory ataxia. Thus, the proprioceptive Ia neurons would play a role in pathogenesis of sensory ataxia in human sensory ataxic neuropathies, but the significance of dorsal column involvement in human sensory ataxia is still needed to evaluate.

  7. Recurrence Quantification Analysis of F-Waves and the Evaluation of Neuropathies

    Directory of Open Access Journals (Sweden)

    Morris A. Fisher


    Full Text Available Electrodiagnostic (EDX patterns of neuropathic dysfunction have been based on axonal/demyelinating criteria requiring prior assumptions. This has not produced classifications of desired sensitivity or specificity. Furthermore, standard nerve conduction studies have limited reproducibility. New methodologies in EDX seem important. Recurrent Quantification Analysis (RQA is a nonlinear method for examining patterns of recurrence. RQA might provide a unique method for the EDX evaluation of neuropathies. RQA was used to analyze F-wave recordings from the abductor hallucis muscle in 61 patients with neuropathies. Twenty-nine of these patients had diabetes as the sole cause of their neuropathies. In the other 32 patients, the etiologies of the neuropathies were diverse. Commonly used EDX variables were also recorded. RQA data could separate the 29 patients with diabetic neuropathies from the other 32 patients (P<0.009. Statistically significant differences in two EDX variables were also present: compound muscle action potential amplitudes (P<0.007 and F-wave persistence (P<0.001. RQA analysis of F-waves seemed able to distinguish diabetic neuropathies from the other neuropathies studied, and this separation was associated with specific physiological abnormalities. This study would therefore support the idea that RQA of F-waves can distinguish between types of neuropathic dysfunction based on EDX data alone without prior assumptions.

  8. Experimental therapeutics in hereditary neuropathies: the past, the present, and the future. (United States)

    Herrmann, David N


    Hereditary neuropathies represent approximately 40% of undiagnosed neuropathies in a tertiary clinic setting. The Charcot-Marie-Tooth neuropathies (CMT) are the most common. Mutations in more than 40 genes have been identified to date in CMT. Approximately 50% of CMT cases are accounted for by CMT type 1A, due to a duplication within the peripheral myelin protein 22 gene (PMP22). Mutations in the gap junction beta 1 gene (GJB1), the myelin protein zero gene (MPZ), and the mitofusin 2 gene (MFN2) account for a substantial proportion of other genetically definable CMT. Some 15% of demyelinating CMT and 70% of axonal CMT await genetic clarification. Other hereditary neuropathies include the hereditary sensory and autonomic neuropathies, the familial amyloid polyneuropathies, and multisystem disorders (e.g., lipid storage diseases and inherited ataxias) that have peripheral neuropathy as a major or minor component. This review surveys the challenges of developing effective therapies for hereditary neuropathies in terms of past, present, and future experimental therapeutics in CMT.

  9. Small Heat Shock Proteins and Distal Hereditary Neuropathies. (United States)

    Nefedova, V V; Muranova, L K; Sudnitsyna, M V; Ryzhavskaya, A S; Gusev, N B


    Classification of small heat shock proteins (sHsp) is presented and processes regulated by sHsp are described. Symptoms of hereditary distal neuropathy are described and the genes whose mutations are associated with development of this congenital disease are listed. The literature data and our own results concerning physicochemical properties of HspB1 mutants associated with Charcot-Marie-Tooth disease are analyzed. Mutations of HspB1, associated with hereditary motor neuron disease, can be accompanied by change of the size of HspB1 oligomers, by decreased stability under unfavorable conditions, by changes in the interaction with protein partners, and as a rule by decrease of chaperone-like activity. The largest part of these mutations is accompanied by change of oligomer stability (that can be either increased or decreased) or by change of intermonomer interaction inside an oligomer. Data on point mutation of HspB3 associated with axonal neuropathy are presented. Data concerning point mutations of Lys141 of HspB8 and those associated with hereditary neuropathy and different forms of Charcot-Marie-Tooth disease are analyzed. It is supposed that point mutations of sHsp associated with distal neuropathies lead either to loss of function (for instance, decrease of chaperone-like activity) or to gain of harmful functions (for instance, increase of interaction with certain protein partners).

  10. Testing for autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J


    Autonomic neuropathy is a common complication in long-term diabetes, about 30% of the patients showing measurable signs of autonomic dysfunction after 10 years duration of disease. The diagnosis is often difficult to establish because clinical symptoms generally occur late in the course...

  11. Hereditary motor-sensory, motor, and sensory neuropathies in childhood. (United States)

    Landrieu, Pierre; Baets, Jonathan; De Jonghe, Peter


    Hereditary neuropathies (HN) are categorized according to clinical presentation, pathogenic mechanism based on electrophysiology, genetic transmission, age of occurrence, and, in selected cases, pathological findings. The combination of these parameters frequently orients towards specific genetic disorders. Ruling out a neuropathy secondary to a generalized metabolic disorder remains the first pediatric concern. Primary, motor-sensory are the most frequent HN and are dominated by demyelinating AD forms (CMT1). Others are demyelinating AR forms, axonal AD/AR forms, and forms with "intermediate" electrophysiological phenotype. Pure motor HN represent40 genes with various biological functions have been found responsible for HN. Many are responsible for various phenotypes, including some without the polyneuropathic trait: for the pediatric neurologist, phenotype/genotype correlations constitute a permanent bidirectional exercise.

  12. Dorsal Root Ganglia Sensory Neuronal Cultures: a tool for drug discovery for peripheral neuropathies (United States)

    Melli, Giorgia; Höke, Ahmet


    Background Peripheral neuropathies affect many people worldwide and are caused by or associated with a wide range of conditions, both genetic and acquired. Current therapies are directed at symptomatic control because no effective regenerative treatment exists. Primary challenge is that mechanisms that lead to distal axonal degeneration, a common feature of all peripheral neuropathies, are largely unknown. Objective/Methods To address the role and specific characteristics of dorsal root ganglia (DRG) derived sensory neuron culture system as a useful model in evaluating the pathogenic mechanisms of peripheral neuropathies and examination and validation of potential therapeutic compounds. A thorough review of the recent literature was completed and select examples of the use of DRG neurons in different peripheral neuropathy models were chosen to highlight the utility of these cultures. Conclusion Many useful models of different peripheral neuropathies have been developed using DRG neuronal culture and potential therapeutic targets have been examined, but so far none of the potential therapeutic compounds have succeeded in clinical trials. In recent years, focus has changed to evaluation of axon degeneration as the primary outcome measure advocating a drug development strategy starting with phenotypic drug screening, followed by validation in primary complex co-cultures and animal models. PMID:20657751

  13. Activity-Dependent Excitability Changes Suggest Na[superscript +]/K[superscript +] Pump Dysfunction in Diabetic Neuropathy (United States)

    Krishnan, Arun V.; Lin, Cindy S.-Y.; Kiernan, Matthew C.


    The present study was undertaken to evaluate the role of Na[superscript +]/K[superscript +] pump dysfunction in the development of diabetic neuropathy (DN). Nerve excitability techniques, which provide information about membrane potential and axonal ion channel function, were undertaken in 15 patients with established DN and in 10 patients with…

  14. Diagnosis of acute neuropathies

    DEFF Research Database (Denmark)

    Crone, Clarissa; Krarup, Christian


    Acute and subacute polyneuropathies present diagnostic challenges since many require prompt initiation of treatment in order to limit axonal degeneration and since an exact and detailed diagnosis is a prerequisite for making the correct choice of treatment. It is for instance of utmost importance...... to recognize whether the underlying pathological changes are due to demyelination or to axonal degeneration and electrodiagnostic tests can thus in most cases contribute considerably to the securing of an exact diagnosis. The specific and characteristic electrophysiological findings in the different types...

  15. Autoimmune reactions in patients with M-component and peripheral neuropathy

    DEFF Research Database (Denmark)

    Jønsson, V; Schrøder, H D; Trojaborg, W;


    A study of 17 patients with autoimmune axonal or demyelinating peripheral neuropathy in combination with M-component is described. The M-component was associated with MGUS (monoclonal gammopathy of undetermined significance) in 12 patients, CLL in one patient, Waldenström's disease in one patient......, and myeloma in three patients. Immunohistological examination with direct and indirect fluorescence showed binding of antibodies to nerve structures of the same class and light chain as seen in the M-component. In five cases of IgM M-component, the demyelinating neuropathy was caused by binding of the IgM M...

  16. Nodes of ranvier and paranodes in chronic acquired neuropathies.

    Directory of Open Access Journals (Sweden)

    Carmen Cifuentes-Diaz

    Full Text Available Chronic acquired neuropathies of unknown origin are classified as chronic inflammatory demyelinating polyneuropathies (CIDP and chronic idiopathic axonal polyneuropathies (CIAP. The diagnosis can be very difficult, although it has important therapeutic implications since CIDP can be improved by immunomodulating treatment. The aim of this study was to examine the possible abnormalities of nodal and paranodal regions in these two types of neuropathies. Longitudinal sections of superficial peroneal nerves were obtained from biopsy material from 12 patients with CIDP and 10 patients with CIAP and studied by immunofluorescence and in some cases electron microscopy. Electron microscopy revealed multiple alterations in the nodal and paranodal regions which predominated in Schwann cells in CIDP and in axons in CIAP. In CIDP paranodin/Caspr immunofluorescence was more widespread than in control nerves, extending along the axon in internodes where it appeared intense. Nodal channels Nav and KCNQ2 were less altered but were also detected in the internodes. In CIAP paranodes, paranodin labeling was irregular and/or decreased. To test the consequences of acquired primary Schwann cells alteration on axonal proteins, we used a mouse model based on induced deletion of the transcription factor Krox-20 gene. In the demyelinated sciatic nerves of these mice we observed alterations similar to those found in CIDP by immunofluorescence, and immunoblotting demonstrated increased levels of paranodin. Finally we examined whether the alterations in paranodin immunoreactivity could have a diagnosis value. In a sample of 16 biopsies, the study of paranodin immunofluorescence by blind evaluators led to correct diagnosis in 70 ± 4% of the cases. This study characterizes for the first time the abnormalities of nodes of Ranvier in CIAP and CIDP, and the altered expression and distribution of nodal and paranodal proteins. Marked differences were observed between CIDP and CIAP

  17. Genetics Home Reference: ataxia neuropathy spectrum (United States)

    ... Understand Genetics Home Health Conditions ataxia neuropathy spectrum ataxia neuropathy spectrum Enable Javascript to view the expand/ ... boxes. Download PDF Open All Close All Description Ataxia neuropathy spectrum is part of a group of ...

  18. Diabetic Neuropathy: Mechanisms to Management



    Neuropathy is the most common and debilitating complication of diabetes and results in pain, decreased motility, and amputation. Diabetic neuropathy encompasses a variety of forms whose impact ranges from discomfort to death. Hyperglycemia induces oxidative stress in diabetic neurons and results in activation of multiple biochemical pathways. These activated pathways are a major source of damage and are potential therapeutic targets in diabetic neuropathy. Though therapies are available to al...

  19. Catecholamines and diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J


    In diabetic patients with autonomic neuropathy plasma noradrenaline concentration, used as an index of sympathetic nervous activity, is low. This decrease is, however, only found in patients with a long duration of diabetes with clinically severe autonomic neuropathy. This apparent insensitivity...... of plasma catecholamine measurements is not due to changes in the clearance of catecholamines in diabetic autonomic neuropathy. The physiological responses to infused adrenaline and to noradrenaline are enhanced, for noradrenaline mainly cardiovascular responses. Adrenoceptors (alpha and beta adrenoceptors...

  20. Inherited autonomic neuropathies. (United States)

    Axelrod, Felicia B; Hilz, Max J


    Inherited autonomic neuropathies are a rare group of disorders associated with sensory dysfunction. As a group they are termed the "hereditary sensory and autonomic neuropathies" (HSAN). Classification of the various autonomic and sensory disorders is ongoing. In addition to the numerical classification of four distinct forms proposed by Dyck and Ohta (1975), additional entities have been described. The best known and most intensively studied of the HSANs are familial dysautonomia (Riley-Day syndrome or HSAN type III) and congenital insensitivity to pain with anhidrosis (HSAN type IV). Diagnosis of the HSANs depends primarily on clinical examinations and specific sensory and autonomic assessments. Pathologic examinations are helpful in confirming the diagnosis and in differentiating between the different disorders. In recent years identification of specific genetic mutations for some disorders has aided diagnosis. Replacement or definitive therapies are not available for any of the disorders so that treatment remains supportive and directed toward specific symptoms.

  1. Study of Autophagy and Microangiopathy in Sural Nerves of Patients with Chronic Idiopathic Axonal Polyneuropathy (United States)

    Samuelsson, Kristin; Osman, Ayman A. M.; Angeria, Maria; Risling, Mårten; Mohseni, Simin; Press, Rayomand


    Twenty-five percent of polyneuropathies are idiopathic. Microangiopathy has been suggested to be a possible pathogenic cause of chronic idiopathic axonal polyneuropathy (CIAP). Dysfunction of the autophagy pathway has been implicated as a marker of neurodegeneration in the central nervous system, but the autophagy process is not explored in the peripheral nervous system. In the current study, we examined the presence of microangiopathy and autophagy-related structures in sural nerve biopsies of 10 patients with CIAP, 11 controls with inflammatory neuropathy and 10 controls without sensory polyneuropathy. We did not find any significant difference in endoneurial microangiopathic markers in patients with CIAP compared to normal controls, though we did find a correlation between basal lamina area thickness and age. Unexpectedly, we found a significantly larger basal lamina area thickness in patients with vasculitic neuropathy. Furthermore, we found a significantly higher density of endoneurial autophagy-related structures, particularly in patients with CIAP but also in patients with inflammatory neuropathy, compared to normal controls. It is unclear if the alteration in the autophagy pathway is a consequence or a cause of the neuropathy. Our results do not support the hypothesis that CIAP is primarily caused by a microangiopathic process in endoneurial blood vessels in peripheral nerves. The significantly higher density of autophagy structures in sural nerves obtained from patients with CIAP and inflammatory neuropathy vs. controls indicates the involvement of this pathway in neuropathy, particularly in CIAP, since the increase in density of autophagy-related structures was more pronounced in patients with CIAP than those with inflammatory neuropathy. To our knowledge this is the first report investigating signs of autophagy process in peripheral nerves in patients with CIAP and inflammatory neuropathy. PMID:27662650

  2. Drug-induced peripheral neuropathy

    DEFF Research Database (Denmark)

    Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed;


    Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical...... substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated...

  3. Painful peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    SUN Bo


    Full Text Available Painful peripheral neuropathy (PPN is characterized by neuropathic pain (NP, which is accompanied by dysfunction of motor, sensory and autonomic nervous system. It always involves small nerve fibers, including A δ and C fibers. PPN can be classified into two types according to etiology: hereditary and acquired. Pain of PPN can manifest as spontaneous pain and stimulus-evoked pain (allodynia, hyperalgesia and hyperpathia. The manifestation of typical cases is length-dependent, which firstly involves the feet, and then progresses proximally and to the hands, presenting a glove-stock pattern. PPN can be either an isolated disease entity or part of other diseases. The former indicates idiopathic small fiber neuropathy (SFN, while the latter contains various diseases involving peripheral nerve fibers, including systemic diseases such as diabetes mellitus and peripheral neuropathy with other causes. The accessory examinations of PPN include quantitative sensory testing (QST, intraepidermal nerve fiber density (IENFD, sympathetic skin response (SSR, etc. Among them, IENFD is the "golden standard" for SFN. The major therapeutic methods are to control primary diseases and relieve pain. Medications alleviating neuropathic pain consist of carbamazepine, pregabalin, gabapentin and amitriptyline, etc.

  4. Myanmarese Neuropathy: Clinical Description of Acute Peripheral Neuropathy Detected among Myanmarese Refugees in Malaysia. (United States)

    Fu Liong, Hiew; Santhi, Datuk Puvanarajah; Shanthi, Viswanathan; Mohd Hanip, Rafia


    Background. Since 2008, we have observed an increasing number of Myanmarese refugees in Malaysia being admitted for acute/subacute onset peripheral neuropathy. Most of them had a preceding history of starvation. Methods. We retrospectively studied the clinical features of all Myanmarese patients admitted with peripheral neuropathy from September 2008 to January 2014. Results. A total of 24 patients from the Chin, Rohingya, and Rakhine ethnicities (mean age, 23.8 years; male, 96%) had symmetrical, ascending areflexic weakness with at least one additional presenting symptom of fever, lower limb swelling, vomiting, abdominal pain, or difficulty in breathing. Twenty (83.3%) had sensory symptoms. Ten (41.6%) had cranial nerve involvement. Nineteen patients had cerebrospinal fluid examinations but none with evidence of albuminocytological dissociation. Neurophysiological assessment revealed axonal polyneuropathy, predominantly a motor-sensory subtype. Folate and vitamin B12 deficiencies were detected in 31.5% of them. These findings suggested the presence of a polyneuropathy related to nutrition against a backdrop of other possible environmental factors such as infections, metabolic disorders, or exposure to unknown toxin. Supportive treatment with appropriate vitamins supplementation improved functional outcome in most patients. Conclusion. We report a spectrum of acquired reversible neurological manifestations among Myanmarese refugees likely to be multifactorial with micronutrient deficiencies playing an important role in the pathogenesis.

  5. The genetics of axonal transport and axonal transport disorders.

    Directory of Open Access Journals (Sweden)

    Jason E Duncan


    Full Text Available Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases.

  6. The Highwire ubiquitin ligase promotes axonal degeneration by tuning levels of Nmnat protein.

    Directory of Open Access Journals (Sweden)

    Xin Xiong

    Full Text Available Axonal degeneration is a hallmark of many neuropathies, neurodegenerative diseases, and injuries. Here, using a Drosophila injury model, we have identified a highly conserved E3 ubiquitin ligase, Highwire (Hiw, as an important regulator of axonal and synaptic degeneration. Mutations in hiw strongly inhibit Wallerian degeneration in multiple neuron types and developmental stages. This new phenotype is mediated by a new downstream target of Hiw: the NAD+ biosynthetic enzyme nicotinamide mononucleotide adenyltransferase (Nmnat, which acts in parallel to a previously known target of Hiw, the Wallenda dileucine zipper kinase (Wnd/DLK MAPKKK. Hiw promotes a rapid disappearance of Nmnat protein in the distal stump after injury. An increased level of Nmnat protein in hiw mutants is both required and sufficient to inhibit degeneration. Ectopically expressed mouse Nmnat2 is also subject to regulation by Hiw in distal axons and synapses. These findings implicate an important role for endogenous Nmnat and its regulation, via a conserved mechanism, in the initiation of axonal degeneration. Through independent regulation of Wnd/DLK, whose function is required for proximal axons to regenerate, Hiw plays a central role in coordinating both regenerative and degenerative responses to axonal injury.

  7. DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease. (United States)

    Hong, Young Bin; Kang, Junghee; Kim, Ji Hyun; Lee, Jinho; Kwak, Geon; Hyun, Young Se; Nam, Soo Hyun; Hong, Hyun Dae; Choi, Yu-Ri; Jung, Sung-Chul; Koo, Heasoo; Lee, Ji Eun; Choi, Byung-Ok; Chung, Ki Wha


    Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy and is a genetically and clinically heterogeneous disorder. We examined a Korean family in which two individuals had an autosomal-dominant axonal CMT with early-onset, sensory ataxia, tremor, and slow disease progression. Pedigree analysis and exome sequencing identified a de novo missense mutation (p.Y223H) in the diacylglycerol O-acyltransferase 2 (DGAT2) gene. DGAT2 encodes an endoplasmic reticulum-mitochondrial-associated membrane protein, acyl-CoA:diacylglycerol acyltransferase, which catalyzes the final step of the triglyceride (TG) biosynthesis pathway. The patient showed consistently decreased serum TG levels, and overexpression of the mutant DGAT2 significantly inhibited the proliferation of mouse motor neuron cells. Moreover, the variant form of human DGAT2 inhibited the axonal branching in the peripheral nervous system of zebrafish. We suggest that mutation of DGAT2 is the novel underlying cause of an autosomal-dominant axonal CMT2 neuropathy. This study will help provide a better understanding of the pathophysiology of axonal CMT and contribute to the molecular diagnostics of peripheral neuropathies.

  8. Profound and persistent painful paclitaxel peripheral neuropathy in a premenopausal patient.

    LENUS (Irish Health Repository)

    Quintyne, K I


    The authors herein report the case of a 35-year-old woman undergoing adjuvant therapy for node positive breast cancer, who presented with short and rapidly progressive history of bilateral lower limb symptoms of peripheral neuropathy following therapy with paclitaxel. MRI of her neural axis revealed no leptomeningeal enhancement or focal metastatic lesions. Neurophysiological tests favoured toxic sensory axonal polyneuropathy. She remains symptomatic following discontinuation of therapy 20 months ago, and is under review with pain management.

  9. [Surgical therapy for entrapment neuropathy]. (United States)

    Tachibana, Shigekuni


    Entrapment neuropathy is not uncommon, and surgical treatment is followed by favorite result. Therefore, to obtain an accurate diagnosis based on precise knowledge of the peripheral nervous system is very important. The most popular and useful symptoms and signs of the entrapment neuropathy is paresthesia, dysesthesia and Tinel's like sign at the lesion site. Nerve conduction study is also valuable for the accurate diagnosis. For the last 30 years, the author operated on 1,399 lesions of entrapment neuropathy. They consist of 877 carpal tunnel syndrome (63%), 284 tarsal tunnel syndrome (20%), 135 ulnar neuropathy at the elbow (10%), 53 piriformis syndrome (4%), 15 thoracic outlet syndrome (1%), and others. From the pathophysiological point to view, except for the carpal tunnel syndrome, several locations and factors come into play producing the entrapment of the nerve. The author would like to stress that the entrapment neuropathy is not severe disease, though, it strongly insult the patient's quality of life.

  10. Painful neuropathy: Mechanisms. (United States)

    Lee-Kubli, Corinne A; Calcutt, Nigel A


    Painful neuropathy, like the other complications of diabetes, is a growing healthcare concern. Unfortunately, current treatments are of variable efficacy and do not target underlying pathogenic mechanisms, in part because these mechanisms are not well defined. Rat and mouse models of type 1 diabetes are frequently used to study diabetic neuropathy, with rats in particular being consistently reported to show allodynia and hyperalgesia. Models of type 2 diabetes are being used with increasing frequency, but the current literature on the progression of indices of neuropathic pain is variable and relatively few therapeutics have yet been developed in these models. While evidence for spontaneous pain in rodent models is sparse, measures of evoked mechanical, thermal and chemical pain can provide insight into the pathogenesis of the condition. The stocking and glove distribution of pain tantalizingly suggests that the generator site of neuropathic pain is found within the peripheral nervous system. However, emerging evidence demonstrates that amplification in the spinal cord, via spinal disinhibition and neuroinflammation, and also in the brain, via enhanced thalamic activity or decreased cortical inhibition, likely contribute to the pathogenesis of painful diabetic neuropathy. Several potential therapeutic strategies have emerged from preclinical studies, including prophylactic treatments that intervene against underlying mechanisms of disease, treatments that prevent gains of nociceptive function, treatments that suppress enhancements of nociceptive function, and treatments that impede normal nociceptive mechanisms. Ongoing challenges include unraveling the complexity of underlying pathogenic mechanisms, addressing the potential disconnect between the perceived location of pain and the actual pain generator and amplifier sites, and finding ways to identify which mechanisms operate in specific patients to allow rational and individualized choice of targeted therapies.

  11. Delayed radiation neuropathy

    Energy Technology Data Exchange (ETDEWEB)

    Nagashima, T.; Miyamoto, K.; Beppu, H.; Hirose, K.; Yamada, K. (Tokyo Metropolitan Neurological Hospital (Japan))


    A case of cervical plexus neuropathy was reported in association with chronic radio-dermatitis, myxedema with thyroid adenoma and epiglottic tumor. A 38-year-old man has noticed muscle weakness and wasting of the right shoulder girdle since age 33. A detailed history taking revealed a previous irradiation to the neck because of the cervical lymphadenopathy at age 10 (X-ray 3,000 rads), keroid skin change at age 19, obesity and edema since 26, and hoarseness at 34. Laryngoscopic examination revealed a tumor on the right vocal cord, diagnosed as benign papilloma by histological study. In addition, there were chronic radio-dermatitis around the neck, primary hypothyroidism with a benign functioning adenoma on the right lobe of the thyroid, the right phrenic nerve palsy and the right recurrent nerve palsy. All these lesions were considered to be the late sequellae of radiation to the neck in childhood. Other neurological signs were weakness and amyotrophy of the right shoulder girdle with patchy sensory loss, and areflexia of the right arm. Gross power was fairly well preserved in the right hand. EMG showed neurogenic changes in the tested muscles, suggesting a peripheral nerve lesion. Nerve conduction velocities were normal. No abnormal findings were revealed by myelography and spinal CT. The neurological findings of the patient were compatible with the diagnosis of middle cervical plexus palsy apparently due to late radiation effect. In the literature eight cases of post-radiation neuropathy with a long latency have been reported. The present case with the longest latency after the radiation should be included in the series of the reported cases of ''delayed radiation neuropathy.'' (author).

  12. Organophosphorus agent induced delayed neuropathy: a case report

    Directory of Open Access Journals (Sweden)

    Harshit Acharya


    Full Text Available A 40-year old male, was presented with complaint of difficulty in walking with inability to flex foot and toes in bilateral feet ( and ldquo;foot drop and rdquo;, which was acute at the onset and gradually progressive since the past 7 days. The patient's wife and their 2 children had similar complaint with the same period of onset. At home, his family used cottonseed oil as cooking oil with wheat grain mixed with castor oil. On neurological examination, he was found to have lower motor neuron weakness with spasticity. After ruling out other common causes of polyneuropathy and lower motor weakness; due to high suspicion of poisoning by food adulterant, RBC acetyl cholinesterase (AChE and plasma cholinesterase (BuChE were tested at National Institute of Occupational Health (NIOH, which came low and confirmed diagnosis of Organophosphorus (OP poisoning. Nerve conduction study was done; which showed decreased amplitude of conduction in bilateral peroneal and right tibial nerve along with decreased mean nerve conduction velocity of bilateral median nerve. Thus patient was diagnosed with organophosphorus agent induced delayed axonal type of polyneuropathy and physiotherapy was started as treatment. OP compounds are a diverse group of chemicals which are principally used as insecticides in agriculture. Following organophosphate poisoning (OPP, 3 well-defined neurological syndromes are recognised: cholinergic crisis, intermediate syndrome and delayed polyneuropathy. Some organophosphates, particularly triorthocresyl phosphate (TOCP and tricresyl phosphate (TCP, produce delayed neuropathy. On ingestion, they do not produce significant cholinergic crisis, but 7 to 20 days later it leads to a pure motor axonal neuropathy with wrist and foot drop. The mechanism may involve inhibition of neuropathy target esterase (NTE, which is found in the brain, peripheral nerves, and lymphocytes. This form of toxicity has been seen occasionally in small epidemics in

  13. A controlled investigation of the cause of chronic idiopathic axonal polyneuropathy. (United States)

    Hughes, R A C; Umapathi, T; Gray, I A; Gregson, N A; Noori, M; Pannala, A S; Proteggente, A; Swan, A V


    To investigate the aetiology of chronic idiopathic axonal polyneuropathy (CIAP), 50 consecutive patients were compared with 50 control subjects from the same region. There were 22 patients with painful neuropathy and 28 without pain, 26 with sensory neuropathy and 24 with sensory and motor neuropathy. The typical picture was a gradually progressive sensory or sensory and motor neuropathy. It caused mild or sometimes moderate disability, and reduced the quality of life. There was no evidence that alcohol, venous insufficiency, arterial disease or antibodies to peripheral nerve antigens played a significant part. There was a possible history of peripheral neuropathy in the first or second-degree relatives of six patients and no controls (P = 0.01), and claw toes were present in 12 patients and four controls (P = 0.03). Thirty-two per cent of the patients and 14% of the controls had impaired glucose tolerance or fasting hyperglycaemia but, after adjusting for age and sex, the difference was not significant (P = 0.45), even in the painful neuropathy subgroup. The mean (SD) fasting insulin concentrations were significantly (P = 0.01) higher in the patients [75.9 (44.4) mmol/l] than the controls [47.3 (37.9) mmol/l], and the mean was higher still in the painful neuropathy subgroup [92.2 (37.1) mmol/l] (P environmental toxin exposure and hypertriglyceridaemia, but not glucose intolerance or alcohol overuse as significant risk factors that deserve further investigation as possible causes of CIAP.

  14. A Stochastic Multiscale Model That Explains the Segregation of Axonal Microtubules and Neurofilaments in Neurological Diseases.

    Directory of Open Access Journals (Sweden)

    Chuan Xue


    Full Text Available The organization of the axonal cytoskeleton is a key determinant of the normal function of an axon, which is a long thin projection of a neuron. Under normal conditions two axonal cytoskeletal polymers, microtubules and neurofilaments, align longitudinally in axons and are interspersed in axonal cross-sections. However, in many neurotoxic and neurodegenerative disorders, microtubules and neurofilaments segregate apart from each other, with microtubules and membranous organelles clustered centrally and neurofilaments displaced to the periphery. This striking segregation precedes the abnormal and excessive neurofilament accumulation in these diseases, which in turn leads to focal axonal swellings. While neurofilament accumulation suggests an impairment of neurofilament transport along axons, the underlying mechanism of their segregation from microtubules remains poorly understood for over 30 years. To address this question, we developed a stochastic multiscale model for the cross-sectional distribution of microtubules and neurofilaments in axons. The model describes microtubules, neurofilaments and organelles as interacting particles in a 2D cross-section, and is built upon molecular processes that occur on a time scale of seconds or shorter. It incorporates the longitudinal transport of neurofilaments and organelles through this domain by allowing stochastic arrival and departure of these cargoes, and integrates the dynamic interactions of these cargoes with microtubules mediated by molecular motors. Simulations of the model demonstrate that organelles can pull nearby microtubules together, and in the absence of neurofilament transport, this mechanism gradually segregates microtubules from neurofilaments on a time scale of hours, similar to that observed in toxic neuropathies. This suggests that the microtubule-neurofilament segregation can be a consequence of the selective impairment of neurofilament transport. The model generates the

  15. A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons.

    Directory of Open Access Journals (Sweden)

    Aniket Ghosh

    Full Text Available Glia are of vital importance for all complex nervous system. One of the many functions of glia is to insulate and provide trophic and metabolic support to axons. Here, using glial-specific RNAi knockdown in Drosophila, we silenced 6930 conserved genes in adult flies to identify essential genes and pathways. Among our screening hits, metabolic processes were highly represented, and genes involved in carbohydrate and lipid metabolic pathways appeared to be essential in glia. One critical pathway identified was de novo ceramide synthesis. Glial knockdown of lace, a subunit of the serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathies in humans, resulted in ensheathment defects of peripheral nerves in Drosophila. A genetic dissection study combined with shotgun high-resolution mass spectrometry of lipids showed that levels of ceramide phosphoethanolamine are crucial for axonal ensheathment by glia. A detailed morphological and functional analysis demonstrated that the depletion of ceramide phosphoethanolamine resulted in axonal defasciculation, slowed spike propagation, and failure of wrapping glia to enwrap peripheral axons. Supplementing sphingosine into the diet rescued the neuropathy in flies. Thus, our RNAi study in Drosophila identifies a key role of ceramide phosphoethanolamine in wrapping of axons by glia.

  16. Treatment of hereditary optic neuropathies. (United States)

    Newman, Nancy J


    The hereditary optic neuropathies are inherited disorders in which optic nerve dysfunction is a prominent feature in the phenotypic expression of disease. Optic neuropathy may be primarily an isolated finding, such as in Leber hereditary optic neuropathy and dominant optic atrophy, or part of a multisystem disorder. The pathophysiological mechanisms underlying the hereditary optic neuropathies involve mitochondrial dysfunction owing to mutations in mitochondrial or nuclear DNA that encodes proteins essential to mitochondrial function. Effective treatments are limited, and current management includes therapies directed at enhancing mitochondrial function and preventing oxidative damage, as well as genetic counselling, and supportive and symptomatic measures. New therapies, including gene therapy, are emerging via animal models and human clinical trials. Leber hereditary optic neuropathy, in particular, provides a unique model for testing promising treatments owing to its characteristic sequential bilateral involvement and the accessibility of target tissue within the eye. Lessons learned from treatment of the hereditary optic neuropathies may have therapeutic implications for other disorders of presumed mitochondrial dysfunction. In this Review, the natural history of the common inherited optic neuropathies, the presumed pathogenesis of several of these disorders, and the literature to date regarding potential therapies are summarized.

  17. Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency? (United States)

    Ishibashi, S; Yokota, T; Shiojiri, T; Matunaga, T; Tanaka, H; Nishina, K; Hirota, H; Inaba, A; Yamada, M; Kanda, T; Mizusawa, H


    Acute axonal polyneuropathy and Wernicke-Korsakoff encephalopathy developed simultaneously in three patients. Nerve conduction studies (NCS) detected markedly decreased compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) with minimal conduction slowing; sympathetic skin responses (SSRs) were also notably decreased. Sural nerve biopsies showed only mild axonal degeneration with scattered myelin ovoid formation. The symptoms of neuropathy lessened within two weeks after an intravenous thiamine infusion. CMAPs, SNAPs, and SSRs also increased considerably. We suggest that this is a new type of peripheral nerve impairment: physiological conduction failure with minimal conduction delay due to thiamine deficiency.

  18. Functional recovery of regenerating motor axons is delayed in mice heterozygously deficient for the myelin protein P(0) gene

    DEFF Research Database (Denmark)

    Rosberg, Mette Romer; Alvarez, Susana; Krarup, Christian;


    Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/-) develop a neuropathy similar to human Charcot-Marie-Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate...... whether the regeneration capacity of early symptomatic P0+/- is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7-8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using...... threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/- had reduced compound motor action potential amplitudes and thinner myelinated...

  19. Auditory Neuropathy - A Case of Auditory Neuropathy after Hyperbilirubinemia

    Directory of Open Access Journals (Sweden)

    Maliheh Mazaher Yazdi


    Full Text Available Background and Aim: Auditory neuropathy is an hearing disorder in which peripheral hearing is normal, but the eighth nerve and brainstem are abnormal. By clinical definition, patient with this disorder have normal OAE, but exhibit an absent or severely abnormal ABR. Auditory neuropathy was first reported in the late 1970s as different methods could identify discrepancy between absent ABR and present hearing threshold. Speech understanding difficulties are worse than can be predicted from other tests of hearing function. Auditory neuropathy may also affect vestibular function. Case Report: This article presents electrophysiological and behavioral data from a case of auditory neuropathy in a child with normal hearing after bilirubinemia in a 5 years follow-up. Audiological findings demonstrate remarkable changes after multidisciplinary rehabilitation. Conclusion: auditory neuropathy may involve damage to the inner hair cells-specialized sensory cells in the inner ear that transmit information about sound through the nervous system to the brain. Other causes may include faulty connections between the inner hair cells and the nerve leading from the inner ear to the brain or damage to the nerve itself. People with auditory neuropathy have OAEs response but absent ABR and hearing loss threshold that can be permanent, get worse or get better.

  20. Unilateral Acute Anterior Ischemic Optic Neuropathy in a Patient with an Already Established Diagnosis of Bilateral Optic Disc Drusen

    Directory of Open Access Journals (Sweden)

    Ziya Ayhan


    Full Text Available Optic disc drusen (ODD are calcific deposits that form in the optic nerve head secondary to abnormalities in axonal metabolism and degeneration. Anterior ischemic optic neuropathy, central retinal artery, and vein occlusion are among the rare vascular complications of disc drusen. We reported the clinical course of a 51-year-old patient with a unilateral acute nonarteritic anterior ischemic optic neuropathy (NAION who received the diagnosis of bilateral optic disc drusen five years earlier and thereby reiterated the association of ODD and acute NAION.

  1. Unilateral Acute Anterior Ischemic Optic Neuropathy in a Patient with an Already Established Diagnosis of Bilateral Optic Disc Drusen (United States)

    Ayhan, Ziya; Yaman, Aylin; Söylev Bajin, Meltem; Saatci, A. Osman


    Optic disc drusen (ODD) are calcific deposits that form in the optic nerve head secondary to abnormalities in axonal metabolism and degeneration. Anterior ischemic optic neuropathy, central retinal artery, and vein occlusion are among the rare vascular complications of disc drusen. We reported the clinical course of a 51-year-old patient with a unilateral acute nonarteritic anterior ischemic optic neuropathy (NAION) who received the diagnosis of bilateral optic disc drusen five years earlier and thereby reiterated the association of ODD and acute NAION. PMID:26550507

  2. Sodium and Potassium Currents Influence Wallerian Degeneration of Injured Drosophila Axons (United States)

    Mishra, Bibhudatta; Carson, Ross; Hume, Richard I.


    Axons degenerate after injury and in neuropathies and disease via a self-destruction program whose mechanism is poorly understood. Axons that have lost connection to their cell bodies have altered electrical and synaptic activities, but whether such changes play a role in the axonal degeneration process is not clear. We have used a Drosophila model to study the Wallerian degeneration of motoneuron axons and their neuromuscular junction synapses. We found that degeneration of the distal nerve stump after a nerve crush is greatly delayed when there is increased potassium channel activity (by overexpression of two different potassium channels, Kir2.1 and dORKΔ-C) or decreased voltage-gated sodium channel activity (using mutations in the para sodium channel). Conversely, degeneration is accelerated when potassium channel activity is decreased (by expressing a dominant-negative mutation of Shaker). Despite the effect of altering voltage-gated sodium and potassium channel activity, recordings made after nerve crush demonstrated that the distal stump does not fire action potentials. Rather, a variety of lines of evidence suggest that the sodium and potassium channels manifest their effects upon degeneration through changes in the resting membrane potential, which in turn regulates the level of intracellular free calcium within the isolated distal axon. PMID:24285879

  3. [Leber's hereditary optic neuropathy]. (United States)

    Leo-Kottler, B; Wissinger, B


    Leber's hereditary optic neuropathy (LHON) is a rare disease primarily affecting the retinal ganglion cells. In most cases patients with LHON develop permanent visual loss with a large central scotoma in the visual field of both eyes. The optic disc becomes partially or completely pale. At the onset of the disease many patients are considered to suffer from an optic neuritis and are treated under the diagnostic and therapeutic regimen of optic neuritis. LHON is mostly only considered when high dose cortisone therapy fails to be effective or the second eye is affected. Thereafter, molecular genetic analysis will prove LHON in these cases. Detailed anamnesis including pedigree analysis in combination with observance of the peripapillary microangiopathic alterations at the fundus will help to speed up the diagnosis of LHON, but even after exact clinical and molecular genetic diagnosis of LHON some aspects of the disease still remain a mystery today.

  4. Transcellular degradation of axonal mitochondria. (United States)

    Davis, Chung-ha O; Kim, Keun-Young; Bushong, Eric A; Mills, Elizabeth A; Boassa, Daniela; Shih, Tiffany; Kinebuchi, Mira; Phan, Sebastien; Zhou, Yi; Bihlmeyer, Nathan A; Nguyen, Judy V; Jin, Yunju; Ellisman, Mark H; Marsh-Armstrong, Nicholas


    It is generally accepted that healthy cells degrade their own mitochondria. Here, we report that retinal ganglion cell axons of WT mice shed mitochondria at the optic nerve head (ONH), and that these mitochondria are internalized and degraded by adjacent astrocytes. EM demonstrates that mitochondria are shed through formation of large protrusions that originate from otherwise healthy axons. A virally introduced tandem fluorophore protein reporter of acidified mitochondria reveals that acidified axonal mitochondria originating from the retinal ganglion cell are associated with lysosomes within columns of astrocytes in the ONH. According to this reporter, a greater proportion of retinal ganglion cell mitochondria are degraded at the ONH than in the ganglion cell soma. Consistently, analyses of degrading DNA reveal extensive mtDNA degradation within the optic nerve astrocytes, some of which comes from retinal ganglion cell axons. Together, these results demonstrate that surprisingly large proportions of retinal ganglion cell axonal mitochondria are normally degraded by the astrocytes of the ONH. This transcellular degradation of mitochondria, or transmitophagy, likely occurs elsewhere in the CNS, because structurally similar accumulations of degrading mitochondria are also found along neurites in superficial layers of the cerebral cortex. Thus, the general assumption that neurons or other cells necessarily degrade their own mitochondria should be reconsidered.

  5. Treatment of chronic inflammatory neuropathies

    NARCIS (Netherlands)

    F. Eftimov


    This thesis focuses on the efficacy of existing and alternative treatments in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) and explores predictors of treatment response in patients with CIDP treated with corticosteroids. The efficacy of intra

  6. Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. (United States)

    Sevilla, Teresa; Lupo, Vincenzo; Martínez-Rubio, Dolores; Sancho, Paula; Sivera, Rafael; Chumillas, María J; García-Romero, Mar; Pascual-Pascual, Samuel I; Muelas, Nuria; Dopazo, Joaquín; Vílchez, Juan J; Palau, Francesc; Espinós, Carmen


    Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a

  7. Organophosphate-induced delayed neuropathy: case report Neuropatia tardia por organofosforado: relato de caso

    Directory of Open Access Journals (Sweden)

    Luiz Felipe R Vasconcellos


    Full Text Available Organophosphate induced delayed neuropathy (OPIDN is an uncommon clinical condition. It occurs in association with the ingestion of great amounts of organophosphate after the stimulation of cholinergic receptor. The clinical picture is characterized by a distal paresis in lower limbs associated with sensitive symptoms. Electrodiagnostic studies show a motor axonal neuropathy. Involvement of the central nervous system may occur. We describe a 39 years-old female patient who developed hyperesthesia associated with lower limbs paresis, fourteen days after she had ingested a Dichlorvos-based insecticide. Electrophysiological study was characterized by an axonal polyneuropathy pattern. Pyramidal tract dysfunction was observed later in upper limbs. Considering that both peripheral and central nervous systems are involved we believe that the more appropriated term would be organophosphate induced delayed neuropathy (OPIDN instead of organophosphate induced delayed polyneuropathy (OPIDP.A neuropatia tardia dos organofosforados (NTOF é condição clinica incomum. Geralmente ocorre após a intoxicação aguda por organofosforados, seguindo-se a fase de hiperestimulação colinérgica. O quadro clínico é caracterizado por déficit motor distal nos membros inferiores associado a sintomas sensitivos. O estudo eletroneuromiográfico tem demonstrado padrão axonal motor na maioria dos casos. Podem ocorrer sinais de comprometimento do sistema nervoso central. Descrevemos o caso de uma paciente de 39 anos que ingeriu inseticida a base de Dichlorvos e quatorze dias após apresentou quadro de hiperestesia associado a paresia distal nos membros inferiores. Realizou eletroneuromiografia que se caracterizou por padrão compatível com polineuropatia axonal. Sinais piramidais, de aparecimento mais tardio, foram observados nos membros superiores. Diante do comprometimento do sistema nervoso periférico e central, também consideramos o termo neuropatia tardia por

  8. Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6. (United States)

    Linnemann, Christoph; Tezenas du Montcel, Sophie; Rakowicz, Maryla; Schmitz-Hübsch, Tanja; Szymanski, Sandra; Berciano, Jose; van de Warrenburg, Bart P; Pedersen, Karine; Depondt, Chantal; Rola, Rafal; Klockgether, Thomas; García, Antonio; Mutlu, Gurkan; Schöls, Ludger


    Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype-specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers.

  9. Novel systems for in vivo monitoring and microenvironmental investigations of diabetic neuropathy in a murine model. (United States)

    Amit, Sharon; Yaron, Avraham


    Peripheral neuropathy is a devastating complication of diabetes conferring vast morbidity and mortality. Despite prolonged efforts to elucidate the mechanisms underlying diabetic related neuropathic phenomena and develop effective therapies, current treatment is for the most part glycemic control and symptomatic care. This is partially due to the intricate pathophysiology of diabetic neuropathy and the scarcity of valid experimental models. The aim of the study was to establish novel systems enabling monitoring and dissection of significant processes in the development of diabetic neuropathy. In a non-invasive in vivo model, two-photon microscopy is applied to evaluate mechanoreceptors (Meissner corpuscles) within an intact footpad of transgenic mice expressing a fluorescent neuronal tracer. By applying this advanced technology, which couples potent tissue penetration with superb resolution, we documented qualitative and quantitative diabetes-specific alterations in these sensory structures. Detection of such changes previously required laborious invasive histopathological techniques. In parallel, we present an ex vivo system that mimics the native microenvironment of the nerve ending via a unique co-culture of primary sensory neurons and thin skin slices. In conjunction with innovative high-throughput digital axonal measurements and computerized quantification tools, this method enables an unbiased exploration of neuronal autonomous and non-autonomous malfunctions. Using this setup we demonstrate that while the diabetic nerve retains a near-normal growth and regeneration capacities, the diabetic skin exhibits a decreased ability to support axonal outgrowth. Thus, an early target organ failure rather than intrinsic neuronal failure may initiate the neuropathy. Overall, the illustrated experimental platforms may greatly facilitate the holistic investigation of diabetic neuropathy.

  10. Action-potential modulation during axonal conduction. (United States)

    Sasaki, Takuya; Matsuki, Norio; Ikegaya, Yuji


    Once initiated near the soma, an action potential (AP) is thought to propagate autoregeneratively and distribute uniformly over axonal arbors. We challenge this classic view by showing that APs are subject to waveform modulation while they travel down axons. Using fluorescent patch-clamp pipettes, we recorded APs from axon branches of hippocampal CA3 pyramidal neurons ex vivo. The waveforms of axonal APs increased in width in response to the local application of glutamate and an adenosine A(1) receptor antagonist to the axon shafts, but not to other unrelated axon branches. Uncaging of calcium in periaxonal astrocytes caused AP broadening through ionotropic glutamate receptor activation. The broadened APs triggered larger calcium elevations in presynaptic boutons and facilitated synaptic transmission to postsynaptic neurons. This local AP modification may enable axonal computation through the geometry of axon wiring.

  11. Evaluation of cochleo-vestibular functions in patients with auditory neuropathy

    Directory of Open Access Journals (Sweden)

    Namea M. Ismail


    Conclusion: Patients with auditory neuropathy could also have vestibular neuropathy. Vestibular neuropathy could be classified into three groups: superior vestibular neuropathy, inferior vestibular neuropathy and superior/inferior vestibular neuropathy.

  12. Hypothyroidism: Can It Cause Peripheral Neuropathy? (United States)

    Hypothyroidism: Can it cause peripheral neuropathy? Can hypothyroidism cause peripheral neuropathy and, if so, how is it treated? Answers from Todd B. Nippoldt, M.D. Hypothyroidism — a condition in which your ...

  13. Peripheral neuropathy: the importance of rare subtypes (United States)

    Callaghan, Brian C.; Price, Ray S.; Chen, Kevin S.; Feldman, Eva L.


    Importance Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination, but limited diagnostic evaluation. Rare localizations of peripheral neuropathy, however, often require more extensive diagnostic testing and different treatments. Objective To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. Evidence Review References were identified from PubMed searches with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the author's own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Findings Diffuse, non-length dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, non-length dependent neuropathies are Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), and amyotrophic lateral sclerosis (ALS). Effective disease modifying therapies exist for many diffuse, non-length dependent neuropathies including GBS, CIDP, MMN, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyoptrophy (radiculoplexus neuropathy) is lacking. Conclusions and Relevance Recognition of rare localizations of periperhal neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important early step in the

  14. An update on electrophysiological studies in neuropathy

    DEFF Research Database (Denmark)

    Krarup, Christian


    The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic...... criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected....

  15. New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

    DEFF Research Database (Denmark)

    Feldman, Eva L; Nave, Klaus-Armin; Jensen, Troels Staehelin


    the mechanisms underlying diabetic neuropathy (DN). In this review, we present the structural components of the peripheral nervous system that underlie its susceptibility to metabolic insults and then discuss the pathways that contribute to peripheral nerve injury in DN. We also discuss systems biology insights......Pre-diabetes and diabetes are a global epidemic, and the associated neuropathic complications create a substantial burden on both the afflicted patients and society as a whole. Given the enormity of the problem and the lack of effective therapies, there is a pressing need to understand...... gleaned from the recent advances in biotechnology and bioinformatics, emerging ideas centered on the axon-Schwann cell relationship and associated bioenergetic crosstalk, and the rapid expansion of our knowledge of the mechanisms contributing to neuropathic pain in diabetes. These recent advances in our...

  16. [Diagnosis and treatment of multifocal motor neuropathy (Lewis-Sumner)]. (United States)

    Kaji, R


    We made a retrospective long-term follow-up study of 25 patients with multifocal motor neuropathy (Lewis-Sumner). The diagnosis was based upon criteria modified from those of AAEM (Sumner 1997). The electrophysiological findings indicating conduction block or focal demyelinative lesions were more diagnostic than anti-GM 1 antibody titers, which were elevated in only 40% of these patients. Demonstration of definite conduction block was not always possible in those patients who responded favorably to intravenous immunoglobulins (IVIg), whereas indirect pieces of evidence such as F-wave abnormalities or focal conduction delay or dispersion were equally helpful. IVIg had superior outcome to cyclophosphamide, which sometimes caused serious adverse effects. Three patients with severe axonal involvement showed elevated monospecific antibodies to GalNAc-GD1a.

  17. P-ANCA vasculitic neuropathy with 12-year latency between onset of neuropathy and systemic symptoms

    Directory of Open Access Journals (Sweden)

    Greenberg Steven A


    Full Text Available Abstract Background The differential diagnosis of chronic progressive multifocal asymmetric neuropathies is challenging. Vasculitic neuropathies, multifocal forms of chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathies, and asymmetric lower motor neuron disorders are important considerations. Case presentation We report a patient with an unusually long 12-year course of nonsystemic vasculitic neuropathy prior to the development of systemic manifestations. Conclusion We discuss some of the difficulties involved in the diagnosis of chronic progressive multifocal asymmetric neuropathies.

  18. [Small fibre neuropathy: knowledge is power].

    NARCIS (Netherlands)

    Hoeijmakers, J.G.; Bakkers, M.; Blom, E.W.; Drenth, J.P.H.; Merkies, I.S.; Faber, C.G.


    Small fibre neuropathy is a neuropathy of the small non-myelinated C-fibres and myelinated Adelta-fibres. Clinically, an isolated small fibre neuropathy is distinguished by sensory and autonomic symptoms, with practically no abnormalities on neurological examination other than possible distorted pai

  19. Study progression of painful diabetic neuropathy%糖尿病痛性神经病变的研究进展

    Institute of Scientific and Technical Information of China (English)



    糖尿病痛性神经病变(painful diabetic neuropathy,PDN)是一种感觉性周围神经病变.糖尿病神经病变的疼痛机制与初级感觉神经元和外周轴突通路的损伤产生过度兴奋和自发的异常放电相关.文中就PDN的病理机制、诊治进展进行综述.%Painful diabetic neuropathy (PDN) is a kind of sensory peripheral neuropathy. Hyperexcitability and aberrant spontaneous impulse generation by damaged first -order sensory neurons and their peripheral axons are well -established processes that strongly contribute to pain associated with diabetic neuropathy . This review describes the pathological mechanism , progression of diagnose and treatment of PDN.

  20. ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease. (United States)

    Montecchiani, Celeste; Pedace, Lucia; Lo Giudice, Temistocle; Casella, Antonella; Mearini, Marzia; Gaudiello, Fabrizio; Pedroso, José L; Terracciano, Chiara; Caltagirone, Carlo; Massa, Roberto; St George-Hyslop, Peter H; Barsottini, Orlando G P; Kawarai, Toshitaka; Orlacchio, Antonio


    Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis. The overlap of axonal Charcot-Marie-Tooth disease with both diseases, as well as the common autosomal recessive inheritance pattern of thin corpus callosum and axonal Charcot-Marie-Tooth disease in three related patients, prompted us to analyse the ALS5/SPG11/KIAA1840 gene in affected individuals with autosomal recessive axonal Charcot-Marie-Tooth disease. We investigated 28 unrelated families with autosomal recessive axonal Charcot-Marie-Tooth disease defined by clinical, electrophysiological, as well as pathological evaluation. Besides, we screened for all the known genes related to axonal autosomal recessive Charcot-Marie-Tooth disease (CMT2A2/HMSN2A2/MFN2, CMT2B1/LMNA, CMT2B2/MED25, CMT2B5/NEFL, ARCMT2F/dHMN2B/HSPB1, CMT2K/GDAP1, CMT2P/LRSAM1, CMT2R/TRIM2, CMT2S/IGHMBP2, CMT2T/HSJ1, CMTRID/COX6A1, ARAN-NM/HINT and GAN/GAN), for the genes related to autosomal recessive hereditary spastic paraplegia with thin corpus callosum and axonal peripheral neuropathy (SPG7/PGN, SPG15/ZFYVE26, SPG21/ACP33, SPG35/FA2H, SPG46/GBA2, SPG55/C12orf65 and SPG56/CYP2U1), as well as for the causative gene of peripheral neuropathy with or without agenesis of the corpus callosum (SLC12A6). Mitochondrial disorders related to Charcot-Marie-Tooth disease type 2 were also excluded by sequencing POLG and TYMP genes. An additional locus for autosomal recessive Charcot

  1. Peripheral neuropathy in mitochondrial disorders. (United States)

    Pareyson, Davide; Piscosquito, Giuseppe; Moroni, Isabella; Salsano, Ettore; Zeviani, Massimo


    Why is peripheral neuropathy common but mild in many mitochondrial disorders, and why is it, in some cases, the predominant or only manifestation? Although this question remains largely unanswered, recent advances in cellular and molecular biology have begun to clarify the importance of mitochondrial functioning and distribution in the peripheral nerve. Mutations in proteins involved in mitochondrial dynamics (ie, fusion and fission) frequently result in a Charcot-Marie-Tooth phenotype. Peripheral neuropathies with different phenotypic presentations occur in mitochondrial diseases associated with abnormalities in mitochondrial DNA replication and maintenance, or associated with defects in mitochondrial respiratory chain complex V. Our knowledge of mitochondrial disorders is rapidly growing as new nuclear genes are identified and new phenotypes described. Early diagnosis of mitochondrial disorders, essential to provide appropriate genetic counselling, has become crucial in a few treatable conditions. Recognising and diagnosing an underlying mitochondrial defect in patients presenting with peripheral neuropathy is therefore of paramount importance.

  2. Entrapment neuropathies in diabetes mellitus (United States)

    Rota, Eugenia; Morelli, Nicola


    Neuropathy is a common complication of diabetes mellitus (DM) with a wide clinical spectrum that encompasses generalized to focal and multifocal forms. Entrapment neuropathies (EN), which are focal forms, are so frequent at any stage of the diabetic disease, that they may be considered a neurophysiological hallmark of peripheral nerve involvement in DM. Indeed, EN may be the earliest neurophysiological abnormalities in DM, particularly in the upper limbs, even in the absence of a generalized polyneuropathy, or it may be superimposed on a generalized diabetic neuropathy. This remarkable frequency of EN in diabetes is underlain by a peculiar pathophysiological background. Due to the metabolic alterations consequent to abnormal glucose metabolism, the peripheral nerves show both functional impairment and structural changes, even in the preclinical stage, making them more prone to entrapment in anatomically constrained channels. This review discusses the most common and relevant EN encountered in diabetic patient in their epidemiological, pathophysiological and diagnostic features. PMID:27660694

  3. Mechanisms of action of IVIg and therapeutic considerations in the treatment of acute and chronic demyelinating neuropathies. (United States)

    Dalakas, Marinos C


    Intravenous immunoglobulin (IVIg) is an immunomodulating agent that has multiple activities, including modulation of complement activation products, suppressing idiotypic antibody, saturating Fc receptors on macrophages, and suppressing various inflammatory mediators including cytokines, chemokines, and metalloproteinases. Because all these factors are implicated to various degrees in the pathogenesis of immune-mediated demyelination of the PNS, administration of IVIg could be beneficial in treating neuropathies by suppressing the immune-mediated processes that are directed against myelin or axonal antigenic targets. This article outlines the actions of IVIg in CIDP and other autoimmune neuropathies based on data derived from in vivo and in vitro studies. The predominant mechanisms by which IVIg exerts its action on these neuropathies appear to be a combined effect on complement inactivation, neutralization of idiotypic antibodies, cytokine inhibition, and saturation of Fc receptors on endoneurial macrophages.

  4. Analysis of dynein intermediate chains, light intermediate chains and light chains in a cohort of hereditary peripheral neuropathies. (United States)

    Tey, Shelisa; Ahmad-Annuar, Azlina; Drew, Alexander P; Shahrizaila, Nortina; Nicholson, Garth A; Kennerson, Marina L


    The cytoplasmic dynein heavy chain (DYNC1H1) gene has been increasingly associated with neurodegenerative disorders including axonal Charcot-Marie-Tooth disease (CMT2), intellectual disability and malformations of cortical development. In addition, evidence from mouse models (Loa, catabolite repressor-activator (Cra) and Sprawling (Swl)) has shown that mutations in Dync1h1 cause a range of neurodegenerative phenotypes with motor and sensory neuron involvement. In this current study, we examined the possible contribution of other cytoplasmic dynein subunits that bind to DYNC1H1 as a cause of inherited peripheral neuropathy. We focused on screening the cytoplasmic dynein intermediate, light intermediate and light chain genes in a cohort of families with inherited peripheral neuropathies. Nine genes were screened and ten variants were detected, but none was identified as pathogenic, indicating that cytoplasmic dynein intermediate, light intermediate and light chains are not a cause of neuropathy in our cohort.

  5. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. (United States)

    Perry, TracyAnn; Holloway, Harold W; Weerasuriya, Ananda; Mouton, Peter R; Duffy, Kara; Mattison, Julie A; Greig, Nigel H


    Pyridoxine (vitamin B6) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated with disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1 (7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1R) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus.

  6. Disulfiram neuropathy: two case reports



    Background Neuropathy is a rare adverse side effect of disulfiram therapy and is under-recognized. There have been few case reports documenting this side effect. Case presentation Two cases of disulfiram peripheral neuropathy are discussed. The first case is that of a 25-year-old Caucasian woman who was exposed to disulfiram therapy for a total of 8 months and developed pain and stiffness that prevented her from walking. The second case is that of a 46-year-old Caucasian woman who developed s...

  7. Dimethyl Fumarate Ameliorates Lewis Rat Experimental Autoimmune Neuritis and Mediates Axonal Protection.

    Directory of Open Access Journals (Sweden)

    Kalliopi Pitarokoili

    Full Text Available Dimethyl fumarate is an immunomodulatory and neuroprotective drug, approved recently for the treatment of relapsing-remitting multiple sclerosis. In view of the limited therapeutic options for human acute and chronic polyneuritis, we used the animal model of experimental autoimmune neuritis in the Lewis rat to study the effects of dimethyl fumarate on autoimmune inflammation and neuroprotection in the peripheral nervous system.Experimental autoimmune neuritis was induced by immunization with the neuritogenic peptide (amino acids 53-78 of P2 myelin protein. Preventive treatment with dimethyl fumarate given at 45 mg/kg twice daily by oral gavage significantly ameliorated clinical neuritis by reducing demyelination and axonal degeneration in the nerve conduction studies. Histology revealed a significantly lower degree of inflammatory infiltrates in the sciatic nerves. In addition, we detected a reduction of early signs of axonal degeneration through a reduction of amyloid precursor protein expressed in axons of the peripheral nerves. This reduction correlated with an increase of nuclear factor (erythroid derived 2-related factor 2 positive axons, supporting the neuroprotective potential of dimethyl fumarate. Furthermore, nuclear factor (erythroid derived 2-related factor 2 expression in Schwann cells was only rarely detected and there was no increase of Schwann cells death during EAN.We conclude that immunomodulatory and neuroprotective dimethyl fumarate may represent an innovative therapeutic option in human autoimmune neuropathies.

  8. Inflammation: therapeutic targets for diabetic neuropathy. (United States)

    Zhou, Jiyin; Zhou, Shiwen


    There are still no approved treatments for the prevention or of cure of diabetic neuropathy, and only symptomatic pain therapies of variable efficacy are available. Inflammation is a cardinal pathogenic mechanism of diabetic neuropathy. The relationships between inflammation and the development of diabetic neuropathy involve complex molecular networks and processes. Herein, we review the key inflammatory molecules (inflammatory cytokines, adhesion molecules, chemokines) and pathways (nuclear factor kappa B, JUN N-terminal kinase) implicated in the development and progression of diabetic neuropathy. Advances in the understanding of the roles of these key inflammatory molecules and pathways in diabetic neuropathy will facilitate the discovery of the potential of anti-inflammatory approaches for the inhibition of the development of neuropathy. Specifically, many anti-inflammatory drugs significantly inhibit the development of different aspects of diabetic neuropathy in animal models and clinical trials.

  9. Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury. (United States)

    Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L


    Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies.

  10. Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice. (United States)

    Wang, Lei; Chopp, Michael; Szalad, Alexandra; Lu, XueRong; Jia, LongFei; Lu, Mei; Zhang, Rui Lan; Zhang, Zheng Gang


    We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy.

  11. Charcot-Marie-Tooth Disease and Related Hereditary Neuropathies: From Gene Function to Associated Phenotypes. (United States)

    Pareyson, D; Saveri, P; Piscosquito, G


    Charcot-Marie-Tooth disease (CMT) and related neuropathies are a genetically highly heterogeneous group of neurodegenerative disorders. CMT affects both the sensory and motor nerves, distal Hereditary Motor Neuropathies (dHMN) are phenotypically similar disorders involving only motor nerves, while Hereditary Sensory and Autonomic Neuropathies (HSAN) are rare distinct disorders affecting sensory and sometimes autonomic nerves. Almost 70 genes have been identified as responsible for these disorders. It is astonishing to learn how diverse are the cellular sublocalisation and the functional roles of the encoded proteins of CMT-associated genes which all lead to similar disorders of the peripheral nervous system. Myelin formation and maintenance, mitochondrial dynamics, cytoskeleton organization, axonal transport, and vesicular trafficking are the most frequently involved pathways. However, dysfunction of several activities from the nucleus to the neuromuscular junction forms the basis for these hereditary neuropathies, making it challenging predicting the functions of newly identified mutated genes. In this review we will discuss the function and related phenotypes of all the genes thus far associated with CMT, dHMN, and HSAN.

  12. [Peripheral sensory neuropathy produced by a megadose of vitamin B6]. (United States)

    Ohnishi, A; Ishibashi, H; Ohtani, K; Matsunaga, K; Yamamoto, T


    Clinical cases of sensory neuropathy produced by a megadose of vitamin B6 have been reported in English literatures. We investigated the ordinary daily dosage and maximal dose of vitamin B6 widely adopted in Japan, and the amount of vitamin B6 per unit (per tablet, capsule or ampule) available in our medical practice. We concluded that in Japan it is very rare to administer such a large dose of vitamin B6 that produced sensory neuropathy described in the literatures. In our experimental study, Sprague-Dawley rats were intraperitoneally given a total amount of 14,000 mg/kg of body weight of pyridoxine hydrochloride in ten separate doses. They developed an ataxic gait. The occurrence of the degeneration of nerve cell bodies and peripheral axons of lumbar primary sensory neurons were histologically demonstrated. Although in Japan no clinical cases of neuropathy produced by a megadose of vitamin B6 have been reported to our knowledge, it is necessary to be aware of the possible occurrence of such neuropathy among patients with polyneuropathy of unknown etiology or who have been receiving vitamin B6 for a long time.

  13. DNA testing in hereditary neuropathies.

    LENUS (Irish Health Repository)

    Murphy, Sinéad M


    The inherited neuropathies are a clinically and genetically heterogeneous group of disorders in which there have been rapid advances in the last two decades. Molecular genetic testing is now an integral part of the evaluation of patients with inherited neuropathies. In this chapter we describe the genes responsible for the primary inherited neuropathies. We briefly discuss the clinical phenotype of each of the known inherited neuropathy subgroups, describe algorithms for molecular genetic testing of affected patients and discuss genetic counseling. The basic principles of careful phenotyping, documenting an accurate family history, and testing the available genes in an appropriate manner should identify the vast majority of individuals with CMT1 and many of those with CMT2. In this chapter we also describe the current methods of genetic testing. As advances are made in molecular genetic technologies and improvements are made in bioinformatics, it is likely that the current time-consuming methods of DNA sequencing will give way to quicker and more efficient high-throughput methods, which are briefly discussed here.

  14. Optic neuropathy in familial dysautonomia. (United States)

    Groom, M; Kay, M D; Corrent, G F


    Optic atrophy, which is indicative of a CNS disorder, is a rarely described manifestation of familial dysautonomia (Riley-Day syndrome). As these patients are now living longer, the prevalence of optic neuropathy also may be increasing. We present a man with familial dysautonomia and visual loss resulting from optic atrophy and visual field defect suggestive of chiasmal pathology.

  15. Pyridoxine-Induced Sensory Neuropathy



    An 18-year-old man with seizures from birth was followed in the Department of Clinical Neurological Sciences, University of Western Ontario, London, and was found to have developed a sensory neuropathy by 2 years of age following treatment with pyridoxine in doses up to 2000 mg/day.

  16. Hereditary sensory neuropathy type I

    Directory of Open Access Journals (Sweden)

    Auer-Grumbach Michaela


    Full Text Available Abstract Hereditary sensory neuropathy type I (HSN I is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7 identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN, especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra

  17. Lifestyle risk factors for ulnar neuropathy and ulnar neuropathy-like symptoms

    DEFF Research Database (Denmark)

    Frost, Poul; Johnsen, Birger; Fuglsang-Frederiksen, Anders;


    Introduction: We examined whether lifestyle factors differ between patients with ulnar neuropathy confirmed by electroneurography (ENG) and those with ulnar neuropathy-like symptoms with normal ulnar nerve ENG. Methods: Among patients examined by ENG for suspected ulnar neuropathy, we identified...... 546 patients with ulnar neuropathy and 633 patients with ulnar neuropathy-like symptoms. These groups were compared with 2 separate groups of matched community referents and to each other. Questionnaire information on lifestyle was obtained. The electrophysiological severity of neuropathy was also...

  18. [Clinical practice of hereditary motor neuropathy (HMN) and hereditary sensory and autonomic neuropathy (HSAN)]. (United States)

    Takashima, Hiroshi


    Inherited neuropathy is a genetically and clinically heterogeneous group of neuropathies, the main category becomes Charcot-Marie-Tooth neuropathy (CMT), also known as hereditary motor and sensory neuropathy (HMSN), distal hereditary motor neuropathy (dHMN), and hereditary sensory autonomic neuropathy (HSAN). At least 80 genes have been associated with CMT, HMN or HSAN, a precise molecular diagnosis is often needed to make a clinical diagnosis accurately, enable genetic counseling of the patient and understanding of their molecular mechanisms. To identify the mutation in each patient, using a high-throughput NGS, we established a diagnostic procedure involving screening of disease causing genes in CMT, HMN or HSAN.

  19. Exenatide Facilitates Recovery from Oxaliplatin-Induced Peripheral Neuropathy in Rats.

    Directory of Open Access Journals (Sweden)

    Shunsuke Fujita

    Full Text Available Oxaliplatin has widely been used as a key drug in the treatment of colorectal cancer; however, it causes peripheral neuropathy. Exenatide, a glucagon-like peptide-1 (GLP-1 agonist, is an incretin mimetic secreted from ileal L cells, which is clinically used to treat type 2 diabetes mellitus. GLP-1 receptor agonists have been reported to exhibit neuroprotective effects on the central and peripheral nervous systems. In this study, we investigated the effects of exenatide on oxaliplatin-induced neuropathy in rats and cultured cells.Oxaliplatin (4 mg/kg was administered intravenously twice per week for 4 weeks, and mechanical allodynia was evaluated using the von Frey test in rats. Axonal degeneration was assessed by toluidine blue staining of sciatic nerves.Repeated administration of oxaliplatin caused mechanical allodynia from day 14 to 49. Although the co-administration of extended-release exenatide (100 μg/kg could not inhibit the incidence of oxaliplatin-induced mechanical allodynia, it facilitated recovery from the oxaliplatin-induced neuropathy with reparation of axonal degeneration. Inhibition of neurite outgrowth was evaluated in cultured pheochromocytoma 12 (PC12 cells. Exenatide inhibited oxaliplatin-induced neurite degeneration, but did not affect oxaliplatin-induced cell injury in cultured PC12 cells. Additionally, extended-release exenatide had no effect on the anti-tumor activity of oxaliplatin in cultured murine colon adenocarcinoma 26 (C-26 cells or C-26 cell-implanted mice.These results suggest that exenatide may be useful for treating peripheral neuropathy induced by oxaliplatin in colorectal cancer patients with type 2 diabetes.

  20. Akt Regulates Axon Wrapping and Myelin Sheath Thickness in the PNS (United States)

    Baloui, Hasna; Meng, Xiaosong; Zhang, Yanqing; Deinhardt, Katrin; Dupree, Jeff L.; Einheber, Steven; Chrast, Roman


    uncertain. This work reveals that Akt controls several key steps of the PNS myelination. First, its activity promotes membrane production and axonal wrapping independent of a transcriptional effect. In myelinated axons, it also enhances myelin thickness through the mTOR pathway. Finally, sustained Akt activation in Schwann cells leads to hypermyelination/dysmyelination, mimicking some features present in neuropathies, such as hereditary neuropathy with liability to pressure palsies or demyelinating forms of Charcot-Marie-Tooth disease. Together, these data demonstrate the role of Akt in regulatory mechanisms underlying axonal wrapping and myelination in the PNS. PMID:27098694

  1. Mouse mtDNA mutant model of Leber hereditary optic neuropathy. (United States)

    Lin, Chun Shi; Sharpley, Mark S; Fan, Weiwei; Waymire, Katrina G; Sadun, Alfredo A; Carelli, Valerio; Ross-Cisneros, Fred N; Baciu, Peter; Sung, Eric; McManus, Meagan J; Pan, Billy X; Gil, Daniel W; Macgregor, Grant R; Wallace, Douglas C


    An animal model of Leber hereditary optic neuropathy (LHON) was produced by introducing the human optic atrophy mtDNA ND6 P25L mutation into the mouse. Mice with this mutation exhibited reduction in retinal function by elecroretinogram (ERG), age-related decline in central smaller caliber optic nerve fibers with sparing of larger peripheral fibers, neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. Mitochondrial analysis revealed partial complex I and respiration defects and increased reactive oxygen species (ROS) production, whereas synaptosome analysis revealed decreased complex I activity and increased ROS but no diminution of ATP production. Thus, LHON pathophysiology may result from oxidative stress.

  2. Evaluation and Prevention of Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Pajouhi M


    Full Text Available Background: Diabetic neuropathy is an incapacitating disease that afflicts almost 50 percent of patients with diabetes. A late finding in type 1 diabetes, diabetic neuropathy can be an early finding in non insulin-dependent diabetes. Diabetic neuropathies are divided primarily into two groups, sensorimotor and autonomic. Patients may acquire only one type of diabetic neuropathy or may present with combinations of neuropathies, such as autonomic neuropathy or distal symmetric polyneuropathy, the latter of which the most common form. Motor deficits, orthostatic hypotension, silent cardiac ischemia, hyperhidrosis, vasomotor instability, gastroparesis, bladder dysfunction, and sexual dysfunction can also result from diabetic neuropathy. Strict control of blood sugar, combined with proper daily foot care, is essential to avoid the complications of this disorder. With the potential to afflict any part of the nervous system, diabetic neuropathy should be suspected in all patients with type 2 diabetes as well as patients who have had type 1 diabetes for over five years. Although some patients with diabetic neuropathy notice few symptoms, upon physical examination mild to moderately severe sensory loss may be noted by the physician. Idiopathic neuropathy has been known to precede the onset of type 2 diabetes.

  3. Misclassification and linkage of hereditary sensory and autonomic neuropathy type 1 as Charcot-Marie-Tooth disease, Type 2B

    Energy Technology Data Exchange (ETDEWEB)

    Vance, J.M.; Speer, M.C.; Stajich, J.M. [Duke Univ. Medical Center, Durham, NC (United States)


    Recently Kwon et al. published in the Journal their work describing linkage of a single large family with an inherited axonal neuropathy to chromosome 3, which they suggest is a second locus for Charcot-Marie-Tooth (CMT) type 2 and subsequently named {open_quotes}CMT2B.{close_quotes} We think that the diagnostic classification of this family as CMT2 is incorrect, since the subjects have a severe sensory neuropathy that fits within the hereditary sensory and autonomic neuropathy (HSAN) type 1 classification of Dyck (1993). Abnormal sensory findings in CMT2 separate it from distal spinal muscular atrophy but are a minor component of clinical symptoms in most CMT patients, as CMT is primarily a motor neuropathy. When Kwon et al. state that {open_quotes}all [patients] had characteristic findings in their physical examinations, including... evidence of foot sores that were slow to heal, or amputated limbs related to the poorly healing foot ulcers,{close_quotes} it suggests that a different diagnosis is more appropriate. In our experience collecting data on >950 individuals in >60 CMT1, CMT2, CMTX and CMT4 families, we have not seen foot ulcers, osteomyelitis, or amputations. Ulcerations leading to osteomyelitis and amputations are usually associated with severe sensory neuropathies. 16 refs., 1 tab.

  4. AxonSeg: Open Source Software for Axon and Myelin Segmentation and Morphometric Analysis. (United States)

    Zaimi, Aldo; Duval, Tanguy; Gasecka, Alicja; Côté, Daniel; Stikov, Nikola; Cohen-Adad, Julien


    Segmenting axon and myelin from microscopic images is relevant for studying the peripheral and central nervous system and for validating new MRI techniques that aim at quantifying tissue microstructure. While several software packages have been proposed, their interface is sometimes limited and/or they are designed to work with a specific modality (e.g., scanning electron microscopy (SEM) only). Here we introduce AxonSeg, which allows to perform automatic axon and myelin segmentation on histology images, and to extract relevant morphometric information, such as axon diameter distribution, axon density and the myelin g-ratio. AxonSeg includes a simple and intuitive MATLAB-based graphical user interface (GUI) and can easily be adapted to a variety of imaging modalities. The main steps of AxonSeg consist of: (i) image pre-processing; (ii) pre-segmentation of axons over a cropped image and discriminant analysis (DA) to select the best parameters based on axon shape and intensity information; (iii) automatic axon and myelin segmentation over the full image; and (iv) atlas-based statistics to extract morphometric information. Segmentation results from standard optical microscopy (OM), SEM and coherent anti-Stokes Raman scattering (CARS) microscopy are presented, along with validation against manual segmentations. Being fully-automatic after a quick manual intervention on a cropped image, we believe AxonSeg will be useful to researchers interested in large throughput histology. AxonSeg is open source and freely available at:

  5. Neuropathies optiques héréditaires

    DEFF Research Database (Denmark)

    Milea, D; Verny, C


    Hereditary optic neuropathies are a group of heterogeneous conditions affecting both optic nerves, with an autosomal dominant, autosomal recessive, X-related or mitochondrial transmission. The two most common non-syndromic hereditary optic neuropathies (Leber's hereditary optic neuropathy...

  6. Axonal interferon responses and alphaherpesvirus neuroinvasion (United States)

    Song, Ren

    Infection by alphaherpesviruses, including herpes simplex virus (HSV) and pseudorabies virus (PRV), typically begins at a peripheral epithelial surface and continues into the peripheral nervous system (PNS) that innervates this tissue. Inflammatory responses are induced at the infected peripheral site prior to viral invasion of the PNS. PNS neurons are highly polarized cells with long axonal processes that connect to distant targets. When the peripheral tissue is first infected, only the innervating axons are exposed to this inflammatory milieu, which include type I interferon (e.g. IFNbeta) and type II interferon (i.e. IFNgamma). IFNbeta can be produced by all types of cells, while IFNgamma is secreted by some specific types of immune cells. And both types of IFN induce antiviral responses in surrounding cells that express the IFN receptors. The fundamental question is how do PNS neurons respond to the inflammatory milieu experienced only by their axons. Axons must act as potential front-line barriers to prevent PNS infection and damage. Using compartmented cultures that physically separate neuron axons from cell bodies, I found that pretreating isolated axons with IFNbeta or IFNgamma significantly diminished the number of HSV-1 and PRV particles moving from axons to the cell bodies in an IFN receptor-dependent manner. Furthermore, I found the responses in axons are activated differentially by the two types of IFNs. The response to IFNbeta is a rapid, axon-only response, while the response to IFNgamma involves long distance signaling to the PNS cell body. For example, exposing axons to IFNbeta induced STAT1 phosphorylation (p-STAT1) only in axons, while exposure of axons to IFNgamma induced p-STAT1 accumulation in distant cell body nuclei. Blocking transcription in cell bodies eliminated IFNgamma-, but not IFNbeta-mediated antiviral effects. Proteomic analysis of IFNbeta- or IFNgamma-treated axons identified several differentially regulated proteins. Therefore

  7. New Generation Antidepressants in Painful Diabetic Neuropathy


    Gutiérrez-Álvarez, Ángela-María; Carlos B. Moreno


    The incidence of diabetic neuropathy increases with the duration of diabetes and the degree of hyperglycaemia. Pain is one of the most common and incapacitating symptoms of diabetic neuropathy and its pharmacological control is complex. The effectiveness of antidepressive agents has been described in different types of neuropathic pain, but their effectiveness, when used as analgesics in painful diabetic neuropathy, still remains controversial. Objective: To review the possible role of new-ge...

  8. Cardiovascular autonomic neuropathy in diabetes

    DEFF Research Database (Denmark)

    Spallone, Vincenza; Ziegler, Dan; Freeman, Roy


    in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: 1. one abnormal cardio-vagal test identifies possible or early CAN; 2. at least two abnormal cardio-vagal tests....... diagnosis of CAN clinical forms, 2. detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, OH, nondipping, QT interval prolongation), 3. risk stratification for diabetic complications and cardiovascular morbidity and mortality, and 4. modulation of targets of diabetes therapy......Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control...

  9. Differential calcium signaling mediated by voltage-gated calcium channels in rat retinal ganglion cells and their unmyelinated axons.

    Directory of Open Access Journals (Sweden)

    Allison Sargoy

    Full Text Available Aberrant calcium regulation has been implicated as a causative factor in the degeneration of retinal ganglion cells (RGCs in numerous injury models of optic neuropathy. Since calcium has dual roles in maintaining homeostasis and triggering apoptotic pathways in healthy and injured cells, respectively, investigation of voltage-gated Ca channel (VGCC regulation as a potential strategy to reduce the loss of RGCs is warranted. The accessibility and structure of the retina provide advantages for the investigation of the mechanisms of calcium signalling in both the somata of ganglion cells as well as their unmyelinated axons. The goal of the present study was to determine the distribution of VGCC subtypes in the cell bodies and axons of ganglion cells in the normal retina and to define their contribution to calcium signals in these cellular compartments. We report L-type Ca channel α1C and α1D subunit immunoreactivity in rat RGC somata and axons. The N-type Ca channel α1B subunit was in RGC somata and axons, while the P/Q-type Ca channel α1A subunit was only in the RGC somata. We patch clamped isolated ganglion cells and biophysically identified T-type Ca channels. Calcium imaging studies of RGCs in wholemounted retinas showed that selective Ca channel antagonists reduced depolarization-evoked calcium signals mediated by L-, N-, P/Q- and T-type Ca channels in the cell bodies but only by L-type Ca channels in the axons. This differential contribution of VGCC subtypes to calcium signals in RGC somata and their axons may provide insight into the development of target-specific strategies to spare the loss of RGCs and their axons following injury.

  10. Imaging of neuropathies about the hip

    Energy Technology Data Exchange (ETDEWEB)

    Martinoli, Carlo, E-mail: [Radiologia – DISC, Università di Genova, Largo Rosanna Benzi 8, I-16132 Genoa (Italy); Miguel-Perez, Maribel [Unit of Human Anatomy and Embryology, Department of Pathology and Experimental Therapy, Faculty of Medicine (C Bellvitge), University of Barcelona, Barcelona (Spain); Padua, Luca [Fondazione Don Gnocchi Onlus and Department of Neurology, Policlinico “A. Gemelli”, Università Cattolica del Sacro Cuore, Rome (Italy); Gandolfo, Nicola [IM2S – Institut Monégasque de Médecine and Chirurgie Sportive, Montecarlo (Monaco); Zicca, Anna [Radiologia – DISC, Università di Genova, Largo Rosanna Benzi 8, I-16132 Genoa (Italy); Tagliafico, Alberto [Radiologia – National Institute for Cancer Research, Genoa (Italy)


    Neuropathies about the hip may be cause of chronic pain and disability. In most cases, these conditions derive from mechanical or dynamic compression of a segment of a nerve within a narrow osteofibrous tunnel, an opening in a fibrous structure, or a passageway close to a ligament or a muscle. Although the evaluation of nerve disorders primarily relies on neurological examination and electrophysiology, diagnostic imaging is currently used as a complement to help define the site and aetiology of nerve compression and exclude other disease possibly underlying the patient’ symptoms. Diagnosis of entrapment neuropathies about the hip with US and MR imaging requires an in-depth knowledge of the normal imaging anatomy and awareness of the anatomic and pathologic factors that may predispose or cause a nerve injury. Accordingly, the aim of this article is to provide a comprehensive review of hip neuropathies with an emphasis on the relevant anatomy, aetiology, clinical presentation, and their imaging appearance. The lateral femoral cutaneous neuropathy (meiralgia paresthetica), femoral neuropathy, sciatic neuropathy, obturator neuropathy, superior and inferior gluteal neuropathies and pudendal neuropathy will be discussed.

  11. Vincristine-Induced Cranial Neuropathy

    Directory of Open Access Journals (Sweden)

    Ahmad TALEBIAN*


    Full Text Available How to Cite This Article: Talebian A, Goudarzi RM, Mohammadzadeh M , Mirzadeh AS. Vincristine-Induced Cranial Neuropathy. Iran J Child Neurol. 2014 Winter; 8(1:66-68. Abstract Vincristine (VCR is a vinca alkaloid that is used for treatment of many malignancies. The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms’ tumor, treated by vincristine (0/067 mg/kg/day and dactinomycin (0/045 mg/kg/day after surgery. Three weeks after treatment, he presented with bilateral ptosis. Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis. Treatment with pyridoxine (150 mg/m2 p.o. BID and pyridostigmine (3 mg/kg p.o. BID started as neuroprotective agents, and after 7 days the problem disappeared. The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later.

  12. Cable energy function of cortical axons. (United States)

    Ju, Huiwen; Hines, Michael L; Yu, Yuguo


    Accurate estimation of action potential (AP)-related metabolic cost is essential for understanding energetic constraints on brain connections and signaling processes. Most previous energy estimates of the AP were obtained using the Na(+)-counting method, which seriously limits accurate assessment of metabolic cost of ionic currents that underlie AP conduction along the axon. Here, we first derive a full cable energy function for cortical axons based on classic Hodgkin-Huxley (HH) neuronal equations and then apply the cable energy function to precisely estimate the energy consumption of AP conduction along axons with different geometric shapes. Our analytical approach predicts an inhomogeneous distribution of metabolic cost along an axon with either uniformly or nonuniformly distributed ion channels. The results show that the Na(+)-counting method severely underestimates energy cost in the cable model by 20-70%. AP propagation along axons that differ in length may require over 15% more energy per unit of axon area than that required by a point model. However, actual energy cost can vary greatly depending on axonal branching complexity, ion channel density distributions, and AP conduction states. We also infer that the metabolic rate (i.e. energy consumption rate) of cortical axonal branches as a function of spatial volume exhibits a 3/4 power law relationship.

  13. Motor axon excitability during Wallerian degeneration

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Alvarez, Susana; Krarup, Christian


    , action potential propagation and structural integrity of the distal segment are maintained. The aim of this study was to investigate in vivo the changes in membrane function of motor axons during the 'latent' phase of Wallerian degeneration. Multiple indices of axonal excitability of the tibial nerve...

  14. Commissural axons of the mouse cochlear nucleus. (United States)

    Brown, M Christian; Drottar, Marie; Benson, Thane E; Darrow, Keith


    The axons of commissural neurons that project from one cochlear nucleus to the other were studied after labeling with anterograde tracer. Injections were made into the dorsal subdivision of the cochlear nucleus in order to restrict labeling only to the group of commissural neurons that gave off collaterals to, or were located in, this subdivision. The number of labeled commissural axons in each injection was correlated with the number of labeled radiate multipolar neurons, suggesting radiate neurons as the predominant origin of the axons. The radiate commissural axons are thick and myelinated, and they exit the dorsal acoustic stria of the injected cochlear nucleus to cross the brainstem in the dorsal half, near the crossing position of the olivocochlear bundle. They enter the opposite cochlear nucleus via the dorsal and ventral acoustic stria and at its medial border. Reconstructions of single axons demonstrate that terminations are mostly in the core and typically within a single subdivision of the cochlear nucleus. Extents of termination range from narrow to broad along both the dorsoventral (i.e., tonotopic) and the rostrocaudal dimensions. In the electron microscope, labeled swellings form synapses that are symmetric (in that there is little postsynaptic density), a characteristic of inhibitory synapses. Our labeled axons do not appear to include excitatory commissural axons that end in edge regions of the nucleus. Radiate commissural axons could mediate the broadband inhibition observed in responses to contralateral sound, and they may balance input from the two ears with a quick time course.

  15. Immunotherapy Prospects for Painful Small-fiber Sensory Neuropathies and Ganglionopathies. (United States)

    Oaklander, Anne Louise


    The best-known peripheral neuropathies are those affecting the large, myelinated motor and sensory fibers. These have well-established immunological causes and therapies. Far less is known about the somatic and autonomic "small fibers"; the unmyelinated C-fibers, thinly myelinated A-deltas, and postganglionic sympathetics. The small fibers sense pain and itch, innervate internal organs and tissues, and modulate the inflammatory and immune responses. Symptoms of small-fiber neuropathy include chronic pain and itch, sensory impairment, edema, and skin color, temperature, and sweating changes. Small-fiber polyneuropathy (SFPN) also causes cardiovascular, gastrointestinal, and urological symptoms, the neurologic origin of which often remains unrecognized. Routine electrodiagnostic study does not detect SFPN, so skin biopsies immunolabeled to reveal axons are recommended for diagnostic confirmation. Preliminary evidence suggests that dysimmunity causes some cases of small-fiber neuropathy. Several autoimmune diseases, including Sjögren and celiac, are associated with painful small-fiber ganglionopathy and distal axonopathy, and some patients with "idiopathic" SFPN have evidence of organ-specific dysimmunity, including serological markers. Dysimmune SFPN first came into focus in children and teenagers as they lack other risk factors, for example diabetes or toxic exposures. In them, the rudimentary evidence suggests humoral rather than cellular mechanisms and complement consumption. Preliminary evidence supports efficacy of corticosteroids and immunoglobulins in carefully selected children and adult patients. This paper reviews the evidence of immune causality and the limited data regarding immunotherapy for small-fiber-predominant ganglionitis, regional neuropathy (complex regional pain syndrome), and distal SFPN. These demonstrate the need to develop case definitions and outcome metrics to improve diagnosis, enable prospective trials, and dissect the mechanisms of

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

    Directory of Open Access Journals (Sweden)

    Samira Yadegari


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

  17. Ascending Midbrain Dopaminergic Axons Require Descending GAD65 Axon Fascicles for Normal Pathfinding

    Directory of Open Access Journals (Sweden)

    Claudia Marcela Garcia-Peña


    Full Text Available The Nigrostriatal pathway (NSP is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold.

  18. Early events in axon/dendrite polarization. (United States)

    Cheng, Pei-lin; Poo, Mu-ming


    Differentiation of axons and dendrites is a critical step in neuronal development. Here we review the evidence that axon/dendrite formation during neuronal polarization depends on the intrinsic cytoplasmic asymmetry inherited by the postmitotic neuron, the exposure of the neuron to extracellular chemical factors, and the action of anisotropic mechanical forces imposed by the environment. To better delineate the functions of early signals among a myriad of cellular components that were shown to influence axon/dendrite formation, we discuss their functions by distinguishing their roles as determinants, mediators, or modulators and consider selective degradation of these components as a potential mechanism for axon/dendrite polarization. Finally, we examine whether these early events of axon/dendrite formation involve local autocatalytic activation and long-range inhibition, as postulated by Alan Turing for the morphogenesis of patterned biological structure.

  19. Dynamics of mitochondrial transport in axons

    Directory of Open Access Journals (Sweden)

    Robert Francis Niescier


    Full Text Available The polarized structure and long neurites of neurons pose a unique challenge for proper mitochondrial distribution. It is widely accepted that mitochondria move from the cell body to axon ends and vice versa; however, we have found that mitochondria originating from the axon ends moving in the retrograde direction never reach to the cell body, and only a limited number of mitochondria moving in the anterograde direction from the cell body arrive at the axon ends of mouse hippocampal neurons. Furthermore, we have derived a mathematical formula using the Fokker-Planck equation to characterize features of mitochondrial transport, and the equation could determine altered mitochondrial transport in axons overexpressing parkin. Our analysis will provide new insights into the dynamics of mitochondrial transport in axons of normal and unhealthy neurons.

  20. Rituximab Improves Subclinical Temporal Dispersion of Distal Compound Muscle Action Potential in Anti-MAG/SGPG Neuropathy Associated with Waldenström Macroglobulinemia: A Case Report

    Directory of Open Access Journals (Sweden)

    Kanji Yamamoto


    Full Text Available Patients with anti-myelin-associated glycoprotein (MAG/sulfated glucuronyl paragloboside (SGPG neuropathy associated with Waldenström macroglobulinemia show demyelinating neuropathy, but the temporal dispersion of distal compound muscle action potential (CMAP in motor nerve conduction studies (NCS, which represents heterogeneous demyelination at the motor nerve terminal, is rare. We report on a 70-year-old man with anti-MAG/SGPG neuropathy associated with Waldenström macroglobulinemia; he had a 2-year history of mild dysesthesia of the foot sole without any motor symptoms. He showed marked temporal dispersion of distal CMAP in the tibial nerve with other demyelinating findings in the NCS. The temporal dispersion of distal CMAP in the tibial nerve improved significantly, and motor function was again normal 1 year after rituximab monotherapy. The temporal dispersion of distal CMAP in anti-MAG/SGPG neuropathy is rare, but it could occur from an early stage when the patients show mild or no motor symptoms. Rituximab therapy before secondary axonal degeneration has great potential to reverse the effects of the demyelination including the temporal dispersion of distal CMAP, and to prevent the deterioration of neuropathy in anti-MAG/SGPG neuropathy.

  1. GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course. (United States)

    Pezzini, I; Geroldi, A; Capponi, S; Gulli, R; Schenone, A; Grandis, M; Doria-Lamba, L; La Piana, C; Cremonte, M; Pisciotta, C; Nolano, M; Manganelli, F; Santoro, L; Mandich, P; Bellone, E


    Mutations in the ganglioside-induced differentiation associated-protein 1 (GDAP1) gene have been associated with both autosomal recessive (AR) and dominant (AD) Charcot-Marie-Tooth (CMT) axonal neuropathy. The relative frequency of heterozygous, dominant mutations in Italian CMT is unknown. We investigated the frequency of dominant mutations in GDAP1 in a cohort of 109 axonal Italian patients by sequencing genomic DNA and search for copy number variations. We also explored correlations with clinical features. All cases had already been tested for variants in common axonal AD genes. Eight patients (7.3%) harbored five already reported heterozygous mutations in GDAP1 (p.Arg120Gly, p.Arg120Trp, p.His123Arg, p.Gln218Glu, p.Arg226Ser). Mutations had different penetrances in the families; the onset of symptoms is in the first decade and progression is slower than usually seen in GDAP1-related AR-CMT. We show that the relative frequency of mutations in GDAP was slightly higher than those observed in MFN2 and MPZ (7.3% vs 6.3% and 5.0%). The relatively milder clinical features and the quite indolent course observed are relevant for prognostic assessment. On the basis of our experience and the data reported here, we suggest GDAP1 as the first gene that should be analysed in Italian patients affected by CMT2.

  2. Progressive axonopathy: an inherited neuropathy of boxer dogs. 2. The nature and distribution of the pathological changes. (United States)

    Griffiths, I R; McCulloch, M C; Abrahams, S


    This report describes the neuropathology of progressive axonopathy (PA), an autosomal recessive inherited neuropathy of Boxer dogs, which affects CNS and PNS. The nerve roots contain numerous myelin bubbles and proximal paranodal axonal swellings containing vesicles, vesiculo-tubular profiles and disorganized neurofilaments. The myelin sheath overlying such swellings is often attenuated. As the disease develops there are progressive changes in the myelin sheath with thinning at paranodal and internodal locations, loss of myelin from lengths of axon and the formation of short internodes with disproportionately thin sheaths. The abnormalities show a very definite selectivity for nerve roots and proximal nerves. Conversely, the frequency of degeneration and regeneration is greater distally except in the cervical ventral roots which contain numerous regenerating clusters. In the CNS numerous axonal spheroids are found in the lateral and ventral columns of the spinal cord and in various brain stem nuclei, particularly the superior olives, accessory cuneate nuclei and lateral lemniscus and its nucleus. Axonal degeneration which occurs mainly in the cord shows no obvious tract or proximal/distal selectivity. The optic pathways are also involved, predominantly adjacent to the chiasma. The autonomic nervous system is affected and distal limb muscles show varying, but usually minor, degrees of neurogenic atrophy. The condition, which has no obvious direct parallel in human or veterinary medicine, shows gross disturbances of axon-glial inter-relationships in both CNS and PNS.

  3. [A case or Leber hereditary optic neuropathy (LHON): differential diagnosis with post inflammatory atrophy of nerve II using the mtDNA analysis]. (United States)

    Lubos, Leszek; Wajgt, Andrzej; Maciejowski, Maciej; Mroczek-Tońska, Katarzyna; Bartnik, Ewa; Dziekanowska, Danuta


    The Leber hereditary optic neuropathy (LHON) is a disease due to a mtDNA mutation. The disorder results from enzymatic perturbations in the mitochondrial respiratory chain. Clinically the LHON may present as a progressive axonal atrophy of the optic nerves with or without other neurological symptoms. The process of reaching the diagnosis of the LHON by means of the molecular analysis of mtDNA is discussed.

  4. Demyelinating polyneuropathy in Leber hereditary optic neuropathy.

    NARCIS (Netherlands)

    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 di

  5. Penicillamin-induced neuropathy in rheumatoid arthritis

    DEFF Research Database (Denmark)

    Pedersen, P B; Hogenhaven, H


    A case of penicillamin-induced severe polyradiculopathy in rheumatoid arthritis is presented. The neuropathy was of demyelinating type, purely motor, proximal and clinically fully reversible when the drug ceased. In case of a progressive neuropathy, during penicillamin treatment, this adverse...

  6. Disulfiram-induced neuropathy: a case report. (United States)

    Mohapatra, Satyakam; Sahoo, Manas Ranjan; Rath, Neelmadhav


    Disulfiram is widely used for aversive treatment of alcoholism. Neuropathy is one of the most severe side effects of disulfiram therapy. We report the case of a young man who developed a neuropathy following disulfiram administration, with a virtually complete recovery within 2 months.

  7. Laser-based single-axon transection for high-content axon injury and regeneration studies.

    Directory of Open Access Journals (Sweden)

    Darío Kunik

    Full Text Available The investigation of the regenerative response of the neurons to axonal injury is essential to the development of new axoprotective therapies. Here we study the retinal neuronal RGC-5 cell line after laser transection, demonstrating that the ability of these cells to initiate a regenerative response correlates with axon length and cell motility after injury. We show that low energy picosecond laser pulses can achieve transection of unlabeled single axons in vitro and precisely induce damage with micron precision. We established the conditions to achieve axon transection, and characterized RGC-5 axon regeneration and cell body response using time-lapse microscopy. We developed an algorithm to analyze cell trajectories and established correlations between cell motility after injury, axon length, and the initiation of the regeneration response. The characterization of the motile response of axotomized RGC-5 cells showed that cells that were capable of repair or regrowth of damaged axons migrated more slowly than cells that could not. Moreover, we established that RGC-5 cells with long axons could not recover their injured axons, and such cells were much more motile. The platform we describe allows highly controlled axonal damage with subcellular resolution and the performance of high-content screening in cell cultures.

  8. Novel High-Throughput Drug Screening Platform for Chemotherapy-Induced Axonal Neuropathy (United States)


    is based upon the bioluminescent measurement of ATP that is present in all metabolically active cells. Since cells need ATP to remain alive the assay...The cells are incubated for 24 hours and cytotoxicity and therapeutic effect of drugs together with taxol are evaluated by the ATP assay, which

  9. Tart Cherry Juice as a Treatment for Peripheral Neuropathy (United States)

    Carson, Cindy Alberts


    Introduction Tart cherries have a long history as a treatment for gout and joint pain. While the exact mechanism of action is unknown, it is believed that acanthocyanin pigments and related bioflavonoids found in tart cherries and other red fruits scavenge free radicals, modulate cytokines, reduce DNA degradation, decrease capillary permeability, inhibit cyclooxygenase, and strengthen biological membranes. Many of these biochemical reactions would be expected to reduce inflammation, pain, and edema. Significance of Study Peripheral polyneuropathies are common and are believed to affect up to 9% of the US population older than 50 y. These neuropathies may develop from direct compression of peripheral nerves, toxic or metabolic injury to nerve tissue, autoimmune attack, or nutritional deficiency. No cause is identified in approximately 30% of patients. The pathophysiology of polyneuropathies is complex and not fully understood, but 3 common patterns of damage occur: (1) distal axonopathy, where the cell bodies remain intact, but axons degenerate from distal to proximal, usually as the result of toxic or metabolic injury; (2) demyelination neuropathy, where damage to the myelin sheath from autoimmune, infectious, or other causes disrupts electrical signaling; and (3) ganglionopathies, where damage occurs at the cell body or neuron, a relatively rare occurrence. While weakness and loss of sensation are common in many peripheral polyneuropathies, “gain of function” symptoms, such as paresthesias and allodynia, are the most distressing and are very difficult to treat. It is believed that these symptoms are caused by alterations in ion channels, alterations in neurotransmitters and their receptors, and altered gene expression. Common conventional treatments include antiepileptics, antidepressants, NSAIDs, and narcotics. These medications alter ion channels and neurotransmitters, decrease the sensitivity of nociceptive receptors, and desensitize C fibers. Most patients

  10. Respiratory muscle weakness in peripheral neuropathies. (United States)

    Burakgazi, Ahmet Z; Höke, Ahmet


    Common peripheral neuropathies do not usually cause diaphragmatic weakness and subsequent respiratory compromise. However, respiratory involvement is relatively common in Guillain-Barré syndrome (GBS). Experience in GBS has led to a standardized approach to manage respiratory problems in peripheral neuropathies. Diaphragmatic weakness is not common in chronic inflammatory demyelinating polyneuropathy and extremely rare in multifocal motor neuropathy. The linkage has been described between certain subtypes of Charcot-Marie-Tooth (CMT) disease such as CMT2C and CMT4B1 and diaphragmatic weakness. A correlation usually has not been found between electrophysiologic findings and clinical respiratory signs or spirometric abnormalities in peripheral neuropathies except in amplitudes of evoked phrenic nerve responses. Careful and frequent assessment of respiratory function by a qualified team of healthcare professionals and physicians is essential. Criteria established for mechanical ventilation in GBS cases may be applied to other peripheral neuropathies with respiratory compromise as necessary.

  11. Phenotyping animal models of diabetic neuropathy

    DEFF Research Database (Denmark)

    Biessels, G J; Bril, V; Calcutt, N A


    NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy...... with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence....... The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current...

  12. Optimal myelin elongation relies on YAP activation by axonal growth and inhibition by Crb3/Hippo pathway (United States)

    Fernando, Ruani N.; Cotter, Laurent; Perrin-Tricaud, Claire; Berthelot, Jade; Bartolami, Sylvain; Pereira, Jorge A.; Gonzalez, Sergio; Suter, Ueli; Tricaud, Nicolas


    Fast nerve conduction relies on successive myelin segments that electrically isolate axons. Segment geometry—diameter and length—is critical for the optimization of nerve conduction and the molecular mechanisms allowing this optimized geometry are partially known. We show here that peripheral myelin elongation is dynamically regulated by stimulation of YAP (Yes-associated protein) transcription cofactor activity during axonal elongation and limited by inhibition of YAP activity via the Hippo pathway. YAP promotes myelin and non-myelin genes transcription while the polarity protein Crb3, localized at the tips of the myelin sheath, activates the Hippo pathway to temper YAP activity, therefore allowing for optimal myelin growth. Dystrophic Dy2j/2j mice mimicking human peripheral neuropathy with reduced internodal lengths have decreased nuclear YAP which, when corrected, leads to longer internodes. These data show a novel mechanism controlling myelin growth and nerve conduction, and provide a molecular ground for disease with short myelin segments. PMID:27435623

  13. Autosomal recessive hereditary auditory neuropathy

    Institute of Scientific and Technical Information of China (English)

    王秋菊; 顾瑞; 曹菊阳


    Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. Autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without

  14. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H


    Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron...... of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal...

  15. Muscular atrophy in diabetic neuropathy

    DEFF Research Database (Denmark)

    Andersen, H; Gadeberg, P C; Brock, B


    Diabetic patients with polyneuropathy develop motor dysfunction. To establish whether motor dysfunction is associated with muscular atrophy the ankle dorsal and plantar flexors of the non-dominant leg were evaluated with magnetic resonance imaging in 8 patients with symptomatic neuropathy, in 8 non...... confirmed that the atrophy predominated distally. We conclude that muscular atrophy underlies motor weakness at the ankle in diabetic patients with polyneuropathy and that the atrophy is most pronounced in distal muscles of the lower leg indicating that a length dependent neuropathic process explains...

  16. Neuronal involvement in cisplatin neuropathy

    DEFF Research Database (Denmark)

    Krarup-Hansen, A; Helweg-Larsen, Susanne Elisabeth; Schmalbruch, H;


    of large dorsal root ganglion cells. Motor conduction studies, autonomic function and warm and cold temperature sensation remained unchanged at all doses of cisplatin treatment. The results of these studies are consistent with degeneration of large sensory neurons whereas there was no evidence of distal......Although it is well known that cisplatin causes a sensory neuropathy, the primary site of involvement is not established. The clinical symptoms localized in a stocking-glove distribution may be explained by a length dependent neuronopathy or by a distal axonopathy. To study whether the whole neuron...

  17. [Treatment of multifocal motor neuropathies]. (United States)

    Azulay, J P; Pouget, J; Rihet, P; Serratrice, G


    Multifocal motor neuropathy is characterized by a progressive asymetrical weakness, predominantly affecting the upper limbs with persistent conduction blocks on motor but not sensory nerves. Treatment woth prednisone and plasma exchanges have failed to demonstrate any positive effects. Some improvements have been reported with cyclophosphamide. Mainly immunoglobulin therapy has been evaluated with a beneficial response in almost 70% of the cases. These benefits obtained over periods of less than six months have recently been confirmed by a long-term evaluation of 18 patients treated by repeated infusions.

  18. Pathogenesis of Painful Diabetic Neuropathy


    Amir Aslam; Jaipaul Singh; Satyan Rajbhandari


    The prevalence of diabetes is rising globally and, as a result, its associated complications are also rising. Painful diabetic neuropathy (PDN) is a well-known complication of diabetes and the most common cause of all neuropathic pain. About one-third of all diabetes patients suffer from PDN. It has a huge effect on a person's daily life, both physically and mentally. Despite huge advances in diabetes and neurology, the exact mechanism of pain causation in PDN is still not clear. The origin o...

  19. [Hereditary optic neuropathies: clinical and molecular genetic characteristics]. (United States)

    Khanakova, N A; Sheremet, N L; Loginova, A N; Chukhrova, A L; Poliakov, A V


    The article presents a review of literature on hereditary optic neuropathies: Leber mitochondrial hereditary optic neuropathy, autosomal dominant and autosomal recessive optic neuropathies, X-linked optic atrophy. Clinical and molecular genetic characteristics are covered. Isolated optic neuropathies, as well as hereditary optic disorders, being a part of a complex syndromic disease are described.

  20. The diagnostic and prognostic value of neurofilament heavy chain levels in immune-mediated optic neuropathies. (United States)

    Petzold, Axel; Plant, Gordon T


    Background. Loss of visual function differs between immune-mediated optic neuropathies and is related to axonal loss in the optic nerve. This study investigated the diagnostic and prognostic value of a biomarker for neurodegeneration, the neurofilament heavy chain (NfH) in three immune-mediated optic neuropathies. Methods. A prospective, longitudinal study including patients with optic neuritis due to multiple sclerosis (MSON, n = 20), chronic relapsing inflammatory optic neuritis (CRION, n = 19), neuromyelitis optica (NMO, n = 9), and healthy controls (n = 28). Serum NfH-SMI35 levels were quantified by ELISA. Findings. Serum NfH-SMI35 levels were highest in patients with NMO (mean 0.79 ± 1.51 ng/mL) compared to patients with CRION (0.13 ± 0.16 ng/mL, P = 0.007), MSON (0.09 ± 0.09, P = 0.008), and healthy controls (0.01 ± 0.02 ng/mL, P = 0.001). High serum NfH-SMI35 levels were related to poor visual outcome. Conclusions. Blood NfH-SMI35 levels are of moderate diagnostic and more important prognostic value in immune-mediated optic neuropathies. We speculate that longitudinal blood NfH levels may help to identify particular disabling events in relapsing conditions.

  1. The Diagnostic and Prognostic Value of Neurofilament Heavy Chain Levels in Immune-Mediated Optic Neuropathies

    Directory of Open Access Journals (Sweden)

    Axel Petzold


    Full Text Available Background. Loss of visual function differs between immune-mediated optic neuropathies and is related to axonal loss in the optic nerve. This study investigated the diagnostic and prognostic value of a biomarker for neurodegeneration, the neurofilament heavy chain (NfH in three immune-mediated optic neuropathies. Methods. A prospective, longitudinal study including patients with optic neuritis due to multiple sclerosis (MSON, n=20, chronic relapsing inflammatory optic neuritis (CRION, n=19, neuromyelitis optica (NMO, n=9, and healthy controls (n=28. Serum NfH-SMI35 levels were quantified by ELISA. Findings. Serum NfH-SMI35 levels were highest in patients with NMO (mean 0.79±1.51 ng/mL compared to patients with CRION (0.13±0.16 ng/mL, P=0.007, MSON (0.09±0.09, P=0.008, and healthy controls (0.01±0.02 ng/mL, P=0.001. High serum NfH-SMI35 levels were related to poor visual outcome. Conclusions. Blood NfH-SMI35 levels are of moderate diagnostic and more important prognostic value in immune-mediated optic neuropathies. We speculate that longitudinal blood NfH levels may help to identify particular disabling events in relapsing conditions.

  2. Axon initial segment Kv1 channels control axonal action potential waveform and synaptic efficacy. (United States)

    Kole, Maarten H P; Letzkus, Johannes J; Stuart, Greg J


    Action potentials are binary signals that transmit information via their rate and temporal pattern. In this context, the axon is thought of as a transmission line, devoid of a role in neuronal computation. Here, we show a highly localized role of axonal Kv1 potassium channels in shaping the action potential waveform in the axon initial segment (AIS) of layer 5 pyramidal neurons independent of the soma. Cell-attached recordings revealed a 10-fold increase in Kv1 channel density over the first 50 microm of the AIS. Inactivation of AIS and proximal axonal Kv1 channels, as occurs during slow subthreshold somatodendritic depolarizations, led to a distance-dependent broadening of axonal action potentials, as well as an increase in synaptic strength at proximal axonal terminals. Thus, Kv1 channels are strategically positioned to integrate slow subthreshold signals, providing control of the presynaptic action potential waveform and synaptic coupling in local cortical circuits.

  3. The Relationship between Dyslipidemia and Acute Axonal Function in Type 2 Diabetes Mellitus In Vivo (United States)

    Kwai, Natalie C. G.; Nigole, William; Poynten, Ann M.; Brown, Christopher; Krishnan, Arun V.


    Objectives Diabetic peripheral neuropathy (DPN) is a common and debilitating complication of diabetes mellitus. Treatment largely consists of symptom alleviation and there is a need to identify therapeutic targets for prevention and treatment of DPN. The objective of this study was to utilise novel neurophysiological techniques to investigate axonal function in patients with type 2 diabetes and to prospectively determine their relationship to serum lipids in type 2 diabetic patients. Methods Seventy-one patients with type 2 diabetes were consecutively recruited and tested. All patients underwent thorough clinical neurological assessments including nerve conduction studies, and median motor axonal excitability studies. Studies were also undertaken in age matched normal control subjects(n = 42). Biochemical studies, including serum lipid levels were obtained in all patients. Patient excitability data was compared to control data and linear regression analysis was performed to determine the relationship between serum triglycerides and low density lipoproteins and excitability parameters typically abnormal in type 2 diabetic patients. Results Patient mean age was 64.2±2.3 years, mean glycosylated haemoglobin (HbA1c%) was 7.8±0.3%, mean triglyceride concentration was 1.6±0.1 mmol/L and mean cholesterol concentration was 4.1±0.2mmol/L. Compared to age matched controls, median motor axonal excitability studies indicated axonal dysfunction in type 2 diabetic patients as a whole (T2DM) and in a subgroup of the patients without DPN (T2DM-NN). These included reduced percentage threshold change during threshold electrotonus at 10–20ms depolarising currents (TEd10–20ms)(controls 68.4±0.8, T2DM63.9±0.8, T2DM-NN64.8±1.6%,P<0.05) and superexcitability during the recovery cycle (controls-22.5±0.9, T2DM-17.5±0.8, T2DM-NN-17.3±1.6%,P<0.05). Linear regression analysis revealed no associations between changes in axonal function and either serum triglyceride or low density

  4. Autonomic neuropathy in diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Alberto eVerrotti


    Full Text Available Diabetic autonomic neuropathy (DAN is a serious and common complication of diabetes, often overlooked and misdiagnosed. It is a systemic-wide disorder that may be asymptomatic in the early stages. The most studied and clinically important form of DAN is cardiovascular autonomic neuropathy (CAN defined as the impairment of autonomic control of the cardiovascular system in patients with diabetes after exclusion of other causes. The reported prevalence of DAN varies widely depending on inconsistent definition, different diagnostic method, different patient cohorts studied. The pathogenesis is still unclear and probably multifactorial. Once DAN becomes clinically evident, no form of therapy has been identified which can effectively stop or reverse it. Prevention strategies are based on strict glycemic control with intensive insulin treatment, multifactorial intervention and lifestyle modification including control of hypertension, dyslipidemia, stop smoking, weight loss and adequate physical exercise. The present review summarizes the latest knowledge regarding clinical presentation, epidemiology, pathogenesis and management of DAN, with some mention to childhood and adolescent population.

  5. Recessively transmitted predominantly motor neuropathies. (United States)

    Parman, Yeşim; Battaloğlu, Esra


    Recessively transmitted predominantly motor neuropathies are rare and show a severe phenotype. They are frequently observed in populations with a high rate of consanguineous marriages. At least 15 genes and six loci have been found to be associated with autosomal recessive CMT (AR-CMT) and X-linked CMT (AR-CMTX) and also distal hereditary motor neuronopathy (AR-dHMN). These disorders are genetically heterogeneous but the clinical phenotype is relatively homogeneous. Distal muscle weakness and atrophy predominating in the lower extremities, diminished or absent deep tendon reflexes, distal sensory loss, and pes cavus are the main clinical features of this disorder with occasional cranial nerve involvement. Although genetic diagnosis of some of subtypes of AR-CMT are now available, rapid advances in the molecular genetics and cell biology show a great complexity. Animal models for the most common subtypes of human AR-CMT disease provide clues for understanding the pathogenesis of CMT and also help to reveal possible treatment strategies of inherited neuropathies. This chapter highlights the clinical features and the recent genetic and biological findings in these disorders based on the current classification.

  6. Vincristine-induced cranial neuropathy. (United States)

    Talebian, Ahmad; Goudarzi, Razieh Moazam; Mohammadzadeh, Mahdi; Mirzadeh, Azadeh Sadat


    Vincristine (VCR) is a vinca alkaloid that is used for treatment of many malignancies. The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms' tumor, treated by vincristine (0.067 mg/kg/day) and dactinomycin (0.045 mg/kg/day) after surgery. Three weeks after treatment, he presented with bilateral ptosis. Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis. Treatment with pyridoxine (150 mg/m2 p.o. BID) and pyridostigmine (3 mg/kg p.o. BID) was started as neuroprotective agents, and after 7 days the problem disappeared. The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later.

  7. Vincristine-Induced Cranial Neuropathy

    Directory of Open Access Journals (Sweden)

    Ahmad TALEBIAN*


    Full Text Available How to Cite This Article: Talebian A, Goudarzi RM, Mohammadzadeh M , Mirzadeh AS. Vincristine-Induced Cranial Neuropathy. Iran J Child Neurol. 2014 Winter; 8(1:66-68. AbstractVincristine (VCR is a vinca alkaloid that is used for treatment of many malignancies.The vinca alkaloids are neurotoxic, usually causing a peripheral neuropathy, but cranial neuropathies are rare as side effects. Described here is the case of a 2.5-year-old boy, a known case of Wilms’ tumor, treated by vincristine (0/067 mg/kg/day and dactinomycin (0/045 mg/kg/day after surgery. Three weeks after treatment, he presented with bilateral ptosis.Neurological examination revealed bilateral ptosis with normal pupillary reflex and eye movement. He received 3.015 mg cumulative dose of vincristine before development of ptosis.Treatment with pyridoxine (150 mg/m2 p.o. BID and pyridostigmine (3 mg/kg p.o. BID started as neuroprotective agents, and after 7 days the problem disappeared.The treatment continued for 6 weeks and there were no signs of ptosis or a recurrence in follow up 2 months later. References:Toopchizade V, Hosseini M, et al. Electrophysiological signs of neuropathy caused by vincristine. Medical Journal of Tabriz University of Medical Sciences. 2010 Autumn;31(3; 19-25.Gursel E.S. Vincristine-Induced Unilateral Ptosis in a Child. Pediatr Neurol 2009; 41:461-463.Ngamphaiboon N, Sweeney R, Wetzler M, Wang ES. Pyridoxine treatment of vincristine-induced cranial polyneuropathy in an adult patient with acute lymphocytic leukemia: Case report and review of the literature. Leuk Res. 2010 Aug;34(8:e194-6.Lash SC, Williams CP, Marsh CS, Crithchley C, Hodgkins PR, Mackie EJ. Acute Sixth-Nerve Palsy After Vincristine Therapy. Journal of AAPOS 2004 Feb;8(1: 67-8.Bay A, Yilmaz C, Yilmaz N, Oner AF. Vincristine induced cranial polyneuropathy. Indian J Pediatr. 2006 Jun;73(6:531-3.Tuxen M K, Hansen SW. Complication of treatment, Neurotoxicity secondary to antineoplastic

  8. Genetic dissection of myelinated axons in zebrafish



    In the vertebrate nervous system, the myelin sheath allows for rapid and efficient conduction of action potentials along axons. Despite the essential function of myelin, many questions remain unanswered about the mechanisms that govern the development of myelinated axons. The fundamental properties of myelin are widely shared among vertebrates, and the zebrafish has emerged as a powerful system to study myelination in vivo. This review will highlight recent advances from genetic screens in ze...

  9. Chronic dysimmune neuropathies: Beyond chronic demyelinating polyradiculoneuropathy

    Directory of Open Access Journals (Sweden)

    Khadilkar Satish


    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.

  10. Drugs for the treatment of peripheral neuropathies. (United States)

    Marmiroli, Paola; Cavaletti, Guido


    Peripheral neuropathies are frequent in association with systemic diseases as well as isolated disorders. Recent advances in the therapy of specific neuropathies led to the approval of new drugs/treatments. This review selected those peripheral neuropathies where the most recent approvals were provided and revised the potential future developments in diabetic and toxic-induced neuropathies, although they do not have a currently available causal therapy in view of their epidemiological and social relevance. Data have been extracted from the most important published trials and from clinical experience. In addition, data from the Food and Drug Administration and European Medicine Agency indications on the treatment of the selected peripheral neuropathies and from recently updated international guidelines have also been included. The website of the U.S. National Institutes of Health registry has been used as the reference database for phase III clinical trials not yet published or ongoing. This review gives a general overview of the most recent advances in the treatment of amyloid, inflammatory, and paraproteinemic peripheral neuropathies. Moreover, it briefly describes the unmet medical need in disabling and frequent conditions, such as diabetic and chemotherapy-induced neuropathy, highlighting the most promising therapeutic approaches to their treatment.

  11. [Sequential nerve conduction studies in a patient with ulnar neuropathy at the elbow treated by night athletic supporter]. (United States)

    Hasegawa, O; Matsumoto, S; Iino, M; Kirigaya, N; Wada, N; Mimura, E


    Ulnar nerve can be stretched with the elbow flexed position. To avoid elbow flexed position in patients with ulnar neuropathy at the elbow we used an athletic elbow supporter. We herein demonstrate a 31-year-old man with right ulnar neuropathy at the elbow whose neuropathy was resolved by using this supporter only at night. He had complained of weakness and paraesthesia in the ulnar side of his right hand. Nerve conduction studies of right ulnar nerve revealed decrease in the amplitude of compound nerve action potentials and a severe motor nerve conduction block with apparent conduction delay around the ulnar groove. A diagnosis of ulnar neuropathy at the elbow was done and we recommended him to wear an athletic elbow supporter at night. Paraesthesia of his right hand improved in a few days after starting this therapy. Three months later paraesthesia was resolved. One year later grip power of his right hand increased to 35 kg from 20 kg, and the conduction block at the elbow completely disappeared. Compound nerve action potentials, recorded at the segment of wrist to above elbow and wrist to finger, were improved equally. These observations suggest that the conduction block at the elbow entrapment site and the distal axonal degeneration gradually recovered together.

  12. The Neurophysiologic Frequency of Hereditary Neuropathy with Liability to Pressure Palsy in Entrapment Neuropathies

    Directory of Open Access Journals (Sweden)

    F Gökçem Yıldız


    Full Text Available Objective: Hereditary neuropathy with liability to pressure palsy (HNPP needs to be differentiated from entrapment neuropathies due to differences in the treatment management. Materials and Methods: Among 5075 patients with entrapment neuropathy, we retrospectively evaluated the neurophysiologic results of 20 patients with three or more entrapments. Results: Ten patients were diagnosed as having HNPP according to their genetic or nerve biopsy results; eight (80% had bilateral Carpal tunnel syndrome, nine (90% had bilateral ulnar entrapment neuropathy, eight (80% had bilateral median and ulnar entrapment together; and three (30% had one-sided peroneal neuropathy. Conclusion: Our data suggest that analyzing the neurophysiologic studies and keeping HNPP in mind are essential to characterize underdiagnosed patients with HNPP referred for entrapment neuropathy.

  13. In vivo gene therapy for pyridoxine-induced neuropathy by herpes simplex virus-mediated gene transfer of neurotrophin-3. (United States)

    Chattopadhyay, Munmun; Wolfe, Darren; Huang, Shaohua; Goss, James; Glorioso, Joseph C; Mata, Marina; Fink, David J


    Neurotrophic factors have been demonstrated to prevent the development of peripheral neuropathy in animal models, but the therapeutic use of these factors in human disease has been limited by the short serum half-life and dose-limiting side effects of these potent peptides. We used peripheral subcutaneous inoculation with a replication-incompetent, genomic herpes simplex virus-based vector containing the coding sequence for neurotrophin-3 to transduce sensory neurons of the rat dorsal root ganglion in vivo, and found that expression of neurotrophin-3 from the vector protected peripheral sensory axons from neuropathy induced by intoxication with pyridoxine assessed by electrophysiological (foot sensory response amplitude, and conduction velocity, and H-wave), histological (nerve morphology and morphometry), and behavioral measures of proprioceptive function. In vivo gene transfer using herpes simplex virus vectors provides a unique option for treatment of diseases of the sensory peripheral nervous system.

  14. Crossing axons in the third nerve nucleus. (United States)

    Bienfang, D C


    The research presented in this paper studied the pathway taken by the crossed fibers of the third nerve nucleus in an animal whose nucleus has been well mapped and found to correlate well with higher mammals and man. Autoradiography using tritiated amino acid labeled the cell bodies an axons of the left side of the oculomotor nucleus of the cat. Axons so labeled could be seen emerging from the ventral portion of the left nucleus through the median longitudinal fasciculus (mlf) to join the left oculomotor nerve. Labeled axons were also seen to emerge from the medial border of the caudal left nucleus, cross the midline, and pass through the right nucleus and the right mlf to join the right oculomotor nerve. These latter axons must be the crossed axons of the superior rectus and levator palpebrae subnuclei. Since the path of these crossed axons is through the caudal portion of the nucleus of the opposite side, the destruction of one lateral half of the oculomotor nucleus would result in a bilateral palsy of the crossed subnuclei. Bilateral palsy of the superior rectus and bilateral assymetrical palsy of the levator palpebrae muscles would result.

  15. Central nervous system involvement in diabetic neuropathy. (United States)

    Selvarajah, Dinesh; Wilkinson, Iain D; Davies, Jennifer; Gandhi, Rajiv; Tesfaye, Solomon


    Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes. Long considered a disease of the peripheral nervous system, there is now increasing evidence of central nervous system involvement. Recent advances in neuroimaging methods detailed in this review have led to a better understanding and refinement of how diabetic neuropathy affects the central nervous system. Recognition that diabetic neuropathy is, in part, a disease that affects the whole nervous system is resulting in a critical rethinking of this disorder, opening a new direction for further research.

  16. Compressive neuropathy in the upper limb

    Directory of Open Access Journals (Sweden)

    Mukund R Thatte


    Full Text Available Entrampment neuropathy or compression neuropathy is a fairly common problem in the upper limb. Carpal tunnel syndrome is the commonest, followed by Cubital tunnel compression or Ulnar Neuropathy at Elbow. There are rarer entities like supinator syndrome and pronator syndrome affecting the Radial and Median nerves respectively. This article seeks to review comprehensively the pathophysiology, Anatomy and treatment of these conditions in a way that is intended for the practicing Hand Surgeon as well as postgraduates in training. It is generally a rewarding exercise to treat these conditions because they generally do well after corrective surgery. Diagnostic guidelines, treatment protocols and surgical technique has been discussed.

  17. Diagnosis and new treatments in genetic neuropathies. (United States)

    Reilly, M M; Shy, M E


    The genetic neuropathies are a clinically and genetically heterogeneous group of diseases of which the most common types are Charcot-Marie-Tooth disease (CMT), the hereditary sensory and autonomic neuropathies and the distal hereditary motor neuropathies. More than 30 causative genes have been described, making an accurate genetic diagnosis increasingly possible. Although no specific therapies are yet available, research into their pathogenesis has revolutionised our understanding of the peripheral nervous system and allowed the development of rational approaches to therapy. The first therapeutic trials in CMT are currently underway. This review will suggest an approach to the diagnosis of these disorders and provide an update on new therapies.

  18. Electrodiagnostic testing in diabetic neuropathy: Which limb? (United States)

    Rota, E; Cocito, D


    Electrodiagnosis of subclinical diabetic neuropathies by nerve conduction studies remains challenging. The question arises about which nerves should be tested and what the best electrodiagnostic protocol to make an early diagnosis of diabetic neuropathies would be. On the basis of our findings and other evidence, which highlighted the remarkable prevalence of electrophysiological abnormalities in nerve conduction studies of the upper limbs, often in the presence of normal lower limb conduction parameters, we suggest that both ulnar and median nerves, in their motor and sensitive component, should be the two target nerves for electrodiagnostic protocols in diabetic neuropathies.

  19. Association of peripheral neuropathy with sleep-related breathing disorders in myotonic dystrophies (United States)

    Banach, Marta; Antczak, Jakub; Rola, Rafał


    Background Myotonic dystrophy (DM) type 1 and type 2 are inherited diseases characterized by myotonia and myopathy. Additional symptoms include, among others, peripheral neuropathy and sleep-related breathing disorders (SRBDs). There is growing evidence for a complex association between DM1 and DM2, which was described in patients with diabetes mellitus and in the general population. In this study, we investigated whether there is an association between peripheral neuropathy and SRBDs also in the population of patients with DM. Methods The study included 16 patients with DM1 (mean age, 37.9±14.1 years; 20–69 years) and eight patients with DM2 (mean age, 47.6±14.1 years; 20–65 years), who underwent a sensory and motor nerve conduction study (NCS) and diagnostic screening for SRBDs. In both groups, the NCS parameters were correlated with respiratory parameters. Results In both groups, the amplitude of the ulnar sensory nerve action potential (SNAP) correlated with the mean arterial oxygen saturation (SaO2). In addition, in the DM2 group, the median SNAP correlated with the mean SaO2. In the DM1 group, the median SNAP and the distal motor latency (DML) of the ulnar nerve correlated with the apnea–hypopnea index, while the oxygen desaturation index correlated with the DML of the tibial nerve and with conduction velocity in the sural nerve. Conclusion Our results indicate a complex association between neuropathy and SRBDs in DM1 and DM2. Axonal degeneration may contribute to nocturnal hypoxemia and vice versa. Neuropathy may contribute to muscle weakness, which in turn may cause respiratory events. PMID:28138246

  20. Genetic aspects of sodium channelopathy in small fiber neuropathy. (United States)

    Hoeijmakers, J G J; Merkies, I S J; Gerrits, M M; Waxman, S G; Faber, C G


    Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na(V)1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na(V)1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies.

  1. Genotype-phenotype correlations in Leber hereditary optic neuropathy. (United States)

    Tońska, Katarzyna; Kodroń, Agata; Bartnik, Ewa


    Leber hereditary optic neuropathy (LHON), acute or subacute vision loss due to retinal ganglion cell death which in the long run leads to optic nerve atrophy is one of the most widely studied maternally inherited diseases caused by mutations in mitochondrial DNA. Although three common mutations, 11778G>A, 14484T>C or 3460G>A are responsible for over 90% of cases and affect genes encoding complex I subunits of the respiratory chain, their influence on bioenergetic properties of the cell is marginal and cannot fully explain the pathology of the disease. The following chain of events was proposed, based on biochemical and anatomical properties of retinal ganglion cells whose axons form the optic nerve: mitochondrial DNA mutations increase reactive oxygen species production in these sensitive cells, leading to caspase-independent apoptosis. As LHON is characterized by low penetrance and sex bias (men are affected about 5 times more frequently than women) the participation of the other factors-genetic and environmental-beside mtDNA mutations was studied. Mitochondrial haplogroups and smoking are some of the factors involved in the complex etiology of this disease.

  2. Diabetic peripheral neuropathy: should a chaperone accompany our therapeutic approach? (United States)

    Farmer, Kevin L; Li, Chengyuan; Dobrowsky, Rick T


    Diabetic peripheral neuropathy (DPN) is a common complication of diabetes that is associated with axonal atrophy, demyelination, blunted regenerative potential, and loss of peripheral nerve fibers. The development and progression of DPN is due in large part to hyperglycemia but is also affected by insulin deficiency and dyslipidemia. Although numerous biochemical mechanisms contribute to DPN, increased oxidative/nitrosative stress and mitochondrial dysfunction seem intimately associated with nerve dysfunction and diminished regenerative capacity. Despite advances in understanding the etiology of DPN, few approved therapies exist for the pharmacological management of painful or insensate DPN. Therefore, identifying novel therapeutic strategies remains paramount. Because DPN does not develop with either temporal or biochemical uniformity, its therapeutic management may benefit from a multifaceted approach that inhibits pathogenic mechanisms, manages inflammation, and increases cytoprotective responses. Finally, exercise has long been recognized as a part of the therapeutic management of diabetes, and exercise can delay and/or prevent the development of painful DPN. This review presents an overview of existing therapies that target both causal and symptomatic features of DPN and discusses the role of up-regulating cytoprotective pathways via modulating molecular chaperones. Overall, it may be unrealistic to expect that a single pharmacologic entity will suffice to ameliorate the multiple symptoms of human DPN. Thus, combinatorial therapies that target causal mechanisms and enhance endogenous reparative capacity may enhance nerve function and improve regeneration in DPN if they converge to decrease oxidative stress, improve mitochondrial bioenergetics, and increase response to trophic factors.

  3. Pathogenesis of Painful Diabetic Neuropathy

    Directory of Open Access Journals (Sweden)

    Amir Aslam


    Full Text Available The prevalence of diabetes is rising globally and, as a result, its associated complications are also rising. Painful diabetic neuropathy (PDN is a well-known complication of diabetes and the most common cause of all neuropathic pain. About one-third of all diabetes patients suffer from PDN. It has a huge effect on a person’s daily life, both physically and mentally. Despite huge advances in diabetes and neurology, the exact mechanism of pain causation in PDN is still not clear. The origin of pain could be in the peripheral nerves of the central nervous system. In this review, we discuss various possible mechanisms of the pathogenesis of pain in PDN. We discuss the role of hyperglycaemia in altering the physiology of peripheral nerves. We also describe central mechanisms of pain.

  4. Linezolid-induced optic neuropathy

    Directory of Open Access Journals (Sweden)

    Divya Karuppannasamy


    Full Text Available Many systemic antimicrobials have been implicated to cause ocular adverse effects. This is especially relevant in multidrug therapy where more than one drug can cause a similar ocular adverse effect. We describe a case of progressive loss of vision associated with linezolid therapy. A 45-year-old male patient who was on treatment with multiple second-line anti-tuberculous drugs including linezolid and ethambutol for extensively drug-resistant tuberculosis (XDR-TB presented to us with painless progressive loss of vision in both eyes. Color vision was defective and fundus examination revealed optic disc edema in both eyes. Ethambutol-induced toxic optic neuropathy was suspected and tablet ethambutol was withdrawn. Deterioration of vision occurred despite withdrawal of ethambutol. Discontinuation of linezolid resulted in marked improvement of vision. Our report emphasizes the need for monitoring of visual function in patients on long-term linezolid treatment.

  5. Hereditary sensory and autonomic neuropathies. (United States)

    Auer-Grumbach, Michaela


    Hereditary sensory and autonomic neuropathies (HSN/HSAN) are clinically and genetically heterogeneous disorders of the peripheral nervous system that predominantly affect the sensory and autonomic neurons. Hallmark features comprise not only prominent sensory signs and symptoms and ulcerative mutilations but also variable autonomic and motor disturbances. Autosomal dominant and autosomal recessive inheritance has been reported. Molecular genetics studies have identified disease-causing mutations in 11 genes. Some of the affected proteins have nerve-specific roles but underlying mechanisms have also been shown to involve sphingolipid metabolism, vesicular transport, structural integrity, and transcription regulation. Genetic and functional studies have substantially improved the understanding of the pathogenesis of the HSN/HSAN and will help to find preventive and causative therapies in the future.

  6. Axon injury triggers EFA-6 mediated destabilization of axonal microtubules via TACC and doublecortin like kinase. (United States)

    Chen, Lizhen; Chuang, Marian; Koorman, Thijs; Boxem, Mike; Jin, Yishi; Chisholm, Andrew D


    Axon injury triggers a series of changes in the axonal cytoskeleton that are prerequisites for effective axon regeneration. In Caenorhabditis elegans the signaling protein Exchange Factor for ARF-6 (EFA-6) is a potent intrinsic inhibitor of axon regrowth. Here we show that axon injury triggers rapid EFA-6-dependent inhibition of axonal microtubule (MT) dynamics, concomitant with relocalization of EFA-6. EFA-6 relocalization and axon regrowth inhibition require a conserved 18-aa motif in its otherwise intrinsically disordered N-terminal domain. The EFA-6 N-terminus binds the MT-associated proteins TAC-1/Transforming-Acidic-Coiled-Coil, and ZYG-8/Doublecortin-Like-Kinase, both of which are required for regenerative growth cone formation, and which act downstream of EFA-6. After injury TAC-1 and EFA-6 transiently relocalize to sites marked by the MT minus end binding protein PTRN-1/Patronin. We propose that EFA-6 acts as a bifunctional injury-responsive regulator of axonal MT dynamics, acting at the cell cortex in the steady state and at MT minus ends after injury.

  7. Pharmacological Treatment Of Diabetic Peripheral Neuropathy



    Pain modulation is a key treatment goal for diabetic peripheral neuropathy patients. Guidelines have recommended antidepressant, anticonvulsant, analgesic, and topical medications—both approved and off-label—to reduce pain in this population.

  8. Peripheral Neuropathy in Mouse Models of Diabetes. (United States)

    Jolivalt, Corinne G; Frizzi, Katie E; Guernsey, Lucie; Marquez, Alex; Ochoa, Joseline; Rodriguez, Maria; Calcutt, Nigel A


    Peripheral neuropathy is a frequent complication of chronic diabetes that most commonly presents as a distal degenerative polyneuropathy with sensory loss. Around 20% to 30% of such patients may also experience neuropathic pain. The underlying pathogenic mechanisms are uncertain, and therapeutic options are limited. Rodent models of diabetes have been used for more than 40 years to study neuropathy and evaluate potential therapies. For much of this period, streptozotocin-diabetic rats were the model of choice. The emergence of new technologies that allow relatively cheap and routine manipulations of the mouse genome has prompted increased use of mouse models of diabetes to study neuropathy. In this article, we describe the commonly used mouse models of type 1 and type 2 diabetes, and provide protocols to phenotype the structural, functional, and behavioral indices of peripheral neuropathy, with a particular emphasis on assays pertinent to the human condition. © 2016 by John Wiley & Sons, Inc.

  9. Genetics Home Reference: small fiber neuropathy (United States)

    ... particular ethnic groups? Genetic Changes Mutations in the SCN9A or SCN10A gene can cause small fiber neuropathy . ... pieces (the alpha subunits) of sodium channels. The SCN9A gene instructs the production of the alpha subunit ...

  10. Enteric neuropathies: Yesterday, Today and Tomorrow. (United States)

    De Giorgio, Roberto; Bianco, Francesca; Latorre, Rocco; Caio, Giacomo; Clavenzani, Paolo; Bonora, Elena


    Enteric neuropathy is a term indicating an impairment of the innervation supplying the gastrointestinal tract. The clinical phenotypes of the enteric neuropathies are the 'tip of the iceberg' of severe functional digestive diseases, such as intestinal pseudo-obstruction syndromes (e.g., chronic intestinal pseudo-obstruction). Despite progress acquired over the years, the pathogenetic mechanisms leading to enteric neuropathies are still far from being elucidated and the therapeutic approaches to these patients are mainly supportive, rather than curative.The purpose of this chapter is to review the advancements that have been done in the knowledge of enteric neuropathies identified in adult patients ('tomorrow'), going through where we currently are ('today') following a brief history of the major milestones on the pioneering discoveries in the field ('yesterday').

  11. [Peripheral neuropathy caused by acute arsenic poisoning]. (United States)

    Ramírez-Campos, J; Ramos-Peek, J; Martínez-Barros, M; Zamora-Peralta, M; Martínez-Cerrato, J


    Although peripheral neuropathy is a fairly common finding in chronic arsenic poisoning, little is known about the acute effects of this metal on peripheral nerves. This report shows clinical and electrophysiological findings in a patient who developed peripheral neuropathy only three days after a high-dose ingestion of this metal due to a failed suicide attempt. We speculate that peripheral nerves and some cranial nerves can show not only clinical but also subclinical involvement that can only be detected by neurophysiological studies.

  12. Leber hereditary optic neuropathy mimicking neuromyelitis optica. (United States)

    McClelland, Collin M; Van Stavern, Gregory P; Tselis, Alex C


    Leber hereditary optic neuropathy (LHON) is rarely associated with multiple sclerosis-like features. We present a case of a 65-year-old African American woman with LHON masquerading as neuromyelitis optica (NMO). We highlight the features of the clinical examination and MRI that were suggestive of an alternative diagnosis and review the literature regarding LHON and multiple sclerosis. The diagnosis of LHON should be considered in all cases of acute or subacute bilateral optic neuropathy, including presumed seronegative NMO.

  13. Sensory neuropathy with low-dose pyridoxine. (United States)

    Parry, G J; Bredesen, D E


    We describe 16 patients with neuropathy associated with pyridoxine abuse. The clinical picture of a pure sensory central-peripheral distal axonopathy was consistent. Pyridoxine dose was 0.2 to 5 g/d, and duration of consumption before symptoms was inversely proportional to the daily intake. In all patients with adequate follow-up, improvement followed discontinuation of pyridoxine. The ready availability of up to 1-gram tablets makes it likely that this neuropathy will continue to be seen.

  14. [Pyridoxine neuropathies. Review of the literature]. (United States)

    Dordain, G; Deffond, D


    Daily needs of vitamin B6 are very low (2 mg per day) and widely covered by normal feeding. Pyridoxine deficiencies are exceptional (congenital metabolic abnormalities, drug or toxic-induced perturbations). First described in animal models, human cases of neuropathy had been encountered in the "megavitamin"-syndrome. They are confirmed by rare case-reports of very high doses given in toxic indication. Sensory peripheral neuropathies can also occur with lower doses taken over a long period of time.

  15. Blood pressure regulation in diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J


    experimental situations insufficient contraction of resistance vessels has been demonstrated. The vasoconstrictor defects demonstrated are of a magnitude sufficient to account for the prevailing hypotension. Furthermore, during exercise cardiac output is low in patients with autonomic neuropathy, a finding...... blood pressure fall ensues in patients with autonomic neuropathy, probably due to excessive muscular vasodilation. It is unresolved why blood pressure regulation is intact during hypoglycemia and severely impaired--at similar catecholamine concentrations--during epinephrine infusions....

  16. Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies. (United States)

    Lopez Sanchez, M I G; Crowston, J G; Mackey, D A; Trounce, I A


    Optic neuropathies are an important cause of blindness worldwide. The study of the most common inherited mitochondrial optic neuropathies, Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) has highlighted a fundamental role for mitochondrial function in the survival of the affected neuron-the retinal ganglion cell. A picture is now emerging that links mitochondrial dysfunction to optic nerve disease and other neurodegenerative processes. Insights gained from the peculiar susceptibility of retinal ganglion cells to mitochondrial dysfunction are likely to inform therapeutic development for glaucoma and other common neurodegenerative diseases of aging. Despite it being a fast-evolving field of research, a lack of access to human ocular tissues and limited animal models of mitochondrial disease have prevented direct retinal ganglion cell experimentation and delayed the development of efficient therapeutic strategies to prevent vision loss. Currently, there are no approved treatments for mitochondrial disease, including optic neuropathies caused by primary or secondary mitochondrial dysfunction. Recent advances in eye research have provided important insights into the molecular mechanisms that mediate pathogenesis, and new therapeutic strategies including gene correction approaches are currently being investigated. Here, we review the general principles of mitochondrial biology relevant to retinal ganglion cell function and provide an overview of the major optic neuropathies with mitochondrial involvement, LHON and ADOA, whilst highlighting the emerging link between mitochondrial dysfunction and glaucoma. The pharmacological strategies currently being trialed to improve mitochondrial dysfunction in these optic neuropathies are discussed in addition to emerging therapeutic approaches to preserve retinal ganglion cell function.

  17. How Schwann Cells Sort Axons: New Concepts. (United States)

    Feltri, M Laura; Poitelon, Yannick; Previtali, Stefano Carlo


    Peripheral nerves contain large myelinated and small unmyelinated (Remak) fibers that perform different functions. The choice to myelinate or not is dictated to Schwann cells by the axon itself, based on the amount of neuregulin I-type III exposed on its membrane. Peripheral axons are more important in determining the final myelination fate than central axons, and the implications for this difference in Schwann cells and oligodendrocytes are discussed. Interestingly, this choice is reversible during pathology, accounting for the remarkable plasticity of Schwann cells, and contributing to the regenerative potential of the peripheral nervous system. Radial sorting is the process by which Schwann cells choose larger axons to myelinate during development. This crucial morphogenetic step is a prerequisite for myelination and for differentiation of Remak fibers, and is arrested in human diseases due to mutations in genes coding for extracellular matrix and linkage molecules. In this review we will summarize progresses made in the last years by a flurry of reverse genetic experiments in mice and fish. This work revealed novel molecules that control radial sorting, and contributed unexpected ideas to our understanding of the cellular and molecular mechanisms that control radial sorting of axons.

  18. Protein phosphorylation: Localization in regenerating optic axons

    Energy Technology Data Exchange (ETDEWEB)

    Larrivee, D. (Cornell Univ. Medical College, New York, NY (USA))


    A number of axonal proteins display changes in phosphorylation during goldfish optic nerve regeneration. (1) To determine whether the phosphorylation of these proteins was closely linked to their synthesis in the retinal ganglion cell body, cycloheximide was injected intraocularly into goldfish whose optic nerves had been regenerating for 3 weeks. Cycloheximide reduced the incorporation of (3H)proline and 32P orthophosphate into total nerve protein by 84% and 46%, respectively. Of the 20 individual proteins examined, 17 contained less than 15% of the (3H)proline label measured in corresponding controls, whereas 18 proteins contained 50% or more of the 32P label, suggesting that phosphorylation was largely independent of synthesis. (2) To determine whether the proteins were phosphorylated in the ganglion cell axons, axonal transport of proteins was blocked by intraocular injection of vincristine. Vincristine reduced (3H)proline labeling of total protein by 88% and 32P labeling by 49%. Among the individual proteins (3H)proline labeling was reduced by 90% or more in 18 cases but 32P labeling was reduced only by 50% or less. (3) When 32P was injected into the cranial cavity near the ends of the optic axons, all of the phosphoproteins were labeled more intensely in the optic tract than in the optic nerve. These results suggest that most of the major phosphoproteins that undergo changes in phosphorylation in the course of regeneration are phosphorylated in the optic axons.


    Directory of Open Access Journals (Sweden)

    T. N. Varsegova


    Full Text Available Purpose – to study histomorphometric characteristics and pathogenic mechanism of peroneal nerve neuropathy in experimental lower leg lengthening by one millimeter per day in four increments. Methods. The authors performed lengthening of lower leg in 12 adult mongrel dogs at 14-15% of initial length by Ilizarov technique. 28 days after the leg distraction, 30 days after its fixation in the device and 30 days after the Ilizarov fixator dismounting the authors withdrew the animals from the experiment. Peroneal nerve portions were examined using light microscopy, histomorphometry of the full-color images of the giant epoxy semifine sections stained with methylene blue and diamond fuchsin. Results. Planimetric investigation demonstrated 15% decrease (p<0.05 in the total area of nerve fiber bundles after distraction confirming transverse contraction of intrafascicular content. Fibrosis, increased cellularity of epineurium as well as the decrease in adipocyte number and size was observed in result of distraction and fixation. Neuropathy of the peroneal nerve was observed in one of the 12 animals – more than 80% of myelinated fibers demonstrated destructive changes, the large arteries of epineurium demonstrated obliterated lumina, part of arteries had necrobiotic changes in the cellular elements of the walls. In the remaining animals the proportion of the transformed myelinated fibers in the experiment time frame amounted to 6.0±1.4%, 4.3±1.3% and 4.2±0.4% (normally: 1.9±0.3%, no marked vascular damage was observed, the number of epineural vascular modules increased up to 6.0±1.5 (contralaterally – up to 4.0±1.6, the number of endoneural microvessels was increased at 35.5%, 10.9% and 38.9% (p<0.05 in respect of intact norm (141.8±8.7 per 1 mm2. Reduced proportion of capillaries with open lumina confirmed vasomotion disorder. The changes analysis in the distribution of myelinated fibers by diameter and mean size indicates the distinct axonal

  20. Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy symptom and diabetic neuropathy examination scores

    NARCIS (Netherlands)

    Meijer, J.W.; Lefrandt, J.D.; Links, T.P.; Smit, J.A.; Stewart, R.E.; van der Hoeven, J.H.; Hoogenberg, K.


    OBJECTIVE - To evaluate the discriminative power of the Diabetic Neuropathy Symptom (DNS) and Diabetic Neuropathy Examination (DNE) scores for diagnosing diabetic polyneuropathy (PNP), as well as their relation with cardiovascular autonomic function testing (cAFT) and electro-diagnostic studies (EDS

  1. Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. (United States)

    Barneo-Muñoz, Manuela; Juárez, Paula; Civera-Tregón, Azahara; Yndriago, Laura; Pla-Martin, David; Zenker, Jennifer; Cuevas-Martín, Carmen; Estela, Anna; Sánchez-Aragó, María; Forteza-Vila, Jerónimo; Cuezva, José M; Chrast, Roman; Palau, Francesc


    Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2), axonal dominant (CMT2K) and demyelinating recessive (CMT4A) forms of Charcot-Marie-Tooth (CMT) neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE) upon mobilization of endoplasmic reticulum (ER) Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs) in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.

  2. Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy.

    Directory of Open Access Journals (Sweden)

    Manuela Barneo-Muñoz


    Full Text Available Mutations in GDAP1, which encodes protein located in the mitochondrial outer membrane, cause axonal recessive (AR-CMT2, axonal dominant (CMT2K and demyelinating recessive (CMT4A forms of Charcot-Marie-Tooth (CMT neuropathy. Loss of function recessive mutations in GDAP1 are associated with decreased mitochondrial fission activity, while dominant mutations result in impairment of mitochondrial fusion with increased production of reactive oxygen species and susceptibility to apoptotic stimuli. GDAP1 silencing in vitro reduces Ca2+ inflow through store-operated Ca2+ entry (SOCE upon mobilization of endoplasmic reticulum (ER Ca2+, likely in association with an abnormal distribution of the mitochondrial network. To investigate the functional consequences of lack of GDAP1 in vivo, we generated a Gdap1 knockout mouse. The affected animals presented abnormal motor behavior starting at the age of 3 months. Electrophysiological and biochemical studies confirmed the axonal nature of the neuropathy whereas histopathological studies over time showed progressive loss of motor neurons (MNs in the anterior horn of the spinal cord and defects in neuromuscular junctions. Analyses of cultured embryonic MNs and adult dorsal root ganglia neurons from affected animals demonstrated large and defective mitochondria, changes in the ER cisternae, reduced acetylation of cytoskeletal α-tubulin and increased autophagy vesicles. Importantly, MNs showed reduced cytosolic calcium and SOCE response. The development and characterization of the GDAP1 neuropathy mice model thus revealed that some of the pathophysiological changes present in axonal recessive form of the GDAP1-related CMT might be the consequence of changes in the mitochondrial network biology and mitochondria-endoplasmic reticulum interaction leading to abnormalities in calcium homeostasis.

  3. Automated Axon Counting in Rodent Optic Nerve Sections with AxonJ (United States)

    Zarei, Kasra; Scheetz, Todd E.; Christopher, Mark; Miller, Kathy; Hedberg-Buenz, Adam; Tandon, Anamika; Anderson, Michael G.; Fingert, John H.; Abràmoff, Michael David


    We have developed a publicly available tool, AxonJ, which quantifies the axons in optic nerve sections of rodents stained with paraphenylenediamine (PPD). In this study, we compare AxonJ’s performance to human experts on 100x and 40x images of optic nerve sections obtained from multiple strains of mice, including mice with defects relevant to glaucoma. AxonJ produced reliable axon counts with high sensitivity of 0.959 and high precision of 0.907, high repeatability of 0.95 when compared to a gold-standard of manual assessments and high correlation of 0.882 to the glaucoma damage staging of a previously published dataset. AxonJ allows analyses that are quantitative, consistent, fully-automated, parameter-free, and rapid on whole optic nerve sections at 40x. As a freely available ImageJ plugin that requires no highly specialized equipment to utilize, AxonJ represents a powerful new community resource augmenting studies of the optic nerve using mice.

  4. MR neurography in ulnar neuropathy as surrogate parameter for the presence of disseminated neuropathy.

    Directory of Open Access Journals (Sweden)

    Philipp Bäumer

    Full Text Available PURPOSE: Patients with ulnar neuropathy of unclear etiology occasionally present with lesion extension from elbow to upper arm level on MRI. This study investigated whether MRI thereby distinguishes multifocal neuropathy from focal-compressive neuropathy at the elbow. METHODS: This prospective study was approved by the institutional ethics committee and written informed consent was obtained from all participants. 122 patients with ulnar mononeuropathy of undetermined localization and etiology by clinical and electrophysiological examination were assessed by MRI at upper arm and elbow level using T2-weighted fat-saturated sequences at 3T. Twenty-one patients were identified with proximal ulnar nerve lesions and evaluated for findings suggestive of disseminated neuropathy (i subclinical lesions in other nerves, (ii unfavorable outcome after previous decompressive elbow surgery, and (iii subsequent diagnosis of inflammatory or other disseminated neuropathy. Two groups served as controls for quantitative analysis of nerve-to-muscle signal intensity ratios: 20 subjects with typical focal ulnar neuropathy at the elbow and 20 healthy subjects. RESULTS: In the group of 21 patients with proximal ulnar nerve lesion extension, T2-w ulnar nerve signal was significantly (p<0.001 higher at upper arm level than in both control groups. A cut-off value of 1.92 for maximum nerve-to-muscle signal intensity ratio was found to be sensitive (86% and specific (100% to discriminate this group. Ten patients (48% exhibited additional T2-w lesions in the median and/or radial nerve. Another ten (48% had previously undergone elbow surgery without satisfying outcome. Clinical follow-up was available in 15 (71% and revealed definitive diagnoses of multifocal neuropathy of various etiologies in four patients. In another eight, diagnoses could not yet be considered definitive but were consistent with multifocal neuropathy. CONCLUSION: Proximal ulnar nerve T2 lesions at upper

  5. Diverse modes of axon elaboration in the developing neocortex.

    Directory of Open Access Journals (Sweden)


    Full Text Available The development of axonal arbors is a critical step in the establishment of precise neural circuits, but relatively little is known about the mechanisms of axonal elaboration in the neocortex. We used in vivo two-photon time-lapse microscopy to image axons in the neocortex of green fluorescent protein-transgenic mice over the first 3 wk of postnatal development. This period spans the elaboration of thalamocortical (TC and Cajal-Retzius (CR axons and cortical synaptogenesis. Layer 1 collaterals of TC and CR axons were imaged repeatedly over time scales ranging from minutes up to days, and their growth and pruning were analyzed. The structure and dynamics of TC and CR axons differed profoundly. Branches of TC axons terminated in small, bulbous growth cones, while CR axon branch tips had large growth cones with numerous long filopodia. TC axons grew rapidly in straight paths, with frequent interstitial branch additions, while CR axons grew more slowly along tortuous paths. For both types of axon, new branches appeared at interstitial sites along the axon shaft and did not involve growth cone splitting. Pruning occurred via retraction of small axon branches (tens of microns, at both CR and TC axons or degeneration of large portions of the arbor (hundreds of microns, for TC axons only. The balance between growth and retraction favored overall growth, but only by a slight margin. Given the identical layer 1 territory upon which CR and TC axons grow, the differences in their structure and dynamics likely reflect distinct intrinsic growth programs for axons of long projection neurons versus local interneurons.

  6. Neural Progenitor Cells Promote Axonal Growth and Alter Axonal mRNA Localization in Adult Neurons (United States)

    Merianda, Tanuja T.; Jin, Ying


    Abstract The inhibitory environment of the spinal cord and the intrinsic properties of neurons prevent regeneration of axons following CNS injury. However, both ascending and descending axons of the injured spinal cord have been shown to regenerate into grafts of embryonic neural progenitor cells (NPCs). Previous studies have shown that grafts composed of glial-restricted progenitors (GRPs) and neural-restricted progenitors (NRPs) can provide a permissive microenvironment for axon growth. We have used cocultures of adult rat dorsal root ganglion (DRG) neurons together with NPCs, which have shown significant enhancement of axon growth by embryonic rat GRP and GRPs/NRPs, both in coculture conditions and when DRGs are exposed to conditioned medium from the NPC cultures. This growth-promoting effect of NPC-conditioned medium was also seen in injury-conditioned neurons. DRGs cocultured with GRPs/NRPs showed altered expression of regeneration-associated genes at transcriptional and post-transcriptional levels. We found that levels of GAP-43 mRNA increased in DRG cell bodies and axons. However, hepcidin antimicrobial peptide (HAMP) mRNA decreased in the cell bodies of DRGs cocultured with GRPs/NRPs, which is distinct from the increase in cell body HAMP mRNA levels seen in DRGs after injury conditioning. Endogenous GAP-43 and β-actin mRNAs as well as reporter RNAs carrying axonally localizing 3'UTRs of these transcripts showed significantly increased levels in distal axons in the DRGs cocultured with GRPs/NRPs. These results indicate that axon growth promoted by NPCs is associated not only with enhanced transcription of growth-associated genes but also can increase localization of some mRNAs into growing axons. PMID:28197547

  7. Genetics Home Reference: neuropathy, ataxia, and retinitis pigmentosa (United States)

    ... Me Understand Genetics Home Health Conditions NARP neuropathy, ataxia, and retinitis pigmentosa Enable Javascript to view the ... Download PDF Open All Close All Description Neuropathy, ataxia, and retinitis pigmentosa ( NARP ) is a condition that ...

  8. Pediatric sciatic neuropathies due to unusual vascular causes

    NARCIS (Netherlands)

    Srinivasan, Jayashri; Escolar, Diane; Ryan, Monique; Darras, Basil; Jones, H. Royden


    Four cases of pediatric sciatic neuropathies due to unusual vascular mechanisms are reported. Pediatric sciatic neuropathies were seen after umbilical artery catheterization, embolization of arteriovenous malformation, meningococcemia, and hypereosinophilic vasculitis. Electrophysiologic studies dem

  9. Genetics Home Reference: hereditary sensory and autonomic neuropathy type V (United States)

    ... Conditions HSAN5 hereditary sensory and autonomic neuropathy type V Enable Javascript to view the expand/collapse boxes. ... All Description Hereditary sensory and autonomic neuropathy type V ( HSAN5 ) is a condition that primarily affects the ...

  10. [The role of the immune system in hereditary demyelinating neuropathies]. (United States)

    Mäurer, M; Toyka, K V; Martini, R


    Hereditary neuropathies, e.g., Charcot-Marie-Tooth (CMT) disease, are inherited diseases of the peripheral nervous system causing chronic progressive motor and sensory dysfunction. Most neuropathies are due to mutations in myelin genes such as PMP22, P0, and the gap junction protein Cx32. Myelin mutant mice are regarded as suitable animal models for several forms of hereditary neuropathies and are important neurobiological tools for the evaluation of pathogenetic and therapeutic concepts in hereditary neuropathies. Using these animal models we could recently show that the immune system is involved in the pathogenesis of hereditary neuropathies. Due to the phenotypic similarities we also consider the immune system important for human inherited neuropathies, in particular since several case reports demonstrate a beneficial effect of immune therapies in patients with hereditary neuropathies. In this review we compare findings from animal models and human disease to elucidate the role of the immune system in hereditary neuropathies.

  11. Myelin-associated glycoprotein and its axonal receptors. (United States)

    Schnaar, Ronald L; Lopez, Pablo H H


    Myelin-associated glycoprotein (MAG) is expressed on the innermost myelin membrane wrap, directly apposed to the axon surface. Although it is not required for myelination, MAG enhances long-term axon-myelin stability, helps to structure nodes of Ranvier, and regulates the axon cytoskeleton. In addition to its role in axon-myelin stabilization, MAG inhibits axon regeneration after injury; MAG and a discrete set of other molecules on residual myelin membranes at injury sites actively signal axons to halt elongation. Both the stabilizing and the axon outgrowth inhibitory effects of MAG are mediated by complementary MAG receptors on the axon surface. Two MAG receptor families have been described, sialoglycans (specifically gangliosides GD1a and GT1b) and Nogo receptors (NgRs). Controversies remain about which receptor(s) mediates which of MAG's biological effects. Here we review the findings and challenges in associating MAG's biological effects with specific receptors.

  12. [Current issues in hereditary neuropathies]. (United States)

    Lacour, A


    This short review highlights five studies published in 2012 in the field of Charcot-Marie-Tooth disease (CMT) and transthyretin familial amyloid neuropathies (TTR-FAN). Regarding CMT, an Australian pediatric study shows the high prevalence of impaired speech perception and hearing disability in children with CMT1 or CMT2 with normal or near normal audiometry (Rance et al., 2012). In a second study, the clinical and electrophysiological characteristics of 14 patients with CMT4C due to mutations in SH3TC2 gene are described (Yger et al., 2012). The 3 clinical hallmarks of CMT4C patients in this French cohort are the high prevalence of scoliosis, the proximal motor weakness and the cranial nerves involvement. Concerning TTR-FAN, the first data from French and international registries are reported (Adams et al., 2012; Coelho et al., 2013) and a phase II trial describes the results of taurourodeoxycholic acid and doxycycline treatment (Obici et al., 2012).

  13. In vivo evaluation of a rat model for diabetic neuropathies


    Wauters, Shana


    Diabetic peripheral neuropathy is considered to be a long-term complication of Diabetes Mellitus. This neuropathy is the most common form of peripheral neuropathy in the Western world and develops in about 50% of diabetes patients affected with either type I or type II diabetes. Despite advances in understanding metabolic causes of diabetic peripheral neuropathy, specific treatments against this complications are far from being used in therapy options. In this study we have eva...

  14. Autoimmune-mediated peripheral neuropathies and autoimmune pain. (United States)

    Klein, Christopher J


    Peripheral neuropathies have diverse acquired and inherited causes. The autoimmune neuropathies represent an important category where treatment is often available. There are overlapping signs and symptoms between autoimmune neuropathies and other forms. Making a diagnosis can be challenging and first assisted by electrophysiologic and sometimes pathologic sampling, with autoimmune biomarkers providing increased assistance. Here we provide a review of the autoimmune and inflammatory neuropathies, their available biomarkers, and approaches to treatment. Also discussed is new evidence to support a mechanism of autoimmune pain.

  15. Clinical Profile of Peripheral Neuropathy in Leprosy. (United States)

    Sarker, U K; Uddin, M J; Chowdhury, R; Roy, N; Bhattacharjee, M; Roy, J


    The objectives of the study were to see the association of peripheral neuropathy in leprosy and to find out the clinical profile of peripheral neuropathy and disability status in leprosy. It was descriptive type of cross sectional study was conducted among the cases of leprosy attended in the out-patient departments of neurology, Mymensingh Medical College Hospital (MMCH) and Mymensingh tuberculosis and leprosy hospital that fulfilled the inclusion criteria were included in this study, during the study period of January 2010 to December 2011.In this study of 62 cases revealed that leprosy is more common in male (71%) people and 21% leprosy patient had contact with known case of leprosy. Leprosy causes peripheral neuropathy (61.3%). Duration of occurrence of peripheral neuropathy was prolonged (>6 month) in most of the patients (47.4%) and the disease progression was also slow (63.2%). Numbness was complained by 89.4% patients and 65.8% subjects complained of weakness of limbs. Deformities and ulcers were present in 26.3% and 50% of patients respectively. Ulnar nerve (43.6%), Lateral popliteal nerve (41.9%), Posterior tibial nerve (41.9%) and Great auricular nerve (17.7%) were the most commonly involved thickened peripheral nerves. The rate of visible physical impairment (WHO Grade 2 disability) among people affected by leprosy in feet was 27.4% and in hands was 16.1%. The position and vibration sense was found to normal all patients of peripheral neuropathy.

  16. The pathophysiology of axonal transport in alzheimer’s disease


    Vicario Orri, Elena; Opazo, Carlos; Muñoz López, Francisco José, 1964-


    Neurons communicate in the nervous system by carrying out information along the length of their axons to finally transmit it at the synapse. Proper function of axons and axon terminals relies on the transport of proteins, organelles, vesicles, and other elements from the site of synthesis in the cell body. Conversely, neurotrophins secreted from axonal targets and other components at nerve terminals need to travel toward the cell body for clearance. Molecular motors, namely kinesins and dynei...

  17. In vivo imaging of alphaherpesvirus infection reveals synchronized activity dependent on axonal sorting of viral proteins. (United States)

    Granstedt, Andrea E; Bosse, Jens B; Thiberge, Stephan Y; Enquist, Lynn W


    A clinical hallmark of human alphaherpesvirus infections is peripheral pain or itching. Pseudorabies virus (PRV), a broad host range alphaherpesvirus, causes violent pruritus in many different animals, but the mechanism is unknown. Previous in vitro studies have shown that infected, cultured peripheral nervous system (PNS) neurons exhibited aberrant electrical activity after PRV infection due to the action of viral membrane fusion proteins, yet it is unclear if such activity occurs in infected PNS ganglia in living animals and if it correlates with disease symptoms. Using two-photon microscopy, we imaged autonomic ganglia in living mice infected with PRV strains expressing GCaMP3, a genetically encoded calcium indicator, and used the changes in calcium flux to monitor the activity of many neurons simultaneously with single-cell resolution. Infection with virulent PRV caused these PNS neurons to fire synchronously and cyclically in highly correlated patterns among infected neurons. This activity persisted even when we severed the presynaptic axons, showing that infection-induced firing is independent of input from presynaptic brainstem neurons. This activity was not observed after infections with an attenuated PRV recombinant used for circuit tracing or with PRV mutants lacking either viral glycoprotein B, required for membrane fusion, or viral membrane protein Us9, required for sorting virions and viral glycoproteins into axons. We propose that the viral fusion proteins produced by virulent PRV infection induce electrical coupling in unmyelinated axons in vivo. This action would then give rise to the synchronous and cyclical activity in the ganglia and contribute to the characteristic peripheral neuropathy.

  18. Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment. (United States)

    Kanai, Kazuaki; Kuwabara, Satoshi; Arai, Kimihito; Sung, Jia-Ying; Ogawara, Kazue; Hattori, Takamichi


    Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an

  19. Long-term evaluation of Leber's hereditary optic neuropathy-like symptoms in rotenone administered rats. (United States)

    Zhang, Li; Liu, Laura; Philip, Ann L; Martinez, Juan C; Guttierez, Juan C; Marella, Mathieu; Patki, Gaurav; Matsuno-Yagi, Akemi; Yagi, Takao; Thomas, Biju B


    Leber's hereditary optic neuropathy (LHON) is an inherited disorder affecting the retinal ganglion cells (RGCs) and their axons that lead to the loss of central vision. This study is aimed at evaluating the LHON symptoms in rats administered with rotenone microspheres into the superior colliculus (SC). Optical coherence tomography (OCT) analysis showed substantial loss of retinal nerve fiber layer (RNFL) thickness in rotenone injected rats. Optokinetic testing in rotenone treated rats showed decrease in head-tracking response. Electrophysiological mapping of the SC surface demonstrated attenuation of visually evoked responses; however, no changes were observed in the ERG data. The progressive pattern of disease manifestation in rotenone administered rats demonstrated several similarities with human disease symptoms. These rats with LHON-like symptoms can serve as a model for future investigators to design and implement reliable tests to assess the beneficial effects of therapeutic interventions for LHON disease.

  20. Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. (United States)

    Dyck, Peter J; Taylor, Bruce V; Davies, Jenny L; Mauermann, Michelle L; Litchy, William J; Klein, Christopher J; Dyck, P James B


    Intravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS-weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response-based immunotherapy (R-IRx) of CIDP. Using efficacious R-IRx, a large early and late therapeutic response (≥ one-fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non-significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons).

  1. Modeling molecular mechanisms in the axon (United States)

    de Rooij, R.; Miller, K. E.; Kuhl, E.


    Axons are living systems that display highly dynamic changes in stiffness, viscosity, and internal stress. However, the mechanistic origin of these phenomenological properties remains elusive. Here we establish a computational mechanics model that interprets cellular-level characteristics as emergent properties from molecular-level events. We create an axon model of discrete microtubules, which are connected to neighboring microtubules via discrete crosslinking mechanisms that obey a set of simple rules. We explore two types of mechanisms: passive and active crosslinking. Our passive and active simulations suggest that the stiffness and viscosity of the axon increase linearly with the crosslink density, and that both are highly sensitive to the crosslink detachment and reattachment times. Our model explains how active crosslinking with dynein motors generates internal stresses and actively drives axon elongation. We anticipate that our model will allow us to probe a wide variety of molecular phenomena—both in isolation and in interaction—to explore emergent cellular-level features under physiological and pathological conditions.

  2. A Microfluidics Approach to Investigate Axon Guidance (United States)


    coat the substrate with PLL. The cells of one dissociated embryonic spinal cord was re-suspended in 3 µl of freshly-prepared Modified Frog Ringer’s...Surround repulsion of spinal sensory axons in higher vertebrate embryos . Neuron 18, 889-897 (1997). 8. Colamarino, S. & Tessier-Lavigne, M. The

  3. Axonal and dendritic changes are associated with diabetic encephalopathy in rats: an important risk factor for Alzheimer's disease. (United States)

    Zhou, Yanping; Luo, Yi; Dai, Jiapei


    Axonopathy is closely linked to and promotes diabetic peripheral neuropathy and a subset of neurological diseases including Alzheimer's disease (AD), but its involvement in the development of diabetic encephalopathy remains unknown. In the present study, we aimed to ascertain the role of axonopathy in the development of diabetic encephalopathy and the possible relationship between diabetic encephalopathy and AD. The streptozotocin (STZ)-induced diabetic rat model was used. A Y-maze task, in vivo neuronal tracing, immunohistochemistry, and western blot analysis were performed to evaluate the cognitive functions, axonal and dendritic changes, and the expressions of amyloid-β (Aβ) and hyperphosphorylated tau in relation to the development of diabetic encephalopathy in this diabetic model. Coincident with significant memory impairment, the diabetic rats showed obvious axonal and dendritic changes, termed axonopathy and dendropathy, respectively, which mainly manifested as the swelling of axons, varicosities, and dendrites in the cognitive-associated brain regions compared to the non-diabetic animals. The site-specific hyperphosphorylated tau, but not deposits of Aβ, was detected in the diabetic rat brains. These data reveal a key role of axonopathy and dendropathy accompanied with the site-specific hyperphosphorylated tau in the course of diabetic encephalopathy, which may be the early link to the neuropathological processes of AD.

  4. Mechanisms of axon degeneration: from development to disease. (United States)

    Saxena, Smita; Caroni, Pico


    Axon degeneration is an active, tightly controlled and versatile process of axon segment self-destruction. Although not involving cell death, it resembles apoptosis in its logics. It involves three distinct steps: induction of competence in specific neurons, triggering of degeneration at defined axon segments of competent neurons, and rapid fragmentation and removal of the segments. The mechanisms that initiate degeneration are specific to individual settings, but the final pathway of pruning is shared; it involves microtubule disassembly, axon swellings, axon fragmentation, and removal of the remnants by locally recruited phagocytes. The tight regulatory properties of axon degeneration distinguish it from passive loss phenomena, and confer significance to processes that involve it. Axon degeneration has prominent roles in development, upon lesions and in disease. In development, it couples the progressive specification of neurons and circuits to the removal of defined axon branches. Competence might involve transcriptional switches, and local triggering can involve axon guidance molecules and synaptic activity patterns. Lesion-induced Wallerian degeneration is inhibited in the presence of Wld(S) fusion protein in neurons; it involves early local, and later, distal degeneration. It has recently become clear that like in other settings, axon degeneration in disease is a rapid and specific process, which should not be confused with a variety of disease-related pathologies. Elucidating the specific mechanisms that initiate axon degeneration should open up new avenues to investigate principles of circuit assembly and plasticity, to uncover mechanisms of disease progression, and to identify ways of protecting synapses and axons in disease.

  5. Morphometry of Axons in Optic Nerves of Siamese's Twins

    Institute of Scientific and Technical Information of China (English)

    Xinzu Gu; Zhenping Zhang; Qi Lin; Jiongji Liang; Wenyu Lu; Xiulan Ye; A A Sadun


    Purpose: To observe the development of optic nerve, we examined four optic nerves from Siameses Twins by absolute counts of axons.Methods: Mean axon diameter, mean axon density, totally axonal population and optic nerve area were noted for each optic nerve. The mean axon diameter and the mean axon density were compared between paraxial (inner sectors)and cortical (outer sectors)areas of the nerves.Results: More myelinated axons were seen in the inner sectors as compared to the outer sectors(average 11 axons/1 000 μm2 in inner sectors and 34 axons/l 000 μm2 in outer sectors( P=0. 036) . The myelinated fibers were also smaller(63 microns) in the outer sectors as compared to the inner sectors(72 microns) ( P = 0. 001 ). The average cross sectors area for the four 40 week stage optical nerves of Siamese Twins was 3.32 × 103 as compared to 1 million axons for 32-week-old normals.Conclusion: Our finding of fewer axonal number and small myelinated fibers in the Siamese Twins suggests hypoplasia. Myelination was more abnormal in the paraxial optic nerve than that in the peripheral sectors, suggesting anomalous development of optic nerve peripherally and delayed developnent centrally. Axonal density is higher in inner sectors than that in outer sectors, suggesting delayed development of the outer nerve sector.

  6. Femoral compressive neuropathy from iliopsoas haematoma complicating dengue hemorrhagic fever

    Institute of Scientific and Technical Information of China (English)

    Sneha Ganu; Yesha Mehta


    Dengue fever is a debilitating mosquito-borne disease caused by dengue virus. We reported a case of femoral compression neuropathy due to iliopsoas hematoma complicating dengue hemorrhagic fever. Iliopsoas muscle hematoma can cause femoral neuropathy with resultant pain and paralysis. Such manifestations are not well documented in the literature. The pathogenesis of hematoma and compressive neuropathy with its appropriate management is discussed.

  7. Impairment of retrograde neuronal transport in oxaliplatin-induced neuropathy demonstrated by molecular imaging.

    Directory of Open Access Journals (Sweden)

    Dawid Schellingerhout

    Full Text Available BACKGROUND AND PURPOSE: The purpose of our study was to utilize a molecular imaging technology based on the retrograde axonal transport mechanism (neurography, to determine if oxaliplatin-induced neurotoxicity affects retrograde axonal transport in an animal model. MATERIALS AND METHODS: Mice (n = 8/group were injected with a cumulative dose of 30 mg/kg oxaliplatin (sufficient to induce neurotoxicity or dextrose control injections. Intramuscular injections of Tetanus Toxin C-fragment (TTc labeled with Alexa 790 fluorescent dye were done (15 ug/20 uL in the left calf muscles, and in vivo fluorescent imaging performed (0-60 min at baseline, and then weekly for 5 weeks, followed by 2-weekly imaging out to 9 weeks. Tissues were harvested for immunohistochemical analysis. RESULTS: With sham treatment, TTc transport causes fluorescent signal intensity over the thoracic spine to increase from 0 to 60 minutes after injection. On average, fluorescence signal increased 722%+/-117% (Mean+/-SD from 0 to 60 minutes. Oxaliplatin treated animals had comparable transport at baseline (787%+/-140%, but transport rapidly decreased through the course of the study, falling to 363%+/-88%, 269%+/-96%, 191%+/-58%, 121%+/-39%, 75%+/-21% with each successive week and stabilizing around 57% (+/-15% at 7 weeks. Statistically significant divergence occurred at approximately 3 weeks (p≤0.05, linear mixed-effects regression model. Quantitative immuno-fluorescence histology with a constant cutoff threshold showed reduced TTc in the spinal cord at 7 weeks for treated animals versus controls (5.2 Arbitrary Units +/-0.52 vs 7.1 AU +/-1.38, p0.56, T-test. CONCLUSION: We show-for the first time to our knowledge-that neurographic in vivo molecular imaging can demonstrate imaging changes in a model of oxaliplatin-induced neuropathy. Impaired retrograde neural transport is suggested to be an important part of the pathophysiology of oxaliplatin-induced neuropathy.

  8. MAPK signaling promotes axonal degeneration by speeding the turnover of the axonal maintenance factor NMNAT2 (United States)

    Walker, Lauren J; Summers, Daniel W; Sasaki, Yo; Brace, EJ; Milbrandt, Jeffrey; DiAntonio, Aaron


    Injury-induced (Wallerian) axonal degeneration is regulated via the opposing actions of pro-degenerative factors such as SARM1 and a MAPK signal and pro-survival factors, the most important of which is the NAD+ biosynthetic enzyme NMNAT2 that inhibits activation of the SARM1 pathway. Here we investigate the mechanism by which MAPK signaling facilitates axonal degeneration. We show that MAPK signaling promotes the turnover of the axonal survival factor NMNAT2 in cultured mammalian neurons as well as the Drosophila ortholog dNMNAT in motoneurons. The increased levels of NMNAT2 are required for the axonal protection caused by loss of MAPK signaling. Regulation of NMNAT2 by MAPK signaling does not require SARM1, and so cannot be downstream of SARM1. Hence, pro-degenerative MAPK signaling functions upstream of SARM1 by limiting the levels of the essential axonal survival factor NMNAT2 to promote injury-dependent SARM1 activation. These findings are consistent with a linear molecular pathway for the axonal degeneration program. DOI: PMID:28095293

  9. Relief of diabetic neuropathy with fluoxetine. (United States)

    Theesen, K A; Marsh, W R


    A 31-year-old woman with advanced diabetes mellitus with secondary autonomic and peripheral neuropathy was admitted for treatment of major depression. Previous therapy with desipramine resulted in exacerbation of the patient's orthostatic hypotension. After admission to the psychiatric facility she was initially stabilized medically and treated with psychotherapy. Subsequent treatment with low-dose fluoxetine 5 mg resulted in a decrease of the patient's diabetic neuropathy pain. Further increases in the fluoxetine dosage resulted in improvement of her depression and increased pain relief. Therapy with fluoxetine did not result in exacerbation of the orthostatic hypotension. This preliminary case report indicates that fluoxetine may be an alternative to the tricyclic antidepressants and trazodone in the treatment of diabetic peripheral neuropathy.

  10. Treatment of Diabetic Neuropathy- Principles and Methods

    Institute of Scientific and Technical Information of China (English)


    @@Diabetic neuropathy (DN) is one of the common complications of diabetes mellitus (DM), its incidence can be as high as over 90%. The lesion can involve the sensory, motor and vegetative nerves. As a whole, the lesion can be divided into symmetric multiple neuropathy and asymmetric single neuropathy. Because the pathogenesis of the disease is not clear, no specific therapy is available so far. Besides control of blood sugar level, vitamin B, vasodilators and analgesics are often used in Western medicine for expectant treatment. Basic studies on chronic complications of DM show that aldose reductase and non-enzymatic glycosylation of protein are factors initiating the pathological changes, inhibitors against them have been tested in experimental studies and proved effective. Unfortunately, they are not used clinically due to severe side effects. Screening for herbal drugs to treat DN is still a popular trend in the TCM circle.

  11. Posterior antebrachial cutaneous neuropathy. Case report. (United States)

    Chang, C W; Oh, S J


    Posterior antebrachial cutaneous (PABC) neuropathy is rare. Two original cases are reported here. In case 1, the neuropathy is probably due to a traction injury in a reduction operation for humeral fracture. In case 2, it is injured associately with an operation in taking a myocutaneous flap. On examination, both cases showed a decreased sensation to pin-prick over the PABC nerve territories and a positive Tinel's sign near the injured sites. Sensory nerve conduction study of the PABC nerves revealed a low amplitude of the compound nerve action potential (CNAP) and a slow sensory nerve conduction velocity (SNCV) in case 1, and absent CNAP in case 2. Our study showed the sensory nerve conduction test is useful in confirming PABC neuropathy.

  12. AxonQuant: A Microfluidic Chamber Culture-Coupled Algorithm That Allows High-Throughput Quantification of Axonal Damage

    Directory of Open Access Journals (Sweden)

    Yang Li


    Full Text Available Published methods for imaging and quantitatively analyzing morphological changes in neuronal axons have serious limitations because of their small sample sizes, and their time-consuming and nonobjective nature. Here we present an improved microfluidic chamber design suitable for fast and high-throughput imaging of neuronal axons. We developed the AxonQuant algorithm, which is suitable for automatic processing of axonal imaging data. This microfluidic chamber-coupled algorithm allows calculation of an ‘axonal continuity index' that quantitatively measures axonal health status in a manner independent of neuronal or axonal density. This method allows quantitative analysis of axonal morphology in an automatic and nonbiased manner. Our method will facilitate large-scale high-throughput screening for genes or therapeutic compounds for neurodegenerative diseases involving axonal damage. When combined with imaging technologies utilizing different gene markers, this method will provide new insights into the mechanistic basis for axon degeneration. Our microfluidic chamber culture-coupled AxonQuant algorithm will be widely useful for studying axonal biology and neurodegenerative disorders. © 2014 S. Karger AG, Basel

  13. [Peripheral neuropathies associated with hereditary cerebellar ataxias]. (United States)

    Anheim, M; Tranchant, C


    Inherited cerebellar ataxias constitute a complicated and heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or spinocerebellar tract, spinal cord and peripheral nerves. A peripheral neuropathy is frequently seen in inherited cerebellar ataxias although it rarely reveals the disease. Moreover, the peripheral neuropathy is helpful for the diagnostic procedure and contributes to the functional prognosis of the disease. Thus, electroneuromyography is essential in the algorithm for the diagnosis of inherited cerebellar ataxias, as well as brain MRI (looking especially for cerebellar atrophy) and the assessment of several biomarkers (alpha-foetoprotein, vitamin E, albumin, LDL cholesterol, lactic acid, phytanic acid).

  14. Peripheral neuropathy is linked to a severe form of myotonic dystrophy in transgenic mice. (United States)

    Panaite, Petrica-Adrian; Kielar, Marie; Kraftsik, Rudolf; Gourdon, Geneviève; Kuntzer, Thierry; Barakat-Walter, Ibtissam


    Myotonic dystrophy type 1 (DM1) is a multisystem disorder with a variable phenotype. The involvement of peripheral nerves in DM1 disease is controversial. The DM1 animal model DM300 transgenic mice that carry 350 to 500 CTG repeats express a mild DM1 phenotype but do not exhibit motor or sensory pathology. Here, we investigated the presence or absence of peripheral neuropathy in transgenic mice (DMSXL) that carry more than 1,300 CTG repeats and display a severe form of DM1. Electrophysiologic, histologic, and morphometric methods were used to investigate the structure and function of peripheral nerves. We observed lower compound muscle action potentials recorded from hind limb muscles and slowing of sciatic nerve conduction velocity in DMSXL versus control mice. Morphometric analyses showed an axonopathy and neuronopathy in the DMSXL mice characterized by a decrease in numbers of myelinated motor axons in sciatic nerve and in spinal cord motor neurons. Pathologic alterations in the structure of hind limb neuromuscular junctions were also detected in the DMSXL mice. These results suggest that peripheral neuropathy can be linked to a large CTG expansion and a severe form of DM1.

  15. Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age. (United States)

    Eschbach, Judith; Sinniger, Jérôme; Bouitbir, Jamal; Fergani, Anissa; Schlagowski, Anna-Isabel; Zoll, Joffrey; Geny, Bernard; René, Frédérique; Larmet, Yves; Marion, Vincent; Baloh, Robert H; Harms, Matthew B; Shy, Michael E; Messadeq, Nadia; Weydt, Patrick; Loeffler, Jean-Philippe; Ludolph, Albert C; Dupuis, Luc


    Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1. Furthermore, heterozygous Dync1h1 mutant mice display progressive mitochondrial dysfunction in muscle and mitochondria progressively increase in size and invade sarcomeres. As a likely consequence of systemic mitochondrial dysfunction, Dync1h1 mutant mice develop hyperinsulinemia and hyperglycemia and progress to glucose intolerance with age. Similar defects in mitochondrial morphology and mitofusin levels are observed in fibroblasts from patients with SMA-LED. Last, we show that Dync1h1 mutant fibroblasts show impaired perinuclear clustering of mitochondria in response to mitochondrial uncoupling. Our results show that dynein function is required for the maintenance of mitochondrial morphology and function with aging and suggest that mitochondrial dysfunction contributes to dynein-dependent neurological diseases, such as SMA-LED.

  16. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. (United States)

    Fernyhough, Paul


    Diabetic neuropathy is a dying back neurodegenerative disease of the peripheral nervous system where mitochondrial dysfunction has been implicated as an etiological factor. Diabetes (type 1 or type 2) invokes an elevation of intracellular glucose concentration simultaneously with impaired growth factor support by insulin, and this dual alteration triggers a maladaptation in metabolism of adult sensory neurons. The energy sensing pathway comprising the AMP-activated protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) signaling axis is the target of these damaging changes in nutrient levels, e.g., induction of nutrient stress, and loss of insulin-dependent growth factor support and instigates an aberrant metabolic phenotype characterized by a suppression of mitochondrial oxidative phosphorylation and shift to anaerobic glycolysis. There is discussion of how this loss of mitochondrial function and transition to overreliance on glycolysis contributes to the diminishment of collateral sprouting and axon regeneration in diabetic neuropathy in the context of the highly energy-consuming nerve growth cone.

  17. Assessment of diabetic peripheral neuropathy in streptozotocin-induced diabetic rats with magnetic resonance imaging

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Dongye; Zhang, Xiang; Lu, Liejing; Li, Haojiang; Zhang, Fang; Chen, Yueyao; Shen, Jun [Sun Yat-Sen University, Department of Radiology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong (China)


    To determine the role of magnetic resonance (MR) imaging and quantitative T2 value measurements in the assessment of diabetic peripheral neuropathy (DPN). Sequential MR imaging, T2 measurement, and quantitative sensory testing of sciatic nerves were performed in streptozotocin-induced diabetic rats (n = 6) and normal control rats (n = 6) over a 7-week follow-up period. Histological assessment was obtained from 48 diabetic rats and 48 control rats once weekly for 7 weeks (n = 6 for each group at each time point). Nerve signal abnormalities were observed, and the T2 values, mechanical withdrawal threshold (MWT), and histological changes were measured and compared between diabetic and control animals. Sciatic nerves in the diabetic rats showed a gradual increase in T2 values beginning at 2 weeks after the induction (P = 0.014), while a decrease in MWT started at 3 weeks after the induction (P = 0.001). Nerve T2 values had a similar time course to sensory functional deficit in diabetic rats. Histologically, sciatic nerves of diabetic rats demonstrated obvious endoneural oedema from 2 to 3 weeks after the induction, followed by progressive axonal degeneration, Schwann cell proliferation, and coexistent disarranged nerve regeneration. Nerve T2 measurement is potentially useful in detecting and monitoring diabetic neuropathy. (orig.)

  18. Limb girdle muscular dystrophy due to LAMA2 mutations: diagnostic difficulties due to associated peripheral neuropathy. (United States)

    Chan, Sophelia H S; Foley, A Reghan; Phadke, Rahul; Mathew, Ann Agnes; Pitt, Matthew; Sewry, Caroline; Muntoni, Francesco


    We report an eleven year old girl with early motor difficulties initially diagnosed with a peripheral neuropathy in another hospital based on abnormal electrophysiological findings. Our clinical assessment did not highlight obvious clinical features supporting a peripheral neuropathy but evidence of mild proximal weakness. Electrophysiological studies performed at our hospital revealed evidence of a sensorimotor demyelinating polyneuropathy with possible axonal involvement. Brain magnetic resonance imaging (MRI) revealed subtle white matter signal abnormalities, interpreted as nonspecific. Given the patient's proximal weakness and a mildly elevated serum creatine kinase, we performed a muscle biopsy. The muscle had mildly dystrophic features and subtly depleted laminin α2 expression. There was diffusely upregulated laminin α5 expression, and depletion of laminin α2 in intramuscular motor nerves, which made us suspect a partial laminin α2 (merosin) deficiency. Muscle MRI showed predominant posterior and medial compartments involvement. The patient was found to have autosomal recessively inherited double heterozygous LAMA2 mutations. This case illustrates the mild end of the partial merosin deficiency phenotypic spectrum, and highlights how careful assessment of laminin α2 expression in intramuscular motor nerves can be a helpful diagnostic clue in partial merosin deficiency.

  19. Molecular genetics and mechanisms of disease in distal hereditary motor neuropathies: insights directing future genetic studies. (United States)

    Drew, A P; Blair, I P; Nicholson, G A


    The distal hereditary motor neuropathies (dHMNs) are a clinically and genetically heterogeneous group of disorders that primarily affect motor neurons, without significant sensory involvement. New dHMN genes continue to be identified. There are now 11 causative genes described for dHMN, and an additional five genetic loci with unidentified genes. This genetic heterogeneity has further delineated the classification of dHMN, which was previously classified according to mode of inheritance, age at onset, and additional complicating features. Some overlap between phenotypically distinct forms of dHMN is also apparent. The mutated genes identified to-date in dHMN include HSPB1, HSPB8, HSPB3, DCTN1, GARS, PLEKHG5, BSCL2, SETX, IGHMBP2, ATP7A and TRPV4. The pathogenesis of mutations remains to be fully elucidated, however common pathogenic mechanisms are emerging. These include disruption of axonal transport, RNA processing defects, protein aggregation and inclusion body formation, disrupted calcium channel activity, and loss of neuroprotective signalling. Some of these dHMN genes are also mutated in Charcot-Marie-Tooth (CMT) disease and spinal muscular atrophy (SMA). This review examines the growing number of identified dHMN genes, discusses recent insights into the functions of these genes and possible pathogenic mechanisms, and looks at the increasing overlap between dHMN and the other neuropathies CMT2 and SMA.

  20. The aqueous layers within the myelin sheath modulate the membrane properties of simulated hereditary demyelinating neuropathies. (United States)

    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.

  1. Plasma dihydroxyphenylglycol (DHPG) as an index of diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Christensen, N J; Dejgaard, Anders; Hilsted, J


    Forearm venous plasma noradrenalin and dihydroxyphenylglycol (DHPG) concentrations were measured in eight diabetic patients with and eight diabetic patients without neuropathy. Plasma noradrenalin was on average the same in patients with and without neuropathy and correlated to serum creatinine....... Plasma DHPG concentrations were significantly reduced in patients with autonomic neuropathy as compared to patients without neuropathy (P less than 0.05). A low plasma DHPG/noradrenalin ratio in forearm venous blood identified all patients with autonomic neuropathy except one (P less than 0...


    Pasnoor, Mamatha; Dimachkie, Mazen M.; Barohn, Richard J.


    Diabetic neuropathies consist of a variety of syndromes resulting from different types of damage to peripheral or cranial nerves. Although distal symmetric polyneuropathy is most common type of diabetic neuropathy, there are many other subtypes of diabetic neuropathies which have been defined since the 1800’s. Included in these descriptions are patients with proximal diabetic, truncal, cranial, median, and ulnar neuropathies. Various theories have been proposed for the pathogenesis of these neuropathies. The treatment of most of these requires tight and stable glycemic control. Spontaneous recovery is seen in most of these conditions with diabetic control Immunotherapies have been tried in some of these conditions but are quite controversial. PMID:23642718

  3. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. (United States)

    Lewis, R A; Sumner, A J


    We compared the electrodiagnostic studies of 40 patients with chronic acquired demyelinative neuropathy and 18 patients with familial demyelinative neuropathy. Patients with acquired neuropathy had differential slowing of conduction velocity when distal latencies were compared with more proximal conduction velocities in the same nerve, when equivalent segments of different nerves were compared, and when dispersion of compound motor action potentials was examined. Conduction block was noted in some patients. Patients with familial disease had uniform conduction slowly of all nerve segments, and conduction block was not seen. Chronic acquired demyelinative neuropathy is characterized by multifocal slowing of nerve conduction, whereas familial demyelinative neuropathy is characterized by uniform conduction slowing.

  4. Motor and dorsal root ganglion axons serve as choice points for the ipsilateral turning of dI3 axons. (United States)

    Avraham, Oshri; Hadas, Yoav; Vald, Lilach; Hong, Seulgi; Song, Mi-Ryoung; Klar, Avihu


    The axons of the spinal intersegmental interneurons are projected longitudinally along various funiculi arrayed along the dorsal-ventral axis of the spinal cord. The roof plate and the floor plate have a profound role in patterning their initial axonal trajectory. However, other positional cues may guide the final architecture of interneuron tracks in the spinal cord. To gain more insight into the organization of specific axonal tracks in the spinal cord, we focused on the trajectory pattern of a genetically defined neuronal population, dI3 neurons, in the chick spinal cord. Exploitation of newly characterized enhancer elements allowed specific labeling of dI3 neurons and axons. dI3 axons are projected ipsilaterally along two longitudinal fascicules at the ventral lateral funiculus (VLF) and the dorsal funiculus (DF). dI3 axons change their trajectory plane from the transverse to the longitudinal axis at two novel checkpoints. The axons that elongate at the DF turn at the dorsal root entry zone, along the axons of the dorsal root ganglion (DRG) neurons, and the axons that elongate at the VLF turn along the axons of motor neurons. Loss and gain of function of the Lim-HD protein Isl1 demonstrate that Isl1 is not required for dI3 cell fate. However, Isl1 is sufficient to impose ipsilateral turning along the motor axons when expressed ectopically in the commissural dI1 neurons. The axonal patterning of dI3 neurons, revealed in this study, highlights the role of established axonal cues-the DRG and motor axons-as intermediate guidepost cues for dI3 axons.

  5. [Hereditary sensory and motor neuropathy and hereditary sensory and autonomic neuropathies: recent advances]. (United States)

    Stojkovic, T


    This review summarizes the recent genetic advances in hereditary sensorimotor neuropathy also called Charcot-Marie-Tooth disease. The different new genes discovered in 2010 and their underlying phenotypes will be presented.

  6. Axon Membrane Skeleton Structure is Optimized for Coordinated Sodium Propagation

    CERN Document Server

    Zhang, Yihao; Li, He; Tzingounis, Anastasios V; Lykotrafitis, George


    Axons transmit action potentials with high fidelity and minimal jitter. This unique capability is likely the result of the spatiotemporal arrangement of sodium channels along the axon. Super-resolution microscopy recently revealed that the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under entropic tension. Sodium channels also exhibit a periodic distribution pattern, as they bind to ankyrin G, which associates with spectrin. Here, we elucidate the relationship between the axon membrane skeleton structure and the function of the axon. By combining cytoskeletal dynamics and continuum diffusion modeling, we show that spectrin filaments under tension minimize the thermal fluctuations of sodium channels and prevent overlap of neighboring channel trajectories. Importantly, this axon skeletal arrangement allows for a highly reproducible band-like activation of sodium channels leading to coordinated sodium propagation along the axon.

  7. Secondary post-geniculate involvement in Leber's hereditary optic neuropathy.

    Directory of Open Access Journals (Sweden)

    Giovanni Rizzo

    Full Text Available Leber's hereditary optic neuropathy (LHON is characterized by retinal ganglion cell (RGC degeneration with the preferential involvement of those forming the papillomacular bundle. The optic nerve is considered the main pathological target for LHON. Our aim was to investigate the possible involvement of the post-geniculate visual pathway in LHON patients. We used diffusion-weighted imaging for in vivo evaluation. Mean diffusivity maps from 22 LHON visually impaired, 11 unaffected LHON mutation carriers and 22 healthy subjects were generated and compared at level of optic radiation (OR. Prefrontal and cerebellar white matter were also analyzed as internal controls. Furthermore, we studied the optic nerve and the lateral geniculate nucleus (LGN in post-mortem specimens obtained from a severe case of LHON compared to an age-matched control. Mean diffusivity values of affected patients were higher than unaffected mutation carriers (P<0.05 and healthy subjects (P<0.01 in OR and not in the other brain regions. Increased OR diffusivity was associated with both disease duration (B = 0.002; P<0.05 and lack of recovery of visual acuity (B = 0.060; P<0.01. Post-mortem investigation detected atrophy (41.9% decrease of neuron soma size in the magnocellular layers and 44.7% decrease in the parvocellular layers and, to a lesser extent, degeneration (28.5% decrease of neuron density in the magnocellular layers and 28.7% decrease in the parvocellular layers in the LHON LGN associated with extremely severe axonal loss (99% in the optic nerve. The post-geniculate involvement in LHON patients is a downstream post-synaptic secondary phenomenon, reflecting de-afferentation rather than a primary neurodegeneration due to mitochondrial dysfunction of LGN neurons.

  8. Unusual presentation of hereditary neuropathy with liability to pressure palsies

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    Andary Michael T


    Full Text Available Abstract Background Hereditary neuropathy with liability to pressure palsies (HNPP is an autosomal-dominant painless peripheral neuropathy characterized by episodes of repeated focal pressure neuropathies at sites of entrapment/compression, with a considerable variability in the clinical course. Electrodiagnostic and genetic testing are important in the diagnostic evaluation of these patients. Case presentation We report an unusual HNPP phenotype, five compression neuropathies in four nerves in a patient with bilateral hand numbness. A 42-year-old female, presented with acute bilateral paresthesias and weakness in her hands after starting yoga exercises requiring hyperextension of her hands at the wrists. Her presentation was complicated by: a a remote history of acute onset foot drop and subsequent improvement, b previous diagnoses of demyelinating peripheral neuropathy, possibly Charcot-Marie-Tooth disease, and c exposure to leprosy. Electrodiagnostic testing showed 5 separate compression neuropathies in 4 nerves including: severe left and right ulnar neuropathies at the wrist, left and right median neuropathies at the wrist and left ulnar neuropathy at the elbow. There was a mild generalized, primarily demyelinating, peripheral polyneuropathy. Based on the clinical suspicion and electrodiagnostic findings, consistent with profound demyelination in areas of compression, genetic analysis was done which identified a deletion of the PMP-22 gene consistent with HNPP. Conclusion HNPP can present with unusual phenotypes, such as 5 separate mononeuropathies, bilateral ulnar and median neuropathies at the wrists and ulnar neuropathy at the elbow with mild peripheral demyelinating polyneuropathy associated with the PMP-22 gene deletion.

  9. Chemotherapy induced peripheral neuropathy: the modified total neuropathy score in clinical practice.


    Vasquez, S.; Guidon, Marie; McHugh, E; Lennon, Olive; Grogan, L.; Breathnach, O S


    BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, potentially reversible side effect of some chemotherapeutic agents. CIPN is associated with decreased balance, function and quality of life (QoL). This association has to date been under-investigated. AIMS: To profile patients presenting with CIPN using the modified Total Neuropathy Score (mTNS) in this cross-sectional study and to examine the relationship between CIPN (measured by mTNS) and indices of balance, qual...

  10. Experimental Alcohol-Related Peripheral Neuropathy: Role of Insulin/IGF Resistance

    Directory of Open Access Journals (Sweden)

    James Gilchrist


    Full Text Available The mechanisms of alcohol-related peripheral neuropathy (ALPN are poorly understood. We hypothesize that, like alcohol-related liver and brain degeneration, ALPN may be mediated by combined effects of insulin/IGF resistance and oxidative stress. Adult male Long Evans rats were chronically pair-fed with diets containing 0% or 37% ethanol (caloric, and subjected to nerve conduction studies. Chronic ethanol feeding slowed nerve conduction in the tibial (p = 0.0021 motor nerve, and not plantar sensory nerve, but it did not affect amplitude. Histological studies of the sciatic nerve revealed reduced nerve fiber diameters with increased regenerative sprouts, and denervation myopathy in ethanol-fed rats. qRT-PCR analysis demonstrated reduced mRNA levels of insulin, IGF-1, and IGF-2 polypeptides, IGF-1 receptor, and IRS2, and ELISAs revealed reduced immunoreactivity for insulin and IGF-1 receptors, IRS-1, IRS-4, myelin-associated glycoprotein, and tau in sciatic nerves of ethanol-fed rats (all p < 0.05 or better. The findings suggest that ALPN is characterized by (1 slowed conduction velocity with demyelination, and a small component of axonal degeneration; (2 impaired trophic factor signaling due to insulin and IGF resistance; and (3 degeneration of myelin and axonal cytoskeletal proteins. Therefore, ALPN is likely mediated by molecular and signal transduction abnormalities similar to those identified in alcoholic liver and brain degeneration.

  11. International Neuropathy Workshop of 2009: introduction to the final reports. (United States)

    Boulton, Andrew J M; Valensi, Paul; Tesfaye, Solomon


    Neuropathies are amongst the most common of the long-term complications of diabetes, affecting up to 50% of patients. Their clinical features vary immensely and patients may present with a wide spectrum of specialties, from neurology to urology, for example, or from cardiology to podiatry. Neuropathies are typically characterized by a progressive loss of nerve fibres which may affect both of the principal divisions of the peripheral nervous system. The epidemiology and natural history of the diabetic neuropathies remain poorly defined. The International Consensus Workshop in Toronto in 2009 arose from the fact that at the moment there are no clear, universally accepted guidelines regarding the definition of diabetic neuropathies. This has resulted in a massive variation in how neuropathy is diagnosed in different centres and countries. A preliminary summary report of the Toronto meeting was published in 2010. The series of papers published in this issue of Diabetes/Metabolism Research and Reviews are the detailed reports that came from each sub-group of this Consensus panel. These reviews cover the problems with definitions and classification of neuropathy, the management of painful neuropathy and then the sub-group of small fibre neuropathies. There are also 3 papers on the autonomic neuropathies, covering cardiovascular autonomic neuropathies, as well as other areas of the autonomic neuropathies including gastrointestinal, urogenital and pseudomotor neuropathies. This series of papers will give the reader detailed information on the diverse aspects of diabetic neuropathies, their measurement and management, and will also assist in the selection of appropriate measures of both autonomic and somatic nerve function in clinical trials. This is clearly work in progress as diagnostic criteria for diabetic neuropathies are likely to evolve with developments in the field.

  12. Schwann cells-axon interaction in myelination. (United States)

    Taveggia, Carla


    The remarkable interaction between glial cells and axons is crucial for nervous system development and homeostasis. Alterations in this continuous communication can cause severe pathologies that can compromise the integrity of the nervous system. The most dramatic consequence of this interaction is the generation of the myelin sheath, made by myelinating glial cells: Schwann cells in the peripheral nervous system and oligodendrocytes in the central nervous system. In this review I will focus on signals coming from axons in the first part and then on those from Schwann cells that promote the formation and the maintenance of peripheral myelin. I will discuss their inter-relationship together with seminal and important advances recently made.

  13. Decrease in neuroimmune activation by HSV-mediated gene transfer of TNFα soluble receptor alleviates pain in rats with diabetic neuropathy. (United States)

    Ortmann, Kathryn L Maier; Chattopadhyay, Munmun


    The mechanisms of diabetic painful neuropathy are complicated and comprise of peripheral and central pathophysiological phenomena. A number of proinflammatory cytokines are involved in this process. Tumor necrosis factor α (TNF-α) is considered to be one of the major contributors of neuropathic pain. In order to explore the potential role of inflammation in the peripheral nervous system of Type 1 diabetic animals with painful neuropathy, we investigated whether TNF-α is a key inflammatory mediator to the diabetic neuropathic pain and whether continuous delivery of TNFα soluble receptor from damaged axons achieved by HSV vector mediated transduction of DRG would block or alter the pain perception in animals with diabetic neuropathy. Diabetic animals exhibited changes in threshold of mechanical and thermal pain perception compared to control rats and also demonstrated increases in TNFα in the DRG, spinal cord dorsal horn, sciatic nerve and in the foot skin, 6 weeks after the onset of diabetes. Therapeutic approaches by HSV mediated expression of p55 TNF soluble receptor significantly attenuated the diabetes-induced hyperalgesia and decreased the expression of TNFα with reduction in the phosphorylation of p38MAPK in the spinal cord dorsal horn and DRG. The overall outcome of this study suggests that neuroinflammatory activation in the peripheral nervous system may be involved in the pathogenesis of painful neuropathy in Type 1 diabetes which can be alleviated by local expression of HSV vector expressing p55 TNF soluble receptor.

  14. Trigeminal Neuropathy in Sjogren′s Syndrome

    Directory of Open Access Journals (Sweden)

    Pinheiro L


    Full Text Available Trigeminal neuropathy is the most common CNS disorder in Sjogren′s syndrome. It is believed to be caused by vasculitis. Unless this is recognised, a diagnosis of trigeminal neuralgia is often made. The therapeutic response to steroids is unpredictable. There are two subgroups - those with associated collagen disorders and those only with the sicca syndrome.

  15. Autonomic neuropathy and diabetic foot ulceration. (United States)

    Edmonds, M E; Nicolaides, K H; Watkins, P J


    Autonomic function was studied in three groups of insulin-dependent diabetic patients. Heart rate changes during deep breathing and on standing were significantly less in 28 patients with a recent history of foot ulceration compared with 40 patients with peripheral neuropathy but without ulceration (p less than 0.001) and 54 patients without neuropathy (p less than 0.001). Sympathetic function was assessed in 36 of these patients from peripheral arterial diastolic flow patterns obtained by Doppler ultrasound measurements and expressed as the pulsatility index (PI). Patients with a history of ulceration (n = 10) showed considerably increased diastolic flow (PI = 4.28 +/- 0.53, mean +/- S.E.M.) compared with 12 neuropathic patients with no history of ulceration (PI = 7.80 +/- 0.68, p less than 0.002) and 14 patients without neuropathy (PI = 9.55 +/- 0.89, p less than 0.002). Severely abnormal autonomic function occurs in association with neuropathic foot ulceration, but patients without ulcers have lesser degrees of autonomic neuropathy, thus a causal relationship has not been established.

  16. Recurrent peroneal neuropathy in adolescent: clinical case

    Directory of Open Access Journals (Sweden)

    V. A. Bulanova


    Full Text Available The clinical case of hereditary neuropathy with liability to pressure palsies (HNPP confirmed the results of DNA diagnostics is described. Clinical and electrophysiological features of the course of HNPP in adolescent is analyzed. Many various illnesses require exclusion in case of the foot extensor paresis.

  17. Recurrent peroneal neuropathy in adolescent: clinical case


    V. A. Bulanova; D. S. Druzhinin


    The clinical case of hereditary neuropathy with liability to pressure palsies (HNPP) confirmed the results of DNA diagnostics is described. Clinical and electrophysiological features of the course of HNPP in adolescent is analyzed. Many various illnesses require exclusion in case of the foot extensor paresis.

  18. [Sudden blindness: consider Leber's hereditary optic neuropathy

    NARCIS (Netherlands)

    Schieving, J.H.; Vries, L.B.A. de; Hol, F.A.; Stroink, H.


    In 3 young male patients, aged 10, 19 and 21 years respectively, sequential, severe, painless bilateral visual loss occurred. Ophthalmological examination revealed no other abnormalities and this delayed the diagnosis Leber's hereditary optic neuropathy (LHON). LHON is a mitochondrial genetic diseas

  19. Glycoconjugates as target antigens in peripheral neuropathies

    Directory of Open Access Journals (Sweden)

    Ljubica Suturkova


    Full Text Available Identification and characterization of antigens present at the human peripheral nerve is a great challenge in the field of neuroimmunology. The latest investigations are focused on the understanding of the biology of glycoconjugates present at the peripheral nerve, and their immunological reactivity. Increased titers of antibodies that recognize carbohydrate determinants of glycoconjugates (glycolipids and glycoproteins are associated with distinct neuropathic syndromes. There is considerable cross-reactivity among anti-ganglioside antibodies, resulting from shared oligosaccharide epitopes, possibly explaining the overlap in syndromes observed in many affected patients. Sera from patients with neuropathies (GBS, chronic inflammatory demielynating polyneuropathy - CIDP, multifocal motor neuropathy - MMN, cross-react with glycoproteins isolated from human peripheral nerve and from Campylobacter jejuni O:19. The frequency of occurrence of antibodies against these glycoproteins is different, depending of the type of neuropathy. Identification of the cross-reactive glycoproteins and possible additional auto antigens could be useful in laboratory evaluation of peripheral neuropathies and help to develop a more effective therapeutic approach.

  20. Suboccipital neuropathy after bone conduction device placement

    NARCIS (Netherlands)

    Faber, H.T.; Ru, J.A. de


    OBJECTIVE: To describe the clinical characteristics of a 70-year-old female with occipital neuropathy following bone conduction device surgery. DESCRIPTION: A 65-year-old woman underwent bone conduction device placement surgery on the left temporal bone. Postoperatively she progressively developed c


    Directory of Open Access Journals (Sweden)

    Mohd. Muneer Ahamed


    Full Text Available Diabetes is a major public health problem. Diabetes mellitus now affects large number of people in many developing countries than western countries where only two or three percent of the population is affected. With on estimated 33 million people in India alone affected by diabetes. It is a major epidemic of the twentieth century. Diabetes is a chronic disorder, which is associated with obesity, hypertension, advancing age, accumulation of harmful agents in the vascular endothelium causing development of microangiopathies or micro vascular complications. These complications include peripheral neuropathy, nephropathy and retinopathy, which cause early death and increased morbidity. These complications vary in prevalence in different populations depending on various factors such as genetic predisposition and ethnicity. Besides these complications cardiovascular changes are also occurring. Peripheral neuropathy (PN is characterized by pain, numbness, and tingling in the extremities with slow nerve conduction. Up to 50% of all patients with diabetes develop neuropathy and the prevalence of painful neuropathy ranges from 10 to 20% of patients with diabetes. Diabetic nephropathy is characterized by increased urinary protein, loss of renal function, excessive deposition of extracellular matrix proteins in the mesangium, and clear cytoplasm of the proximal tubular epithelial cells due to excessive reabsorbed glycogen. Evaluation of diabetes and its complications is very essential for proper control and prevention of the disease associated complications.

  2. An update on electrophysiological studies in neuropathy

    DEFF Research Database (Denmark)

    Krarup, Christian


    The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic...

  3. Idiopathic trigeminal neuropathy in a poodle

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Aparicio


    Full Text Available A seven years old, male poodle is examined presenting acute mandible paralysis (dropped jaw, drooling and difficulty for the apprehension and chewing; not evidence of an other alteration of cranial nerves. The muscular biopsy rules out a myositisof masticatory muscles. The disorder is resolved completely in 3 weeks confirming diagnosis of idiopathic trigeminal neuropathy.

  4. Multifunctional Silk Nerve Guides for Axon Outgrowth (United States)

    Tupaj, Marie C.

    Peripheral nerve regeneration is a critical issue as 2.8% of trauma patients present with this type of injury, estimating a total of 200,000 nerve repair procedures yearly in the United States. While the peripheral nervous system exhibits slow regeneration, at a rate of 0.5 mm -- 9 mm/day following trauma, this regenerative ability is only possible under certain conditions. Clinical repairs have changed slightly in the last 30 years and standard methods of treatment include suturing damaged nerve ends, allografting, and autografting, with the autograft the gold standard of these approaches. Unfortunately, the use of autografts requires a second surgery and there is a shortage of nerves available for grafting. Allografts are a second option however allografts have lower success rates and are accompanied by the need of immunosuppressant drugs. Recently there has been a focus on developing nerve guides as an "off the shelf" approach. Although some natural and synthetic guidance channels have been approved by the FDA, these nerve guides are unfunctionalized and repair only short gaps, less than 3 cm in length. The goal of this project was to identify strategies for functionalizing peripheral nerve conduits for the outgrowth of neuron axons in vitro . To accomplish this, two strategies (bioelectrical and biophysical) were indentified for increasing axon outgrowth and promoting axon guidance. Bioelectrical strategies exploited electrical stimulation for increasing neurite outgrowth. Biophysical strategies tested a range of surface topographies for axon guidance. Novel methods were developed for integrating electrical and biophysical strategies into silk films in 2D. Finally, a functionalized nerve conduit system was developed that integrated all strategies for the purpose of attaching, elongating, and guiding nervous tissue in vitro. Future directions of this work include silk conduit translation into a rat sciatic nerve model in vivo for the purpose of repairing long

  5. Interspecies variation in axon-myelin relationships. (United States)

    Fraher, J P; O'Sullivan, A W


    The primary objective of this paper was to determine the extent and nature of interspecies differences in axon calibre and myelin sheath thickness and in the various relationships between these. Morphometric analysis of the axon perimeter-myelin sheath thickness relationship was performed on an equivalent nerve fibre population in a mammal, the rat, a bird, the chicken, an amphibian, the frog, a bony fish, the trout, and a cartilaginous fish, the dogfish. The abducent nerve was studied. It is especially suitable for this purpose because its fibres are closely similar in type and in peripheral distribution across the species studied. The relationship differed substantially between species. Differences were present in its setting, as described by the positions of the scatterplots, in the g ratio and in the regression and correlation data relating the parameters. Both parameters were markedly larger in the fish species than in all of the others. In addition, in rat, chicken, frog and trout, where large and small fibre classes could be differentiated clearly, the setting of the relationship between the two parameters was different for the two classes. In the main, variation in each of the parameters was greater between than within species. The larger fibres in the fish species were closely similar in axon perimeter and sheath thickness despite their long evolutionary separation. From this study and from others in the series, it may be concluded that there is no fixed or constant relationship between axon calibre and the thickness of the surrounding myelin sheath. Each nerve tends to have its own particular relationship and this differs between species.

  6. DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma. (United States)

    Kim, K-Y; Perkins, G A; Shim, M S; Bushong, E; Alcasid, N; Ju, S; Ellisman, M H; Weinreb, R N; Ju, W-K


    Glaucoma is the leading cause of irreversible blindness and is characterized by slow and progressive degeneration of the optic nerve head axons and retinal ganglion cell (RGC), leading to loss of visual function. Although oxidative stress and/or alteration of mitochondrial (mt) dynamics induced by elevated intraocular pressure (IOP) are associated with this neurodegenerative disease, the mechanisms that regulate mt dysfunction-mediated glaucomatous neurodegeneration are poorly understood. Using a mouse model of glaucoma, DBA/2J (D2), which spontaneously develops elevated IOP, as well as an in vitro RGC culture system, we show here that oxidative stress, as evidenced by increasing superoxide dismutase 2 (SOD2) and mt transcription factor A (Tfam) protein expression, triggers mt fission and loss by increasing dynamin-related protein 1 (DRP1) in the retina of glaucomatous D2 mice as well as in cultured RGCs exposed to elevated hydrostatic pressure in vitro. DRP1 inhibition by overexpressing DRP1 K38A mutant blocks mt fission and triggers a subsequent reduction of oxidative stress, as evidenced by decreasing SOD2 and Tfam protein expression. DRP1 inhibition promotes RGC survival by increasing phosphorylation of Bad at serine 112 in the retina and preserves RGC axons by maintaining mt integrity in the glial lamina of glaucomatous D2 mice. These findings demonstrate an important vicious cycle involved in glaucomatous neurodegeneration that starts with elevated IOP producing oxidative stress; the oxidative stress then leads to mt fission and a specific form of mt dysfunction that generates further oxidative stress, thus perpetuating the cycle. Our findings suggest that DRP1 is a potential therapeutic target for ameliorating oxidative stress-mediated mt fission and dysfunction in RGC and its axons during glaucomatous neurodegeneration. Thus, DRP1 inhibition may provide a new therapeutic strategy for protecting both RGCs and their axons in glaucoma and other optic

  7. Retinoic acid signaling in axonal regeneration

    Directory of Open Access Journals (Sweden)

    Radhika ePuttagunta


    Full Text Available Following an acute central nervous system injury, axonal regeneration and functional recovery are extremely limited. This is due to an extrinsic inhibitory growth environment and the lack of intrinsic growth competence. Retinoic acid (RA signaling, essential in developmental dorsoventral patterning and specification of spinal motor neurons, has been shown through its receptor, the transcription factor RA receptor β2 (RARß2, to induce axonal regeneration following spinal cord injury (SCI. Recently, it has been shown that in dorsal root ganglia neurons, cAMP levels were greatly increased by lentiviral RARβ2 expression and contributed to neurite outgrowth. Moreover, RARβ agonists, in cerebellar granule neurons and in the brain in vivo, induced phosphoinositide 3-kinase dependent phosphorylation of AKT that was involved in RARβ-dependent neurite outgrowth. More recently, RA-RARß pathways were shown to directly transcriptionally repress a member of the inhibitory Nogo receptor complex, Lingo-1, under an axonal growth inhibitory environment in vitro as well as following spinal injury in vivo. This perspective focuses on these newly discovered molecular mechanisms and future directions in the field.

  8. Synaptic Democracy and Vesicular Transport in Axons (United States)

    Bressloff, Paul C.; Levien, Ethan


    Synaptic democracy concerns the general problem of how regions of an axon or dendrite far from the cell body (soma) of a neuron can play an effective role in neuronal function. For example, stimulated synapses far from the soma are unlikely to influence the firing of a neuron unless some sort of active dendritic processing occurs. Analogously, the motor-driven transport of newly synthesized proteins from the soma to presynaptic targets along the axon tends to favor the delivery of resources to proximal synapses. Both of these phenomena reflect fundamental limitations of transport processes based on a localized source. In this Letter, we show that a more democratic distribution of proteins along an axon can be achieved by making the transport process less efficient. This involves two components: bidirectional or "stop-and-go" motor transport (which can be modeled in terms of advection-diffusion), and reversible interactions between motor-cargo complexes and synaptic targets. Both of these features have recently been observed experimentally. Our model suggests that, just as in human societies, there needs to be a balance between "efficiency" and "equality".

  9. MRI of the diffuse axonal injury

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    Joo, Yang Gu; Woo, Young Hoon; Suh, Soo Jhi [Keimyung University School of Medicine, Daegu (Korea, Republic of)


    CT has facilitated early recognition and treatment of focal brain injuries in patients with head trauma. However, CT shows relatively low sensitivity in identifying non hemorrhage contusion and injuries of white matter. MR is known to be superior to CT in detection of white matter injuries, such as diffuse axonal injury. MR imaging in 14 cases of diffuse axonal injury on 2.0T was studied. The corpus callosum, especially the body portion, was the most commonly involved site. The lesions ranged from 5 to 20mm in size with ovoid to elliptical shape. T2WI was the most sensitive pulse sequence in detecting lesions such as white matter degeneration, hemorrhagic and non hemorrhagic contusion. The lesions were nonspecific as high and low signal intensities on T2WI and T1WI respectively. CT showed white matter abnormality in only 1 case of 14 cases. We propose MR imaging as the primary imaging procedure for the detection of diffuse axonal injury because of its multiplanar capabilities and higher sensitivity.

  10. Where does slow axonal transport go? (United States)

    Terada, Sumio


    Axonal transport is the specialized and well-developed intracellular transport system for regulated and/or long-distance transport based on generalized cellular machineries. Among them, slow axonal transport conveys cytoplasmic proteins. The motor molecule, the nature of transporting complex and the transport regulation mechanism for slow transport are still unclarified. There has been a dispute regarding the nature of transporting complex of cytoskeletal proteins, polymer-sliding hypothesis versus subunit-transport theory. Recent data supporting the hypothesis of polymer sliding in cultured neurons only reconfirm the previously reported structure and this inference suffers from the lack of ultrastructural evidence and the direct relevance to the physiological slow transport phenomenon in vivo. Observation of the moving cytoskeletal proteins in vivo using transgenic mice or squid giant axons revealed that subunits do move in a microtubule-dependent manner, strongly indicating the involvement of microtubule-based motor kinesin. If the slow transport rate reflects the intermittent fast transport dependent on kinesin motor, we have to investigate the molecular constituents of the transporting complex in more detail and evaluate why the motor and cargo interaction is so unstable. This kind of weak and fluctuating interaction between various molecular pairs could not be detected by conventional techniques, thus necessitating the establishment of a new experimental system before approaching the molecular regulation problem.

  11. Shh goes multidirectional in axon guidance

    Institute of Scientific and Technical Information of China (English)

    Paola Bovolenta; Luisa Sanchez-Arrones


    Shh and Wnts,secreted by the floor and roof plate of the spinal cord,direct longitudinal growth of the axons from the adjacent ventral funiculus and cortico-spinal tract.Whether these midline cues influencethe directionality of axons elongating in more lateral positions of the spinal cord is unexplored.Song and colleagues investigate this possibility and demonstrate that the location of descending raphe-spinal tract in the ventrolateral spinal cord is dictated by the simultaneous repellent activity of Shh gradients in both the anteriorto-posterior (A-P) and medial-tolateral (M-L) axis. The spinal cord is the main pathway for exchange of information between the brain and the rest of the body.Sensory information collected in the body periphery is conveyed to the brain by axonal tracts that ascend along the spinal cord whereas motor information travels from the brain to the periphery in descending tracts.Precise spatial organization of these fiber tracts is thus essential for animal behavior and survival.

  12. Axon-glial relations during regeneration of axons in the adult rat anterior medullary velum. (United States)

    Berry, M; Hunter, A S; Duncan, A; Lordan, J; Kirvell, S; Tsang, W L; Butt, A M


    The anterior medullary velum (AMV) of adult Wistar rats was lesioned in the midsagittal plane, transecting all decussating axons including those of the central projection of the IVth nerve. At selected times up to 200 days after transection, the degenerative and regenerative responses of axons and glia were analyzed using transmission and scanning electron microscopy and immunohistochemistry. In particular, both the capacity of oligodendrocytes to remyelinate regenerated fibers and the stability of the CNS/PNS junctional zone of the IVth nerve rootlet were documented. Transected central AMV axons exhibited four patterns of fiber regeneration in which fibers grew: rostrocaudally in the reactive paralesion neuropil (Group 1); randomly within the AMV (Group 2); into the ipsilateral IVth nerve rootlet, after turning at the lesion edge and growing recurrently through the old degenerated contralateral central trochlear nerve trajectory (Group 3); and ectopically through paralesion tears in the ependyma onto the surface of the IVth ventricle (Group 4). Group 1-3 axons regenerated unperturbed through degenerating central myelin, reactive astrocytes, oligodendrocytes, microglia, and large accumulations of hematogenous macrophages. Only Group 3 axons survived long term in significant numbers, and all became myelinated by oligodendrocytes, ultimately establishing thin sheaths with relatively normal nodal gaps and intersegmental myelin sheath lengths. Schwann cells at the CNS/PNS junction of the IVth nerve rootlet did not invade the CNS, but astrocyte processes grew across the junction into the PNS portion of the IVth nerve. The basal lamina of the junctional glia limitans remained stable throughout the experimental period.

  13. Ciliary neurotrophic factor activates NF-κB to enhance mitochondrial bioenergetics and prevent neuropathy in sensory neurons of streptozotocin-induced diabetic rodents. (United States)

    Saleh, Ali; Roy Chowdhury, Subir K; Smith, Darrell R; Balakrishnan, Savitha; Tessler, Lori; Martens, Corina; Morrow, Dwane; Schartner, Emily; Frizzi, Katie E; Calcutt, Nigel A; Fernyhough, Paul


    Diabetes causes mitochondrial dysfunction in sensory neurons that may contribute to peripheral neuropathy. Ciliary neurotrophic factor (CNTF) promotes sensory neuron survival and axon regeneration and prevents axonal dwindling, nerve conduction deficits and thermal hypoalgesia in diabetic rats. In this study, we tested the hypothesis that CNTF protects sensory neuron function during diabetes through normalization of impaired mitochondrial bioenergetics. In addition, we investigated whether the NF-κB signal transduction pathway was mobilized by CNTF. Neurite outgrowth of sensory neurons derived from streptozotocin (STZ)-induced diabetic rats was reduced compared to neurons from control rats and exposure to CNTF for 24 h enhanced neurite outgrowth. CNTF also activated NF-κB, as assessed by Western blotting for the NF-κB p50 subunit and reporter assays for NF-κB promoter activity. Conversely, blockade of NF-κB signaling using SN50 peptide inhibited CNTF-mediated neurite outgrowth. Studies in mice with STZ-induced diabetes demonstrated that systemic therapy with CNTF prevented functional indices of peripheral neuropathy along with deficiencies in dorsal root ganglion (DRG) NF-κB p50 expression and DNA binding activity. DRG neurons derived from STZ-diabetic mice also exhibited deficiencies in maximal oxygen consumption rate and associated spare respiratory capacity that were corrected by exposure to CNTF for 24 h in an NF-κB-dependent manner. We propose that the ability of CNTF to enhance axon regeneration and protect peripheral nerve from structural and functional indices of diabetic peripheral neuropathy is associated with targeting of mitochondrial function, in part via NF-κB activation, and improvement of cellular bioenergetics.

  14. Correlation between PMP-22 messenger RNA expression and phenotype in hereditary neuropathy with liability to pressure palsies. (United States)

    Schenone, A; Nobbio, L; Caponnetto, C; Abbruzzese, M; Mandich, P; Bellone, E; Ajmar, F; Gherardi, G; Windebank, A J; Mancardi, G


    Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of "tomacula," or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.

  15. Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy.

    Directory of Open Access Journals (Sweden)

    Gang Zhang

    Full Text Available Guillain-Barré syndrome (GBS is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO, a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.

  16. Erythropoietin enhances nerve repair in anti-ganglioside antibody-mediated models of immune neuropathy. (United States)

    Zhang, Gang; Lehmann, Helmar C; Bogdanova, Nataliia; Gao, Tong; Zhang, Jiangyang; Sheikh, Kazim A


    Guillain-Barré syndrome (GBS) is a monophasic immune neuropathic disorder in which a significant proportion of patients have incomplete recovery. The patients with incomplete recovery almost always have some degree of failure of axon regeneration and target reinnervation. Anti-ganglioside antibodies (Abs) are the most commonly recognized autoimmune markers in all forms of GBS and specific Abs are associated with the slow/poor recovery. We recently demonstrated that specific anti-ganglioside Abs inhibit axonal regeneration and nerve repair in preclinical models by activation of small GTPase RhoA and its downstream effectors. The objective of this study was to determine whether erythropoietin (EPO), a pleiotropic cytokine with neuroprotective and neurotrophic properties, enhances nerve regeneration in preclinical cell culture and animal models of autoimmune neuropathy/nerve repair generated with monoclonal and patient derived Abs. Primary neuronal cultures and a standardized sciatic crush nerve model were used to assess the efficacy of EPO in reversing inhibitory effects of anti-ganglioside Abs on nerve repair. We found that EPO completely reversed the inhibitory effects of anti-ganglioside Abs on axon regeneration in cell culture models and significantly improved nerve regeneration/repair in an animal model. Moreover, EPO-induced proregenerative effects in nerve cells are through EPO receptors and Janus kinase 2/Signal transducer and activator of transcription 5 pathway and not via early direct modulation of small GTPase RhoA. These preclinical studies indicate that EPO is a viable candidate drug to develop further for neuroprotection and enhancing nerve repair in patients with GBS.


    Directory of Open Access Journals (Sweden)

    Rajan Ganesan


    Full Text Available BACKGROUND Thyroid dysfunction is associated with characteristic symptoms, signs and functional alterations in many organs and systems. The purpose of this study was to evaluate objectively the functional changes in the peripheral nervous system and to determine the type and the prevalence of these diseases. The prevalence of neuromuscular disorders related to thyroid dysfunction has been reported to be between 20-80%. AIMS AND OBJECTIVES  To study the correlation and prevalence of nerve conduction abnormalities in patients with thyroid dysfunction.  To determine the type of peripheral neuropathy in these patients. MATERIALS AND METHODS This study was carried out in Medicine OPD and Endocrinology OPD over a period of 8 months; 50 consecutive patients with newly detected thyroid dysfunction and who fulfilled the inclusion criteria were included in the study and the required data were recorded from each subject with an in-person interview by administering a specific questionnaire. Nerve Conduction Study was performed in all these subjects by using the Standard RMS ENMG EP MARK II machine and results were correlated. RESULTS Out of the 50 patients studied 18 patients had neuropathy, of which 14 of them were hypothyroid and 4 of them had hyperthyroidism; 2 patients had mononeuropathy and 16 of them had polyneuropathy. Carpal tunnel syndrome was present in 2 individuals who had hypothyroidism; 14 patients had predominantly sensory neuropathy and 4 individuals had both sensory and motor polyneuropathy. The most common neurological abnormalities detected were sensory axonal polyneuropathy, mononeuropathy involving the sural nerve, mononeuritis multiplex pattern, carpal tunnel syndrome. CONCLUSION This study concludes that hypothyroid patients are more prone to develop neuropathy predominantly involving the sensory nerves of both lower limbs. This study clearly depicts that peripheral nervous system involvement is more often seen in patients with

  18. Peptide mimetic of the S100A4 protein modulates peripheral nerve regeneration and attenuates the progression of neuropathy in myelin protein P0 null mice

    DEFF Research Database (Denmark)

    Moldovan, Mihai; Pinchenko, Volodymyr; Dmytriyeva, Oksana


    We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro...... and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro......, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 null mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1...

  19. Dynamics of axon fasciculation in the presence of neuronal turnover

    CERN Document Server

    Chaudhuri, Debasish; Mohanty, P K; Zapotocky, Martin


    We formulate and characterize a model aiming to describe the formation of fascicles of axons mediated by contact axon-axon interactions. The growing axons are represented as interacting directed random walks in two spatial dimensions. To mimic axonal turnover in the mammalian olfactory system, the random walkers are injected and removed at specified rates. In the dynamical steady state, the position-dependent distribution of fascicle sizes obeys a scaling law. We identify several distinct time scales that emerge from the dynamics, are sensitive functions of the microscopic parameters of the model, and can exceed the average axonal lifetime by orders of magnitude. We discuss our findings in terms of an analytically tractable, effective model of fascicle dynamics.

  20. [Neuropathy in angioimmunoblastic lymphadenopathy (author's transl)]. (United States)

    Brunet, P; Binet, J L; de Saxce, H; Gray, F; De Baecque, C; Raphael, M; Lyon-Caen, O


    Four cases of angioimmunoblastic lymphadenopathy associated to peripheral neuropathy are described. The neuropathy was mixed, sensory and motor, more or less extensive, always asymetrical. In two cases, the clinical symptomatology and the clinical course were very peculiar, characterized by sensory disorders of a precise topography, circumscribed and sometimes suspended and by a relapsing and remitting course. In the third case, the neurological signs were acute and rapidly extensive with mandatory respiratory assistance. In this case, death occurred after a few weeks and the exact diagnosis was only attained at post-mortem examination. In the fourth case the neuropathy was very painful but the course was slow. In all four cases marked and extensive pain was present prior to the neurological disorders. Electrophysiological abnormalities were a constant feature with a marked slowing down of nerve conduction velocity. CSF was normal at the beginning in one case but was otherwise markedly pathological with an increased number of cells due to a large number of lymphocytes ranging from 6 to 40 cells while protein ranged from 60 to 160 mg per 100 ml. Nerve and muscle biopsies were non specific, i.e. neurogenous muscular atrophy and demyelination, except in case n. 4 where specific angioimmunoblastic lymphadenopathy infiltrates were present both in nerve and muscle. In cases 1 and 3 a non specific lymphohistiocytic infiltrate was present in spinal roots and meninges. Corticotherapy was used and efficient in two cases. These data are compared with a review of the literature. Since 1976, 7 cases of angioimmunoblastic lymphadenopathy associated to peripheral neuropathy have been reported. Clinical, electrophysiological and biological features are similar. Only one case underwent a post mortem examination of the central nervous system: a non specific lymphocytic infiltration in the spinal roots and meninges was mentioned. The role of the dysproteinemia associated with the AIL

  1. Chlorpyrifos-Oxon Disrupts Zebrafish Axonal Growth and Motor Behavior


    Yang, Dongren; Lauridsen, Holly; Buels, Kalmia; Chi, Lai-Har; La Du, Jane; Bruun, Donald A.; Olson, James R.; Tanguay, Robert L.; Lein, Pamela J.


    Axonal morphology is a critical determinant of neuronal connectivity, and perturbation of the rate or extent of axonal growth during development has been linked to neurobehavioral deficits in animal models and humans. We previously demonstrated that the organophosphorus pesticide (OP) chlorpyrifos (CPF) inhibits axonal growth in cultured neurons. In this study, we used a zebrafish model to determine whether CPF, its oxon metabolite (CPFO), or the excreted metabolite trichloro-2-pyridinol (TCP...

  2. A unified cell biological perspective on axon-myelin injury


    Simons, Mikael; Misgeld, Thomas; Kerschensteiner, Martin


    Demyelination and axon loss are pathological hallmarks of the neuroinflammatory disorder multiple sclerosis (MS). Although we have an increasingly detailed understanding of how immune cells can damage axons and myelin individually, we lack a unified view of how the axon–myelin unit as a whole is affected by immune-mediated attack. In this review, we propose that as a result of the tight cell biological interconnection of axons and myelin, damage to either can spread, which might convert a loc...

  3. Axon-glia interaction and membrane traffic in myelin formation



    In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is...

  4. Surgical approach to lower extremity nerve decompression in the patient with diabetic neuropathy

    NARCIS (Netherlands)

    Dellon, A.L.


    Neuropathy associated with Diabetes is increasing at epidemic rates throughout the world. Traditionally, this neuropathy causes loss of protective sensation leading to ulceration, infection , and amputation. Even with good glycemic control, this neuropathy is still considered progressive and irrever

  5. Medial arterial calcification in diabetes and its relationship to neuropathy

    DEFF Research Database (Denmark)

    Jeffcoate, W J; Rasmussen, Lars Melholt; Hofbauer, L C


    Calcification of the media of arterial walls is common in diabetes and is particularly associated with distal symmetrical neuropathy. Arterial calcification also complicates chronic kidney disease and is an independent risk factor for cardiovascular and all-cause mortality. The term calcification...... factor linked to the development of arterial calcification is distal symmetrical neuropathy; indeed, it has been suggested that neuropathy explains the distal distribution of arterial calcification in diabetes. It has also been suggested that the link with neuropathy results from loss of neuropeptides......, such as calcitonin gene-related peptide, which are inherently protective. The association between distal symmetrical neuropathy and calcification of the arterial wall highlights the fact that neuropathy may be an independent risk factor for cardiovascular mortality....

  6. Sympathetic vasoconstrictor nerve function in alcoholic neuropathy

    DEFF Research Database (Denmark)

    Jensen, K; Andersen, K; Smith, T;


    The peripheral sympathetic vasomotor nerve function was investigated in 18 male chronic alcoholics admitted for intellectual impairment or polyneuropathy. By means of the local 133Xenon washout technique, the sympathetic veno-arteriolar axon-reflex was studied. This normally is responsible for a ...

  7. Corticostriatal combinatorics: the implications of corticostriatal axonal arborizations. (United States)

    Zheng, T; Wilson, C J


    The complete striatal axonal arborizations of 16 juxtacellularly stained cortical pyramidal cells were analyzed. Corticostriatal neurons were located in the medial agranular or anterior cingulate cortex of rats. All axons were of the extended type and formed synaptic contacts in both the striosomal and matrix compartments as determined by counterstaining for the mu-opiate receptor. Six axonal arborizations were from collaterals of brain stem-projecting cells and the other 10 from bilaterally projecting cells with no brain stem projections. The distribution of synaptic boutons along the axons were convolved with the average dendritic tree volume of spiny projection neurons to obtain an axonal innervation volume and innervation density map for each axon. Innervation volumes varied widely, with single axons occupying between 0.4 and 14.2% of the striatum (average = 4%). The total number of boutons formed by individual axons ranged from 25 to 2,900 (average = 879). Within the innervation volume, the density of innervation was extremely sparse but inhomogeneous. The pattern of innervation resembled matrisomes, as defined by bulk labeling and functional mapping experiments, superimposed on a low background innervation. Using this sample as representative of all corticostriatal axons, the total number of corticostriatal neurons was estimated to be 17 million, about 10 times the number of striatal projection neurons.

  8. Molecular analysis of axon repulsion by the notochord. (United States)

    Anderson, Christopher N G; Ohta, Kunimasa; Quick, Marie M; Fleming, Angeleen; Keynes, Roger; Tannahill, David


    During development of the amniote peripheral nervous system, the initial trajectory of primary sensory axons is determined largely by the action of axon repellents. We have shown previously that tissues flanking dorsal root ganglia, the notochord lying medially and the dermamyotomes lying laterally, are sources of secreted molecules that prevent axons from entering inappropriate territories. Although there is evidence suggesting that SEMA3A contributes to the repellent activity of the dermamyotome, the nature of the activity secreted by the notochord remains undetermined. We have employed an expression cloning strategy to search for axon repellents secreted by the notochord, and have identified SEMA3A as a candidate repellent. Moreover, using a spectrum of different axon populations to assay the notochord activity, together with neuropilin/Fc receptor reagents to block semaphorin activity in collagen gel assays, we show that SEMA3A probably contributes to notochord-mediated repulsion. Sympathetic axons that normally avoid the midline in vivo are also repelled, in part, by a semaphorin-based notochord activity. Although our results implicate semaphorin signalling in mediating repulsion by the notochord, repulsion of early dorsal root ganglion axons is only partially blocked when using neuropilin/Fc reagents. Moreover, retinal axons, which are insensitive to SEMA3A, are also repelled by the notochord. We conclude that multiple factors act in concert to guide axons in this system, and that further notochord repellents remain to be identified.

  9. Differences in excitability properties of FDI and ADM motor axons. (United States)

    Bae, Jong Seok; Sawai, Setsu; Misawa, Sonoko; Kanai, Kazuaki; Isose, Sagiri; Kuwabara, Satoshi


    The first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are innervated by the same ulnar nerve, but studies have shown that the former is much more severely affected in amyotrophic lateral sclerosis. In this study, threshold tracking was used to investigate whether membrane properties differ between FDI and ADM motor axons. In 12 normal subjects, compound muscle action potentials were recorded from FDI and ADM after ulnar nerve stimulation at the wrist. The strength-duration time constant was significantly longer in the FDI axons than in the ADM axons, and latent addition studies showed greater threshold changes at the conditioning-test stimulus of 0.2 ms in FDI than in ADM axons. These findings suggest that nodal persistent sodium conductances are more prominent in FDI axons than in ADM axons, and therefore excitability is physiologically higher in FDI axons. Even in the same nerve at the same sites, membrane properties of FDI and ADM motor axons differ significantly, and thus their axonal/neuronal responses to disease may also differ.

  10. Fast axonal transport in early experimental disc edema. (United States)

    Radius, R L; Anderson, D R


    Previous work has documented impairment of slow axonal transport in papilledema, but the abnormalities in rapid transport were less certain. Therefore fast axonal transport was studied in 19 primate eyes subjected to ocular hypotony for 6 to 72 hr following surgical fistulization of the anterior chamber. Mild, irregular alterations in fast axonal transport were detected only after nerve head swelling was apparent. These changes in fast transport mechanisms in cases of nerve head edema occur after, and may be secondary to, impaired slow axoplasmic flow and the resultant axonal swelling. Furthermore, since prolonged complete interruption of axonal transport is theoretically inconsistent with the continued normal neuron function characteristic of papilledema and, moreover, since previous data shows a "slowdown" rather than complete blockade of axonal transport in papilledema, it is likely that in eyes with papilledema there does not exist a complete flock of axonal transport. Therefore we hypothesize that the swelling results when slow axoplasmic flow is locally slowed down but not totally stopped, with the axon distention producing secondary mild, irregular changes in fast axonal transport.

  11. Axonal autophagy during regeneration of the rat sciatic nerve

    Institute of Scientific and Technical Information of China (English)

    Kangrong Lu; Zhongxian Piao; Zhenxi Liu; Weiwang Gu; Wanshan Wang; Nngjie Piao


    BACKGROUND: The removal of degenerated axonal debris during Wallerian degeneration is very important for nerve regeneration. However, the mechanism by which debris is removed is not been completely understood. Considerable controversy remains as to the clearance pathway and cells that are involved. OBJECTIVE: To investigate axonal autophagy during removal of degenerated axonal debris by transecting the sciatic nerve in a rat Wallerian degeneration model.DESIGN, TIME AND SETTING: Experimental neuropathological analysis. The experiment was conducted at the Laboratory Animal Service Center of the Southern Medical University between January and June 2005. MATERIALS: Fifty-four adult, Wistar rats of either sex, weighing 180-250 g, were obtained from the Laboratory Animal Service Center of the Southern Medical University. Animals were randomly divided into nine groups of six rats. METHODS: Wallerian degeneration was induced by transecting the rat sciatic nerve, and tissue samples from the distal stump were obtained 0.2, 0.4, 1, 2, 3, 4, 7, 10, and 15 days post-transection. Ultrathin sections were prepared for electron microscopy to study ultrastructure and enzyme cytochemistry staining. MAIN OUTCOME MEASURES: Ultrastructure (axon body, autophagic body, and cystoskeleton) of axons and myelin sheaths observed with electron microscopy; acidic phosphatase activity detected by Gomori staining using electron microscopy. RESULTS: The major changes of degenerating axons after transection were axoplasm swelling and separation of axons from their myelin sheath between five hours and two days post-transection. At four days post-transection, the axoplasm condensed and axons were completely separated from the myelin sheath, forming dissociative axon bodies. Vacuoles of different sizes formed in axons during the early phase after lesion. Larger dissociative axon bodies were formed when the axons were completely separated from the myelin sheath during a late phase. The axolemma

  12. Crossing the Border: Molecular Control of Motor Axon Exit

    Directory of Open Access Journals (Sweden)

    Arlene Bravo-Ambrosio


    Full Text Available Living organisms heavily rely on the function of motor circuits for their survival and for adapting to ever-changing environments. Unique among central nervous system (CNS neurons, motor neurons (MNs project their axons out of the CNS. Once in the periphery, motor axons navigate along highly stereotyped trajectories, often at considerable distances from their cell bodies, to innervate appropriate muscle targets. A key decision made by pathfinding motor axons is whether to exit the CNS through dorsal or ventral motor exit points (MEPs. In contrast to the major advances made in understanding the mechanisms that regulate the specification of MN subtypes and the innervation of limb muscles, remarkably little is known about how MN axons project out of the CNS. Nevertheless, a limited number of studies, mainly in Drosophila, have identified transcription factors, and in some cases candidate downstream effector molecules, that are required for motor axons to exit the spinal cord. Notably, specialized neural crest cell derivatives, referred to as Boundary Cap (BC cells, pre-figure and demarcate MEPs in vertebrates. Surprisingly, however, BC cells are not required for MN axon exit, but rather restrict MN cell bodies from ectopically migrating along their axons out of the CNS. Here, we describe the small set of studies that have addressed motor axon exit in Drosophila and vertebrates, and discuss our fragmentary knowledge of the mechanisms, which guide motor axons out of the CNS.

  13. A unified cell biological perspective on axon-myelin injury. (United States)

    Simons, Mikael; Misgeld, Thomas; Kerschensteiner, Martin


    Demyelination and axon loss are pathological hallmarks of the neuroinflammatory disorder multiple sclerosis (MS). Although we have an increasingly detailed understanding of how immune cells can damage axons and myelin individually, we lack a unified view of how the axon-myelin unit as a whole is affected by immune-mediated attack. In this review, we propose that as a result of the tight cell biological interconnection of axons and myelin, damage to either can spread, which might convert a local inflammatory disease process early in MS into the global progressive disorder seen during later stages. This mode of spreading could also apply to other neurological disorders.

  14. Present status of studies on diffuse axonal injury

    Institute of Scientific and Technical Information of China (English)

    Jie Ma; Chonggong Zhang; Yi Li


    OBJECTIVE: To explain the present status of study on diffuse axonal injury,investigate its pathogenesis and pathophysiological changes ,and suggest principles for the diagnosis and treatment.DATA SOURCES: Articles about diffuse axonal injury published in English from January 1994 to October 2006 were searched in Pubmed database using the keywords of "diffuse axonal injury,pathogenesis,therapy".STUDY SELECTION: The collected articles were primarily screened to select those associated with diffuse axonal injury,the obviously irrelated articles were excluded,and the rest ones were retrieved manually,and the full-texes were searched.DATA EXTRACTION: Totally 98 articles were collected,41 of them were involved.and the other 57 were excluded.DATA SYNTHESIS: Diffuse axonal injury is mainly caused by acceleratory or deceleratory injury,and its pathophysiological change is a progressive duration,local axonal injury finally develops to axonal breakage,mainly includes inactivation of natrium channel,intracellular Ca2+ overloading,activation of calcium protease,caspase etc.,and mitochondrial injury.At present,there is still lack of effective therapeutic methods for diffuse axonal injury,so we should actively explore more effective methods to relieve the pain of patients and improve their prognosis.CONCLUSION: At present,diffuse axonal injury has not attracted enough attentions in China,the mechanisms for its diagnosis and attack are still unclear,and the treatments are mainly aiming at the symptoms.

  15. Dopaminergic axon guidance: which makes what?

    Directory of Open Access Journals (Sweden)

    Laetitia ePrestoz


    Full Text Available Mesotelencephalic pathways in the adult central nervous system have been studied in great detail because of their implication in major physiological functions as well as in psychiatric, neurological and neurodegenerative diseases. However, the ontogeny of these pathways and the molecular mechanisms that guide dopaminergic axons during embryogenesis have been only recently studied. This line of research is of crucial interest for the repair of lesioned circuits in adulthood following neurodegenerative diseases or common traumatic injuries. For instance, in the adult, the anatomic and functional repair of the nigrostriatal pathway following dopaminergic embryonic neuron transplantation suggests that specific guidance cues exist which govern embryonic fibers outgrowth, and suggests that axons from transplanted embryonic cells are able to respond to theses cues, which then guide them to their final targets. In this review, we first synthesize the work that has been performed in the last few years on developing mesotelencephalic pathways, and summarize the current knowledge on the identity of cellular and molecular signals thought to be involved in establishing mesotelencephalic dopaminergic neuronal connectivity during embryogenesis in the central nervous system of rodents. Then, we review the modulation of expression of these molecular signals in the lesioned adult brain and discuss their potential role in remodeling the mesotelencephalic dopaminergic circuitry, with a particular focus on Parkinson’s disease. Identifying guidance molecules involved in the connection of grafted cells may be useful for cellular therapy in Parkinsonian patients, as these molecules may help direct axons from grafted cells along the long distance they have to travel from the substantia nigra to the striatum.

  16. Axonal regeneration and development of de novo axons from distal dendrites of adult feline commissural interneurons after a proximal axotomy

    DEFF Research Database (Denmark)

    Fenrich, Keith K; Skelton, Nicole; MacDermid, Victoria E


    at 4-5 weeks post injury. The somata of axotomized CINs were identified by the presence of immunoreactivity for the axonal growth-associated protein-43 (GAP-43). Nearly half of the CINs had de novo axons that emerged from distal dendrites. These axons lacked immunoreactivity for the dendritic protein......Following proximal axotomy, several types of neurons sprout de novo axons from distal dendrites. These processes may represent a means of forming new circuits following spinal cord injury. However, it is not know whether mammalian spinal interneurons, axotomized as a result of a spinal cord injury......, develop de novo axons. Our goal was to determine whether spinal commissural interneurons (CINs), axotomized by 3-4-mm midsagittal transection at C3, form de novo axons from distal dendrites. All experiments were performed on adult cats. CINs in C3 were stained with extracellular injections of Neurobiotin...

  17. Optic neuropathy in a patient with pyruvate dehydrogenase deficiency

    Energy Technology Data Exchange (ETDEWEB)

    Small, Juan E. [Massachusetts General Hospital and Harvard Medical School, Department of Radiology, Boston, MA (United States); Gonzalez, Guido E. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Radiology, Boston, MA (United States); Clinica Alemana de Santiago, Departmento de Imagenes, Santiago (Chile); Nagao, Karina E.; Walton, David S. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Ophthalmology, Boston, MA (United States); Caruso, Paul A. [Massachusetts Eye and Ear Infirmary and Harvard Medical School, Department of Radiology, Boston, MA (United States)


    Pyruvate dehydrogenase (PDH) deficiency is a genetic disorder of mitochondrial metabolism. The clinical manifestations range from severe neonatal lactic acidosis to chronic neurodegeneration. Optic neuropathy is an uncommon clinical sequela and the imaging findings of optic neuropathy in these patients have not previously been described. We present a patient with PDH deficiency with bilateral decreased vision in whom MRI demonstrated bilateral optic neuropathy and chiasmopathy. (orig.)

  18. Painful diabetic neuropathies, cases report and diagnostic criteria


    Marco Lacerenza


    Painful diabetic neuropathy is a model for the investigation of drug’s efficacy in neuropathic pain. Diabetes, through multiple pathophysiological mechanisms causes several painful neuropathies. In this paper two clinical cases of painful diabetic neuropathic conditions are described and clinical and neurophysiological criteria to make the correct diagnosis are examined. Diabetes causes different painful diabetic neuropathies, at times even in a single patient. Different types of pai...

  19. North America and South America (NA-SA) neuropathy project. (United States)

    Pasnoor, Mamatha; Nascimento, Osvaldo J M; Trivedi, Jaya; Wolfe, Gil I; Nations, Sharon; Herbelin, Laura; de Freitas, M G; Quintanilha, Giseli; Khan, Saud; Dimachkie, Mazen; Barohn, Richard


    Peripheral neuropathy is a common neurological disorder. There may be important differences and similarities in the diagnosis of peripheral neuropathy between North America (NA) and South America (SA). Neuromuscular databases were searched for neuropathy diagnosis at two North American sites, University of Kansas Medical Center and University of Texas Southwestern Medical Center, and one South American site, Federal Fluminense University in Brazil. All patients were included into one of the six major categories: immune-mediated, diabetic, hereditary, infectious/inflammatory, systemic/metabolic/toxic (not diabetic) and cryptogenic. A comparison of the number of patients in each category was made between North America and South America databases. Total number of cases in North America was 1090 and in South America was 1034 [immune-mediated: NA 215 (19.7%), SA 191 (18%); diabetic: NA 148 (13.5%), SA 236 (23%); hereditary: NA 292 (26.7%), SA 103 (10%); infectious/inflammatory: NA 53 (4.8%), SA 141 (14%); systemic/metabolic/toxic: NA 71 (6.5%), SA 124 (12%); cryptogenic: NA 311 (28.5%), SA 239 (23%)]. Some specific neuropathy comparisons were hereditary neuropathies [Charcot-Marie-Tooth (CMT) cases] in NA 246/292 (84.2%) and SA 60/103 (58%); familial amyloid neuropathy in SA 31/103 (30%) and none in NA. Among infectious neuropathies, cases of human T-lymphotropic virus type 1 (HTLV-1) neuropathy in SA were 36/141(25%), Chagas disease in SA were 13/141(9%) and none for either in NA; cases of neuropathy due to leprosy in NA were 26/53 (49%) and in SA were 39/141(28%). South American tertiary care centers are more likely to see patients with infectious, diabetic and hereditary disorders such as familial amyloid neuropathies. North American tertiary centers are more likely to see patients with CMT. Immune neuropathies and cryptogenic neuropathies were seen equally in North America and South America.

  20. Tumefactive Brain Demyelination Accompanying MADSAM Neuropathy

    Directory of Open Access Journals (Sweden)

    Şefik Evren Erdener


    Full Text Available Multifocal acquired demyelinating sensory and motor (MADSAM neuropathy is characterized by asymmetric multifocal motor and sensory loss and conduction blocks in peripheral nerves. Peripheral demyelinating diseases may be accompanied by demyelination in central nervous system (CNS. In this report, a MADSAM patient with a solitary tumefactive demyelinating lesion in brain is presented. Neuroimaging due to a visual field defect revealed a right parietooccipital lesion, which was initially misdiagnosed as a tumor. Pathological examination showed that it was demyelinating in nature. Peripheral nervous symptoms of the patient developed two years later and she was then diagnosed with MADSAM. There was prominent clinical and electrophysiological response to steroid treatment. Tumefactive brain involvement was not previously reported for MADSAM neuropathy, although it was documented in a single case with typical chronic inflammatory demyelinating polyneuropathy (CIDP. CNS involvement should therefore be considered in MADSAM patients.

  1. Cardiovascular autonomic neuropathy in the diabetic patients.

    Directory of Open Access Journals (Sweden)

    Maria Eugenia Niño Mantilla


    Full Text Available the dysfunction of the autonomic nervous system is a serious problem in diabetic patients. The cardiovacular autonomic neuropathy is the most important autonomic dysfuntion for it´s implication in the increasesof the mortality rate in diabetis patients. tis ethiopatogenesis is the result of a multifactorial process caused by chronic hyperglycemia, ending up in damage of the autonomic fibers thet innervate the heart and blood vessels, leading to dysfuntional hearth rate control and abnormal vascular dynamics. the associated clinical manifestations include orthotatic hypotension, excecise intolerance, intraoperative cardiovascular liability and silent myocardial ischemia. Being important its recognition, quantitative test to evaluate the cardiovascular funtion, to value its evolution and the effects of the treatment ahould be done, being the most used, the hearth rate response to standing test, and teh valsalva maneuver. the handling of this entity is done improving control of glucose blood levels its the most effective way to prevent the cardiovascular autonomic neuropathy in the diabetic patients.

  2. IMP2 axonal localization, RNA interactome, and function in the development of axon trajectories

    DEFF Research Database (Denmark)

    Preitner, Nicolas; Quan, Jie; Li, Xinmin


    RNA-based regulatory mechanisms play important roles in the development and plasticity of neural circuits and neurological disease. Developing axons provide a model well suited to the study of RNA-based regulation, and contain specific subsets of mRNAs that are locally translated and have roles i...

  3. White-matter astrocytes, axonal energy metabolism, and axonal degeneration in multiple sclerosis

    NARCIS (Netherlands)

    Cambron, Melissa; D'haeseleer, Miguel; Laureys, Guy; Clinckers, Ralph; Debruyne, Jan; De Keyser, Jacques


    In patients with multiple sclerosis (MS), a diffuse axonal degeneration occurring throughout the white matter of the central nervous system causes progressive neurologic disability. The underlying mechanism is unclear. This review describes a number of pathways by which dysfunctional astrocytes in M

  4. Abnormal calcium homeostasis in peripheral neuropathies



    Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The cent...

  5. Ischemic Neuropathy Associated with Livedoid Vasculitis


    Kim, Jee-Eun; Park, Su-Yeon; Sinn, Dong In; Kim, Sung-Min; Hong, Yoon-Ho; Park, Kyung Seok; Sung, Jung-Joon; Lee, Kwang-Woo


    Background Livedoid vasculitis is a chronic dermatological problem with an unclear etiology. Clinical findings are petechiae with painful ulcers in both lower extremities, which heal to become hyperpigmented and porcelain-white satellite lesions. There are only a few reported cases of livedoid vasculitis presenting in combination with peripheral neuropathy. Case Report We report the first case of a Korean patient presenting with mononeuritis multiplex combined with livedoid vasculitis, which ...

  6. Evaluation of Ulnar neuropathy on hemodialysis patients

    Directory of Open Access Journals (Sweden)

    Babak Vahdatpour


    Full Text Available Background: Ulnar nerve entrapment at the elbow is the second most common upper extremity nerve involvement after median nerve involvement at the wrist or carpal tunnel syndrome (CTS considering the frequency of occurrence in the upper limb with variable causes. Hemodialysis, because of elbow positioning during dialysis, upper extremity vascular-access, and underlying disease is one cause of ulnar entrapment. This study considers evaluating the effect of elbow positioning on ulnar involvement prevalence during dialysis. Materials and Methods: This cross-sectional study started in June 2011 and completed in December 2011. The patients receiving dialysis with at least one symptom or sign of ulnar nerve involvement underwent nerve conduction studies. Electromyography testing (EMG performed to confirm the ulnar neuropathy. To review the ulnar nerve, patients must be in supine position with arm in 90° abduction and elbow in 135° flexion. We stimulated the ulnar nerve at three different points, including 6 cm above and 4 cm below the elbow and over the wrist. According to the electrophysiological data, the intensity of nerve entrapment and possibility of associated polyneuropathy determined. Results: Clinically and electrodiagnostically, evidence confirmed that ulnar neuropathy was present in 11 (27.5% of 40 hemodialysis patients and in 10 (25% of 40 peritoneal patients (P value: 0.83. Also, the prevalence of median neuropathy in hemodialysis and peritoneal dialysis patients was 14 (35% and 10 (25%, respectively (P value: 0.33. Conclusion: The frequency of median and ulnar neuropathy in hemodialysis patients is more than peritoneal dialysis, but this different is not significant. In addition, comparing sitting position with prolonged elbow flexion and supine position with elbow extension during hemodialysis, recommended doing hemodialysis in later position with using an elbow pad.

  7. AxonPacking: An Open-Source Software to Simulate Arrangements of Axons in White Matter. (United States)

    Mingasson, Tom; Duval, Tanguy; Stikov, Nikola; Cohen-Adad, Julien


    HIGHLIGHTS AxonPacking: Open-source software for simulating white matter microstructure.Validation on a theoretical disk packing problem.Reproducible and stable for various densities and diameter distributions.Can be used to study interplay between myelin/fiber density and restricted fraction. Quantitative Magnetic Resonance Imaging (MRI) can provide parameters that describe white matter microstructure, such as the fiber volume fraction (FVF), the myelin volume fraction (MVF) or the axon volume fraction (AVF) via the fraction of restricted water (fr). While already being used for clinical application, the complex interplay between these parameters requires thorough validation via simulations. These simulations required a realistic, controlled and adaptable model of the white matter axons with the surrounding myelin sheath. While there already exist useful algorithms to perform this task, none of them combine optimisation of axon packing, presence of myelin sheath and availability as free and open source software. Here, we introduce a novel disk packing algorithm that addresses these issues. The performance of the algorithm is tested in term of reproducibility over 50 runs, resulting density, and stability over iterations. This tool was then used to derive multiple values of FVF and to study the impact of this parameter on fr and MVF in light of the known microstructure based on histology sample. The standard deviation of the axon density over runs was lower than 10(-3) and the expected hexagonal packing for monodisperse disks was obtained with a density close to the optimal density (obtained: 0.892, theoretical: 0.907). Using an FVF ranging within [0.58, 0.82] and a mean inter-axon gap ranging within [0.1, 1.1] μm, MVF ranged within [0.32, 0.44] and fr ranged within [0.39, 0.71], which is consistent with the histology. The proposed algorithm is implemented in the open-source software AxonPacking ( and can be useful for

  8. Effect of Tinospora cordifolia on experimental diabetic neuropathy

    Directory of Open Access Journals (Sweden)

    Pratibha D Nadig


    Conclusions: Tinospora cordifolia prevents the hyperalgesia in experimental diabetic neuropathy. It has an aldose reductase inhibitory activity in-vitro which may contribute to the beneficial effects.

  9. Validity of the neurological examination in diagnosing diabetic peripheral neuropathy. (United States)

    Höliner, Isabella; Haslinger, Vera; Lütschg, Jürg; Müller, Guido; Barbarini, Daniela Seick; Fussenegger, Jörg; Zanier, Ulrike; Saely, Christoph H; Drexel, Heinz; Simma, Burkhard


    The aim of this study was to evaluate the prevalence of diabetic peripheral neuropathy in children and adolescents with type 1 diabetes mellitus and examine whether the neurological examination validly diagnoses diabetic peripheral neuropathy as compared with the gold standard of nerve conduction velocity in these patients. Nerve conduction velocity was measured in an unselected consecutive series of patients aged 8-18 years who had been suffering from type 1 diabetes mellitus for at least 1 year. For the neurological examination, neuropathy disability scores and neuropathy sign scores were used. Of the 39 patients, six (15%) had clinically evident diabetic peripheral neuropathy, whereas nerve conduction velocity testing revealed diabetic peripheral neuropathy in 15 (38%) patients. Sensitivity and specificity of the neurological examination for the diagnosis of diabetic peripheral neuropathy were 40% and 100%, respectively. The corresponding positive and negative predictive values were 100% and 72.7%, respectively. This conclusions from this study are that in children and adolescents with type 1 diabetes mellitus, diabetic peripheral neuropathy is highly prevalent, but in the majority of patients it is subclinical. Sensitivity and negative predictive values of the neurological examination are low. Therefore, routine nerve conduction velocity measurement for the assessment of diabetic peripheral neuropathy appears to be warranted in these patients.

  10. Painful diabetic neuropathies, cases report and diagnostic criteria

    Directory of Open Access Journals (Sweden)

    Marco Lacerenza


    Full Text Available Painful diabetic neuropathy is a model for the investigation of drug’s efficacy in neuropathic pain. Diabetes, through multiple pathophysiological mechanisms causes several painful neuropathies. In this paper two clinical cases of painful diabetic neuropathic conditions are described and clinical and neurophysiological criteria to make the correct diagnosis are examined. Diabetes causes different painful diabetic neuropathies, at times even in a single patient. Different types of pains may originate from different nerve injuries, and harbour different pathophysiological mechanisms. A comprehensive and accurate evaluation of clinical and neurophysiological abnormalities in painful diabetic neuropathies provides insight on the pathophysiological mechanism and directs the clinician towards rational treatment strategies.

  11. Diabetic neuropathy part 2: proximal and asymmetric phenotypes. (United States)

    Pasnoor, Mamatha; Dimachkie, Mazen M; Barohn, Richard J


    Diabetic neuropathies consist of a variety of syndromes resulting from different types of damage to peripheral or cranial nerves. Although distal symmetric polyneuropathy is the most common type of diabetic neuropathy, many other subtypes have been defined since the 1800s, including proximal diabetic, truncal, cranial, median, and ulnar neuropathies. Various theories have been proposed for the pathogenesis of these neuropathies. The treatment of most requires tight and stable glycemic control. Spontaneous recovery is seen in most of these conditions with diabetic control. Immunotherapies have been tried in some of these conditions however are controversial.

  12. Leber hereditary optic neuropathy: current perspectives

    Directory of Open Access Journals (Sweden)

    Meyerson C


    Full Text Available Cherise Meyerson, Greg Van Stavern, Collin McClelland Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, MO, USA Abstract: Leber hereditary optic neuropathy (LHON is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. Keywords: Leber hereditary optic neuropathy, mitochondria, neuro-ophthalmology, mitochondrial DNA

  13. Bilateral optic neuropathy in acute cryptococcal meningitis

    Institute of Scientific and Technical Information of China (English)

    Qi Zhe Ngoo; Li Min Evelyn Tai; Wan Hazabbah Wan Hitam; John Tharakan


    We reported a case of cryptococcal meningitis presenting with bilateral optic neuropathy in an immunocompetent patient. A 64-year-old Malay gentleman with no medical comorbidities presented with acute bilateral blurring of vision for a week, which was associated with generalised throbbing headache and low grade fever. He also had som-nolence and altered consciousness. Visual acuity in both eyes was no perception of light with poor pupillary reflexes. Extraocular muscle movements were normal. Anterior segments were unremarkable bilaterally. Fundoscopy revealed bilateral optic disc swelling. CT scan of the brain showed multifocal infarct, but no meningeal enhancement or mass. Cerebrospinal fluid opening pressure was normal, while its culture grew Cryptococcus neoformans. A diagnosis of cryptococcal meningitis with bilateral optic neuropathy was made. Patient was treated with a six-week course of intravenous flu-conazole and started concomitantly on a fortnight's course of intravenous amphotericin B. After that, his general condition improved, but there was still no improvement in his visual acuity. On reviewing at two months post-initiation of treatment, fundi showed bilateral optic atrophy. Bilateral optic neuropathy secondary to cryptococcal meningitis was rare. The prognosis was guarded due to the sequelae of optic atrophy. Anti-fungal medication alone may not be sufficient to manage this condition. However, evidence for other treatment modalities is still lacking and further clinical studies are required.

  14. Irreversible optic neuropathy in wernicke encephalopathy and leber hereditary optic neuropathy. (United States)

    Li, John-Michael; Rucker, Janet C


    A 52-year-old woman with alcohol abuse presented with recent worsening of vision, imbalance, and confusion. Examination revealed counting fingers acuity in both eyes with central scotomas, color vision loss, horizontal nystagmus, and gait ataxia. Thiamine was initiated as treatment for a presumptive diagnosis of Wernicke encephalopathy (WE). Brain MRI revealed high T2 signal in the dorsal midbrain and thalami characteristic of WE. The lack of optic disc edema, usually present in patients with WE who have severe optic neuropathy, and lack of visual loss reversibility with thiamine treatment, led to the suspicion of coexisting Leber hereditary optic neuropathy (LHON), which was later confirmed when testing revealed the 14484 mitochondrial DNA mutation. Over the ensuing months, vision did not recover despite improvement of other neurologic findings. Irreversible optic neuropathy in WE should prompt consideration of a coexisting mitochondrial disorder such as LHON.

  15. TRPA1 insensitivity of human sural nerve axons after exposure to lidocaine. (United States)

    Docherty, Reginald J; Ginsberg, Lionel; Jadoon, Saqiba; Orrell, Richard W; Bhattacharjee, Anupam


    TRPA1 is an ion channel of the TRP family that is expressed in some sensory neurons. TRPA1 activity provokes sensory symptoms of peripheral neuropathy, such as pain and paraesthesia. We have used a grease gap method to record axonal membrane potential and evoked compound action potentials (ECAPs) in vitro from human sural nerves and studied the effects of mustard oil (MO), a selective activator of TRPA1. Surprisingly, we failed to demonstrate any depolarizing response to MO (50, 250 μM) in any human sural nerves. There was no effect of MO on the A wave of the ECAP, but the C wave was reduced at 250 μM. In rat saphenous nerve fibres MO (50, 250 μM) depolarized axons and reduced the C wave of the ECAP but had no effect on the A wave. By contrast, both human and rat nerves were depolarized by capsaicin (0.5 to 5 μM) or nicotine (50 to 200 μM). Capsaicin caused a profound reduction in C fibre conduction in both species but had no effect on the amplitude of the A component. Lidocaine (30 mM) depolarized rat saphenous nerves acutely, and when rat nerves were pretreated with 30 mM lidocaine to mimic the exposure of human nerves to local anaesthetic during surgery, the effects of MO were abolished whilst the effects of capsaicin were unchanged. This study demonstrates that the local anaesthetic lidocaine desensitizes TRPA1 ion channels and indicates that it may have additional mechanisms for treating neuropathic pain that endure beyond simple sodium channel blockade.

  16. Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy

    Directory of Open Access Journals (Sweden)

    Manju Jayaraman


    Full Text Available Purpose: To investigate the effect of optic neuritis (ON, ischemic optic neuropathy (ION and compressive optic neuropathy (CON on multifocal visual evoked potential (mfVEP amplitudes and latencies, and to compare the parameters among three optic nerve disorders. Materials and Methods: mfVEP was recorded for 71 eyes of controls and 48 eyes of optic nerve disorders with subgroups of optic neuritis (ON, n = 21 eyes, ischemic optic neuropathy (ION, n = 14 eyes, and compressive optic neuropathy (CON, n = 13 eyes. The size of defect in mfVEP amplitude probability plots and relative latency plots were analyzed. The pattern of the defect in amplitude probability plot was classified according to the visual field profile of optic neuritis treatment trail (ONTT. Results: Median of mfVEP amplitude (log SNR averaged across 60 sectors were reduced in ON (0.17 (0.13-0.33, ION (0.14 (0.12-0.21 and CON (0.21 (0.14-0.30 when compared to controls. The median mfVEP relative latencies compared to controls were significantly prolonged in ON and CON group of 10.53 (2.62-15.50 ms and 5.73 (2.67-14.14 ms respectively compared to ION group (2.06 (-4.09-13.02. The common mfVEP amplitude defects observed in probability plots were diffuse pattern in ON, inferior altitudinal defect in ION and temporal hemianopia in CON eyes. Conclusions: Optic nerve disorders cause reduction in mfVEP amplitudes. The extent of delayed latency noted in ischemic optic neuropathy was significantly lesser compared to subjects with optic neuritis and compressive optic neuropathy. mfVEP amplitudes can be used to objectively assess the topography of the visual field defect.

  17. Differential extraction of axonally transported proteoglycans

    Energy Technology Data Exchange (ETDEWEB)

    Elam, J.S. (Florida State Univ., Tallahassee (USA))


    Axonally transported proteoglycans were differentially solubilized by a sequence of extractions designed to infer their relationship to nerve terminal membranes. Groups of goldfish were injected unilaterally with 35SO4 and contralateral optic tecta containing axonally transported molecules were removed 16 h later. Tecta were homogenized in isotonic buffer and centrifuged at 100,000 g for 60 min to create a total supernatant fraction. Subsequent homogenizations followed by recentrifugation were with hypotonic buffer (lysis extract), 1 M NaCl, Triton X-100 or alternatively Triton-1 M NaCl. Populations of proteoglycans in each extract were isolated on DEAE ion exchange columns and evaluated for content of glycosaminoglycans (GAGs). Results show the distribution of transported proteoglycans to be 26.3% total soluble, 13.7% lysis extract, 13.8% NaCl extract, 12.2% Triton extract, and 46.2% Triton-NaCl extract. Proteoglycans from all fractions contained heparan sulfate as the predominant GAG, with lesser amounts of chondroitin (4 or 6) sulfate. The possible localizations of transported proteoglycans suggested by the extraction results are discussed.

  18. Neuronal Logistics : Axonal Transport in Development and Disease

    NARCIS (Netherlands)

    R. van den Berg (Robert)


    markdownabstractBrain cells are uniquely shaped among the many cell types of the body. While most cells are more or less rounded or square-shaped, neurons grow one or more long axons that can reach lengths of a meter or more. To keep these axons alive and functional, neurons are dependent on an intr

  19. Molecular Determinants Fundamental to Axon Regeneration after SCI (United States)


    TITLE: Molecular Determinants Fundamental to Axon Regeneration after SCI PRINCIPAL INVESTIGATOR: Jeffrey Alan Plunkett, Ph.D. Martin...TYPE FINAL 3. DATES COVERED (From - To) 1 Sept 2011 - 1 Sept 2014 4. TITLE AND SUBTITLE Molecular Determinants Fundamental to Axon Regeneration...available that restore motor impairments resulting fromspinal cord injury (SCI). Soldiers with SCI are permanently paralyzed and in needof lifelong care

  20. Molecular Determinants Fundamental to Axon Regeneration after SCI (United States)


    currently employed to investigate the evolution of the scar and the time course of axon regeneration after spinal cord injury. The data from these...Medicine, Pittsburgh, PA. It has been established in amphibians and fish that neurons can successfully regenerate their axons in the damaged central

  1. Spontaneous axonal regeneration in rodent spinal cord after ischemic injury

    DEFF Research Database (Denmark)

    von Euler, Mia; Janson, A M; Larsen, Jytte Overgaard;


    Here we present evidence for spontaneous and long-lasting regeneration of CNS axons after spinal cord lesions in adult rats. The length of 200 kD neurofilament (NF)-immunolabeled axons was estimated after photochemically induced ischemic spinal cord lesions using a stereological tool. The total l...

  2. Inhibiting poly(ADP-ribosylation) improves axon regeneration (United States)

    Byrne, Alexandra B; McWhirter, Rebecca D; Sekine, Yuichi; Strittmatter, Stephen M; Miller, David M; Hammarlund, Marc


    The ability of a neuron to regenerate its axon after injury depends in part on its intrinsic regenerative potential. Here, we identify novel intrinsic regulators of axon regeneration: poly(ADP-ribose) glycohodrolases (PARGs) and poly(ADP-ribose) polymerases (PARPs). PARGs, which remove poly(ADP-ribose) from proteins, act in injured C. elegans GABA motor neurons to enhance axon regeneration. PARG expression is regulated by DLK signaling, and PARGs mediate DLK function in enhancing axon regeneration. Conversely, PARPs, which add poly(ADP-ribose) to proteins, inhibit axon regeneration of both C. elegans GABA neurons and mammalian cortical neurons. Furthermore, chemical PARP inhibitors improve axon regeneration when administered after injury. Our results indicate that regulation of poly(ADP-ribose) levels is a critical function of the DLK regeneration pathway, that poly-(ADP ribosylation) inhibits axon regeneration across species, and that chemical inhibition of PARPs can elicit axon regeneration. DOI:

  3. Axon guidance of rat cortical neurons by microcontact printed gradients. (United States)

    Fricke, Rita; Zentis, Peter D; Rajappa, Lionel T; Hofmann, Boris; Banzet, Marko; Offenhäusser, Andreas; Meffert, Simone H


    Substrate-bound gradients expressed in numerous spatio-temporal patterns play a crucial role during the development of complex neural circuits. A deeper understanding of the axon guidance mechanism is provided by studying the effect of a defined substrate-bound cue on a confined neural network. In this study, we constructed a discontinuous substrate-bound gradient to control neuronal cell position, the path of neurite growth, and axon directionality. A variety of gradient patterns, with slight changes in slope, width, and length were designed and fabricated by microcontact printing using laminin/poly-l-lysine (PLL) or PLL alone. The gradients were tested for neurite growth and their impact on axon guidance of embryonic rat cortical neurons. The neurite length was determined and the axon was evaluated by Tau-1 immunostaining. We found that the microgradients of laminin/PLL and PLL directed neurons' adhesion, differentially controlled the neurite growth, and guided up to 84% of the axons. The effect of the protein micropattern on axon guidance and neurite growth depended on the protein and geometric parameters used. Our approach proved to be very successful in guiding axons of single multipolar neurons with very high efficiency. It could thereby be useful to engineer defined neural networks for analyzing signal processing of functional circuits, as well as to unravel fundamental questions of the axon guidance mechanism.

  4. Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models


    Smith, Karen D.B.; Erica Peethumnongsin; Han Lin; Hui Zheng; Pautler, Robia G.


    Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport ...

  5. SnoN facilitates axonal regeneration after spinal cord injury.

    Directory of Open Access Journals (Sweden)

    Jiun L Do

    Full Text Available Adult CNS neurons exhibit a reduced capacity for growth compared to developing neurons, due in part to downregulation of growth-associated genes as development is completed. We tested the hypothesis that SnoN, an embryonically regulated transcription factor that specifies growth of the axonal compartment, can enhance growth in injured adult neurons. In vitro, SnoN overexpression in dissociated adult DRG neuronal cultures significantly enhanced neurite outgrowth. Moreover, TGF-β1, a negative regulator of SnoN, inhibited neurite outgrowth, and SnoN over-expression overcame this inhibition. We then examined whether SnoN influenced axonal regeneration in vivo: indeed, expression of a mutant form of SnoN resistant to degradation significantly enhanced axonal regeneration following cervical spinal cord injury, despite peri-lesional upregulation of TGF-β1. Thus, a developmental mechanism that specifies extension of the axonal compartment also promotes axonal regeneration after adult CNS injury.

  6. Internodal function in normal and regenerated mammalian axons

    DEFF Research Database (Denmark)

    Moldovan, M; Krarup, C


    AIM: Following Wallerian degeneration, peripheral myelinated axons have the ability to regenerate and, given a proper pathway, establish functional connections with targets. In spite of this capacity, the clinical outcome of nerve regeneration remains unsatisfactory. Early studies have found...... that regenerated internodes remain persistently short though this abnormality did not seem to influence recovery in conduction. It remains unclear to which extent abnormalities in axonal function itself may contribute to the poor outcome of nerve regeneration. METHODS: We review experimental evidence indicating...... that internodes play an active role in axonal function. RESULTS: By investigating internodal contribution to axonal excitability we have found evidence that axonal function may be permanently compromised in regenerated nerves. Furthermore, we illustrate that internodal function is also abnormal in regenerated...

  7. Acrylamide induces accelerated endothelial aging in a human cell model. (United States)

    Sellier, Cyril; Boulanger, Eric; Maladry, François; Tessier, Frédéric J; Lorenzi, Rodrigo; Nevière, Rémi; Desreumaux, Pierre; Beuscart, Jean-Baptiste; Puisieux, François; Grossin, Nicolas


    Acrylamide (AAM) has been recently discovered in food as a Maillard reaction product. AAM and glycidamide (GA), its metabolite, have been described as probably carcinogenic to humans. It is widely established that senescence and carcinogenicity are closely related. In vitro, endothelial aging is characterized by replicative senescence in which primary cells in culture lose their ability to divide. Our objective was to assess the effects of AAM and GA on human endothelial cell senescence. Human umbilical vein endothelial cells (HUVECs) cultured in vitro were used as model. HUVECs were cultured over 3 months with AAM or GA (1, 10 or 100 μM) until growth arrest. To analyze senescence, β-galactosidase activity and telomere length of HUVECs were measured by cytometry and semi-quantitative PCR, respectively. At all tested concentrations, AAM or GA reduced cell population doubling compared to the control condition (p < 0.001). β-galactosidase activity in endothelial cells was increased when exposed to AAM (≥10 μM) or GA (≥1 μM) (p < 0.05). AAM (≥10 μM) or GA (100 μM) accelerated telomere shortening in HUVECs (p < 0.05). In conclusion, in vitro chronic exposure to AAM or GA at low concentrations induces accelerated senescence. This result suggests that an exposure to AAM might contribute to endothelial aging.

  8. Effects of Lipoic Acid on Acrylamide Induced Testicular Damage


    Lebda, Mohamed; Gad, Shereen; Gaafar, Hossam


    Introduction: Acrylamide is very toxic to various organs and associated with significant increase of oxidative stress and depletion of antioxidants. Alpha-lipoic acid enhances cellular antioxidant defense capacity, thereby protecting cells from oxidative stress. Aim of the study: This study aimed to evaluate the protective role of alpha-lipoic acid on the oxidative damage induced by acrylamide in testicular and epididymal tissues. Material and methods: Forty adult male rats were divided into ...

  9. Signaling mechanisms in cortical axon growth, guidance and branching

    Directory of Open Access Journals (Sweden)

    Katherine eKalil


    Full Text Available Precise wiring of cortical circuits during development depends upon axon extension, guidance and branching to appropriate targets. Motile growth cones at axon tips navigate through the nervous system by responding to molecular cues, which modulate signaling pathways within axonal growth cones. Intracellular calcium signaling has emerged as a major transducer of guidance cues but exactly how calcium signaling pathways modify the actin and microtubule cytoskeleton to evoke growth cone behaviors and axon branching is still mysterious. Axons must often pause in their outgrowth while their branches extend into targets. Some evidence suggests a competition between growth of axons and branches but the mechanisms are poorly understood. Since it is difficult to study growing axons deep within the mammalian brain, much of what we know about signaling pathways and cytoskeletal dynamics has come from studies of axonal growth cones, in many cases from non-mammalian species, growing in tissue culture. Consequently it is not well understood how guidance cues relevant to mammalian neural development in vivo signal to the growth cone cytoskeleton during axon outgrowth and guidance. In this review we describe our recent work in dissociated cultures of developing rodent sensorimotor cortex in the context of the current literature on molecular guidance cues, calcium signaling pathways and cytoskeletal dynamics that regulate growth cone behaviors. A major challenge is to relate findings in tissue culture to mechanisms of cortical development in vivo. Toward this goal, we describe our recent work in cortical slices, which preserve the complex cellular and molecular environment of the mammalian brain but allow direct visualization of growth cone behaviors and calcium signaling. Findings from this work suggest that mechanisms regulating axon growth and guidance in dissociated culture neurons also underlie development of cortical connectivity in vivo.

  10. An early diagnostic tool for diabetic peripheral neuropathy in rats

    NARCIS (Netherlands)

    S. Kambiz (Shoista); J.W. van Neck (Han); S.G. Cosgun (Saniye G.); M.H.N. van Velzen (M. H N); J.A.M.J.L. Janssen (Joseph); Avazverdi, N. (Naim); S.E.R. Hovius (Steven); E.T. Walbeehm (Erik)


    textabstractThe skin's rewarming rate of diabetic patients is used as a diagnostic tool for early diagnosis of diabetic neuropathy. At present, the relationship between microvascular changes in the skin and diabetic neuropathy is unclear in streptozotocin (STZ) diabetic rats. The aim of this study w

  11. An early diagnostic tool for diabetic peripheral neuropathy in rats

    NARCIS (Netherlands)

    Kambiz, S.; Neck, J.W. van; Cosgun, S.G.; Velzen, M.H. van; Janssen, J.A.M.; Avazverdi, N.; Hovius, S.E.; Walbeehm, E.T.


    The skin's rewarming rate of diabetic patients is used as a diagnostic tool for early diagnosis of diabetic neuropathy. At present, the relationship between microvascular changes in the skin and diabetic neuropathy is unclear in streptozotocin (STZ) diabetic rats. The aim of this study was to invest

  12. Leber's hereditary optic neuropathy and vitamin B12 deficiency

    NARCIS (Netherlands)

    Pott, Jan Willem R.; Wong, Kwok H.


    Background: Leber's hereditary optic neuropathy (LHON) is a maternally inherited optic neuropathy caused by mutations in mitochondrial DNA (mtDNA). It is also believed that several epigenetic factors have an influence on the development of LHON. Methods: A case series was observed. Results: Three pa

  13. Ischemic neuropathy and rhabdomyolysis as presenting symptoms of postpartum cardiomyopathy. (United States)

    Helmich, Rick C G; van Laarhoven, Hanneke W M; Schoonderwaldt, Hennie C; Janssen, Mirian C H


    Rhabdomyolysis and peripheral neuropathy are two distinct disease entities which are rarely encountered in combination. We present a woman with rhabdomyolysis and peripheral neuropathy 3 weeks postpartum. Her symptoms were caused by bilateral femoral artery thrombosis due to postpartum cardiomyopathy (PPCM). This demonstrates that PPCM may present with predominantly non-cardial symptoms and underscores the importance of rapidly recognizing this disorder.

  14. Congenital cataract facial dysmorphism neuropathy syndrome: a clinically recognizable entity.

    NARCIS (Netherlands)

    Shabo, G.; Scheffer, H.; Cruysberg, J.R.M.; Lammens, M.M.Y.; Pasman, J.W.; Spruit, M.; Willemsen, M.A.A.P.


    Congenital cataracts facial dysmorphism neuropathy syndrome is a recently delineated autosomal recessive condition exclusively found in the Gypsy population. Congenital cataracts facial dysmorphism neuropathy syndrome is caused by a homozygous mutation in the CTDP1 gene, leading to disruption of the

  15. Pyridoxine and pyridostigmine treatment in vincristine-induced neuropathy. (United States)

    Ozyurek, Hamit; Turker, Hande; Akbalik, Mehtap; Bayrak, Ayse Oytun; Ince, Hulya; Duru, Feride


    Vincristine is a commonly used antineoplastic drug and frequently causes neurotoxicity. Here the authors report a 4-year-old boy with acute lymphoblastic leukemia in whom vincristine-induced peripheral and cranial neuropathy developed during remission induction therapy. The patient seemed to benefit from pyridoxine and pyridostigmine therapy greatly and this therapy is recommended in patients with severe vincristine-induced neuropathy.

  16. Amitriptyline-related peripheral neuropathy relieved during pyridoxine hydrochloride administration. (United States)

    Meadows, G G; Huff, M R; Fredericks, S


    Tricyclic antidepressants rarely cause peripheral neuropathy. In fact, this class of drugs has been used to control the symptoms of pain and paresthesia that accompany peripheral neuropathy. We report peripheral paresthesias that occurred in a 39-year-old female during five years of amitriptyline administration. The patient's symptoms were relieved by oral pyridoxine hydrochloride, associated with elevated plasma pyridoxal phosphate.

  17. Rhesus anti-D immunoglobulin in chronic autoimmune neuropathy

    NARCIS (Netherlands)

    de Jager, AEJ; van der Hoeven, JH


    Objective - To investigate the effect of Rhesus anti-D immunoglobulin (anti-D) in patients with an autoimmune demyelinating neuropathy. Material and methods - Three patients with an autoimmune mediated neuropathy received 1000 IU anti-D weekly for 2 months. Results - Two patients worsened gradually

  18. Clinical features of diffuse axonal injury

    Institute of Scientific and Technical Information of China (English)


    Objective: To analyze the mechanism of diffuse axonal injury (DAI) and study the relationship between DAI and brain concussion, brain contusion, and primary brain stem injury.Methods: The clinical data and iconographic characteristics of 56 patients with DAI were analyzed retrospectively.Results: Traffic accidents were the main cause of DAI. Among the 56 cases, 34 were injured for at least twice, and 71.43% of the patients were complicated with contusion.Conclusions: It is considered that DAI is a common pattern of primary brain injury, which is often underestimated. And DAI includes cerebral concussion and primary brain injury, and is often complicated by cerebral cortex contusion. Therefore, it is very simple and practical to divide primary brain injuries into local and diffuse injuries.

  19. Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Hilsted, J; Richter, E; Madsbad, S


    . To study these responses, we administered epinephrine in a graded intravenous infusion (0.5 to 5 micrograms per minute) to seven diabetic patients without neuropathy, seven diabetic patients with autonomic neuropathy, and seven normal subjects. Mean arterial pressure decreased significantly in the patients...... with autonomic neuropathy than in the other groups (P less than 0.05). These findings indicate that several beta-receptor-mediated responses to epinephrine are enhanced in patients with diabetic autonomic neuropathy. The underlying mechanism remains to be elucidated.......Norepinephrine-induced vasoconstriction, which is mediated by alpha-adrenergic receptors, is accentuated in patients with autonomic neuropathy. In contrast, responses mediated by beta-adrenergic receptors, including vasodilatation and metabolic changes, have not been evaluated in these patients...

  20. Decreased myocardial perfusion reserve in diabetic autonomic neuropathy

    DEFF Research Database (Denmark)

    Taskiran, Mustafa; Fritz-Hansen, Thomas; Rasmussen, Verner


    The pathophysiological mechanisms responsible for increased cardiovascular mortality in diabetic autonomic neuropathy are unknown. To investigate the effect of autonomic neuropathy on myocardial function, we performed dynamic contrast-enhanced magnetic resonance perfusion imaging during baseline...... conditions and after Dipyridamole-induced vasodilatation in nine type 1 diabetic patients with autonomic neuropathy (AN+), defined by cardiovascular tests, as well as in 10 type 1 diabetic patients without autonomic neuropathy (AN-) and 10 healthy control subjects. Baseline myocardial perfusion index (K...... blood pressure response to Dipyridamole and myocardial perfusion reserve index. We conclude that type 1 diabetic patients with autonomic neuropathy have a decreased myocardial perfusion reserve capacity when challenged with a vasodilatator, a finding that may in part be the pathophysiological substrate...

  1. Optic neuropathy associated with periostitis in relapsing polychondritis. (United States)

    Hirunwiwatkul, Parima; Trobe, Jonathan D


    Optic neuropathy is an uncommon manifestation of relapsing polychondritis (RPC), a rare systemic disease affecting cartilaginous and proteoglycan-rich structures. The optic neuropathy has been attributed to ischemia, intrinsic inflammation of the optic nerve, or spread of inflammation to the nerve from adjacent intraconal orbital tissues. We report a case of recurrent corticosteroid-responsive optic neuropathy in which MRI did not show ocular, optic nerve, or intraconal orbital abnormalities but did show periosteal thickening and enhancement in the apical orbit and adjacent intracranial space consistent with periostitis. The periostitis, which is a manifestation of a systemic vasculitis or an autoimmune reaction to progenitors of cartilage, probably caused the optic neuropathy by compression or inflammation. It is important to recognize this mechanism of optic neuropathy as its imaging features may be a subtle yet critical clue to an underlying systemic condition that can be life-threatening if not properly managed.

  2. Clinical, neurophysiological and morphological study of dominant intermediate Charcot-Marie-Tooth type C neuropathy. (United States)

    Thomas, Florian P; Guergueltcheva, Velina; Gondim, Francisco A A; Tournev, Ivailo; Rao, Chitharanjan V; Ishpekova, Boryana; Kinsella, Laurence J; Pan, Yi; Geller, Thomas J; Litvinenko, Ivan; De Jonghe, Peter; Scherer, Steven S; Jordanova, Albena


    Dominant intermediate Charcot-Marie-Tooth neuropathy subtype C (DI-CMTC) was associated with mutations in the YARS gene, encoding tyrosyl-tRNA synthetase, in two large unrelated Bulgarian and US pedigrees and one sporadic case. Here for the first time we describe the clinical, neurophysiological and histopathological features, and phenotypic differences between these two DI-CMTC families. Twenty-one affected individuals from the US family and 27 from the Bulgarian family were evaluated. The mean age of onset in US subjects was 10.7 years in men and 7.3 years in women, while in the Bulgarian participants it was 18.2 years in men and 33.7 years in women. The course was slowly progressive. Extensor digitorum brevis atrophy was uniform. Atrophy and/or weakness of upper and lower limb muscles were found in over 50 % of the subjects. Nerve conduction studies (NCS) were abnormal in all US adults and five of six children and all Bulgarian patients except one asymptomatic 25-year-old man. Median motor NCS were in the range of 29.5-45.6 m/s in the US family and 24.7-57.8 m/s in the Bulgarian family. Sural sensory nerve action potentials were absent in 14/21 and 4/12 NCS from adult US and Bulgarian participants, respectively. Analysis of sural nerve biopsies from US patients revealed age-dependent morphological changes of axonal degeneration, absence of onion bulbs, and <10 % fibers with segmental remyelination. Our findings provide further insights into the diagnosis and pathology of intermediate CMT. They also extend the phenotypic spectrum of peripheral neuropathies associated with aminoacyl-tRNA synthetase mutations.

  3. Fuzzy expert system for diagnosing diabetic neuropathy (United States)

    Rahmani Katigari, Meysam; Ayatollahi, Haleh; Malek, Mojtaba; Kamkar Haghighi, Mehran


    AIM To design a fuzzy expert system to help detect and diagnose the severity of diabetic neuropathy. METHODS The research was completed in 2014 and consisted of two main phases. In the first phase, the diagnostic parameters were determined based on the literature review and by investigating specialists’ perspectives (n = 8). In the second phase, 244 medical records related to the patients who were visited in an endocrinology and metabolism research centre during the first six months of 2014 and were primarily diagnosed with diabetic neuropathy, were used to test the sensitivity, specificity, and accuracy of the fuzzy expert system. RESULTS The final diagnostic parameters included the duration of diabetes, the score of a symptom examination based on the Michigan questionnaire, the score of a sign examination based on the Michigan questionnaire, the glycolysis haemoglobin level, fasting blood sugar, blood creatinine, and albuminuria. The output variable was the severity of diabetic neuropathy which was shown as a number between zero and 10, had been divided into four categories: absence of the disease, (the degree of severity) mild, moderate, and severe. The interface of the system was designed by ASP.Net (Active Server Pages Network Enabled Technology) and the system function was tested in terms of sensitivity (true positive rate) (89%), specificity (true negative rate) (98%), and accuracy (a proportion of true results, both positive and negative) (93%). CONCLUSION The system designed in this study can help specialists and general practitioners to diagnose the disease more quickly to improve the quality of care for patients. PMID:28265346

  4. Anterior ischemic optic neuropathy following dengue fever. (United States)

    Ramakrishnan, Reshma; Shrivastava, Saurabh; Deshpande, Shrikant; Patkar, Priyanka


    Dengue fever is caused by a flavivirus. This infection is endemic in the tropics and warm temperate regions of the world. Ocular manifestations of dengue fever include subconjunctival, vitreous, and retinal haemorrhages; posterior uveitis; optic neuritis; and maculopathies, haemorrhage, and oedema. However anterior ischemic optic neuropathy is a rare presentation. Optic nerve ischemia most frequently occurs at the optic nerve head, where structural crowding of nerve fibers and reduction of the vascular supply may combine to impair perfusion to a critical degree and produce optic disc oedema. Here we present a case of anterior ischemic optic neurapathy associated with dengue fever.

  5. [Ulnar neuropathy in a poultry worker]. (United States)

    Svendsen, Susanne Wulff; Juhl, Anne Haase


    Three months after he was employed as a poultry worker, a 48-year-old man developed involuntary jerks of his right first, fourth, and fifth fingers, paraesthesiae, weakness, and eventually wasting of the first dorsal interosseous muscle. His job entailed repetitive lifting of boxes weighing 10-25 kg with flexion of the elbow, pronation of the forearm, and ulnar deviation of the wrist. A nerve conduction study indicated ulnar neuropathy just distal to the elbow. Surgery at this level alleviated the symptoms, but shortly after his return to work, he changed jobs because of aggravation.

  6. Recurrent painful ophthalmoplegic neuropathy; A case report

    Directory of Open Access Journals (Sweden)

    Semra Saygi


    Full Text Available Recurrent painful ophthalmoplegic neuropathy, typically seen as a serious childhood migraine attack which is followed by ptosis and diplopia due to oculomotor nerve palsy. This is regarded as a form of migraine in the previous classifications but according to the latest classification of the International Headache Society has been recognized as cranial neuralgia. Due to the poor pathological and radiological findings of oculomotor nerve during attack, it is difficult to make differential diagnosis. In this manuscript we report 11-year-old female patient with ophtalmoplegic migraine. [Cukurova Med J 2014; 39(4.000: 938-941

  7. Clinical features and electrodiagnosis of ulnar neuropathies. (United States)

    Landau, Mark E; Campbell, William W


    In this review, we delineate clinical, electrodiagnostic, and radiographic features of ulnar mononeuropathies. Ulnar neuropathy at the elbow (UNE) is most commonly due to lesions at the level of the retroepicondylar groove (RTC), with approximately 25% at the humeroulnar arcade (HUA). The term 'cubital tunnel syndrome' should be reserved for the latter. The diagnostic accuracy of nerve conduction studies is limited by biological (e.g. low elbow temperature) and technical factors. Across-elbow distance measurements greater than 10 cm improve diagnostic specificity at the expense of decreased sensitivity. Short-segment incremental studies can differentiate lesions at the HUA from those at the RTC.

  8. Neuro-vascular-desmal relationship disturbances in peripheral nerves, dorsal root ganglions and motor segmental centers in the etoposide-induced neuropathy.

    Directory of Open Access Journals (Sweden)

    Gerashchenko S.B.


    Full Text Available The purpose of work was to determine the mechanisms of pathologic morphogenesis of the toxic neuropathy caused by etoposide taking into consideration all complex the neuro-vascular-desmal relationship disturbances in peripheral nerves, their motor and sensor segmental centers. It has been shown in the experiments on 86 white rats that single intravenous injection of etoposide at dose of 22 mg/kg body weight induse peripheral neuropathy. The complex of morphologic methods included the neurohistological and electronic microscopic methods of the research, the histochemical markers for study transmissivity of the vessels of the circulatory bed on the light microscopic and ultrastructural levels was used. The recommendations of the Interagency Committee of Neurotoxicology were considered to choose the methods of the research. The presence of 3 stages of morphogenesis has been established - phase of primary axonal reaction (3d day of experiment, phase of disturbance of the microcirculation of peripheral nerves and their segmental centers (7th day of experiment, phase of degenerative changes (15th day. Etoposide-indused neuropathy features are determined by a singularity of interdependent reactive changes, alteration and compensation processes in sensory and motor neurons, glial cells, microcirculatory bed and connective tissue.

  9. Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. (United States)

    Stimpson, Scott E; Coorssen, Jens R; Myers, Simon J


    Axonal degeneration is the final common path in many neurological disorders. Subsets of neuropathies involving the sensory neuron are known as hereditary sensory neuropathies (HSNs). Hereditary sensory neuropathy type I (HSN-I) is the most common subtype of HSN with autosomal dominant inheritance. It is characterized by the progressive degeneration of the dorsal root ganglion (DRG) with clinical symptom onset between the second or third decade of life. Heterozygous mutations in the serine palmitoyltransferase (SPT) long chain subunit 1 (SPTLC1) gene were identified as the pathogenic cause of HSN-I. Ultrastructural analysis of mitochondria from HSN-I patient cells has displayed unique morphological abnormalities that are clustered to the perinucleus where they are wrapped by the endoplasmic reticulum (ER). This investigation defines a small subset of proteins with major alterations in abundance in mitochondria harvested from HSN-I mutant SPTLC1 cells. Using mitochondrial protein isolates from control and patient lymphoblasts, and a combination of 2D gel electrophoresis, immunoblotting and mass spectrometry, we have shown the increased abundance of ubiquinol-cytochrome c reductase core protein 1, an electron transport chain protein, as well as the immunoglobulin, Ig kappa chain C. The regulation of these proteins may provide a new route to understanding the cellular and molecular mechanisms underlying HSN-I.

  10. Vasculitis neuropathy mimicking lower limb mono-radiculopathy: a study and follow-up of 8 cases. (United States)

    Lozeron, Pierre; Lacroix, Catherine; Michon, Mathilde; Theaudin, Marie; Petit Lacour, Marie-Christine; Denier, Christian; Adams, David


    The aim of this study was to describe misleading lower limb mono radiculopathy revealing peripheral nerve vasculitis. Retrospective review of eight patients with biopsy confirmed vasculitis presenting as mono-radicululopathy in a tertiary referral centre dedicated to patients with rare peripheral neuropathies. Patients presented with chronic (6/8) or acute (n = 2) radiculopathy in L4, L5 or S1 territories associated with subtle systemic signs. A diagnostic workup was performed because of secondary motor deficit, the absence of clear radicular compression or failure of initial treatment focused on pain relief. In all, nerve conduction studies showed signs of asymmetrical axonal peripheral neuropathy (mononeuritis multiplex). Necrotizing vasculitis was eventually confirmed by peripheral nerve biopsy. Biological markers of inflammation or eosinophilia were present in 5/8 and a progressive motor deficit (7/8) is suggestive of the diagnosis. Under steroid treatment, all patients improved during a mean of 2 years 6 months of follow-up (Mean Rankin score improvement 1.9 point), but five relapsed including three mononeuritis multiplex, and one had acral necrosis. Vasculitis presenting as LL radiculopathy is rare; EMG studies with signs of mononeuritis multiplex and nerve biopsy studies are useful for making the diagnosis.

  11. Dose response, coasting, and differential fiber vulnerability in human toxic neuropathy: a prospective study of pyridoxine neurotoxicity. (United States)

    Berger, A R; Schaumburg, H H; Schroeder, C; Apfel, S; Reynolds, R


    We administered either 1 or 3 g/d of pyridoxine (vitamin B6) to five healthy volunteers and repeatedly followed serum pyridoxal phosphate levels, clinical symptoms and signs, quantitative sensory thresholds (QSTs), and sural nerve electrophysiology. Pyridoxine was discontinued at the first sign of either clinical or laboratory abnormality. In all subjects, sensory symptoms and QST abnormalities occurred concurrently. Subjects receiving higher doses became symptomatic earlier than low-dose subjects. Elevation of thermal QSTs preceded or exceeded that for vibration in the three low-dose subjects; vibration and thermal QST became abnormal simultaneously in the higher-dose subjects. A reduction in the amplitude of the sural sensory potential lagged behind QST changes in two of three subjects. Symptoms continued to progress ("coasting") for 2 to 3 weeks despite stopping pyridoxine administration and the return of serum pyridoxal phosphate levels to normal. This study suggests that (1) there is a clear dose-percent relationship for pyridoxine-induced neuropathy, (2) QST is a sensitive measurement for detecting early peripheral neuropathy; QST abnormalities may precede changes in nerve conduction studies, (3) coasting appears unrelated to persistently elevated blood levels of the toxin, and (4) a dose-dependent vulnerability may exist among nerve fibers of different caliber when exposed to an axonal toxin, such as pyridoxine.

  12. Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration. (United States)

    Ma, Marek; Ferguson, Toby A; Schoch, Kathleen M; Li, Jian; Qian, Yaping; Shofer, Frances S; Saatman, Kathryn E; Neumar, Robert W


    In both the central nervous system (CNS) and peripheral nervous system (PNS), transected axons undergo Wallerian degeneration. Even though Augustus Waller first described this process after transection of axons in 1850, the molecular mechanisms may be shared, at least in part, by many human diseases. Early pathology includes failure of synaptic transmission, target denervation, and granular disintegration of the axonal cytoskeleton (GDC). The Ca(2+)-dependent protease calpains have been implicated in GDC but causality has not been established. To test the hypothesis that calpains play a causal role in axonal and synaptic degeneration in vivo, we studied transgenic mice that express human calpastatin (hCAST), the endogenous calpain inhibitor, in optic and sciatic nerve axons. Five days after optic nerve transection and 48 h after sciatic nerve transection, robust neurofilament proteolysis observed in wild-type controls was reduced in hCAST transgenic mice. Protection of the axonal cytoskeleton in sciatic nerves of hCAST mice was nearly complete 48 h post-transection. In addition, hCAST expression preserved the morphological integrity of neuromuscular junctions. However, compound muscle action potential amplitudes after nerve transection were similar in wild-type and hCAST mice. These results, in total, provide direct evidence that calpains are responsible for the morphological degeneration of the axon and synapse during Wallerian degeneration.

  13. Local erythropoietin signaling enhances regeneration in peripheral axons. (United States)

    Toth, C; Martinez, J A; Liu, W Q; Diggle, J; Guo, G F; Ramji, N; Mi, R; Hoke, A; Zochodne, D W


    Erythropoietin (EPO) and its receptor (EPO-R), mediate neuroprotection from axonopathy and apoptosis in the peripheral nervous system (PNS). We examined the impact and potential mechanisms of local EPO signaling on regenerating PNS axons in vivo and in vitro. As a consequence of injury, peripheral nerve axons and DRG neurons have a marked increase in the expression of EPO and EPO-R. Local delivery of EPO via conduit over 2 weeks to rat sciatic nerve following crush injury increased the density and maturity of regenerating myelinated axons growing distally from the crush site. In addition, EPO also rescued retrograde degeneration and atrophy of axons. EPO substantially increased the density and intensity of calcitonin gene-related peptide (CGRP) expression within outgrowing axons. Behavioral improvements in sensorimotor function also occurred in rats exposed to near nerve EPO delivery. EPO delivery led to decreased nuclear factor kappaB (NFkB) activation but increased phosphorylation of Akt and STAT3 within nerve and dorsal root ganglia neurons indicating rescue from an injury phenotype. Spinal cord explant studies also demonstrated a similar dose-dependent effect of EPO upon motor axonal outgrowth. Local EPO signaling enhances regenerating peripheral nervous system axons in addition to its known neuroprotection. Exogenous EPO may have a therapeutic role in a large number of peripheral nerve diseases through its impact on regeneration.

  14. The frequency of peripheral neuropathy in a group of HIV positive patients in Brazil Freqüência da neuropatia periférica no Brasil em um grupo de pacientes HIV positivo

    Directory of Open Access Journals (Sweden)

    Claudia Zanetti


    Full Text Available Peripheral neuropathy is a common neurological complication occurring in asymptomatic and symptomatic stages of HIV infection. The most common syndromes are distal symmetric polyneuropathy, inflammatory demielinating polyneuropathy, poliradiculopathy, mononeuropathy, mononeuropathy multiplex and autonomic neuropathy. PURPOSE: To evaluate the frequency of peripheral neuropathy in a group of HIV seropositive outpatients in São Paulo, Brazil. METHOD: Over a period of 17 months, 49 HIV+ patients where evaluated clinically. Laboratory analysis and electroneuromyography were requested to all patients. RESULTS: >Thirty four (69.4% of the 49 patients had the diagnosis of peripheral neuropathy established on clinical grounds. The most common sign was impairment (97.1% of sensibility. Thirteen (33.3% of the 39 that were subjected to electroneuromyography had features of peripheral neuropathy, being a sensitive-motor axonal neuropathy the most common. No abnormalities were found in the laboratory analysis performed in 42 patients, except in four who had VDRL positive. CONCLUSION: A peripheral neuropathy was frequently found upon clinical examination in our group of HIV positive individuals.A neuropatia periférica é complicação neurológica comum, podendo ocorrer nas fases assintomáticas e sintomáticas da infecção pelo vírus da imunodeficiência humana (HIV. As síndromes mais comuns são a polineuropatia distal simétrica, polineuropatia desmielinizante inflamatória, polirradiculopatia, mononeuropatia, mononeuropatia múltipla e neuropatia autonômica. OBJETIVO: Avaliar a freqüência da neuropatia periférica em um grupo de pacientes HIV positivo em São Paulo, Brasil. MÉTODO: Em um período de 17 meses, foram avaliados clinicamente 49 pacientes HIV positivos. Foram solicitados exames laboratoriais e eletroneuromiografia (ENMG para todos os pacientes. RESULTADOS: Foi estabelecido o diagnóstico clínico de neuropatia periférica em 34 (69

  15. Pathophysiological actions of neuropathy-related anti-ganglioside antibodies at the neuromuscular junction. (United States)

    Plomp, Jaap J; Willison, Hugh J


    The outer leaflet of neuronal membranes is highly enriched in gangliosides. Therefore, specific neuronal roles have been attributed to this family of sialylated glycosphingolipids, e.g. in modulation of ion channels and transporters, neuronal interaction and recognition, temperature adaptation, Ca(2+) homeostasis, axonal growth, (para)node of Ranvier stability and synaptic transmission. Recent developmental, ageing and injury studies on transgenic mice lacking subsets of gangliosides indicate that gangliosides are involved in maintenance rather than development of the nervous system and that ganglioside family members are able to act in a mutually compensatory manner. Besides having physiological functions, gangliosides are the likely antigenic targets of autoantibodies present in Guillain-Barré syndrome (GBS), a group of neuropathies with clinical symptoms of motor- and/or sensory peripheral nerve dysfunction. Antibody binding to peripheral nerves is thought to either interfere with ganglioside function or activate complement, causing axonal damage and thereby disturbed action potential conduction. The presynaptic motor nerve terminal at the neuromuscular junction (NMJ) may be a prominent target because it is highly enriched in gangliosides and lies outside the blood-nerve barrier, allowing antibody access. The ensuing neuromuscular synaptopathy might contribute to the muscle weakness in GBS patients. Several groups, including our own, have studied the effects of anti-ganglioside antibodies in ex vivo and in vivo experimental settings at mouse NMJs. Here, after providing a background overview on ganglioside synthesis, localization and physiology, we will review those studies, which clearly show that anti-ganglioside antibodies are capable of binding to NMJs and thereby can exert a variety of pathophysiological effects. Furthermore, we will discuss the human clinical electrophysiological and histological evidence produced so far of the existence of a neuromuscular

  16. Immediate and delayed cochlear neuropathy after noise exposure in pubescent mice.

    Directory of Open Access Journals (Sweden)

    Jane Bjerg Jensen

    Full Text Available Moderate acoustic overexposure in adult rodents is known to cause acute loss of synapses on sensory inner hair cells (IHCs and delayed degeneration of the auditory nerve, despite the completely reversible temporary threshold shift (TTS and morphologically intact hair cells. Our objective was to determine whether a cochlear synaptopathy followed by neuropathy occurs after noise exposure in pubescence, and to define neuropathic versus non-neuropathic noise levels for pubescent mice. While exposing 6 week old CBA/CaJ mice to 8-16 kHz bandpass noise for 2 hrs, we defined 97 dB sound pressure level (SPL as the threshold for this particular type of neuropathic exposure associated with TTS, and 94 dB SPL as the highest non-neuropathic noise level associated with TTS. Exposure to 100 dB SPL caused permanent threshold shift although exposure of 16 week old mice to the same noise is reported to cause only TTS. Amplitude of wave I of the auditory brainstem response, which reflects the summed activity of the cochlear nerve, was complemented by synaptic ribbon counts in IHCs using confocal microscopy, and by stereological counts of peripheral axons and cell bodies of the cochlear nerve from 24 hours to 16 months post exposure. Mice exposed to neuropathic noise demonstrated immediate cochlear synaptopathy by 24 hours post exposure, and delayed neurodegeneration characterized by axonal retraction at 8 months, and spiral ganglion cell loss at 8-16 months post exposure. Although the damage was initially limited to the cochlear base, it progressed to also involve the cochlear apex by 8 months post exposure. Our data demonstrate a fine line between neuropathic and non-neuropathic noise levels associated with TTS in the pubescent cochlea.

  17. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies.

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    Ilaria Vaccari


    Full Text Available We previously reported that autosomal recessive demyelinating Charcot-Marie-Tooth (CMT type 4B1 neuropathy with myelin outfoldings is caused by loss of MTMR2 (Myotubularin-related 2 in humans, and we created a faithful mouse model of the disease. MTMR2 dephosphorylates both PtdIns3P and PtdIns(3,5P(2, thereby regulating membrane trafficking. However, the function of MTMR2 and the role of the MTMR2 phospholipid phosphatase activity in vivo in the nerve still remain to be assessed. Mutations in FIG4 are associated with CMT4J neuropathy characterized by both axonal and myelin damage in peripheral nerve. Loss of Fig4 function in the plt (pale tremor mouse produces spongiform degeneration of the brain and peripheral neuropathy. Since FIG4 has a role in generation of PtdIns(3,5P(2 and MTMR2 catalyzes its dephosphorylation, these two phosphatases might be expected to have opposite effects in the control of PtdIns(3,5P(2 homeostasis and their mutations might have compensatory effects in vivo. To explore the role of the MTMR2 phospholipid phosphatase activity in vivo, we generated and characterized the Mtmr2/Fig4 double null mutant mice. Here we provide strong evidence that Mtmr2 and Fig4 functionally interact in both Schwann cells and neurons, and we reveal for the first time a role of Mtmr2 in neurons in vivo. Our results also suggest that imbalance of PtdIns(3,5P(2 is at the basis of altered longitudinal myelin growth and of myelin outfolding formation. Reduction of Fig4 by null heterozygosity and downregulation of PIKfyve both rescue Mtmr2-null myelin outfoldings in vivo and in vitro.

  18. Axon guidance and neuronal migration research in China

    Institute of Scientific and Technical Information of China (English)


    Proper migration of neuronal somas and axonal growth cones to designated locations in the developing brain is essential for the assembly of functional neuronal circuits.Rapid progress in research of axon guidance and neuronal migration has been made in the last twenty years.Chinese researchers began their exploration in this field ten years ago and have made significant contributions in clarifying the signal transduction of axon guidance and neuronal migration.Several unique experimental approaches,including the migration assay of single isolated neurons in response to locally delivered guidance cues,have been developed by Chinese neuroscientists to investigate the molecular machinery underlying these guidance events.

  19. Early diabetic neuropathy: Triggers and mechanisms

    Institute of Scientific and Technical Information of China (English)

    Maxim Dobretsov; Dmitry Romanovsky; Joseph R Stimers


    Peripheral neuropathy, and specifically distal peripheral neuropathy (DPN), is one of the most frequent and troublesome complications of diabetes mellitus. It is the major reason for morbidity and mortality among diabetic patients, It is also frequently associated with debilitating pain. Unfortunately, our knowledge of the natural history and pathogenesis of this disease remains limited. For a long time hyperglycemia was viewed as a major, if not the sole factor, responsible for all symptomatic presentations of DPN. Multiple clinical observations and animal studies supported this view. The control of blood glucose as an obligatory step of therapy to delay or reverse DPN is no longer an arguable issue. However, while supporting evidence for the glycemic hypothesis has accumulated, multiple controversies accumulated as well.It is obvious now that DPN cannot be fully understood without considering factors besides hyperglycemia. Some symptoms of DPN may develop with little, if any, correlation with the glycemic status of a patient. It is also clear that identification of these putative non-glycemic mechanisms of DPN is of utmost importance for our understanding of failures with existing treatments and for the development of new approaches for diagnosis and therapy of DPN. In this work we will review the strengths and weaknesses of the glycemic hypothesis, focusing on clinical and animal data and on the pathogenesis of early stages and triggers of DPN other than hyperglycemia.

  20. Computer aided diagnosis of diabetic peripheral neuropathy (United States)

    Chekh, Viktor; Soliz, Peter; McGrew, Elizabeth; Barriga, Simon; Burge, Mark; Luan, Shuang


    Diabetic peripheral neuropathy (DPN) refers to the nerve damage that can occur in diabetes patients. It most often affects the extremities, such as the feet, and can lead to peripheral vascular disease, deformity, infection, ulceration, and even amputation. The key to managing diabetic foot is prevention and early detection. Unfortunately, current existing diagnostic techniques are mostly based on patient sensations and exhibit significant inter- and intra-observer differences. We have developed a computer aided diagnostic (CAD) system for diabetic peripheral neuropathy. The thermal response of the feet of diabetic patients following cold stimulus is captured using an infrared camera. The plantar foot in the images from a thermal video are segmented and registered for tracking points or specific regions. The temperature recovery of each point on the plantar foot is extracted using our bio-thermal model and analyzed. The regions that exhibit abnormal ability to recover are automatically identified to aid the physicians to recognize problematic areas. The key to our CAD system is the segmentation of infrared video. The main challenges for segmenting infrared video compared to normal digital video are (1) as the foot warms up, it also warms up the surrounding, creating an ever changing contrast; and (2) there may be significant motion during imaging. To overcome this, a hybrid segmentation algorithm was developed based on a number of techniques such as continuous max-flow, model based segmentation, shape preservation, convex hull, and temperature normalization. Verifications of the automatic segmentation and registration using manual segmentation and markers show good agreement.

  1. Diagnosis and classification of autoimmune optic neuropathy. (United States)

    Petzold, Axel; Plant, Gordon T


    The spectrum of autoimmune optic neuropathies (ON) is extending. The phenotypic spectrum includes single isolated optic neuritis (SION), relapsing isolated optic neuritis (RION), chronic relapsing inflammatory optic neuropathy (CRION), the neuromyelitis optica (NMO) spectrum disorder, multiple sclerosis associated optic neuritis (MSON) and unclassified optic neuritis (UCON) forms. Epidemiological data suggests a slight female predominance. The ethnic heritage is relevant as Caucasian patients are more likely to suffer from MSON, whilst SION, RION, CRION and NMO are more frequent in non-Caucasian patients. Importantly, prognosis for recovery of visual function is good in MSON, but poorer in NMO and CRION which also have a high chance for recurrent episodes. Testing for serum anti-AQP4 autoantibodies is advised in all patients with severe, atypical or recurrent ON because of the high diagnostic specificity. The diagnostic specificity may be aided by testing for glial biomarkers in the CSF and prognostic accuracy by testing for biomarkers for neuroaxonal degeneration. Optical coherence tomography is a highly accurate tool to document the final outcome. The current clinical classification criteria rely on the phenotype, response to treatment and presence of anti-AQP4 autoantibodies.

  2. Leber hereditary optic neuropathy: current perspectives (United States)

    Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin


    Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells. PMID:26170609

  3. Leber hereditary optic neuropathy: current perspectives. (United States)

    Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin


    Leber hereditary optic neuropathy (LHON) is one of the most common inherited optic neuropathies causing bilateral central vision loss. The disorder results from point mutations in mitochondrial DNA and subsequent mitochondrial dysfunction. The primary cell type that is lost in LHON is the retinal ganglion cell, which is highly susceptible to disrupted ATP production and oxidative stress. Inheritance of LHON follows that of mitochondrial genetics, and it has a highly variable clinical phenotype, as other genetic and environmental factors also play a role. Although LHON usually presents with isolated vision loss, some patients suffer other neurological sequelae. For ill-defined reasons, male LHON mutation carriers are more affected than females. Most LHON patients remain legally blind, but a small proportion can experience spontaneous partial recovery, often within the first year of symptom onset. Unfortunately, at this time there are no established curative interventions and treatment is largely supportive. Patients should be offered low vision services and counseled on mitigating risk factors for additional vision loss, such as smoking and consuming alcohol. Encouraging treatments currently undergoing investigation includes ubiquinone analogs, such as idebenone, as well as gene therapy and stem cells to restore ATP synthesis and provide neuroprotection to surviving retinal ganglion cells.

  4. Molecular genetics of hereditary sensory neuropathies. (United States)

    Auer-Grumbach, Michaela; Mauko, Barbara; Auer-Grumbach, Piet; Pieber, Thomas R


    Hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), are a clinically and genetically heterogeneous group of disorders. They are caused by neuronal atrophy and degeneration, predominantly affecting peripheral sensory and autonomic neurons. Both congenital and juvenile to adulthood onset is possible. Currently, the classification of the HSN depends on the mode of inheritance, age at onset, and clinical presentation. Hallmark features are progressive sensory loss, chronic skin ulcers, and other skin abnormalities. Spontaneous fractures and neuropathic arthropathy are frequent complications and often necessitate amputations. Autonomic features vary between different subgroups. Distal muscle weakness and wasting may be present and is sometimes so prominent that it becomes difficult to distinguish HSN from Charcot-Marie-Tooth syndrome. Recent major advances in molecular genetics have led to the identification of seven gene loci and six-disease causing genes for autosomal-dominant and autosomal-recessive HSN. These genes have been shown to play roles in lipid metabolism and the regulation of intracellular vesicular transport, but also a presumptive transcriptional regulator, a nerve growth factor receptor, and a nerve growth factor have been described among the causative genes in HSN. Nevertheless, it remains unclear how mutations in the known genes lead to the phenotype of HSN. In this review, we summarize the recent progress of the molecular genetics of the HSN and the implicated genes.

  5. Action potentials initiate in the axon initial segment and propagate through axon collaterals reliably in cerebellar Purkinje neurons. (United States)

    Foust, Amanda; Popovic, Marko; Zecevic, Dejan; McCormick, David A


    Purkinje neurons are the output cells of the cerebellar cortex and generate spikes in two distinct modes, known as simple and complex spikes. Revealing the point of origin of these action potentials, and how they conduct into local axon collaterals, is important for understanding local and distal neuronal processing and communication. By using a recent improvement in voltage-sensitive dye imaging technique that provided exceptional spatial and temporal resolution, we were able to resolve the region of spike initiation as well as follow spike propagation into axon collaterals for each action potential initiated on single trials. All fast action potentials, for both simple and complex spikes, whether occurring spontaneously or in response to a somatic current pulse or synaptic input, initiated in the axon initial segment. At discharge frequencies of less than approximately 250 Hz, spikes propagated faithfully through the axon and axon collaterals, in a saltatory manner. Propagation failures were only observed for very high frequencies or for the spikelets associated with complex spikes. These results demonstrate that the axon initial segment is a critical decision point in Purkinje cell processing and that the properties of axon branch points are adjusted to maintain faithful transmission.

  6. Peripheral Nerve Ultrasonography in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy: Correlations with Clinical and Neurophysiological Data

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    Aristide Merola


    Full Text Available Objective. This cross-sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP and multifocal motor neuropathy (MMN at different stages of functional disability. Material and Methods. 22 CIDP and 10 MMN patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median, ulnar, peroneal, tibial, and sural nerves. Results were correlated with clinical disability scales and nerve conduction studies. Results. Patients with intermediate functional impairment showed relatively larger cross-sectional areas than subjects with either a milder (p<0.05 or more severe impairment (p<0.05, both in CIDP and in MMN. In addition, MMN was associated with greater side-to-side intranerve variability (p<0.05, while higher cross-sectional areas were observed in CIDP (p<0.05 and in nerve segments with predominantly demyelinating features (p<0.05. Higher CSA values were observed in nerves with demyelinating features versus axonal damage (p<0.05 for CIDP; p<0.05 for MMN. Discussion and Conclusions. Greater extent of quantitative and qualitative US alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage. CIDP and MMN showed differential US aspects, with greater side-to-side intranerve variability in MMN and higher cross-sectional areas in CIDP.

  7. Diabetic peripheral neuropathy: current perspective and future directions. (United States)

    Singh, Randhir; Kishore, Lalit; Kaur, Navpreet


    Diabetic neuropathy is a heterogeneous group of disorders with extremely complex pathophysiology and affects both somatic and autonomic components of the nervous system. Neuropathy is the most common chronic complication of diabetes mellitus. Metabolic disruptions in the peripheral nervous system, including altered protein kinase C activity, and increased polyol pathway activity in neurons and Schwann cells resulting from hyperglycemia plays a key role in the development of diabetic neuropathy. These pathways are related to the metabolic and/or redox state of the cell and are the major source of damage. Activation of these metabolic pathways leads to oxidative stress, which is a mediator of hyperglycemia induced cell injury and a unifying theme for all mechanisms of diabetic neuropathy. The therapeutic intervention of these metabolic pathways is capable of ameliorating diabetic neuropathy but therapeutics which target one particular mechanism may have a limited success. Available therapeutic approaches are based upon the agents that modulate pathogenetic mechanisms (glycemic control) and relieve the symptoms of diabetic neuropathy. This review emphasizes the pathogenesis, presently available therapeutic approaches and future directions for the management of diabetic neuropathy.

  8. Wherefore Art Thou, O Treatment for Diabetic Neuropathy? (United States)

    Malik, R A


    As of March 2016, we continue to advocate the diagnosis of diabetic neuropathy using a simple foot examination or monofilament, which identifies only those with severe neuropathy and hence risk of foot ulceration. Given the fact that the 5-year mortality rate of diabetic patients with foot ulceration is worse than that of most common cancers, surely we should be identifying patients at an earlier stage of neuropathy to prevent its progression to a stage with such a high mortality? Of course, we lament that there is no licensed treatment for diabetic neuropathy. Who is to blame? As researchers and carers, we have a duty of care to our patients with diabetic neuropathy. So, we have to look forward not backwards, and move away from our firmly entrenched views on the design and conduct of clinical trials for diabetic neuropathy. Relevant organizations such as Neurodiab, the American Diabetes Association and the Peripheral Nerve Society have to acknowledge that they cannot continue to endorse a bankrupt strategy. The FDA needs an open and self-critical dialogue with these organizations, to give pharmaceutical companies at least a fighting chance to deliver effective new therapies for diabetic neuropathy.

  9. Peripheral autonomic neuropathy: diagnostic contribution of skin biopsy. (United States)

    Donadio, Vincenzo; Incensi, Alex; Giannoccaro, Maria Pia; Cortelli, Pietro; Di Stasi, Vitantonio; Pizza, Fabio; Jaber, Masen Abdel; Baruzzi, Agostino; Liguori, Rocco


    Skin biopsy has gained widespread use for the diagnosis of somatic small-fiber neuropathy, but it also provides information on sympathetic fiber morphology. We aimed to ascertain the diagnostic accuracy of skin biopsy in disclosing sympathetic nerve abnormalities in patients with autonomic neuropathy. Peripheral nerve fiber autonomic involvement was confirmed by routine autonomic laboratory test abnormalities. Punch skin biopsies were taken from the thigh and lower leg of 28 patients with various types of autonomic neuropathy for quantitative evaluation of skin autonomic innervation. Results were compared with scores obtained from 32 age-matched healthy controls and 25 patients with somatic neuropathy. The autonomic cutoff score was calculated using the receiver operating characteristic curve analysis. Skin biopsy disclosed a significant autonomic innervation decrease in autonomic neuropathy patients versus controls and somatic neuropathy patients. Autonomic innervation density was abnormal in 96% of patients in the lower leg and in 79% of patients in the thigh. The abnormal findings disclosed by routine autonomic tests ranged from 48% to 82%. These data indicate the high sensitivity and specificity of skin biopsy in detecting sympathetic abnormalities; this method should be useful for the diagnosis of autonomic neuropathy, together with currently available routine autonomic testing.

  10. Motor Nerve Conduction Velocity In Postmenopausal Women with Peripheral Neuropathy (United States)

    Asif, Naiyer; Singh, Paras Nath; Hossain, Mohd Mobarak


    Introduction The post-menopausal phase is characterized by a decline in the serum oestrogen and progesterone levels. This phase is also associated with higher incidence of peripheral neuropathy. Aim To explore the relationship between the peripheral motor nerve status and serum oestrogen and progesterone levels through assessment of Motor Nerve Conduction Velocity (MNCV) in post-menopausal women with peripheral neuropathy. Materials and Methods This cross-sectional study was conducted at Jawaharlal Nehru Medical College during 2011-2013. The study included 30 post-menopausal women with peripheral neuropathy (age: 51.4±7.9) and 30 post-menopausal women without peripheral neuropathy (control) (age: 52.5±4.9). They were compared for MNCV in median, ulnar and common peroneal nerves and serum levels of oestrogen and progesterone estimated through enzyme immunoassays. To study the relationship between hormone levels and MNCV, a stepwise linear regression analysis was done. Results The post-menopausal women with peripheral neuropathy had significantly lower MNCV and serum oestrogen and progesterone levels as compared to control subjects. Stepwise linear regression analysis showed oestrogen with main effect on MNCV. Conclusion The findings of the present study suggest that while the post-menopausal age group is at a greater risk of peripheral neuropathy, it is the decline in the serum estrogen levels which is critical in the development of peripheral neuropathy. PMID:28208850

  11. Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb.

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    Rosa-Eva Huettl


    Full Text Available The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1 in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG, we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

  12. Npn-1 contributes to axon-axon interactions that differentially control sensory and motor innervation of the limb. (United States)

    Huettl, Rosa-Eva; Soellner, Heidi; Bianchi, Elisa; Novitch, Bennett G; Huber, Andrea B


    The initiation, execution, and completion of complex locomotor behaviors are depending on precisely integrated neural circuitries consisting of motor pathways that activate muscles in the extremities and sensory afferents that deliver feedback to motoneurons. These projections form in tight temporal and spatial vicinities during development, yet the molecular mechanisms and cues coordinating these processes are not well understood. Using cell-type specific ablation of the axon guidance receptor Neuropilin-1 (Npn-1) in spinal motoneurons or in sensory neurons in the dorsal root ganglia (DRG), we have explored the contribution of this signaling pathway to correct innervation of the limb. We show that Npn-1 controls the fasciculation of both projections and mediates inter-axonal communication. Removal of Npn-1 from sensory neurons results in defasciculation of sensory axons and, surprisingly, also of motor axons. In addition, the tight coupling between these two heterotypic axonal populations is lifted with sensory fibers now leading the spinal nerve projection. These findings are corroborated by partial genetic elimination of sensory neurons, which causes defasciculation of motor projections to the limb. Deletion of Npn-1 from motoneurons leads to severe defasciculation of motor axons in the distal limb and dorsal-ventral pathfinding errors, while outgrowth and fasciculation of sensory trajectories into the limb remain unaffected. Genetic elimination of motoneurons, however, revealed that sensory axons need only minimal scaffolding by motor axons to establish their projections in the distal limb. Thus, motor and sensory axons are mutually dependent on each other for the generation of their trajectories and interact in part through Npn-1-mediated fasciculation before and within the plexus region of the limbs.

  13. Structural plasticity of axon terminals in the adult. (United States)

    Gogolla, Nadine; Galimberti, Ivan; Caroni, Pico


    There is now conclusive evidence for widespread ongoing structural plasticity of presynaptic boutons and axon side-branches in the adult brain. The plasticity complements that of postsynaptic spines, but axonal plasticity samples larger volumes of neuropil, and has a larger impact on circuit remodeling. Axons from distinct neurons exhibit unique ratios of stable (t1/2>9 months) and dynamic (t1/2 5-20 days) boutons, which persist as spatially intermingled subgroups along terminal arbors. In addition, phases of side-branch dynamics mediate larger scale remodeling guided by synaptogenesis. The plasticity is most pronounced during critical periods; its patterns and outcome are controlled by Hebbian mechanisms and intrinsic neuronal factors. Novel experience, skill learning, life-style, and age can persistently modify local circuit structure through axonal structural plasticity.

  14. Spheniodal mucocele causing bilateral optic neuropathy and ophthalmoplegia

    Directory of Open Access Journals (Sweden)

    Ambika Selvakumar


    Full Text Available Sphenoid sinus mucocele comprises only 2% of all paranasal sinus mucoceles. In literature, there is a case report on sphenoidal mucocele causing bilateral optic neuropathy, with unilateral partial recovery and cranial nerve palsy, but we did not come across any literature with bilateral optic neuropathy and ophthalmoplegia together caused by spheno-ethmoidal mucocele. We present such a rare case of spheno-ethmoidal mucocele causing bilateral optic neuropathy and unilateral sixth nerve palsy who had postsurgery, unilateral good vision recovery, and complete resolution of sixth nerve palsy.

  15. Contribution of mitochondria to pain in diabetic neuropathy. (United States)

    Hernández-Beltrán, Natalia; Moreno, Carlos B; Gutiérrez-Álvarez, Angela María


    Diabetes is a metabolic disease affecting approximately 300 million people worldwide. Neuropathy is one of its frequent complications, and may affect sensory, motor, and autonomic nerves. Its pathophysiology has not fully been elucidated. Several hypotheses have been proposed, and mitochondria have been suggested to play a significant role. This article reviews the mechanisms involved in mitochondrial dysfunction and development of diabetic neuropathy, consisting mainly of oxidative and inflammatory stress, changes in intracellular calcium regulation, apoptotic processes, and changes in mitochondrial structure and function that may lead to development of diabetic neuropathy.

  16. Chemotherapy-induced peripheral neuropathy: Current status and progress. (United States)

    Brewer, Jamie R; Morrison, Gladys; Dolan, M Eileen; Fleming, Gini F


    As there are increasing numbers of cancer survivors, more attention is being paid to the long term unwanted effects patients may experience as a result of their treatment and the impact these side effects can have on their quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common long-term toxicities from chemotherapy. In this review we will briefly review the clinical presentation, evaluation and management of chemotherapy-induced peripheral neuropathy, with a focus on CIPN related to platinum and taxane agents. We will then discuss current clinical models of peripheral neuropathy and ongoing research to better understand CIPN and develop potential treatment options.

  17. Hereditary optic neuropathies share a common mitochondrial coupling defect. (United States)

    Chevrollier, Arnaud; Guillet, Virginie; Loiseau, Dominique; Gueguen, Naïg; de Crescenzo, Marie-Anne Pou; Verny, Christophe; Ferre, Marc; Dollfus, Hélène; Odent, Sylvie; Milea, Dan; Goizet, Cyril; Amati-Bonneau, Patrizia; Procaccio, Vincent; Bonneau, Dominique; Reynier, Pascal


    Hereditary optic neuropathies are heterogeneous diseases characterized by the degeneration of retinal ganglion cells leading to optic nerve atrophy and impairment of central vision. We found a common coupling defect of oxidative phosphorylation in fibroblasts of patients affected by autosomal dominant optic atrophy (mutations of OPA1), autosomal dominant optic atrophy associated with cataract (mutations of OPA3), and Leber's hereditary optic neuropathy, a disorder associated with point mutations of mitochondrial DNA complex I genes. Interestingly, the energetic defect was significantly more pronounced in Leber's hereditary optic neuropathy and autosomal dominant optic atrophy patients with a more complex phenotype, the so-called plus phenotype.

  18. The optic nerve head in hereditary optic neuropathies. (United States)

    O'Neill, Evelyn C; Mackey, David A; Connell, Paul P; Hewitt, Alex W; Danesh-Meyer, Helen V; Crowston, Jonathan G


    Hereditary optic neuropathies are a prominent cause of blindness in both children and adults. The disorders in this group share many overlapping clinical characteristics, including morphological changes that occur at the optic nerve head. Accurate and prompt clinical diagnosis, supplemented with imaging when indicated, is essential for optimum management of the relevant optic neuropathy and appropriate counseling of the patient on its natural history. Patient history, visual field assessment, optic disc findings and imaging are the cornerstones of a correct diagnosis. This Review highlights the characteristic optic nerve head features that are common to the various hereditary optic neuropathies, and describes the features that enable the conditions to be differentiated.

  19. Exacerbation of isoniazid induced peripheral neuropathy by pyridoxine. (United States)

    Nisar, M; Watkin, S W; Bucknall, R C; Agnew, R A


    Mycobacterium kansasii was isolated from an area of cavitating pneumonia in a man with rheumatoid arthritis. Standard antituberculosis treatment, including isoniazid 300 mg daily, had to be stopped because of peripheral neuropathy. The patient, a slow acetylator, subjectively deteriorated despite withdrawal of isoniazid and treatment with pyridoxine 150 mg daily. Improvement occurred only after the pyridoxine had also been withdrawn. Pyridoxine may cause peripheral neuropathy and this case illustrates the need for caution in the use of this vitamin in the prevention and treatment of isoniazid induced peripheral neuropathy.

  20. Morphology of axonal transport abnormalities in primate eyes. (United States)

    Radius, R L; Anderson, D R


    The ultrastructure of the retina and optic nerve head was studied in primate eyes after central retinal artery occlusion. Within 2 hours of the vascular occlusion the inner retinal layers undergo watery (isosmotic) swelling. This watery swelling of axons and astroglia extends into the nerve head as far back as the anterior boundary of the scleral lamina cribrosa. The swelling is increased 4 hours after the occlusion, and by 24 hours disintegration has occurred. At the optic nerve head mitochondria and vesicles of smooth endoplasmic reticulum begin to accumulate within 2 hours. The accumulation increases at 4 hours and persists to 24 hours. The watery swelling seems characteristic of ischaemic axons. Membranous organelles accumulate at the boundary of an ischaemic zone when material carried by axonal transport is brought via the healthy axon segment to the boundary, but they cannot proceed further into the ischaemic zone. Such accumulation is typical of locations where rapid orthograde axonal transport or retrograde axonal transport is blocked. In contrast, when slow axonal flow is impaired, the swelling is characterised by an excess of cytoplasmic gel without a marked accumulation of organelles. Rapid orthograde transport and retrograde transport seem to be closely related to one another, while slow axoplasmic flow seems fundamentally different. From morphological findings we suspect that, in experimental glaucoma, intraocular pressure first affects the intracellular physiological process of rapid orthograde and retrograde axonal transport. Watery swelling may not occur unless the ischaemic injury to cell metabolism is more advanced. In contrast, in experimental papilloedema, the swelling results predominantly from impaired slow axoplasmic flow.

  1. Modality-Specific Axonal Regeneration: Towards selective regenerative neural interfaces

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    Parisa eLotfi


    Full Text Available Regenerative peripheral nerve interfaces have been proposed as viable alternatives for the natural control of robotic prosthetic devices. However, sensory and motor axons at the neural interface are of mixed submodality types, which difficult the specific recording from motor axons and the eliciting of precise sensory modalities through selective stimulation. Here we evaluated the possibility of using type-specific neurotrophins to preferentially entice the regeneration of defined axonal populations from transected peripheral nerves into separate compartments. Segregation of mixed sensory fibers from dorsal root ganglion neurons was evaluated in vitro by compartmentalized diffusion delivery of nerve growth factor (NGF and neurotrophin-3 (NT-3, to preferentially entice the growth of TrkA+ nociceptive and TrkC+ proprioceptive subsets of sensory neurons, respectively. The average axon length in the NGF channel increased 2.5 fold compared to that in saline or NT-3, whereas the number of branches increased 3 fold in the NT-3 channels. These results were confirmed using a 3-D Y-shaped in vitro assay showing that the arm containing NGF was able to entice a 5-fold increase in axonal length of unbranched fibers. To address if such segregation can be enticed in vivo, a Y-shaped tubing was used to allow regeneration of the transected adult rat sciatic nerve into separate compartments filled with either NFG or NT-3. A significant increase in the number of CGRP+ pain fibers were attracted towards the sural nerve, while N-52+ large diameter axons were observed in the tibial and NT-3 compartments. This study demonstrates the guided enrichment of sensory axons in specific regenerative chambers, and supports the notion that neurotrophic factors can be used to segregate sensory and perhaps motor axons in separate peripheral interfaces.

  2. Electrophysiology of a nonmyelinated glutamatergic axon in rat hippocampus


    Alle, Henrik


    The common theme of the presented work on the nonmyelinated hippocampal mossy fiber (the axon of the granule cell in the dentate gyrus) is the generation of subthreshold and suprathreshold electrical signals. Subthreshold depolarizations in the axon can occur due to passive propagation of excitatory postsynaptic potentials, which are generated in the somato-dendritic domain. The remote passive propagation of these comparatively slow but transient signals is due to a space constant...

  3. 6-Sulphated chondroitins have a positive influence on axonal regeneration.

    Directory of Open Access Journals (Sweden)

    Rachel Lin

    Full Text Available Chondroitin sulphate proteoglycans (CSPGs upregulated in the glial scar inhibit axon regeneration via their sulphated glycosaminoglycans (GAGs. Chondroitin 6-sulphotransferase-1 (C6ST-1 is upregulated after injury leading to an increase in 6-sulphated GAG. In this study, we ask if this increase in 6-sulphated GAG is responsible for the increased inhibition within the glial scar, or whether it represents a partial reversion to the permissive embryonic state dominated by 6-sulphated glycosaminoglycans (GAGs. Using C6ST-1 knockout mice (KO, we studied post-injury changes in chondroitin sulphotransferase (CSST expression and the effect of chondroitin 6-sulphates on both central and peripheral axon regeneration. After CNS injury, wild-type animals (WT showed an increase in mRNA for C6ST-1, C6ST-2 and C4ST-1, but KO did not upregulate any CSSTs. After PNS injury, while WT upregulated C6ST-1, KO showed an upregulation of C6ST-2. We examined regeneration of nigrostriatal axons, which demonstrate mild spontaneous axon regeneration in the WT. KO showed many fewer regenerating axons and more axonal retraction than WT. However, in the PNS, repair of the median and ulnar nerves led to similar and normal levels of axon regeneration in both WT and KO. Functional tests on plasticity after the repair also showed no evidence of enhanced plasticity in the KO. Our results suggest that the upregulation of 6-sulphated GAG after injury makes the extracellular matrix more permissive for axon regeneration, and that the balance of different CSs in the microenvironment around the lesion site is an important factor in determining the outcome of nervous system injury.

  4. Fast and reliable identification of axons, axon initial segments and dendrites with local field potential recording

    DEFF Research Database (Denmark)

    Petersen, Anders V.; Johansen, Emil O.; Perrier, Jean-Francois


    The axon initial segment (AIS) is an essential neuronal compartment. It is usually where action potentials are initiated. Recent studies demonstrated that the AIS is a plastic structure that can be regulated by neuronal activity and by the activation of metabotropic receptors. Studying the AIS...... of neurons, we can detect sinks caused by inward currents flowing across the membrane. We determine the location of the AIS by comparing the timing of these events with the action potential. We demonstrate that this method allows the unequivocal identification of the AIS of different types of neurons from...

  5. Pyridoxine-induced neuropathy in rats: a sensory neuropathy that responds to 4-methylcatechol. (United States)

    Callizot, N; Warter, J M; Poindron, P


    Sensory neuropathies are frequently associated with diabetes or with antimitotic treatments in humans suffering from cancer, and are in this case the most important limitation to the use of antimitotic drugs. For this reason, there is a need to establish and validate animal models of sensory neuropathies that could be routinely used, together with the already known models, for studying and evaluating the effects of putative neuroprotective compounds. In the present study, we prove by behavioral and electromyographical analyses that (a) it is possible to induce a nonlethal, exclusively sensory, reversible neuropathy by intoxicating rats with large amounts of pyridoxine, using a new schedule of intoxication; (b) 4-methylcatechol, a drug known to induce nerve growth factor synthesis, improves the clinical status of pyridoxine-intoxicated animals, shortens the duration of the disease, and restores the morphological integrity of the sensory fibers. Owing to its mode of installation and its clinical features, we propose that this model be used as an additional model for preclinical studies of neuroprotective drugs.

  6. Axon-glia interaction and membrane traffic in myelin formation. (United States)

    White, Robin; Krämer-Albers, Eva-Maria


    In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialized glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarization followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasizing the central role of the Src-family kinase Fyn during central nervous system (CNS) myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of proteolipid protein (PLP) transport by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.

  7. Axon morphology at the lamina cribrosa in monkey eyes. (United States)

    Radius, R L; Klewin, K M


    The eyes of 8 monkeys (Aotus trivirgatus) were studied. The mean cross-section area and the least diameter of axon cylinders were calculated from measurements made by computer assisted planimetry of electron photomicrographs of sections through the optic nerve head at the level of the lamina cribrosa. The density of intrabundle connective tissue and glial cell elements in nerve fiber bundles was also calculated. The mean cross-section area and minimum diameter of axons in the temporal part were less than in the nasal part of the nerve. The values for axons in the superior and inferior parts of the nerve were intermediate. A similar pattern of increasing dimensions was seen in axons from the more axial nerve compared to neurons in the more circumferential nerve sectors. The density of the intrabundle, nonaxonal tissue elements did not differ significantly across the nerve. Although axon dimensions may play some role in defining the vulnerability of neuronal tissue to a pressure insult, the results of this anatomic investigation do not support the hypothesis that differences in axonal distribution by size across the nerve section define the regional vulnerability of the nerve head to elevated intraocular pressure.

  8. Axon-glia interaction and membrane traffic in myelin formation

    Directory of Open Access Journals (Sweden)

    Robin eWhite


    Full Text Available In vertebrate nervous systems myelination of neuronal axons has evolved to increase conduction velocity of electrical impulses with minimal space and energy requirements. Myelin is formed by specialised glial cells which ensheath axons with a lipid-rich insulating membrane. Myelination is a multi-step process initiated by axon-glia recognition triggering glial polarisation followed by targeted myelin membrane expansion and compaction. Thereby, a myelin sheath of complex subdomain structure is established. Continuous communication between neurons and glial cells is essential for myelin maintenance and axonal integrity. A diverse group of diseases, from multiple sclerosis to schizophrenia, have been linked to malfunction of myelinating cells reflecting the physiological importance of the axon-glial unit. This review describes the mechanisms of axonal signal integration by oligodendrocytes emphasising the central role of the Src-family kinase Fyn during CNS myelination. Furthermore, we discuss myelin membrane trafficking with particular focus on endocytic recycling and the control of PLP (proteolipid protein transport by SNARE proteins. Finally, PLP mistrafficking is considered in the context of myelin diseases.

  9. Hepatitis C virus infection, cryoglobulinemia, and peripheral neuropathy: a case report

    Directory of Open Access Journals (Sweden)

    Vigani A.G.


    Full Text Available Hepatitis C virus (HCV is essentially hepatotropic but its manifestations can extend beyond the liver. It can be associated with autoimmune diseases, such as mixed cryoglobulinemia, membranoproliferative glomerulonephritis, autoimmune thyroiditis, and lymphoproliferative disorders. The mechanisms that trigger these manifestations are not completely understood. We describe a 48-year-old man with chronic HCV infection (circulating HCV RNA and moderate hepatitis as indicated by liver biopsy, cryoglobulinemia, and sensory and motor peripheral neuropathy. The diagnosis of multineuropathy was confirmed by clinical examination and electromyographic tests. A nerve biopsy revealed an inflammatory infiltrate in the perineurial space and signs of demyelination and axonal degeneration. The patient had no improvement of neurological symptoms with the use of analgesics and neuro-modulators. He was then treated with interferon-alpha (3 million units subcutaneously, 3 times per week and ribavirin (500 mg orally, twice a day for 48 weeks. Six months after the end of therapy, the patient had sustained viral response (negative HCV RNA and remission of neurological symptoms, but cryoglobulins remained positive. A review of the literature on the pathogenesis and treatment of neurological manifestations associated with HCV infection is presented. This report underscores the need for a thorough evaluation of HCV-infected patients because of the possibility of extrahepatic manifestations. Antiviral treatment with interferon and ribavirin can be effective and should be considered in patients with neurological complications associated with HCV infection.

  10. Alpha-lipoic acid prevents mitochondrial damage and neurotoxicity in experimental chemotherapy neuropathy. (United States)

    Melli, Giorgia; Taiana, Michela; Camozzi, Francesca; Triolo, Daniela; Podini, Paola; Quattrini, Angelo; Taroni, Franco; Lauria, Giuseppe


    The study investigates if alpha-lipoic acid is neuroprotective against chemotherapy induced neurotoxicity, if mitochondrial damage plays a critical role in toxic neurodegenerative cascade, and if neuroprotective effects of alpha-lipoic acid depend on mitochondria protection. We used an in vitro model of chemotherapy induced peripheral neuropathy that closely mimic the in vivo condition by exposing primary cultures of dorsal root ganglion (DRG) sensory neurons to paclitaxel and cisplatin, two widely used and highly effective chemotherapeutic drugs. This approach allowed investigating the efficacy of alpha-lipoic acid in preventing axonal damage and apoptosis and the function and ultrastructural morphology of mitochondria after exposure to toxic agents and alpha-lipoic acid. Our results demonstrate that both cisplatin and paclitaxel cause early mitochondrial impairment with loss of membrane potential and induction of autophagic vacuoles in neurons. Alpha-lipoic acid exerts neuroprotective effects against chemotherapy induced neurotoxicity in sensory neurons: it rescues the mitochondrial toxicity and induces the expression of frataxin, an essential mitochondrial protein with anti-oxidant and chaperone properties. In conclusion mitochondrial toxicity is an early common event both in paclitaxel and cisplatin induced neurotoxicity. Alpha-lipoic acid protects sensory neurons through its anti-oxidant and mitochondrial regulatory functions, possibly inducing the expression of frataxin. These findings suggest that alpha-lipoic acid might reduce the risk of developing peripheral nerve toxicity in patients undergoing chemotherapy and encourage further confirmatory clinical trials.

  11. Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside

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    Rajeshwari D. Koilkonda


    Full Text Available Leber's hereditary optic neuropathy (LHON is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA. Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC. These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS. Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease.

  12. Optic atrophy differentially diagnosed as spinocerebellar ataxia from Leber hereditary optic neuropathy by gene mutation analysis. (United States)

    Song, Y P; Chen, Z S; Mo, G Y; Ding, Q; Zhu, L; Yan, M


    Optic atrophy describes a group of diseases of retinal ganglion cells and axons that eventually lead to loss of vision. Optic atrophy has both congenital and acquired causes, and its diagnosis (or differential diagnosis) is complicated. This case report describes a 20-year-old man who presented with a 1-year history of progressive vision loss in both eyes and no obvious systemic symptoms. Fundus examination revealed bilateral optic atrophy. Based on clinical characteristics, visual field analysis and pattern visual evoked potential examination, the presumptive diagnosis was Leber hereditary optic neuropathy (LHON). Analysis of mitochondrial DNA indicated the absence of all of three common mutations associated with LHON (m.3460G>A, m.11778G>A, m.14484T>C). Detailed questioning of the patient revealed a history of prolonged language development and poor balance. Neurological examination indicated abnormal co-ordination, suggesting the presence of inherited spinocerebellar ataxia (SCA). Analysis of the SCA7 gene revealed a high number of trinucleotide repeats [(CAG)(n), n > 64], confirming the diagnosis of SCA. The aetiology of optic atrophies is complicated and the molecular genetic detection approach provides the best information for diagnosing these diseases.

  13. Sporadic hereditary motor and sensory neuropathies: Advances in the diagnosis using next generation sequencing technology. (United States)

    Fallerini, Chiara; Carignani, Giulia; Capoccitti, Giorgio; Federico, Antonio; Rufa, Alessandra; Pinto, Anna Maria; Rizzo, Caterina Lo; Rossi, Alessandro; Mari, Francesca; Mencarelli, Maria Antonietta; Giannini, Fabio; Renieri, Alessandra


    Hereditary motor and sensory neuropathies (HMSN) are genetically heterogeneous disorders affecting peripheral motor and sensory functions. Many different pathogenic variants in several genes involved in the demyelinating, the axonal and the intermediate HMSN forms have been identified, for which all inheritance patterns have been described. The mutation screening currently available is based on Sanger sequencing and is time-consuming and relatively expensive due to the high number of genes involved and to the absence of mutational hot spots. To overcome these limitations, we have designed a custom panel for simultaneous sequencing of 28 HMSN-related genes. We have applied this panel to three representative patients with variable HMSN phenotype and uncertain diagnostic classifications. Using our NGS platform we rapidly identified three already described pathogenic heterozygous variants in MFN2, MPZ and DNM2 genes. Here we show that our pre-custom platform allows a fast, specific and low-cost diagnosis in sporadic HMSN cases. This prompt diagnosis is useful for providing a well-timed treatment, establishing a recurrence risk and preventing further investigations poorly tolerated by patients and expensive for the health system. Importantly, our study illustrates the utility and successful application of NGS to mutation screening of a Mendelian disorder with extreme locus heterogeneity.

  14. Hereditary motor and sensory neuropathies or Charcot-Marie-Tooth diseases: an update. (United States)

    Tazir, Meriem; Hamadouche, Tarik; Nouioua, Sonia; Mathis, Stephane; Vallat, Jean-Michel


    Hereditary motor and sensory neuropathies (HMSN) or Charcot-Marie-Tooth (CMT) diseases are the most common degenerative disorders of the peripheral nervous system. However, the frequency of the different subtypes varies within distinct populations. Although more than seventy clinical and genetic forms are known to date, more than 80% of CMT patients in Western countries have genetic abnormalities associated with PMP22, MPZ, MFN2 and GJB1. Given the considerable genetic heterogeneity of CMT, we emphasize the interest of both clinical and pathological specific features such that focused genetic testing could be performed. In this regard, peripheral nerve lesions in GDAP1 mutations (AR CMT1A), such as mitochondrial abnormalities, have been newly demonstrated. Otherwise, while demyelinating autosomal recessive CMT used to be classified as CMT4 (A, B, C …), we propose a simplified classification such as AR CMT1 (A, B, C …), and AR CMT2 for axonal forms. Also, we stress that next generation sequencing techniques, now considered to be the most efficient methods of genetic testing in CMT, will be helpful in molecular diagnosis and research of new genes involved. Finally, while no effective therapy is known to date, ongoing new therapeutic trials such as PXT3003 (a low dose combination of the three already approved drugs baclofen, naltrexone, and D-sorbitol) give hopes for potential curative treatment.

  15. Ultrastructural observation of effect of moderate hypothermia on axonal damage in an animal model of diffuse axonal injury

    Institute of Scientific and Technical Information of China (English)

    孙晓川; 唐文渊; 郑履平


    Objective: To investigate the effect of moderate hypothermia on responses of axonal cytoskeleton to axonal injury in the acute stage of injury. Methods: Of fifteen adult guinea pigs, twelve animals were subjected to stretch injury to the right optic nerves and divided into the normothermic group (n=6) in which the animal's core temperature was maintained at 36.0-37.5℃ and the hypothermia group (n=6) in which the core temperature was reduced to 32.0-32.5℃ after stretch injury. Remaining three animals sustained no injury to the right optic nerves and served as control group. Half of injured animals (n=3) of either normothermic group or hypothermic group were killed at either 2 hours or 4 hours after injury. The ultrastructural changes of axonal cytoskeleton of the right optic nerve fibers from the animals were examined under a transmission electron microscope and analyzed by quantitative analysis with a computer image analysis system. Results: At 2 hours after stretch injury, there was a significant reduction in the mean number of microtubules (P<0.001), and a significant increase in the mean intermicrotubule spacing (P<0.05 or P<0.01) in axons of all sizes in normothermic animals. The mean number of neurofilaments also decreased statistically (P<0.01) in large and medium subgroups of axons in the same experimental group at 2 hours. By 4 hours, the large subgroup of axons in normothermic animals still demonstrated a significant decline in the mean number of microtubules (P<0.01) and an increase in the mean intermicrotubule spacing (P<0.05), while the medium and small subgroups of axons displayed a significant increase in the mean number of neurofilaments (P<0.05) and reduction in the mean interneurofilament spacing (P<0.05). On the contrary, either the mean number of microtubules and the mean intermicrotubule spacing, or the mean number of neurofilaments and interneurofilament spacing in axons of all sizes in hypothermic stretch-injured animals was not

  16. Chikungunya fever presenting with acute optic neuropathy. (United States)

    Mohite, Abhijit Anand; Agius-Fernandez, Adriana


    Chikungunya fever is a vector borne virus that typically causes a self-limiting systemic illness with fever, skin rash and joint aches 2 weeks after infection. We present the case of a 69-year-old woman presenting with an acute unilateral optic neuropathy as a delayed complication of Chikungunya virus (CHIKV) infection contracted during a recent trip to the West Indies. She presented to our ophthalmology department with acute painless visual field loss in the right eye and a recent flu-like illness. She was found to have a right relative afferent pupillary defect (RAPD) with unilateral optic disc swelling. Serology confirmed recent CHIKV infection. Treatment with intravenous methylprednisolone was delayed while awaiting MRI scans and serology results. At 5-month follow-up, there was a persistent right RAPD and marked optic atrophy with a corresponding inferior scotoma in the visual field.

  17. Targeting mitochondrial function to treat optic neuropathy. (United States)

    Gueven, Nuri; Nadikudi, Monila; Daniel, Abraham; Chhetri, Jamuna


    Many reports have illustrated a tight connection between vision and mitochondrial function. Not only are most mitochondrial diseases associated with some form of vision impairment, many ophthalmological disorders such as glaucoma, age-related macular degeneration and diabetic retinopathy also show signs of mitochondrial dysfunction. Despite a vast amount of evidence, vision loss is still only treated symptomatically, which is only partially a consequence of resistance to acknowledge that mitochondria could be the common denominator and hence a promising therapeutic target. More importantly, clinical support of this concept is only emerging. Moreover, only a few drug candidates and treatment strategies are in development or approved that selectively aim to restore mitochondrial function. This review rationalizes the currently developed therapeutic approaches that target mitochondrial function by discussing their proposed mode(s) of action and provides an overview on their development status with regards to optic neuropathies.

  18. Idebenone for Leber's hereditary optic neuropathy. (United States)

    Gueven, N


    Idebenone is a rapidly absorbed, safe and well-tolerated drug and is currently the only clinically proven treatment option for Leber's hereditary optic neuropathy (LHON) patients. Idebenone (Raxone®) is approved by the European Medicines Agency for the treatment of LHON and has been available on the European market since 2015. Due to its molecular mode of action of bypassing the defective mitochondrial complex I, idebenone leads to improved energy supply and a functional recovery of retinal ganglion cells during the acute stage of the disease, thereby preventing further vision loss and promoting recovery of vision. Thus, commencing treatment shortly after the onset of symptoms is likely to have the best therapeutic effect, a hypothesis that is supported by the available clinical data.

  19. [Research progress of Leber hereditary optic neuropathy]. (United States)

    Zhang, A-Mei; Yao, Yong-Gang


    Leber hereditary optic neuropathy (LHON; MIM 535000) is one of the most common mitochondrial diseases, with a clinical manifestation of painless, acute or sub-acute bilateral visual loss in young adults leading to blindness and central scotoma. Over 95% of LHON patients were caused by one of three primary mtDNA mutations (m.11778G>A, m.3460G>A and m.14484T>C). Incomplete penetrance and gender bias are two riddles of this disease. Here we summarized recent research progress of LHON, with a focus on the molecular pathogenic mechanisms, clinical features, in vitro experiments and animal models, and prevention and treatment of LHON. In particular, we presented the main findings and challenges in our recent efforts to decipher genetic susceptibility and mechanism of LHON in Chinese patients.

  20. Isoniazid induced motor-dominant neuropathy. (United States)

    Arsalan, Rabeeya; Sabzwari, Saniya


    Isoniazid though a very effective treatment for tuberculosis can cause severe motor-dominant neuropathy which can be reversible with pyridoxine supplementation. A 45-year-old female diagnosed with psoas abscess, culture positive for mycobacterium tuberculosis, was started on anti- tuberculous treatment with four drugs, including isoniazid at a dose of 5 mg/kg/day. Three months later she developed severe motor weakness of lower limbs with loss of ankle and knee reflexes. She was treated with vitamin B6 injections and isoniazid treatment was continued. Her motor weakness gradually improved in a few months, but mild sensory impairment persisted even after two years. There is need for vigilance regarding neurological effects of isoniazid in seemingly low-risk individuals in whom development of symptoms should raise the suspicion about slow acetylator status. Timely therapeutic intervention with high-dose vitamin B6 can reduce the long-term morbidity associated with this easily reversible condition.