Peripheral neuropathy in complex inherited diseases: an approach to diagnosis.

PubMed

Rossor, Alexander M; Carr, Aisling S; Devine, Helen; Chandrashekar, Hoskote; Pelayo-Negro, Ana Lara; Pareyson, Davide; Shy, Michael E; Scherer, Steven S; Reilly, Mary M

2017-10-01

Peripheral neuropathy is a common finding in patients with complex inherited neurological diseases and may be subclinical or a major component of the phenotype. This review aims to provide a clinical approach to the diagnosis of this complex group of patients by addressing key questions including the predominant neurological syndrome associated with the neuropathy, for example, spasticity, the type of neuropathy and the other neurological and non-neurological features of the syndrome. Priority is given to the diagnosis of treatable conditions. Using this approach, we associated neuropathy with one of three major syndromic categories: (1) ataxia, (2) spasticity and (3) global neurodevelopmental impairment. Syndromes that do not fall easily into one of these three categories can be grouped according to the predominant system involved in addition to the neuropathy, for example, cardiomyopathy and neuropathy. We also include a separate category of complex inherited relapsing neuropathy syndromes, some of which may mimic Guillain-Barré syndrome, as many will have a metabolic aetiology and be potentially treatable. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Segmental somatosensory-evoked potentials as a diagnostic tool in chronic inflammatory demyelinating polyneuropathies, and other sensory neuropathies.

PubMed

Koutlidis, R M; Ayrignac, X; Pradat, P-F; Le Forestier, N; Léger, J-M; Salachas, F; Maisonobe, T; Fournier, E; Viala, K

2014-09-01

Somatosensory-evoked potentials with segmental recordings were performed with the aim of distinguishing chronic inflammatory demyelinating polyneuropathy from other sensory neuropathies. Four groups of 20 subjects each corresponded to patients with (1) possible sensory chronic inflammatory demyelinating polyneuropathy, (2) patients with sensory polyneuropathy of unknown origin, (3) patients with amyotrophic lateral sclerosis and (4) normal subjects. The patients selected for this study had preserved sensory potentials on electroneuromyogram and all waves were recordable in evoked potentials. Somatosensory-evoked potentials evaluations were carried out by stimulation of the posterior tibial nerve at the ankle, recording peripheral nerve potential in the popliteal fossa, radicular potential and spinal potential at the L4-L5 and T12 levels, and cortical at C'z, with determination of distal conduction time, proximal and radicular conduction time and central conduction time. In the group of chronic inflammatory demyelinating polyneuropathy, 80% of patients had abnormal conduction in the N8-N22 segment and 95% had abnormal N18-N22 conduction time. In the group of neuropathies, distal conduction was abnormal in most cases, whereas 60% of patients had no proximal abnormality. None of the patients in the group of amyotrophic lateral sclerosis had an abnormal N18-N22 conduction time. Somatosensory-evoked potentials with segmental recording can be used to distinguish between atypical sensory chronic inflammatory demyelinating polyneuropathy and other sensory neuropathies, at the early stage of the disease. Graphical representation of segmental conduction times provides a rapid and accurate visualization of the profile of each patient. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Diagnosis and treatment of chronic acquired demyelinating polyneuropathies.

PubMed

Latov, Norman

2014-08-01

Chronic neuropathies are operationally classified as primarily demyelinating or axonal, on the basis of electrodiagnostic or pathological criteria. Demyelinating neuropathies are further classified as hereditary or acquired-this distinction is important, because the acquired neuropathies are immune-mediated and, thus, amenable to treatment. The acquired chronic demyelinating neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein (MAG; anti-MAG neuropathy), multifocal motor neuropathy (MMN), and POEMS syndrome. They have characteristic--though overlapping--clinical presentations, are mediated by distinct immune mechanisms, and respond to different therapies. CIDP is the default diagnosis if the neuropathy is demyelinating and no other cause is found. Anti-MAG neuropathy is diagnosed on the basis of the presence of anti-MAG antibodies, MMN is characterized by multifocal weakness and motor conduction blocks, and POEMS syndrome is associated with IgG or IgA λ-type monoclonal gammopathy and osteosclerotic myeloma. The correct diagnosis, however, can be difficult to make in patients with atypical or overlapping presentations, or nondefinitive laboratory studies. First-line treatments include intravenous immunoglobulin (IVIg), corticosteroids or plasmapheresis for CIDP; IVIg for MMN; rituximab for anti-MAG neuropathy; and irradiation or chemotherapy for POEMS syndrome. A correct diagnosis is required for choosing the appropriate treatment, with the aim of preventing progressive neuropathy.

Chronic inflammatory demyelinating polyneuropathy-like neuropathy as an initial presentation of Crohn's disease.

PubMed

Kim, Suji; Kang, Seok-Jae; Oh, Ki-Wook; Ahn, Byung Kyu; Lee, Hang Lak; Han, Dong Soo; Jang, Kiseok; Kim, Young Seo

2015-03-28

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare complication of Crohn's disease (CD), and it is uncertain whether it is associated with CD itself or with its treatment. We describe a case of CIDP-like neuropathy as an initial symptom of CD. The neurologic symptoms of the patient which responded partially to intravenous immunoglobulin (IVIG) recovered after resection of the appendiceal CD. A 17-year-old male had experienced three separate attacks of motor weakness and paresthesia of all four extremities over a period of 7 months. The electrophysiologic findings revealed a demyelinating sensory-motor polyneuropathy which was compatible with CIDP. However, repeated intravenous IVIG (2 g/kg) treatment gave only a partial response. Four days after the last discharge, he was diagnosed as appendiceal CD after surgical resection of a periappendiceal abscess. His neurologic symptoms and electrophysiologic findings recovered without any maintenance therapy. CIDP-like neuropathy can be an initial presentation of CD, and recovery of the CIDP symptoms may result from resection of the CD. Clinicians should be aware of the possibility of CD in patients with intractable CIDP symptoms.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

PubMed Central

Sames, Lori; Moore, Allison; Arnold, Renee; Ekins, Sean

2014-01-01

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, we can

Autosomal-recessive and X-linked forms of hereditary motor and sensory neuropathy in childhood.

PubMed

Ouvrier, Robert; Geevasingha, Nimeshan; Ryan, Monique M

2007-08-01

The hereditary motor and sensory neuropathies (HMSNs, Charcot-Marie-Tooth neuropathies) are the most common degenerative disorders of the peripheral nervous system. In recent years a dramatic expansion has occurred in our understanding of the molecular basis and cell biology of the recessively inherited demyelinating and axonal neuropathies, with delineation of a number of new neuropathies. Mutations in some genes cause a wide variety of clinical, neurophysiologic, and pathologic phenotypes, rendering diagnosis difficult. The X-linked forms of HMSN represent at least 10%-15% of all HMSNs and have an expanded disease spectrum including demyelinating, intermediate, and axonal neuropathies, transient central nervous system (CNS) dysfunction, mental retardation, and hearing loss. This review presents an overview of the recessive and X-linked forms of HMSN observed in childhood, with particular reference to disease phenotype and neurophysiologic and pathologic abnormalities suggestive of specific diagnoses. These findings can be used by the clinician to formulate a differential diagnosis and guide targeted genetic testing.

Peripheral nerve proteins as potential autoantigens in acute and chronic inflammatory demyelinating polyneuropathies.

PubMed

Lim, Jia Pei; Devaux, Jérôme; Yuki, Nobuhiro

2014-10-01

Guillain-Barré syndrome is classified into acute inflammatory demyelinating polyneuropathy and acute motor axonal neuropathy. Whereas autoantibodies to GM1 or GD1a induce the development of acute motor axonal neuropathy, pathogenic autoantibodies have yet to be identified in acute inflammatory demyelinating polyneuropathy and chronic inflammatory demyelinating polyneuropathy. This review highlights the importance of autoantibodies to peripheral nerve proteins in the physiopathology of acute and chronic inflammatory demyelinating polyneuropathies. Moreover, we listed up other potential antigens, which may become helpful biomarkers for acquired, dysimmune demyelinating neuropathies based on their critical functions during myelination and their implications in hereditary demyelinating neuropathies. Copyright © 2014 Elsevier B.V. All rights reserved.

Neurophysiological aspects of peripheral neuropathies.

PubMed

MacKenzie, R A; Skuse, N F; Lethlean, A K

1976-01-01

1. Eighty-eight intrafascicular neural recordings were obtained in 10 normal subjects, 5 patients with axonal degeneration and 11 patients with demyelinating neuropathy. 2. Stimulus levels required for perception and fibre activation were higher in neuropathic subjects. Fibres transmitting touch perception had significantly lower conduction velocities in both patient groups, but were very much lower in the group with demyelinating neuropahty than the group with axonal degeneration. Maximum electrical stimulation evoked dispersed fibre responses in the axonal degeneration group and more dispersed, slowly conducting fibre potentials in the demyelinating group. In patients with hypertrophic Charcot-Marie-Tooth disorder, usually only a small group of slowly conducting low amplitude potentials was recorded. 3. Delivery of a train of supramaximal stimuli caused prolongation of latency and dispersion of fibre potentials in all microneurographic recordings. The changes were significantly greater in the axonal neuropathy group than in normals, and recovery was slower. The demyelinating neuropathies showed significantly greater changes than both the normal and the axonal neuropathy groups, and post-tetanic conduction slowing became even more marked after limb temperature was raised. 4. Surface SAP recordings showed normal refractory period in chronic axonal neuropathy but significant latency prolongation occurred in demyelinating neuropathy. 5. It is concluded that both receptor and nerve fibre abnormalities contribute to sensory dysfunction in degenerative and demyelinating neuropathies.

Waardenburg syndrome: a rare cause of inherited neuropathy due to SOX10 mutation.

PubMed

Bogdanova-Mihaylova, Petya; Alexander, Michael D; Murphy, Raymond P J; Murphy, Sinéad M

2017-09-01

Waardenburg syndrome (WS) is a rare disorder comprising sensorineural deafness and pigmentation abnormalities. Four distinct subtypes are defined based on the presence or absence of additional symptoms. Mutations in six genes have been described in WS. SOX10 mutations are usually associated with a more severe phenotype of WS with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, and Hirschsprung disease. Here we report a 32-year-old man with a novel heterozygous missense variant in SOX10 gene, who presented with congenital deafness, Hirschsprung disease, iris heterochromia, foot deformity, and intermediate conduction velocity length-dependent sensorimotor neuropathy. This case highlights that the presence of other non-neuropathic features in a patient with presumed hereditary neuropathy should alert the clinician to possible atypical rare causes. © 2017 Peripheral Nerve Society.

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies.

PubMed

van Paassen, Barbara W; van der Kooi, Anneke J; van Spaendonck-Zwarts, Karin Y; Verhamme, Camiel; Baas, Frank; de Visser, Marianne

2014-03-19

PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal.

PMP22 related neuropathies: Charcot-Marie-Tooth disease type 1A and Hereditary Neuropathy with liability to Pressure Palsies

PubMed Central

2014-01-01

PMP22 related neuropathies comprise (1) PMP22 duplications leading to Charcot-Marie-Tooth disease type 1A (CMT1A), (2) PMP22 deletions, leading to Hereditary Neuropathy with liability to Pressure Palsies (HNPP), and (3) PMP22 point mutations, causing both phenotypes. Overall prevalence of CMT is usually reported as 1:2,500, epidemiological studies show that 20-64% of CMT patients carry the PMP22 duplication. The prevalence of HNPP is not well known. CMT1A usually presents in the first two decades with difficulty walking or running. Distal symmetrical muscle weakness and wasting and sensory loss is present, legs more frequently and more severely affected than arms. HNPP typically leads to episodic, painless, recurrent, focal motor and sensory peripheral neuropathy, preceded by minor compression on the affected nerve. Electrophysiological evaluation is needed to determine whether the polyneuropathy is demyelinating. Sonography of the nerves can be useful. Diagnosis is confirmed by finding respectively a PMP22 duplication, deletion or point mutation. Differential diagnosis includes other inherited neuropathies, and acquired polyneuropathies. The mode of inheritance is autosomal dominant and de novo mutations occur. Offspring of patients have a chance of 50% to inherit the mutation from their affected parent. Prenatal testing is possible; requests for prenatal testing are not common. Treatment is currently symptomatic and may include management by a rehabilitation physician, physiotherapist, occupational therapist and orthopaedic surgeon. Adult CMT1A patients show slow clinical progression of disease, which seems to reflect a process of normal ageing. Life expectancy is normal. PMID:24646194

[Importance of electromiographic examination in diagnostification and monitoring of chronic inflammatory demyelinating polyneuropathy].

PubMed

Damjan, Igor; Cvijanović, Milan; Erak, Marko

2010-01-01

Polyneuropathies or peripheral neuropathies present a dysfunction or disease of larger number of peripheral nerves or their dysfunction. Considering their morbidity - mortality characteristics they present an important aspect in daily clinical practice. One particular polyneuropathy that deserves special review is chronic inflammatory demyelinating polyneuropathy, which, due to its clinical-laboratory presentation, does not include the group of "simple" neuropathies, thus requiring further examinations. Neurophysiological testing should be performed using the protocol for neuropathy examinations. Neurophysiological examination, during the electroneurographic examination, shows neurographic parameters referring to polyneuropatic demyelinating type of lesion, while the electromyographic finding records the presence of neuropathic lesions (denervation activity, great action potentials with a reduced sample). A 54-year-old patient was diagnosed to have a "complicated" demyelinating polyneuropathy according to the clinical-laboratory findings and electromyographic examination. Exclusion criteria, targeted diagnostic examinations, considering the mentioned peripheral neuropathies, pointed to acute inflammatory demyelinating polyneuropathy. However, the chronic inflammatory demyelinating polyneuropathy was finally differentiated during the clinical and electromyographic monitoring.

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

PubMed

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

2018-05-01

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

Clinical approach to optic neuropathies

PubMed Central

Behbehani, Raed

2007-01-01

Optic neuropathy is a frequent cause of vision loss encountered by ophthalmologist. The diagnosis is made on clinical grounds. The history often points to the possible etiology of the optic neuropathy. A rapid onset is typical of demyelinating, inflammatory, ischemic and traumatic causes. A gradual course points to compressive, toxic/nutritional and hereditary causes. The classic clinical signs of optic neuropathy are visual field defect, dyschromatopsia, and abnormal papillary response. There are ancillary investigations that can support the diagnosis of optic neuropathy. Visual field testing by either manual kinetic or automated static perimetry is critical in the diagnosis. Neuro-imaging of the brain and orbit is essential in many optic neuropathies including demyelinating and compressive. Newer technologies in the evaluation of optic neuropathies include multifocal visual evoked potentials and optic coherence tomography. PMID:19668477

Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

PubMed

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

2015-10-01

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). © 2015 Wiley Periodicals, Inc.

Office Immunotherapy in Chronic Inflammatoryh Demyelinating Polyneuropathy and Multifocal Motor Neuropathy

PubMed Central

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

2015-01-01

Background 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]. Objective and Methods Results and Conclusions 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-basedimmunotherapy (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). PMID:25976871

A comparative study of brachial plexus sonography and magnetic resonance imaging in chronic inflammatory demyelinating neuropathy and multifocal motor neuropathy.

PubMed

Goedee, H S; Jongbloed, B A; van Asseldonk, J-T H; Hendrikse, J; Vrancken, A F J E; Franssen, H; Nikolakopoulos, S; Visser, L H; van der Pol, W L; van den Berg, L H

2017-10-01

To compare the performance of neuroimaging techniques, i.e. high-resolution ultrasound (HRUS) and magnetic resonance imaging (MRI), when applied to the brachial plexus, as part of the diagnostic work-up of chronic inflammatory demyelinating neuropathy (CIDP) and multifocal motor neuropathy (MMN). Fifty-one incident, treatment-naive patients with CIDP (n = 23) or MMN (n = 28) underwent imaging of the brachial plexus using (i) a standardized MRI protocol to assess enlargement or T2 hyperintensity and (ii) bilateral HRUS to determine the extent of nerve (root) enlargement. We found enlargement of the brachial plexus in 19/51 (37%) and T2 hyperintensity in 29/51 (57%) patients with MRI and enlargement in 37/51 (73%) patients with HRUS. Abnormal results were only found in 6/51 (12%) patients with MRI and 12/51 (24%) patients with HRUS. A combination of the two imaging techniques identified 42/51 (83%) patients. We found no association between age, disease duration or Medical Research Council sum-score and sonographic nerve size, MRI enlargement or presence of T2 hyperintensity. Brachial plexus sonography could complement MRI in the diagnostic work-up of patients with suspected CIDP and MMN. Our results indicate that combined imaging studies may add value to the current diagnostic consensus criteria for chronic inflammatory neuropathies. © 2017 EAN.

Hereditary neuropathy with liability to pressure palsy: two cases of difficult diagnosis.

PubMed

Beydoun, Said R; Cho, Justin

2013-09-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is an inherited autosomal dominant disorder that causes a polyneuropathy with predisposition for involvement at sites of compression and is often underdiagnosed or misdiagnosed due to its heterogeneity in clinical and electrophysiological presentation. We report 2 cases of HNPP, which were initially diagnosed and treated as either an acquired demyelinating disorder or alternative inherited demyelinating disorder. Thorough evaluation of repeat electrodiagnostic studies and genetic testing confirmed the diagnosis of HNPP in both cases. One case showed the classic peripheral myelin protein 22 (PMP22) deletion and the other case showed a previously reported single base pair deletion at Leu145 causing a frameshift mutation at the PMP22 gene. These cases underscore the difficulty of diagnosing HNPP, because of the variations in clinical and electrophysiological findings and reinforce the importance of a combination high index of clinical suspicion, electrodiagnostic testing, and genetic testing to make the diagnosis.

Challenges in pediatric chronic inflammatory demyelinating polyneuropathy.

PubMed

Haliloğlu, Göknur; Yüksel, Deniz; Temoçin, Cağri Mesut; Topaloğlu, Haluk

2016-12-01

Chronic inflammatory demyelinating neuropathy, a treatable immune-mediated disease of the peripheral nervous system is less common in childhood compared to adults. Despite different sets of diagnostic criteria, lack of a reliable biologic marker leads to challenges in diagnosis, follow-up and treatment. Our first aim was to review clinical presentation, course, response to treatment, and prognosis in our childhood patients. We also aimed to document diagnostic and therapeutic pitfalls and challenges at the bedside. Our original cohort consisted of 23 pediatric patients who were referred to us with a clinical diagnosis of chronic inflammatory demyelinating neuropathy. Seven patients reaching to an alternative diagnosis were excluded. In the remaining patients, diagnostic, treatment and follow-up data were compared in typical patients who satisfied both clinical and electrodiagnostic criteria and atypical patients who failed to meet minimal research chronic inflammatory demyelinating neuropathy electrodiagnostic requirements. Eight of 16 patients (50%) met the minimal chronic inflammatory demyelinating neuropathy research diagnostic requirements. There was only a statistically significant difference (p = 0.010) in terms of European Neuromuscular Centre childhood chronic inflammatory diagnostic mandatory clinical criteria between the two groups. Misdiagnosis due to errors in electrophysiological interpretation (100%, n = 8), cerebrospinal fluid cytoalbuminologic dissociation (100%, n = 4 and/or subjective improvement on any immunotherapy modality (80 ± 19.27%)) was frequent. Pediatric CIDP is challenging in terms of diagnostic and therapeutic pitfalls at the bedside. Diagnostic errors due to electrophysiological interpretation, cerebrospinal fluid cytoalbuminologic dissociation, and/or subjective improvement on immunotherapy should be considered. Copyright © 2016 Elsevier B.V. All rights reserved.

Chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis.

PubMed

Murata, Ken-ya; Ishiguchi, Hiroshi; Ando, Ryuki; Miwa, Hideto; Kondo, Tomoyoshi

2013-12-01

We report a patient with chronic inflammatory demyelinating polyneuropathy associated with primary biliary cirrhosis (PBC). Except for minimal biochemical abnormalities, clinical symptoms of PBC were not observed, and we diagnosed our patient with asymptomatic PBC from the results of a liver biopsy. Although the patient noticed little muscle weakness, an electrophysiological study demonstrated slow conduction velocities and prolonged distal latencies, with definite conduction blocks in the median, ulnar, and tibial nerves. The disturbed sensory pattern was asymmetrical, and sensory nerve action potentials were not evoked. From these observations, we diagnosed this patient with chronic inflammatory demyelinating polyneuropathy. Neuropathy associated with PBC is very rare. We must differentiate demyelinating neuropathy with PBC in patients with asymmetrical sensory dominant neuropathy with high immunoglobulin M titers, and investigate for the presence of anti-mitochondrial antibodies to rule out a complication of asymptomatic PBC. Copyright © 2013 Elsevier Ltd. All rights reserved.

Chronic inflammatory demyelinating polyneuropathy in two siblings.

PubMed Central

Gabreëls-Festen, A A; Hageman, A T; Gabreëls, F J; Joosten, E M; Renier, W O; Weemaes, C M; ter Laak, H J

1986-01-01

A familial occurrence of chronic inflammatory demyelinating polyneuropathy is reported. The diagnostic problems in distinguishing the progressive form of this disease in childhood from hereditary motor and sensory neuropathy types I and III are discussed. Criteria for a definite diagnosis of chronic inflammatory demyelinating polyneuropathy are proposed. Images PMID:3456424

Wallerian demyelination: chronicle of a cellular cataclysm.

PubMed

Tricaud, Nicolas; Park, Hwan Tae

2017-11-01

Wallerian demyelination is characteristic of peripheral nerve degeneration after traumatic injury. After axonal degeneration, the myelinated Schwann cell undergoes a stereotypical cellular program that results in the disintegration of the myelin sheath, a process termed demyelination. In this review, we chronologically describe this program starting from the late and visible features of myelin destruction and going backward to the initial molecular steps that trigger the nuclear reprogramming few hours after injury. Wallerian demyelination is a wonderful model for myelin degeneration occurring in the diverse forms of demyelinating peripheral neuropathies that plague human beings.

IgM-monoclonal gammopathy neuropathy and tremor: A first epidemiologic case control study

PubMed Central

Ahlskog, Matthew C.; Kumar, Neeraj; Mauermann, Michelle L.; Klein, Christopher J.

2012-01-01

Introduction Small case series suggest tremor occurs frequently in IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) neuropathy. Epidemiologic study to confirm this association is lacking. Whether the neuropathy or another remote IgM-effect is causal remains unsettled. Materials and methods An IgM-MGUS neuropathy case cohort (n=207) was compared to age, gender, and neuropathy impairment score (NIS) matched, other-cause neuropathy controls (n=414). Tremor details were extracted from structured neurologic evaluation. All patients underwent nerve conductions. Results Tremor occurrence was significantly higher in IgM-MGUS case cohort (29%) than in control cohort (9.2%) (p=0.001). In IgM-MGUS cases, tremor was associated with worse NIS (p=0.025) and demyelinating nerve conductions (p=0.020), but 11 of 60 (18%) IgM-MGUS cases with tremor had axonal neuropathy. In other-cause neuropathy controls, tremor was associated with axonal nerve conductions (p=0.03) but not with NIS severity (p=0.57). Tremor occurrence associated with older age in controls, (p=0.004) but not in IgM-MGUS cases (p=0.272). Most IgM-MGUS tremor cases (49/60) had a postural-kinetic tremor, 8 had rest tremor, 3 had mixed rest-action. Alternative causes of tremor was identified in 42% of IgM-MGUS cases, the most common type is inherited essential tremor 6/60 (p=0.04). Conclusions This first epidemiologic case-control study validates association between IgM-MGUS neuropathy and tremor. Among IgM-MGUS neuropathy cases, severity as well as type of neuropathy (demyelinating over axonal) correlated with tremor occurrence. IgM-MGUS paraproteinemia may increase tremor expression in persons recognized with common other risk factors for tremor. PMID:22475624

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

PubMed

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

2008-12-15

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

c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy

PubMed Central

Hantke, Janina; Carty, Lucy; Wagstaff, Laura J.; Turmaine, Mark; Wilton, Daniel K.; Quintes, Susanne; Koltzenburg, Martin; Baas, Frank; Mirsky, Rhona

2014-01-01

Charcot–Marie–Tooth disease type 1A is the most frequent inherited peripheral neuropathy. It is generally due to heterozygous inheritance of a partial chromosomal duplication resulting in over-expression of PMP22. A key feature of Charcot–Marie–Tooth disease type 1A is secondary death of axons. Prevention of axonal loss is therefore an important target of clinical intervention. We have previously identified a signalling mechanism that promotes axon survival and prevents neuron death in mechanically injured peripheral nerves. This work suggested that Schwann cells respond to injury by activating/enhancing trophic support for axons through a mechanism that depends on upregulation of the transcription factor c-Jun in Schwann cells, resulting in the sparing of axons that would otherwise die. As c-Jun orchestrates Schwann cell support for distressed neurons after mechanical injury, we have now asked: do Schwann cells also activate a c-Jun dependent neuron-supportive programme in inherited demyelinating disease? We tested this by using the C3 mouse model of Charcot–Marie–Tooth disease type 1A. In line with our previous findings in humans with Charcot–Marie–Tooth disease type 1A, we found that Schwann cell c-Jun was elevated in (uninjured) nerves of C3 mice. We determined the impact of this c-Jun activation by comparing C3 mice with double mutant mice, namely C3 mice in which c-Jun had been conditionally inactivated in Schwann cells (C3/Schwann cell-c-Jun−/− mice), using sensory-motor tests and electrophysiological measurements, and by counting axons in proximal and distal nerves. The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence. This suggests that Schwann cells have two contrasting functions in Charcot–Marie–Tooth disease type 1A: on the one hand they are the genetic source of

Decreased electrical excitability of peripheral nerves in demyelinating polyneuropathies.

PubMed Central

Meulstee, J; Darbas, A; van Doorn, P A; van Briemen, L; van der Meché, F G

1997-01-01

Not recognising the presence of decreased excitability may give rise to a seemingly low compound muscle action potential, which may lead erroneously to the conclusion of conduction block. To quantify decreased electrical excitability, stimulation-response curves and the current needed to achieve 90% of the maximal compound muscle action potential amplitude, i90, were obtained in 17 healthy controls, eight patients with Guillain-Barre syndrome, 14 with chronic inflammatory demyelinating polyneuropathy, and 10 with hereditary motor sensory neuropathy type I. Decreased electrical excitability was found in patients with chronic inflammatory demyelinating polyneuropathy and hereditary motor sensory neuropathy type I, by contrast with patients with Guillain-Barré syndrome. Recognising decreased excitability prevents the false assertion of conduction block and has electrodiagnostic importance for the differential diagnosis of demyelinating polyneuropathies. PMID:9120460

Variant pathogenicity evaluation in the community-driven Inherited Neuropathy Variant Browser.

PubMed

Saghira, Cima; Bis, Dana M; Stanek, David; Strickland, Alleene; Herrmann, David N; Reilly, Mary M; Scherer, Steven S; Shy, Michael E; Züchner, Stephan

2018-05-01

Charcot-Marie-Tooth disease (CMT) is an umbrella term for inherited neuropathies affecting an estimated one in 2,500 people. Over 120 CMT and related genes have been identified and clinical gene panels often contain more than 100 genes. Such a large genomic space will invariantly yield variants of uncertain clinical significance (VUS) in nearly any person tested. This rise in number of VUS creates major challenges for genetic counseling. Additionally, fewer individual variants in known genes are being published as the academic merit is decreasing, and most testing now happens in clinical laboratories, which typically do not correlate their variants with clinical phenotypes. For CMT, we aim to encourage and facilitate the global capture of variant data to gain a large collection of alleles in CMT genes, ideally in conjunction with phenotypic information. The Inherited Neuropathy Variant Browser provides user-friendly open access to currently reported variation in CMT genes. Geneticists, physicians, and genetic counselors can enter variants detected by clinical tests or in research studies in addition to genetic variation gathered from published literature, which are then submitted to ClinVar biannually. Active participation of the broader CMT community will provide an advance over existing resources for interpretation of CMT genetic variation. © 2018 Wiley Periodicals, Inc.

Hairy cell leukaemia complicated by anti-MAG paraproteinemic demyelinating neuropathy: resolution of neurological syndrome after cladribrine treatment.

PubMed

Rossi, Davide; Franceschetti, Silvia; Cerri, Michaela; Conconi, Annarita; Lunghi, Monia; Capello, Daniela; Cantello, Roberto; Gaidano, Gianluca

2007-06-01

Hairy cell leukaemia (HCL) occasionally displays a monoclonal gammopathy, yet the association of HCL with paraproteinemic demyelinating neuropathy (PDN) has not been reported. We describe a HCL case complicated by PDN and high titers of monoclonal IgM against myelin associated glycoprotein (MAG). Heavy and light chains of the patient's anti-MAG monoclonal protein were consistent with those expressed by HCL cells. After treatment with cladribrine, remission of HCL strictly paralleled disappearance of the IgM monoclonal protein and of the serum anti-MAG activity, and led to PDN clinical and electrophysiological improvement. Purine analogs may represent a choice in IgM PDN associated with lymphoproliferative disorders.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy: From Bench to Bedside

PubMed Central

Peltier, Amanda C.; Donofrio, Peter D.

2015-01-01

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is the most common treatable chronic autoimmune neuropathy. Multiple diagnostic criteria have been established, with the primary goal of identifying neurophysiologic hallmarks of acquired demyelination. Treatment modalities have expanded to include numerous immuno-modulatory therapies, although the best evidence continues to be for corticosteroids, plasma exchange, and intravenous immunoglobulins (IVIg). This review describes the pathology, epidemiology, pathogenesis, diagnosis, and treatment of CIDP. PMID:23117943

Bochum ultrasound score allows distinction of chronic inflammatory from multifocal acquired demyelinating polyneuropathies.

PubMed

Kerasnoudis, A; Pitarokoili, K; Gold, R; Yoon, M-S

2015-01-15

The aim of this observational study was to evaluate the applicability of a recently introduced ultrasound score (Bochum ultrasound score; BUS) in distinguishing the chronic inflammatory demyelinating polyneuropathy (CIDP) from the multifocal motor neuropathy (MMN) or the multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). The BUS underwent prospective evaluation of its applicability in a group of 13 patients (mean age 47.2, SD ± 13.7, 9 women), who were referred to our department between January 2012 and August 2013 with the clinical picture of a chronic symmetrical or asymmetrical sensory/sensorimotor neuropathy. The cut-off value of ≥ 2 points in the "Bochum ultrasound score" showed a sensitivity of 80% and specificity of 87.5% (PPV=80%, NPV=87.5%) in distinguishing CIDP from MMN or MADSAM. The BUS seems to allow a reliable distinction of CIDP from multifocal acquired demyelinating polyneuropathies causing predominantly motor nerve dysfunction, such as MMN or MADSAM. Our ultrasound findings indicate a stronger relationship of MADSAM to MMN, than to CIDP. Copyright © 2014 Elsevier B.V. All rights reserved.

The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review.

PubMed

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

2015-12-01

Peripheral neuropathy is a prevalent condition that usually warrants a thorough history and examination but has limited diagnostic evaluation. However, rare localizations of peripheral neuropathy often require more extensive diagnostic testing and different treatments. To describe rare localizations of peripheral neuropathy, including the appropriate diagnostic evaluation and available treatments. References were identified from PubMed searches conducted on May 29, 2015, with an emphasis on systematic reviews and randomized clinical trials. Articles were also identified through the use of the authors' own files. Search terms included common rare neuropathy localizations and their causes, as well as epidemiology, pathophysiology, diagnosis, and treatment. Diffuse, nonlength-dependent neuropathies, multiple mononeuropathies, polyradiculopathies, plexopathies, and radiculoplexus neuropathies are rare peripheral neuropathy localizations that often require extensive diagnostic testing. Atypical neuropathy features, such as acute/subacute onset, asymmetry, and/or motor predominant signs, are frequently present. The most common diffuse, nonlength-dependent neuropathies are Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and amyotrophic lateral sclerosis. Effective disease-modifying therapies exist for many diffuse, nonlength-dependent neuropathies including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and some paraprotein-associated demyelinating neuropathies. Vasculitic neuropathy (multiple mononeuropathy) also has efficacious treatment options, but definitive evidence of a treatment effect for IgM anti-MAG neuropathy and diabetic amyotrophy (radiculoplexus neuropathy) is lacking. Recognition of rare localizations of peripheral neuropathy is essential given the implications for diagnostic testing and treatment. Electrodiagnostic studies are an important

Recurrent Isolated Sixth Nerve Palsy in Relapsing-Remitting Chronic Inflammatory Demyelinating Polyneuropathy.

PubMed

Al-Bustani, Najwa; Weiss, Michael D

2015-09-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated sensory and motor demyelinating polyneuropathy that typically presents as a relapsing-remitting or progressive disorder. Cranial neuropathies infrequently occur in association with other more typical symptoms of CIDP. We report a case of CIDP with recurrent isolated sixth nerve palsy. Her physical examination showed a right sixth nerve palsy and absent deep tendon reflexes as the only indicator of her disease. Magnetic resonance imaging revealed thickening without enhancement of the trigeminal and sixth cranial nerves. Nerve conduction study (NCS) revealed a sensory and motor demyelinating polyneuropathy with conduction block and temporal dispersion in multiple nerves consistent with CIDP. Cerebrospinal fluid demonstrated albuminic-cytologic dissociation. She had a remarkable response to intravenous immunoglobulin and remains asymptomatic without any additional immunomodulating therapy. Isolated cranial neuropathies can rarely occur as the sole manifestation of relapsing-remitting CIDP. The profound demyelination found on NCS in this case demonstrates that there can be a dramatic discordance between the clinical and electrodiagnostic findings in some patients with this disorder.

Destruction of paranodal architecture in inflammatory neuropathy with anti-contactin-1 autoantibodies.

PubMed

Doppler, Kathrin; Appeltshauser, Luise; Wilhelmi, Kai; Villmann, Carmen; Dib-Hajj, Sulayman D; Waxman, Stephen G; Mäurer, Mathias; Weishaupt, Andreas; Sommer, Claudia

2015-07-01

Autoantibodies against paranodal proteins have been described in patients with inflammatory neuropathies, but their association with pathology of nodes of Ranvier is unclear. We describe the clinical phenotype and histopathological changes of paranodal architecture of patients with autoantibodies against contactin-1, identified from a cohort with chronic inflammatory demyelinating polyradiculoneuropathy (n=53) and Guillain-Barré syndrome (n=21). We used ELISA to detect autoantibodies against contactin-1. Specificity of the autoantibodies was confirmed by immunoblot assay, binding to contactin-1-transfected human embryonic kidney cells, binding to paranodes of murine teased fibres and preabsorption experiments. Paranodal pathology was investigated by immunofluorescence labelling of dermal myelinated fibres. High reactivity to contactin-1 by ELISA was found in four patients with chronic inflammatory demyelinating polyradiculoneuropathy and in none of the patients with Guillain-Barré syndrome, which was confirmed by cell binding assays in all four patients. The four patients presented with a typical clinical picture, namely acute onset of disease and severe motor symptoms, with three patients manifesting action tremor. Immunofluorescence-labelling of paranodal proteins of dermal myelinated fibres revealed disruption of paranodal architecture. Semithin sections showed axonal damage but no classical signs of demyelination. We conclude that anti-contactin-1-related neuropathy constitutes a presumably autoantibody-mediated form of inflammatory neuropathy with distinct clinical symptoms and disruption of paranodal architecture as a pathological correlate. Anti-contactin-1-associated neuropathy does not meet morphological criteria of demyelinating neuropathy and therefore, might rather be termed a 'paranodopathy' rather than a subtype of demyelinating inflammatory neuropathy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted

[Demyelinating polyneuropathies in patients with diabetes mellitus and chronic alcoholic intoxication].

PubMed

Kovrazhkina, E A

2012-01-01

Frequency and nosological attribution of demyelinating polyneuropathies in patients with diabetes mellitus and alcoholism were determined. Eighty-six inpatients with alcoholic (n=46) and diabetic (n=40) polyneuropathy were examined clinically and using electroneuromyography (ENMG). A demyelinating pathogenetic variant was identified by clinical and ENMG data in 27 (31%) patients. Nine patients (33%) had dysimmune polyneuropathies (acute and chronic inflammatory demyelinating polyneuropathy). Polyneuropathies were specified as toxic/metabolic with the prevalence of a demyelinating component within the main disease in 18 (67%) patients. Clinical and ENMG-signs of the demyelinating variant of alcoholic and diabetic neuropathy are presented. The efficacy of the antioxidant berlition was shown for toxic/metabolic polyneuropathies while the addition of immune modulators was needed for treatment of dysimmune polyneuropathy.

Peripheral neuropathy in genetically characterized patients with mitochondrial disorders: A study from south India.

PubMed

Bindu, Parayil Sankaran; Govindaraju, Chikanna; Sonam, Kothari; Nagappa, Madhu; Chiplunkar, Shwetha; Kumar, Rakesh; Gayathri, Narayanappa; Bharath, M M Srinivas; Arvinda, Hanumanthapura R; Sinha, Sanjib; Khan, Nahid Akthar; Govindaraj, Periyasamy; Nunia, Vandana; Paramasivam, Arumugam; Thangaraj, Kumarasamy; Taly, Arun B

2016-03-01

There are relatively few studies, which focus on peripheral neuropathy in large cohorts of genetically characterized patients with mitochondrial disorders. This study sought to analyze the pattern of peripheral neuropathy in a cohort of patients with mitochondrial disorders. The study subjects were derived from a cohort of 52 patients with a genetic diagnosis of mitochondrial disorders seen over a period of 8 years (2006-2013). All patients underwent nerve conduction studies and those patients with abnormalities suggestive of peripheral neuropathy were included in the study. Their phenotypic features, genotype, pattern of peripheral neuropathy and nerve conduction abnormalities were analyzed retrospectively. The study cohort included 18 patients (age range: 18 months-50 years, M:F- 1.2:1).The genotype included mitochondrial DNA point mutations (n=11), SURF1 mutations (n=4) and POLG1(n=3). Axonal neuropathy was noted in 12 patients (sensori-motor:n=4; sensory:n=4; motor:n=4) and demyelinating neuropathy in 6. Phenotype-genotype correlations revealed predominant axonal neuropathy in mtDNA point mutations and demyelinating neuropathy in SURF1. Patients with POLG related disorders had both sensory ataxic neuropathy and axonal neuropathy. A careful analysis of the family history, clinical presentation, biochemical, histochemical and structural analysis may help to bring out the mitochondrial etiology in patients with peripheral neuropathy and may facilitate targeted gene testing. Presence of demyelinating neuropathy in Leigh's syndrome may suggest underlying SURF1 mutations. Sensory ataxic neuropathy with other mitochondrial signatures should raise the possibility of POLG related disorder. Copyright © 2015. Published by Elsevier B.V.

Acute-onset chronic inflammatory demyelinating polyneuropathy with focal segmental glomerulosclerosis.

PubMed

Quek, Amy May Lin; Soon, Derek; Chan, Yee Cheun; Thamboo, Thomas Paulraj; Yuki, Nobuhiro

2014-06-15

Inflammatory neuropathies have been reported to occur in association with nephrotic syndrome. Their underlying immuno-pathogenic mechanisms remain unknown. A 50-year-old woman concurrently presented with acute-onset chronic inflammatory demyelinating polyneuropathy and nephrotic syndrome secondary to focal segmental glomerulosclerosis. Both neuropathy and proteinuria improved after plasma exchange and steroids. Literature review of cases of concurrent inflammatory neuropathies and nephrotic syndrome revealed similar neuro-renal presentations. This neuro-renal condition may be mediated by autoantibodies targeting myelin and podocytes. Copyright © 2014 Elsevier B.V. All rights reserved.

A patient with PMP22-related hereditary neuropathy and DBH-gene-related dysautonomia.

PubMed

Bartoletti-Stella, Anna; Chiaro, Giacomo; Calandra-Buonaura, Giovanna; Contin, Manuela; Scaglione, Cesa; Barletta, Giorgio; Cecere, Annagrazia; Garagnani, Paolo; Tieri, Paolo; Ferrarini, Alberto; Piras, Silvia; Franceschi, Claudio; Delledonne, Massimo; Cortelli, Pietro; Capellari, Sabina

2015-10-01

Recurrent focal neuropathy with liability to pressure palsies is a relatively frequent autosomal-dominant demyelinating neuropathy linked to peripheral myelin protein 22 (PMP22) gene deletions. The combination of PMP22 gene mutations with other genetic variants is known to cause a more severe phenotype than expected. We present the case of a patient with severe orthostatic hypotension since 12 years of age, who inherited a PMP22 gene deletion from his father. Genetic double trouble was suspected because of selective sympathetic autonomic disturbances. Through exome-sequencing analysis, we identified two novel mutations in the dopamine beta hydroxylase gene. Moreover, with interactome analysis, we excluded a further influence on the origin of the disease by variants in other genes. This case increases the number of unique patients presenting with dopamine-β-hydroxylase deficiency and of cases with genetically proven double trouble. Finding the right, complete diagnosis is crucial to obtain adequate medical care and appropriate genetic counseling.

Different electrophysiological profiles and treatment response in 'typical' and 'atypical' chronic inflammatory demyelinating polyneuropathy.

PubMed

Kuwabara, Satoshi; Isose, Sagiri; Mori, Masahiro; Mitsuma, Satsuki; Sawai, Setsu; Beppu, Minako; Sekiguchi, Yukari; Misawa, Sonoko

2015-10-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into 'typical' CIDP and 'atypical' subtypes such as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). To assess the frequency of CIDP subtypes, and to elucidate clinical and electrophysiological features, and treatment response in each subtype. We reviewed data from 100 consecutive patients fulfilling criteria for CIDP proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. The Kaplan-Meier curve was used to estimate long-term outcome. Patients were classified as having typical CIDP (60%), MADSAM (34%), demyelinating acquired distal symmetric neuropathy (8%) or pure sensory CIDP (1%). Compared with patients with MADSAM, patients with typical CIDP showed more rapid progression and severe disability, and demyelination predominant in the distal nerve segments. MADSAM was characterised by multifocal demyelination in the nerve trunks. Abnormal median-normal sural sensory responses were more frequently found for typical CIDP (53% vs 13%). Patients with typical CIDP invariably responded to corticosteroids, immunoglobulin or plasmapheresis, whereas patients with MADSAM were more refractory to these treatments. The Kaplan-Meier analyses showed that 64% of patients with typical CIDP and 41% of patients with MADSAM had a clinical remission 5 years later (p=0.02). Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. In typical CIDP, the distal nerve terminals and possibly the nerve roots, where the blood-nerve barrier is anatomically deficient, are preferentially affected, raising the possibility of antibody-mediated demyelination, whereas cellular immunity with breakdown of the barrier may be important in MADSAM neuropathy. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Congenital cataract, facial dysmorphism and demyelinating neuropathy (CCFDN) in 10 Czech gypsy children – frequent and underestimated cause of disability among Czech gypsies

PubMed Central

2014-01-01

Background Congenital Cataract Facial Dysmorphism and demyelinating Neuropathy (CCFDN, OMIM 604468) is an autosomal recessive multi-system disorder which was first described in Bulgarian Gypsies in 1999. It is caused by the homozygous founder mutation c.863 + 389C > T in the CTDP1 gene. The syndrome has been described exclusively in patients of Gypsy ancestry. The prevalence of this disorder in the Gypsy population in the Czech Republic and Central Europe is not known and is probably underestimated and under-diagnosed. Methods We clinically diagnosed and assessed 10 CCFDN children living in the Czech Republic. All patients are children of different ages, all of Gypsy origin born in the Czech Republic. Molecular genetic testing for the founder CTDP1 gene mutation was performed. Results All patients are homozygous for the c.863 + 389C > T mutation in the CTDP1 gene. All patients presented a bilateral congenital cataract and microphthalmos and had early cataract surgery. Correct diagnosis was not made until the age of two. All patients had variably delayed motor milestones. Gait is characteristically paleocerebellar in all the patients. Mental retardation was variable and usually mild. Conclusions Clinical diagnosis of CCFDN should be easy for an informed pediatrician or neurologist by the obligate signalling trias of congenital bilateral cataract, developmental delay and later demyelinating neuropathy. Our data indicate a probably high prevalence of CCFDN in the Czech Gypsy ethnic subpopulation. PMID:24690360

First pathological report of a de novo CD5-positive diffuse large B-cell lymphoma patient presenting with Guillain-Barré syndrome-like neuropathy due to neurolymphomatosis.

PubMed

Kobayashi, Mikiko; Sakai, Yasuhiro; Kariya, Yuta; Sakai, Hitoshi; Hineno, Akiyo; Oyanagi, Kiyomitsu; Kanno, Hiroyuki

2018-05-02

Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5-positive diffuse large B-cell lymphoma (DLBCL) who presented with Guillain-Barré syndrome (GBS)-like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS-like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, "CD5-positive" DLBCL may tend to develop neurolymphomatosis. If a patient with "CD5-positive" DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5-positive DLBCL with neurolymphomatosis who presented with GBS-like neuropathy. © 2018 Japanese Society of Neuropathology.

Paraneoplastic neuropathies.

PubMed

Antoine, Jean-Christophe; Camdessanché, Jean-Philippe

2017-10-01

To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Familial auditory neuropathy.

PubMed

Wang, Qiuju; Gu, Rui; Han, Dongyi; Yang, Weiyan

2003-09-01

Auditory neuropathy is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses and normal cochlear outer hair cell function as measured by otoacoustic emission recordings. Many risk factors are thought to be involved in its etiology and pathophysiology. Four Chinese pedigrees with familial auditory neuropathy were presented to demonstrate involvement of genetic factors in the etiology of auditory neuropathy. Probands of the above-mentioned pedigrees, who had been diagnosed with auditory neuropathy, were evaluated and followed in the Department of Otolaryngology-Head and Neck Surgery, China People Liberation Army General Hospital (Beijing, China). Their family members were studied, and the pedigree maps established. History of illness, physical examination, pure-tone audiometry, acoustic reflex, auditory brainstem responses, and transient evoked and distortion-product otoacoustic emissions were obtained from members of these families. Some subjects received vestibular caloric testing, computed tomography scan of the temporal bone, and electrocardiography to exclude other possible neuropathic disorders. In most affected patients, hearing loss of various degrees and speech discrimination difficulties started at 10 to 16 years of age. Their audiological evaluation showed absence of acoustic reflex and auditory brainstem responses. As expected in auditory neuropathy, these patients exhibited near-normal cochlear outer hair cell function as shown in distortion product otoacoustic emission recordings. Pure-tone audiometry revealed hearing loss ranging from mild to profound in these patients. Different inheritance patterns were observed in the four families. In Pedigree I, 7 male patients were identified among 43 family members, exhibiting an X-linked recessive pattern. Affected brothers were found in Pedigrees II and III, whereas in pedigree IV, two sisters were affected. All the patients were otherwise normal without evidence of

Four novel cases of periaxin-related neuropathy and review of the literature.

PubMed

Marchesi, C; Milani, M; Morbin, M; Cesani, M; Lauria, G; Scaioli, V; Piccolo, G; Fabrizi, G M; Cavallaro, T; Taroni, F; Pareyson, D

2010-11-16

To report 4 cases of autosomal recessive hereditary neuropathy associated with novel mutations in the periaxin gene (PRX) with a review of the literature. Periaxin protein is required for the maintenance of peripheral nerve myelin. Patients with PRX mutations have early-onset autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT4F) or Déjèrine-Sottas neuropathy (DSN). Only 12 different mutations have been described thus far. Case reports and literature review. Four patients from 3 unrelated families (2 siblings and 2 unrelated patients) were affected by an early-onset, slowly progressive demyelinating neuropathy with relevant sensory involvement. All carried novel frameshift or nonsense mutations in the PRX gene. The 2 siblings were compound heterozygotes for 2 PRX null mutations (p.Q547X and p.K808SfsX2), the third patient harbored a homozygous nonsense mutation (p.E682X), and the last patient had a homozygous 2-nt insertion predicting a premature protein truncation (p.S259PfsX55). Electrophysiologic analysis showed a severe slowing of motor nerve conduction velocities (MNCVs, between 3 and 15.3 m/s) with undetectable sensory nerve action potentials (SNAPs). Sural nerve biopsy, performed in 2 patients, demonstrated a severe demyelinating neuropathy and onion bulb formations. Interestingly, we observed some variability of disease severity within the same family. These cases and review of the literature indicate that PRX-related neuropathies have early onset but overall slow progression. Typical features are prominent sensory involvement, often with sensory ataxia; a moderate-to-dramatic reduction of MNCVs and almost invariable absence of SNAPs; and pathologic demyelination with classic onion bulbs, and less commonly myelin folding and basal lamina onion bulbs.

DIABETIC NEUROPATHY PART 1: OVERVIEW AND SYMMETRIC PHENOTYPES

PubMed Central

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

2014-01-01

Diabetes is the most common cause of neuropathy in US and neuropathies are the most common complication of diabetes mellitus affecting up to 50% of patients with type 1 and type 2 diabetes mellitus. Various types of neuropathies can be associated with diabetes mellitus.1 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. Pathologically 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. Many medications are available for the treatment of neuropathic pain. PMID:23642717

Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy

PubMed Central

Goebbels, Sandra; Oltrogge, Jan H; Wolfer, Susanne; Wieser, Georg L; Nientiedt, Tobias; Pieper, Alexander; Ruhwedel, Torben; Groszer, Matthias; Sereda, Michael W; Nave, Klaus-Armin

2012-01-01

‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies. PMID:22488882

Autophagy as an Emerging Common Pathomechanism in Inherited Peripheral Neuropathies

PubMed Central

Haidar, Mansour; Timmerman, Vincent

2017-01-01

The inherited peripheral neuropathies (IPNs) comprise a growing list of genetically heterogeneous diseases. With mutations in more than 80 genes being reported to cause IPNs, a wide spectrum of functional consequences is expected to follow this genotypic diversity. Hence, the search for a common pathomechanism among the different phenotypes has become the holy grail of functional research into IPNs. During the last decade, studies on several affected genes have shown a direct and/or indirect correlation with autophagy. Autophagy, a cellular homeostatic process, is required for the removal of cell aggregates, long-lived proteins and dead organelles from the cell in double-membraned vesicles destined for the lysosomes. As an evolutionarily highly conserved process, autophagy is essential for the survival and proper functioning of the cell. Recently, neuronal cells have been shown to be particularly vulnerable to disruption of the autophagic pathway. Furthermore, autophagy has been shown to be affected in various common neurodegenerative diseases of both the central and the peripheral nervous system including Alzheimer’s, Parkinson’s, and Huntington’s diseases. In this review we provide an overview of the genes involved in hereditary neuropathies which are linked to autophagy and we propose the disruption of the autophagic flux as an emerging common pathomechanism. We also shed light on the different steps of the autophagy pathway linked to these genes. Finally, we review the concept of autophagy being a therapeutic target in IPNs, and the possibilities and challenges of this pathway-specific targeting. PMID:28553203

Clinical spectrum of Castleman disease–associated neuropathy

PubMed Central

Naddaf, Elie; Dispenzieri, Angela; Mandrekar, Jay

2016-01-01

Objective: To define the peripheral neuropathy phenotypes associated with Castleman disease. Methods: We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. Results: There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. Conclusion: There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. PMID:27807187

Clinical spectrum of Castleman disease-associated neuropathy.

PubMed

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

2016-12-06

To define the peripheral neuropathy phenotypes associated with Castleman disease. We conducted a retrospective chart review for patients with biopsy-proven Castleman disease evaluated between January 2003 and December 2014. Patients with associated peripheral neuropathy were identified and divided into 2 groups: those with Castleman disease without POEMS syndrome (CD-PN) and those with Castleman disease with POEMS syndrome (CD-POEMS). We used a cohort of patients with POEMS as controls. Clinical, electrodiagnostic, and laboratory characteristics were collected and compared among patient subgroups. There were 7 patients with CD-PN, 20 with CD-POEMS, and 122 with POEMS. Patients with CD-PN had the mildest neuropathy characterized by predominant sensory symptoms with no pain and mild distal sensory deficits (median Neuropathy Impairment Score of 7 points). Although both patients with CD-POEMS and patients with POEMS had a severe sensory and motor neuropathy, patients with CD-POEMS were less affected (median Neuropathy Impairment Score of 33 and 66 points, respectively). The degree of severity was also reflected on electrodiagnostic testing in which patients with CD-PN demonstrated a mild degree of axonal loss, followed by patients with CD-POEMS and then those with POEMS. Demyelinating features, defined by European Federation of Neurologic Societies/Peripheral Nerve Society criteria, were present in 43% of the CD-PN, 78% of the CD-POEMS, and 86% of the POEMS group. There is a spectrum of demyelinating peripheral neuropathies associated with Castleman disease. CD-PN is sensory predominant and is the mildest phenotype, whereas CD-POEMS is a more severe sensory and motor neuropathy. Compared to the POEMS cohort, those with CD-POEMS neuropathy have a similar but less severe phenotype. Whether these patients respond differently to treatment deserves further study. © 2016 American Academy of Neurology.

Subacute diabetic proximal neuropathy

NASA Technical Reports Server (NTRS)

Pascoe, M. K.; Low, P. A.; Windebank, A. J.; Litchy, W. J.

1997-01-01

OBJECTIVE: To evaluate the clinical, electrophysiologic, autonomic, and neuropathologic characteristics and the natural history of subacute diabetic proximal neuropathy and its response to immunotherapy. MATERIAL AND METHODS: For the 12-year period from 1983 to 1995, we conducted a retrospective review of medical records of Mayo Clinic patients with diabetes who had subacute onset and progression of proximal weakness. The responses of treated versus untreated patients were compared statistically. RESULTS: During the designated study period, 44 patients with subacute diabetic proximal neuropathy were encountered. Most patients were middle-aged or elderly, and no sex preponderance was noted. The proximal muscle weakness often was associated with reduced or absent lower extremity reflexes. Associated weight loss was a common finding. Frequently, patients had some evidence of demyelination on nerve conduction studies, but it invariably was accompanied by concomitant axonal degeneration. The cerebrospinal fluid protein concentration was usually increased. Diffuse and substantial autonomic failure was generally present. In most cases, a sural nerve biopsy specimen suggested demyelination, although evidence of an inflammatory infiltrate was less common. Of 12 patients who received treatment (with prednisone, intravenous immune globulin, or plasma exchange), 9 had improvement of their conditions, but 17 of 29 untreated patients (59%) with follow-up also eventually had improvement, albeit at a much slower rate. Improvement was usually incomplete. CONCLUSION: We suggest that the entity of subacute diabetic proximal neuropathy is an extensive and severe variant of bilateral lumbosacral radiculoplexopathy, with some features suggestive of an immune-mediated cause. It differs from chronic inflammatory demyelinating polyradiculoneuropathy in that most cases have a more restricted distribution and seem to be monophasic and self-limiting. The efficacy of immunotherapy is unproved

N-hexane neuropathy in offset printers.

PubMed Central

Chang, C M; Yu, C W; Fong, K Y; Leung, S Y; Tsin, T W; Yu, Y L; Cheung, T F; Chan, S Y

1993-01-01

In an offset printing factory with 56 workers, 20 (36%) developed symptomatic peripheral neuropathy due to exposure to n-hexane. Another 26 workers (46%) were found to have subclinical neuropathy. The initial change in the nerve conduction study was reduced amplitude of the sensory action potentials, followed by reduced amplitude of the motor action potentials, reduction in motor conduction velocities and increase in distal latencies. These changes indicate primary axonal degeneration with secondary demyelination. Sural nerve biopsy in a severe case showed giant axonal swellings due to accumulation of 10nm neurofilaments, myelin sheath attenuation and widening of nodal gaps. The development of neuropathy bore no direct relationship to the duration of exposure, hence factors such as individual susceptibility may be important. Optic neuropathy and CNS involvement were uncommon and autonomic neuropathy was not encountered. Images PMID:8505647

Treatment strategies for inherited optic neuropathies: past, present and future

PubMed Central

Yu-Wai-Man, P; Votruba, M; Moore, A T; Chinnery, P F

2014-01-01

Bilateral visual loss secondary to inherited optic neuropathies is an important cause of registrable blindness among children and young adults. The two prototypal disorders seen in clinical practice are Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA). About 90% of LHON cases are due to one of three mitochondrial DNA (mtDNA) point mutations: m.3460G>A, m.11778G>A, and m.14484T>C, which affect critical complex I subunits of the mitochondrial respiratory chain. The majority of patients with DOA harbour pathogenic mutations within OPA1, a nuclear gene that codes for a multifunctional inner mitochondrial membrane protein. Despite their contrasting genetic basis, LHON and DOA share overlapping pathological and clinical features that serve to highlight the striking tissue-specific vulnerability of the retinal ganglion cell (RGC) layer to disturbed mitochondrial function. In addition to severe visual loss secondary to progressive optic nerve degeneration, a subgroup of patients will also develop a more aggressive syndromic phenotype marked by significant neurological deficits. The management of LHON and DOA remains largely supportive, but major advances in our understanding of the mechanisms underpinning RGC loss in these two disorders are paving the way for novel forms of treatment aimed at halting or reversing visual deterioration at different stages of the disease process. In addition to neuroprotective strategies for rescuing RGCs from irreversible cell death, innovative in vitro fertilisation techniques are providing the tantalising prospect of preventing the germline transmission of pathogenic mtDNA mutations, eradicating in so doing the risk of disease in future generations. PMID:24603424

Childhood chronic inflammatory demyelinating polyneuropathy: an overview of 10 cases in the modern era.

PubMed

Ware, Tyson L; Kornberg, Andrew J; Rodriguez-Casero, M Victoria; Ryan, Monique M

2014-01-01

Chronic inflammatory demyelinating polyneuropathy is a rare condition in children. In this article, we report our experience in the management of 10 cases of childhood chronic inflammatory demyelinating polyneuropathy in a single center, in the era of contrast-enhanced magnetic resonance imaging (MRI), genetic microarray, and chronic inflammatory demyelinating polyneuropathy disease activity status. Robust neurophysiologic abnormalities were present in all cases and both MRI and lumbar puncture were useful adjuncts in diagnosis. Genetic microarray is a simple technique useful in excluding the most common hereditary demyelinating neuropathy. Intravenous immunoglobulin was an effective first-line therapy in most cases, with refractory cases responding to corticosteroids and rituximab. We found the chronic inflammatory demyelinating polyneuropathy disease activity status useful for assessing outcome at final follow-up, whereas the modified Rankin score was better for assessing peak motor disability.

Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6.

PubMed

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

2016-04-01

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.

Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy.

PubMed

Mathis, Stéphane; Vallat, Jean-Michel; Magy, Laurent

2016-02-01

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic immune-mediated neuropathy: it is clinically heterogeneous (relapsing-remitting form, chronic progressive form, monophasic form or CIDP having a Guillain-Barré syndrome-like onset), but potentially treatable. Although its pathophysiology remains largely unknown, CIDP is considered an immune-mediated neuropathy. Therefore, many immunotherapies have been proposed in this peripheral nervous system disorder, the most known efficient treatments being intravenous immunoglobulin, corticosteroids and plasma exchange. However, these therapies remain unsatisfactory for many patients, so numerous other immunotherapeutic strategies have been evaluated, based on their immunosuppressant or immunomodulatory potency. We have performed a large review of the literature about treatment in CIDP, with a special emphasis on novel and alternative immunotherapeutic strategies.

Prospective comparison of acute motor axonal neuropathy and acute inflammatory demyelinating polyradiculoneuropathy in 140 children with Guillain-Barré syndrome in India.

PubMed

Kalita, Jayantee; Kumar, Mritunjai; Misra, Usha K

2018-05-01

There have been few reports on subtypes of Guillain-Barré syndrome (GBS) in children. We compared clinical and laboratory findings of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). One hundred forty children with GBS were included. Based on nerve conduction study (NCS) findings, patients were subclassified as AIDP, AMAN, acute motor sensory axonal neuropathy (AMSAN), and equivocal. Clinically, 72.1% of patients had pure motor, 24.3% motor sensory, and 3.4% Miller Fisher syndrome. Based on NCS, 67.8% of patients had AIDP, 23.6% had AMAN, and 4.3% had AMSAN. By 3 months, 2.1% patients had died, 47.1% had complete recovery, and 24.3% had poor recovery (wheelchair-bound). Children with AMAN had more frequent lower limb weakness (P = 0.02) and a lower probability of complete recovery (P = 0.01) at 3 months than children with AIDP (56% vs. 30%). AIDP is the most common GBS subtype in children. It is characterized by better recovery at 3 months when compared with AMAN. Muscle Nerve 57: 761-765, 2018. © 2017 Wiley Periodicals, Inc.

Genetics Home Reference: hereditary sensory neuropathy type IA

MedlinePlus

... by nerve abnormalities in the legs and feet (peripheral neuropathy). Many people with this condition experience prickling or ... Research Network: Inherited Neuropathies Consortium The Foundation for Peripheral Neuropathy: Symptoms General Information from MedlinePlus (5 links) Diagnostic ...

Neurophysiological profile of peripheral neuropathy associated with childhood mitochondrial disease.

PubMed

Menezes, Manoj P; Rahman, Shamima; Bhattacharya, Kaustuv; Clark, Damian; Christodoulou, John; Ellaway, Carolyn; Farrar, Michelle; Pitt, Matthew; Sampaio, Hugo; Ware, Tyson L; Wedatilake, Yehani; Thorburn, David R; Ryan, Monique M; Ouvrier, Robert

2016-09-01

Peripheral nerve involvement is common in mitochondrial disease but often unrecognised due to the prominent central nervous system features. Identification of the underlying neuropathy may assist syndrome classification, targeted genetic testing and rehabilitative interventions. Clinical data and the results of nerve conduction studies were obtained retrospectively from the records of four tertiary children's hospital metabolic disease, neuromuscular or neurophysiology services. Nerve conductions studies were also performed prospectively on children attending a tertiary metabolic disease service. Results were classified and analysed according to the underlying genetic cause. Nerve conduction studies from 27 children with mitochondrial disease were included in the study (mitochondrial DNA (mtDNA) - 7, POLG - 7, SURF1 - 10, PDHc deficiency - 3). Four children with mtDNA mutations had a normal study while three had mild abnormalities in the form of an axonal sensorimotor neuropathy when not acutely unwell. One child with MELAS had a severe acute axonal motor neuropathy during an acute stroke-like episode that resolved over 12months. Five children with POLG mutations and disease onset beyond infancy had a sensory ataxic neuropathy with an onset in the second decade of life, while the two infants with POLG mutations had a demyelinating neuropathy. Seven of the 10 children with SURF1 mutations had a demyelinating neuropathy. All three children with PDHc deficiency had an axonal sensorimotor neuropathy. Unlike CMT, the neuropathy associated with mitochondrial disease was not length-dependent. This is the largest study to date of peripheral neuropathy in genetically- classified childhood mitochondrial disease. Characterising the underlying neuropathy may assist with the diagnosis of the mitochondrial syndrome and should be an integral part of the assessment of children with suspected mitochondrial disease. Copyright © 2016 Elsevier B.V. and Mitochondria Research Society

Structure and Functional Characterization of Human Histidine Triad Nucleotide-Binding Protein 1 Mutations Associated with Inherited Axonal Neuropathy with Neuromyotonia.

PubMed

Shah, Rachit M; Maize, Kimberly M; West, Harrison T; Strom, Alexander M; Finzel, Barry C; Wagner, Carston R

2018-05-19

Inherited peripheral neuropathies are a group of neurodegenerative disorders that clinically affect 1 in 2500 individuals. Recently, genetic mutations in human histidine nucleotide-binding protein 1 (hHint1) have been strongly and most frequently associated with patients suffering from axonal neuropathy with neuromyotonia. However, the correlation between the impact of these mutations on the hHint1 structure, enzymatic activity and in vivo function has remained ambiguous. Here, we provide detailed biochemical characterization of a set of these hHint1 mutations. Our findings indicate that half of the mutations (R37P, G93D and W123*) resulted in a destabilization of the dimeric state and a significant decrease in catalytic activity and HINT1 inhibitor binding affinity. The H112N mutant was found to be dimeric, but devoid of catalytic activity, due to the loss of the catalytically essential histidine; nevertheless, it exhibited high affinity to AMP and a HINT1 inhibitor. In contrast to the active-site mutants, the catalytic activity and dimeric structure of the surface mutants, C84R and G89V, were found to be similar to the wild-type enzyme. Taken together, our results suggest that the pathophysiology of inherited axonal neuropathy with neuromyotonia can be induced by conversion of HINT1 from a homodimer to monomer, by modification of select surface residues or by a significant reduction of the enzyme's catalytic efficiency. Copyright © 2018. Published by Elsevier Ltd.

Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy.

PubMed

Rachana, Kuruvanthe S; Manu, Mallahalli S; Advirao, Gopal M

2018-03-17

Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath. Since, lipoprotein lipase (LPL) provides the lipid for myelin sheath by hydrolysing the triglyceride rich lipoproteins, and also helps in the uptake of lipids by the Schwann cells (SCs) for its utilization, LPL is considered as the important factor in the regeneration of myelin sheath during diabetic neuropathy. Earlier reports from our laboratory have provided the insights of insulin and its receptor in SCs during diabetic neuropathy. In order to evaluate the long term effect of insulin on lipid metabolism during diabetic neuropathy, in this study, we analyzed the expression of LPL in SCs under normal, high glucose and insulin treated conditions. A decrease in the expression of LPL was observed in SCs of high glucose condition and it was reversed upon insulin treatment. Histochemical observations of sciatic nerve of insulin treated neuropathy subjects showed the improved nerve morphology, signifying the importance of insulin in restoring the pathophysiology of diabetic neuropathy. Copyright © 2018 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

PubMed Central

Mathey, Emily K; Park, Susanna B; Hughes, Richard A C; Pollard, John D; Armati, Patricia J; Barnett, Michael H; Taylor, Bruce V; Dyck, P James B; Kiernan, Matthew C; Lin, Cindy S-Y

2015-01-01

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. PMID:25677463

Distal acquired demyelinating symmetric polyneuropathy progressing to classic chronic inflammatory demyelinating polyneuropathy and response to fludarabine and cyclophosphamide.

PubMed

Leitch, Megan M; Sherman, William H; Brannagan, Thomas H

2013-02-01

Distal acquired demyelinating symmetric polyneuropathy (DADS) is proposed as a distinct entity from classic chronic inflammatory demyelinating polyneuropathy (CIDP). We report a 58-year-old woman with DADS that progressed to a severe case of classic CIDP. She had distal numbness and paresthesias, minimal distal weakness and impaired vibratory sensation. She had anti-MAG antibodies, negative Western blot, and lacked a monoclonal gammopathy. There were prolonged distal motor latencies. She remained stable for 6 years until developing proximal and distal weakness. Nerve conduction studies showed multiple conduction blocks. She developed quadriparesis despite first-line treatment for CIDP. She was started on cyclophosphamide and fludarabine. Twenty-five months after receiving chemotherapy, she had only mild signs of neuropathy off all immunotherapy. DADS may progress to classic CIDP and is unlikely to be a separate disorder. Fludarabine and cyclophosphamide may be effective for refractory CIDP. Copyright © 2012 Wiley Periodicals, Inc.

Whole-exome sequencing reveals a novel missense mutation in the MARS gene related to a rare Charcot-Marie-Tooth neuropathy type 2U.

PubMed

Sagi-Dain, Lena; Shemer, Lilach; Zelnik, Nathanel; Zoabi, Yusri; Orit, Sadeh; Adir, Vardit; Schif, Aharon; Peleg, Amir

2018-06-01

Charcot-Marie-Tooth (CMT) is a heterogeneous group of progressive disorders, characterized by chronic motor and sensory polyneuropathy. This hereditary disorder is related to numerous genes and varying inheritance patterns. Thus, many patients do not reach a final genetic diagnosis. We describe a 13-year-old girl presenting with progressive bilateral leg weakness and gait instability. Extensive laboratory studies and spinal magnetic resonance imaging scan were normal. Nerve conduction studies revealed severe lower limb peripheral neuropathy with prominent demyelinative component. Following presumptive diagnosis of chronic inflammatory demyelinating polyneuropathy, the patient received treatment with steroids and intravenous immunoglobulins courses for several months, with no apparent improvement. Whole-exome sequencing revealed a novel heterozygous c.2209C>T (p.Arg737Trp) mutation in the MARS gene (OMIM 156560). This gene has recently been related to CMT type 2U. In-silico prediction programs classified this mutation as a probable cause for protein malfunction. Allele frequency data reported this variant in 0.003% of representative Caucasian population. Family segregation analysis study revealed that the patient had inherited the variant from her 60-years old mother, reported as healthy. Neurologic examination of the mother demonstrated decreased tendon reflexes, while nerve conduction studies were consistent with demyelinative and axonal sensory-motor polyneuropathy. Our report highlights the importance of next-generation sequencing approach to facilitate the proper molecular diagnosis of highly heterogeneous neurologic disorders. Amongst other numerous benefits, this approach might prevent unnecessary diagnostic testing and potentially harmful medical treatment. © 2018 Peripheral Nerve Society.

Myasthenia gravis and chronic inflammatory demyelinating polyneuropathy in the same patient - a case report.

PubMed

Quan, Weiwei; Xia, Junhui; Tong, Qiuling; Lin, Jie; Zheng, Xiaolu; Yang, Xuezhi; Xie, Dewei; Weng, Yiyun; Zhang, Xu

2018-06-01

To investigate the clinical character, diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy accompanying myasthenia gravis so as to improve the understanding of such diseases. A case of chronic inflammatory demyelinating polyneuropathy combined with myasthenia gravis were analyzed retrospectively with review of the literature. This man was presented with chronic progressive sensory symptoms, flaccid tetraparesis, areflexia and protein-cell dissociation of cerebrospinal fluid. Nerve conduction study was indicative of demyelinating neuropathy. He was suspected as chronic inflammatory demyelinating polyneuropathy and treated with high-dose glucocorticoids. However, his condition worsened. Four months later, he was admitted and was diagnosed as combination of chronic inflammatory demyelinating polyneuropathy and myasthenia gravis. Good clinical results were observed after he was treated with pyridostigmine bromide, prednisone and mycophenolate mofetil. This case warns clinicians to be aware of these two diseases presenting in the same patient, and the possible implications on treatment choices. A common immunological abnormality might exist in this rare association, but it still remains unknown.

Elevated serum levels of endothelin-1 in patients with chronic inflammatory demyelinating polyneuropathy.

PubMed

Chang, Chun-Wei; Wu, Hsiu-Chuan; Lyu, Rong-Kuo; Lo, Yen-Shi; Chen, Chiung-Mei; Ro, Long-Sun; Chang, Hong-Shiu; Huang, Ching-Chang; Liao, Ming-Feng; Wu, Yih-Ru; Kuo, Hung-Chou; Chu, Chun-Che; Weng, Yi-Ching; Wei, Pei-Tsi; Lo, Ai-Lun; Chang, Kuo-Hsuan

2018-01-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired, or non-hereditary, chronic demyelinating neuropathy. Currently, there is no reliable molecular biomarker that can identify CIDP patients as well as monitor disease severity. We measured serum levels of endothelin-1 (ET-1), a factors involved in vasoconstrictive, inflammatory and nerve regenerative processes, in 20 CIDP, 21 acute inflammatory demyelinating polyneuropathy (AIDP), 37 multiple sclerosis (MS), and 10 Alzheimer's disease (AD) patients, as well as 26 healthy control (HC) subjects. Patients with CIDP demonstrated higher serum levels of ET-1 (2.07±1.07pg/mL) than those with AIDP (0.75±0.62ng/mL, P<0.001), AD (0.78±0.49pg/mL, P<0.001), as well as HCs (1.16±0.63pg/mL, P=0.002), while levels of ET-1 in patients with MS (2.10±0.81pg/mL) and CIDP were similar. Furthermore, the serum ET-1 levels significantly correlated with Inflammatory Neuropathy Cause And Treatment (INCAT) disability scale in CIDP patients. Receiver operating characteristic (ROC) curve showed good discrimination ability for ET-1 to distinguish CIDP patients from AIDP (AUC=0.883) or HCs (AUC=0.763). This study discloses the potential of serum ET-1 as a biomarker for CIDP. Copyright © 2017 Elsevier B.V. All rights reserved.

Peripheral neuropathy associated with mitochondrial disease in children.

PubMed

Menezes, Manoj P; Ouvrier, Robert A

2012-05-01

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. © The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.

Genotype/phenotype correlations in AARS-related neuropathy in a cohort of patients from the United Kingdom and Ireland.

PubMed

Bansagi, Boglarka; Antoniadi, Thalia; Burton-Jones, Sarah; Murphy, Sinead M; McHugh, John; Alexander, Michael; Wells, Richard; Davies, Joanna; Hilton-Jones, David; Lochmüller, Hanns; Chinnery, Patrick; Horvath, Rita

2015-08-01

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy with heterogeneous clinical presentation and genetic background. The axonal form (CMT2) is characterised by decreased action potentials indicating primary axonal damage. The underlying pathology involves axonal degeneration which is supposed to be related to axonal protein dysfunction caused by various gene mutations. The overlapping clinical manifestation of CMT2 with distal hereditary motor neuropathy (dHMN) and intermediate CMT causes further diagnostic difficulties. Aminoacyl-tRNA synthetases have been implicated in the pathomechanism of CMT2. They have an essential role in protein translation by attaching amino acids to their cognate tRNAs. To date six families have been reported worldwide with dominant missense alanyl-tRNA synthetase (AARS) mutations leading to clinically heterogeneous axonal neuropathies. The pathomechanism of some variants could be explained by impaired amino acylation activity while other variants implicating an editing defect need to be further investigated. Here, we report a cohort of six additional families originating from the United Kingdom and Ireland with dominant AARS-related neuropathies. The phenotypic manifestation was distal lower limb predominant sensorimotor neuropathy but upper limb impairment with split hand deformity occasionally associated. Nerve conduction studies revealed significant demyelination accompanying the axonal lesion in motor and sensory nerves. Five families have the c.986G>A, p.(Arg329His) variant, further supporting that this is a recurrent loss of function variant. The sixth family, of Irish origin, had a novel missense variant, c.2063A>G, p.(Glu688Gly). We discuss our findings and the associated phenotypic heterogeneity in these families, which expands the clinical spectrum of AARS-related neuropathies.

Sarcoid polyneuropathy masquerading as chronic inflammatory demyelinating polyneuropathy.

PubMed

Singhal, Neel S; Irodenko, Viktoriya S; Margeta, Marta; Layzer, Robert B

2015-10-01

Sarcoid polyneuropathy is a rare and clinically heterogeneous disorder that may be the initial presentation of sarcoidosis. We report the clinical, electrophysiological, and pathological findings of a patient who carried a diagnosis of sensory-predominant chronic inflammatory demyelinating polyneuropathy (CIDP) for over a decade but was ultimately found to have sarcoid polyneuropathy. A 36-year-old man presented with a several-week history of gait difficulty and muscle cramps. He had a diagnosis of CIDP but had not received lasting benefit from steroid-sparing immunosuppressive drugs. Electrodiagnostic studies were consistent with a chronic demyelinating polyradiculoneuropathy with conduction blocks. After he developed systemic symptoms, tissue biopsies revealed granulomatous disease. Symptoms improved with steroid therapy. Sarcoid polyneuropathy presents a diagnostic challenge, but, in patients with atypical neuropathy, characteristic systemic symptoms, or a poor response to standard treatment, nerve and muscle biopsies can help diagnose this treatable disorder. © 2015 Wiley Periodicals, Inc.

MCM3AP in recessive Charcot-Marie-Tooth neuropathy and mild intellectual disability.

PubMed

Ylikallio, Emil; Woldegebriel, Rosa; Tumiati, Manuela; Isohanni, Pirjo; Ryan, Monique M; Stark, Zornitza; Walsh, Maie; Sawyer, Sarah L; Bell, Katrina M; Oshlack, Alicia; Lockhart, Paul J; Shcherbii, Mariia; Estrada-Cuzcano, Alejandro; Atkinson, Derek; Hartley, Taila; Tetreault, Martine; Cuppen, Inge; van der Pol, W Ludo; Candayan, Ayse; Battaloglu, Esra; Parman, Yesim; van Gassen, Koen L I; van den Boogaard, Marie-José H; Boycott, Kym M; Kauppi, Liisa; Jordanova, Albena; Lönnqvist, Tuula; Tyynismaa, Henna

2017-08-01

Defects in mRNA export from the nucleus have been linked to various neurodegenerative disorders. We report mutations in the gene MCM3AP, encoding the germinal center associated nuclear protein (GANP), in nine affected individuals from five unrelated families. The variants were associated with severe childhood onset primarily axonal (four families) or demyelinating (one family) Charcot-Marie-Tooth neuropathy. Mild to moderate intellectual disability was present in seven of nine affected individuals. The affected individuals were either compound heterozygous or homozygous for different MCM3AP variants, which were predicted to cause depletion of GANP or affect conserved amino acids with likely importance for its function. Accordingly, fibroblasts of affected individuals from one family demonstrated severe depletion of GANP. GANP has been described to function as an mRNA export factor, and to suppress TDP-43-mediated motor neuron degeneration in flies. Thus our results suggest defective mRNA export from nucleus as a potential pathogenic mechanism of axonal degeneration in these patients. The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Development profile in a patient with monosomy 10q and Dup(17p) associated with a peripheral neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pellegrino, J.E.; Spinner, N.B.; Zackai, E.H.

1996-02-02

We report on a patient with dup(17p) and monosomy (10q) resulting from a familial translocation. Manifestations typical of both syndromes were present. The overall development of this patient was better by comparison with similar reported cases of either anomaly. Our evaluation detected severe gross motor delay and signs of a demyelinating peripheral neuropathy. This patient is trisomic for the region of 17p which includes the peripheral myelin protein-22 (PMP-22) gene, known to be duplicated in Charcot-Marie-Tooth neuropathy type 1A (CMT1A). Our analysis in this patient suggests that trisomy for the PMP-22 gene led to the demyelinating neuropathy and contributed tomore » his severe motor development delay. 33 refs., 3 figs., 1 tab.« less

Serum cytokine and chemokine profiles in patients with chronic inflammatory demyelinating polyneuropathy.

PubMed

Beppu, Minako; Sawai, Setsu; Misawa, Sonoko; Sogawa, Kazuyuki; Mori, Masahiro; Ishige, Takayuki; Satoh, Mamoru; Nomura, Fumio; Kuwabara, Satoshi

2015-02-15

To identify serum cytokine networks specific to chronic inflammatory demyelinating polyneuropathy (CIDP), serum samples of two subgroups (18 patients with typical CIDP and 12 patients with multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]) were analyzed with multiplex magnetic bead-based cytokine assay. TNF-α, HGF, MIP-1β and IL-1β levels were significantly higher in total CIDP patients than in normal controls. Of these, HGF levels were elevated in typical CIDP patients, but not in MADSAM patients. Patients with high HGF levels showed good responses to steroid treatment. Different cytokine profiles among the CIDP subtypes presumably reflect differences in pathophysiology. Copyright © 2014 Elsevier B.V. All rights reserved.

The dilemma of diabetes in chronic inflammatory demyelinating polyneuropathy.

PubMed

Bril, Vera; Blanchette, Christopher M; Noone, Joshua M; Runken, M Chris; Gelinas, Deborah; Russell, James W

2016-01-01

We reviewed the literature on chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetes mellitus (DM) and explored real-world data on the prevalence and treatment of CIDP within DM. A literature search of Scopus was performed for the terms chronic inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, and prevalence, incidence, epidemiology, or diabetes; peripheral neuropathy and prevalence or diabetes. We also searched through the reference lists of the resulting publications for additional findings that may have been missed. Additional publications on guidelines for the diagnosis of CIDP and diabetic neuropathy were also included. A descriptive analysis of the 2009-2013 PharMetrics Plus™ Database was performed to estimate the prevalence and treatment of CIDP within the DM population. There is an increasing body of literature suggesting that the prevalence of CIDP tends to be higher in diabetic patients, especially in those of older age. Our real-world data seem to support published findings from the literature. For the total cohort (N=101,321,694), the percent prevalence of CIDP (n=8,173) was 0.008%; DM (n=4,026,740) was 4%. The percent prevalence of CIDP without DM (n=5,986) was 0.006%; CIDP with DM (n=2,187) was 9-fold higher at 0.054%. For patients >50years old, there was a significantly higher percentage of CIDP with DM than CIDP without DM. Approximately 50% of CIDP patients were treated with IVIg, 23%-24% with steroids, 1%-2% with PE, and 20%-23% received no treatment. In addition to the growing evidence of higher prevalence of CIDP in DM, our findings reinforce the need for heightened awareness of the association of CIDP and DM. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The dilemma of diabetes in chronic inflammatory demyelinating polyneuropathy

PubMed Central

Bril, Vera; Blanchette, Christopher M.; Noone, Joshua M.; Runken, M. Chris; Gelinas, Deborah; Russell, James W.

2017-01-01

Purpose We reviewed the literature on chronic inflammatory demyelinating polyneuropathy (CIDP) in diabetes mellitus (DM) and explored real-world data on the prevalence and treatment of CIDP within DM. Methods: A literature search of Scopus was performed for the terms chronic inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, and prevalence, incidence, epidemiology, or diabetes; peripheral neuropathy and prevalence or diabetes. We also searched through the reference lists of the resulting publications for additional findings that may have been missed. Additional publications on guidelines for the diagnosis of CIDP and diabetic neuropathy were also included. A descriptive analysis of the 2009–2013 PharMetrics Plus™ Database was performed to estimate the prevalence and treatment of CIDP within the DM population. Results There is an increasing body of literature suggesting that the prevalence of CIDP tends to be higher in diabetic patients, especially in those of older age. Our real-world data seem to support published findings from the literature. For the total cohort (N = 101,321,694), the percent prevalence of CIDP (n = 8,173) was 0.008%; DM (n = 4,026,740) was 4%. The percent prevalence of CIDP without DM (n = 5,986) was 0.006%; CIDP with DM (n = 2,187) was 9-fold higher at 0.054%. For patients >50 years old, there was a significantly higher percentage of CIDP with DM than CIDP without DM. Approximately 50% of CIDP patients were treated with IVIg, 23%–24% with steroids, 1%–2% with PE, and 20%–23% received no treatment. Conclusions In addition to the growing evidence of higher prevalence of CIDP in DM, our findings reinforce the need for heightened awareness of the association of CIDP and DM. PMID:27389526

Sensory neuropathy in two Border collie puppies.

PubMed

Vermeersch, K; Van Ham, L; Braund, K G; Bhatti, S; Tshamala, M; Chiers, K; Schrauwen, E

2005-06-01

A peripheral sensory neuropathy was diagnosed in two Border collie puppies. Neurological, electrophysiological and histopathological examinations suggested a purely sensory neuropathy with mainly distal involvement. Urinary incontinence was observed in one of the puppies and histological examination of the vagus nerve revealed degenerative changes. An inherited disorder was suspected.

Binaural speech processing in individuals with auditory neuropathy.

PubMed

Rance, G; Ryan, M M; Carew, P; Corben, L A; Yiu, E; Tan, J; Delatycki, M B

2012-12-13

Auditory neuropathy disrupts the neural representation of sound and may therefore impair processes contingent upon inter-aural integration. The aims of this study were to investigate binaural auditory processing in individuals with axonal (Friedreich ataxia) and demyelinating (Charcot-Marie-Tooth disease type 1A) auditory neuropathy and to evaluate the relationship between the degree of auditory deficit and overall clinical severity in patients with neuropathic disorders. Twenty-three subjects with genetically confirmed Friedreich ataxia and 12 subjects with Charcot-Marie-Tooth disease type 1A underwent psychophysical evaluation of basic auditory processing (intensity discrimination/temporal resolution) and binaural speech perception assessment using the Listening in Spatialized Noise test. Age, gender and hearing-level-matched controls were also tested. Speech perception in noise for individuals with auditory neuropathy was abnormal for each listening condition, but was particularly affected in circumstances where binaural processing might have improved perception through spatial segregation. Ability to use spatial cues was correlated with temporal resolution suggesting that the binaural-processing deficit was the result of disordered representation of timing cues in the left and right auditory nerves. Spatial processing was also related to overall disease severity (as measured by the Friedreich Ataxia Rating Scale and Charcot-Marie-Tooth Neuropathy Score) suggesting that the degree of neural dysfunction in the auditory system accurately reflects generalized neuropathic changes. Measures of binaural speech processing show promise for application in the neurology clinic. In individuals with auditory neuropathy due to both axonal and demyelinating mechanisms the assessment provides a measure of functional hearing ability, a biomarker capable of tracking the natural history of progressive disease and a potential means of evaluating the effectiveness of interventions

"Mitochondrial neuropathies": A survey from the large cohort of the Italian Network.

PubMed

Mancuso, Michelangelo; Orsucci, Daniele; Angelini, Corrado; Bertini, Enrico; Carelli, Valerio; Comi, Giacomo Pietro; Federico, Antonio; Minetti, Carlo; Moggio, Maurizio; Mongini, Tiziana; Tonin, Paola; Toscano, Antonio; Bruno, Claudio; Ienco, Elena Caldarazzo; Filosto, Massimiliano; Lamperti, Costanza; Diodato, Daria; Moroni, Isabella; Musumeci, Olimpia; Pegoraro, Elena; Spinazzi, Marco; Ahmed, Naghia; Sciacco, Monica; Vercelli, Liliana; Ardissone, Anna; Zeviani, Massimo; Siciliano, Gabriele

2016-01-01

Involvement of the peripheral nervous system in mitochondrial disorders has been previously reported. However, the prevalence of peripheral neuropathy in mitochondrial disorders is still unclear. Based on the large database of the "Nation-wide Italian Collaborative Network of Mitochondrial Diseases", we reviewed the clinical data of 1200 patients, with special regard to peripheral neuropathy (mean age at onset 24.3 ± 20.1 years; age at last evaluation 39.8 ± 22.3 years; females 52.7%; childhood onset [before age 16 years] 43.1%). Peripheral neuropathy was present in 143/1156 patients (12.4%), being one of the ten most common signs and symptoms. POLG mutations cause a potentially painful, axonal/mixed, mainly sensory polyneuropathy; TYMP mutations lead to a demyelinating sensory-motor polyneuropathy; SURF1 mutations are associated with a demyelinating/mixed sensory-motor polyneuropathy. The only mtDNA mutation consistently associated with peripheral neuropathy (although less severely than in the above-considered nuclear genes) was the m.8993T > G (or the rarer T > C) changes, which lead to an axonal, mainly sensory polyneuropathy. In conclusion, peripheral neuropathy is one of the most common features of a mitochondrial disorder, and may negatively impact on the quality of life of these patients. Furthermore, the presence or absence of peripheral neuropathy, as well as its specific forms and the association with neuropathic pain (indicative of a POLG-associated disease) can guide the molecular analysis. Copyright © 2016 Elsevier B.V. All rights reserved.

Autoimmune neuropathies associated to rheumatic diseases.

PubMed

Martinez, Alberto R M; Faber, Ingrid; Nucci, Anamarli; Appenzeller, Simone; França, Marcondes C

2017-04-01

Systemic manifestations are frequent in autoimmune rheumatic diseases and include peripheral nervous system damage. Neuron cell body, axons and myelin sheath may all be affected in this context. This involvement results in severe and sometimes disabling symptoms. Sensory, motor and autonomic features may be present in different patterns that emerge as peculiar clinical pictures. Prompt recognition of these neuropathies is pivotal to guide treatment and reduce the risks of long term disability. In this review, we aim to describe the main immune-mediated neuropathies associated to rheumatic diseases: sensory neuronopathies, multiple mononeuropathies and chronic inflammatory demyelinating polyradiculoneuropathy, with an emphasis on clinical features and therapeutic options. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetics Home Reference: autosomal recessive axonal neuropathy with neuromyotonia

MedlinePlus

... with neuromyotonia is a rare form of inherited peripheral neuropathy. This group of conditions affects an estimated 1 ... Page National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy Fact Sheet Educational Resources (3 links) MalaCards: neuromyotonia ...

[Chronic Inflammatory Demyelinating Polyneuropathy].

PubMed

Balke, M; Wunderlich, G; Brunn, A; Fink, G R; Lehmann, H C

2016-12-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic progressive or relapsing autoimmune neuropathy with heterogeneous clinical presentation. Symptoms typically include symmetrical, proximal and/or distal paresis and sensory loss. Atypical CIDP variants are increasingly recognized, including subtypes with rapid onset as well as variants with pure sensory, focal or marked asymmetrical deficits. Diagnosis is established by compatible symptoms, characteristic electrophysiological features and cerebrospinal fluid analysis. In unequivocal cases, inflammatory infiltrates in sural nerve biopsy support the diagnosis. Recent studies suggest that diagnostic imaging techniques such as MRI and nerve ultrasound may become useful tools for establishing the diagnosis. First-line therapies include immunoglobulines, steroids, and plasmapheresis. Immunosuppressant agents and monoclonal antibodies are used in therapy-refractory cases or as cortison-saving agents. © Georg Thieme Verlag KG Stuttgart · New York.

Motor and sensory neuropathy due to myelin infolding and paranodal damage in a transgenic mouse model of Charcot–Marie–Tooth disease type 1C

PubMed Central

Lee, Samuel M.; Sha, Di; Mohammed, Anum A.; Asress, Seneshaw; Glass, Jonathan D.; Chin, Lih-Shen; Li, Lian

2013-01-01

Charcot–Marie–Tooth disease type 1C (CMT1C) is a dominantly inherited motor and sensory neuropathy. Despite human genetic evidence linking missense mutations in SIMPLE to CMT1C, the in vivo role of CMT1C-linked SIMPLE mutations remains undetermined. To investigate the molecular mechanism underlying CMT1C pathogenesis, we generated transgenic mice expressing either wild-type or CMT1C-linked W116G human SIMPLE. Mice expressing mutant, but not wild type, SIMPLE develop a late-onset motor and sensory neuropathy that recapitulates key clinical features of CMT1C disease. SIMPLE mutant mice exhibit motor and sensory behavioral impairments accompanied by decreased motor and sensory nerve conduction velocity and reduced compound muscle action potential amplitude. This neuropathy phenotype is associated with focally infolded myelin loops that protrude into the axons at paranodal regions and near Schmidt–Lanterman incisures of peripheral nerves. We find that myelin infolding is often linked to constricted axons with signs of impaired axonal transport and to paranodal defects and abnormal organization of the node of Ranvier. Our findings support that SIMPLE mutation disrupts myelin homeostasis and causes peripheral neuropathy via a combination of toxic gain-of-function and dominant-negative mechanisms. The results from this study suggest that myelin infolding and paranodal damage may represent pathogenic precursors preceding demyelination and axonal degeneration in CMT1C patients. PMID:23359569

[Leber's hereditary optic neuropathy].

PubMed

Hilo, Wasseem; Jabaly-Habib, Haneen; Modi, Naftali; Briscoe, Daniel

2013-08-01

Lebers hereditary optic neuropathy (LHON) is a maternally inherited disease characterized by subacute severe visual loss in both eyes, which usually manifests in young adulthood. The disease has maternal inheritance due to mitochondrial DNA mutation. The final diagnosis is genetic. There is still no proven treatment, but there is significant progress in developments on the genetics of the disease to reach gene therapy. In this article we review the latest literature relevant to this disease.

Genetic heterogeneity of motor neuropathies

PubMed Central

Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G.; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F.

2017-01-01

Objective: To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Methods: Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). Results: The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62–2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Conclusions: Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. PMID:28251916

[Chronic demyelinating polyneuropathy and B6 hypervitaminosis].

PubMed

Castagnet, S; Blasco, H; Vourc'h, P; Andres, C R; Praline, J

2010-12-01

We report a 62-year-old patient who presented with a several month history of a peripheral sensory neuropathy with ataxia that was attributed to a chronic immune demyelinating polyneuropathy but was resistant to corticosteroid therapy. Diagnostic workup finally showed a high serum level of pyridoxin related to a chronic intake of oral vitamin medication for several years. We discuss the link between the clinical and electrophysiological manifestations of the chronic polyneuropathy, based on similar reported observations in the literature. This observation highlights the possibility of important long-term deleterious effects of vitamin oral supplementations, particularly pyridoxin. Copyright © 2010. Published by Elsevier SAS.

Genetic Screening for OPA1 and OPA3 Mutations in Patients with Suspected Inherited Optic Neuropathies

PubMed Central

Yu-Wai-Man, Patrick; Shankar, Suma P.; Biousse, Valérie; Miller, Neil R.; Bean, Lora J.H.; Coffee, Bradford; Hegde, Madhuri; Newman, Nancy J.

2010-01-01

Purpose Autosomal-dominant optic atrophy (DOA) is one of the most common inherited optic neuropathies, and it is genetically heterogeneous, with mutations in both OPA1 and OPA3 known to cause disease. About 60% of cases harbor OPA1 mutations, whereas OPA3 mutations have only been reported in two pedigrees with DOA and premature cataracts. The aim of this study was to determine the yield of OPA1 and OPA3 screening in a cohort of presumed DOA cases referred to a tertiary diagnostic laboratory. Design Retrospective case series. Participants One hundred and eighty-eight probands with bilateral optic atrophy referred for molecular genetic investigations at a tertiary diagnostic facility: 38 patients with an autosomal-dominant pattern of inheritance and 150 sporadic cases. Methods OPA1 and OPA3 genetic testing was initially performed using PCR-based sequencing methods. The presence of large-scale OPA1 and OPA3 genomic rearrangements was further assessed with a targeted comparative genomic hybridization (CGH) microarray platform. The three primary Leber hereditary optic neuropathy (LHON) mutations, m.3460G>A, m.11778G>A, and m.14484T>C, were also screened in all patients. Main Outcome Measures The proportion of patients with OPA1 and OPA3 pathogenic mutations. The clinical profile observed in molecularly confirmed DOA cases. Results We found 21 different OPA1 mutations in 27 of the 188 (14.4%) probands screened. The mutations included six novel pathogenic variants and the first reported OPA1 initiation codon mutation at c.1A>T. An OPA1 missense mutation, c.239A>G (p.Y80C), was identified in an 11-year-old African-American girl with optic atrophy and peripheral sensori-motor neuropathy in her lower limbs. The OPA1 detection rate was significantly higher among individuals with a positive family history of visual failure (50.0%) compared with sporadic cases (5.3%). The primary LHON screen was negative in our patient cohort, and additional molecular investigations did not

POEMS Syndrome Diagnosed 10 Years after Disabling Peripheral Neuropathy.

PubMed

Nguyen, Viet H

2011-01-01

Peripheral neuropathy is characterized as a generalized, relatively homogeneous process affecting many peripheral nerves and predominantly affecting distal nerves. The epidemiology of peripheral neuropathy is limited since the disease presents with varying etiology, pathology, and severity. Toxic, inflammatory, hereditary, and infectious factors can cause damage to the peripheral nerves resulting in peripheral neuropathy. Peripheral neuropathy is most commonly caused by diabetes, alcohol, HIV infection, and malignancy. We report a case of a 42-year-old female with 10-year history of progressively worsening peripheral neuropathy, hypothyroidism, and skin changes who presents with dyspnea secondary to recurrent pleural and pericardial effusions. Prior to her arrival, her peripheral neuropathy was believed to be secondary to chronic demyelinating inflammatory polyneuropathy (CDIP) given elevated protein in the cerebral spinal fluid (CSF) which was treated with intravenous immunoglobulin (IVIG) and corticosteroids. Unfortunately, her peripheral neuropathy did not have any improvement. Incidentally, patient was found to have splenomegaly and papilledema on physical exam. Serum protein electrophoresis showed a monoclonal pattern of IgA lambda. Patient met the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. An underlying diagnosis of POEMS syndrome should be considered in patients with chronic debilitating neuropathy and an elevated protein in the CSF.

POEMS Syndrome Diagnosed 10 Years after Disabling Peripheral Neuropathy

PubMed Central

Nguyen, Viet H.

2011-01-01

Peripheral neuropathy is characterized as a generalized, relatively homogeneous process affecting many peripheral nerves and predominantly affecting distal nerves. The epidemiology of peripheral neuropathy is limited since the disease presents with varying etiology, pathology, and severity. Toxic, inflammatory, hereditary, and infectious factors can cause damage to the peripheral nerves resulting in peripheral neuropathy. Peripheral neuropathy is most commonly caused by diabetes, alcohol, HIV infection, and malignancy. We report a case of a 42-year-old female with 10-year history of progressively worsening peripheral neuropathy, hypothyroidism, and skin changes who presents with dyspnea secondary to recurrent pleural and pericardial effusions. Prior to her arrival, her peripheral neuropathy was believed to be secondary to chronic demyelinating inflammatory polyneuropathy (CDIP) given elevated protein in the cerebral spinal fluid (CSF) which was treated with intravenous immunoglobulin (IVIG) and corticosteroids. Unfortunately, her peripheral neuropathy did not have any improvement. Incidentally, patient was found to have splenomegaly and papilledema on physical exam. Serum protein electrophoresis showed a monoclonal pattern of IgA lambda. Patient met the diagnostic criteria for POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes) syndrome. An underlying diagnosis of POEMS syndrome should be considered in patients with chronic debilitating neuropathy and an elevated protein in the CSF. PMID:22013451

Prevalence and predictors of peripheral neuropathy in nondiabetic children with chronic kidney disease.

PubMed

Yoganathan, Sangeetha; Bagga, Arvind; Gulati, Sheffali; Toteja, G S; Hari, Pankaj; Sinha, Aditi; Pandey, Ravindra Mohan; Irshad, Mohammad

2018-05-01

This study sought to determine the prevalence and predictors of peripheral neuropathy in nondiabetic children with chronic kidney disease (CKD). Fifty-one consecutive normally nourished children, 3-18 years of age, with CKD stages IV and V of nondiabetic etiology were enrolled from May to December 2012. Nerve conduction studies were performed in 50 children. Blood samples were analyzed for the biochemical parameters, trace elements, and micronutrients. The prevalence of peripheral neuropathy in our cohort was 52% (95% confidence interval 37.65, 66.34). The majority (80.8%) of the children had axonal neuropathy, and 11.5% had demyelinating neuropathy. Isolated motor neuropathy was identified in 92.3% of the children, and sensorimotor neuropathy was identified in 7.6%. The significant risk factors associated with peripheral neuropathy were older age, low serum copper, and dialysis therapy. Electrodiagnostic studies should be performed in children with CKD to assess for peripheral neuropathy for the purpose of optimizing medical care. Muscle Nerve 57: 792-798, 2018. © 2017 Wiley Periodicals, Inc.

Genetic heterogeneity of motor neuropathies.

PubMed

Bansagi, Boglarka; Griffin, Helen; Whittaker, Roger G; Antoniadi, Thalia; Evangelista, Teresinha; Miller, James; Greenslade, Mark; Forester, Natalie; Duff, Jennifer; Bradshaw, Anna; Kleinle, Stephanie; Boczonadi, Veronika; Steele, Hannah; Ramesh, Venkateswaran; Franko, Edit; Pyle, Angela; Lochmüller, Hanns; Chinnery, Patrick F; Horvath, Rita

2017-03-28

To study the prevalence, molecular cause, and clinical presentation of hereditary motor neuropathies in a large cohort of patients from the North of England. Detailed neurologic and electrophysiologic assessments and next-generation panel testing or whole exome sequencing were performed in 105 patients with clinical symptoms of distal hereditary motor neuropathy (dHMN, 64 patients), axonal motor neuropathy (motor Charcot-Marie-Tooth disease [CMT2], 16 patients), or complex neurologic disease predominantly affecting the motor nerves (hereditary motor neuropathy plus, 25 patients). The prevalence of dHMN is 2.14 affected individuals per 100,000 inhabitants (95% confidence interval 1.62-2.66) in the North of England. Causative mutations were identified in 26 out of 73 index patients (35.6%). The diagnostic rate in the dHMN subgroup was 32.5%, which is higher than previously reported (20%). We detected a significant defect of neuromuscular transmission in 7 cases and identified potentially causative mutations in 4 patients with multifocal demyelinating motor neuropathy. Many of the genes were shared between dHMN and motor CMT2, indicating identical disease mechanisms; therefore, we suggest changing the classification and including dHMN also as a subcategory of Charcot-Marie-Tooth disease. Abnormal neuromuscular transmission in some genetic forms provides a treatable target to develop therapies. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens.

PubMed

Antoine, J-C

2014-10-01

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

WES homozygosity mapping in a recessive form of Charcot-Marie-Tooth neuropathy reveals intronic GDAP1 variant leading to a premature stop codon.

PubMed

Masingue, Marion; Perrot, Jimmy; Carlier, Robert-Yves; Piguet-Lacroix, Guenaelle; Latour, Philippe; Stojkovic, Tanya

2018-05-01

Charcot-Marie-Tooth disease (CMT) refers to a group of clinically and genetically heterogeneous inherited neuropathies. Ganglioside-induced differentiation-associated protein 1 GDAP1-related CMT has been reported in an autosomal dominant or recessive form in patients presenting either axonal or demyelinating neuropathy. We report two Sri Lankan sisters born to consanguineous parents and presenting with a severe axonal sensorimotor neuropathy. The early onset of the disease, the distal and proximal weakness and atrophy leading to major disability, along with areflexia, and, most notably, vocal cord and diaphragm paralysis were highly evocative of a GDAP1-related CMT. However, sequencing of the coding regions of the gene was normal. Whole-exome sequencing (WES) was performed and revealed that the largest region of homozygosity was around GDAP1 with several variants, mostly in non-coding regions. In view of the high clinical suspicion of GDAP1 gene involvement, we examined the variants in this gene and this, along with functional studies, allowed us to identify an alternative splicing site revealing a cryptic in-frame stop codon in intron 4 responsible for a severe loss of wild-type GDAP1. This work is the first to describe a deleterious mutation in GDAP1 gene outside of coding sequences or intronic junctions and emphasizes the importance of interpreting molecular analysis, and in particular WES results, in light of the clinical and electrophysiological phenotype.

Upper Extremity Multifocal Neuropathy in a 10-Year-Old Boy Associated With NS6S Disaccharide Antibodies.

PubMed

Edelman, Frederick; Naddaf, Elie; Waclawik, Andrew J

2015-06-01

We present a 10-year-old boy with a predominantly motor multifocal neuropathy with demyelinating and axonal changes with sensory involvement, affecting only one upper extremity. Laboratory studies revealed an elevated titer of immunoglobulin M (IgM) antibodies against the NS6S antigen. He responded to treatment with high dose intravenous immunoglobulins. Focal or multifocal immune-mediated neuropathies are not common in children and may be underdiagnosed. © The Author(s) 2014.

Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia

PubMed Central

Diouf, Barthelemy; Crews, Kristine R.; Lew, Glen; Pei, Deqing; Cheng, Cheng; Bao, Ju; Zheng, Jie J.; Yang, Wenjian; Fan, Yiping; Wheeler, Heather E.; Wing, Claudia; Delaney, Shannon M.; Komatsu, Masaaki; Paugh, Steven W.; McCorkle, Joseph Robert; Lu, Xiaomin; Winick, Naomi J.; Carroll, William L.; Loh, Mignon L.; Hunger, Stephen P.; Devidas, Meenakshi; Pui, Ching-Hon; Dolan, M. Eileen; Relling, Mary V.; Evans, William E.

2015-01-01

the St. Jude cohort and in 22.2% of patients (n=22 of 99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta p =6.3 × 10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%, 95% CI 11.6%–19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 patients (56%, 95% CI 41.2–70.0) developed at least one episode of grade 2–4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotype (58 of 271 patients; 21.4%, 95% CI 16.9–26.7); p=2.4×10−6. The severity (grade) of neuropathy was greater (2.4-fold by Poisson regression (p<0.0001), 2.7-fold based on mean grade of neuropathy (1.23 [95% CI 0.74 – 1.72] versus 0.45 [95% CI 0.3 – 0.6]; t test p=0.004)) in patients homozygous for the CEP72 risk allele (TT genotype), compared to patients with the CC or CT genotype. The CEP72 promoter SNP was shown to create a binding site for a transcriptional repressor causing lower mRNA expression, and reducing CEP72 expression in human neurons and leukemia cells increased their sensitivity to vincristine. Conclusions In this preliminary study of children with ALL, an inherited polymorphism in the promoter region of CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy. If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent. PMID:25710658

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): An Uncommon Manifestation of Systemic Lupus Erythematosus (SLE)

PubMed Central

Abraham, Hrudya; Kuzhively, Jose; Rizvi, Syed W.

2017-01-01

Patient: Female, 40 Final Diagnosis: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) Symptoms: Gait disorder Medication: — Clinical Procedure: — Specialty: Rheumatology Objective: Rare disease Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE). We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP. Case Report: A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy. Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait. Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds-DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia. Electromyography (EMG) confirmed the diagnosis of CIDP. The patient’s neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids. Conclusions: The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids. Most patients with CIDP are treated successfully with steroids if the diagnosis is made early. IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids. PMID:28894082

Hereditary motor and sensory neuropathy-russe: new autosomal recessive neuropathy in Balkan Gypsies.

PubMed

Thomas, P K; Kalaydjieva, L; Youl, B; Rogers, T; Angelicheva, D; King, R H; Guergueltcheva, V; Colomer, J; Lupu, C; Corches, A; Popa, G; Merlini, L; Shmarov, A; Muddle, J R; Nourallah, M; Tournev, I

2001-10-01

A novel peripheral neuropathy of autosomal recessive inheritance has been identified in Balkan Gypsies and termed hereditary motor and sensory neuropathy-Russe (HMSN-R). We investigated 21 affected individuals from 10 families. Distal lower limb weakness began between the ages of 8 and 16 years, upper limb involvement beginning between 10 and 43 years, with an average of 22 years. This progressive disorder led to severe weakness of the lower limbs, generalized in the oldest subject (aged 57 years), and marked distal upper limb weakness. Prominent distal sensory loss involved all modalities, resulting in neuropathic joint degeneration in two instances. All patients showed foot deformity, and most showed hand deformity. Motor nerve conduction velocity was moderately reduced in the upper limbs but unobtainable in the legs. Sensory nerve action potentials were absent. There was loss of larger myelinated nerve fibers and profuse regenerative activity in the sural nerve. HMSN-R is a new form of autosomal recessive inherited HMSN caused by a single founder mutation in a 1 Mb interval on chromosome 10q.

Neurofascin-155 IGG4 Neuropathy: Pathophysiological Insights, Spectrum of Clinical Severity and Response To treatment.

PubMed

Garg, Nidhi; Park, Susanna B; Yiannikas, Con; Vucic, Steve; Howells, James; Noto, Yu-Ichi; Mathey, Emily K; Pollard, John D; Kiernan, Matthew C

2018-05-01

Sensorimotor neuropathy associated with IgG4 antibodies to neurofascin-155 (NF155) was recently described. The clinical phenotype is typically associated with young onset, distal weakness, and in some cases, tremor. From a consecutive cohort of 55 patients diagnosed with chronic inflammatory demyelinating polyneuropathy, screening for anti-NF155 antibodies was undertaken. Patients underwent clinical assessment, diagnostic neurophysiology, including peripheral axonal excitability studies and nerve ultrasound. Three of 55 chronic inflammatory demyelinating polyneuropathy patients (5%) tested positive for anti-NF155 IgG4. Patients presenting with more severe disease had higher antibody titers. Ultrasound demonstrated diffuse nerve enlargement. Axonal excitability studies were markedly abnormal, with subsequent mathematical modeling of the results supporting disruption of the paranodal seal. A broad spectrum of disease severity and treatment response may be observed in anti-NF155 neuropathy. Excitability studies support the pathogenic role of anti-NF155 IgG4 antibodies targeting the paranodal region. Muscle Nerve 57: 848-851, 2018. © 2017 Wiley Periodicals, Inc.

[The place of neuropathy in the early diagnosis of Cockayne syndrome: Report on two siblings].

PubMed

Blin-Rochemaure, N; Allani-Essid, N; Carlier, R; Laugel, V; Quijano-Roy, S

2017-04-01

Two siblings affected with Cockayne syndrome (CS) are described: this diagnosis was suggested by the finding of a demyelinating neuropathy on electromyography in both children and consistent clinical features. CS is a rare genetic disorder with severe prognosis and a highly varied phenotype, making early diagnosis difficult. Taking into account these two cases and the literature, the current diagnosis criteria are insufficiently specific and appear late: the diagnosis may be delayed because multi-organ involvement and sensorial impairment suggests more frequent neurometabolic disorders. Neuroradiologic abnormalities are suggestive but may occur later. The finding of a demyelinating peripheral neuropathy seems to be a more useful marker to suspect this disorder in the presence of other clinical features. Further studies are required to better define the chronology of the symptoms, not only for adequate genetic counseling and eventual prenatal diagnosis, but also to assess the efficacy of future therapies. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Exome sequencing establishes a gelsolin mutation as the cause of inherited bulbar-onset neuropathy.

PubMed

Caress, James B; Johnson, Janel O; Abramzon, Yevgeniya A; Hawkins, Gregory A; Gibbs, J Raphael; Sullivan, Elizabeth A; Chahal, Chamanpreet S; Traynor, Bryan J

2017-11-01

Progressive bulbar motor neuropathy is primarily caused by bulbar-onset ALS. Hereditary amyloidosis type IV also presents with a bulbar neuropathy that mimics motor neuron disease. The disease is prevalent in Finland only and is not commonly included in the differential diagnosis of ALS. We studied 18 members of a family in which some had bulbar motor neuropathy, and we performed exome sequencing. Five affected family members were found to have a D187Y substitution in the GSN gene known to cause hereditary amyloidosis type IV. This American family presented with progressive bulbar neuropathy due to a gelsolin mutation not found in Finland. Hereditary amyloidosis type IV presents with bulbar motor neuropathy and not with peripheral neuropathy as occurs with common forms of amyloidosis. This report demonstrates the power of exome sequencing to determine the cause of rare hereditary diseases with incomplete or atypical phenotypes. Muscle Nerve 56: 1001-1005, 2017. © 2016 Wiley Periodicals, Inc.

[Axonopathy in the pathogenesis of multiple sclerosis, peripheral diffuse and local motor neuropathies and motor neuron disease].

PubMed

Merkulov, Iu A; Merkulova, D M; Iosifova, O A; Zavalishin, I A

2010-01-01

Two hundreds and seventy-six patients including 43 patients with multiple sclerosis, 24 - with acute inflammatory demyelinating polyneuropathy (AIDP), 144 - with chronic inflammatory demyelinating polyneuropathy (CIDP), 27 - with motor multifocal neuropathy (MMN), 38 - with lateral amyotrophic sclerosis (LAS) have been examined. Symptoms of axonal degeneration, manifested in denervation phenomena in both clinical and instrumental studies (electromyography, transcranial magnetic stimulation, MRT), were revealed in all groups of patients. The formation of excitation conduction blocks is an universal pathophysiological mechanism of the axonopathy development in AIDP, CIDP, MMN and LAS. Symptoms of axonopathy and peripheral demyelinization in patients with multiple sclerosis and LAS suggest the possibility of transformation of immunopathological process from the central nervous system to the peripheral one.

Familial Idiopathic Cranial Neuropathy in a Chinese Family.

PubMed

Zhang, Li; Liang, Jianfeng; Yu, Yanbing

Cranial neuropathy is usually idiopathic and familial cases are uncommon. We describe a family with 5 members with cranial neuropathy over 3 generations. All affected patients were women, indicating an X-linked dominant or an autosomal dominant mode of inheritance. Our cases and a review of the literature suggest that familial idiopathic cranial neuropathy is a rare condition which may be related to autosomal dominant vascular disorders (e.g. vascular tortuosity, sclerosis, elongation or extension), small posterior cranial fossas, anatomical variations of the posterior circulation, hypersensitivity of cranial nerves and other abnormalities. Moreover, microvascular decompression is the treatment of choice because vascular compression is the main factor in the pathogenesis. To the best of our knowledge, this is the first report of familial cranial neuropathy in China.

Analysis of anti-ganglioside antibodies by a line immunoassay in patients with chronic-inflammatory demyelinating polyneuropathies (CIDP).

PubMed

Klehmet, Juliane; Märschenz, Stefanie; Ruprecht, Klemens; Wunderlich, Benjamin; Büttner, Thomas; Hiemann, Rico; Roggenbuck, Dirk; Meisel, Andreas

2018-05-24

Unlike for acute immune-mediated neuropathies (IN), anti-ganglioside autoantibody (aGAAb) testing has been recommended for only a minority of chronic IN yet. Thus, we used a multiplex semi-quantitative line immunoassay (LIA) to search for aGAAb in chronic-inflammatory demyelinating polyneuropathy (CIDP) and its clinical variants. Anti-GAAb to 11 gangliosides and sulfatide (SF) were investigated by LIA in 61 patients with IN (27 typical CIDP, 12 distal-acquired demyelinating polyneuropathy, 6 multifocal-acquired demyelinating sensory/motor polyneuropathy, 10 sensory CIDP, 1 focal CIDP and 5 multifocal-motoric neuropathy), 40 with other neuromuscular disorders (OND) (15 non-immune polyneuropathies, 25 myasthenia gravis), 29 with multiple sclerosis (MS) and 54 healthy controls (HC). In contrast to IgG, positive anti-GAAB IgM against at least one ganglioside/SF was found in 17/61 (27.9%) IN compared to 2/40 (5%) in OND, 2/29 MS (6.9%) and 4/54 (7.4%) in HC (p=0.001). There was a statistically higher prevalence of anti-sulfatide (aSF) IgM in IN compared to OND (p=0.008). Further, aGM1 IgM was more prevalent in IN compared to OND and HC (p=0.009) as well as GD1b in IN compared to HC (p<0.04). The prevalence of aGM1 IgM in CIDP was lower compared to in multifocal motor neuropathy (MMN) (12% vs. 60%, p=0.027). Patients showing aSF, aGM1 and aGM2 IgM were younger compared to aGAAb negatives (p<0.05). Patients with aSF IgM positivity presented more frequently typical CIDP and MMN phenotypes (p<0.05, respectively). The aGAAb LIA revealed an elevated frequency of at least one aGAAb IgM in CIDP/MMN patients. Anti-SF, aGM1 and aGM2 IgM were associated with younger age and anti-SF with IN phenotypes.

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

PubMed Central

Yadegari, Samira; Nafissi, Shahriar; Kazemi, Neda

2014-01-01

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

Topiramate induced peripheral neuropathy: A case report and review of literature.

PubMed

Hamed, Sherifa Ahmed

2017-12-16

Drug-induced peripheral neuropathy had been rarely reported as an adverse effect of some antiepileptic drugs (AEDs) at high cumulative doses or even within the therapeutic drug doses or levels. We describe clinical and diagnostic features of a patient with peripheral neuropathy as an adverse effect of chronic topiramate (TPM) therapy. A 37-year-old woman was presented for the control of active epilepsy (2010). She was resistant to some AEDs as mono- or combined therapies (carbamazepine, sodium valproate, levetiracetam, oxcarbazepine and lamotrigine). She has the diagnosis of frontal lobe epilepsy with secondary generalization and has a brother, sister and son with active epilepsies. She became seizure free on TPM (2013-2017) but is complaining of persistent distal lower extremities paresthesia in a stocking distribution. Neurological examination revealed presence of diminished Achilles tendon reflexes, stocking hypesthesia and delayed distal latencies, reduced conduction velocities and amplitudes of action potentials of posterior tibial and sural nerves, indicating demyelinating and axonal peripheral neuropathy of the lower extremities. After exclusion of the possible causes of peripheral neuropathy, chronic TPM therapy is suggested as the most probable cause of patient's neuropathy. This is the first case report of topiramate induced peripheral neuropathy in the literature.

Acute Toxic Neuropathy Mimicking Guillain Barre Syndrome

PubMed Central

Jalal, Muhammed Jasim Abdul; Fernandez, Shirley Joan; Menon, Murali Krishna

2015-01-01

Case: A 30 year old male presented with numbness of palms and soles followed by weakness of upper limbs and lower limbs of 5 days duration, which was ascending and progressive. Three months back he was treated for oral and genital ulcers with oral steroids. His ulcers improved and shifted to indigenous medication. His clinical examination showed polyneuropathy. CSF study did not show albuminocytological dissociation. Nerve conduction study showed demyelinating polyneuropathy. His blood samples and the ayurvedic drug samples were sent for toxicological analysis. Inference: Acute toxic neuropathy - Arsenic PMID:25811007

Advances in the Treatment of Paraproteinemic Neuropathy.

PubMed

Nobile-Orazio, Eduardo; Bianco, Mariangela; Nozza, Andrea

2017-10-16

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy. Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly

Demyelinating diseases.

PubMed

Love, S

2006-11-01

A diagnosis of demyelination carries important therapeutic and prognostic implications. In most cases the diagnosis is made clinically, and involvement of the histopathologist is largely confined to postmortem confirmation and clinicopathological correlation. However, every now and then, accurate diagnosis of the presence or cause of demyelination before death hinges on the histopathological assessment. Recognition of demyelination depends on an awareness of this as a diagnostic possibility, and on the use of appropriate tinctorial and immunohistochemical stains to identify myelin, axons and inflammatory cells. In biopsy specimens, the critical distinction is usually from ischaemic or neoplastic disease, and the types of demyelinating disease most likely to be encountered are multiple sclerosis, acute-disseminated encephalomyelitis, progressive multifocal leucoencephalopathy and extrapontine myelinolysis. Interpretation of the pathology has to be made in the context of the clinical, radiological and biochemical findings. Freezing of a small amount of fresh tissue allows for later virological studies, and electron microscopy is occasionally helpful for demonstration of viral particles.

Cryoglobulinemic neuropathy: a pathological study.

PubMed

Vallat, J M; Desproges-Gotteron, R; Leboutet, M J; Loubet, A; Gualde, N; Treves, R

1980-08-01

A 53-year-old woman developed symmetrical polyneuropathy of the lower limbs a few months after she was found to have myeloma with cryoglobulinemia. In musculocutaneous nerve biopsy material, electron microscopy showed both axonal degeneration and demyelination. The most striking finding was the presence, in the endoneurial space, of numerous masses of closely packed tubular structures. These masses also were found in the walls of all the vasa nervorum and within the lumen of some vessels. The morphological features and dimensions of the deposits within nerve were identical to those of cryoprecipitates extracted from serum and examined with the electron microscope. An example of myeloma neuropathy with cryoglobulin deposits within the endoneurial space has not been reported previously.

Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy.

PubMed

Fujisawa, Miwako; Sano, Yasuteru; Omoto, Masatoshi; Ogasawara, Jyun-Ichi; Koga, Michiaki; Takashima, Hiroshi; Kanda, Takashi

2017-09-30

We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.

A nationwide survey of combined central and peripheral demyelination in Japan.

PubMed

Ogata, Hidenori; Matsuse, Dai; Yamasaki, Ryo; Kawamura, Nobutoshi; Matsushita, Takuya; Yonekawa, Tomomi; Hirotani, Makoto; Murai, Hiroyuki; Kira, Jun-ichi

2016-01-01

To clarify the clinical features of combined central and peripheral demyelination (CCPD) via a nationwide survey. The following characteristics were used to define CCPD: T2 high-signal intensity lesions in the brain, optic nerves or spinal cord on MRI, or abnormalities on visual-evoked potentials; conduction delay, conduction block, temporal dispersion or F-wave abnormalities suggesting demyelinating neuropathy based on nerve conduction studies; exclusion of secondary demyelination. We conducted a nationwide survey in 2012, sending questionnaires to 1332 adult and paediatric neurology institutions in Japan. We collated 40 CCPD cases, including 29 women. Age at onset was 31.7±14.1 years (mean±SD). Sensory disturbance (94.9%), motor weakness (92.5%) and gait disturbance (79.5%) were common. Although cerebrospinal fluid protein levels were increased in 82.5%, oligoclonal IgG bands and elevated IgG indices were detected in 7.4% and 18.5% of cases, respectively. Fifteen of 21 patients (71.4%) had abnormal visual-evoked potentials. Antineurofascin 155 antibodies were positive in 5/11 (45.5%). Corticosteroids, intravenous immunoglobulins and plasmapheresis resulted in an 83.3%, 66.7% and 87.5% improvement, respectively, whereas interferon-β was effective in only 10% of cases. CCPD cases with simultaneous onset of central nervous system (CNS) and peripheral nervous system (PNS) involvement exhibited greater disability, but less recurrence and more frequent extensive cerebral and spinal cord MRI lesions compared to those with temporarily separated onset, whereas optic nerve involvement was more common in the latter. CCPD shows different characteristics from classical demyelinating diseases, and distinctive features exist between cases with simultaneous and temporarily separated onset of CNS and PNS involvement. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Exercise for people with peripheral neuropathy.

PubMed

White, C M; Pritchard, J; Turner-Stokes, L

2004-10-18

Peripheral neuropathies are a wide range of diseases affecting the peripheral nerves. Demyelination or axonal degeneration gives rise to a variety of symptoms including reduced or altered sensation, pain, muscle weakness and fatigue. Secondary disability arises and this may result in adjustments to psychological and social function. Exercise therapy, with a view to developing strength and stamina, forms part of the treatment for people with peripheral neuropathy, particularly in the later stages of recovery from acute neuropathy and in chronic neuropathies. The primary objective was to examine the effect of exercise therapy on functional ability in the treatment of people with peripheral neuropathy. In addition, secondary outcomes of muscle strength, endurance, broader measures of health and well being, as well as unfavourable outcomes were examined. We searched the Cochrane Neuromuscular Disease Group register (July 2002 and updated February 2004) and MEDLINE (from January 1966 to June 2004), EMBASE (from January 1980 to June 2004), CINAHL (from January 1982 to July 2002) and LILACS (from January 1982 to July 2002) electronic databases. Bibliographies of all selected randomised controlled trials were checked and authors contacted to identify additional published or unpublished data. Any randomised or quasi-randomised controlled trial comparing the effect of exercise therapy with no exercise therapy or drugs or an alternative non-drug treatment on functional ability (or disability) in people with peripheral neuropathy at least eight weeks after randomisation was included. Two reviewers independently selected eligible studies, rated the methodological quality and extracted data. Only one trial fully met the inclusion criteria. An additional two trials assessed outcomes less than eight weeks after randomisation and were also included. Methodological quality was poor for several criteria in each study. Data used in the three studies could not be pooled due to

A community-based epidemiological study of peripheral neuropathies in Assiut, Egypt.

PubMed

Kandil, Mahmoud R; Darwish, Esam S; Khedr, Eman M; Sabry, Mahmoud M; Abdulah, Mohamed A

2012-12-01

There is very little published information about the prevalence, patterns, and predictors of peripheral neuropathies. The current study is a community-based survey was conducted in the Assiut Governorate to estimate their prevalence and clinical profile. A door-to-door study was carried out on 42,223 persons from rural and urban communities in the Assiut Governorate, Egypt. There were 13,288 (31.5%) subjects from the urban and 28,935 (68·5%) from the rural area. All subjects filled in a questionnaire designed specifically for diagnosis of peripheral neuropathy. Positive cases were then given a complete medical and neurological examination, routine laboratory tests, neurophysiology, and neuroimaging (magnetic resonance). The crude prevalence rate (CPR) of peripheral neuropathy was 3181/100,000 inhabitants. There was a significantly higher prevalence in the rural compared with the urban population (3795 versus 1844/100,000) and in females than males (4473 versus 1943/100,000; P<0.001 for both). The most common type reported was entrapment neuropathy (736 cases with CPR of 1743/100,000), particularly carpal tunnel syndrome (1686/100,000). Diabetic neuropathy was the most common non-compressive neuropathy with a CPR of 649/100,000. Type II diabetes was recorded in 241 patients with a CPR of 571/100,000. Compressive radiculopathy had a crude prevalence of 358/100,000; traumatic and iatrogenic radiculopathy had a prevalence rate of 149/100,000. Less common conditions were: uremic neuropathy (21/100,000) hepatic neuropathy (14/100,000), Bell's palsy (28/100,000), Guillian-Barre' syndrome (12/100,000), chronic inflammatory demyelinating polyneuropathy (12/100,000), hereditary sensory motor neuropathy (12/100,000), and idiopathic neuropathy (92/100,000). The overall prevalence of peripheral neuropathies was high in comparison to other studies. Entrapment neuropathy, diabetic neuropathy, and spondylotic radiculopathy were the most common. Overall, the prevalence of

Perk Ablation Ameliorates Myelination in S63del-Charcot–Marie–Tooth 1B Neuropathy

PubMed Central

Musner, Nicolò; Sidoli, Mariapaola; Zambroni, Desireè; Del Carro, Ubaldo; Ungaro, Daniela; D’Antonio, Maurizio; Feltri, Maria L.

2016-01-01

In peripheral nerves, P0 glycoprotein accounts for more than 20% of myelin protein content. P0 is synthesized by Schwann cells, processed in the endoplasmic reticulum (ER) and enters the secretory pathway. However, the mutant P0 with S63 deleted (P0S63del) accumulates in the ER lumen and induces a demyelinating neuropathy in Charcot–Marie–Tooth disease type 1B (CMT1B)–S63del mice. Accumulation of P0S63del in the ER triggers a persistent unfolded protein response. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is an ER stress sensor that phosphorylates eukaryotic initiation factor 2 alpha (eIF2alpha) in order to attenuate protein synthesis. We have shown that increasing phosphophorylated-eIF2alpha (P-eIF2alpha) is a potent therapeutic strategy, improving myelination and motor function in S63del mice. Here, we explore the converse experiment: Perk haploinsufficiency reduces P-eIF2alpha in S63del nerves as expected, but surprisingly, ameliorates, rather than worsens S63del neuropathy. Motor performance and myelin abnormalities improved in S63del//Perk+/− compared with S63del mice. These data suggest that mechanisms other than protein translation might be involved in CMT1B/S63del neuropathy. In addition, Perk deficiency in other cells may contribute to demyelination in a non–Schwann-cell autonomous manner. PMID:27095827

Peripheral neuropathy is a common manifestation of mitochondrial diseases: a single-centre experience.

PubMed

Luigetti, M; Sauchelli, D; Primiano, G; Cuccagna, C; Bernardo, D; Lo Monaco, M; Servidei, S

2016-06-01

Peripheral neuropathy in mitochondrial diseases (MDs) may vary from a subclinical finding in a multisystem syndrome to a severe, even isolated, manifestation in some patients. To investigate the involvement of the peripheral nervous system in MDs extensive electrophysiological studies were performed in 109 patients with morphological, biochemical and genetic diagnosis of MD [12 A3243G progressive external ophthalmoplegia (PEO)/mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), 16 myoclonic epilepsy with ragged-red fibres (MERRF), four mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), 67 PEO with single or multiple deletions of mitochondrial DNA, 10 others]. A neuropathy was found in 49 patients (45%). The incidence was very high in MNGIE (100%), MELAS (92%) and MERRF (69%), whilst 28% of PEO patients had evidence of peripheral involvement. The most frequent abnormality was a sensory axonal neuropathy found in 32/49 patients (65%). A sensory-motor axonal neuropathy was instead detected in 16% of the patients and sensory-motor axonal demyelinating neuropathy in 16%. Finally one Leigh patient had a motor axonal neuropathy. It is interesting to note that the great majority had preserved tendon reflexes and no sensory disturbances. In conclusion, peripheral involvement in MD is frequent even if often mild or asymptomatic. The correct identification and characterization of peripheral neuropathy through electrophysiological studies represents another tile in the challenge of MD diagnosis. © 2016 EAN.

Peripheral neuropathy in patients with myotonic dystrophy type 2.

PubMed

Leonardis, L

2017-05-01

Myotonic dystrophy type 2 (dystrophia myotonica type 2-DM2) is an autosomal dominant multi-organ disorder. The involvement of the peripheral nervous system was found in 25%-45% of patients with myotonic dystrophy type 1, although limited data are available concerning polyneuropathy in patients with DM2, which was the aim of this study with a thorough presentation of the cases with peripheral neuropathy. Patients with genetically confirmed DM2 underwent motor nerve conduction studies of the median, ulnar, tibial and fibular nerves and sensory nerve conduction studies of the median (second finger), ulnar (fifth finger), radial (forearm) and sural nerves. Seventeen adult patients with DM2 participated in the study. Fifty-three percent (9/17) of our patients had abnormality of one or more attributes (latency, amplitude or conduction velocity) in two or more separate nerves. Four types of neuropathies were found: (i) predominantly axonal motor and sensory polyneuropathy, (ii) motor polyneuropathy, (iii) predominantly demyelinating motor and sensory polyneuropathy and (iv) mutilating polyneuropathy with ulcers. The most common forms are axonal motor and sensory polyneuropathy (29%) and motor neuropathy (18% of all examined patients). No correlations were found between the presence of neuropathy and age, CCTG repeats, blood glucose or HbA1C. Peripheral neuropathy is common in patients with DM2 and presents one of the multisystemic manifestations of DM2. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A recurrent WARS mutation is a novel cause of autosomal dominant distal hereditary motor neuropathy.

PubMed

Tsai, Pei-Chien; Soong, Bing-Wen; Mademan, Inès; Huang, Yen-Hua; Liu, Chia-Rung; Hsiao, Cheng-Tsung; Wu, Hung-Ta; Liu, Tze-Tze; Liu, Yo-Tsen; Tseng, Yen-Ting; Lin, Kon-Ping; Yang, Ueng-Cheng; Chung, Ki Wha; Choi, Byung-Ok; Nicholson, Garth A; Kennerson, Marina L; Chan, Chih-Chiang; De Jonghe, Peter; Cheng, Tzu-Hao; Liao, Yi-Chu; Züchner, Stephan; Baets, Jonathan; Lee, Yi-Chung

2017-05-01

Distal hereditary motor neuropathy is a heterogeneous group of inherited neuropathies characterized by distal limb muscle weakness and atrophy. Although at least 15 genes have been implicated in distal hereditary motor neuropathy, the genetic causes remain elusive in many families. To identify an additional causal gene for distal hereditary motor neuropathy, we performed exome sequencing for two affected individuals and two unaffected members in a Taiwanese family with an autosomal dominant distal hereditary motor neuropathy in which mutations in common distal hereditary motor neuropathy-implicated genes had been excluded. The exome sequencing revealed a heterozygous mutation, c.770A > G (p.His257Arg), in the cytoplasmic tryptophanyl-tRNA synthetase (TrpRS) gene (WARS) that co-segregates with the neuropathy in the family. Further analyses of WARS in an additional 79 Taiwanese pedigrees with inherited neuropathies and 163 index cases from Australian, European, and Korean distal hereditary motor neuropathy families identified the same mutation in another Taiwanese distal hereditary motor neuropathy pedigree with different ancestries and one additional Belgian distal hereditary motor neuropathy family of Caucasian origin. Cell transfection studies demonstrated a dominant-negative effect of the p.His257Arg mutation on aminoacylation activity of TrpRS, which subsequently compromised protein synthesis and reduced cell viability. His257Arg TrpRS also inhibited neurite outgrowth and led to neurite degeneration in the neuronal cell lines and rat motor neurons. Further in vitro analyses showed that the WARS mutation could potentiate the angiostatic activities of TrpRS by enhancing its interaction with vascular endothelial-cadherin. Taken together, these findings establish WARS as a gene whose mutations may cause distal hereditary motor neuropathy and alter canonical and non-canonical functions of TrpRS. © The Author (2017). Published by Oxford University Press on behalf of

Serial electrophysiological studies in a Guillain-Barré subtype with bilateral facial neuropathy.

PubMed

Chan, Yee-Cheun; Therimadasamy, Aravind-Kannan; Sainuddin, Nurul M; Wilder-Smith, Einar; Yuki, Nobuhiro

2016-02-01

Bifacial weakness with paraesthesias subtype of Guillain-Barré syndrome (GBS) is thought to be demyelinating in nature but the evolution of serial nerve conduction study (NCS) findings has not been studied. We retrospectively analyzed the changes on serial NCS of patients with bilateral facial neuropathy. We described the clinical features, serial blink reflex, facial nerve and limb NCS of such patients. Five patients fulfilled our study criteria. Patients 1 and 2 were diagnosed clinically to have bilateral Bell's palsy, patients 3 and 4 as bifacial GBS subtype and patient 5 as facial palsy associated with acute HIV infection. In all, the initial neurophysiological tests showed absent blink response and normal facial NCS. Patient 1's repeat tests were normal. Patient 2's repeat blink reflex showed mildly prolonged latency. Repeat blink reflex latency of patients 3, 4 and 5 were in the demyelinating range. Patient 3 also had prolonged facial nerve latency. Patients 3 and 4 had serial limb NCS showing progressively prolonged latency. Serial NCS suggests that the bifacial GBS subtype is demyelinating in nature. This study provides further evidence for a bifacial subtype of GBS with a demyelinating pathophysiology. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Autosomal recessive type II hereditary motor and sensory neuropathy with acrodystrophy.

PubMed

Thomas, P K; Claus, D; King, R H

1999-02-01

A family is described with presumed autosomal recessive inheritance in which three siblings developed a progressive neuropathy that combined limb weakness and severe distal sensory loss leading to prominent mutilating changes. Electrophysiological and nerve biopsy findings indicated an axonopathy. The disorder is therefore classifiable as type II hereditary motor and sensory neuropathy (HMSN II). The clinical features differ from those reported in previously described cases of autosomal recessive HMSN II. This disorder may therefore represent a new variant.

Subacute peripheral and optic neuropathy syndrome with no evidence of a toxic or nutritional cause.

PubMed

Allen, D; Riordan-Eva, P; Paterson, R W; Hadden, R D M

2013-08-01

The syndrome of subacute simultaneous peripheral neuropathy and bilateral optic neuropathy is known to occur in tropical countries, probably due to malnutrition or toxicity, but not often seen in developed countries. We report seven patients in London who were not malnourished or alcoholic, and in whom no clear cause was found. We retrospectively reviewed the case notes and arranged some further investigations. All patients developed peripheral and bilateral optic neuropathy within 6 months. Patients were aged 30-52, and all of Jamaican birth and race but lived in the UK. Most had subacute, painful ataxic sensory axonal neuropathy or neuronopathy, some with myelopathy. Nerve conduction studies revealed minor demyelinating features in two cases. The optic neuropathy was symmetrical, subacute and monophasic, usually with marked reduction in visual acuity. CSF protein concentration was usually elevated but other laboratory investigations were normal. Patients showed only modest improvement at follow-up. These patients share a common clinical and electrophysiological phenotype, age, ethnicity and elevated CSF protein, but otherwise normal laboratory investigations. The syndrome is a cause of significant morbidity in young people. The cause remains uncertain despite thorough investigation. Copyright © 2013 Elsevier B.V. All rights reserved.

A dominantly inherited form of arthrogryposis multiplex congenita with unusual dermatoglyphics.

PubMed

Sack, G H

1978-12-01

A father and daughter with arthrogryposis multiplex congenita and similar dermatoglyphic patterns are described. No evidence was found of chromosomal abnormality, neuropathy or myopathy, and there were no other affected family members. The findings are compatible with autosomal dominant inheritance.

Utility of coronal contrast-enhanced fat-suppressed FLAIR in the evaluation of optic neuropathy and atrophy.

PubMed

Boegel, Kevin H; Tyan, Andrew E; Iyer, Veena R; Rykken, Jeffrey B; McKinney, Alexander M

2017-01-01

Evaluating chronic sequelae of optic neuritis, such as optic neuropathy with or without optic nerve atrophy, can be challenging on whole brain MRI. This study evaluated the utility of dedicated coronal contrast-enhanced fat-suppressed FLAIR (CE-FS-FLAIR) MR imaging to detect optic neuropathy and optic nerve atrophy. Over 4.5 years, a 3 mm coronal CE-FS-FLAIR sequence at 1.5T was added to the routine brain MRIs of 124 consecutive patients, 102 of whom had suspected or known demyelinating disease. Retrospective record reviews confirmed that 28 of these 102 had documented onset of optic neuritis >4 weeks prior to the brain MRI. These 28 were compared to the other 22 ("controls") of the 124 patients who lacked a history of demyelinating disease or visual symptoms. Using coronal CE-FS-FLAIR, two neuroradiologists separately graded each optic nerve (n = 50 patients, 100 total nerves) as either negative, equivocal, or positive for optic neuropathy or atrophy. The scoring was later repeated. The mean time from acute optic neuritis onset to MRI was 4.1 ± 4.6 years (range 34 days-17.4 years). Per individual nerve grading, the range of sensitivity, specificity, and accuracy of coronal CE-FS-FLAIR in detecting optic neuropathy was 71.4-77.1%, 93.8-95.4%, and 85.5-89.0%, respectively, with strong interobserver (k = 0.667 - 0.678, p < 0.0001), and intraobserver (k = 0.706 - 0.763, p < 0.0001) agreement. For optic atrophy, interobserver agreement was moderate (k = 0.437 - 0.484, p < 0.0001), while intraobserver agreement was moderate-strong (k = 0.491 - 0.596, p < 0.0001). Coronal CE-FS-FLAIR is quite specific in detecting optic neuropathy years after the onset of acute optic neuritis, but is less useful in detecting optic nerve atrophy.

Chronic inflammatory demyelinating polyneuropathy.

PubMed

Lewis, Richard A

2017-10-01

As a syndrome with typical and atypical cases, chronic inflammatory demyelinating polyneuropathy (CIDP) has been a difficult disorder to diagnose and treat. The pathophysiologic basis for CIDP has not been established, contributing to the challenges in dealing with these patients. However, as one of only a handful of treatable peripheral neuropathies, there has been a tendency to diagnose CIDP to attempt a therapeutic intervention. We are also aware that there has also been overtreatment of some patients. This combination of overdiagnosis and prolonged treatment has been a concern. This chapter will review these challenges and discuss recent findings that will lead to improved diagnosis and treatment. The factors leading to misdiagnosis of CIDP were explored in a cohort of patients referred to a neuromuscular center. On a more positive note, the identification of two disorders with antibodies directed at paranodal constituents has excited the field. Treatment options have increased and been clarified. Pulse corticosteroids have been compared with oral prednisone and with intravenous immunoglobulin. The clinical trial of subcutaneous immunoglobulin in CIDP has shown both efficacy and a very low side effect profile adding to our therapeutic options. The current review will identify recent developments that show both the challenges and the exciting growth in our ability to diagnose and treat CIDP.

Spastic paraplegia gene 7 in patients with spasticity and/or optic neuropathy

PubMed Central

Klebe, Stephan; Depienne, Christel; Gerber, Sylvie; Challe, Georges; Anheim, Mathieu; Charles, Perrine; Fedirko, Estelle; Lejeune, Elodie; Cottineau, Julien; Brusco, Alfredo; Dollfus, Hélène; Chinnery, Patrick F.; Mancini, Cecilia; Ferrer, Xavier; Sole, Guilhem; Destée, Alain; Mayer, Jean-Michel; Fontaine, Bertrand; de Seze, Jérôme; Clanet, Michel; Ollagnon, Elisabeth; Busson, Philippe; Cazeneuve, Cécile; Stevanin, Giovanni; Kaplan, Josseline; Rozet, Jean-Michel; Brice, Alexis

2012-01-01

Mutations in the spastic paraplegia 7 (SPG7) gene encoding paraplegin are responsible for autosomal recessive hereditary spasticity. We screened 135 unrelated index cases, selected in five different settings: SPG7-positive patients detected during SPG31 analysis using SPG31/SPG7 multiplex ligation-dependent probe amplification (n = 7); previously reported ambiguous SPG7 cases (n = 5); patients carefully selected on the basis of their phenotype (spasticity of the lower limbs with cerebellar signs and/or cerebellar atrophy on magnetic resonance imaging/computer tomography scan and/or optic neuropathy and without other signs) (n = 24); patients with hereditary spastic paraparesis referred consecutively from attending neurologists and the national reference centre in a diagnostic setting (n = 98); and the index case of a four-generation family with autosomal dominant optic neuropathy but no spasticity linked to the SPG7 locus. We identified two SPG7 mutations in 23/134 spastic patients, 21% of the patients selected according to phenotype but only 8% of those referred directly. Our results confirm the pathogenicity of Ala510Val, which was the most frequent mutation in our series (65%) and segregated at the homozygous state with spastic paraparesis in a large family with autosomal recessive inheritance. All SPG7-positive patients tested had optic neuropathy or abnormalities revealed by optical coherence tomography, indicating that abnormalities in optical coherence tomography could be a clinical biomarker for SPG7 testing. In addition, the presence of late-onset very slowly progressive spastic gait (median age 39 years, range 18–52 years) associated with cerebellar ataxia (39%) or cerebellar atrophy (47%) constitute, with abnormal optical coherence tomography, key features pointing towards SPG7-testing. Interestingly, three relatives of patients with heterozygote SPG7 mutations had cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower

Plasma exchanges for severe acute neurological deterioration in patients with IgM anti-myelin-associated glycoprotein (anti-MAG) neuropathy.

PubMed

Baron, M; Lozeron, P; Harel, S; Bengoufa, D; Vignon, M; Asli, B; Malphettes, M; Parquet, N; Brignier, A; Fermand, J P; Kubis, N; Arnulf, Bertrand

2017-06-01

Monoclonal IgM anti-myelin-associated glycoprotein (MAG) antibody-related peripheral neuropathy (anti-MAG neuropathy) is predominantly a demyelinating sensory neuropathy with ataxia and distal paresthesia. The clinical course of anti-MAG neuropathy is usually slowly progressive making difficult the identification of clear criteria to start a specific treatment. Although no consensus treatment is yet available, a rituximab-based regimen targeting the B-cell clone producing the monoclonal IgM may be proposed, alone or in combination with alkylating agents or purine analogs. However, in some rare cases, an acute and severe neurological deterioration can occur in few days leading to a rapid loss of autonomy. In these cases, a treatment rapidly removing the monoclonal IgM from the circulation might be useful before initiating a specific therapy. We report successful treatment with plasma exchanges (PE) in four patients presenting with acute neurological deterioration. PE allowed a dramatic and rapid neurological improvement in all patients. PE are safe and may be useful at the initial management of these cases of anti-MAG neuropathy.

Leber hereditary optic neuropathy: current perspectives

PubMed Central

Meyerson, Cherise; Van Stavern, Greg; McClelland, Collin

2015-01-01

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

Biology of the blood-nerve barrier and its alteration in immune mediated neuropathies.

PubMed

Kanda, Takashi

2013-02-01

The blood-nerve barrier (BNB) is a dynamic and competent interface between the endoneurial microenvironment and the surrounding extracellular space or blood. It is localised at the innermost layer of the multilayered ensheathing perineurium and endoneurial microvessels, and is the key structure that controls the internal milieu of the peripheral nerve parenchyma. Since the endoneurial BNB is the point of entry for pathogenic T cells and various soluble factors, including cytokines, chemokines and immunoglobulins, understanding this structure is important to prevent and treat human immune mediated neuropathies such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome and a subset of diabetic neuropathy. However, compared with the blood-brain barrier, only limited knowledge has been accumulated regarding the function, cell biology and clinical significance of the BNB. This review describes the basic structure and functions of the endoneurial BNB, provides an update of the biology of the cells comprising the BNB, and highlights the pathology and pathomechanisms of BNB breakdown in immune mediated neuropathies. The human immortalised cell lines of BNB origin established in our laboratory will facilitate the future development of BNB research. Potential therapeutic strategies for immune mediated neuropathies manipulating the BNB are also discussed.

Emerging Mitochondrial Therapeutic Targets in Optic Neuropathies.

PubMed

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

2016-09-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Contactin-1 and Neurofascin-155/-186 Are Not Targets of Auto-Antibodies in Multifocal Motor Neuropathy.

PubMed

Doppler, Kathrin; Appeltshauser, Luise; Krämer, Heidrun H; Ng, Judy King Man; Meinl, Edgar; Villmann, Carmen; Brophy, Peter; Dib-Hajj, Sulayman D; Waxman, Stephen G; Weishaupt, Andreas; Sommer, Claudia

2015-01-01

Multifocal motor neuropathy is an immune mediated disease presenting with multifocal muscle weakness and conduction block. IgM auto-antibodies against the ganglioside GM1 are detectable in about 50% of the patients. Auto-antibodies against the paranodal proteins contactin-1 and neurofascin-155 and the nodal protein neurofascin-186 have been detected in subgroups of patients with chronic inflammatory demyelinating polyneuropathy. Recently, auto-antibodies against neurofascin-186 and gliomedin were described in more than 60% of patients with multifocal motor neuropathy. In the current study, we aimed to validate this finding, using a combination of different assays for auto-antibody detection. In addition we intended to detect further auto-antibodies against paranodal proteins, specifically contactin-1 and neurofascin-155 in multifocal motor neuropathy patients' sera. We analyzed sera of 33 patients with well-characterized multifocal motor neuropathy for IgM or IgG anti-contactin-1, anti-neurofascin-155 or -186 antibodies using enzyme-linked immunosorbent assay, binding assays with transfected human embryonic kidney 293 cells and murine teased fibers. We did not detect any IgM or IgG auto-antibodies against contactin-1, neurofascin-155 or -186 in any of our multifocal motor neuropathy patients. We conclude that auto-antibodies against contactin-1, neurofascin-155 and -186 do not play a relevant role in the pathogenesis in this cohort with multifocal motor neuropathy.

Anti-ganglioside antibodies in Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy in Chinese patients.

PubMed

Fan, Chenghe; Jin, Haiqiang; Hao, Hongjun; Gao, Feng; Sun, Yongan; Lu, Yuanyuan; Liu, Yuanyuan; Lv, Pu; Cui, Wei; Teng, Yuming; Huang, Yining

2017-04-01

In this study we investigated the relationships between anti-ganglioside antibodies and Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). Samples from 48 Chinese patients diagnosed with GBS and 18 patients diagnosed with CIDP were retrospectively reviewed. In the GBS patients, 62.5% were classified as having acute inflammatory demyelinating polyneuropathy (AIDP), 27.1% were found to have acute motor axonal neuropathy (AMAN), and 10.4% were unclassified. Serum IgG anti-ganglioside antibodies were detected in 46.2% of the AMAN patients and in 6.7% of the AIDP patients (P < 0.05); 5.6% of the 18 CIDP patients were IgG antibody positive, and 27.8% were IgM antibody positive. Facial palsy and sensory impairment were significantly associated with IgM antibodies. These results suggest that IgG anti-GM1 antibodies are associated with AMAN, but not with AIDP, and that IgM antibodies against GM1, GM2, and GM3 are associated with facial nerve palsy. Muscle Nerve 55: 470-475, 2017. © 2016 Wiley Periodicals, Inc.

Expression analysis of the N-Myc downstream-regulated gene 1 indicates that myelinating Schwann cells are the primary disease target in hereditary motor and sensory neuropathy-Lom.

PubMed

Berger, Philipp; Sirkowski, Erich E; Scherer, Steven S; Suter, Ueli

2004-11-01

Mutations in the gene encoding N-myc downstream-regulated gene-1 (NDRG1) lead to truncations of the encoded protein and are associated with an autosomal recessive demyelinating neuropathy--hereditary motor and sensory neuropathy-Lom. NDRG1 protein is highly expressed in peripheral nerve and is localized in the cytoplasm of myelinating Schwann cells, including the paranodes and Schmidt-Lanterman incisures. In contrast, sensory and motor neurons as well as their axons lack NDRG1. NDRG1 mRNA levels in developing and injured adult sciatic nerves parallel those of myelin-related genes, indicating that the expression of NDRG1 in myelinating Schwann cells is regulated by axonal interactions. Oligodendrocytes also express NDRG1, and the subtle CNS deficits of affected patients may result from a lack of NDRG1 in these cells. Our data predict that the loss of NDRG1 leads to a Schwann cell autonomous phenotype resulting in demyelination, with secondary axonal loss.

Relapsing Painful Ophthalmoplegic Neuropathy: No longer a "Migraine," but Still a Headache.

PubMed

Smith, Stacy V; Schuster, Nathaniel M

2018-06-14

Recurrent painful ophthalmoplegic neuropathy (RPON), formerly known as ophthalmoplegic migraine, is an uncommon disorder with repeated episodes of ocular cranial nerve neuropathy associated with ipsilateral headache. This review discusses the clinical presentation, current understanding of the pathophysiology, key differential diagnoses, and evaluation and treatment of RPON. The literature is limited due to the rarity of the disorder. Recent case reports and series continue to suggest the age of first attack is most often during childhood or adolescence as well as a female predominance. Multiple recent case reports and series demonstrate focal enhancement of the affected cranial nerve, as the nerve root exits the brainstem. This finding contributed to the current classification of the disorder as a neuropathy, with the present understanding that it is due to a relapsing-remitting inflammatory or demyelinating process. The link to migraine remains a cause of disagreement in the literature. RPON is a complex disorder with features of inflammatory neuropathy and an unclear association with migraine. Regardless, the overall prognosis is good for individual episodes, but permanent nerve damage may accumulate with repeated attacks. A better understanding of the pathogenesis is needed to clarify whether it truly represents a single disorder and to guide its treatment. Until that time, a combined approach with acute and preventive therapies can mitigate acute symptoms as well as attempt to limit recurrence of this disabling syndrome.

IgM ganglioside GM1 antibodies in patients with autoimmune disease or neuropathy, and controls.

PubMed Central

Bansal, A S; Abdul-Karim, B; Malik, R A; Goulding, P; Pumphrey, R S; Boulton, A J; Holt, P L; Wilson, P B

1994-01-01

AIMS--To compare the titre of anti-ganglioside antibodies (AGA) to GM1 ganglioside in patients with central and peripheral neurological disease and pure motor and sensorimotor neuropathy, in patients with classic autoimmune diseases, and controls. METHODS--AGA to GM1 were measured using an enzyme linked immunosorbent assay (ELISA) technique, highly purified bovine GM1 ganglioside, and sequential dilution of control and test sera. Antibody titre was calculated using the optical density readings of three consecutive serum dilutions multiplied by the dilution factor. RESULTS--A considerable overlap was evident in the titre of AGA to GM1 in control and test sera. High antibody titres were most frequent in patients with multifocal motor neuropathy with conduction block (MMNCB). Low AGA titre were observed in several patient groups. Compared with the controls, the median titre of AGA to GM1 was significantly higher in patients with multiple sclerosis, rheumatoid arthritis, primary Sjögren's syndrome and systemic lupus erythematosus. In contrast, the median titre in patients with diabetic peripheral neuropathy, motor neurone disease, sensorimotor neuropathy and chronic inflammatory demyelinating polyneuropathy was no different from that in normal control subjects. CONCLUSIONS--Estimation of AGA to GM1 may be helpful in the diagnosis of MMNCB in patients with a pure motor neuropathy but in few other conditions. Low titre AGA to GM1 are evident in several autoimmune conditions. The pathogenetic importance of AGA to GM1 in patients with neuropathy is not clear. PMID:8027366

Chronic inflammatory demyelinating polyneuropathy in Waldenström's macroglobulinemia.

PubMed

Cassereau, J; Letournel, F; François, S; Dubas, F; Nicolas, G

2011-04-01

Waldenström's disease (WD) is frequently associated with a predominantly sensory neuropathy with a progressive course due to the monoclonal IgM activity against Myelin Associated Glycoprotein (MAG). However, neurolymphomatosis or chronic demyelinating inflammatory polyneuropathy (CDIP) may occur in some patients with WD. We report a case of Waldenström's macroglobulinemia in an adult male presenting with cranial nerve palsy and rapidly progressive asymmetric polyneuropathy. Intravenous IgM treatment that provided transient amelioration was followed by a relapse involving tetraparesis. Cerebrospinal fluid analysis, medullar magnetic resonance imaging, and electrophysiological studies led to equivocal findings suggesting the presence of either neurolymphomatosis or CIDP. Finally, sural nerve biopsy results supported the diagnosis of CIDP, which then received appropriate treatment. In patients with WD, the possible occurrence of CIDP should be investigated with a neuromuscular biopsy when other investigations are equivocal since the disease calls for a specific treatment. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

[Chronic inflammatory demyelinating polyradiculoneuropathy in childhood: outcomes after methylprednisolone pulse therapy].

PubMed

Rafai, M A; Moutaouakil, F; El Otmani, H; Fadel, H; Boulaajaj, F Z; El Moutawakil, B; Gam, I; Slassi, I

2006-06-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) in children is relatively rare and treatment is based primarily on intravenous immunoglobulins or oral corticosteroids. Boluses of methylprednisolone (MP) are a seldom used alternative. We report the case of an 8-year-old child, first presented at the age of 3 years, with recurring episodes of functional impotence of both lower limbs and walking impairment, partially reversible without treatment. Clinical, progressive, and electrophysiological data and the analysis of the cerebrospinal fluid were compatible with CIDP. MP boluses were administered: after a total eight monthly boluses, very satisfactory progression on the clinical and electrophysiological fronts was noted after 24 months. Childhood CIDP presents clinical, electrophysiological, progressive, and prognostic particularities, they recur readily and the outcome is good. Boluses of methylprednisolone are an alternative to the treatment of these neuropathies in childhood.

Hereditary sensory neuropathy type I.

PubMed

Auer-Grumbach, Michaela

2008-03-18

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 neuropathy, or decaying skin

Hereditary sensory neuropathy type I

PubMed Central

Auer-Grumbach, Michaela

2008-01-01

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 neuropathy, or decaying skin

Auditory function in children with Charcot-Marie-Tooth disease.

PubMed

Rance, Gary; Ryan, Monique M; Bayliss, Kristen; Gill, Kathryn; O'Sullivan, Caitlin; Whitechurch, Marny

2012-05-01

The peripheral manifestations of the inherited neuropathies are increasingly well characterized, but their effects upon cranial nerve function are not well understood. Hearing loss is recognized in a minority of children with this condition, but has not previously been systemically studied. A clear understanding of the prevalence and degree of auditory difficulties in this population is important as hearing impairment can impact upon speech/language development, social interaction ability and educational progress. The aim of this study was to investigate auditory pathway function, speech perception ability and everyday listening and communication in a group of school-aged children with inherited neuropathies. Twenty-six children with Charcot-Marie-Tooth disease confirmed by genetic testing and physical examination participated. Eighteen had demyelinating neuropathies (Charcot-Marie-Tooth type 1) and eight had the axonal form (Charcot-Marie-Tooth type 2). While each subject had normal or near-normal sound detection, individuals in both disease groups showed electrophysiological evidence of auditory neuropathy with delayed or low amplitude auditory brainstem responses. Auditory perception was also affected, with >60% of subjects with Charcot-Marie-Tooth type 1 and >85% of Charcot-Marie-Tooth type 2 suffering impaired processing of auditory temporal (timing) cues and/or abnormal speech understanding in everyday listening conditions.

An inherited genetic variant in CEP72 promoter predisposes to vincristine-induced peripheral neuropathy in adults with acute lymphoblastic leukemia

PubMed Central

Stock, Wendy; Diouf, Barthelemy; Crews, Kristine R.; Pei, Deqing; Cheng, Cheng; Laumann, Kristina; Mandrekar, Sumithra J.; Luger, Selina; Advani, Anjali; Stone, Richard M.; Larson, Richard A.; Evans, William E.

2016-01-01

Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying at-risk adult patients. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI Grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by NCI criteria. CEP72 promoter genotype (rs924607) was determined using PCR based SNP genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs 10%, p=0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (p=0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy. PMID:27618250

Treatment of oxaliplatin-induced peripheral neuropathy by intravenous mangafodipir

PubMed Central

Coriat, Romain; Alexandre, Jérôme; Nicco, Carole; Quinquis, Laurent; Benoit, Evelyne; Chéreau, Christiane; Lemaréchal, Hervé; Mir, Olivier; Borderie, Didier; Tréluyer, Jean-Marc; Weill, Bernard; Coste, Joel; Goldwasser, François; Batteux, Frédéric

2013-01-01

Background. The majority of patients receiving the platinum-based chemotherapy drug oxaliplatin develop peripheral neurotoxicity. Because this neurotoxicity involves ROS production, we investigated the efficacy of mangafodipir, a molecule that has antioxidant properties and is approved for use as an MRI contrast enhancer. Methods. The effects of mangafodipir were examined in mice following treatment with oxaliplatin. Neurotoxicity, axon myelination, and advanced oxidized protein products (AOPPs) were monitored. In addition, we enrolled 23 cancer patients with grade ≥2 oxaliplatin-induced neuropathy in a phase II study, with 22 patients receiving i.v. mangafodipir following oxaliplatin. Neuropathic effects were monitored for up to 8 cycles of oxaliplatin and mangafodipir. Results. Mangafodipir prevented motor and sensory dysfunction and demyelinating lesion formation. In mice, serum AOPPs decreased after 4 weeks of mangafodipir treatment. In 77% of patients treated with oxaliplatin and mangafodipir, neuropathy improved or stabilized after 4 cycles. After 8 cycles, neurotoxicity was downgraded to grade ≥2 in 6 of 7 patients. Prior to enrollment, patients received an average of 880 ± 239 mg/m2 oxaliplatin. Patients treated with mangafodipir tolerated an additional dose of 458 ± 207 mg/m2 oxaliplatin despite preexisting neuropathy. Mangafodipir responders managed a cumulative dose of 1,426 ± 204 mg/m2 oxaliplatin. Serum AOPPs were lower in responders compared with those in nonresponders. Conclusion. Our study suggests that mangafodipir can prevent and/or relieve oxaliplatin-induced neuropathy in cancer patients. Trial registration. Clinicaltrials.gov NCT00727922. Funding. Université Paris Descartes, Ministère de la Recherche et de l’Enseignement Supérieur, and Assistance Publique-Hôpitaux de Paris. PMID:24355920

Whole Genome Sequencing Identifies a 78 kb Insertion from Chromosome 8 as the Cause of Charcot-Marie-Tooth Neuropathy CMTX3

PubMed Central

Brewer, Megan H.; Chaudhry, Rabia; Qi, Jessica; Kidambi, Aditi; Drew, Alexander P.; Ryan, Monique M.; Subramanian, Gopinath M.; Young, Helen K.; Zuchner, Stephan; Reddel, Stephen W.; Nicholson, Garth A.; Kennerson, Marina L.

2016-01-01

With the advent of whole exome sequencing, cases where no pathogenic coding mutations can be found are increasingly being observed in many diseases. In two large, distantly-related families that mapped to the Charcot-Marie-Tooth neuropathy CMTX3 locus at chromosome Xq26.3-q27.3, all coding mutations were excluded. Using whole genome sequencing we found a large DNA interchromosomal insertion within the CMTX3 locus. The 78 kb insertion originates from chromosome 8q24.3, segregates fully with the disease in the two families, and is absent from the general population as well as 627 neurologically normal chromosomes from in-house controls. Large insertions into chromosome Xq27.1 are known to cause a range of diseases and this is the first neuropathy phenotype caused by an interchromosomal insertion at this locus. The CMTX3 insertion represents an understudied pathogenic structural variation mechanism for inherited peripheral neuropathies. Our finding highlights the importance of considering all structural variation types when studying unsolved inherited peripheral neuropathy cases with no pathogenic coding mutations. PMID:27438001

Genotype–phenotype characteristics and baseline natural history of heritable neuropathies caused by mutations in the MPZ gene

PubMed Central

Feely, Shawna; Scherer, Steven S.; Herrmann, David N.; Burns, Joshua; Muntoni, Francesco; Li, Jun; Siskind, Carly E.; Day, John W.; Laura, Matilde; Sumner, Charlotte J.; Lloyd, Thomas E.; Ramchandren, Sindhu; Shy, Rosemary R.; Grider, Tiffany; Bacon, Chelsea; Finkel, Richard S.; Yum, Sabrina W.; Moroni, Isabella; Piscosquito, Giuseppe; Pareyson, Davide; Reilly, Mary M.; Shy, Michael E.

2015-01-01

We aimed to characterize genotype–phenotype correlations and establish baseline clinical data for peripheral neuropathies caused by mutations in the myelin protein zero (MPZ) gene. MPZ mutations are the second leading cause of Charcot–Marie–Tooth disease type 1. Recent research makes clinical trials for patients with MPZ mutations a realistic possibility. However, the clinical severity varies with different mutations and natural history data on progression is sparse. We present cross-sectional data to begin to define the phenotypic spectrum and clinical baseline of patients with these mutations. A cohort of patients with MPZ gene mutations was identified in 13 centres of the Inherited Neuropathies Consortium - Rare Disease Clinical Research Consortium (INC-RDCRC) between 2009 and 2012 and at Wayne State University between 1996 and 2009. Patient phenotypes were quantified by the Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and the Charcot–Marie–Tooth disease paediatric scale outcome instruments. Genetic testing was performed in all patients and/or in first- or second-degree relatives to document mutation in MPZ gene indicating diagnosis of Charcot–Marie–Tooth disease type 1B. There were 103 patients from 71 families with 47 different MPZ mutations with a mean age of 40 years (range 3–84 years). Patients and mutations were separated into infantile, childhood and adult-onset groups. The infantile onset group had higher Charcot–Marie–Tooth disease neuropathy score version 1 or 2 and slower nerve conductions than the other groups, and severity increased with age. Twenty-three patients had no family history of Charcot–Marie–Tooth disease. Sixty-one patients wore foot/ankle orthoses, 19 required walking assistance or support, and 10 required wheelchairs. There was hearing loss in 21 and scoliosis in 17. Forty-two patients did not begin walking until after 15 months of age. Half of the infantile onset patients then required

Premature aging-related peripheral neuropathy in a mouse model of progeria.

PubMed

Goss, James R; Stolz, Donna Beer; Robinson, Andria Rasile; Zhang, Mingdi; Arbujas, Norma; Robbins, Paul D; Glorioso, Joseph C; Niedernhofer, Laura J

2011-08-01

Peripheral neuropathy is a common aging-related degenerative disorder that interferes with daily activities and leads to increased risk of falls and injury in the elderly. The etiology of most aging-related peripheral neuropathy is unknown. Inherited defects in several genome maintenance mechanisms cause tissue-specific accelerated aging, including neurodegeneration. We tested the hypothesis that a murine model of XFE progeroid syndrome, caused by reduced expression of ERCC1-XPF DNA repair endonuclease, develops peripheral neuropathy. Nerve conduction studies revealed normal nerve function in young adult (8 week) Ercc1(-/Δ) mice, but significant abnormalities in 20 week-old animals. Morphologic and ultrastructural analysis of the sciatic nerve from mutant mice revealed significant alterations at 20 but not 8 weeks of age. We conclude that Ercc1(-/Δ) mice have accelerated spontaneous peripheral neurodegeneration that mimics aging-related disease. This provides strong evidence that DNA damage can drive peripheral neuropathy and offers a rapid and novel model to test therapies. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Inherited Mitochondrial Diseases of DNA Replication

PubMed Central

Copeland, William C.

2007-01-01

Mitochondrial genetic diseases can result from defects in mitochondrial DNA (mtDNA) in the form of deletions, point mutations, or depletion, which ultimately cause loss of oxidative phosphorylation. These mutations may be spontaneous, maternally inherited, or a result of inherited nuclear defects in genes that maintain mtDNA. This review focuses on our current understanding of nuclear gene mutations that produce mtDNA alterations and cause mitochondrial depletion syndrome (MDS), progressive external ophthalmoplegia (PEO), ataxia-neuropathy, or mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). To date, all of these etiologic nuclear genes fall into one of two categories: genes whose products function directly at the mtDNA replication fork, such as POLG, POLG2, and TWINKLE, or genes whose products supply the mitochondria with deoxynucleotide triphosphate pools needed for DNA replication, such as TK2, DGUOK, TP, SUCLA2, ANT1, and possibly the newly identified MPV17. PMID:17892433

Transthyretin amyloid polyneuropathies mimicking a demyelinating polyneuropathy.

PubMed

Lozeron, Pierre; Mariani, Louise-Laure; Dodet, Pauline; Beaudonnet, Guillemette; Théaudin, Marie; Adam, Clovis; Arnulf, Bertrand; Adams, David

2018-06-15

To clearly define transthyretin familial amyloid polyneuropathies (TTR-FAPs) fulfilling definite clinical and electrophysiologic European Federation of Neurological Societies/Peripheral Nerve Society criteria for chronic inflammatory demyelinating polyneuropathy (CIDP). From a cohort of 194 patients with FAP, 13 of 84 patients (15%) of French ancestry had late-onset demyelinating TTR-FAP. We compared clinical presentation and electrophysiology to a cohort with CIDP and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome. We assessed nerve histology and the correlation between motor/sensory amplitudes/velocities. Predictors of demyelinating TTR-FAP were identified from clinical and electrophysiologic data. Pain, dysautonomia, small fiber sensory loss above the wrists, upper limb weakness, and absence of ataxia were predictors of demyelinating TTR-FAP ( p < 0.01). The most frequent demyelinating features were prolonged distal motor latency of the median nerve and reduced sensory conduction velocity of the median and ulnar nerves. Motor axonal loss was severe and frequent in the median, ulnar, and tibial nerves ( p < 0.05) in demyelinating FAP. Ulnar nerve motor amplitude <5.4 mV and sural nerve amplitude <3.95 μV were distinguishing characteristics of demyelinating TTR-FAP. Nerve biopsy showed severe axonal loss and occasional segmental demyelination-remyelination. Misleading features of TTR-FAP fulfilling criteria for CIDP are not uncommon in sporadic late-onset TTR-FAP, which highlights the limits of European Federation of Neurological Societies/Peripheral Nerve Society criteria. Specific clinical aspects and marked electrophysiologic axonal loss are red flag symptoms that should alert to this diagnosis and prompt TTR gene sequencing. © 2018 American Academy of Neurology.

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP): An Uncommon Manifestation of Systemic Lupus Erythematosus (SLE).

PubMed

Abraham, Hrudya; Kuzhively, Jose; Rizvi, Syed W

2017-09-12

BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) is an uncommon manifestation of systemic lupus erythematosus (SLE). We report a case of SLE presenting as CIDP and discuss the diagnosis, management, and prognosis of CIDP. CASE REPORT A 40-year-old woman with a past medical history of SLE treated with hydroxychloroquine presented with bilateral, progressive, ascending, sensory and motor neuropathy. Physical examination showed weakness and reduced temperature of all extremities, reduced pinprick and vibration sense of the distal extremities, loss of reflexes, and walking with a wide-based unsteady gait. Laboratory investigations showed positive antinuclear antibodies (ANA), anti-(smooth muscle (SM) antibody, anti-RNP antibody, anti-SSA antibody, anti-ds-DNA antibody, and an erythrocyte sedimentation rate (ESR) of 75 mm/hr, low C4, leukopenia, and anemia. Electromyography (EMG) confirmed the diagnosis of CIDP. The patient's neuropathy and muscle weakness improved on treatment with intravenous immunoglobulin (IVIG) and high-dose steroids. CONCLUSIONS The early clinical diagnosis of CIDP, supported by serological autoantibody profiles associated with SLE, can predict a good response to steroids. Most patients with CIDP are treated successfully with steroids if the diagnosis is made early. IVIG, plasmapheresis, or immunosuppressive therapy should be considered if there is no response to steroids.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2014-01-01

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

Hypothalamic demyelination causing panhypopituitarism.

PubMed

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

2018-05-01

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

[Progress in research on pathogenic genes and gene therapy for inherited retinal diseases].

PubMed

Zhu, Ling; Cao, Cong; Sun, Jiji; Gao, Tao; Liang, Xiaoyang; Nie, Zhipeng; Ji, Yanchun; Jiang, Pingping; Guan, Minxin

2017-02-10

Inherited retinal diseases (IRDs), including retinitis pigmentosa, Usher syndrome, Cone-Rod degenerations, inherited macular dystrophy, Leber's congenital amaurosis, Leber's hereditary optic neuropathy are the most common and severe types of hereditary ocular diseases. So far more than 200 pathogenic genes have been identified. With the growing knowledge of the genetics and mechanisms of IRDs, a number of gene therapeutic strategies have been developed in the laboratory or even entered clinical trials. Here the progress of IRD research on the pathogenic genes and therapeutic strategies, particularly gene therapy, are reviewed.

Peripheral neuropathy in diabetes: it's not always what it looks like.

PubMed

Maltese, G; Tan, S V; Bruno, E; Brackenridge, A; Thomas, S

2018-06-04

Hereditary Neuropathy with liability to Pressure Palsies (HNPP) is an autosomal dominant neuropathy, associated with deletion of the Peripheral Myelin Protein-22 (PMP-22) gene, causing recurrent painless palsies with age of onset between 10 and 30 years old. Only a few cases of Type 2 Diabetes and HNPP have been described and the coexistence of HNPP and Type 1 diabetes has never been reported. A 54-year old man with a history of Type 1 diabetes, managed with continuous subcutaneous insulin infusion (CSII), presented with deterioration of long-standing motor and sensory symptoms, previously attributed to golfer's elbow, diabetic neuropathy and spinal degenerative disease. He had multilevel severe spine degenerative changes and L4/L5 and L5/S1 root impingements with a L4/L5 discectomy performed when he was 25 years old. On physical examination he had normal power and distal hypoaesthesia of the digits and plantar aspect of the feet. Investigations revealed normal full blood count, liver and renal function, electrolytes, vitamin B12 and serum folate. He suffered from primary hypothyroidism and thyroid function tests indicated adequate levothyroxine replacement. Nerve conduction studies revealed a generalized demyelinating sensorimotor neuropathy, with more severe involvement of nerves over entrapment sites. Further history that his father suffered from episodes of weakness and numbness was elicited. Genetic analysis revealed one copy of the PMP22 gene at 17p11.2 confirming the diagnosis of HNPP. In people with diabetes the evaluation of peripheral neuropathy should include a careful history, a comprehensive physical examination, blood tests and in some cases nerve conduction studies and genetic testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Paranodal lesions in chronic inflammatory demyelinating polyneuropathy associated with anti-Neurofascin 155 antibodies.

PubMed

Vallat, Jean-Michel; Yuki, Nobuhiro; Sekiguchi, Kenji; Kokubun, Norito; Oka, Nobuyuki; Mathis, Stéphane; Magy, Laurent; Sherman, Diane L; Brophy, Peter J; Devaux, Jérôme J

2017-03-01

Antibodies to Contactin-1 and Neurofascin 155 (Nfasc155) have recently been associated with subsets of patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Contactin-1 and Nfasc155 are cell adhesion molecules that constitute the septate-like junctions observed by electron microscopy in the paranodes of myelinated axons. Antibodies to Contactin-1 have been shown to affect the localization of paranodal proteins both in patient nerve biopsies and in animal models after passive transfer. However, it is unclear whether these antibodies alter the paranodal ultrastructure. We examined by electron microscopy sural nerve biopsies from two patients presenting with anti-Nfasc155 antibodies, and also four patients lacking antibodies, three normal controls, and five patients with other neuropathies. We found that patients with anti-Nfasc155 antibodies presented a selective loss of the septate-like junctions at all paranodes examined. Further, cellular processes penetrated into the expanded spaces between the paranodal myelin loops and the axolemma in these patients. These patients presented with important nerve conduction slowing and demyelination. Also, the reactivity of anti-Nfasc155 antibodies from these patients was abolished in neurofascin-deficient mice, confirming that the antibodies specifically target paranodal proteins. Our data indicate that anti-Nfasc155 destabilizes the paranodal axo-glial junctions and may participate in conduction deterioration. Copyright © 2016 Elsevier B.V. All rights reserved.

Early identification of 'acute-onset' chronic inflammatory demyelinating polyneuropathy.

PubMed

Sung, Jia-Ying; Tani, Jowy; Park, Susanna B; Kiernan, Matthew C; Lin, Cindy Shin-Yi

2014-08-01

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased

Analysis of neural crest cells from Charcot-Marie-Tooth disease patients demonstrates disease-relevant molecular signature.

PubMed

Kitani-Morii, Fukiko; Imamura, Keiko; Kondo, Takayuki; Ohara, Ryo; Enami, Takako; Shibukawa, Ran; Yamamoto, Takuya; Sekiguchi, Kazuya; Toguchida, Junya; Mizuno, Toshiki; Nakagawa, Masanori; Inoue, Haruhisa

2017-09-06

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The majority of CMT is demyelinating type (demyelinating CMT) caused by Schwann cell involvement. Although a large number of genes responsible for demyelinating CMT have been found, the common molecular target of the pathophysiology caused by these different genes in demyelinating CMT is still unknown. We generated induced pluripotent stem cells (iPSCs) from healthy controls and patients with demyelinating CMT caused by duplication in peripheral myelin protein 22 kDa (PMP22) or point mutations in myelin protein zero (MPZ) or early growth response 2 (EGR2). iPSCs were differentiated into neural crest cells, progenitors of Schwann cells, followed by purification using the neural crest cell markers p75 and human natural killer-1. To identify a disease-relevant molecular signature at the early stage of demyelinating CMT, we conducted global gene expression analysis of iPSC-derived neural crest cells and found that a glutathione-mediated detoxification pathway was one of the related pathways in demyelinating CMT. mRNA expression of glutathione S-transferase theta 2 (GSTT2), encoding an important enzyme for glutathione-mediated detoxification, and production of reactive oxygen species were increased in demyelinating CMT. Our study suggested that patient-iPSC-derived neural crest cells could be a cellular model for investigating genetically heterogeneous disease CMT and might provide a therapeutic target for the disease.

Clinical, electrophysiological, genetic, and imaging features of six Chinese Han patients with hereditary neuropathy with liability to pressure palsies (HNPP).

PubMed

Chen, Bin; Niu, Songtao; Wang, Xingao; Li, Wei; Chen, Na; Zhang, Zaiqiang

2018-02-01

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy caused by mutations in the peripheral myelin protein 22 (PMP22) gene. This study summarizes the clinical, electrophysiological, genetic, and imaging features of six unrelated Chinese Han patients with HNPP. Age of onset was within the second decade in five patients, and 46 years of age in one patient. Weakness or numbness in a unilateral lower extremity was the most common symptom in 5 patients, and bilateral sensorineural hearing loss was also detected in one patient. Electrophysiological presentations suggested demyelinating sensory-motor polyneuropathy in the group. Magnetic resonance imaging (MRI) of the cervical and lumbar spine revealed varying degrees of degeneration in five patients, and mild kyphosis of cervical vertebral bodies in 2 teen-aged patients. In addition, cranial MRI of one patient showed scattered demyelination in the frontal lobes. Targeted next-generation-sequencing (NGS) revealed a PMP22 deletion in five patients and a heterozygous c.199G>A mutation in exon 4 of PMP22 in one patient. The I92V variant of lipopolysaccharide-induced tumor necrosis factor (LITAF) gene was found in one patient. There was no relationship between the Ile92Val variant of LITAF and age of onset in this group, albeit the sample size was very small. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stance Postural Strategies in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy

PubMed Central

Missori, Paolo; Trompetto, Carlo; Fattapposta, Francesco

2016-01-01

Introduction Polyneuropathy leads to postural instability and an increased risk of falling. We investigated how impaired motor impairment and proprioceptive input due to neuropathy influences postural strategies. Methods Platformless bisegmental posturography data were recorded in healthy subjects and patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Each subject stood on the floor, wore a head and a hip electromagnetic tracker. Sway amplitude and velocity were recorded and the mean direction difference (MDD) in the velocity vector between trackers was calculated as a flexibility index. Results Head and hip postural sway increased more in patients with CIDP than in healthy controls. MDD values reflecting hip strategies also increased more in patients than in controls. In the eyes closed condition MDD values in healthy subjects decreased but in patients remained unchanged. Discussion Sensori-motor impairment changes the balance between postural strategies that patients adopt to maintain upright quiet stance. Motor impairment leads to hip postural strategy overweight (eyes open), and prevents strategy re-balancing when the sensory context predominantly relies on proprioceptive input (eyes closed). PMID:26977594

Novel C12orf65 mutations in patients with axonal neuropathy and optic atrophy.

PubMed

Tucci, Arianna; Liu, Yo-Tsen; Preza, Elisabeth; Pitceathly, Robert D S; Chalasani, Annapurna; Plagnol, Vincent; Land, John M; Trabzuni, Daniah; Ryten, Mina; Jaunmuktane, Zane; Reilly, Mary M; Brandner, Sebastian; Hargreaves, Iain; Hardy, John; Singleton, Andrew B; Abramov, Andrey Y; Houlden, Henry

2014-05-01

Charcot-Marie Tooth disease (CMT) forms a clinically and genetically heterogeneous group of disorders. Although a number of disease genes have been identified for CMT, the gene discovery for some complex form of CMT has lagged behind. The association of neuropathy and optic atrophy (also known as CMT type 6) has been described with autosomaldominant, recessive and X-linked modes of inheritance. Mutations in Mitofusin 2 have been found to cause dominant forms of CMT6. Phosphoribosylpyrophosphate synthetase-I mutations cause X-linked CMT6, but until now, mutations in the recessive forms of disease have never been identified. We here describe a family with three affected individuals who inherited in an autosomal recessive fashion a childhood onset neuropathy and optic atrophy. Using homozygosity mapping in the family and exome sequencing in two affected individuals we identified a novel protein-truncating mutation in the C12orf65 gene, which encodes for a protein involved in mitochondrial translation. Using a variety of methods we investigated the possibility of mitochondrial impairment in the patients cell lines. We described a large consanguineous family with neuropathy and optic atrophy carrying a loss of function mutation in the C12orf65 gene. We report mitochondrial impairment in the patients cell lines, followed by multiple lines of evidence which include decrease of complex V activity and stability (blue native gel assay), decrease in mitochondrial respiration rate and reduction of mitochondrial membrane potential. This work describes a mutation in the C12orf65 gene that causes recessive form of CMT6 and confirms the role of mitochondrial dysfunction in this complex axonal neuropathy.

Evidence from Human and Animal Studies: Pathological Roles of CD8+ T Cells in Autoimmune Peripheral Neuropathies

PubMed Central

Yang, Mu; Peyret, Corentin; Shi, Xiang Qun; Siron, Nicolas; Jang, Jeong Ho; Wu, Sonia; Fournier, Sylvie; Zhang, Ji

2015-01-01

Autoimmune peripheral neuropathies such as Guillain-Barre Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) affect millions of people worldwide. Despite significant advances in understanding the pathology, the molecular and cellular mechanisms of immune-mediated neuropathies remain elusive. T lymphocytes definitely play an important role in disease pathogenesis and CD4+ T cells have been the main area of research for decades. This is partly due to the fact that the most frequent animal model to study autoimmune peripheral neuropathy is experimental allergic neuritis (EAN). As it is induced commonly by immunization with peripheral nerve proteins, EAN is driven mainly by CD4+ T cells. However, similarly to what has been reported for patients suffering from multiple sclerosis, a significant body of evidence indicates that CD8+ T cells may play a pathogenic role in GBS and CIDP disease development and/or progression. Here, we summarize clinical studies pertaining to the presence and potential role of CD8+ T cells in autoimmune peripheral neuropathies. We also discuss the findings from our most recent studies using a transgenic mouse line (L31 mice) in which the T cell co-stimulator molecule B7.2 (CD86) is constitutively expressed in antigen presenting cells of the nervous tissues. L31 mice spontaneously develop peripheral neuropathy, and CD8+ T cells are found accumulating in peripheral nerves of symptomatic animals. Interestingly, depletion of CD4+ T cells accelerates disease onset and increases disease prevalence. Finally, we point out some unanswered questions for future research to dissect the critical roles of CD8+ T cells in autoimmune peripheral neuropathies. PMID:26528293

Evidence from Human and Animal Studies: Pathological Roles of CD8(+) T Cells in Autoimmune Peripheral Neuropathies.

PubMed

Yang, Mu; Peyret, Corentin; Shi, Xiang Qun; Siron, Nicolas; Jang, Jeong Ho; Wu, Sonia; Fournier, Sylvie; Zhang, Ji

2015-01-01

Autoimmune peripheral neuropathies such as Guillain-Barre Syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) affect millions of people worldwide. Despite significant advances in understanding the pathology, the molecular and cellular mechanisms of immune-mediated neuropathies remain elusive. T lymphocytes definitely play an important role in disease pathogenesis and CD4(+) T cells have been the main area of research for decades. This is partly due to the fact that the most frequent animal model to study autoimmune peripheral neuropathy is experimental allergic neuritis (EAN). As it is induced commonly by immunization with peripheral nerve proteins, EAN is driven mainly by CD4(+) T cells. However, similarly to what has been reported for patients suffering from multiple sclerosis, a significant body of evidence indicates that CD8(+) T cells may play a pathogenic role in GBS and CIDP disease development and/or progression. Here, we summarize clinical studies pertaining to the presence and potential role of CD8(+) T cells in autoimmune peripheral neuropathies. We also discuss the findings from our most recent studies using a transgenic mouse line (L31 mice) in which the T cell co-stimulator molecule B7.2 (CD86) is constitutively expressed in antigen presenting cells of the nervous tissues. L31 mice spontaneously develop peripheral neuropathy, and CD8(+) T cells are found accumulating in peripheral nerves of symptomatic animals. Interestingly, depletion of CD4(+) T cells accelerates disease onset and increases disease prevalence. Finally, we point out some unanswered questions for future research to dissect the critical roles of CD8(+) T cells in autoimmune peripheral neuropathies.

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations.

PubMed

Brockmann, Knut; Dreha-Kulaczewski, Steffi; Dechent, Peter; Bönnemann, Carsten; Helms, Gunther; Kyllerman, Marten; Brück, Wolfgang; Frahm, Jens; Huehne, Kathrin; Gärtner, Jutta; Rautenstrauss, Bernd

2008-07-01

Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.

[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital].

PubMed

Fernández-Ramos, Joaquín A; López-Laso, Eduardo; Camino-León, Rafael; Gascón-Jiménez, Francisco J; Jiménez-González, M Dolores

2015-12-01

Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.

The role of sulfoglucuronosyl glycosphingolipids in the pathogenesis of monoclonal IgM paraproteinemia and peripheral neuropathy

PubMed Central

ARIGA, Toshio

2011-01-01

In IgM paraproteinemia and peripheral neuropathy, IgM M-protein secretion by B cells leads to a T helper cell response, suggesting that it is antibody-mediated autoimmune disease involving carbohydrate epitopes in myelin sheaths. An immune response against sulfoglucuronosyl glycosphingolipids (SGGLs) is presumed to participate in demyelination or axonal degeneration in the peripheral nervous system (PNS). SGGLs contain a 3-sulfoglucuronic acid residue that interacts with anti-myelin-associated glycoprotein (MAG) and the monoclonal antibody anti-HNK-1. Immunization of animals with sulfoglucuronosyl paragloboside (SGPG) induced anti-SGPG antibodies and sensory neuropathy, which closely resembles the human disease. These animal models might help to understand the disease mechanism and lead to more specific therapeutic strategies. In an in vitro study, destruction or malfunction of the blood-nerve barrier (BNB) was found, resulting in the leakage of circulating antibodies into the PNS parenchyma, which may be considered as the initial key step for development of disease. PMID:21785257

Early identification of ‘acute-onset’ chronic inflammatory demyelinating polyneuropathy

PubMed Central

Sung, Jia-Ying; Tani, Jowy; Park, Susanna B.; Kiernan, Matthew C.

2014-01-01

Distinguishing patients with acute-onset chronic inflammatory demyelinating polyneuropathy from acute inflammatory demyelinating polyneuropathy prior to relapse is often challenging at the onset of their clinical presentation. In the present study, nerve excitability tests were used in conjunction with the clinical phenotype and disease staging, to differentiate between patients with acute-onset chronic inflammatory demyelinating polyneuropathy and patients with acute inflammatory demyelinating polyneuropathy at an early stage, with the aim to better guide treatment. Clinical assessment, staging and nerve excitability tests were undertaken on patients initially fulfilling the diagnostic criteria of acute inflammatory demyelinating polyneuropathy soon after symptom onset and their initial presentation. Patients were subsequently followed up for minimum of 12 months to determine if their clinical presentations were more consistent with acute-onset chronic inflammatory demyelinating polyneuropathy. Clinical severity as evaluated by Medical Research Council sum score and Hughes functional grading scale were not significantly different between the two cohorts. There was no difference between the time of onset of initial symptoms and nerve excitability test assessment between the two cohorts nor were there significant differences in conventional nerve conduction study parameters. However, nerve excitability test profiles obtained from patients with acute inflammatory demyelinating polyneuropathy demonstrated abnormalities in the recovery cycle of excitability, including significantly reduced superexcitability (P < 0.001) and prolonged relative refractory period (P < 0.01), without changes in threshold electrotonus. In contrast, in patients with acute-onset chronic inflammatory demyelinating polyneuropathy, a different pattern occurred with the recovery cycle shifted downward (increased superexcitability, P < 0.05; decreased subexcitability, P < 0.05) and increased

Clinical Neuropathy Scales in Neuropathy Associated with Impaired Glucose Tolerance

PubMed Central

Zilliox, Lindsay A.; Ruby, Sandra K.; Singh, Sujal; Zhan, Min; Russell, James W.

2015-01-01

AIMS Disagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. METHODS Data was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms < 2 years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). RESULTS All seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large than small fiber neuropathy. CONCULSIONS All seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy. PMID:25690405

Mitochondrial optic neuropathies – Disease mechanisms and therapeutic strategies

PubMed Central

Yu-Wai-Man, Patrick; Griffiths, Philip G.; Chinnery, Patrick F.

2011-01-01

Leber hereditary optic neuropathy (LHON) and autosomal-dominant optic atrophy (DOA) are the two most common inherited optic neuropathies in the general population. Both disorders share striking pathological similarities, marked by the selective loss of retinal ganglion cells (RGCs) and the early involvement of the papillomacular bundle. Three mitochondrial DNA (mtDNA) point mutations; m.3460G>A, m.11778G>A, and m.14484T>C account for over 90% of LHON cases, and in DOA, the majority of affected families harbour mutations in the OPA1 gene, which codes for a mitochondrial inner membrane protein. Optic nerve degeneration in LHON and DOA is therefore due to disturbed mitochondrial function and a predominantly complex I respiratory chain defect has been identified using both in vitro and in vivo biochemical assays. However, the trigger for RGC loss is much more complex than a simple bioenergetic crisis and other important disease mechanisms have emerged relating to mitochondrial network dynamics, mtDNA maintenance, axonal transport, and the involvement of the cytoskeleton in maintaining a differential mitochondrial gradient at sites such as the lamina cribosa. The downstream consequences of these mitochondrial disturbances are likely to be influenced by the local cellular milieu. The vulnerability of RGCs in LHON and DOA could derive not only from tissue-specific, genetically-determined biological factors, but also from an increased susceptibility to exogenous influences such as light exposure, smoking, and pharmacological agents with putative mitochondrial toxic effects. Our concept of inherited mitochondrial optic neuropathies has evolved over the past decade, with the observation that patients with LHON and DOA can manifest a much broader phenotypic spectrum than pure optic nerve involvement. Interestingly, these phenotypes are sometimes clinically indistinguishable from other neurodegenerative disorders such as Charcot-Marie-Tooth disease, hereditary spastic

Diagnostic criteria of chronic inflammatory demyelinating polyneuropathy in diabetes mellitus.

PubMed

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

2015-10-01

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

Oligodendrocytes and Progenitors Become Progressively Depleted within Chronically Demyelinated Lesions

PubMed Central

Mason, Jeffrey L.; Toews, Arrel; Hostettler, Janell D.; Morell, Pierre; Suzuki, Kinuko; Goldman, James E.; Matsushima, Glenn K.

2004-01-01

To understand mechanisms that may underlie the progression of a demyelinated lesion to a chronic state, we have used the cuprizone model of chronic demyelination. In this study, we investigated the fate of oligodendrocytes during the progression of a demyelinating lesion to a chronic state and determined whether transplanted adult oligodendrocyte progenitors could remyelinate the chronically demyelinated axons. Although there is rapid regeneration of the oligodendrocyte population following an acute lesion, most of these newly regenerated cells undergo apoptosis if mice remain on a cuprizone diet. Furthermore, the oligodendrocyte progenitors also become progressively depleted within the lesion, which appears to contribute to the chronic demyelination. Interestingly, even if the mice are returned to a normal diet following 12 weeks of exposure to cuprizone, remyelination and oligodendrocyte regeneration does not occur. However, if adult O4+ progenitors are transplanted into the chronically demyelinated lesion of mice treated with cuprizone for 12 weeks, mature oligodendrocyte regeneration and remyelination occurs after the mice are returned to a normal diet. Thus, the formation of chronically demyelinated lesions induced by cuprizone appears to be the result of oligodendrocyte depletion within the lesion and not due to the inability of the chronically demyelinated axons to be remyelinated. PMID:15111314

Immunological Demyelination Triggers Macrophage/Microglial Cells Activation without Inducing Astrogliosis

PubMed Central

Sears-Kraxberger, Ilse; Keirstead, Hans S.

2013-01-01

The glial scar formed by reactive astrocytes and axon growth inhibitors associated with myelin play important roles in the failure of axonal regeneration following central nervous system (CNS) injury. Our laboratory has previously demonstrated that immunological demyelination of the CNS facilitates regeneration of severed axons following spinal cord injury. In the present study, we evaluate whether immunological demyelination is accompanied with astrogliosis. We compared the astrogliosis and macrophage/microglial cell responses 7 days after either immunological demyelination or a stab injury to the dorsal funiculus. Both lesions induced a strong activated macrophage/microglial cells response which was significantly higher within regions of immunological demyelination. However, immunological demyelination regions were not accompanied by astrogliosis compared to stab injury that induced astrogliosis which extended several millimeters above and below the lesions, evidenced by astroglial hypertrophy, formation of a glial scar, and upregulation of intermediate filaments glial fibrillary acidic protein (GFAP). Moreover, a stab or a hemisection lesion directly within immunological demyelination regions did not induced astrogliosis within the immunological demyelination region. These results suggest that immunological demyelination creates a unique environment in which astrocytes do not form a glial scar and provides a unique model to understand the putative interaction between astrocytes and activated macrophage/microglial cells. PMID:24319469

[Review of the recent literature on hereditary neuropathies].

PubMed

Birouk, N

2014-12-01

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. Copyright © 2014. Published by Elsevier Masson SAS.

Ultrasonographic findings in hereditary neuropathy with liability to pressure palsies.

PubMed

Bayrak, Ayse O; Bayrak, Ilkay Koray; Battaloglu, Esra; Ozes, Burcak; Yildiz, Onur; Onar, Musa Kazim

2015-02-01

The aims of this study were to evaluate the sonographic findings of patients with hereditary neuropathy with liability to pressure palsies (HNPP) and to examine the correlation between sonographic and electrophysiological findings. Nine patients whose electrophysiological findings indicated HNPP and whose diagnosis was confirmed by genetic analysis were enrolled in the study. The median, ulnar, peroneal, and tibial nerves were evaluated by ultrasonography. We ultrasonographically evaluated 18 median, ulnar, peroneal, and tibial nerves. Nerve enlargement was identified in the median, ulnar, and peroneal nerves at the typical sites of compression. None of the patients had nerve enlargement at a site of noncompression. None of the tibial nerves had increased cross-sectional area (CSA) values. There were no significant differences in median, ulnar, and peroneal nerve distal motor latencies (DMLs) between the patients with an increased CSA and those with a normal CSA. In most cases, there was no correlation between electrophysiological abnormalities and clinical or sonographic findings. Although multiple nerve enlargements at typical entrapment sites on sonographic evaluation can suggest HNPP, ultrasonography cannot be used as a diagnostic tool for HNPP. Ultrasonography may contribute to the differential diagnosis of HNPP and other demyelinating polyneuropathies or compression neuropathies; however, further studies are required.

Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene.

PubMed

Rudnik-Schöneborn, S; Hehr, U; von Kalle, T; Bornemann, A; Winkler, J; Zerres, K

2009-06-01

Andermann syndrome is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum (ACC), progressive motor-sensory neuropathy, mental retardation and facial features. We report on two siblings with the clinical picture of a demyelinating hereditary motor and sensory neuropathy (HMSN), where only the presence of ACC in the younger brother pointed to the diagnosis of Andermann syndrome. Mutation analysis of the KCC3 (SLC12A6) gene showed a compound heterozygous mutation; a maternal missense mutation c.1616G>A (p.G539D) and a paternal splice mutation c.1118+1G>A in both siblings. We hypothesize that mutations of the KCC3 gene may result in non-syndromic childhood onset HMSN.

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

PubMed

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

2018-02-19

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

Complete neurologic and cognitive recovery after plasmapheresis in a patient with chronic inflammatory demyelinating polyneuropathy after allogeneic hematopoietic stem cell transplantation.

PubMed

Vogl, Ursula; Leitner, Gerda; Dal-Bianco, Assunta; Bojic, Marija; Mitterbauer, Margit; Rabitsch, Werner; Kalhs, Peter; Schulenburg, Axel

2016-05-01

Neurologic complications after allogeneic hematopoietic stem cell transplantation (HSCT) are rare but poorly understood. We present a case report of a 57-year-old-male patient who was diagnosed in 2009 with acute myeloid leukemia (AML). He received two standard induction chemotherapies, as well as a following consolidation. Six months later, an allogeneic HSCT was performed. Shortly after HSCT the patient developed progressive polyneuropathy of the lower legs and hypoesthesia. Five months later a severe dementia followed. All images of the brain and spine showed no specific pathologies. High dose corticosteroids and immunoglobulins did not improve the neurologic symptoms. Due to severe worsening of the neuropsychiatric status and the clinical presentation, chronic inflammatory demyelinating polyneuropathy (CIDP) was suspected. Therefore, the patient received ten cycles of plasmapheresis. The patient showed a significant improvement of the neuropsychiatric symptoms and cognitive status. Immune mediated neuropathies after allogeneic HSCT, such as CIDP, have great variability in symptoms and presentation and are challenging to diagnose and treat. Plasmapheresis is a safe and efficient treatment for patients with unclear persisting autoimmune neuropathy after HSCT.

Different nerve ultrasound patterns in charcot-marie-tooth types and hereditary neuropathy with liability to pressure palsies.

PubMed

Padua, Luca; Coraci, Daniele; Lucchetta, Marta; Paolasso, Ilaria; Pazzaglia, Costanza; Granata, Giuseppe; Cacciavillani, Mario; Luigetti, Marco; Manganelli, Fiore; Pisciotta, Chiara; Piscosquito, Giuseppe; Pareyson, Davide; Briani, Chiara

2018-01-01

Nerve ultrasound in Charcot-Marie-Tooth (CMT) disease has focused mostly on the upper limbs. We performed an evaluation of a large cohort of CMT patients in which we sonographically characterized nerve abnormalities in different disease types, ages, and nerves. Seventy patients affected by different CMT types and hereditary neuropathy with liability to pressure palsies (HNPP) were evaluated, assessing median, ulnar, fibular, tibial, and sural nerves bilaterally. Data were correlated with age. Nerve dimensions were correlated with CMT type, age, and nerve site. Nerves were larger in demyelinating than in axonal neuropathies. Nerve involvement was symmetric. CMT1 patients had larger nerves than did patients with other CMT types. Patients with HNPP showed enlargement at entrapment sites. Our study confirms the general symmetry of ultrasound nerve patterns in CMT. When compared with ultrasound studies of nerves of the upper limbs, evaluation of the lower limbs did not provide additional information. Muscle Nerve 57: E18-E23, 2018. © 2017 Wiley Periodicals, Inc.

Mitochondrial DNA Mutation Associated with Leber's Hereditary Optic Neuropathy

NASA Astrophysics Data System (ADS)

Wallace, Douglas C.; Singh, Gurparkash; Lott, Marie T.; Hodge, Judy A.; Schurr, Theodore G.; Lezza, Angela M. S.; Elsas, Louis J.; Nikoskelainen, Eeva K.

1988-12-01

Leber's hereditary optic neuropathy is a maternally inherited disease resulting in optic nerve degeneration and cardiac dysrhythmia. A mitochondrial DNA replacement mutation was identified that correlated with this disease in multiple families. This mutation converted a highly conserved arginine to a histidine at codon 340 in the NADH dehydrogenase subunit 4 gene and eliminated an Sfa NI site, thus providing a simple diagnostic test. This finding demonstrated that a nucleotide change in a mitochondrial DNA energy production gene can result in a neurological disease.

Monophasic demyelination reduces brain growth in children

PubMed Central

Weier, Katrin; Longoni, Giulia; Fonov, Vladimir S.; Bar-Or, Amit; Marrie, Ruth Ann; Yeh, E. Ann; Narayanan, Sridar; Arnold, Douglas L.; Verhey, Leonard H.; Banwell, Brenda; Collins, D. Louis

2017-01-01

Objective: To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. Methods: We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. Results: Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. Conclusions: Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process. PMID:28381515

Monophasic demyelination reduces brain growth in children.

PubMed

Aubert-Broche, Bérengère; Weier, Katrin; Longoni, Giulia; Fonov, Vladimir S; Bar-Or, Amit; Marrie, Ruth Ann; Yeh, E Ann; Narayanan, Sridar; Arnold, Douglas L; Verhey, Leonard H; Banwell, Brenda; Collins, D Louis

2017-05-02

To investigate how monophasic acquired demyelinating syndromes (ADS) affect age-expected brain growth over time. We analyzed 83 pediatric patients imaged serially from initial demyelinating attack: 18 with acute disseminated encephalomyelitis (ADEM) and 65 with other monophasic ADS presentations (monoADS). We further subdivided the monoADS group by the presence (n = 33; monoADSlesion) or absence (n = 32; monoADSnolesion) of T2 lesions involving the brain at onset. We used normative data to compare brain volumes and calculate age- and sex-specific z scores, and used mixed-effect models to investigate their relationship with time from demyelinating illness. Children with monophasic demyelination (ADEM, non-ADEM with brain lesions, and those without brain involvement) demonstrated reduced age-expected brain growth on serial images, driven by reduced age-expected white matter growth. Cortical gray matter volumes were not reduced at onset but demonstrated reduced age-expected growth afterwards in all groups. Brain volumes differed from age- and sex-expected values to the greatest extent in children with ADEM. All patient groups failed to recover age-expected brain growth trajectories. Brain volume, and more importantly age-expected brain growth, is negatively affected by acquired demyelination, even in the absence of chronicity, implicating factors other than active inflammation as operative in this process. © 2017 American Academy of Neurology.

Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy: Diagnostic Accuracy and Correlation With Electrophysiology.

PubMed

Kronlage, Moritz; Pitarokoili, Kalliopi; Schwarz, Daniel; Godel, Tim; Heiland, Sabine; Yoon, Min-Suk; Bendszus, Martin; Bäumer, Philipp

2017-11-01

The aims of this study were to assess diagnostic accuracy of diffusion tensor imaging (DTI) in chronic inflammatory demyelinating polyneuropathy (CIDP), to correlate DTI with electrophysiological parameters, and to evaluate whether radial diffusivity (RD) and axial diffusivity (AD) might serve as specific biomarkers of demyelinating and axonal pathology. This prospective study was approved by the institutional ethics committee, and written informed consent was obtained from all participants. Magnetic resonance neurography of upper and lower extremity nerves (median, ulnar, radial, sciatic, tibial) was performed by single-shot DTI sequences at 3.0 T in 18 patients with a diagnosis of CIDP and 18 healthy controls, matched to age and sex. The scalar readout parameters nerve fractional anisotropy (FA), mean diffusivity (MD), RD, and AD were obtained after manual segmentation and postprocessing and compared between patients and controls. Diagnostic accuracy was assessed by receiver operating characteristic analysis, and cutoff values were calculated by maximizing the Youden index. All patients underwent a complementary electroneurography and correlation of electrophysiological markers and DTI parameters was analyzed and described by Pearson and Spearman coefficients. Nerve FA was decreased to a mean of 0.42 ± 0.08 in patients compared with 0.52 ± 0.04 in healthy controls (P < 0.001). This decrease in FA was a result of an increase of RD (P = 0.02), whereas AD did not differ between the two groups. Of all DTI parameters, FA showed best diagnostic accuracy with a receiver operating characteristic area under the curve of 0.90. Optimal cutoff for an average FA of all analyzed nerves was 0.47, yielding a sensitivity of 0.83 and a specificity of 0.94. Fractional anisotropy and RD correlated strongly with electrophysiological markers of demyelination, whereas AD did not correlate with markers of axonal neuropathy. Diffusion tensor imaging yields valid quantitative biomarkers

Beneficial effects of minocycline on cuprizone induced cortical demyelination.

PubMed

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

2010-09-01

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

Leber's Hereditary Optic Neuropathy: The Mitochondrial Connection Revisited.

PubMed

Abu-Amero, Khaled K

2011-01-01

Our current understanding of Leber's hereditary optic neuropathy (LHON)-mitochondrial connection falls short of comprehensive. Twenty years of intensive investigation have yielded a wealth of information about mitochondria, the mitochondrial genome, the metabolism of the optic nerve and other structures, and the phenotypic variability of classic LHON. However, we still cannot completely explain how primary LHON mutations injure the optic nerve or why the optic nerve is particularly at risk. We cannot explain the incomplete penetrance or the male predominance of LHON, the typical onset in young adult life without warning, or the synchronicity of visual loss. Moreover, primary LHON mutations clearly are not present in every family with the LHON phenotype (including multigenerational maternal inheritance), and they are present in only a minority of individuals who have the LHON optic neuropathy phenotype without a family history. All lines of evidence point to abnormalities of the mitochondria as the direct or indirect cause of LHON. Therefore, the mitochondria-LHON connection needs to be revisited and examined closely. This review will attempt to do that and provide an update on various aspects of LHON.

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

PubMed

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

2017-10-01

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

Asymmetric type F botulism with cranial nerve demyelination.

PubMed

Filozov, Alina; Kattan, Jessica A; Jitendranath, Lavanya; Smith, C Gregory; Lúquez, Carolina; Phan, Quyen N; Fagan, Ryan P

2012-01-01

We report a case of type F botulism in a patient with bilateral but asymmetric neurologic deficits. Cranial nerve demyelination was found during autopsy. Bilateral, asymmetric clinical signs, although rare, do not rule out botulism. Demyelination of cranial nerves might be underrecognized during autopsy of botulism patients.

Platelet-Derived Growth Factor Promotes Repair of Chronically Demyelinated White Matter

PubMed Central

Vana, Adam C.; Flint, Nicole C.; Harwood, Norah E.; Le, Tuan Q.; Fruttiger, Marcus; Armstrong, Regina C.

2009-01-01

In multiple sclerosis, remyelination becomes limited after repeated or prolonged episodes of demyelination. To test the effect of platelet-derived growth factor-A (PDGF-A) in recovery from chronic demyelination we induced corpus callosum demyelination using cuprizone treatment in hPDGF-A transgenic (tg) mice with the human PDGF-A gene under control of an astrocyte-specific promoter. After chronic demyelination and removal of cuprizone from the diet, remyelination and oligodendrocyte density improved significantly in hPDGF-A tg mice compared with wild-type mice. In hPDGF-A tg mice, oligodendrocyte progenitor density and proliferation values were increased in the corpus callosum during acute demyelination but not during chronic demyelination or the subsequent recovery period, compared with hPDGF-A tg mice without cuprizone or to treatment-matched wild-type mice. Proliferation within the subventricular zone and subcallosal zone was elevated throughout cuprizone treatment but was not different between hPDGF-A tg and wild-type mice. Importantly, hPDGF-A tg mice had reduced apoptosis in the corpus callosum during the recovery period after chronic demyelination. Therefore, PDGF-A may support oligodendrocyte generation and survival to promote remyelination of chronic lesions. Furthermore, preventing oligodendrocyte apoptosis may be important not only during active demyelination but also for supporting the generation of new oligodendrocytes to remyelinate chronic lesions. PMID:17984680

Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury

PubMed Central

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

2018-01-01

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-LE397K, 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-LE397K mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gaitusing the Catwalk system. hNF-LE397K mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-LE397K 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-LE397K. Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-LE397K mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-LE397K mice provide a model for determining the efficacy of novel therapies. PMID:26423936

Asymmetric Type F Botulism with Cranial Nerve Demyelination

PubMed Central

Kattan, Jessica A.; Jitendranath, Lavanya; Smith, C. Gregory; Lúquez, Carolina; Phan, Quyen N.; Fagan, Ryan P.

2012-01-01

We report a case of type F botulism in a patient with bilateral but asymmetric neurologic deficits. Cranial nerve demyelination was found during autopsy. Bilateral, asymmetric clinical signs, although rare, do not rule out botulism. Demyelination of cranial nerves might be underrecognized during autopsy of botulism patients. PMID:22257488

Phosphorylation of αB-crystallin supports reactive astrogliosis in demyelination

PubMed Central

Yoon, Jane; van Horssen, Jack; Han, May H.; Bollyky, Paul L.; Palmer, Theo D.; Steinman, Lawrence

2017-01-01

The small heat shock protein αB-crystallin (CRYAB) has been implicated in multiple sclerosis (MS) pathogenesis. Earlier studies have indicated that CRYAB inhibits inflammation and attenuates clinical disease when administered in the experimental autoimmune encephalomyelitis model of MS. In this study, we evaluated the role of CRYAB in primary demyelinating events. Using the cuprizone model of demyelination, a noninflammatory model that allows the analysis of glial responses in MS, we show that endogenous CRYAB expression is associated with increased severity of demyelination. Moreover, we demonstrate a strong correlation between the expression of CRYAB and the extent of reactive astrogliosis in demyelinating areas and in in vitro assays. In addition, we reveal that CRYAB is differentially phosphorylated in astrocytes in active demyelinating MS lesions, as well as in cuprizone-induced lesions, and that this phosphorylation is required for the reactive astrocyte response associated with demyelination. Furthermore, taking a proteomics approach to identify proteins that are bound by the phosphorylated forms of CRYAB in primary cultured astrocytes, we show that there is clear differential binding of protein targets due to the specific phosphorylation of CRYAB. Subsequent Ingenuity Pathway Analysis of these targets reveals implications for intracellular pathways and biological processes that could be affected by these modifications. Together, these findings demonstrate that astrocytes play a pivotal role in demyelination, making them a potential target for therapeutic intervention, and that phosphorylation of CRYAB is a key factor supporting the pathogenic response of astrocytes to oligodendrocyte injury. PMID:28196893

Vasculitic Neuropathies.

PubMed

Naddaf, Elie; Dyck, P James Bonham

2015-10-01

From pathological standpoint, we divide vasculitic neuropathies in two categories: nerve large arteriole vasculitides and nerve microvasculitis. It is also important to determine whether a large arteriole vasculitis has an infectious etiology as it entails different treatment approach. Treatment of non-infectious large arteriole vasculitides consists initially of induction therapy with corticosteroids. Adding an immunosuppressant, mainly cyclophosphamide, is often needed. Treatment of infectious large arteriole vasculitides needs a multidisciplinary approach to target both the underlying infection and the vasculitis. Corticosteroids are the first-line therapy for classic non-systemic vasculitic neuropathy. Stable or improving patients without biopsy evidence of active vasculitis can be either observed or treated. Currently, adding an immunosuppressant is only indicated for patients who continue to progress on corticosteroids alone or patients with a rapidly progressive course. The treatment of the radiculoplexus neuropathies such as diabetic lumbosacral radiculoplexus neuropathy, lumbosacral radiculoplexus neuropathy (in non-diabetic patients), and diabetic cervical radiculoplexus neuropathy, as well as painless diabetic motor neuropathy, is not well established yet. We treat patients, if they present early on in the disease course or if they have severe disabling symptoms, with IV methylprednisolone 1 g once a week for 12 weeks.

Disease activity in chronic inflammatory demyelinating polyneuropathy.

PubMed

Albulaihe, Hana; Alabdali, Majed; Alsulaiman, Abdulla; Abraham, Alon; Breiner, Ari; Barnett, Carolina; Katzberg, Hans D; Lovblom, Leif E; Perkins, Bruce A; Bril, Vera

2016-10-15

Evaluation of disease status in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is often done by a combination of clinical evaluation and electrodiagnostic studies. A CIDP disease activity status (CDAS) was developed to standardize outcomes in CIDP patients. We aimed to determine if the CDAS was concordant with classical evaluation and whether CDAS enables benchmarking of CIDP. We performed a retrospective chart review of 305 CIDP patients and identified 206 patients with >1 visit and applied the CDAS to this cohort. We examined relationships between the CDAS and classical evaluation as to outcomes and compared our cohort to other CIDP cohorts who had CDAS. We found that the CDAS mirrored disease severity as measured by electrophysiology and vibration perception thresholds in that CDAS class 5 had more severe neuropathy. Our results are similar to other cohorts in the middle CDAS strata with the exception of fewer subjects in CDAS 1 and more in CDAS 5. The only demographic factor predicting CDAS 5 in our cohort was age, and the overall treatment response rate using the CDAS classification was 79.3%. CDAS appears to have sufficient face-validity as a grading system to assess disease activity in relation to treatment status. The use of CDAS appears to allow benchmarking of patients with CIDP that may be useful in subject selection for clinical trials and also to highlight differences in practice. Copyright © 2016 Elsevier B.V. All rights reserved.

Aggregation of MBP in chronic demyelination

PubMed Central

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

2015-01-01

Objectives Misfolding of key disease proteins to an insoluble state is associated with most neurodegenerative conditions, such as prion, Parkinson, and Alzheimer’s diseases. In this work, and by studying animal models of multiple sclerosis, we asked whether this is also the case for myelin basic protein (MBP) in the late and neurodegenerative phases of demyelinating diseases. Methods To this effect, we tested whether MBP, an essential myelin component, present prion-like properties in animal models of MS, as is the case for Cuprizone-induced chronic demyelination or chronic phases of Experimental Autoimmune Encephalomyelitis (EAE). Results We show here that while total levels of MBP were not reduced following extensive demyelination, part of these molecules accumulated thereafter as aggregates inside oligodendrocytes or around neuronal cells. In chronic EAE, MBP precipitated concomitantly with Tau, a marker of diverse neurodegenerative conditions, including MS. Most important, analysis of fractions from Triton X-100 floatation gradients suggest that the lipid composition of brain membranes in chronic EAE differs significantly from that of naïve mice, an effect which may relate to oxidative insults and subsequently prevent the appropriate insertion and compaction of new MBP in the myelin sheath, thereby causing its misfolding and aggregation. Interpretation Prion-like aggregation of MBP following chronic demyelination may result from an aberrant lipid composition accompanying this pathological status. Such aggregation of MBP may contribute to neuronal damage that occurs in the progressive phase of MS. PMID:26273684

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

PubMed

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

2017-12-01

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

Contrast Sensitivity, First-Order Motion and Initial Ocular Following in Demyelinating Optic Neuropathy

PubMed Central

Rucker, Janet C.; Sheliga, Boris M.; FitzGibbon, Edmond J.; Miles, Frederick A.; Leigh, R. John

2008-01-01

The ocular following response (OFR) is a measure of motion vision elicited at ultra-short latencies by sudden movement of a large visual stimulus. We compared the OFR to vertical sinusoidal gratings (spatial frequency 0.153 cycles/° or 0.458 cycles/°) of each eye in a subject with evidence of left optic nerve demyelination due to multiple sclerosis (MS). The subject showed substantial differences in vision measured with stationary low-contrast Sloan letters (20/63 OD and 20/200 OS at 2.5% contrast) and the Lanthony Desaturated 15-hue color test (Color Confusion Index 1.11 OD and 2.14 OS). Compared with controls, all of the subject's OFR to increasing contrast showed a higher threshold. The OFR of each of the subject's eyes were similar for the 0.153 cycles/° stimulus, and psychophysical measurements of his ability to detect these moving gratings were also similar for each eye. However, with the 0.458 cycles/° stimulus, the subject's OFR was asymmetric and the affected eye showed decreased responses (smaller slope constant as estimated by the Naka-Rushton equation). These results suggest that, in this case, optic neuritis caused a selective deficit that affected parvocellular pathways mediating higher spatial frequencies, lower-contrast, and color vision, but spared the field-holding mechanism underlying the OFR to lower spatial frequencies. The OFR may provide a useful method to study motion vision in individuals with disorders affecting anterior visual pathways. PMID:16649097

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

NASA Astrophysics Data System (ADS)

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

2016-03-01

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

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

PubMed Central

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

2016-01-01

Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination. PMID:26932543

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

PubMed

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

2016-03-02

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

Examination of a demyelinated fiber by action-potential-encoded second harmonic generation

NASA Astrophysics Data System (ADS)

Chen, Xin-guang; Luo, Zhi-hui; Yang, Hong-qin; Huang, Yi-mei; Xie, Shu-sen

2012-03-01

Axonal demyelination is a common phenomenon in the nervous system in human. Conventional measured approaches such as surface recording electrode and diffusion tensor imaging, are hard to fast and accurately determine the demyelinated status of a fiber. In this study, we first presented a mathematical model of nerve fiber demyelination, and it was combined with second harmonic generation(SHG) technique to study the characteristics of action-potential-encoded SHG and analyze the sensitivity of SHG signals responded to membrane potential. And then, we used this approach to fast examine the injured myelin sheaths resulted from demyelination. Each myelin sheath of a fiber was examined simultaneously by this approach. The results showed that fiber demyelination led to observable attenuation of action potential amplitude. The delay of action potential conduction would be markedly observed when the fiber demyelination was more than 80%. Furthermore, the normal and injured myelin sheaths of a myelinated fiber could be distinguished via the changes of SHG signals, which revealed the possibility of SHG technique in the examination of a demyelinated fiber. Our study shows that this approach may have potential application values in clinic.

Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

PubMed

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

2015-11-19

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. Copyright © 2015 Elsevier B.V. All rights reserved.

Hereditary sensory ataxic neuropathy associated with proximal muscle weakness in the lower extremities.

PubMed

Murakami, Tatsufumi; Fukai, Yuta; Rikimaru, Mitsue; Henmi, Shoji; Ohsawa, Yutaka; Sunada, Yoshihide

2010-04-15

We describe three patients from the same family with hereditary sensory ataxic neuropathy followed by proximal muscle weakness in the lower extremities. Sensory ataxic gait began as an initial symptom when patients were in their 50s. Mild proximal weakness in the lower extremities appeared several years later. Serum creatine kinase was mildly elevated. Nerve conduction studies revealed sensory dominant axonal neuropathy, and short sensory evoked potentials showed involvement of the sensory nerve axon, dorsal root ganglia and posterior funiculus of the spinal cord. Needle electromyography showed fibrillation, positive sharp waves, and multiple giant motor unit potentials, suggesting the involvement of anterior horn motor neurons or the anterior root. Autosomal recessive inheritance was considered, because of consanguinity. The disorder described here may be a new clinical entity with unique clinical manifestations. Copyright 2009 Elsevier B.V. All rights reserved.

A case of chronic inflammatory demyelinating polyneuropathy presented with unilateral ptosis.

PubMed

Izadi, Sadegh; Karamimagham, Sina; Poursadeghfard, Maryam

2014-01-01

Chronic Inflammatory Demyelinating Polyneuropathy is an autoimmune disease with progressive and relapsing courses. The main clinical presentations are diffuse deep tendon hyporeflexia or areflexia and symmetric proximal-distal muscles weakness. Myasthenia gravis is also an immune mediated disease with fluctuating ocular and bulbar symptoms and sometimes weakness. Although both myasthenia gravis and chronic inflammatory demyelinating polyneuropathy are immune mediated disorders, clinical presentations are obviously different in the two diseases. Herein, we will report a case of chronic inflammatory demyelinating polyneuropathy who presented with isolated unilateral ptosis. Initially, the patient was managed as ocular type of myasthenia gravis, but after progression to general limb weakness and areflexia, the diagnosis of chronic inflammatory demyelinating polyneuropathy was made. Although unilateral ptosis is a typical feature of myasthenia gravis, it may be seen as the first presentation of chronic inflammatory demyelinating polyneuropathy as well which mimics myasthenia gravis disease.

Genetics of the Charcot-Marie-Tooth disease in the Spanish Gypsy population: the hereditary motor and sensory neuropathy-Russe in depth.

PubMed

Sevilla, T; Martínez-Rubio, D; Márquez, C; Paradas, C; Colomer, J; Jaijo, T; Millán, J M; Palau, F; Espinós, C

2013-06-01

Four private mutations responsible for three forms demyelinating of Charcot-Marie-Tooth (CMT) or hereditary motor and sensory neuropathy (HMSN) have been associated with the Gypsy population: the NDRG1 p.R148X in CMT type 4D (CMT4D/HMSN-Lom); p.C737_P738delinsX and p.R1109X mutations in the SH3TC2 gene (CMT4C); and a G>C change in a novel alternative untranslated exon in the HK1 gene causative of CMT4G (CMT4G/HMSN-Russe). Here we address the findings of a genetic study of 29 Gypsy Spanish families with autosomal recessive demyelinating CMT. The most frequent form is CMT4C (57.14%), followed by HMSN-Russe (25%) and HMSN-Lom (17.86%). The relevant frequency of HMSN-Russe has allowed us to investigate in depth the genetics and the associated clinical symptoms of this CMT form. HMSN-Russe probands share the same haplotype confirming that the HK1 g.9712G>C is a founder mutation, which arrived in Spain around the end of the 18th century. The clinical picture of HMSN-Russe is a progressive CMT disorder leading to severe weakness of the lower limbs and prominent distal sensory loss. Motor nerve conduction velocity was in the demyelinating or intermediate range. © 2012 John Wiley & Sons A/S.

Role of "Sural Sparing" Pattern (Absent/Abnormal Median and Ulnar with Present Sural SNAP) Compared to Absent/Abnormal Median or Ulnar with Normal Sural SNAP in Acute Inflammatory Demyelinating Polyneuropathy.

PubMed

Surpur, Spurthi Sunil; Govindarajan, Raghav

2017-01-01

Sural sparing defined as absent/abnormal median sensory nerve action potential (SNAP) amplitude or absent/abnormal ulnar SNAP amplitude with a normal sural SNAP amplitude is thought to be a marker for inflammatory demyelinating polyneuropathies. If sural sparing pattern specifically defined as absent/abnormal median and ulnar SNAP amplitude with normal sural SNAP amplitude (AMUNS) is sensitive and specific when compared with either absent/abnormal median and normal sural (AMNS) or absent/abnormal ulnar and normal sural (AUNS) for acute inflammatory demyelinating polyneuropathy (AIDP), chronic inflammatory demyelinating polyneuropathy (CIDP), select non-diabetic axonopathies (AXPs), and diabetic neuropathies (DNs). Retrospective analysis from 2001 to 2010 on all newly diagnosed AIDP, CIDP, select non-diabetic AXP, and DN. There were 20 AIDP and 23 CIDP. Twenty AXP and 50 DN patients between 2009 and 2010 were included as controls. AMUNS was seen in 65% of AIDP, 39% CIDP compared with 10% of AXP and 6% for DN with sensitivity of 51%, specificity of 92%, whereas the specificity of AMNS/AUNS was 73% and its sensitivity was 58%. If a patient has AMUNS they are >12 times more likely to have AIDP ( p  < 0.001). Sural sparing is highly specific but not sensitive when compared with either AMNS or AUNS in AIDP but does not add to sensitivity or specificity in CIDP.

Peripheral neuropathy

MedlinePlus

... peripheral; Neuritis - peripheral; Nerve disease; Polyneuropathy; Chronic pain - peripheral neuropathy ... Philadelphia, PA: Elsevier; 2016:chap 107. Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

Amplitudes of Pain-Related Evoked Potentials Are Useful to Detect Small Fiber Involvement in Painful Mixed Fiber Neuropathies in Addition to Quantitative Sensory Testing – An Electrophysiological Study

PubMed Central

Hansen, Niels; Kahn, Ann-Kathrin; Zeller, Daniel; Katsarava, Zaza; Sommer, Claudia; Üçeyler, Nurcan

2015-01-01

To investigate the usefulness of pain-related evoked potentials (PREP) elicited by electrical stimulation for the identification of small fiber involvement in patients with mixed fiber neuropathy (MFN). Eleven MFN patients with clinical signs of large fiber impairment and neuropathic pain and ten healthy controls underwent clinical and electrophysiological evaluation. Small fiber function, electrical conductivity and morphology were examined by quantitative sensory testing (QST), PREP, and skin punch biopsy. MFN was diagnosed following clinical and electrophysiological examination (chronic inflammatory demyelinating neuropathy: n = 6; vasculitic neuropathy: n = 3; chronic axonal ­neuropathy: n = 2). The majority of patients with MFN characterized their pain by descriptors that mainly represent C-fiber-mediated pain. In QST, patients displayed elevated cold, warm, mechanical, and vibration detection thresholds and cold pain thresholds indicative of MFN. PREP amplitudes in patients correlated with cold (p < 0.05) and warm detection thresholds (p < 0.05). Burning pain and the presence of par-/dysesthesias correlated negatively with PREP amplitudes (p < 0.05). PREP amplitudes correlating with cold and warm detection thresholds, burning pain, and par-/dysesthesias support employing PREP amplitudes as an additional tool in conjunction with QST for detecting small fiber impairment in patients with MFN. PMID:26696950

Alcoholic neuropathy

MedlinePlus

Neuropathy - alcoholic; Alcoholic polyneuropathy ... The exact cause of alcoholic neuropathy is unknown. It likely includes both a direct poisoning of the nerve by the alcohol and the effect of poor nutrition ...

Inherited tertiary hypothyroidism in Sprague-Dawley rats.

PubMed

Stoica, George; Lungu, Gina; Xie, Xueyi; Abbott, Louise C; Stoica, Heidi M; Jaques, John T

2007-05-07

Thyroid hormones (THs) are important in the development and maturation of the central nervous system (CNS). The significant actions of THs during CNS development occur at the time when TH levels are lower than those in the mother and the hypothalamic-thyroid (HPT) axis is not fully functional. In the developing rat nervous system, primarily the cerebellum, the first three postnatal weeks represent a period of significant sensitivity to thyroid hormones. This study presents a spontaneous, inherited recessive hypothyroidism in Sprague-Dawley rats with devastating functional consequences to the development of the CNS. The clinical signs develop around 14 day's postnatal (dpn) and are characterized by ataxia, spasticity, weight loss and hypercholesterolemia. The afflicted rats died at 30 days due to severe neurological deficits. The deterioration affects the entire CNS and is characterized by progressive neuronal morphological and biochemical changes, demyelination and astrogliosis. The cerebellum, brain stem, neocortex, hippocampus and adrenal gland medulla appear to be most affected. Thyroid Stimulating Hormone (TSH), T3 and T4 levels were significantly lower in hypothyroid rats than control. Immunohistochemistry and RT-PCR demonstrated a reduction of Thyrotropin Releasing Hormone (TRH) in the hypothalamus of hypothyroid rats. The weight of both thyroid and pituitary glands were significantly less in hypothyroid rats than the corresponding normal littermate controls. Transmission electron microscopy demonstrates consistent postsynaptic dendritic, synaptic and spine alterative changes in the brain of hypothyroid rats. These data suggest that we discovered a tertiary form of inherited hypothyroidism involving the hypothalamus.

The Characteristics of Chronic Inflammatory Demyelinating Polyneuropathy in Patients with and without Diabetes – An Observational Study

PubMed Central

Dunnigan, Samantha K.; Ebadi, Hamid; Breiner, Ari; Katzberg, Hans D.; Barnett, Carolina; Perkins, Bruce A.; Bril, Vera

2014-01-01

Introduction We aimed to determine whether the clinical characteristics and electrodiagnostic classification of nerve injury, and response to treatment differed in patients diagnosed with chronic inflammatory demyelinating polyneuropathy (CIDP) with and without diabetes. Methods CIDP patients with diabetes (CIDP+DM) (n = 67) and without diabetes (CIDP-DM) (n = 67) underwent clinical examination and nerve conduction studies (NCS). CIDP-DM patients were selected using age and gender matching with the existing CIDP+DM cohort. Patients treated with immunotherapies were classified as responders (R) (n = 46) or non-responders (NR) (n = 54) based on clinical response to treatment. The groups were compared using analysis of variance, contingency tables and Kruskal-Wallis analyses. Results CIDP+DM subjects had more severe neuropathy based on higher lower limb vibration potential thresholds (VPT)(p = 0.004), higher Toronto Clinical Neuropathy Score (TCNS) (p = 0.0009), more proximal weakness (p = 0.03), more gait abnormality (p = 0.03) and more abnormal NCS. CIDP+DM subjects had more abnormal sural NCS with lower sural sensory nerve action potential amplitudes (2.4±3.0 µV, 6.6±6.0 µV, p<0.0001) and slower sural nerve conduction velocities (38.6±5.4 m/s, 41.0±5.3 m/s, p = 0.04). CIDP-DM subjects were more likely to receive immune therapies (93% vs 57%, p = <0.0001), despite no significant differences in treatment responder rates (p = 0.71). Patients who responded to therapy had shorter duration of CIDP than non-responders (8.0±6.0 y vs 11.9±7.6 y, p = 0.004). Discussion The clinical phenotype and electrophysiological profile of CIDP patients differs according to the presence or absence of diabetes. Despite CIDP+DM patients having more severe clinical and electrophysiological neuropathy, they are less likely to receive disease-modifying/specific therapy, yet have similar response rates to treatment as those without

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain

PubMed Central

Haider, Lukas; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang

2016-01-01

Abstract Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645

The protective role of nitric oxide in a neurotoxicant-induced demyelinating model.

PubMed

Arnett, Heather A; Hellendall, Ron P; Matsushima, Glenn K; Suzuki, Kinuko; Laubach, Victor E; Sherman, Paula; Ting, Jenny P-Y

2002-01-01

Demyelination is often associated with acute inflammatory events involving the recruitment-activation of microglia/macrophage, astrocytes, and leukocytes. The ultimate role of inflammatory products in demyelinating disease and in the survival of oligodendrocytes, the myelin forming cells, is unresolved. The current study examines the role of inducible NO synthase (iNOS)-derived NO in a neurotoxicant-induced model of demyelination. NO levels were greatly elevated in the midline corpus callosum during demyelination in genetically intact C57BL/6 mice, and this NO was due solely to the induction of iNOS, as the correlates of NO were not found in mice lacking iNOS. C57BL/6 mice lacking iNOS exhibited more demyelination, but did not display an increased overall cellularity in the corpus callosum, attributable to an unimpeded microglia/macrophage presence. An enhanced course of pathology was noted in mice lacking iNOS. This was associated with a greater depletion of mature oligodendrocytes, most likely due to apoptosis of oligodendrocytes. Microglia and astrocytes did not undergo apoptosis during treatment. Our results suggest a moderately protective role for NO during acute inflammation-association demyelination.

Acquired neuropathies.

PubMed

Lozeron, Pierre; Trocello, Jean-Marc; Kubis, Nathalie

2013-09-01

Acquired neuropathies represent most of the neuropathies encountered in clinical practice. Hundreds of causes have been identified even though up to 41% of patients are still classified as idiopathic (Rajabally and Shah in J Neurol 258:1431-1436, 1). Routine evaluation relies on comprehensive medical history taking, clinical examination, nerve conduction studies and laboratory tests. Other investigations such as nerve biopsy or nerve or muscle imaging are performed in specific settings. This review focuses on recent advances in acquired neuropathies.

Autonomic neuropathies

NASA Technical Reports Server (NTRS)

Low, P. A.

1998-01-01

A limited autonomic neuropathy may underlie some unusual clinical syndromes, including the postural tachycardia syndrome, pseudo-obstruction syndrome, heat intolerance, and perhaps chronic fatigue syndrome. Antibodies to autonomic structures are common in diabetes, but their specificity is unknown. The presence of autonomic failure worsens prognosis in the diabetic state. Some autonomic neuropathies are treatable. Familial amyloid polyneuropathy may respond to liver transplantation. There are anecdotal reports of acute panautonomic neuropathy responding to intravenous gamma globulin. Orthostatic hypotension may respond to erythropoietin or midodrine.

Neuropathy Tests

MedlinePlus

... Mutation Mycophenolic Acid Mycoplasma Myoglobin Nicotine and Cotinine Non-High Density Lipoprotein Cholesterol Opioid Testing Osmolality Ova ... that make neuropathy worse Detect and evaluate complications Non-laboratory tests The diagnostic workup for neuropathy begins ...

Tacrolimus Optic Neuropathy.

PubMed

Rasool, Nailyn; Boudreault, Katherine; Lessell, Simmons; Prasad, Sashank; Cestari, Dean M

2018-06-01

Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. Case series and review of the literature. We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit.

PubMed

Wang, Hongkai; Li, Chengren; Wang, Hanzhi; Mei, Feng; Liu, Zhi; Shen, Hai-Ying; Xiao, Lan

2013-04-01

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

PubMed Central

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

2015-01-01

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

Influence of laser irradiation on demyelination of nervous fibers

NASA Astrophysics Data System (ADS)

Melnik, Nataly O.; Plaksij, Yu. S.; Mamilov, Serge A.

2000-11-01

Problem demyelinating diseases from actual in modern of neurology. Main disease of this group - multiple sclerosis, which morphological manifestation is the process demyelineation - disintegration of myelin, which covers axial cylinders of nervous filaments. The outcome of such damage is violation of realization of nervous impulses, dissonance of implement and coordination functions. Most typical the feature of a multiple sclerosis is origin of repeated remissions, which compact with indication remyelination. In development of disease the large role is played by modifications of immunological of a reactivity of an organism. The purpose of the title is development of new methods of treatment of a multiple sclerosis because of lasertherapy. For thsi purpose the influence of a laser exposure on demyelination and remyelination processes will be investigated, is investigated pathological fabrics at microscopic and submicroscopic levels. The study of proceses demyelination and remyelination will be conducted on experimental animals (rats), which are sick experimental allergic encephalomyelitis (EAE), that is the most adequate model of a multiple sclerosis. The patients' EAE animals will be subjected to treatment by a laser exposure. For want of it there will be determinate optimum lengths of waves, dozes and modes of laser radiation.

Structure and stability of internodal myelin in mouse models of hereditary neuropathy.

PubMed

Avila, Robin L; Inouye, Hideyo; Baek, Rena C; Yin, Xinghua; Trapp, Bruce D; Feltri, M Laura; Wrabetz, Lawrence; Kirschner, Daniel A

2005-11-01

showed that the amount of P0 affected myelin's stability against swelling, thus directly supporting the hypothesis that packing defects underlie instability in "live" or intact myelin. Our findings demonstrate that diffraction can provide a quantitative basis for understanding, at a molecular level, the membrane packing defects that occur in internodal myelin in demyelinating peripheral neuropathies.

Peripheral neuropathy in liver cirrhosis.

PubMed

Kharbanda, Parampreet S; Prabhakar, Sudesh; Chawla, Yogesh K; Das, Chandi P; Syal, Puneet

2003-08-01

Neuropathy in association with chronic liver disease, including cirrhosis, is recognized; however, there are differences in the incidence and type of neuropathy reported. The causal relationship of liver disease to neuropathy has been questioned. This study was designed to evaluate the incidence and character of peripheral neuropathy in patients with liver cirrhosis. The effect of alcohol consumption, severity of liver disease and encephalopathy on the incidence and severity of neuropathy were also studied. Patients having an identifiable cause of peripheral neuropathy, except alcohol, were excluded from the study. Patients with evidence of vitamin B12 deficiency or diabetes were also excluded from the study. In this study, 33 patients with liver cirrhosis were evaluated clinically and electrophysiologically to detect any evidence of peripheral neuropathy. Nerve conduction studies were performed in the upper and lower limbs using surface electrodes. These patients also underwent a detailed clinical examination. Clinical signs of peripheral neuropathy were found in seven (21%) patients. Nerve conduction studies were abnormal in 24 (73%) patients. The pattern of involvement was predominantly of an axonal sensory motor polyneuropathy. Neuropathy was found both in patients with alcohol-related and non-alcohol-related cirrhosis. The presence of encephalopathy did not have a significant bearing on the incidence and severity of neuropathy. The neuropathy was also not significantly related to the severity of liver disease. The present study reveals that a significant number of patients with liver cirrhosis show evidence of peripheral neuropathy, which is present regardless of the etiology of cirrhosis, and is subclinical in a majority of these patients. The cause of neuropathy was probably the liver disease itself, as the incidence and severity of neuropathy in the alcohol-related cirrhosis, although higher, was not significantly different from the neuropathy in patients

[Hereditary neuropathy with liability to pressure palsies in childhood: Report of three cases].

PubMed

Bar, C; Villéga, F; Espil, C; Husson, M; Pedespan, J-M; Rouanet, M-F

2017-03-01

Hereditary neuropathy with liability to pressure palsy (HNPP) is an autosomal dominant neuropathy. It is characterized by recurrent sensory and motor nerve palsies, usually precipitated by minor trauma or compression. Even though rare in childhood, this disorder is probably underdiagnosed given its wide spectrum of clinical symptoms. We review three separate cases of HNPP diagnosed in children with various phenotypes: fluctuating and distal paresthesias disrupting learning at school, cramps related to intensive piano practice, and discrete muscle weakness with no functional complaint. Family history should be carefully reviewed to identify potential undiagnosed HNPP cases, as in our three reports. Electrophysiological study is essential for the diagnosis, with a double advantage: to confirm the presence of focal abnormalities in clinically symptomatic areas and to guide molecular biology by revealing an underlying demyelinating polyneuropathy. The diagnosis of HNPP is confirmed by genetic testing, which in 90% of cases shows a 1.5-Mb deletion of chromosome 17p11.2 including the PMP22 gene. Patients are expected to make a full recovery after each relapse. However, it is very important for both the patient and his or her family to establish a diagnosis in order to prevent recurrent palsy brought on by situations involving prolonged immobilizations leading to nerve compression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain.

PubMed

Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang; Lassmann, Hans

2016-03-01

Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Interleukin-10 Overexpression Promotes Fas-Ligand-Dependent Chronic Macrophage-Mediated Demyelinating Polyneuropathy

PubMed Central

Dace, Dru S.; Khan, Aslam A.; Stark, Jennifer L.; Kelly, Jennifer; Cross, Anne H.; Apte, Rajendra S.

2009-01-01

Background Demyelinating polyneuropathy is a debilitating, poorly understood disease that can exist in acute (Guillain-Barré syndrome) or chronic forms. Interleukin-10 (IL-10), although traditionally considered an anti-inflammatory cytokine, has also been implicated in promoting abnormal angiogenesis in the eye and in the pathobiology of autoimmune diseases such as lupus and encephalomyelitis. Principal Findings Overexpression of IL-10 in a transgenic mouse model leads to macrophage-mediated demyelinating polyneuropathy. IL-10 upregulates ICAM-1 within neural tissues, promoting massive macrophage influx, inflammation-induced demyelination, and subsequent loss of neural tissue resulting in muscle weakness and paralysis. The primary insult is to perineural myelin followed by secondary axonal loss. Infiltrating macrophages within the peripheral nerves demonstrate a highly pro-inflammatory signature. Macrophages are central players in the pathophysiology, as in vivo depletion of macrophages using clodronate liposomes reverses the phenotype, including progressive nerve loss and paralysis. Macrophage-mediate demyelination is dependent on Fas-ligand (FasL)-mediated Schwann cell death. Significance These findings mimic the human disease chronic idiopathic demyelinating polyneuropathy (CIDP) and may also promote further understanding of the pathobiology of related conditions such as acute idiopathic demyelinating polyneuropathy (AIDP) or Guillain-Barré syndrome. PMID:19771172

Ultrasonographic nerve enlargement of the median and ulnar nerves and the cervical nerve roots in patients with demyelinating Charcot-Marie-Tooth disease: distinction from patients with chronic inflammatory demyelinating polyneuropathy.

PubMed

Sugimoto, Takamichi; Ochi, Kazuhide; Hosomi, Naohisa; Takahashi, Tetsuya; Ueno, Hiroki; Nakamura, Takeshi; Nagano, Yoshito; Maruyama, Hirofumi; Kohriyama, Tatsuo; Matsumoto, Masayasu

2013-10-01

Demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyneuropathy (CIDP) are both demyelinating polyneuropathies. The differences in nerve enlargement degree and pattern at multiple evaluation sites/levels are not well known. We investigated the differences in nerve enlargement degree and the distribution pattern of nerve enlargement in patients with demyelinating CMT and CIDP, and verified the appropriate combination of sites/levels to differentiate between these diseases. Ten patients (aged 23-84 years, three females) with demyelinating CMT and 16 patients (aged 30-85 years, five females) with CIDP were evaluated in this study. The nerve sizes were measured at 24 predetermined sites/levels from the median and ulnar nerves and the cervical nerve roots (CNR) using ultrasonography. The evaluation sites/levels were classified into three regions: distal, intermediate and cervical. The number of sites/levels that exhibited nerve enlargement (enlargement site number, ESN) in each region was determined from the 24 sites/levels and from the selected eight screening sites/levels, respectively. The cross-sectional areas of the peripheral nerves were markedly larger at all evaluation sites in patients with demyelinating CMT than in patients with CIDP (p < 0.01). However, the nerve sizes of CNR were not significantly different between patients with either disease. When we evaluated ESN of four selected sites for screening from the intermediate region, the sensitivity and specificity to distinguish between demyelinating CMT and CIDP were 0.90 and 0.94, respectively, with the cut-off value set at four. Nerve ultrasonography is useful to detect nerve enlargement and can clarify morphological differences in nerves between patients with demyelinating CMT and CIDP.

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort

PubMed Central

Davidson, G. L.; Murphy, S. M.; Polke, J. M.; Laura, M.; Salih, M. A. M.; Muntoni, F.; Blake, J.; Brandner, S.; Davies, N.; Horvath, R.; Price, S.; Donaghy, M.; Roberts, M.; Foulds, N.; Ramdharry, G.; Soler, D.; Lunn, M. P.; Manji, H.; Davis, M. B.; Houlden, H.; Reilly, M. M.

2013-01-01

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. PMID:22302274

Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort.

PubMed

Davidson, G L; Murphy, S M; Polke, J M; Laura, M; Salih, M A M; Muntoni, F; Blake, J; Brandner, S; Davies, N; Horvath, R; Price, S; Donaghy, M; Roberts, M; Foulds, N; Ramdharry, G; Soler, D; Lunn, M P; Manji, H; Davis, M B; Houlden, H; Reilly, M M

2012-08-01

The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN.

Progressive solitary sclerosis: Gradual motor impairment from a single CNS demyelinating lesion.

PubMed

Keegan, B Mark; Kaufmann, Timothy J; Weinshenker, Brian G; Kantarci, Orhun H; Schmalstieg, William F; Paz Soldan, M Mateo; Flanagan, Eoin P

2016-10-18

To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis. Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details. The patients' median age was 48.5 years (range 23-71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15-343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1). Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease. © 2016 American Academy of Neurology.

Fibronectin connecting segment-1 peptide inhibits pathogenic leukocyte trafficking and inflammatory demyelination in experimental models of chronic inflammatory demyelinating polyradiculoneuropathy.

PubMed

Dong, Chaoling; Greathouse, Kelsey M; Beacham, Rebecca L; Palladino, Steven P; Helton, E Scott; Ubogu, Eroboghene E

2017-06-01

The molecular determinants of pathogenic leukocyte migration across the blood-nerve barrier (BNB) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) are unknown. Specific disease modifying therapies for CIDP are also lacking. Fibronectin connecting segment-1 (FNCS1), an alternatively spliced fibronectin variant expressed by microvascular endothelial cells at sites of inflammation in vitro and in situ, is a counterligand for leukocyte α 4 integrin (also known as CD49d) implicated in pathogenic leukocyte trafficking in multiple sclerosis and inflammatory bowel disease. We sought to determine the role of FNCS1 in CIDP patient leukocyte trafficking across the BNB in vitro and in severe chronic demyelinating neuritis in vivo using a representative spontaneous murine CIDP model. Peripheral blood mononuclear leukocytes from 7 untreated CIDP patients were independently infused into a cytokine-treated, flow-dependent in vitro BNB model system. Time-lapse digital video microscopy was performed to visualize and quantify leukocyte trafficking, comparing FNCS1 peptide blockade to relevant controls. Fifty 24-week old female B7-2 deficient non-obese diabetic mice with spontaneous autoimmune peripheral polyneuropathy (SAPP) were treated daily with 2mg/kg FNCS1 peptide for 5days via intraperitoneal injection with appropriate controls. Neurobehavioral measures of disease severity, motor nerve electrophysiology assessments and histopathological quantification of inflammation and morphometric assessment of demyelination were performed to determine in vivo efficacy. The biological relevance of FNCS1 and CD49d in CIDP was evaluated by immunohistochemical detection in affected patient sural nerve biopsies. 25μM FNCS1 peptide maximally inhibited CIDP leukocyte trafficking at the human BNB in vitro. FNCS1 peptide treatment resulted in significant improvements in disease severity, motor electrophysiological parameters of demyelination and histological measures of

Cochlear implantation in chronic demyelinating inflammatory polyneuropathy.

PubMed

Mowry, Sarah E; King, Sarah

2017-03-01

To describe a case of chronic inflammatory demyelinating polyneuropathy (CDIP) with bilateral sudden sensorineural hearing loss who subsequently benefited from unilateral cochlear implantation. case history review and review of the literature for the terms CDIP, hearing loss, cochleovestibular dysfunction, and cochlear implantation. A 49-year-old woman presented with bilateral rapidly progressive sensorineural hearing loss (SNHL) 1 month after an upper respiratory tract infection. Hearing loss was not responsive to high-dose steroids and there were no other laboratory abnormalities or physical findings. Within 1 month, she developed ascending motor palsy, requiring long-term ventilator support. This neurologic condition was diagnosed as CDIP and she was successfully treated with plasmapheresis and intravenous immunoglobulin. Her hearing never recovered. At the time of cochlear implant, she had no response at the limits of the audiometer and obtained 0% on AzBio testing. No ABR could be recorded preoperatively. She underwent uneventful cochlear implantation with a perimodilar electrode. One year after activation, she had a PTA of 20 dB and 40% on AzBio sentence testing. Her eABR demonstrated a neuropathy pattern. Only two other cases of CDIP associated with dysfunction of the eighth nerve have been described, and neither had documented profound hearing loss. Severe SNHL associated with CDIP is rare. Although this patient has good access to sound, speech discrimination is poor at 1-year post implantation. This outcome may be due to incomplete recovery of myelination of the eighth nerve. Other possibilities include loss of peripheral nerve fibers due to the initial viral upper respiratory infection, which may lead to less neural substrate to stimulate.

Vestibular evoked myogenic potential (VEMP) in patients with auditory neuropathy: Auditory neuropathy or audiovestibular neuropathy?

PubMed

Sazgar, Amir Arvin; Yazdani, Nasrin; Rezazadeh, Nima; Yazdi, Alireza Karimi

2010-10-01

Our results suggest that isolated auditory or vestibular involvement is unlikely and in fact audiovestibular neuropathy can better explain auditory neuropathy. The purpose of this study was to investigate saccule and related neural pathways in auditory neuropathy patients. Three males and five females diagnosed with auditory neuropathy were included in this prospective study. Patients' ages ranged from 21 to 45 years with a mean age of 28.6 ± 8.1 years and the history of disease was between 4 and 19 years. A group of 30 normal subjects served as the control group. The main outcome measures were the mean peak latency (in ms) of the two early waves (p13 and n23) of the vestibular evoked myogenic potential (VEMP) test in patients and controls. Of the 8 patients (16 ears), normal response was detected in 3 ears (1 in right and 2 in left ears). There were unrepeatable waves in four ears and absent VEMPs in nine ears.

Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation*

PubMed Central

Hao, Wu; Tashiro, Syoichi; Hasegawa, Tomoka; Sato, Yuiko; Kobayashi, Tami; Tando, Toshimi; Katsuyama, Eri; Fujie, Atsuhiro; Watanabe, Ryuichi; Morita, Mayu; Miyamoto, Kana; Morioka, Hideo; Nakamura, Masaya; Matsumoto, Morio; Amizuka, Norio; Toyama, Yoshiaki; Miyamoto, Takeshi

2015-01-01

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition. PMID:25998127

Ultrasound and MRI of nerves for monitoring disease activity and treatment effects in chronic dysimmune neuropathies - Current concepts and future directions.

PubMed

Décard, Bernhard F; Pham, Mirko; Grimm, Alexander

2018-01-01

New imaging modalities like high-resolution-ultrasound (HRUS) and MR-Neurography (MRN) are increasingly used for the evaluation of the peripheral nervous system. The increasing knowledge on morphological changes observed in different neuropathies has led to a better understanding of underlying pathophysiological processes. The diagnosis of acquired chronic dysimmune neuropathies (CDN) like chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis-Sumner Syndrome (LSS) or multifocal motor neuropathy (MMN) can be challenging. The current diagnostic criteria and outcome parameters are mainly based on clinical and electrophysiological parameters. Especially in CDN cases with atypical presentation or during early disease stages, the diagnostic accuracy is low and standardized protocols for the evaluation of disease activity and treatment response are lacking. The establishment of combined diagnostic criteria for CDN including imaging modalities could help to improve the diagnostic accuracy, allow a better differentiation of subtypes and facilitate the follow-up of disease course. The appropriate selection of eligible patients and sensitive monitoring of treatment response is mandatory future in treatment trials. In this article, we briefly summarize the clinical presentations and pathophysiological concepts of different CDN like CIDP, LSS and MMN. Furthermore, this review focuses on the diagnostic value of HRUS/MRN and its potential role for the monitoring of disease activity. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Cyclic phosphatidic acid treatment suppress cuprizone-induced demyelination and motor dysfunction in mice.

PubMed

Yamamoto, Shinji; Gotoh, Mari; Kawamura, Yuuki; Yamashina, Kota; Yagishita, Sosuke; Awaji, Takeo; Tanaka, Motomu; Maruyama, Kei; Murakami-Murofushi, Kimiko; Yoshikawa, Keisuke

2014-10-15

Multiple sclerosis is a chronic demyelinating disease of the central nervous system leading to progressive cognitive and motor dysfunction, which is characterized by neuroinflammation, demyelination, astrogliosis, loss of oligodendrocytes, and axonal pathologies. Cyclic phosphatidic acid (cPA) is a naturally occurring phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. In this study, we investigated the effects of cPA on cuprizone-induced demyelination, which is a model of multiple sclerosis. Mice were fed a diet containing 0.2% cuprizone for 5 weeks, which induces severe demyelination, astrocyte and microglial activation, and motor dysfunction. Simultaneous administration of cPA effectively attenuated cuprizone-induced demyelination, glial activation, and motor dysfunction. These data indicate that cPA may be a useful treatment to reduce the extent of demyelination and the severity of motor dysfunction in multiple sclerosis. cPA is a potential lead compound in the development of drugs for the treatment of this devastating disease. Copyright © 2014 Elsevier B.V. All rights reserved.

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vance, J.M.; Speer, M.C.; Stajich, J.M.

1996-07-01

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 mostmore » 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.« less

A review of MRI evaluation of demyelination in cuprizone murine model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krutenkova, E., E-mail: len--k@yandex.ru; Pan, E.; Khodanovich, M., E-mail: khodanovich@mail.tsu.ru

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

A review of MRI evaluation of demyelination in cuprizone murine model

NASA Astrophysics Data System (ADS)

Krutenkova, E.; Pan, E.; Khodanovich, M.

2015-11-01

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

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber’s hereditary optic neuropathy

PubMed Central

Iommarini, Luisa; Giordano, Luca; Maresca, Alessandra; Pisano, Annalinda; Valentino, Maria Lucia; Caporali, Leonardo; Liguori, Rocco; Deceglie, Stefania; Roberti, Marina; Fanelli, Francesca; Fracasso, Flavio; Ross-Cisneros, Fred N.; D’Adamo, Pio; Hudson, Gavin; Pyle, Angela; Yu-Wai-Man, Patrick; Chinnery, Patrick F.; Zeviani, Massimo; Salomao, Solange R.; Berezovsky, Adriana; Belfort, Rubens; Ventura, Dora Fix; Moraes, Milton; Moraes Filho, Milton; Barboni, Piero; Sadun, Federico; De Negri, Annamaria; Sadun, Alfredo A.; Tancredi, Andrea; Mancini, Massimiliano; d’Amati, Giulia; Loguercio Polosa, Paola; Cantatore, Palmiro

2014-01-01

Leber’s hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber’s hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber’s hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies. PMID:24369379

[Two cases of hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P)].

PubMed

Mori, Chiaki; Saito, Tomoko; Saito, Toshio; Fujimura, Harutoshi; Sakoda, Saburo

2015-01-01

We, herein, report two independent cases with hereditary motor and sensory neuropathy with proximal dominant involvement (HMSN-P) inherited in an autosomal dominant fashion. Their common clinical features are slowly progressive proximal dominant muscular atrophy, fasciculations and mild to moderate distal sensory disturbance with areflexia. Nerve conduction study revealed an absence of sensory nerve action potentials, in contrast to almost normal compound muscle action potentials. Gene analysis in both patients elucidated heterozygous mutation (c.854C>T, p.Pro285Leu) in the TFG, which is an identical mutation, already described by Ishiura et al. Okinawa and Shiga are two foci of HMSN-P in Japan. Eventually, one patient is from Okinawa and the other is from a mountain village in Shiga prefecture. When we see a patient who has symptoms suggestive of motor neuron disease with sensory neuropathy, HMSN-P should be considered as a differential diagnosis despite the patient's actual resident place.

Axon Transport and Neuropathy

PubMed Central

Tourtellotte, Warren G.

2017-01-01

Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. PMID:26724390

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P).

PubMed

Campellone, Joseph V

2013-06-01

Hereditary motor and sensory neuropathy with proximal predominance (HMSN-P) is a rare disorder inherited in an autosomal dominant fashion. Patients present with slowly progressive proximal-predominant weakness, painful muscle cramps, fasciculations, large-fiber sensory loss, and areflexia. Electrodiagnostic (EDX) studies typically reveal abnormalities consistent with a sensorimotor neuronopathy. A patient with HMSN-P underwent EDX studies, revealing ongoing and chronic neurogenic denervation, motor unit instability, and neuromyotonic discharges, further defining the spectrum of EDX findings in HMSN-P. The clinical, pathological, and genetic features are also reviewed. The appearance of HMSN-P in the United States and elsewhere calls for clinicians in nonendemic regions to be familiar with this rare disorder, which has typically been geographically confined.

Pyrexia-associated Relapse in Chronic Inflammatory Demyelinating Polyradiculoneuropathy: A Case Report.

PubMed

Ueda, Jun; Yoshimura, Hajime; Kohara, Nobuo

2018-04-27

Chronic inflammatory demyelinating polyradiculoneuropathy is a relapsing-remitting or chronic progressive demyelinating polyradiculoneuropathy. We report the case of a patient with chronic inflammatory demyelinating polyradiculoneuropathy who experienced relapses on four occasions after experiencing pyrexia and flu-like symptoms. Our patient showed characteristic features, such as relapse after pyrexia and flu-like symptoms, remission after pyretolysis without treatment, and the absence of remarkable improvement in a nerve conduction study in the remission phase. The serum level of tumor necrosis factor-α was elevated in the relapse phase and reduced in the remission phase; thus, the induction of cytokine release by viral infection might have caused the relapses.

The Relationship Between Total Neuropathy Score-reduced, Neuropathy Symptoms and Function

NASA Astrophysics Data System (ADS)

Abulhaija, Ashraf

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common problem among cancer patients who receive a wide range of chemotherapy. This problem causes a decline in quality of life and increased disabilities. CIPN assessment instruments are either subjective, objective, or a combination of both. So far, there is no agreement on the best way for assessment. The goal of this study was to explore the relationships among subjective and objective CIPN assessment instruments. Specifically, this study aimed to 1) evaluate the relationship between the Total Neuropathy Score-reduced (mainly objective) and patients' function, as measured by the interference scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (subjective); and 2) evaluate the relationship between the Total Neuropathy Score-reduced and neuropathy symptom experience, as measured by the symptom experience scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Subjective). To achieve those aims, a secondary data analysis for 56 participants who participated in a study entitled: Group Acupuncture for Treatment of Neuropathy from Chemotherapy was done. After Pearson correlations were calculated, the study found that there is a positive, weak relationship between the TNSr and the symptom experience scale of the CIPNAT(r=0.34). A positive, week relationship was found between the TNSr and the interference with activity scale of the CIPNAT(r=0.28). These results suggest that objective and subjective assessment are not highly correlated, and likely measure different aspects of CIPN. A comprehensive assessment approach is needed for decision making in the clinical oncology setting.

Improvement of hemoglobin levels after a switch from intravenous to subcutaneous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

PubMed

Markvardsen, Lars Høj; Christiansen, Ingelise; Jakobsen, Johannes

2016-10-01

Intravenous immunoglobulin (IVIG) is recommended treatment for chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). Recent studies have demonstrated that subcutaneous immunoglobulin (SCIG) is feasible, safe, and effective in both disorders. IVIG leads to transient hemolysis and, consequently, we hypothesized that frequent small doses of SCIG exerts less hemolytic activity than a few larger doses of IVIG. In an open-label study, 23 three patients treated with IVIG for CIDP or MMN were switched to SCIG at an equal dosage. IVIG was administered two to three times for 6 weeks. Two weeks after the last IVIG infusion at Week 8, SCIG was initiated with injections twice or thrice weekly until Week 20. Blood samples were drawn 2 weeks after IVIG at Weeks 2 and 8 and during SCIG at Weeks 14 and 20 determining hemoglobin (Hb) and hemolytic variables. Seventeen patients completed the study. At enrollment, the Hb level was 138 ± 12 g/L, haptoglobin level was 1.4 ± 0.5 g/L, reticulocyte count was 58.7 × 10 9  ± 21.3 × 10 9 /L, and bilirubin level was 6.6 ± 2.3 µmol/L. The average of the two blood samples drawn at comparable intervals during IVIG and SCIG showed that Hb increased from 135 ± 15 to 138 ± 15 g/L (p = 0.03). During IVIG the hemolytic variables showed signs of mild hemolysis that improved during SCIG, haptoglobin increasing from 1.2 ± 0.5 to 1.5 ± 0.6 g/L (p = 0.002), reticulocytes decreasing from 71.9 × 10 9  ± 35.8 × 10 9 to 54.5 × 10 9  ± 16.3 × 10 9 /L (p = 0.02), and bilirubin decreasing from 7.3 ± 2.8 to 5.8 ± 1.8 µmol/L (p = 0.001). A switch from IVIG to SCIG was associated with a slight increase of Hb levels and an improvement of laboratory variables related to hemolytic activity. © 2016 AABB.

Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.

PubMed

Higuchi, Yujiro; Okunushi, Ryuta; Hara, Taichi; Hashiguchi, Akihiro; Yuan, Junhui; Yoshimura, Akiko; Murayama, Kei; Ohtake, Akira; Ando, Masahiro; Hiramatsu, Yu; Ishihara, Satoshi; Tanabe, Hajime; Okamoto, Yuji; Matsuura, Eiji; Ueda, Takehiro; Toda, Tatsushi; Yamashita, Sumimasa; Yamada, Kenichiro; Koide, Takashi; Yaguchi, Hiroaki; Mitsui, Jun; Ishiura, Hiroyuki; Yoshimura, Jun; Doi, Koichiro; Morishita, Shinichi; Sato, Ken; Nakagawa, Masanori; Yamaguchi, Masamitsu; Tsuji, Shoji; Takashima, Hiroshi

2018-06-01

Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition

Vitamin D status and age of onset of demyelinating disease.

PubMed

Brenton, J Nicholas; Koenig, Scott; Goldman, Myla D

2014-11-01

To evaluate the prevalence of and associated factors impacting vitamin D insufficiency and deficiency in childhood versus adult-onset demyelinating disease. We conducted a retrospective, cross-sectional, chart-review, cohort study on geographically-similar pediatric, young adult, and adult patients with a diagnosis of demyelinating disease identified at the University of Virginia from 2008 to 2013. Group prevalence of vitamin D insufficiency and deficiency as well as relevant factors associated with vitamin D status was analyzed and compared. We identified 24 childhood-onset (CO), 33 young adult-onset (Y-AO), and 59 adult-onset (AO) cases. There was no difference in the prevalence of vitamin D insufficiency or deficiency between the cohorts. Non-Caucasian race and elevated body mass index were significantly associated with low vitamin D levels, regardless of age of onset. In regression models, race and obesity were independent predictors of vitamin D status. The prevalence of obesity was significantly higher in the childhood-onset cohort (CO=58.5%; Y-AO=31%; AO=34%; p=0.02). Our findings demonstrate no difference in the prevalence of vitamin D insufficiency/deficiency between childhood and adult-onset demyelinating disease, suggesting age at disease onset is irrelevant to vitamin D status in demyelinating disease. Both race and obesity are independent factors associated with vitamin D insufficiency/deficiency, regardless of age of disease onset. Obesity, independent of gender, is significantly higher in children compared to adult patients diagnosed with multiple sclerosis and may have a role in the development of childhood-onset demyelinating disease. Copyright © 2014 Elsevier B.V. All rights reserved.

Adenosine A2A receptor blockade attenuates spatial memory deficit and extent of demyelination areas in lyolecithin-induced demyelination model.

PubMed

Akbari, Atefeh; Khalili-Fomeshi, Mohsen; Ashrafpour, Manouchehr; Moghadamnia, Ali Akbar; Ghasemi-Kasman, Maryam

2018-05-03

In recent years, inactivation of A 2A adenosine receptors has been emerged as a novel strategy for treatment of several neurodegenerative diseases. Although numerous studies have shown the beneficial effects of A 2A receptors blockade on spatial memory, the impacts of selective adenosine A 2A receptors on memory performance has not yet been examined in the context of demyelination. In the present study, we evaluated the effect of A 2A receptor antagonist SCH58261 on spatial memory and myelination in an experimental model of focal demyelination in rat fimbria. Demyelination was induced by local injection of lysolecithin (LPC) 1% (2 μl) into the hippocampus fimbria. SCH58261 (20 μg/0.5 μl or 40 μg/0.5 μl) was daily injected intracerebroventricularly (i.c.v.) for 10 days post LPC injection. The Morris water maze test was used to assess the spatial learning and memory on day 6 post lesion. Myelin staining and immunostaining against astrocytes/microglia were carried out 10 days post LPC injection. The administration of adenosine A 2A receptor antagonist prevented the spatial memory impairment in LPC receiving animals. Myelin staining revealed that application of SCH58261 reduces the extent of demyelination areas in the fimbria. Furthermore, the level of astrocytes and microglia activation was attenuated following administration of A 2A receptor antagonist. Collectively, the results of this study suggest that A 2A receptor blockade can improve the spatial memory and protect myelin sheath, which might be considered as a novel therapeutic approach for multiple sclerosis disease. Copyright © 2017. Published by Elsevier Inc.

Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy.

PubMed

Topakian, Raffi; Wimmer, Sibylle; Pischinger, Barbara; Pichler, Robert

2014-10-17

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing. 2014 BMJ Publishing Group Ltd.

Apoptosis of oligodendrocytes in the CNS results in rapid focal demyelination

PubMed Central

Caprariello, Andrew; Mangla, Saisho; Miller, Robert H.; Selkirk, Stephen M.

2012-01-01

Objective Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that presents with variable pathologies that may reflect different disease-causing mechanisms. Existing animal models of MS induce pathology using either local injection of gliotoxins or stimulation of the immune system with myelin-related peptides. In none of these models is the primary cellular target well characterized and although demyelination is a hallmark pathological feature in MS, it is unclear to what extent this reflects local oligodendrocyte loss. To unambiguously identify the effects of oligodendrocyte death in the absence of inflammatory stimulation, we developed a method for experimentally inducing programmed cell death selectively in mature oligodendrocytes and assessed the effects on demyelination, immunological stimulation and gliosis. The resulting pathology is discussed relative to observed MS pathologies. Methods Oligodendrocyte apoptosis was induced in the adult rat brain using a lentivirus to express experimentally-inducible caspase 9 (iCP9) cDNA under transcriptional control of the promoter for myelin basic protein (MBP), which is oligodendrocyte-specific. Activation of iCP9 was achieved by distal injection of a small molecule dimerizer into the lateral ventricle resulting in localized, acute oligodendrocyte apoptosis. Results Induced oligodendrocyte apoptosis resulted in rapid demyelination and robust, localized microglial activation in the absence of peripheral immune cell infiltration. Lesion borders showed layers of preserved and degraded myelin, while lesion cores were demyelinated but only partially cleared of myelin debris. This resulted in local proliferation and mobilization of the oligodendrocyte progenitor pool. Interpretation This approach provides a novel model to understand the pathological changes that follow from localized apoptosis of myelinating oligodendrocytes. It provides the first direct proof that initiation of apoptosis in

DTI fiber tracking to differentiate demyelinating diseases from diffuse brain stem glioma.

PubMed

Giussani, Carlo; Poliakov, Andrew; Ferri, Raymond T; Plawner, Lauren L; Browd, Samuel R; Shaw, Dennis W W; Filardi, Tanya Z; Hoeppner, Corrine; Geyer, J Russell; Olson, James M; Douglas, James G; Villavicencio, Elisabeth H; Ellenbogen, Richard G; Ojemann, Jeffrey G

2010-08-01

Intrinsic diffuse brainstem tumors and demyelinating diseases primarily affecting the brainstem can share common clinical and radiological features, sometimes making the diagnosis difficult especially at the time of first clinical presentation. To explore the potential usefulness of new MRI sequences in particular diffusion tensor imaging fiber tracking in differentiating these two pathological entities, we review a series of brainstem tumors and demyelinating diseases treated at our institution. The clinical history including signs and symptoms and MRI findings of three consecutive demyelinating diseases involving the brainstem that presented with diagnostic uncertainty and three diffuse intrinsic brainstem tumors were reviewed, along with a child with a supratentorial tumor for comparison. Fiber tracking of the pyramidal tracts was performed for each patient using a DTI study at the time of presentation. Additionally Fractional Anisotropy values were calculated for each patient in the pons and the medulla oblongata. Routine MR imaging was unhelpful in differentiating between intrinsic tumor and demyelination. In contrast, retrospective DTI fiber tracking clearly differentiated the pathology showing deflection of the pyramidal tracts posteriorly and laterally in the case of intrinsic brainstem tumors and, in the case of demyelinating disease, poorly represented and truncated fibers. Regionalized FA values were variable and of themselves were not predictive either pathology. DTI fiber tracking of the pyramid tracts in patients with suspected intrinsic brainstem tumor or demyelinating disease presents two clearly different patterns that may help in differentiating between these two pathologies when conventional MRI and clinical data are inconclusive. Copyright 2010 Elsevier Inc. All rights reserved.

Heterogeneity of Polyneuropathy Associated with Anti-MAG Antibodies

PubMed Central

Magy, Laurent; Kaboré, Raphaël; Mathis, Stéphane; Lebeau, Prisca; Ghorab, Karima; Caudie, Christiane; Vallat, Jean-Michel

2015-01-01

Polyneuropathy associated with IgM monoclonal gammopathy and anti-myelin associated glycoprotein (MAG) antibodies is an immune-mediated demyelinating neuropathy. The pathophysiology of this condition is likely to involve anti-MAG antibody deposition on myelin sheaths of the peripheral nerves and it is supposed to be distinct from chronic inflammatory demyelinating neuropathy (CIDP), another immune-mediated demyelinating peripheral neuropathy. In this series, we have retrospectively reviewed clinical and laboratory findings from 60 patients with polyneuropathy, IgM gammopathy, and anti-MAG antibodies. We found that the clinical picture in these patients is highly variable suggesting a direct link between the monoclonal gammopathy and the neuropathy. Conversely, one-third of patients had a CIDP-like phenotype on electrodiagnostic testing and this was correlated with a low titer of anti-MAG antibodies and the absence of widening of myelin lamellae. Our data suggest that polyneuropathy associated with anti-MAG antibodies is less homogeneous than previously said and that the pathophysiology of the condition is likely to be heterogeneous as well with the self-antigen being MAG in most of the patients but possibly being another component of myelin in the others. PMID:26065001

Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter.

PubMed

Armstrong, Regina C; Le, Tuan Q; Frost, Emma E; Borke, Rosemary C; Vana, Adam C

2002-10-01

This study takes advantage of fibroblast growth factor 2 (FGF2) knock-out mice to determine the contribution of FGF2 to the regeneration of oligodendrocytes in the adult CNS. The role of FGF2 during spontaneous remyelination was examined using two complementary mouse models of experimental demyelination. The murine hepatitis virus strain A59 (MHV-A59) model produces focal areas of spinal cord demyelination with inflammation. The cuprizone neurotoxicant model causes extensive corpus callosum demyelination without a lymphocytic cell response. In both models, FGF2 expression is upregulated in areas of demyelination in wild-type mice. Surprisingly, in both models, oligodendrocyte repopulation of demyelinated white matter was significantly increased in FGF2 -/- mice compared with wild-type mice and even surpassed the oligodendrocyte density of nonlesioned mice. This dramatic result indicated that the absence of FGF2 promoted oligodendrocyte regeneration, possibly by enhancing oligodendrocyte progenitor proliferation and/or differentiation. FGF2 -/- and +/+ mice had similar oligodendrocyte progenitor densities in normal adult CNS, as well as similar progenitor proliferation and accumulation during demyelination. To directly analyze progenitor differentiation, glial cultures from spinal cords of wild-type mice undergoing remyelination after MHV-A59 demyelination were treated for 3 d with either exogenous FGF2 or an FGF2 neutralizing antibody. Elevating FGF2 favored progenitor proliferation, whereas attenuating endogenous FGF2 activity promoted the differentiation of progenitors into oligodendrocytes. These in vitro results are consistent with enhanced progenitor differentiation in FGF2 -/- mice. These studies demonstrate that the FGF2 genotype regulates oligodendrocyte regeneration and that FGF2 appears to inhibit oligodendrocyte lineage differentiation during remyelination.

Diabetic Neuropathy: Mechanisms to Management

PubMed Central

Edwards, James L.; Vincent, Andrea; Cheng, Thomas; Feldman, Eva L.

2014-01-01

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 alleviate the symptoms of diabetic neuropathy, few options are available to eliminate the root causes. The immense physical, psychological, and economic cost of diabetic neuropathy underscores the need for causally targeted therapies. This review covers the pathology, epidemiology, biochemical pathways, and prevention of diabetic neuropathy, as well as discusses current symptomatic and causal therapies and novel approaches to identify therapeutic targets. PMID:18616962

A prospective study comparing tryptophan immunoadsorption with therapeutic plasma exchange for the treatment of chronic inflammatory demyelinating polyneuropathy.

PubMed

Lieker, Ina; Slowinski, Torsten; Harms, Lutz; Hahn, Katrin; Klehmet, Juliane

2017-12-01

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare paralyzing inflammatory neuropathy with probably autoimmune origin. While plasma exchange (PE) constitutes a first-line treatment option for CIDP, there is only little known about the efficacy and safety of immunoadsorption (IA), a more selective apheresis procedure with assumed better tolerability. In this prospective-randomized pilot trial, patients were randomly assigned to receive 6 sessions of PE (n = 10) or IA (n = 10) treating equal plasma volumes. To evaluate efficacy, we calculated the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score and the Medical Research Council (MRC) sum score at baseline (V1), after completion of 6 sessions (V2) as well as 4 weeks after completion (V3) in 9 patients per group (1 patient in each group did not complete follow-up). We additionally assessed safety and tolerability of treatments by monitoring adverse event and blood parameters. With IA, 6 out of 9 (66.7%) patients improved clinically, whereas with PE, 4 out of 9 (44.4%) patients improved, most of them immediately with completion of the apheresis treatment series. There was one adverse event (AE) out of 52 treatment sessions for the 9 patients in the IA group. In the PE group of 9 patients, there was 1 AE out of 51 sessions and a trend of greater fibrinogen reduction. No severe AE occurred in either group. The results of this pilot study suggest that IA is at least equally effective and safe compared to PE in CIDP patients. © 2017 Wiley Periodicals, Inc.

Paraesthesia and peripheral neuropathy.

PubMed

Beran, Roy

2015-03-01

Paraesthesia reflects an abnormality affecting the sensory pathways anywhere between the peripheral sensory nervous system and the sensory cortex. As with all neurology, the fundamental diagnostic tool is a concise history, devoid of potentially ambiguous jargon, which properly reflects the true nature of what the patient is experiencing, provocateurs, precipitating and relieving factors, concomitant illnesses, such as diabetes, and any treatments that could evoke neuropathies. Some localised neuropathies, such as carpal tunnel syndrome (CTS) or ulnar neuropathy, produce classical features, such as weakness of the 'LOAF' (lateral two lumbricals, opponens pollicis, abductor pollicis brevis and flexor pollicis brevis) median innervated muscles, thereby obviating need for further neurophysiology. Nerve conduction studies may be necessary to diagnose peripheral neuropathy, but they may also be normal with small fibre neuropathy. Even with a diagnosis of peripheral neuropathy, definition of the underlying cause may remain elusive in a significant proportion of cases, despite involvement of consultants. Treatment is based on the relevant diagnosis and mechanism to address the cause. This includes better glycaemic control for diabetes, night splint for CTS or elbow padding for ulnar neuropathy, modifying lifestyle with reduced alcohol consumption or replacing dietary deficiencies or changing medications where appropriate and practical. Should such intervention fail to relieve symptoms, consideration of intervention to relieve symptoms of neuropathic pain may be required.

The formation of inflammatory demyelinated lesions in cerebral white matter

PubMed Central

Maggi, Pietro; Cummings Macri, Sheila M.; Gaitán, María I.; Leibovitch, Emily; Wholer, Jillian E; Knight, Heather L.; Ellis, Mary; Wu, Tianxia; Silva, Afonso C.; Massacesi, Luca; Jacobson, Steven; Westmoreland, Susan; Reich, Daniel S.

2016-01-01

Objective Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. Methods At 7 tesla MRI, T1 maps, proton density and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain-barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. Results On average, BBB permeability increased 3.5 fold (p<0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, though permeability within the foci, but not outside, increased in the weeks before the animals died (p<0.0001). Interpretation This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. PMID:25088017

The formation of inflammatory demyelinated lesions in cerebral white matter.

PubMed

Maggi, Pietro; Macri, Sheila M Cummings; Gaitán, María I; Leibovitch, Emily; Wholer, Jillian E; Knight, Heather L; Ellis, Mary; Wu, Tianxia; Silva, Afonso C; Massacesi, Luca; Jacobson, Steven; Westmoreland, Susan; Reich, Daniel S

2014-10-01

Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset. By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination. On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001). This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions. © 2014 American Neurological Association.

Peripheral Neuropathy: Symptoms and Signs

MedlinePlus

... Utah Research News Make a Difference Symptoms of Peripheral Neuropathy Print This Page Peripheral Neuropathy symptoms usually start ... more slowly over many years. The symptoms of peripheral neuropathy often include: A sensation of wearing an invisible “ ...

Comparison of Cerebrospinal Fluid Opening Pressure in Children With Demyelinating Disease to Children With Primary Intracranial Hypertension.

PubMed

Morgan-Followell, Bethanie; Aylward, Shawn C

2017-03-01

The authors aimed to compare the opening pressures of children with demyelinating disease to children with primary intracranial hypertension. Medical records were reviewed for a primary diagnosis of demyelinating disease, or primary intracranial hypertension. Diagnosis of demyelinating disease was made according to either the 2007 or 2012 International Pediatric Multiple Sclerosis Study Group criteria. Primary intracranial hypertension diagnosis was confirmed by presence of elevated opening pressure, normal cerebrospinal fluid composition and neuroimaging. The authors compared 14 children with demyelinating disease to children with primary intracranial hypertension in 1:1 and 1:2 fashions. There was a statistically significant higher BMI in the primary intracranial hypertension group compared to the demyelinating group ( P = .0203). The mean cerebrospinal fluid white blood cell count was higher in the demyelinating disease group compared to primary intracranial hypertension ( P = .0002). Among both comparisons, the cerebrospinal fluid opening pressure, glucose, protein and red blood cell counts in children with demyelinating disease were comparable to age- and sex-matched controls with primary intracranial hypertension.

Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.

PubMed

Shi, Hong; Hu, Xiaoming; Leak, Rehana K; Shi, Yejie; An, Chengrui; Suenaga, Jun; Chen, Jun; Gao, Yanqin

2015-10-01

Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. Copyright © 2015 Elsevier Inc. All rights reserved.

Connexin mutations in X-linked Charcot-Marie-Tooth disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bergoffen, J.; Scherer, S.S.; Wang, S.

1993-12-24

X-linked Charcot-Marie-Tooth disease (CMTX) is a form of hereditary neuropathy with demyelination. Recently, this disorder was mapped to chromosome Xq13.1. The gene for the gap junction protein connexin32 is located in the same chromosomal segment, which led to its consideration as a candidate gene for CMTX. With the use of Northern (RNA) blot and immunohistochemistry techniques, it was found that connexin32 is normally expressed in myelinated peripheral nerve. Direct sequencing of the connexin32 gene showed seven different mutations in affected persons from eight CMTX families. These findings, a demonstration of inherited defects in a gap junction protein, suggest that connexin32more » plays an important role in peripheral nerve.« less

Hereditary motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough.

PubMed

Miura, Shiroh; Shibata, Hiroki; Kida, Hiroshi; Noda, Kazuhito; Tomiyasu, Katsuro; Yamamoto, Ken; Iwaki, Akiko; Ayabe, Mitsuyoshi; Aizawa, Hisamichi; Taniwaki, Takayuki; Fukumaki, Yasuyuki

2008-10-15

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of <-3 on both 3p12-q13 and 3p22-p24. Mutation scanning of the entire coding regions of the MPZ and PMP22 genes revealed no mutations. We conclude that the disorder described here is a newly classified hereditary motor and sensory neuropathy with autosomal dominant inheritance.

HSJ1-related hereditary neuropathies: novel mutations and extended clinical spectrum.

PubMed

Gess, Burkhard; Auer-Grumbach, Michaela; Schirmacher, Anja; Strom, Tim; Zitzelsberger, Manuela; Rudnik-Schöneborn, Sabine; Röhr, Dominik; Halfter, Hartmut; Young, Peter; Senderek, Jan

2014-11-04

To determine the nature and frequency of HSJ1 mutations in patients with hereditary motor and hereditary motor and sensory neuropathies. Patients were screened for mutations by genome-wide or targeted linkage and homozygosity studies, whole-exome sequencing, and Sanger sequencing. RNA and protein studies of skin fibroblasts were used for functional characterization. We describe 2 additional mutations in the HSJ1 gene in a cohort of 90 patients with autosomal recessive distal hereditary motor neuropathy (dHMN) and Charcot-Marie-Tooth disease type 2 (CMT2). One family with a dHMN phenotype showed the homozygous splice-site mutation c.229+1G>A, which leads to retention of intron 4 in the HSJ1 messenger RNA with a premature stop codon and loss of protein expression. Another family, presenting with a CMT2 phenotype, carried the homozygous missense mutation c.14A>G (p.Tyr5Cys). This mutation was classified as likely disease-related by several automatic algorithms for prediction of possible impact of an amino acid substitution on the structure and function of proteins. Both mutations cosegregated with autosomal recessive inheritance of the disease and were absent from the general population. Taken together, in our cohort of 90 probands, we confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. We provide clinical and functional information on an HSJ1 splice-site mutation and report the detailed phenotype of 2 patients with CMT2, broadening the phenotypic spectrum of HSJ1-related neuropathies. © 2014 American Academy of Neurology.

Diagnostic value of the near-nerve needle sensory nerve conduction in sensory inflammatory demyelinating polyneuropathy.

PubMed

Odabasi, Zeki; Oh, Shin J

2018-03-01

In this study we report the diagnostic value of the near-nerve needle sensory nerve conduction study (NNN-SNCS) in sensory inflammatory demyelinating polyneuropathy (IDP) in which the routine nerve conduction study was normal or non-diagnostic. The NNN-SNCS was performed to identify demyelination in the plantar nerves in 14 patients and in the median or ulnar nerve in 2 patients with sensory IDP. In 16 patients with sensory IDP, routine NCSs were either normal or non-diagnostic for demyelination. Demyelination was identified by NNN-SNCS by dispersion and/or slow nerve conduction velocity (NCV) below the demyelination marker. Immunotherapy was initiated in 11 patients, 10 of whom improved or remained stable. NNN-SNCS played an essential role in identifying demyelinaton in 16 patients with sensory IDP, leading to proper treatment. Muscle Nerve 57: 414-418, 2018. © 2017 Wiley Periodicals, Inc.

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

PubMed

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

2018-01-01

The cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination. MicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis. miR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP + oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2 + OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3 + and Iba1 + macrophages/microglia was

Gasoline sniffing multifocal neuropathy.

PubMed

Burns, T M; Shneker, B F; Juel, V C

2001-11-01

The polyneuropathy caused by chronic gasoline inhalation is reported to be a gradually progressive, symmetric, sensorimotor polyneuropathy. We report unleaded gasoline sniffing by a female 14 years of age that precipitated peripheral neuropathy. In contrast with the previously reported presentation of peripheral neuropathy in gasoline inhalation, our patient developed multiple mononeuropathies superimposed on a background of sensorimotor polyneuropathy. The patient illustrates that gasoline sniffing neuropathy may present with acute multiple mononeuropathies resembling mononeuritis multiplex, possibly related to increased peripheral nerve susceptibility to pressure in the setting of neurotoxic components of gasoline. The presence of tetraethyl lead, which is no longer present in modern gasoline mixtures, is apparently not a necessary factor in the development of gasoline sniffer's neuropathy.

Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation.

PubMed

Hao, Wu; Tashiro, Syoichi; Hasegawa, Tomoka; Sato, Yuiko; Kobayashi, Tami; Tando, Toshimi; Katsuyama, Eri; Fujie, Atsuhiro; Watanabe, Ryuichi; Morita, Mayu; Miyamoto, Kana; Morioka, Hideo; Nakamura, Masaya; Matsumoto, Morio; Amizuka, Norio; Toyama, Yoshiaki; Miyamoto, Takeshi

2015-07-10

Diabetes mellitus (DM) is frequently accompanied by complications, such as peripheral nerve neuropathy. Schwann cells play a pivotal role in regulating peripheral nerve function and conduction velocity; however, changes in Schwann cell differentiation status in DM are not fully understood. Here, we report that Schwann cells de-differentiate into immature cells under hyperglycemic conditions as a result of sorbitol accumulation and decreased Igf1 expression in those cells. We found that de-differentiated Schwann cells could be re-differentiated in vitro into mature cells by treatment with an aldose reductase inhibitor, to reduce sorbitol levels, or with vitamin D3, to elevate Igf1 expression. In vivo DM models exhibited significantly reduced nerve function and conduction, Schwann cell de-differentiation, peripheral nerve de-myelination, and all conditions were significantly rescued by aldose reductase inhibitor or vitamin D3 administration. These findings reveal mechanisms underlying pathological changes in Schwann cells seen in DM and suggest ways to treat neurological conditions associated with this condition. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Novel OTOF mutations in Brazilian patients with auditory neuropathy.

PubMed

Romanos, Jihane; Kimura, Lilian; Fávero, Mariana Lopes; Izarra, Fernanda Attanasio R; de Mello Auricchio, Maria Teresa Balester; Batissoco, Ana Carla; Lezirovitz, Karina; Abreu-Silva, Ronaldo Serafim; Mingroni-Netto, Regina Célia

2009-07-01

The OTOF gene encoding otoferlin is associated with auditory neuropathy (AN), a type of non-syndromic deafness. We investigated the contribution of OTOF mutations to AN and to non-syndromic recessive deafness in Brazil. A test for the Q829X mutation was carried out on a sample of 342 unrelated individuals with non-syndromic hearing loss, but none presented this mutation. We selected 48 cases suggestive of autosomal recessive inheritance, plus four familial and seven isolated cases of AN, for genotyping of five microsatellite markers linked to the OTOF gene. The haplotype analysis showed compatibility with linkage in 11 families (including the four families with AN). Samples of the 11 probands from these families and from seven isolated cases of AN were selected for an exon-by-exon screening for mutations in the OTOF gene. Ten different pathogenic variants were detected, among which six are novel. Among the 52 pedigrees with autosomal recessive inheritance (including four familial cases of AN), mutations were identified in 4 (7.7%). Among the 11 probands with AN, seven had at least one pathogenic mutation in the OTOF gene. Mutations in the OTOF gene are frequent causes of AN in Brazil and our results confirm that they are spread worldwide.

Generation of Demyelination Models by Targeted Ablation of Oligodendrocytes in the Zebrafish CNS

PubMed Central

Chung, Ah-Young; Kim, Pan-Soo; Kim, Suhyun; Kim, Eunmi; Kim, Dohyun; Jeong, Inyoung; Kim, Hwan-Ki; Ryu, Jae-Ho; Kim, Cheol-Hee; Choi, June; Seo, Jin-Ho; Park, Hae-Chul

2013-01-01

Demyelination is the pathological process by which myelin sheaths are lost from around axons, and is usually caused by a direct insult targeted at the oligodendrocytes in the vertebrate central nervous system (CNS). A demyelinated CNS is usually remyelinated by a population of oligodendrocyte progenitor cells, which are widely distributed throughout the adult CNS. However, myelin disruption and remyelination failure affect the normal function of the nervous system, causing human diseases such as multiple sclerosis. In spite of numerous studies aimed at understanding the remyelination process, many questions still remain unanswered. Therefore, to study remyelination mechanisms in vivo, a demyelination animal model was generated using a transgenic zebrafish system in which oligodendrocytes are conditionally ablated in the larval and adult CNS. In this transgenic system, bacterial nitroreductase enzyme (NTR), which converts the prodrug metronidazole (Mtz) into a cytotoxic DNA cross-linking agent, is expressed in oligodendrocyte lineage cells under the control of the mbp and sox10 promoter. Exposure of transgenic zebrafish to Mtz-containing media resulted in rapid ablation of oligodendrocytes and CNS demyelination within 48 h, but removal of Mtz medium led to efficient remyelination of the demyelinated CNS within 7 days. In addition, the demyelination and remyelination processes could be easily observed in living transgenic zebrafish by detecting the fluorescent protein, mCherry, indicating that this transgenic system can be used as a valuable animal model to study the remyelination process in vivo, and to conduct high-throughput primary screens for new drugs that facilitate remyelination. PMID:23807048

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model.

PubMed

Liang, Junjie; Li, Ning; Zhang, Yanli; Hou, Changyi; Yang, Xiaohan; Shimizu, Takahiro; Wang, Xiaoyu; Ikenaka, Kazuhiro; Fan, Kai; Ma, Jianmei

2016-01-01

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future.

Disinhibition of Cathepsin C Caused by Cystatin F Deficiency Aggravates the Demyelination in a Cuprizone Model

PubMed Central

Liang, Junjie; Li, Ning; Zhang, Yanli; Hou, Changyi; Yang, Xiaohan; Shimizu, Takahiro; Wang, Xiaoyu; Ikenaka, Kazuhiro; Fan, Kai; Ma, Jianmei

2016-01-01

Although the precise mechanism underlying initial lesion development in multiple sclerosis (MS) remains unclear, CNS inflammation has long been associated with demyelination, and axonal degeneration. The activation of microglia/macrophages, which serve as innate immune cells in the CNS, is the first reaction to even minor pathologic changes in the CNS and is considered an initial pathogenic event in MS. Microglial activation accompanies a variety of gene expressions, including cystatin F (Cys F), which belongs to the cystatin superfamily and is one of the cathepsin inhibitors. In our previous study we showed that Cys F has a unique expression pattern in microglia/macrophages in the demyelination process. Specifically, the timing of Cys F induction correlated with ongoing demyelination, and the sites of Cys F expression overlapped with areas of remyelination. Cys F induction ceased in chronic demyelination when remyelination capacity was lost, suggesting that Cys F expressed by microglia/macrophages may play an important role in demyelination and/or remyelination. The functional role of Cys F in demyelinating disease of the CNS, however, is unclear. Cys F gene knockout mice were used in the current study to clarify the functional role of Cys F in the demyelination process in a cuprizone-induced demyelination animal model. We demonstrated that absence of the Cys F gene and the resulting disinhibition of cathepsin C (Cat C) aggravates the demyelination, and this finding may be related to the increased expression of the glia-derived chemokine, CXCL2, which may attract inflammatory cells to sites of myelin sheath damage. This effect was reversed by knock down of the Cat C gene. The findings gain further insight to function of Cat C in pathophysiology of MS, which may have implications for therapeutics for the prevention of neuroinflammation-involved neurological disorders in the future. PMID:28066178

[Preimplantation genetic diagnosis and monogenic inherited eye diseases].

PubMed

Hlavatá, L; Ďuďáková, Ľ; Trková, M; Soldátová, I; Skalická, P; Kousal, B; Lišková, P

Preimplantation genetic diagnosis (PGD) is an established application of genetic testing in the context of in vitro fertilization. PGD is an alternative method to prenatal diagnosis which aims to prevent the transmission of an inherited disorder to the progeny by implanting only embryos that do not carry genetic predisposition for a particular disease. The aim of this study is to provide an overview of eye disorders for which PGD has been carried out. The European literature search focused on best practices, ethical issues, risks and results of PGD for inherited eye disorders. PGD is performed for a number of ocular disorders; a prerequisite for its application is however, the knowledge of a disease-causing mutation(s). The main advantage of this method is that the couple is not exposed to a decision of whether or not to undergo an abortion. Qualified counselling must be provided prior to the PGD in order to completely understand the risk of disability in any child conceived, consequences of disease manifestation, and advantages as well as limitations of this method. In the group of non-syndromic eye diseases and diseases in which ocular findings dominate, PGD has been performed in European countries for aniridia, choroideremia, congenital fibrosis of extraocular muscles, Leber congenital amaurosis, ocular albinism, retinitis pigmentosa, X-linked retinoschisis, Stargardt disease, blepharophimosis-ptosis-inverse epicanthus syndrome and retinoblastoma. Sexing for X-linked or mitochondrial diseases has been carried out for blue cone monochromatism, choroideremia, familial exudative vitreoretinopathy, Leber hereditary optic neuropathy, macular dystrophy (not further specified), Norrie disease, X-linked congenital stationary night blindness, X-linked retinoschisis and nystagmus (not further specified). In recent years, there has been an increase in potential to use PGD. The spectrum of diseases for this method has widened to include severe inherited eye diseases

Osmotic demyelination syndrome associated with hypophosphataemia: 2 cases and a review of literature.

PubMed

Turnbull, Jessica; Lumsden, Daniel; Siddiqui, Ata; Lin, Jean-Pierre; Lim, Ming

2013-04-01

Central and extrapontine myelinolysis are collectively known as osmotic demyelination syndrome. This encephalopathic illness has been well documented in the adult literature, occurring most commonly in the context of chronic alcoholism, correction of hyponatraemia and liver transplantation. Aetiology and outcome in the paediatric population are less well understood. Two cases of osmotic demyelination syndrome occurring in children with transient severe hypophosphataemia during the course of their illness are presented. Both had very different neurological outcomes, but the changes of central and extrapontine myelinolysis were apparent on neuroimaging. Sixty-one cases in the paediatric literature were then reviewed. We summarize aetiology and outcome in paediatric cases of osmotic demyelination syndrome and postulate a role for hypophosphataemia as a contributing factor in the development of these sometimes devastating conditions. Hypophosphataemia may contribute to the risk of developing osmotic demyelination syndrome in at-risk paediatric patients and further study of this association should be undertaken. ©2012 The Author(s)/Acta Paediatrica ©2013 Foundation Acta Paediatrica.

Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease.

PubMed

Yamamoto, Shinji; Yamashina, Kota; Ishikawa, Masaki; Gotoh, Mari; Yagishita, Sosuke; Iwasa, Kensuke; Maruyama, Kei; Murakami-Murofushi, Kimiko; Yoshikawa, Keisuke

2017-07-21

Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis. To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. We demonstrated that 2ccPA suppressed the CoCl 2 -induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model. We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE

Mutation analysis of genes within the dynactin complex in a cohort of hereditary peripheral neuropathies.

PubMed

Tey, S; Ahmad-Annuar, A; Drew, A P; Shahrizaila, N; Nicholson, G A; Kennerson, M L

2016-08-01

The cytoplasmic dynein-dynactin genes are attractive candidates for neurodegenerative disorders given their functional role in retrograde transport along neurons. The cytoplasmic dynein heavy chain (DYNC1H1) gene has been implicated in various neurodegenerative disorders, and dynactin 1 (DCTN1) genes have been implicated in a wide spectrum of disorders including motor neuron disease, Parkinson's disease, spinobulbar muscular atrophy and hereditary spastic paraplegia. However, the involvement of other dynactin genes with inherited peripheral neuropathies (IPN) namely, hereditary sensory neuropathy, hereditary motor neuropathy and Charcot-Marie-Tooth disease is under reported. We screened eight genes; DCTN1-6 and ACTR1A and ACTR1B in 136 IPN patients using whole-exome sequencing and high-resolution melt (HRM) analysis. Eight non-synonymous variants (including one novel variant) and three synonymous variants were identified. Four variants have been reported previously in other studies, however segregation analysis within family members excluded them from causing IPN in these families. No variants of disease significance were identified in this study suggesting the dynactin genes are unlikely to be a common cause of IPNs. However, with the ease of querying gene variants from exome data, these genes remain worthwhile candidates to assess unsolved IPN families for variants that may affect the function of the proteins. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Neuropathy secondary to drugs

MedlinePlus

... drugs URL of this page: //medlineplus.gov/ency/article/000700.htm Neuropathy secondary to drugs To use the sharing features on this page, please enable JavaScript. Neuropathy secondary to drugs is a loss of ...

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

PubMed

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

2015-03-01

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

Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice.

PubMed

Klein, Dennis; Patzkó, Ágnes; Schreiber, David; van Hauwermeiren, Anemoon; Baier, Michaela; Groh, Janos; West, Brian L; Martini, Rudolf

2015-11-01

See Scherer (doi:10.1093/awv279) for a scientific commentary on this article.Charcot-Marie-Tooth type 1 neuropathies are inherited disorders of the peripheral nervous system caused by mutations in Schwann cell-related genes. Typically, no causative cure is presently available. Previous preclinical data of our group highlight the low grade, secondary inflammation common to distinct Charcot-Marie-Tooth type 1 neuropathies as a disease amplifier. In the current study, we have tested one of several available clinical agents targeting macrophages through its inhibition of the colony stimulating factor 1 receptor (CSF1R). We here show that in two distinct mouse models of Charcot-Marie-Tooth type 1 neuropathies, the systemic short- and long-term inhibition of CSF1R by oral administration leads to a robust decline in nerve macrophage numbers by ∼70% and substantial reduction of the typical histopathological and functional alterations. Interestingly, in a model for the dominant X-linked form of Charcot-Marie-Tooth type 1 neuropathy, the second most common form of the inherited neuropathies, macrophage ablation favours maintenance of axonal integrity and axonal resprouting, leading to preserved muscle innervation, increased muscle action potential amplitudes and muscle strengths in the range of wild-type mice. In another model mimicking a mild, demyelination-related Charcot-Marie-Tooth type 1 neuropathy caused by reduced P0 (MPZ) gene dosage, macrophage blockade causes an improved preservation of myelin, increased muscle action potential amplitudes, improved nerve conduction velocities and ameliorated muscle strength. These observations suggest that disease-amplifying macrophages can produce multiple adverse effects in the affected nerves which likely funnel down to common clinical features. Surprisingly, treatment of mouse models mimicking Charcot-Marie-Tooth type 1A neuropathy also caused macrophage blockade, but did not result in neuropathic or clinical improvements

Genetics Home Reference: small fiber neuropathy

MedlinePlus

... Small fiber neuropathy is considered a form of peripheral neuropathy because it affects the peripheral nervous system, which ... Page National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy Information Page Educational Resources (4 links) Johns Hopkins ...

Burn-related peripheral neuropathy: A systematic review.

PubMed

Tu, Yiji; Lineaweaver, William C; Zheng, Xianyou; Chen, Zenggan; Mullins, Fred; Zhang, Feng

2017-06-01

Peripheral neuropathy is the most frequent disabling neuromuscular complication of burns. However, the insidious and progressive onset of burn neuropathy makes it often undiagnosed or overlooked. In our study, we reviewed the current studies on the burn-related peripheral neuropathy to summarize the morbidity, mechanism, detecting method and management of peripheral neuropathy in burn patients. Of the 1533 burn patients included in our study, 98 cases (6.39%) were presented with peripheral neuropathy. Thermal and electrical burns were the most common etiologies. Surgical procedures, especially nerve decompression, showed good effect on functional recovery of both acute and delayed peripheral neuropathy in burn patients. It is noteworthy that, for early detection and prevention of peripheral neuropathy, electrodiagnostic examinations should be performed on burn patients independent of symptoms. Still, the underlying mechanisms of burn-related peripheral neuropathy remain to be clarified. Copyright © 2016 Elsevier Ltd and ISBI. All rights reserved.

Experimental models of demyelination and remyelination.

PubMed

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

2017-08-29

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

[Chronic inflammatory demyelinating polyneuropathy. Findings in 30 patients].

PubMed

Villa, A M; Molina, H; Sanz, O P; Sica, R E

1999-01-01

Chronic demyelinating inflammatory polineuropathy (CIDP) is a disease which was recognized several years ago. However, the mechanism underlying its pathogenesis remains poorly understood. Nevertheless, there are some clues which strongly suggest that it constitutes an autoimmune disease. Since 1992 we have studied 30 cases. All them were clinically assessed and submitted to laboratory investigations encompassing nerve conduction studies, sera proteins immunoelectrophoresis, spinal fluid analysis and sural nerve biopsies. Upon clinical examination the usual findings were weakness, muscle atrophy, absence or diminished tendon jerks, paresthesias and hyposthesias. Electrophysiological studies disclosed marked slowing of the nerve conduction velocities, suggesting demyelination. Sera immunoelectrophoresis detected monoclonal gammopathy in 17% of the studied patients, which was not associated with lymphoproliferative illnesses. Of the patients 79% had increased levels of spinal fluid proteins. Seventeen patients gave their consent for performing a sural nerve biopsy; all the samples showed demyelination. In conclusion, we think that CDIP is a disease which can be recognized when the clinical assessment, the nerve conduction studies and the spinal fluid findings suggest the diagnosis. Although nerve biopsy may be strongly supporting, we believe that it has to be performed only if doubts arise from the clinical, electrophysiological or spinal fluid observations. It is worth noting that its early detection may benefit the patient through the administration of the right therapy precluding the eventual sequelae of the disease.

Progesterone Alleviates Neural Behavioral Deficits and Demyelination with Reduced Degeneration of Oligodendroglial Cells in Cuprizone-Induced Mice

PubMed Central

Su, Le; Liu, Yun-Lai; Cai, Qi-Yan; Zhan, Xiao-Li; Xu, Yan; Zhao, Shi-Fu; Yao, Zhong-Xiang

2013-01-01

Demyelination occurs widely in neurodegenerative diseases. Progesterone has neuroprotective effects, is known to reduce the clinical scores and the inflammatory response. Progesterone also promotes remyelination in experimental autoimmune encephalomyelitis and cuprizone-induced demyelinating brain. However, it still remains unclear whether progesterone can alleviate neural behavioral deficits and demyelination with degeneration of oligodendroglial cells in cuprizone-induced mice. In this study, mice were fed with 0.2% cuprizone to induce demyelination, and treated with progesterone to test its potential protective effect on neural behavioral deficits, demyelination and degeneration of oligodendroglial cells. Our results showed noticeable alleviation of neural behavioral deficits following progesterone treatment as assessed by changes in average body weight, and activity during the open field and Rota-rod tests when compared with the vehicle treated cuprizone group. Progesterone treatment alleviated demyelination as shown by Luxol fast blue staining, MBP immunohistochemical staining, and electron microscopy. There was an obvious decrease in TUNEL and Caspase-3-positive apoptotic cells, and an increase in the number of oligodendroglial cells staining positive for PDGFRα, Olig2, Sox10 and CC-1 antibody in the brains of cuprizone-induced mice after progesterone administration. These results indicate that progesterone can alleviate neural behavioral deficits and demyelination against oligodendroglial cell degeneration in cuprizone-induced mice. PMID:23359803

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

PubMed

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

2018-04-01

As reliable biomarkers of disease activity are lacking, monitoring of therapeutic response in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains a challenge. We sought to determine whether nerve ultrasound and electrophysiology scoring could close this gap. In CIDP patients (fulfilling EFNS/PNS criteria), we performed high-resolution nerve ultrasound to determine ultrasound pattern sum scores (UPSS) and predominant echotexture nerve conduction study scores (NCSS) as well as Medical Research Council sum scores (MRCSS) and inflammatory neuropathy cause and treatment disability scores (INCAT) at baseline and after 12 months of standard treatment. We retrospectively correlated ultrasound morphology with nerve histology when available. 72/80 CIDP patients featured multifocal nerve enlargement, and 35/80 were therapy-naïve. At baseline, clinical scores correlated with NCSS (r 2  = 0.397 and r 2  = 0.443, p < 0.01), but not or hardly with UPSS (Medical Research Council sum scores MRCSS r 2  = 0.013, p = 0.332; inflammatory neuropathy cause and treatment disability scores INCAT r 2  = 0.053, p = 0.048). Longitudinal changes in clinical scores, however, correlated significantly with changes in both UPSS and NCSS (r 2  = 0.272-0.414, p < 0.0001). Combining nerve/fascicle size with echointensity and histology at baseline, we noted 3 distinct classes: 1) hypoechoic enlargement, reflecting active inflammation and onion bulbs; 2) nerve enlargement with additional hyperechogenic fascicles/perifascicular tissue in > 50% of measured segments, possibly reflecting axonal degeneration; and 3) almost no enlargement, reflecting "burned-out" or "cured" disease without active inflammation. Clinical improvement after 12 months was best in patients with pattern 1 (up to 75% vs up to 43% in pattern 2/3, Fisher's exact test p < 0.05). Nerve ultrasound has additional value not only for diagnosis, but also for classification

Diabetic neuropathy and painful diabetic neuropathy: Cinderella complications in South East Asia.

PubMed

Almuhannadi, Hamad; Ponirakis, Georgios; Khan, Adnan; Malik, Rayaz Ahmed

2018-01-01

The most common and debilitating microvascular complication of diabetes is diabetic peripheral neuropathy (DPN), affecting 50-90% of people with diabetes. The major manifestations of DPN are painful (pDPN) and painless diabetic peripheral neuropathy. Painful symptoms, occur in the feet and are worse at night and whilst they alert both the patient and physician, are often misdiagnosed and mismanaged. The devastating presentation of painless neuropathy with loss of sensation is foot ulceration and Charcot foot. The explosion of diabetes, especially in the South East Asian (SEA) region will result in an increasing prevalence of both painful and painless diabetic peripheral neuropathy. PubMed, EMBASE, Medline and Google Scholar databases were searched between 1990 and 2017. This highlights the widely varying prevalence of DPN and pDPN in the World Health Organization (WHO) defined SEA countries and the dearth of published studies, especially in pDPN. We believe this will provide new direction for future research on DPN in the SEA region.

Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies.

PubMed

Salter, Claire G; Beijer, Danique; Hardy, Holly; Barwick, Katy E S; Bower, Matthew; Mademan, Ines; De Jonghe, Peter; Deconinck, Tine; Russell, Mark A; McEntagart, Meriel M; Chioza, Barry A; Blakely, Randy D; Chilton, John K; De Bleecker, Jan; Baets, Jonathan; Baple, Emma L; Walk, David; Crosby, Andrew H

2018-04-01

To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7 , predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction.

Treatment options in painful diabetic neuropathy.

PubMed

Nash, T P

1999-01-01

Diabetic neuropathy is common in patients with diabetes mellitus, and 7.5% of diabetics experience pain from diabetic neuropathy. Complications of diabetes mellitus are more common where control of the disease is not optimal. By improving the control of the disease, both the neuropathy and the pain it can produce may be improved. The pain of diabetic neuropathy can frequently be controlled using analgesics, antidepressants, anticonvulsants, topical capsaicin, and neuromodulation, either alone or in any combination.

Predicting Acute and Persistent Neuropathy Associated with Oxaliplatin

PubMed Central

Alejandro, Linh; Behrendt, Carolyn E.; Chen, Kim; Openshaw, Harry; Shibata, Stephen

2014-01-01

Objectives We sought to predict oxaliplatin-associated peripheral neuropathy during modified FOLFOX6 (mFOLFOX6) therapy. Methods In a 50% female sample, patients with previously untreated, primary or recurrent colorectal cancer were followed through a first course of mFOLFOX6 with oxaliplatin 85 mg/m2 every 2 weeks. Accounting for correlation among a subject's cycles, logistic regression estimated per-cycle risk of acute (under 14 days) and persistent (14 days or more) neuropathy. Proportional hazards regression predicted time to persistent neuropathy. Results Among mFOLFOX6 recipients (n=50, age 58.9 +10.1 years), 36% received concomitant bevacizumab. Of total cycles, 94.2% (422/448) were evaluable. Most (84%) subjects reported neuropathy at least once: 74% reported acute and 48% reported persistent symptoms. On multivariate analysis, risk factors shared by acute and persistent neuropathy were body-surface area >2.0, acute neuropathy in a past cycle, and lower body weight. In addition, risk of acute neuropathy decreased with age (adjusted for renal function and winter season), while risk of persistent neuropathy increased with cumulative dose of oxaliplatin and persistent neuropathy in a past cycle. Concomitant bevacizumab was not a risk factor when administered in Stage IV disease but was associated with persistent neuropathy when administered experimentally in Stage III. Females had no increased risk of either form of neuropathy. After 3 cycles, weight, body-surface area, and prior acute neuropathy predicted time to persistent neuropathy. Conclusions Routinely available clinical factors predict acute and persistent neuropathy associated with oxaliplatin. When validated, the proposed prognostic score for persistent neuropathy can help clinicians counsel patients about chemotherapy. PMID:22547012

Longitudinal patient-oriented outcomes in neuropathy

PubMed Central

Kerber, Kevin; Langa, Kenneth M.; Banerjee, Mousumi; Rodgers, Ann; McCammon, Ryan; Burke, James; Feldman, Eva

2015-01-01

Objective: To evaluate longitudinal patient-oriented outcomes in peripheral neuropathy over a 14-year time period including time before and after diagnosis. Methods: The 1996–2007 Health and Retirement Study (HRS)–Medicare Claims linked database identified incident peripheral neuropathy cases (ICD-9 codes) in patients ≥65 years. Using detailed demographic information from the HRS and Medicare claims, a propensity score method identified a matched control group without neuropathy. Patient-oriented outcomes, with an emphasis on self-reported falls, pain, and self-rated health (HRS interview), were determined before and after neuropathy diagnosis. Generalized estimating equations were used to assess differences in longitudinal outcomes between cases and controls. Results: We identified 953 peripheral neuropathy cases and 953 propensity-matched controls. The mean (SD) age was 77.4 (6.7) years for cases, 76.9 (6.6) years for controls, and 42.1% had diabetes. Differences were detected in falls 3.0 years before neuropathy diagnosis (case vs control; 32% vs 25%, p = 0.008), 5.0 years for pain (36% vs 27%, p = 0.002), and 5.0 years for good to excellent self-rated health (61% vs 74%, p < 0.0001). Over time, the proportion of fallers increased more rapidly in neuropathy cases compared to controls (p = 0.002), but no differences in pain (p = 0.08) or self-rated health (p = 0.9) were observed. Conclusions: In older persons, differences in falls, pain, and self-rated health can be detected 3–5 years prior to peripheral neuropathy diagnosis, but only falls deteriorates more rapidly over time in neuropathy cases compared to controls. Interventions to improve early peripheral neuropathy detection are needed, and future clinical trials should incorporate falls as a key patient-oriented outcome. PMID:26019191

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

DOE Office of Scientific and Technical Information (OSTI.GOV)

Armstrong, R.; Friedrich, V.L. Jr.; Holmes, K.V.

1990-09-01

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

Diabetic peripheral neuropathy, is it an autoimmune disease?

PubMed

Janahi, Noor M; Santos, Derek; Blyth, Christine; Bakhiet, Moiz; Ellis, Mairghread

2015-11-01

Autoimmunity has been identified in a significant number of neuropathies, such as, proximal neuropathies, and autonomic neuropathies associated with diabetes mellitus. However, possible correlations between diabetic peripheral neuropathy and autoimmunity have not yet been fully investigated. This study was conducted to investigate whether autoimmunity is associated with the pathogenesis of human diabetic peripheral neuropathy. A case-control analysis included three groups: 30 patients with diabetic peripheral neuropathy, 30 diabetic control patients without neuropathy, and 30 healthy controls. Blood analysis was conducted to compare the percentages of positive antinuclear antibodies (ANA) between the three groups. Secondary analysis investigated the correlations between the presence of autoimmune antibodies and sample demographics and neurological manifestations. This research was considered as a pilot study encouraging further investigations to take place in the near future. Antinuclear antibodies were significantly present in the blood serum of patients with diabetic peripheral neuropathy in comparison to the control groups (p<0.001). The odds of positive values of ANA in the neuropathy group were 50 times higher when compared to control groups. Secondary analysis showed a significant correlation between the presence of ANA and the neurological manifestation of neuropathy (Neuropathy symptom score, Neuropathy disability score and Vibration Perception Threshold). The study demonstrated for the first time that human peripheral diabetic neuropathy may have an autoimmune aetiology. The new pathogenic factors may lead to the consideration of new management plans involving new therapeutic approaches and disease markers. Copyright © 2015 Elsevier B.V. All rights reserved.

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

PubMed

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

2017-01-24

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

Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

PubMed Central

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

2017-01-01

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes. PMID:28117328

Decreased number and increased volume with mitochondrial enlargement of cerebellar synaptic terminals in a mouse model of chronic demyelination.

PubMed

Nguyen, Huy Bang; Sui, Yang; Thai, Truc Quynh; Ikenaka, Kazuhiro; Oda, Toshiyuki; Ohno, Nobuhiko

2018-05-23

Impaired nerve conduction, axonal degeneration, and synaptic alterations contribute to neurological disabilities in inflammatory demyelinating diseases. Cerebellar dysfunction is associated with demyelinating disorders, but the alterations of axon terminals in cerebellar gray matter during chronic demyelination are still unclear. We analyzed the morphological and ultrastructural changes of climbing fiber terminals in a mouse model of hereditary chronic demyelination. Three-dimensional ultrastructural analyses using serial block-face scanning electron microscopy and immunostaining for synaptic markers were performed in a demyelination mouse model caused by extra copies of myelin gene (PLP4e). At 1 month old, many myelinated axons were observed in PLP4e and wild-type mice, but demyelinated axons and axons with abnormally thin myelin were prominent in PLP4e mice at 5 months old. The density of climbing fiber terminals was significantly reduced in PLP4e mice at 5 months old. Reconstruction of climbing fiber terminals revealed that PLP4e climbing fibers had increased varicosity volume and enlarged mitochondria in the varicosities at 5-month-old mice. These results suggest that chronic demyelination is associated with alterations and loss of climbing fiber terminals in the cerebellar cortex, and that synaptic changes may contribute to cerebellar phenotypes observed in hereditary demyelinating disorders.

The Oligodendrocyte Progenitor Response to Demyelination

DTIC Science & Technology

2006-01-01

DATE 2006 2. REPORT TYPE 3. DATES COVERED 00-00-2006 to 00-00-2006 4. TITLE AND SUBTITLE The Oligodendrocyte Progenitor Response to Demyelination...material in the thesis manuscript entitled: “The Oligodendrocyte Progenitor Response to Demyelination” is appropriately acknowledged and, beyond... oligodendrocyte progenitor (OP) amplification prior to remyelination. Myelin transcription factor 1 (Myt1) influences OP proliferation, differentiation, and

Novel insights on diagnosis, cause and treatment of diabetic neuropathy: focus on painful diabetic neuropathy

PubMed Central

Tavakoli, Mitra; Asghar, Omar; Alam, Uazman; Petropoulos, Ioannis N.; Fadavi, Hassan; Malik, Rayaz A.

2010-01-01

Diabetic neuropathy is common, under or misdiagnosed, and causes substantial morbidity with increased mortality. Defining and developing sensitive diagnostic tests for diabetic neuropathy is not only key to implementing earlier interventions but also to ensure that the most appropriate endpoints are employed in clinical intervention trials. This is critical as many potentially effective therapies may never progress to the clinic, not due to a lack of therapeutic effect, but because the endpoints were not sufficiently sensitive or robust to identify benefit. Apart from improving glycaemic control, there is no licensed treatment for diabetic neuropathy, however, a number of pathogenetic pathways remain under active study. Painful diabetic neuropathy is a cause of considerable morbidity and whilst many pharmacological and nonpharmacological interventions are currently used, only two are approved by the US Food and Drug Administration. We address the important issue of the ‘placebo effect’ and also consider potential new pharmacological therapies as well as nonpharmacological interventions in the treatment of painful diabetic neuropathy. PMID:23148152

Correlation of Michigan neuropathy screening instrument, United Kingdom screening test and electrodiagnosis for early detection of diabetic peripheral neuropathy.

PubMed

Fateh, Hamid R; Madani, Seyed Pezhman; Heshmat, Ramin; Larijani, Bagher

2015-01-01

Almost half of Diabetic Peripheral Neuropathies (DPNs) are symptom-free. Methods including questionnaires and electrodiagnosis (EDx) can be fruitful for easy reach to early diagnosis, correct treatments of diabetic neuropathy, and so decline of complications for instance diabetic foot ulcer and prevention of high costs. The goal of our study was to compare effectiveness of the Michigan neuropathy screening instrument (MNSI), United Kingdom screening test (UKST) and electrophysiological evaluation in confirming diabetic peripheral neuropathy. One hundred twenty five known diabetes mellitus male and female subjects older than 18 with or without symptoms of neuropathy comprised in this research. All of them were interviewed in terms of demographic data, lipid profile, HbA1C, duration of disease, and history of retinopathy, so examined by Michigan neuropathy screening instrument (MNSI), United Kingdom screening test (UKST), and nerve conduction studies (NCS). The collected data were analyzed by SPSS software 18. One hundred twenty five diabetic patients (70 female, 55 male) were recruited in this study with a mean age of 58.7 ± 10.2, and mean duration of diabetes was 10.17 ± 6.9 years. The mean neuropathy score of MNSI and UKST were 2.3 (1.7) and 4.16 (2.9), respectively. Each instrument detected the peripheral neuropathy in 78 (69 %) and 91 (73 %) of patients, respectively. There was a significant relationship between number of neuropathies and mean of diabetes duration and development of retinopathy in both questionnaire evaluations and NCS. By nerve conduction study, neuropathy was detected in 121 (97 %) diabetic patients were reported in order 15 (12 %) mononeuropathy (as 33 % sensory and 67 % motor neuropathy) and 106 (85 %) polyneuropathy (as 31 % motor and 69 % sensorimotor neuropathy). As regards NCS is an objective, simple, and non-invasive tool and also can determine level of damage and regeneration in peripheral nerves, this study

Renal Involvement in Neuropathy, Ataxia, Retinitis Pigmentosa (NARP) Syndrome: A Case Report.

PubMed

Lemoine, Sandrine; Panaye, Marine; Rabeyrin, Maud; Errazuriz-Cerda, Elisabeth; Mousson de Camaret, Bénédicte; Petiot, Philippe; Juillard, Laurent; Guebre-Egziabher, Fitsum

2018-05-01

We report a case of a patient who had the mitochondrial cytopathy complex of neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome diagnosed at age 11 years with a biopsy-proven kidney involvement that progressed to end-stage renal disease at age 21 years. Mutations of mitochondrial DNA (mtDNA) are maternally inherited and lead to mitochondrial cytopathies with predominant neurologic manifestations: psychomotor retardation, epilepsy, ataxia, neuropathy, and myopathy. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. Mutations in the MT-ATP6 gene of mtDNA have been shown to cause NARP syndrome without renal involvement. We report a patient who had NARP syndrome diagnosed at age 11 years in whom glomerular proteinuria was present very early after diagnosis. Although neurologic manifestations were stable over time, he developed worsening proteinuria and kidney function. He started dialysis therapy at age 21 years. Kidney biopsy confirmed the mitochondrial cytopathy histologically, with abnormal mitochondria seen on electron microscopy. The MT-ATP6 gene mutation was detected in the kidney biopsy specimen. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.

PubMed

Kornak, Uwe; Mademan, Inès; Schinke, Marte; Voigt, Martin; Krawitz, Peter; Hecht, Jochen; Barvencik, Florian; Schinke, Thorsten; Gießelmann, Sebastian; Beil, F Timo; Pou-Serradell, Adolf; Vílchez, Juan J; Beetz, Christian; Deconinck, Tine; Timmerman, Vincent; Kaether, Christoph; De Jonghe, Peter; Hübner, Christian A; Gal, Andreas; Amling, Michael; Mundlos, Stefan; Baets, Jonathan; Kurth, Ingo

2014-03-01

Many neurodegenerative disorders present with sensory loss. In the group of hereditary sensory and autonomic neuropathies loss of nociception is one of the disease hallmarks. To determine underlying factors of sensory neurodegeneration we performed whole-exome sequencing in affected individuals with the disorder. In a family with sensory neuropathy with loss of pain perception and destruction of the pedal skeleton we report a missense mutation in a highly conserved amino acid residue of atlastin GTPase 3 (ATL3), an endoplasmic reticulum-shaping GTPase. The same mutation (p.Tyr192Cys) was identified in a second family with similar clinical outcome by screening a large cohort of 115 patients with hereditary sensory and autonomic neuropathies. Both families show an autosomal dominant pattern of inheritance and the mutation segregates with complete penetrance. ATL3 is a paralogue of ATL1, a membrane curvature-generating molecule that is involved in spastic paraplegia and hereditary sensory neuropathy. ATL3 proteins are enriched in three-way junctions, branch points of the endoplasmic reticulum that connect membranous tubules to a continuous network. Mutant ATL3 p.Tyr192Cys fails to localize to branch points, but instead disrupts the structure of the tubular endoplasmic reticulum, suggesting that the mutation exerts a dominant-negative effect. Identification of ATL3 as novel disease-associated gene exemplifies that long-term sensory neuronal maintenance critically depends on the structural organisation of the endoplasmic reticulum. It emphasizes that alterations in membrane shaping-proteins are one of the major emerging pathways in axonal degeneration and suggests that this group of molecules should be considered in neuroprotective strategies.

Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice

PubMed Central

Mozafari, Sabah; Laterza, Cecilia; Roussel, Delphine; Bachelin, Corinne; Marteyn, Antoine; Deboux, Cyrille; Martino, Gianvito; Evercooren, Anne Baron-Van

2015-01-01

Induced pluripotent stem cell–derived (iPS-derived) neural precursor cells may represent the ideal autologous cell source for cell-based therapy to promote remyelination and neuroprotection in myelin diseases. So far, the therapeutic potential of reprogrammed cells has been evaluated in neonatal demyelinating models. However, the repair efficacy and safety of these cells has not been well addressed in the demyelinated adult CNS, which has decreased cell plasticity and scarring. Moreover, it is not clear if these induced pluripotent–derived cells have the same reparative capacity as physiologically committed CNS-derived precursors. Here, we performed a side-by-side comparison of CNS-derived and skin-derived neural precursors in culture and following engraftment in murine models of adult spinal cord demyelination. Grafted induced neural precursors exhibited a high capacity for survival, safe integration, migration, and timely differentiation into mature bona fide oligodendrocytes. Moreover, grafted skin–derived neural precursors generated compact myelin around host axons and restored nodes of Ranvier and conduction velocity as efficiently as CNS-derived precursors while outcompeting endogenous cells. Together, these results provide important insights into the biology of reprogrammed cells in adult demyelinating conditions and support use of these cells for regenerative biomedicine of myelin diseases that affect the adult CNS. PMID:26301815

Hyperacute peripheral neuropathy is a predictor of oxaliplatin-induced persistent peripheral neuropathy.

PubMed

Tanishima, Hiroyuki; Tominaga, Toshiji; Kimura, Masamichi; Maeda, Tsunehiro; Shirai, Yasutsugu; Horiuchi, Tetsuya

2017-05-01

Chronic peripheral neuropathy is a major adverse response to oxaliplatin-containing chemotherapy regimens, but there are no established risk factors pertaining to it. We investigated the efficacy of hyperacute peripheral neuropathy (HAPN) as a predictor of oxaliplatin-induced persistent peripheral neuropathy (PPN). Forty-seven cases of stage III colorectal cancer who received adjuvant chemotherapy with oxaliplatin after curative surgery between January 2010 and August 2014 were retrospectively reviewed. HAPN was defined as acute peripheral neuropathy (APN) occurring on day 1 (≤24 h after oxaliplatin infusion) of the first cycle. PPN was defined as neuropathy lasting >1 year after oxaliplatin discontinuation. The average total dose of oxaliplatin was 625.8 mg/m 2 , and the average relative dose intensity was 66.7%. Twenty-two of the 47 patients (46.8%) had PPN and 13 (27.7%) had HAPN. Male sex, treatment for neuropathy, HAPN, and APN were significantly more frequent in patients with PPN (p = 0.013, 0.02, <0.001, and 0.023, respectively). There was no significant difference in the total oxaliplatin dose between patients with and without PPN (p = 0.061). Multivariate analyses revealed total dose of oxaliplatin and HAPN as independent predictors of PPN [p = 0.015; odds ratio (OR) = 1.005, 95% confidence interval (CI), 1.001-1.009 and p = 0.001; OR = 75.307, 5.3-1070.123, respectively]. The total dose of oxaliplatin was relatively lower in patients with HAPN than that in those without HAPN in the PPN-positive group (not significant, p = 0.068). HAPN was found to be a predictor of oxaliplatin-induced PPN.

Autonomic neuropathy in an alcoholic population.

PubMed

Barter, F; Tanner, A R

1987-12-01

Autonomic nervous system integrity has been assessed in 30 alcoholic subjects and 30 age-sex matched controls using five simple tests of cardiovascular responses. There was evidence of parasympathetic neuropathy alone in five of the alcoholic subjects (16%) and of combined parasympathetic and sympathetic neuropathy in an additional six (20%). None of the controls showed any abnormality. Within the alcoholic group, those with autonomic neuropathy were older, were more likely to be female and to have established alcoholic liver disease. Symptoms were a poor guide to the presence or absence of autonomic neuropathy.

Giant axonal neuropathy-like disease in an Alexandrine parrot (Psittacula eupatria).

PubMed

Stent, Andrew; Gosbell, Matthew; Tatarczuch, Liliana; Summers, Brian A

2015-09-01

A chronic progressive neurological condition in an Alexandrine parrot (Psittacula eupatria) was manifest as intention tremors, incoordination, and seizure activity. Histology revealed large eosinophilic bodies throughout the central nervous system, and electron microscopy demonstrated that these bodies were greatly expanded axons distended by short filamentous structures that aggregated to form long strands. The presence of periodic acid-Schiff-positive material within the neuronal bodies of Purkinje cells and ganglionic neurons is another distinctive feature of this disease. The histological features of this case display some features consistent with giant axonal neuropathy as reported in humans and dogs. Based on investigation of the lineage in this case, an underlying inherited defect is suspected, but some additional factor appears to have altered the specific disease presentation in this bird. © 2015 The Author(s).

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

PubMed

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

2009-09-01

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

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

PubMed

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

2016-01-01

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

Clinical Significance of A Waves in Acute Inflammatory Demyelinating Polyradiculoneuropathy.

PubMed

Lakshminarasimhan, Sindhuja; Venkatraman, Chandramouleeswaran; Vellaichamy, Kannan; Ranganathan, Lakshminarasimhan

2018-05-25

A wave is a late response recognized during recording of F waves. Though they might be seen in healthy subjects, their presence assumes significance in a patient presenting with polyradiculoneuropathy. In this prospective study, 75 patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) were enrolled. They were divided into two groups based on the presence or absence of A waves. Clinical features, electrophysiological parameters and extent of clinical recovery in short-term follow-up were analyzed. A waves were present in 49 out of 75 patients (65%). Most common pattern observed was multiple A waves. Prevalence of A waves was more in lower limb nerves than upper limb nerves. Occurrence of A waves correlated with the presence of conduction block. Patients with A waves had higher Hughes grade (P = 0.003) and lower Medical Research Council sum score at 6 weeks of follow-up (P = 0.04) as compared to patients without A waves. A waves are common in acute inflammatory demyelinating polyradiculoneuropathy form of Guillain Barre syndrome and are considered as a marker of demyelination. Long-term follow-up studies are required to ascertain their significance in prognostication and assessing recovery.

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

PubMed

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

2013-04-01

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

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

PubMed Central

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

2014-01-01

In multiple sclerosis (MS), diffuse degenerative processes in the deep grey matter have been associated with clinical disabilities. We performed a systematic study in MS deep grey matter with a focus on the incidence and topographical distribution of lesions in relation to white matter and cortex in a total sample of 75 MS autopsy patients and 12 controls. In addition, detailed analyses of inflammation, acute axonal injury, iron deposition and oxidative stress were performed. MS deep grey matter was affected by two different processes: the formation of focal demyelinating lesions and diffuse neurodegeneration. Deep grey matter demyelination was most prominent in the caudate nucleus and hypothalamus and could already be seen in early MS stages. Lesions developed on the background of inflammation. Deep grey matter inflammation was intermediate between low inflammatory cortical lesions and active white matter lesions. Demyelination and neurodegeneration were associated with oxidative injury. Iron was stored primarily within oligodendrocytes and myelin fibres and released upon demyelination. In addition to focal demyelinated plaques, the MS deep grey matter also showed diffuse and global neurodegeneration. This was reflected by a global reduction of neuronal density, the presence of acutely injured axons, and the accumulation of oxidised phospholipids and DNA in neurons, oligodendrocytes and axons. Neurodegeneration was associated with T cell infiltration, expression of inducible nitric oxide synthase in microglia and profound accumulation of iron. Thus, both focal lesions as well as diffuse neurodegeneration in the deep grey matter appeared to contribute to the neurological disabilities of MS patients. PMID:24899728

Sciatic neuropathy due to popliteal fossa nerve block.

PubMed

Aubuchon, Adam; Arnold, W David; Bracewell, Anna; Hoyle, J Chad

2017-10-01

Sciatic neuropathy after popliteal nerve block (PNB) for regional anesthesia is considered uncommon but has been increasingly recognized in the literature. We identified a case of sciatic neuropathy that occurred after bunionectomy during which a PNB had been performed. To understand the frequency of PNB-related sciatic neuropathy, we performed a retrospective review of sciatic neuropathies at our center over a 5-year period. Forty-five cases of sciatic neuropathy were reviewed. Similar to earlier reports, common etiologies of sciatic neuropathy, including compression, trauma, fractures, and hip arthroplasty, were noted in the majority of our cases (60%, n = 27). Unexpectedly, PNB was the third most common etiology (16%, n = 7). Our results suggest PNB is a relatively common etiology of sciatic neuropathy and is an important consideration in the differential diagnosis. These findings should urge electromyographers to assess history of PNB in sciatic neuropathies, particularly with onset after surgery. Muscle Nerve 56: 822-824, 2017. © 2017 Wiley Periodicals, Inc.

Rapid screening for inflammatory neuropathies by standardized clinical criteria

PubMed Central

Tramontozzi, Louis A.

2016-01-01

Abstract Background: Delay in recognition and treatment of inflammatory neuropathies increases morbidity and mortality. We have developed and standardized 3 clinical screening criteria that rapidly detect inflammatory neuropathies. Methods: We reviewed all patients with definite large fiber neuropathy in 2 different patient populations: 1 from a private neurology clinic and the other from a tertiary care center. Patients were divided into 2 groups: those with an inflammatory neuropathy and those with a noninflammatory neuropathy. We specifically noted the 3 key neuropathy characteristics: onset, distribution, and associated systemic features (ODS). We studied the sensitivity and specificity of ODS in differentiating between inflammatory and noninflammatory neuropathies. Results: A total of 206 patients were included: 51 from the private clinic and 155 from the tertiary care center. The sensitivity of using ODS in detecting an inflammatory neuropathy was 96% and the specificity was 85%. The positive predictive value of ODS was 0.8 and negative predictive value was 0.97. Conclusions: Rapid screening for inflammatory neuropathies by ODS clinical criteria is highly sensitive and has a high negative predictive value for noninflammatory neuropathies. ODS uses simple clinical criteria to rapidly screen for patients with a potentially treatable form of neuropathy and accelerate their diagnostic evaluation. Classification of evidence: This study provides Class IV evidence that 3 neuropathy characteristics—onset, distribution, and associated systemic features—accurately identify patients with inflammatory neuropathies. PMID:29443273

Demyelination during tumour necrosis factor antagonist therapy for psoriasis: a case report and review of the literature.

PubMed

Mahil, Satveer K; Andrews, Thomasin C; Brierley, Charlotte; Barker, Jonathan N; Smith, Catherine H

2013-02-01

Central nervous system (CNS) demyelination in a patient receiving tumour necrosis factor alpha (TNF-α) antagonist therapy in our practice prompted a search of the literature to assess the evidence for a causal relationship between TNF antagonist therapy and demyelination. We summarise clinical data extracted on 65 reported cases of CNS demyelination in patients receiving TNF antagonist therapy and show that the data are consistent with a drug-related aetiology given the temporal relationship between TNF antagonist initiation and symptoms, de-challenge-re-challenge phenomenon and the later age of disease onset compared with sporadic multiple sclerosis. Research on TNF signalling pathways also suggests a plausible causative role of TNF antagonist therapy in demyelination. However to date, controlled trial and pharmacovigilance data do not show an increased risk of demyelination in patients receiving TNF antagonist therapy. These data may be underpowered to exclude such a risk and pooled, collaborative data from multiple registries are warranted. Given the uncertainty in this area, clinicians should adhere to existing clinical guidance advising avoidance of TNF antagonist therapy in patients with a personal or family history of demyelination, and ensure all suitable patients are enrolled in long term safety registries in countries where these are established.

Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies

PubMed Central

Salter, Claire G.; Beijer, Danique; Hardy, Holly; Barwick, Katy E.S.; Bower, Matthew; Mademan, Ines; De Jonghe, Peter; Deconinck, Tine; Russell, Mark A.; McEntagart, Meriel M.; Chioza, Barry A.; Blakely, Randy D.; Chilton, John K.; De Bleecker, Jan; Baets, Jonathan; Baple, Emma L.

2018-01-01

Objective To identify the genetic cause of disease in 2 previously unreported families with forms of distal hereditary motor neuropathies (dHMNs). Methods The first family comprises individuals affected by dHMN type V, which lacks the cardinal clinical feature of vocal cord paralysis characteristic of dHMN-VII observed in the second family. Next-generation sequencing was performed on the proband of each family. Variants were annotated and filtered, initially focusing on genes associated with neuropathy. Candidate variants were further investigated and confirmed by dideoxy sequence analysis and cosegregation studies. Thorough patient phenotyping was completed, comprising clinical history, examination, and neurologic investigation. Results dHMNs are a heterogeneous group of peripheral motor neuron disorders characterized by length-dependent neuropathy and progressive distal limb muscle weakness and wasting. We previously reported a dominant-negative frameshift mutation located in the concluding exon of the SLC5A7 gene encoding the choline transporter (CHT), leading to protein truncation, as the likely cause of dominantly-inherited dHMN-VII in an extended UK family. In this study, our genetic studies identified distinct heterozygous frameshift mutations located in the last coding exon of SLC5A7, predicted to result in the truncation of the CHT C-terminus, as the likely cause of the condition in each family. Conclusions This study corroborates C-terminal CHT truncation as a cause of autosomal dominant dHMN, confirming upper limb predominating over lower limb involvement, and broadening the clinical spectrum arising from CHT malfunction. PMID:29582019

A case report of hereditary neuropathy with liability to pressure palsies accompanied by type 2 diabetes mellitus and psoriasis.

PubMed

Li, Jing; Niu, Bing; Wang, Xiaoling; Hu, Huaiqiang; Cao, Bingzhen

2017-05-01

Hereditary neuropathy with liability to pressure palsy (HNPP) is an episodic, multifocal neuropathy, with a typical clinical presentation of recurrent transient pressure palsies, which is induced by a PMP22 deletion. Another neuropathy caused by a PMP22 duplication is Charcot-Marie-Tooth disease type 1A (CMT1A). PMP22 is a gene coding a protein called peripheral myelin protein 22 (PMP22), which plays an essential role in the formation and maintenance of compact myelin. Coexistence of type 2 diabetes mellitus (T2DM) and CMT1A has been reported in many work, however HNPP patients with T2DM are rare, and comorbidity of HNPP and psoriasis has not been reported previously. Electrophysiological features of HNPP has been found progressing with aging. Patient concerns: Here we present a 20-year-old man who exhibited lower extremity weakness and foot drop as the initial manifestation. HNPP was diagnosed on the basis of clinical features, positive sural nerve biopsy findings, and genetic testing results. Moreover, physical examination, blood/urine glucose test, and diabetes-related autoantibodies investigations demonstrated that he had psoriasis and T2DM. The electrophysiological manifestations revealed profound demyelinating injuries and axonal injuries in distal peripheral nerves and facial nerves, which were more severe than general HNPP cases. The young patient was treated with continuous subcutaneous insulin infusion and blood glucose monitoring, and then transferred to oral acarbose therapy. The psoriatic lesions were treated with calcipotriol ointment. In the follow-up, the right leg weakness was alleviated, and his gait was improved. The findings indicate that diabetes mellitus may have an impact on the severity of HNPP. Physicians should consider that worsening of symptoms might result from newly diagnosed diabetes mellitus while treating patients with HNPP.

Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord.

PubMed

Keirstead, H S; Levine, J M; Blakemore, W F

1998-02-01

Elucidation of the response of oligodendrocyte progenitor cell populations to demyelination in the adult central nervous system (CNS) is critical to understanding why remyelination fails in multiple sclerosis. Using the anti-NG2 monoclonal antibody to identify oligodendrocyte progenitor cells, we have documented their response to antibody-induced demyelination in the dorsal column of the adult rat spinal cord. The number of NG2+ cells in the vicinity of demyelinated lesions increased by 72% over the course of 3 days following the onset of demyelination. This increase in NG2+ cell numbers did not reflect a nonspecific staining of reactive cells, as GFAP, OX-42, and Rip antibodies did not co-localise with NG2 + cells in double immunostained tissue sections. NG2 + cells incorporated BrdU 48-72 h following the onset of demyelination. After the onset of remyelination (10-14 days), the number of NG2+ cells decreased to 46% of control levels and remained consistently low for 2 months. When spinal cords were exposed to 40 Grays of x-irradiation prior to demyelination, the number of NG2+ cells decreased to 48% of control levels by 3 days following the onset of demyelination and remained unchanged at 3 weeks. Since 40 Grays of x-irradiation kills dividing cells, these studies illustrate a responsive and nonresponsive NG2+ cell population following demyelination in the adult spinal cord and suggest that the responsive NG2+ cell population does not renew itself.

[Inherited thrombocytopenias].

PubMed

Leverger, G; Petit, A; Fasola, S; Landman-Parker, J; Favier, R

2010-08-01

Secondary causes of thrombocytopenia as immunologic thrombopenia purpura, or ITP, are far more common than inherited causes, which even as a group, are rare. Nevertheless, diagnosis is important and progress made in uncovering the molecular basis of these disorders has contributed greatly to our knowledge of these diseases. Inherited thrombocytopenias are a heterogeneous group of disorders. Different criteria have been suggested to classify the forms, such as the inheritance mechanism and the platelet volume as well as the associated platelet dysfunctions or clinical abnormality. This paper describes the clinical and biological data, and current knowledge of the molecular findings of inherited thrombocytopenia, allowing a diagnostic approach to these diseases. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Lack of Neuropathy-Related Phenotypes in Hint1 Knockout Mice

PubMed Central

Seburn, Kevin L.; Morelli, Kathryn H.; Jordanova, Albena; Burgess, Robert W.

2014-01-01

Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that involves primarily motor dysfunction and is usually associated with neuromyotonia, i.e. prolonged muscle contraction resulting from hyperexcitability of the peripheral nerve. Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 were normal in appearance and in behavioral tests or motor performance, although they moved slower and for a smaller fraction of time than wild-type (WT) mice in an open field arena. Muscles, neuromuscular junctions, and nodes of Ranvier are anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at 4 and 13 months of age. Axons were slightly smaller than those in WT mice at 4 months of age, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. Using electromyography, we were unable to detect neuromyotonia, even using supra-physiological stimuli and stressors such as reduced temperature or 3,4 diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia. PMID:24918641

[Tunnel neuropathies].

PubMed

Averochkin, A I; Shtul'man, D R

1991-01-01

Analysis is made of 261 patients operated on for tunnel neuropathies. Of these, there were 152 men and 109 women aged 15 to 82 years, the mean age being 46 years. Among 22 patterns of neuropathy, there dominated compression of the ulnar nerve in the cubital canal (104 patients) and compression of the median nerve in the carpal canal (76 patients) accounting for 69% of all the cases. 76 patients had two and more tunnel syndromes; double operative interventions were made in 23 patients. 58 patients (22.2%) recovered, 163 (62.75%) improved, no changes were recorded in 40 (15.3%) patients. There were no deteriorations.

[Distal hereditary motor neuropathy].

PubMed

Devic, P; Petiot, P

2011-11-01

Distal hereditary motor neuropathy (dHMN), also known as spinal muscular atrophy, represents a group of clinically and genetically heterogeneous diseases caused by degenerations of spinal motor neurons and leading to distal muscle weakness and wasting. Nerve conduction studies reveal a pure motor axonopathy and needle examination shows chronic denervation. dHMN were initially subdivided into seven subtypes according to mode of inheritance, age at onset, and clinical evolution. Recent studies have shown that these subtypes are still heterogeneous at the molecular genetic level and novel clinical and genetic entities have been characterized. To date, mutations in 11 different genes have been identified for autosomal-dominant, autosomal-recessive, and X-linked recessive dHMN. Most of the genes encode protein involved in housekeeping functions, endosomal trafficking, axonal transport, translation synthesis, RNA processing, oxidative stress response and apoptosis. The pathophysiological mechanisms underlying dHMN seem to be related to the "length-dependent" death of motor neurons of the anterior horn of the spinal cord, likely because their large axons have higher metabolic requirements for maintenance. dHMN remain heterogeneous at the clinical and molecular genetic level. The molecular pathomechanisms explaining why mutations in these ubiquitously expressed housekeeping genes result in the selective involvement of spinal motor neurons remain to be unravelled. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Peripheral neuropathy in HIV: prevalence and risk factors

PubMed Central

Evans, Scott R.; Ellis, Ronald J.; Chen, Huichao; Yeh, Tzu-min; Lee, Anthony J.; Schifitto, Giovanni; Wu, Kunling; Bosch, Ronald J.; McArthur, Justin C.; Simpson, David M.; Clifford, David B.

2011-01-01

Objectives To estimate neuropathic sign/symptom rates with initiation of combination antiretroviral therapy (cART) in HIV-infected ART-naive patients, and to investigate risk factors for: peripheral neuropathy and symptomatic peripheral neuropathy (SPN), recovery from peripheral neuropathy/SPN after neurotoxic ART (nART) discontinuation, and the absence of peripheral neuropathy/SPN while on nART. Design AIDS Clinical Trials Group (ACTG) Longitudinal Linked Randomized Trial participants who initiated cART in randomized trials for ART-naive patients were annually screened for symptoms/signs of peripheral neuropathy. ART use and disease characteristics were collected longitudinally. Methods Peripheral neuropathy was defined as at least mild loss of vibration sensation in both great toes or absent/hypoactive ankle reflexes bilaterally. SPN was defined as peripheral neuropathy and bilateral symptoms. Generalized estimating equation logistic regression was used to estimate associations. Results Two thousand, one hundred and forty-one participants were followed from January 2000 to June 2007. Rates of peripheral neuropathy/SPN at 3 years were 32.1/8.6% despite 87.1% with HIV-1RNA 400 copies/ml or less and 70.3% with CD4 greater than 350 cells/µl. Associations with higher odds of peripheral neuropathy included older patient age and current nART use. Associations with higher odds of SPN included older patient age, nART use, and history of diabetes mellitus. Associations with lower odds of recovery after nART discontinuation included older patient age. Associations with higher odds of peripheral neuropathy while on nART included older patient age and current protease inhibitor use. Associations with higher odds of SPN while on nART included older patient age, history of diabetes, taller height, and protease inhibitor use. Conclusion Signs of peripheral neuropathy remain despite virologic/immunologic control but frequently occurs without symptoms. Aging is a risk factor for

Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery.

PubMed

Mei, Feng; Lehmann-Horn, Klaus; Shen, Yun-An A; Rankin, Kelsey A; Stebbins, Karin J; Lorrain, Daniel S; Pekarek, Kara; A Sagan, Sharon; Xiao, Lan; Teuscher, Cory; von Büdingen, H-Christian; Wess, Jürgen; Lawrence, J Josh; Green, Ari J; Fancy, Stephen Pj; Zamvil, Scott S; Chan, Jonah R

2016-09-27

Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.

TRPA1 deficiency is protective in cuprizone-induced demyelination-A new target against oligodendrocyte apoptosis.

PubMed

Sághy, Éva; Sipos, Éva; Ács, Péter; Bölcskei, Kata; Pohóczky, Krisztina; Kemény, Ágnes; Sándor, Zoltán; Szőke, Éva; Sétáló, György; Komoly, Sámuel; Pintér, Erika

2016-12-01

Multiple sclerosis is a chronic inflammatory, demyelinating degenerative disease of the central nervous system. Current treatments target pathological immune responses to counteract the inflammatory processes. However, these drugs do not restrain the long-term progression of clinical disability. For this reason, new therapeutic approaches and identification of novel target molecules are needed to prevent demyelination or promote repair mechanisms. Transient Receptor Potential Ankyrin 1 (TRPA1) is a nonselective cation channel with relatively high Ca 2+ permeability. Its pathophysiological role in central nervous system disorders has not been elucidated yet. In the present study, we aimed to assess the distribution of TRPA1 in the mouse brain and reveal its regulatory role in the cuprizone-induced demyelination. This toxin-induced model, characterized by oligodendrocyte apoptosis and subsequent primary demyelination, allows us to investigate the nonimmune aspects of multiple sclerosis. We found that TRPA1 is expressed on astrocytes in the mouse central nervous system. Interestingly, TRPA1 deficiency significantly attenuated cuprizone-induced demyelination by reducing the apoptosis of mature oligodendrocytes. Our data suggest that TRPA1 regulates mitogen-activated protein kinase pathways, as well as transcription factor c-Jun and a proapoptotic Bcl-2 family member (Bak) expression resulting in enhanced oligodendrocyte apoptosis. In conclusion, we propose that TRPA1 receptors enhancing the intracellular Ca 2+ concentration modulate astrocyte functions, and influence the pro or anti-apoptotic pathways in oligodendrocytes. Inhibition of TRPA1 receptors might successfully diminish the degenerative pathology in multiple sclerosis and could be a promising therapeutic target to limit central nervous system damage in demyelinating diseases. GLIA 2016;64:2166-2180. © 2016 Wiley Periodicals, Inc.

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches

PubMed Central

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

2018-01-01

Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4+ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4+ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4+ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions. PMID:29659554

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

PubMed

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

2014-12-01

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

Treatment of peripheral neuropathies.

PubMed Central

Hallett, M; Tandon, D; Berardelli, A

1985-01-01

There are three general approaches to treatment of peripheral neuropathy. First, an attempt should be made to reverse the pathophysiological process if its nature can be elucidated. Second, nerve metabolism can be stimulated and regeneration encouraged. Third, even if the neuropathy itself cannot be improved, symptomatic therapy can be employed. This review outlines the options available for each approach. PMID:3003254

Treatment of painful diabetic peripheral neuropathy.

PubMed

Rosenberg, Casandra J; Watson, James C

2015-02-01

Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. To discuss current treatment recommendations for painful diabetic peripheral neuropathy. Literature review. Systematic review of the literature discussing treatment of painful diabetic peripheral neuropathy. Existing treatment guidelines were studied and compared. Painful diabetic peripheral neuropathy occurs in about one in six people with diabetes. This condition impairs quality of life and increases healthcare costs. Treatment recommendations exist, but individual patient therapy can require a trial-and-error approach. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Adequate medication titration and a reasonable trial period should be allowed. The treatment of painful diabetic peripheral neuropathy can be challenging, but effective management can improve patient's quality of life. Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. © The International Society for Prosthetics and Orthotics 2014.

Cutaneous manifestations of diabetic peripheral neuropathy.

PubMed

Dogiparthi, S N; Muralidhar, K; Seshadri, K G; Rangarajan, S

2017-01-01

There is a rise in number of people diagnosed with Diabetes Mellitus. The incidence is rising in modern Indian society because of Industrial development and drastically changing lifestyles. Diabetic neuropathies are microvascular disorders that are usually associated with the duration of Diabetes. Among the various forms, the most common is Diabetic Peripheral Neuropathy. The disease if neglected leads to chronic ulcer formation leading to amputations frequently. Hence the aim of this study is to document the early cutaneous changes and create an early awareness in the importance of controlling Diabetes. The study consisted of 205 patients with Type 2 DM. Participant's neuropathy status was determined based on Neuropathy Disability Score and Diabetic Neuropathy Symptom Score. Among the Skin changes documented, the common changes seen were: Peripheral hair loss in 185 (90.2%), Xerosis in 168 (82%), Anhydrosis in 162 (79%), Plantar Fissures in 136 (66.3%), Plantar Ulcer in 80 (39%), common nail changes documented were Onychomycosis in 165 (80.5%) and Onychauxis in 53 (25.8%) patients in relation to the occupation and duration of Diabetes mellitus. In conclusion, it is important to control glycemic levels in the all stages of Diabetes and institute foot care measures to prevent the complications of neuropathy.

Herpes Zoster Optic Neuropathy.

PubMed

Kaufman, Aaron R; Myers, Eileen M; Moster, Mark L; Stanley, Jordan; Kline, Lanning B; Golnik, Karl C

2018-06-01

Herpes zoster optic neuropathy (HZON) is a rare manifestation of herpes zoster ophthalmicus (HZO). The aim of our study was to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON. A retrospective chart review was performed at multiple academic eye centers with the inclusion criteria of all eyes presenting with optic neuropathy within 1 month of cutaneous zoster of the ipsilateral trigeminal dermatome. Data were collected regarding presenting features, treatment regimen, and visual acuity outcomes. Six patients meeting the HZON inclusion criteria were identified. Mean follow-up was 2.75 months (range 0.5-4 months). Herpes zoster optic neuropathy developed at a mean of 14.1 days after initial rash (range 6-30 days). Optic neuropathy was anterior in 2 eyes and retrobulbar in 4 eyes. Other manifestations of HZO included keratoconjunctivitis (3 eyes) and iritis (4 eyes). All patients were treated with systemic antiviral therapy in addition to topical and/or systemic corticosteroids. At the last follow-up, visual acuity in 3 eyes had improved relative to presentation, 2 eyes had worsened, and 1 eye remained the same. The 2 eyes that did not receive systemic corticosteroids had the best observed final visual acuity. Herpes zoster optic neuropathy is an unusual but distinctive complication of HZO. Visual recovery after HZON is variable. Identification of an optimal treatment regiment for HZON could not be identified from our patient cohort. Systemic antiviral agents are a component of HZON treatment regimens. Efficacy of systemic corticosteroids for HZON remains unclear and should be considered on a case-by-case basis.

Painful Traumatic Trigeminal Neuropathy.

PubMed

Rafael, Benoliel; Sorin, Teich; Eli, Eliav

2016-08-01

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantitative fluorescence-polymerase chain reaction assay for the detection of the duplication of the Charcot Marie Tooth disease type 1A critical region.

PubMed

De Toffol, Simona; Bellone, Emilia; Dulcetti, Francesca; Ruggeri, Anna Maria; Maggio, Pietro Paolo; Pulimeno, Maria Rosaria; Mandich, Paola; Maggi, Federico; Simoni, Giuseppe; Grati, Francesca Romana

2010-04-01

Charcot Marie Tooth (CMT) syndrome is the most common hereditary peripheral neuropathy, with an incidence of about 1 in 2500. The subtype 1A (CMT1A) is caused by a tandem duplication of a 1.5-Mb region encompassing the PMP22 gene. Conventional short tandem repeat (STR) analysis can reveal this imbalance if a triallelic pattern, defining with certainty the presence of duplication, is present. In case of duplication with a biallelic pattern, it can only indicate a semiquantitative dosage of the fluorescence intensity ratio of the two fragments. In this study we developed a quantitative fluorescence-PCR using seven highly informative STRs within the CMT1A critical region that successfully disclosed or excluded the presence of the pathogenic imbalance in a cohort of 60 samples including 40 DNAs from samples with the CMT1A duplication previously characterized with two different molecular approaches, and 20 diagnostic samples from 10 members of a five-generation pedigree segregating CMT1A, 8 unrelated cases and 2 prenatal samples. The application of the quantitative fluorescence-PCR using STRs located in the critical region could be a reliable method to evaluate the presence of the PMP22 duplication for the diagnosis and classification of hereditary neuropathies in asymptomatic subjects with a family history of inherited neuropathy, in prenatal samples in cases with one affected parent, and in unrelated patients with a sporadic demyelinating neuropathy with clinical features resembling CMT (i.e., pes cavus with hammer toes) or with conduction velocities in the range of CMT1A.

Diagnosis and therapeutic options for peripheral vasculitic neuropathy

PubMed Central

2015-01-01

Vasculitis can affect the peripheral nervous system alone (nonsystemic vasculitic neuropathy) or can be a part of primary or secondary systemic vasculitis. In cases of pre-existing systemic vasculitis, the diagnosis can easily be made, whereas suspected vasculitic neuropathy as initial or only manifestation of vasculitis requires careful clinical, neurophysiological, laboratory and histopathological workout. The typical clinical syndrome is mononeuropathia multiplex or asymmetric neuropathy, but distal-symmetric neuropathy can frequently be seen. Standard treatments include steroids, azathioprine, methotrexate and cyclophosphamide. More recently the B-cell antibody rituximab and intravenous immunoglobulins have shown to be effective in some vasculitic neuropathy types. PMID:25829955

HSMNR belongs to the most frequent types of hereditary neuropathy in the Czech Republic and is twice more frequent than HMSNL.

PubMed

Šafka Brožková, D; Haberlová, J; Mazanec, R; Laštůvková, J; Seeman, P

2016-08-01

Hereditary motor and sensory neuropathy type Russe (HMSNR), also called CMT4G, is an autosomal recessive inherited peripheral neuropathy (IPN) caused by a founder mutation in the HK1 gene. HMSNR affects only patients with Roma origin, similar to the better known HMSN type Lom clarified earlier. By testing IPN patients with Roma origin, we realized that HMSNR affects surprisingly many patients in the Czech Republic. HMSNR is one of the most frequent types of IPN in this country and appears to be twice more frequent than HMSNL. Pronounced lower limb atrophies and severe deformities often lead to walking inability in even young patients, but hands are usually only mildly affected even after many years of disease duration. The group of 20 patients with HMSNR presented here is the first report about the prevalence of HMSNR from central Europe. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Galectin-3 controls the response of microglial cells to limit cuprizone-induced demyelination.

PubMed

Hoyos, H C; Rinaldi, M; Mendez-Huergo, S P; Marder, M; Rabinovich, G A; Pasquini, J M; Pasquini, L A

2014-02-01

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that plays an important role in inflammatory and neurodegenerative diseases. Cuprizone (CPZ)-induced demyelination is characterized by the loss of mature oligodendrocytes (OLG) by apoptosis, myelin sheath degeneration and recruitment of microglia and astrocytes to the lesioned area. We compared CPZ-induced demyelination of 8-week-old Lgals3(-/-) vs WT mice. Lgals3(-/-) mice displayed a similar susceptibility to CPZ-induced demyelination up to the fifth week, as evaluated by MBP immunostaining and electronic microscopy. However, OLG progenitors (OPC) generated in CPZ-treated Lgals3(-/-) mice showed diminished arborization, suggesting decreased ability of these cells to differentiate. Surprisingly, while WT mice experienced spontaneous remyelination in the fifth week of CPZ treatment-even though the CPZ diet was maintained up to sixth week-Lgals3(-/-) mice lacked this capacity and suffered continuous demyelination up to the sixth week, accompanied by pronounced astroglial activation. Moreover, after 2weeks of CPZ treatment, WT and Lgals3(-/-) mice showed lower innate anxiety as compared with respective naive mice, but only CPZ-treated Lgals3(-/-) mice showed decreased locomotor activity and exhibited spatial working memory impairment. Expression of Gal-3 increased during CPZ-induced demyelination in microglia but not in astrocytes. While CPZ-treated WT mice displayed heightened microglial activation associated with ED1 expression and pronounced upregulation of the phagocytic receptor TREM-2b, this effect was not observed in CPZ-treated Lgals3(-/-) mice which, in spite of showing an increased number of microglia, these cells evidenced caspase-3 activation. Our results indicate that Gal-3 is expressed in microglial cells to modulate their phenotype, facilitating the onset of remyelination and OLG differentiation. © 2013.

Demyelination in Multiple Sclerosis: Reprogramming Energy Metabolism and Potential PPARγ Agonist Treatment Approaches.

PubMed

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

2018-04-16

Demyelination in multiple sclerosis (MS) cells is the site of several energy metabolic abnormalities driven by dysregulation between the opposed interplay of peroxisome proliferator-activated receptor γ (PPARγ) and WNT/β-catenin pathways. We focus our review on the opposing interactions observed in demyelinating processes in MS between the canonical WNT/β-catenin pathway and PPARγ and their reprogramming energy metabolism implications. Demyelination in MS is associated with chronic inflammation, which is itself associated with the release of cytokines by CD4⁺ Th17 cells, and downregulation of PPARγ expression leading to the upregulation of the WNT/β-catenin pathway. Upregulation of WNT/β-catenin signaling induces activation of glycolytic enzymes that modify their energy metabolic behavior. Then, in MS cells, a large portion of cytosolic pyruvate is converted into lactate. This phenomenon is called the Warburg effect, despite the availability of oxygen. The Warburg effect is the shift of an energy transfer production from mitochondrial oxidative phosphorylation to aerobic glycolysis. Lactate production is correlated with increased WNT/β-catenin signaling and demyelinating processes by inducing dysfunction of CD4⁺ T cells leading to axonal and neuronal damage. In MS, downregulation of PPARγ decreases insulin sensitivity and increases neuroinflammation. PPARγ agonists inhibit Th17 differentiation in CD4⁺ T cells and then diminish release of cytokines. In MS, abnormalities in the regulation of circadian rhythms stimulate the WNT pathway to initiate the demyelination process. Moreover, PPARγ contributes to the regulation of some key circadian genes. Thus, PPARγ agonists interfere with reprogramming energy metabolism by directly inhibiting the WNT/β-catenin pathway and circadian rhythms and could appear as promising treatments in MS due to these interactions.

Multifocal visual evoked potential in optic neuritis, ischemic optic neuropathy and compressive optic neuropathy

PubMed Central

Jayaraman, Manju; Gandhi, Rashmin Anilkumar; Ravi, Priya; Sen, Parveen

2014-01-01

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. PMID:24088641

Symptomatic and Electrodiagnostic Features of Peripheral Neuropathy in Scleroderma.

PubMed

Paik, Julie J; Mammen, Andrew L; Wigley, Fredrick M; Shah, Ami A; Hummers, Laura K; Polydefkis, Michael

2016-08-01

To determine the prevalence of peripheral neuropathy in scleroderma. The prevalence of length-dependent peripheral neuropathy was rigorously assessed using signs and symptoms of neuropathy derived from the Total Neuropathy Score (TNS), and standardized nerve conduction study (NCS). All subjects underwent TNS and NCS. Those who were symptomatic or had NCS evidence of peripheral neuropathy underwent laboratory evaluation for secondary causes of neuropathy. A total of 130 subjects were approached for participation and 60 enrolled. Of the 60 subjects, 50 (83.3%) were female and 37 (61.7%) were of the limited cutaneous subtype. The mean ± SD age was 55 ± 11.1 years, and mean ± SD disease duration was 15.3 ± 10.1 years. A total of 17 of 60 (28%) had evidence of a peripheral neuropathy as defined by the presence of neuropathic symptoms on the TNS (12 of 60) and/or electrophysiologic evidence of neuropathy (5 subjects with neuropathic symptoms and 5 without neuropathic symptoms). Subjects with neuropathy were more likely to be male (60% versus 40%; P = 0.02), African American (41% versus 4.6%; P = 0.001), have diabetes mellitus (17.7% versus 0%; P = 0.02), have limited cutaneous scleroderma (82.3% versus 53.5%; P = 0.04), and have anti-U1 RNP antibodies (23.5% versus 0%; P = 0.009) than those without neuropathy. A potential nonscleroderma etiology for the peripheral neuropathy such as diabetes mellitus was found in 82.3% (14 of 17) of subjects with neuropathy. While symptoms or objective evidence of peripheral neuropathy are common among patients with scleroderma, the cause may often be attributed to comorbid nonscleroderma-related conditions. © 2016, American College of Rheumatology.

Neuropathy in a petrol sniffer.

PubMed

Hall, D M; Ramsey, J; Schwartz, M S; Dookun, D

1986-09-01

A 4 year old boy developed a profound motor neuropathy after repeated deliberate inhalation of petroleum vapour. The condition was characterised by extreme slowing of the nerve conduction velocity. He made a gradual recovery over six months. The neuropathy was attributed to the N-hexane component of petroleum.

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

PubMed Central

Starobova, Hana; Vetter, Irina

2017-01-01

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches. PMID:28620280

Hereditary neuropathy with liability to pressure palsy: an investigation in a rare and large Chinese family.

PubMed

He, Yuan; Wu, Qiang; Xu, Zhipeng; Wang, Qianqian; Wang, Weili; Li, Dezhong; Liu, Wanhong; He, Xiaohua

2012-01-01

Hereditary neuropathy with liability to pressure palsy (HNPP), mainly associated with the peripheral myelin protein 22 (PMP22) gene, is generally an autosomal-dominant inherited peripheral neuropathy. The present large family including four generations provides an exciting opportunity to gain important insights into HNPP in China. A large 43-member family with ten members suspected to be affected by HNPP was studied. Neurologic examinations, electrophysiological and neuropathological studies and molecular genetic testing were used for these kindred. Clinically, the proband had limb hyposthenia and atrophy, and his mother showed declined tendon reflexes in the right lower limb. Electrophysiologically, sensory and motor nerve conduction velocities were generalized reduced. Sural nerve biopsy for the proband showed focal thickesning of the myelin sheaths. Furthermore, real-time quantitative PCR demonstrated that the PMP22 gene has a higher Ct value than reference gene in all suspected patients. These results indicated that the family is indeed a rare and large pedigree of HNPP caused by the deletion of PMP22 gene. Given that the suspected patient in the fourth generation is absent, this family is still worthy of further follow-up study. Copyright © 2012 S. Karger AG, Basel.

Identification of small molecules that improve ATP synthesis defects conferred by Leber’s hereditary optic neuropathy mutations

PubMed Central

Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino

2016-01-01

Inherited mitochondrial complex I mutations cause blinding Leber's hereditary Optic Neuropathy (LHON), for which no curative therapy exists. A specific biochemical consequence of LHON mutations in the presence of trace rotenone was observed: deficient complex I-dependent ATP synthesis (CIDAS) and mitochondrial O2 consumption, proportional to the clinical severity of the three primary LHON mutations. We optimized a high-throughput assay of CIDAS to screen 1600 drugs to 2, papaverine and zolpidem, which protected CIDAS in LHON cells concentration-dependently. TSPO and cAMP were investigated as protective mechanisms, but a conclusive mechanism remains to be elucidated; next steps include testing in animal models. PMID:27497748

Remyelination after Lysophosphatidyl Choline-Induced Demyelination Is Stimulated by Bone Marrow Stromal Cell-Derived Oligoprogenitor Cell Transplantation.

PubMed

Nazm Bojnordi, M; Ghasemi, H H; Akbari, E

2015-01-01

Bone marrow stromal cells (BMSCs) are a desirable cell source that may be useful for the treatment of neurodegenerative diseases given their capacity to differentiate into various types of cells. The current study aimed to investigate whether oligoprogenitor cell (OPC)-derived BMSCs have therapeutic benefits in an animal model of local demyelination. BMSCs were transdifferentiated into OPCs using a defined culture medium supplemented with a combination of inducers. The differentiation capacity of the BMSCs was evaluated at the end of the induction phase by assessing the expression levels of the glial-specific markers oligodendrocyte transcription factor 2 and O4 surface antigen. Local demyelination was induced in the corpus callosum of adult female rats via direct injection of lysophosphatidylcholine (LPC) followed by engraftment of BMSC-generated OPCs. The rats were divided into sham control, vehicle control, and cell-transplanted groups. The changes in the extent of demyelination and the robustness of the remyelination event were assessed using Luxol Fast Blue staining and immunohistochemical analysis 1 week after LPC injection and 2 weeks after cell transplantation. Consequently, transplantation of OPCs into the demyelinated corpus callosum model resulted in differentiation of the cells into mature oligodendrocytes that were immunopositive for myelin basic protein. Furthermore, OPC transplantation mitigated demyelination and augmented remyelination relative to controls. These findings suggest that BMSC-derived OPCs can be utilized in therapeutic approaches for the management of demyelination-associated diseases such as multiple sclerosis. © 2015 S. Karger AG, Basel.

Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies.

PubMed

Dohrn, Maike F; Glöckle, Nicola; Mulahasanovic, Lejla; Heller, Corina; Mohr, Julia; Bauer, Christine; Riesch, Erik; Becker, Andrea; Battke, Florian; Hörtnagel, Konstanze; Hornemann, Thorsten; Suriyanarayanan, Saranya; Blankenburg, Markus; Schulz, Jörg B; Claeys, Kristl G; Gess, Burkhard; Katona, Istvan; Ferbert, Andreas; Vittore, Debora; Grimm, Alexander; Wolking, Stefan; Schöls, Ludger; Lerche, Holger; Korenke, G Christoph; Fischer, Dirk; Schrank, Bertold; Kotzaeridou, Urania; Kurlemann, Gerhard; Dräger, Bianca; Schirmacher, Anja; Young, Peter; Schlotter-Weigel, Beate; Biskup, Saskia

2017-12-01

Hereditary neuropathies comprise a wide variety of chronic diseases associated to more than 80 genes identified to date. We herein examined 612 index patients with either a Charcot-Marie-Tooth phenotype, hereditary sensory neuropathy, familial amyloid neuropathy, or small fiber neuropathy using a customized multigene panel based on the next generation sequencing technique. In 121 cases (19.8%), we identified at least one putative pathogenic mutation. Of these, 54.4% showed an autosomal dominant, 33.9% an autosomal recessive, and 11.6% an X-linked inheritance. The most frequently affected genes were PMP22 (16.4%), GJB1 (10.7%), MPZ, and SH3TC2 (both 9.9%), and MFN2 (8.3%). We further detected likely or known pathogenic variants in HINT1, HSPB1, NEFL, PRX, IGHMBP2, NDRG1, TTR, EGR2, FIG4, GDAP1, LMNA, LRSAM1, POLG, TRPV4, AARS, BIC2, DHTKD1, FGD4, HK1, INF2, KIF5A, PDK3, REEP1, SBF1, SBF2, SCN9A, and SPTLC2 with a declining frequency. Thirty-four novel variants were considered likely pathogenic not having previously been described in association with any disorder in the literature. In one patient, two homozygous mutations in HK1 were detected in the multigene panel, but not by whole exome sequencing. A novel missense mutation in KIF5A was considered pathogenic because of the highly compatible phenotype. In one patient, the plasma sphingolipid profile could functionally prove the pathogenicity of a mutation in SPTLC2. One pathogenic mutation in MPZ was identified after being previously missed by Sanger sequencing. We conclude that panel based next generation sequencing is a useful, time- and cost-effective approach to assist clinicians in identifying the correct diagnosis and enable causative treatment considerations. © 2017 International Society for Neurochemistry.

[Leber hereditary optic neuropathy].

PubMed

Mazunin, I O; Volodko, N V

2018-01-01

Leber hereditary optic neuropathy is characterized by bilateral, painless loss of vision in children and young adults (generally up to 25 years old). Since its first description in 1871, the understanding of its etiology and pathogenesis has improved considerably. The article considers Leber neuropathy from the points of view of ophthalmology, neurology and molecular genetics, and presents data on experimental treatment methods, one of which is undergoing clinical trial.

Querectin improves myelin repair of optic chiasm in lyolecithin-induced focal demyelination model.

PubMed

Naeimi, Reza; Baradaran, Saeideh; Ashrafpour, Manouchehr; Moghadamnia, Ali Akbar; Ghasemi-Kasman, Maryam

2018-05-01

Although the beneficial effects of quercetin on oligodendrocyte precursor cell (OPCs) population has been evaluated in-vitro, there are few studies about the effects of quercetin on myelin repair in the context of demyelination. The aim of this study was to investigate the effects of querectin on functional recovery and myelin repair of optic chiasm in lysolecithin (LPC)-induced demyelination model. Demyelination was induced by local injection of LPC 1% (2 μl) into rat optic chiasm. Querectin at doses 25 or 50 mg/kg was administrated daily by oral gavage for 7 or 14 days post LPC. Visual evoked potential (VEPs) recordings were used to assess the functional property of the optic pathway. Immunostaining and myelin staining were performed on brain sections 7 or 14 days post lesion. Electrophysiological data indicated that LPC injection increased the latency of VEPs waves and quercetin effectively reduced the delay of visual signals. The level of glial activation was alleviated in animals under treatment of quercetin compared to vehicle group. Furthermore, quercetin treatment decreased the extent of demyelination areas and increased the remyelination process following LPC injection. Overall, our findings indicate that quercetin could remarkably improve the functional recovery of the optic pathway by its protective effects on myelin sheath and attenuation of glial activation. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Diabetic corneal neuropathy: clinical perspectives.

PubMed

Bikbova, Guzel; Oshitari, Toshiyuki; Baba, Takayuki; Bikbov, Mukharram; Yamamoto, Shuichi

2018-01-01

Diabetic keratopathy is characterized by impaired innervation of the cornea that leads to decreased sensitivity, with resultant difficulties with epithelial wound healing. These difficulties in wound healing put patients at risk for ocular complications such as surface irregularities, corneal infections, and stromal opacification. Pathological changes in corneal innervations in diabetic patients are an important early indicator of diabetic neuropathy. The decrease in corneal sensitivity is strongly correlated with the duration of diabetes as well as the severity of the neuropathy. This review presents recent findings in assessing the ocular surface as well as the recent therapeutic strategies for optimal management of individuals with diabetes who are susceptible to developing diabetic neuropathy.

Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system

PubMed Central

Gonzalez, Ginez A.; Hofer, Matthias P.; Syed, Yasir A.; Amaral, Ana I.; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R. N.

2016-01-01

Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models. PMID:27554391

Demyelination of vestibular nerve axons in unilateral Ménière's disease.

PubMed

Spencer, Robert F; Sismanis, Aristides; Kilpatrick, Jefferson K; Shaia, Wayne T

2002-11-01

We conducted a study to determine whether vestibular nerves in patients with unilateral Ménière's disease whose symptoms are refractory to medical management exhibit neuropathologic changes. We also endeavored to determine whether retrocochlear abnormalities are primary or secondary factors in the disease process. To these ends, we obtained vestibular nerve segments from five patients during retrosigmoid (posterior fossa) neurectomy, immediately fixed them, and processed them for light and electron microscopy. We found that all five segments exhibited moderate to severe demyelination with axonal sparing. Moreover, we noted that reactive astrocytes produced an extensive proliferation of fibrous processes and that the microglia assumed a phagocytic role. We conclude that the possible etiologies of demyelination include viral and/or immune-mediated factors similar to those seen in other demyelinating diseases, such as multiple sclerosis and Guillain-Barré syndrome. Our findings suggest that some forms of Ménière's disease that are refractory to traditional medical management might be the result of retrocochlear pathology that affects the neuroglial portion of the vestibular nerve.

Neuropathy in a petrol sniffer.

PubMed Central

Hall, D M; Ramsey, J; Schwartz, M S; Dookun, D

1986-01-01

A 4 year old boy developed a profound motor neuropathy after repeated deliberate inhalation of petroleum vapour. The condition was characterised by extreme slowing of the nerve conduction velocity. He made a gradual recovery over six months. The neuropathy was attributed to the N-hexane component of petroleum. PMID:3021070

Sonographic evaluation of peripheral nerves in subtypes of Guillain-Barré syndrome.

PubMed

Mori, Atsuko; Nodera, Hiroyuki; Takamatsu, Naoko; Maruyama-Saladini, Keiko; Osaki, Yusuke; Shimatani, Yoshimitsu; Kaji, Ryuji

2016-05-15

Sonography of peripheral nerves can depict alteration of nerve sizes that could reflect inflammation and edema in inflammatory and demyelinating neuropathies. Guillain-Barré syndrome (GBS). Information on sonographic comparison of an axonal subtype (acute motor [and sensory] axonal neuropathy [AMAN and AMSAN]) and a demyelinating subtype (acute inflammatory demyelinating polyneuropathy [AIDP]) has been sparse. Sonography of peripheral nerves and cervical nerve roots were prospectively recorded in patients with GBS who were within three weeks of disease onset. Five patients with AIDP and nine with AMAN (n=6)/AMSAN (n=3) were enrolled. The patients with AIDP showed evidence of greater degrees of demyelination (e.g., slower conduction velocities and increased distal latencies) than those with AMAN/AMSAN. The patients with AIDP tended to show enlarged nerves in the proximal segments and in the cervical roots, whereas the patients with AMAN/AMSAN had greater enlargement in the distal neve segment, especially in the median nerve (P = 0.03; Wrist-axilla cross-sectional ratio). In this small study, two subtypes of GBS showed different patterns of involvement that might reflect different pathomechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

Metronidazole: newly recognized cause of autonomic neuropathy.

PubMed

Hobson-Webb, Lisa D; Roach, E Steve; Donofrio, Peter D

2006-05-01

Metronidazole is a commonly used antibiotic prescribed for the treatment of anaerobic and protozoal infections of the gastrointestinal and genitourinary tracts. It is associated with numerous neurologic complications, including peripheral neuropathy. Neuropathy is typically detected in patients on chronic therapy, although it has been documented in those taking large doses for acute infections. Numerous case reports have been published describing motor and sensory neuropathy, yet autonomic neuropathy has not been described with metronidazole use. A previously healthy 15-year-old girl presented with complaints of burning pain in her feet following a short course of metronidazole for vaginitis. She could obtain pain relief only by submerging her feet in ice water. Examination revealed cold and swollen lower extremities that became erythematous and very warm when removed from the ice water. Temperature perception was reduced to the upper third of the shin bilaterally. Deep tendon reflexes and strength were preserved. Nerve conduction studies demonstrated a peripheral neuropathy manifested by reduced sensory nerve and compound muscle action potentials. Reproducible sympathetic skin potential responses could not be obtained in the hand and foot, providing evidence of a concurrent autonomic neuropathy. A thorough evaluation revealed no other cause for her condition. Repeated nerve conduction studies and sympathetic skin potentials returned to normal over the course of 6 months, paralleling the patient's clinical improvement. Metronidazole is a potential cause of reversible autonomic neuropathy.

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy

PubMed Central

Devaux, Jérôme J.; Miura, Yumako; Fukami, Yuki; Inoue, Takayuki; Manso, Constance; Belghazi, Maya; Sekiguchi, Kenji; Kokubun, Norito; Ichikawa, Hiroo; Wong, Anna Hiu Yi

2016-01-01

Objective: We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. Methods: In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested. Results: Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155–negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n = 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes. Conclusion: Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. PMID:26843559

Neurofascin-155 IgG4 in chronic inflammatory demyelinating polyneuropathy.

PubMed

Devaux, Jérôme J; Miura, Yumako; Fukami, Yuki; Inoue, Takayuki; Manso, Constance; Belghazi, Maya; Sekiguchi, Kenji; Kokubun, Norito; Ichikawa, Hiroo; Wong, Anna Hiu Yi; Yuki, Nobuhiro

2016-03-01

We report the clinical and serologic features of Japanese patients with chronic inflammatory demyelinating polyneuropathy (CIDP) displaying anti-neurofascin-155 (NF155) immunoglobulin G4 (IgG4) antibodies. In sera from 533 patients with CIDP, anti-NF155 IgG4 antibodies were detected by ELISA. Binding of IgG antibodies to central and peripheral nerves was tested. Anti-NF155 IgG4 antibodies were identified in 38 patients (7%) with CIDP, but not in disease controls or normal participants. These patients were younger at onset as compared to 100 anti-NF155-negative patients with CIDP. Twenty-eight patients (74%) presented with sensory ataxia, 16 (42%) showed tremor, 5 (13%) presented with cerebellar ataxia associated with nystagmus, 3 (8%) had demyelinating lesions in the CNS, and 20 of 25 (80%) had poor response to IV immunoglobulin. The clinical features of the antibody-positive patients were statistically more frequent as compared to negative patients with CIDP (n = 100). Anti-NF155 IgG antibodies targeted similarly central and peripheral paranodes. Anti-NF155 IgG4 antibodies were associated with a subgroup of patients with CIDP showing a younger age at onset, ataxia, tremor, CNS demyelination, and a poor response to IV immunoglobulin. The autoantibodies may serve as a biomarker to improve patients' diagnosis and guide treatments. © 2016 American Academy of Neurology.

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

PubMed Central

2014-01-01

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

New Treatments for Nonarteritic Anterior Ischemic Optic Neuropathy.

PubMed

Foroozan, Rod

2017-02-01

Despite increasing knowledge about the risk factors and clinical findings of nonarteritic anterior ischemic optic neuropathy (NAION), the treatment of this optic neuropathy has remained limited and without clear evidence-based benefit. Historical treatments of NAION are reviewed, beginning with the Ischemic Optic Neuropathy Decompression Trial. More recent treatments are placed within the historical context and illustrate the need for evidence-based therapy for ischemic optic neuropathy. Copyright © 2016 Elsevier Inc. All rights reserved.

Association between MTHFR variant and diabetic neuropathy.

PubMed

Kakavand Hamidi, Armita; Radfar, Mania; Amoli, Mahsa M

2018-02-01

Methylene-tetrahydrofolate reductase (MTHFR) gene variant may play an important role in the pathophysiology of diabetes and its complications due to its influence on plasma homocysteine levels and also its effect on scavenging peroxynitrite radicals. Diabetic peripheral neuropathy (DPN) is one of the most common diabetic chronic complications. The aim of this study was to investigate the relationship between diabetic neuropathy and MTHFR gene C677T and 1298A ⁄C polymorphisms. Patients with type 2 diabetes N=248 were enrolled in the study, consisting of patients with neuropathy (N=141) and patients without neuropathy (N=107). MTHFR C677T polymorphism was analyzed using polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP) of genomic DNA for genotyping of samples. 1298A/C polymorphism was evaluated using ARMS-PCR. There was a significant difference in MTHFR polymorphism between the groups with and without neuropathy. Our results suggest that MTHFR 677 variant confer risk for diabetic neuropathy among Iranian patients with type 2 diabetes. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury.

PubMed

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

2017-02-08

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

Creatine Enhances Mitochondrial-Mediated Oligodendrocyte Survival After Demyelinating Injury

PubMed Central

Nanescu, Sonia E.

2017-01-01

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

Corneal markers of diabetic neuropathy.

PubMed

Pritchard, Nicola; Edwards, Katie; Shahidi, Ayda M; Sampson, Geoff P; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

2011-01-01

Diabetic neuropathy is a significant clinical problem that currently has no effective therapy, and in advanced cases, leads to foot ulceration and lower limb amputation. The accurate detection, characterization and quantification of this condition are important in order to define at-risk patients, anticipate deterioration, monitor progression, and assess new therapies. This review evaluates novel corneal methods of assessing diabetic neuropathy. Two new noninvasive corneal markers have emerged, and in cross-sectional studies have demonstrated their ability to stratify the severity of this disease. Corneal confocal microscopy allows quantification of corneal nerve parameters and noncontact corneal esthesiometry, the functional correlate of corneal structure, assesses the sensitivity of the cornea. Both these techniques are quick to perform, produce little or no discomfort for the patient, and are suitable for clinical settings. Each has advantages and disadvantages over traditional techniques for assessing diabetic neuropathy. Application of these new corneal markers for longitudinal evaluation of diabetic neuropathy has the potential to reduce dependence on more invasive, costly, and time-consuming assessments, such as skin biopsy.

[Demyelinating disease and vaccination of the human papillomavirus].

PubMed

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

2011-04-16

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

Diffusion-weighted imaging and demyelinating diseases: new aspects of an old advanced sequence.

PubMed

Rueda-Lopes, Fernanda C; Hygino da Cruz, Luiz C; Doring, Thomas M; Gasparetto, Emerson L

2014-01-01

The purpose of this article is to discuss classic applications in diffusion-weighted imaging (DWI) in demyelinating disease and progression of DWI in the near future. DWI is an advanced technique used in the follow-up of demyelinating disease patients, focusing on the diagnosis of a new lesion before contrast enhancement. With technical advances, diffusion-tensor imaging; new postprocessing techniques, such as tract-based spatial statistics; new ways of calculating diffusion, such as kurtosis; and new applications for DWI and its spectrum are about to arise.

Identifying Common Genetic Risk Factors of Diabetic Neuropathies

PubMed Central

Witzel, Ini-Isabée; Jelinek, Herbert F.; Khalaf, Kinda; Lee, Sungmun; Khandoker, Ahsan H.; Alsafar, Habiba

2015-01-01

Type 2 diabetes mellitus (T2DM) is a global public health problem of epidemic proportions, with 60–70% of affected individuals suffering from associated neurovascular complications that act on multiple organ systems. The most common and clinically significant neuropathies of T2DM include uremic neuropathy, peripheral neuropathy, and cardiac autonomic neuropathy. These conditions seriously impact an individual’s quality of life and significantly increase the risk of morbidity and mortality. Although advances in gene sequencing technologies have identified several genetic variants that may regulate the development and progression of T2DM, little is known about whether or not the variants are involved in disease progression and how these genetic variants are associated with diabetic neuropathy specifically. Significant missing heritability data and complex disease etiologies remain to be explained. This article is the first to provide a review of the genetic risk variants implicated in the diabetic neuropathies and to highlight potential commonalities. We thereby aim to contribute to the creation of a genetic-metabolic model that will help to elucidate the cause of diabetic neuropathies, evaluate a patient’s risk profile, and ultimately facilitate preventative and targeted treatment for the individual. PMID:26074879

Peripheral neuropathy in prediabetes and the metabolic syndrome.

PubMed

Stino, Amro M; Smith, Albert G

2017-09-01

Peripheral neuropathy is a major cause of disability worldwide. Diabetes is the most common cause of neuropathy, accounting for 50% of cases. Over half of people with diabetes develop neuropathy, and diabetic peripheral neuropathy (DPN) is a major cause of reduced quality of life due to pain, sensory loss, gait instability, fall-related injury, and foot ulceration and amputation. Most patients with non-diabetic neuropathy have cryptogenic sensory peripheral neuropathy (CSPN). A growing body of literature links prediabetes, obesity and metabolic syndrome to the risk of both DPN and CSPN. This association might be particularly strong in type 2 diabetes patients. There are no effective medical treatments for CSPN or DPN, and aggressive glycemic control is an effective approach to neuropathy risk reduction only in type 1 diabetes. Several studies suggest lifestyle-based treatments that integrate dietary counseling with exercise might be a promising therapeutic approach to early DPN in type 2 diabetes and CSPN associated with prediabetes, obesity and metabolic syndrome. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

[Two novel pathogenic mutations of GAN gene identified in a patient with giant axonal neuropathy].

PubMed

Wang, Juan; Ma, Qingwen; Cai, Qin; Liu, Yanna; Wang, Wei; Ren, Zhaorui

2016-06-01

To explore the disease-causing mutations in a patient suspected for giant axonal neuropathy(GAN). Target sequence capture sequencing was used to screen potential mutations in genomic DNA extracted from peripheral blood sample of the patient. Sanger sequencing was applied to confirm the detected mutation. The mutation was verified among 400 GAN alleles from 200 healthy individuals by Sanger sequencing. The function of the mutations was predicted by bioinformatics analysis. The patient was identified as a compound heterozygote carrying two novel pathogenic GAN mutations, i.e., c.778G>T (p.Glu260Ter) and c.277G>A (p.Gly93Arg). Sanger sequencing confirmed that the c.778G>T (p.Glu260Ter) mutation was inherited from his father, while c.277G>A (p.Gly93Arg) was inherited from his mother. The same mutations was not found in the 200 healthy individuals. Bioinformatics analysis predicted that the two mutations probably caused functional abnormality of gigaxonin. Two novel GAN mutations were detected in a patient with GAN. Both mutations are pathogenic and can cause abnormalities of gigaxonin structure and function, leading to pathogenesis of GAN. The results may also offer valuable information for similar diseases.

Chronic Inflammatory Demyelinating Polyneuropathy

PubMed Central

Dimachkie, Mazen M.; Barohn, Richard J.

2014-01-01

Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system.

PubMed

Matsushima, G K; Morell, P

2001-01-01

Myelin of the adult CNS is vulnerable to a variety of metabolic, toxic, and autoimmune insults. That remyelination can ensue, following demyelinating insult, has been well demonstrated. Details of the process of remyelination are, however difficult to ascertain since in most experimental models of demyelination/remyelination the severity, localization of lesion site, or time course of the pathophysiology is variable from animal to animal. In contrast, an experimental model in which massive demyelination can be reproducibly induced in large areas of mouse brain is exposure to the copper chelator, cuprizone, in the diet. We review work from several laboratories over the past 3 decades, with emphasis on our own recent studies, which suggest an overall picture of cellular events involved in demyelination/remyelination. When 8 week old C57BL/6 mice are fed 0.2% cuprizone in the diet, mature olidgodendroglia are specifically insulted (cannot fulfill the metabolic demand of support of vast amounts of myelin) and go through apoptosis. This is closely followed by recruitment of microglia and phagoctytosis of myelin. Studies of myelin gene expression, coordinated with morphological studies, indicate that even in the face of continued metabolic challenge, oligodendroglial progenitor cells proliferate and invade demyelinated areas. If the cuprizone challenge is terminated, an almost complete remyelination takes place in a matter of weeks. Communication between different cell types by soluble factors may be inferred. This material is presented in the context of a model compatible with present data -- and which can be tested more rigorously with the cuprizone model. The reproducibility of the model indicates that it may allow for testing of manipulations (e.g. available knockouts or transgenics on the common genetic background, or pharmacological treatments) which may accelerate or repress the process of demyelination and or remyelination.

Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene.

PubMed

Frasquet, Marina; Lupo, Vincenzo; Chumillas, María José; Vázquez-Costa, Juan Francisco; Espinós, Carmen; Sevilla, Teresa

2018-04-15

PHARC (Polyneuropathy, Hearing loss, Ataxia, Retinitis pigmentosa and Cataracts) (MIM# 612674) is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene. We evaluated two Spanish siblings affected with pes cavus, sensorimotor neuropathy, hearing loss, retinitis pigmentosa and juvenile cataracts in whom the genetic test of ABHD12 revealed a novel homozygous frameshift mutation, c.211_223del (p.Arg71Tyrfs*26). The earliest clinical manifestation in these patients was a demyelinating neuropathy manifested with a Charcot-Marie-Tooth phenotype over three decades. Progressive hearing loss, cataracts and retinitis pigmentosa appeared after the age of 30. We herein describe the complete clinical picture of these two patients, and focus particularly on neuropathy characteristics. This study supports the fact that although PHARC is rare, its phenotype is very characteristic and we should include its study in patients affected with demyelinating polyneuropathy, hearing loss and retinopathy. Copyright © 2018 Elsevier B.V. All rights reserved.

Electrodiagnostic and clinical aspects of Guillain-Barré syndrome: an analysis of 142 cases.

PubMed

Gupta, Deepak; Deepak, Gupta; Nair, Muraleedharan; Muraleedharan, Nair; Baheti, Neeraj N; Sarma, P Sankara; Sarma, Sankara P; Kuruvilla, Abraham; Abraham, Kuruvilla

2008-12-01

The incidence of Guillain-Barré syndrome (GBS) and its subtypes varies throughout the world. We present a retrospective analysis of 142 GBS cases, treated at our center, aimed at classifying GBS electrophysiologically, to study the sequential electrophysiological changes in cases with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and to look for any clinical and cerebrospinal fluid parameters that can also help in distinguishing the subtypes. One hundred twenty-one (85.2%) cases had AIDP, 15 (10.6%) had acute motor axonal neuropathy, and 6 (4.2%) were unclassifiable. Motor conduction blocks and temporal dispersion could be observed from days 3 and 5 onward, respectively. Progression of motor conduction slowing in AIDP was most impressive in the median nerves. Varying affection of deep tendon reflexes, cranial nerves, and cerebrospinal fluid albuminocytological dissociation can also help make a distinction between AIDP and acute motor axonal neuropathy. Sural sparing, a marker of demyelinating neuropathy, is more commonly seen in later than in early stages of AIDP.

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination.

PubMed

Palumbo, S; Toscano, C D; Parente, L; Weigert, R; Bosetti, F

2011-07-01

Phospholipases A(2) (PLA(2)) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of pro-inflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA(2) enzymes and the terminal prostagland in levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for 6 weeks to allow spontaneous remyelination. We found that after 4-6 weeks of cuprizone, sPLA(2)(V) and cPLA(2), but not iPLA(2)(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA(2)(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE(2), PGD(2), PGI(2) and TXB(2) were also increased during demyelination. During remyelination, none of the PLA(2) isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE(2), PGI(2) and PGD(2) levels returned to normal, whereas TXB(2) was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time-dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and

Time-dependent changes in the brain arachidonic acid cascade during cuprizone-induced demyelination and remyelination

PubMed Central

Palumbo, S.; Toscano, C.D.; Parente, L.; Weigert, R.; Bosetti, F.

2011-01-01

Phospholipases A2 (PLA2) are the enzymatic keys for the activation of the arachidonic acid (AA) cascade and the subsequent synthesis of proinflammatory prostanoids (prostaglandins and tromboxanes). Prostanoids play critical roles in the initiation and modulation of inflammation and their levels have been reported increased in several neurological and neurodegenerative disorders, including multiple sclerosis (MS). Here, we aimed to determine whether brain expression PLA2 enzymes and the terminal prostaglandin levels are changed during cuprizone-induced demyelination and in the subsequent remyelination phase. Mice were given the neurotoxicant cuprizone through the diet for six weeks to induce brain demyelination. Then, cuprizone was withdrawn and mice were returned to a normal diet for six weeks to allow spontaneous remyelination. We found that after 4–6 weeks of cuprizone, sPLA2(V) and cPLA2, but not iPLA2(VI), gene expression was upregulated in the cortex, concomitant with an increase in the expression of astrocyte and microglia markers. Cyclooxygenase (COX)-2 gene expression was consistently upregulated during all the demyelination period, whereas COX-1 sporadically increased only at week 5 of cuprizone exposure. However, we found that at the protein level only sPLA2(V) and COX-1 were elevated during demyelination, with COX-1 selectively expressed by activated and infiltrated microglia/macrophages and astrocytes. Levels of PGE2, PGD2, PGI2 and TXB2 were also increased during demyelination. During remyelination, none of the PLA2 isoforms was significantly changed, whereas COX-1 and -2 were sporadically upregulated only at the gene expression level. PGE2, PGI2, and PGD2 levels returned to normal, whereas TXB2 was still upregulated after 3 weeks of cuprizone withdrawal. Our study characterizes for the first time time-dependent changes in the AA metabolic pathway during cuprizone-induced demyelination and the subsequent remyelination and suggests that sPLA2(V) is

Peripheral neuropathy in HIV: an analysis of evidence-based approaches.

PubMed

Nicholas, Patrice K; Corless, Inge B; Evans, Linda A

2014-01-01

Peripheral neuropathy is a common and vexing symptom for people living with HIV infection (PLWH). Neuropathy occurs in several different syndromes and is identified in the literature as distal sensory polyneuropathy or distal sensory peripheral neuropathy. More recently, the HIV literature has focused on the syndrome as painful HIV-associated sensory neuropathy, addressing the symptom rather than the underlying pathophysiology. Assessment of neuropathy in PLWH is critical and must be incorporated into nursing practice for each visit. Neuropathy has been attributed to the direct effects of HIV, exposure to antiretroviral medications (particularly the nucleoside reverse transcriptase inhibitors), advanced immune suppression, and comorbid tuberculosis infection and exposure to antituberculosis medications. Evidence supports the importance of addressing neuropathy in PLWH with pharmacologic treatment regimens and complementary/alternative approaches. This paper examines the pathophysiology, evidence, and approaches to managing peripheral neuropathy. A case study has been included to illustrate a patient's experience with neuropathy symptoms. Copyright © 2014 Association of Nurses in AIDS Care. Published by Elsevier Inc. All rights reserved.

Sensory chronic inflammatory demyelinating polyneuropathy: an under-recognized entity?

PubMed

Ayrignac, Xavier; Viala, Karine; Koutlidis, Régine Morizot; Taïeb, Guillaume; Stojkovic, Tanya; Musset, Lucille; Léger, Jean-Marc; Fournier, Emmanuel; Maisonobe, Thierry; Bouche, Pierre

2013-11-01

Sensory chronic inflammatory demyelinating polyneuropathy (CIDP) can be difficult to diagnose. We report 22 patients with chronic sensory polyneuropathy with ≥1 clinical sign atypical for chronic idiopathic axonal polyneuropathy (CIAP) but no electrodiagnostic criteria for CIDP. Clinical signs atypical for CIAP were: sensory ataxia (59%), generalized areflexia (36%), cranial nerve involvement (32%), rapid upper limb involvement (40%), and age at onset ≤55 years (50%). Additional features were: normal sensory nerve action potentials (36%), abnormal radial/normal sural pattern (23%), abnormal somatosensory evoked potentials (SSEPs) (100%), elevated cerebrospinal fluid (CSF) protein (73%), and demyelinating features in 5/7 nerve biopsies. Over 90% of patients responded to immunotherapy. We conclude that all patients had sensory CIDP. Sensory CIDP patients can be misdiagnosed as having CIAP. If atypical clinical/electrophysiologic features are present, we recommend performing SSEPs and CSF examination. Nerve biopsy should be restricted to disabled patients if other examinations are inconclusive. Copyright © 2013 Wiley Periodicals, Inc.

Alphabet soup: making sense of genetic testing in CMT.

PubMed

Lawson, Victoria; Gharibshahi, Shahram

2010-09-01

The diagnosis of inherited neuropathies can be challenging in several ways. First, a hereditary neuropathy must be suspected. Although some family histories are clear with multiple members affected, other families require directed inquiry. Second, even when a hereditary neuropathy is clear, it can be difficult to make a genetic characterization. The field of genotyping is expanding so rapidly, it is difficult to know what tests to order. The authors share their guidelines for the diagnosis of inherited neuropathies. © Thieme Medical Publishers.

Genetics Home Reference: distal hereditary motor neuropathy, type II

MedlinePlus

... hereditary motor neuropathy, type II Distal hereditary motor neuropathy, type II Printable PDF Open All Close All ... the expand/collapse boxes. Description Distal hereditary motor neuropathy, type II is a progressive disorder that affects ...

Remote acute demyelination after focal proton radiation therapy for optic nerve meningioma.

PubMed

Redjal, Navid; Agarwalla, Pankaj K; Dietrich, Jorg; Dinevski, Nikolaj; Stemmer-Rachamimov, Anat; Nahed, Brian V; Loeffler, Jay S

2015-08-01

We present a unique patient with delayed onset, acute demyelination that occurred distant to the effective field of radiation after proton beam radiotherapy for an optic nerve sheath meningioma. The use of stereotactic radiotherapy as an effective treatment modality for some brain tumors is increasing, given technological advances which allow for improved targeting precision. Proton beam radiotherapy improves the precision further by reducing unnecessary radiation to surrounding tissues. A 42-year-old woman was diagnosed with an optic nerve sheath meningioma after initially presenting with vision loss. After biopsy of the lesion to establish diagnosis, the patient underwent stereotactic proton beam radiotherapy to a small area localized to the tumor. Subsequently, the patient developed a large enhancing mass-like lesion with edema in a region outside of the effective radiation field in the ipsilateral frontal lobe. Given imaging features suggestive of possible primary malignant brain tumor, biopsy of this new lesion was performed and revealed an acute demyelinating process. This patient illustrates the importance of considering delayed onset acute demyelination in the differential diagnosis of enhancing lesions in patients previously treated with radiation. Copyright © 2015 Elsevier Ltd. All rights reserved.

Epidemiology of Peripheral Neuropathy: An Indian Perspective

PubMed Central

Trivedi, Sweety; Pandit, Alak; Ganguly, Goutam; Das, Shyamal Kumar

2017-01-01

Peripheral neuropathy (PN) is a common disorder and presents as diagnostic and therapeutic challenge to physicians and neurologists. In epidemiological studies from India from various regions the overall prevalence of PN varied from 5 to 2400 per 10,000 population in various community studies. India is composed of a multiethnic, multicultural population who are exposed to different adverse environmental factors such as arsenic and lead. Use of different chemotherapeutic agents with propensity to affect peripheral nerves, increasing methods of diagnosis of connective tissue disorders and use of immunomodulating drugs, growing aging population is expected to change the spectrum and burden of peripheral neuropathy in the community. The other important aspect of peripheral neuropathies is in terms of the geographical and occupational distribution especially of toxic neuropathies like arsenic which is common in eastern belt; lead, mercury and organo-phosphorous compounds where occupational exposures are major sources. Inflammatory neuropathies either due to vasculitis or G B Syndrome, chronic inflammatory polyradiculopathies are another major group of neuropathies which is increasing due to increase longevity of Indian subjects and immunological impairment, also adds to morbidity of the patients and are potentially treatable. Leprous neuropathy is common in India and although its frequency is significantly decreasing because of national control program yet pure neuritic form still remains a cause of concern and similar is the case with another infective cause like diptheric neurpathy. Thus this article is an attempt to cover major categories and also highlight the areas where further studies are needed. PMID:28904445

Clinical research for neuropathies.

PubMed

Kaufmann, Petra

2012-05-01

The National Institutes of Health (NIH) has a long-standing commitment to neuropathy research. From 2005-2009, the NIH has committed US $115 million each year. A collaborative effort between researchers and patients can accelerate the translation of pre-clinical discoveries into better treatments for neuropathy patients. Clinical trials are needed to test these new treatments, but they can only be implemented in a timely fashion if patients with neuropathies are willing to participate. This perspective focuses on the value of having various outlets for informing both the patients and the physicians about existing clinical research opportunities and on the potential benefit of establishing patient registries to help with trial recruitment. Once data have been collected, there is a need to broadly share the data in order to inform future trials, and a first step would be to harmonize data collection by using Common Data Elements (CDEs). Published 2012. This article is a U.S. Government work and is in the public domain in the USA.

Lymphotoxin beta receptor (Lt betaR): dual roles in demyelination and remyelination and successful therapeutic intervention using Lt betaR-Ig protein.

PubMed

Plant, Sheila R; Iocca, Heather A; Wang, Ying; Thrash, J Cameron; O'Connor, Brian P; Arnett, Heather A; Fu, Yang-Xin; Carson, Monica J; Ting, Jenny P-Y

2007-07-11

Inflammation mediated by macrophages is increasingly found to play a central role in diseases and disorders that affect a myriad of organs, prominent among these are diseases of the CNS. The neurotoxicant-induced, cuprizone model of demyelination is ideally suited for the analysis of inflammatory events. Demyelination on exposure to cuprizone is accompanied by predictable microglial activation and astrogliosis, and, after cuprizone withdrawal, this activation reproducibly diminishes during remyelination. This study demonstrates enhanced expression of lymphotoxin beta receptor (Lt betaR) during the demyelination phase of this model, and Lt betaR is found in areas enriched with microglial and astroglial cells. Deletion of the Lt betaR gene (Lt betaR-/-) resulted in a significant delay in demyelination but also a slight delay in remyelination. Inhibition of Lt betaR signaling by an Lt betaR-Ig fusion decoy protein successfully delayed demyelination in wild-type mice. Unexpectedly, this Lt betaR-Ig decoy protein dramatically accelerated the rate of remyelination, even after the maximal pathological disease state had been reached. This strongly indicates the beneficial role of Lt betaR-Ig in the delay of demyelination and the acceleration of remyelination. The discrepancy between remyelination rates in these systems could be attributed to developmental abnormalities in the immune systems of Lt betaR-/- mice. These findings bode well for the use of an inhibitory Lt betaR-Ig as a candidate biological therapy in demyelinating disorders, because it is beneficial during both demyelination and remyelination.

Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0389 TITLE: Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury...2015 4. TITLE AND SUBTITLE Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury 5a. CONTRACT NUMBER 5b...disabling behavioral and cognitive abnormalities noted in significant number of combat veterans. These clinical phenotypes suggest impairment in

Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury

DTIC Science & Technology

2015-10-01

AWARD NUMBER: W81XWH-13-1-0388 TITLE: Demyelination as a Target for Cell-Based Therapy of Chronic Blast- Induced Traumatic Brain Injury...SUBTITLE Demyelination as a Target for Cell-Based Therapy of Chronic Blast-Induced Traumatic Brain Injury 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH...disabling behavioral and cognitive abnormalities noted in significant number of combat veterans. These clinical phenotypes suggest impairment in

Autonomic neuropathy

MedlinePlus

... Philadelphia, PA: Elsevier; 2016:chap 107. Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Editorial team. Autonomic Nervous System Disorders Read more Peripheral Nerve Disorders Read more NIH MedlinePlus Magazine Read more A. ...

Peripheral Neuropathy: A Practical Approach to Diagnosis and Symptom Management.

PubMed

Watson, James C; Dyck, P James B

2015-07-01

Peripheral neuropathy is one of the most prevalent neurologic conditions encountered by physicians of all specialties. Physicians are faced with 3 distinct challenges in caring for patients with peripheral neuropathy: (1) how to efficiently and effectively screen (in less than 2 minutes) an asymptomatic patient for peripheral neuropathy when they have a disorder in which peripheral neuropathy is highly prevalent (eg, diabetes mellitus), (2) how to clinically stratify patients presenting with symptoms of neuropathy to determine who would benefit from specialty consultation and what testing is appropriate for those who do not need consultation, and (3) how to treat the symptoms of painful peripheral neuropathy. In this concise review, we address these 3 common clinical scenarios. Easily defined clinical patterns of involvement are used to identify patients in need of neurologic consultation, the yield of laboratory and other diagnostic testing is reviewed for the evaluation of length-dependent, sensorimotor peripheral neuropathies (the most common form of neuropathy), and an algorithmic approach with dosing recommendations is provided for the treatment of neuropathic pain associated with peripheral neuropathy. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Unipedal stance testing in the assessment of peripheral neuropathy.

PubMed

Hurvitz, E A; Richardson, J K; Werner, R A

2001-02-01

To define further the relation between unipedal stance testing and peripheral neuropathy. Prospective cohort. Electroneuromyography laboratory of a Veterans Affairs medical center and a university hospital. Ninety-two patients referred for lower extremity electrodiagnostic studies. A standardized history and physical examination designed to detect peripheral neuropathy, 3 trials of unipedal stance, and electrodiagnostic studies. Peripheral neuropathy was identified by electrodiagnostic testing in 32%. These subjects had a significantly shorter (p <.001) unipedal stance time (15.7s, longest of 3 trials) than the patients without peripheral neuropathy (37.1s). Abnormal unipedal stance time (<45s) identified peripheral neuropathy with a sensitivity of 83% and a specificity of 71%, whereas a normal unipedal stance time had a negative predictive value of 90%. Abnormal unipedal stance time was associated with an increased risk of having peripheral neuropathy on univariate analysis (odds ratio = 8.8, 95% confidence interval = 2.5--31), and was the only significant predictor of peripheral neuropathy in the regression model. Aspects of the neurologic examination did not add to the regression model compared with abnormal unipedal stance time. Unipedal stance testing is useful in the clinical setting both to identify and to exclude the presence of peripheral neuropathy.

Ethambutol/Linezolid Toxic Optic Neuropathy.

PubMed

Libershteyn, Yevgeniya

2016-02-01

To report a rare toxic optic neuropathy after long-term use of two medications: ethambutol and linezolid. A 65-year-old man presented to the Miami Veterans Affairs Medical Center in December 2014 for evaluation of progressive vision decrease in both eyes. The patient presented with best-corrected visual acuities of 20/400 in the right eye and counting fingers at 5 feet in the left eye. Color vision was significantly reduced in both eyes. Visual fields revealed a cecocentral defect in both eyes. His fundus and optic nerve examination was unremarkable. Because vision continued to decline after discontinuation of ethambutol, linezolid was also discontinued, after which vision, color vision, and visual fields improved. Because of these findings, the final diagnosis was toxic optic neuropathy. Final visual outcome was 20/30 in the right eye and 20/40 in the left eye. Drug-associated toxic optic neuropathy is a rare but vision-threatening condition. Diagnosis is made based on an extensive case history and careful clinical examination. The examination findings include varying decrease in vision, normal pupils and extraocular muscles, and unremarkable fundoscopy, with the possibility of swollen optic discs in the acute stage of the optic neuropathy. Other important findings descriptive of toxic optic neuropathy include decreased color vision and cecocentral visual field defects. This case illustrates the importance of knowledge of all medications and/or substances a patient consumes that may cause a toxic reaction and discontinuing them immediately if the visual functions are worsening or not improving.

Grand Rounds: Could Occupational Exposure to n-Hexane and Other Solvents Precipitate Visual Failure in Leber Hereditary Optic Neuropathy?

PubMed Central

Carelli, Valerio; Franceschini, Flavia; Venturi, Silvia; Barboni, Piero; Savini, Giacomo; Barbieri, Giuseppe; Pirro, Ettore; La Morgia, Chiara; Valentino, Maria L.; Zanardi, Francesca; Violante, Francesco S.; Mattioli, Stefano

2007-01-01

Context Leber hereditary optic neuropathy (LHON) is a maternally inherited loss of central vision related to pathogenic mutations in the mitochondrial genome, which are a necessary but not sufficient condition to develop the disease. Investigation of precipitating environmental/occupational (and additional genetic) factors could be relevant for prevention. Case presentation After a 6-month period of occupational exposure to n-hexane and other organic solvents, a 27-year-old man (a moderate smoker) developed an optic neuropathy. The patient had a full ophthalmologic and neurologic investigation, including standardized cycloergometer test for serum lactic acid levels and a skeletal muscle biopsy. His exposure history was also detailed, and he underwent genetic testing for LHON mitochondrial DNA mutations. The patient suffered a sequential optic neuropathy with the hallmarks of LHON and tested positive for the homoplasmic 11778G → A/ND4 mutation. Routine laboratory monitoring revealed increased concentrations of urinary 2.5 hexandione (n-hexane metabolite) and hippuric acid (toluene metabolite) in the period immediately preceding the visual loss. Discussion In a subject carrying an LHON mutation, the strict temporal sequence of prolonged appreciable occupational exposure followed by sudden onset of visual loss must raise a suspicion of causality (with a possible further interaction with tobacco smoke). Relevance In this article, we add to the candidate occupational/environmental triggers of LHON and highlight the need for appropriate case–control (and laboratory) studies to validate the causal effect of mixed toxic exposures. PMID:17366829

Peripheral Neuropathy

MedlinePlus

... of days, weeks, or years. They can be acute or chronic. In acute neuropathies such as Guillain-Barré syndrome (in which ... that warns of impending heart attack or other acute conditions. Loss of pain sensation is a particularly ...

Genetics Home Reference: congenital cataracts, facial dysmorphism, and neuropathy

MedlinePlus

... sensory cells. This nerve damage is known as peripheral neuropathy. Weakness in the legs, followed by the arms, ... and Neuropathy MedlinePlus Encyclopedia: Congenital Cataract MedlinePlus Encyclopedia: Peripheral Neuropathy General Information from MedlinePlus (5 links) Diagnostic Tests ...

POEMS syndrome with Guillan-Barre syndrome-like acute onset: a case report and review of neurological progression in 30 cases.

PubMed

Isose, S; Misawa, S; Kanai, K; Shibuya, K; Sekiguchi, Y; Nasu, S; Fujimaki, Y; Noto, Y; Nakaseko, C; Kuwabara, S

2011-06-01

POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare cause of demyelinating neuropathy with monoclonal plasma cell proliferation, and POEMS neuropathy is usually chronically progressive. Herein, the authors report a 34-year-old woman with POEMS syndrome presenting as acute polyneuropathy. Within 2 weeks of disease onset, she became unable to walk with electrodiagnostic features of demyelination and was initially diagnosed as having Guillan-Barré syndrome. Other systemic features (oedema and skin changes) developed later, and an elevated serum level of vascular endothelial growth factor led to the diagnosis of POEMS syndrome. She received high-dose chemotherapy with autologous peripheral blood stem cell transplantation, resulting in good recovery. The authors also reviewed patterns and speed of progression of neuropathy in the 30 patients with POEMS syndrome; 22 (73%) of them were unable to walk independently with the median period of 9.5 months from POEMS onset (range 0.5-51 months). Whereas the speed of neuropathy progression varies considerably among patients, some POEMS patients can show acute or subacute polyneuropathy. The early diagnosis and treatment could result in rapid improvement as shown in the present patient.

[Vasculitic neuropathy: novel classification, diagnosis and treatment].

PubMed

Kanda, Takashi

2014-01-01

The international standard of nomenclature and classification in vasculitis, CHCC 1994,was revised as CHCC 2012. In the first part of this review article I briefly summarized the CHCC 2012 and pointed out the changes in this revision, especially on the disorders related to vasculitic neuropathy. Notable changes include the introduction of new terms such as granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis. In the second part, I mentioned the tips for the diagnosis and treatment of vasculitic neuropathy. Because most of the vasculitic neuropathy patients require rigorous, long-standing immunosuppressive therapy, the accurate diagnosis based on the pathological detection of vasculitic changes is mandatory. In this regard, the value of sural nerve biopsy is still not ignorable. In the treatment of vascultic neuropathy, there are no controlled treatment trials and clinical practice is guided by experience from case series and indirectly by analogy with systemic vasculitis. Although combined therapy using prednisolone and cyclophosphamide is usually recommended by experts, tailor-made treatment regimen based on the conditions of each patient would produce the best outcome in vasculitic neuropathy.

Ulnar neuropathy and ulnar neuropathy-like symptoms in relation to biomechanical exposures assessed by a job exposure matrix: a triple case-referent study.

PubMed

Svendsen, Susanne Wulff; Johnsen, Birger; Fuglsang-Frederiksen, Anders; Frost, Poul

2012-11-01

We aimed to evaluate relations between occupational biomechanical exposures and (1) ulnar neuropathy confirmed by electroneurography (ENG) and (2) ulnar neuropathy-like symptoms with normal ENG. In this triple case-referent study, we identified all patients aged 18-65 years, examined with ENG at a neurophysiological department on suspicion of ulnar neuropathy, 2001-2007. We mailed a questionnaire to 546 patients with ulnar neuropathy, 633 patients with ulnar neuropathy-like symptoms and two separate groups of community referents, matched on sex, age and primary care centre (risk set sampling). The two patient groups were also compared to each other directly. We constructed a Job Exposure Matrix to provide estimates of exposure to non-neutral postures, repetitive movements, hand-arm vibrations and forceful work. Conditional and unconditional logistic regressions were used. The proportion who responded was 59%. Ulnar neuropathy was related to forceful work with an exposure-response pattern reaching an OR of 3.85 (95% CI 2.04 to 7.24); non-neutral postures strengthened effects of forceful work. No relation was observed with repetitive movements. Ulnar neuropathy-like symptoms were related to repetitive movements with an OR of 1.89 (95% CI 1.01 to 3.52) in the highest-exposure category (≥2.5 h/day); forceful work was unrelated to the outcome. Ulnar neuropathy and ulnar neuropathy-like symptoms differed with respect to associations with occupational biomechanical exposures. Findings suggested specific effects of forceful work on the ulnar nerve. Thus, results corroborated the importance of an electrophysiological diagnosis when evaluating risk factors for ulnar neuropathy. Preventive effects may be achieved by reducing biomechanical exposures at work.

Severe oxidative stress in an acute inflammatory demyelinating model in the rhesus monkey.

PubMed

Dunham, Jordon; van de Vis, Reinofke; Bauer, Jan; Wubben, Jacqueline; van Driel, Nikki; Laman, Jon D; 't Hart, Bert A; Kap, Yolanda S

2017-01-01

Oxidative stress is increasingly implicated as a co-factor of tissue injury in inflammatory/demyelinating disorders of the central nervous system (CNS), such as multiple sclerosis (MS). While rodent experimental autoimmune encephalomyelitis (EAE) models diverge from human demyelinating disorders with respect to limited oxidative injury, we observed that in a non-human primate (NHP) model for MS, namely EAE in the common marmoset, key pathological features of the disease were recapitulated, including oxidative tissue injury. Here, we investigated the presence of oxidative injury in another NHP EAE model, i.e. in rhesus macaques, which yields an acute demyelinating disease, which may more closely resemble acute disseminated encephalomyelitis (ADEM) than MS. Rhesus monkey EAE diverges from marmoset EAE by abundant neutrophil recruitment into the CNS and destructive injury to white matter. This difference prompted us to investigate to which extent the oxidative pathway features elicited in MS and marmoset EAE are reflected in the acute rhesus monkey EAE model. The rhesus EAE brain was characterized by widespread demyelination and active lesions containing numerous phagocytic cells and to a lesser extent T cells. We observed induction of the oxidative stress pathway, including injury, with a predilection of p22phox expression in neutrophils and macrophages/microglia. In addition, changes in iron were observed. These results indicate that pathogenic mechanisms in the rhesus EAE model may differ from the marmoset EAE and MS brain due to the neutrophil involvement, but may in the end lead to similar induction of oxidative stress and injury.

[Electrodiagnostic criteria for childhood Guillain-Barre syndrome. Eight years' experience].

PubMed

Lopez-Esteban, Pilar; Gallego, Isabel; Gil-Ferrer, Victoria

2013-03-01

INTRODUCTION. The Guillan-Barre syndrome is the most frequent case of acute flacid paralysis in children. The diagnostic criteria differ according to the demyelinating or axonal variant and the prevalence by geographical area. The electro-myographic study permits identifying variants, evaluating the prognosis and predicting the evolution, is in addition an objective tool for the monitoring. AIM. To describe the electromyographic characteristics of the Guillain-Barre syndrome evaluated in hospital and its classification by physiopathological pattern. PATIENTS AND METHODS. All the cases diagnosed between 2005 and 2012 are included. Studies of motor and sensitive nervous conduction and F waves in 14 girls and 11 boys between 1 and 13 years of age. RESULTS. 19 cases of acute inflammatory demyelinating polyneuropathy (AIDP) and five of acute motor axonal neuropathy (AMAN) were diagnosed. The electromyogram was performed between 1 and 30 days after the beginning of symptoms. In AIDP cases, multifocal demyelination, four of them with the preserved sural and 13 with alteration and absence of F wave were objectified. In the cases of AMAN, four had low amplitude potential and in one of them they were not evoked. CONCLUSIONS. The demyelinating form of the illness is the most frequent although the high number of AMAN cases stands out, probably related to the population object of study. The evolution was favorable in three cases of motor axonal neuropathy and in 15 accute demyelinating polyneuropathy. In four cases the symptoms became chronic; three of them with persistent demyelination a similar occurrence in other studies with children.

Demyelinating Guillain-Barré syndrome recurs more frequently than axonal subtypes.

PubMed

Notturno, Francesca; Kokubun, Norito; Sekiguki, Yukari; Nagashima, Takahide; De Lauretis, Angelo; Yuki, Nobuhiro; Kuwabara, Satoshi; Uncini, Antonino

2016-06-15

Guillain-Barré syndrome (GBS) is considered a monophasic disorder yet recurrences occur in up to 6% of patients. We retrospectively studied an Italian-Japanese population of 236 GBS and 73 Miller Fisher syndrome (MFS) patients and searched for factors which may be associated with recurrence. A recurrent patient was defined as having at least two episodes that fulfilled the diagnostic criteria for GBS and MFS with an identifiable recovery after each episode and a minimum of 2months between episodes. Preceding Campylobacter jejuni (C. jejuni) infection and antiganglioside antibodies were also assessed. Seven (3%) recurrent GBS and one (1.4%) recurrent MFS patients were identified. In the individual patient the clinical features during episodes were usually similar varying in severity whereas the preceding infection differed. None of the patients had GBS in one episode and MFS in the recurrence or vice versa. Recurrent GBS patients, compared with monophasic GBS, did not have preceding diarrhea at the first episode and considering the electrophysiological subtypes, acute inflammatory demyelinating polyneuropathies recurred more frequently than axonal GBS (6.5% vs 0.9%, p=0.04). In conclusion in a GBS population with a balanced number of demyelinating and axonal subtypes less frequent diarrhea and demyelination at electrophysiology were associated with recurrence. Copyright © 2016. Published by Elsevier B.V.

Autonomic nervous system involvement in the giant axonal neuropathy (GAN) KO mouse: implications for human disease.

PubMed

Armao, Diane; Bailey, Rachel M; Bouldin, Thomas W; Kim, Yongbaek; Gray, Steven J

2016-08-01

Giant axonal neuropathy (GAN) is an inherited severe sensorimotor neuropathy. The aim of this research was to investigate the neuropathologic features and clinical autonomic nervous system (ANS) phenotype in two GAN knockout (KO) mouse models. Little is known about ANS involvement in GAN in humans, but autonomic signs and symptoms are commonly reported in early childhood. Routine histology and immunohistochemistry was performed on GAN KO mouse specimens taken at various ages. Enteric dysfunction was assessed by quantifying the frequency, weight, and water content of defecation in GAN KO mice. Histological examination of the enteric, parasympathetic and sympathetic ANS of GAN KO mice revealed pronounced and widespread neuronal perikaryal intermediate filament inclusions. These neuronal inclusions served as an easily identifiable, early marker of GAN in young GAN KO mice. Functional studies identified an age-dependent alteration in fecal weight and defecation frequency in GAN KO mice. For the first time in the GAN KO mouse model, we described the early, pronounced and widespread neuropathologic features involving the ANS. In addition, we provided evidence for a clinical autonomic phenotype in GAN KO mice, reflected in abnormal gastrointestinal function. These findings in GAN KO mice suggest that consideration should be given to ANS involvement in human GAN, especially when considering treatments and patient care.

Fibroblast Growth Factor 1 (FGFR1) Modulation Regulates Repair Capacity of Oligodendrocyte Progenitor Cells Following Chronic Demyelination

PubMed Central

Zhou, Yong-Xing; Pannu, Ravinder; Le, Tuan Q.; Armstrong, Regina C.

2011-01-01

The adult mammalian brain contains multiple populations of endogenous progenitor cell types. However, following CNS trauma or disease, the regenerative capacity of progenitor populations is typically insufficient and may actually be limited by non-permissive or inhibitory signals in the damaged parenchyma. Remyelination is the most effective and simplest regenerative process in the adult CNS yet is still insufficient following repeated or chronic demyelination. Our previous in vitro studies demonstrated that fibroblast growth factor receptor 1 (FGFR1) signaling inhibited oligodendrocyte progenitor (OP) differentiation into mature oligodendrocytes. Therefore, we questioned whether FGFR1 signaling may inhibit the capacity of OP cells to generate oligodendrocytes in a demyelinating disease model and whether genetically reducing FGFR1 signaling in oligodendrocyte lineage cells could enhance the capacity for remyelination. FGFR1 was found to be upregulated in the corpus callosum during cuprizone mediated demyelination and expressed on OP cells just prior to remyelination. Plp/CreERT:Fgfr1fl/flmice were administered tamoxifen to induce conditional Fgfr1 deletion in oligodendrocyte lineage cells. Tamoxifen administration during chronic demyelination resulted in reduced FGFR1 expression in OP cells. OP proliferation and population size were not altered one week after tamoxifen treatment. Tamoxifen was then administered during chronic demyelination and mice were given a six week recovery period without cuprizone in the chow. After the recovery period, OP numbers were reduced and the number of mature oligodendrocytes was increased, indicating an effect of FGFR1 reduction on OP differentiation. Importantly, tamoxifen administration in Plp/CreERT:Fgfr1fl/fl mice significantly promoted remyelination and axon integrity. These results demonstrate a direct effect of FGFR1 signaling in oligodendrocyte lineage cells as inhibiting the repair capacity of OP cells following chronic

Human papillomavirus vaccine and demyelinating diseases-A systematic review and meta-analysis.

PubMed

Mouchet, Julie; Salvo, Francesco; Raschi, Emanuel; Poluzzi, Elisabetta; Antonazzo, Ippazio Cosimo; De Ponti, Fabrizio; Bégaud, Bernard

2018-06-01

Approved in 2006, human papillomavirus (HPV) vaccines were initially targeted for girls aged 9-14 years. Although the safety of these vaccines has been monitored through post-licensure surveillance programmes, cases of neurological events have been reported worldwide. The present study aimed to assess the risk of developing demyelination after HPV immunization by meta-analysing risk estimates from pharmacoepidemiologic studies. A systematic review was conducted in Medline, Embase, ISI Web of Science and the Cochrane Library from inception to 10 May 2017, without language restriction. Only observational studies including a control group were retained. Study selection was performed by two independent reviewers with disagreements solved through discussion. This meta-analysis was performed using a generic inverse variance random-effect model. Outcomes of interest included a broad category of central demyelination, multiple sclerosis (MS), optic neuritis (ON), and Guillain-Barré syndrome (GBS), each being considered independently. Heterogeneity was investigated; sensitivity and subgroup analyses were performed when necessary. In parallel, post-licensure safety studies were considered for a qualitative review. This study followed the PRISMA statement and the MOOSE reporting guideline. Of the 2,863 references identified, 11 articles were selected for meta-analysis. No significant association emerged between HPV vaccination and central demyelination, the pooled odds ratio being 0.96 [95% CI 0.77-1.20], with a moderate but non-significant heterogeneity (I 2  = 29%). Similar results were found for MS and ON. Sensitivity analyses did not alter our conclusions. Findings from qualitative review of 14 safety studies concluded in an absence of a relevant signal. Owing to limited data on GBS, no meta-analysis was performed for this outcome. This study strongly supports the absence of association between HPV vaccines and central demyelination. Copyright © 2018 Elsevier Ltd

Matrix metalloproteinases-2 and -9 in Campylobacter jejuni-induced paralytic neuropathy resembling Guillain-Barré syndrome in chickens.

PubMed

Nyati, Kishan Kumar; Prasad, Kashi Nath; Agrawal, Vinita; Husain, Nuzhat

2017-10-01

Inflammation in Guillain-Barré syndrome (GBS) is manifested by changes in matrix metalloproteinase (MMP) and pro-inflammatory cytokine expression. We investigated the expression of MMP-2, -9 and TNF-α and correlated it with pathological changes in sciatic nerve tissue from Campylobacter jejuni-induced chicken model for GBS. Campylobacter jejuni and placebo were fed to chickens and assessed for disease symptoms. Sciatic nerves were examined by histopathology and immunohistochemistry. Expressions of MMPs and TNF-α, were determined by real-time PCR, and activities of MMPs by zymography. Diarrhea developed in 73.3% chickens after infection and 60.0% of them developed GBS like neuropathy. Pathology in sciatic nerves showed perinodal and/or patchy demyelination, perivascular focal lymphocytic infiltration and myelin swelling on 10th- 20th post infection day (PID). MMP-2, -9 and TNF-α were up-regulated in progressive phase of the disease. Enhanced MMP-2, -9 and TNF-α production in progressive phase correlated with sciatic nerve pathology in C. jejuni-induced GBS chicken model. Copyright © 2017 Elsevier Ltd. All rights reserved.

Activation of Neuregulin 1/ErbB Signaling Is Involved in the Development of TOCP-Induced Delayed Neuropathy.

PubMed

Xu, Hai-Yang; Wang, Pan; Sun, Ying-Jian; Xu, Ming-Yuan; Zhu, Li; Wu, Yi-Jun

2018-01-01

Organophosphate-induced delayed neuropathy (OPIDN) is characterized by progressive axonal degeneration and demyelination of the spinal cord and sciatic nerves. The neuregulin 1/epidermal growth factor receptor (ErbB) signaling pathway is crucial for axonal myelination. In this study, we investigated whether the neuregulin 1/ErbB signaling pathway mediated the progression of OPIDN. Adult hens were given tri- o -cresyl phosphate (TOCP), a typical neuropathic organophosphorus compound, to induce OPIDN. The ErbB inhibitor lapatinib was administered to hens 4 h prior to and 4 days after TOCP exposure. The neuregulin 1/ErbB signaling pathway was examined for their role in maintaining spinal cord and sciatic nerve fiber integrity. Schwann cell line sNF96.2 was used as the in vitro cell model. The in vivo results showed that TOCP (750 mg/kg body weight, p.o .) induced prominent ataxia and significant axon degeneration in the spinal cord and sciatic nerves. Lapatinib (25 mg/kg body weight, p.o .) treatment attenuated OPIDN clinically and histopathlogically and partially prevented the TOCP-induced activation of neuregulin 1/ErbB signaling pathway. Lapatinib also prevented the TOCP-induced inhibition of neuropathy target esterase (NTE), a key enzyme during the development of OPIDN, and the disturbed metabolism of phosphatidylcholine in sciatic nerves. In addition, lapatinib was shown, in vitro , to protect sNF96.2 cells from TOCP-induced dedifferentiation through neuregulin 1/ErbB signaling. Our results suggest that neuregulin 1/ErbB, through regulation of NTE activity in the peripheral nervous system, mediates the progression of OPIDN. Thus, this signal may serve as a potential target for the treatment of OPIDN.

Immune mediated neuropathy following checkpoint immunotherapy.

PubMed

Gu, Yufan; Menzies, Alexander M; Long, Georgina V; Fernando, S L; Herkes, G

2017-11-01

Checkpoint immunotherapy has revolutionised cancer therapy and is now standard treatment for many malignancies including metastatic melanoma. Acute inflammatory neuropathies, often labelled as Guillain-Barre syndrome, are an uncommon but potentially severe complication of checkpoint immunotherapy with individual cases described but never characterised as a group. We describe a case of acute sensorimotor and autonomic neuropathy following a single dose of combination ipilimumab and nivolumab for metastatic melanoma. A literature search was performed, identifying 14 other cases of acute neuropathy following checkpoint immunotherapy, with the clinical, electrophysiological and laboratory features summarised. Most cases described an acute sensorimotor neuropathy (92%) with hyporeflexia (92%) that could occur from induction up till many weeks after the final dose of therapy. In contrast to Guillain-Barre syndrome, the cerebrospinal fluid (CSF) analysis often shows a lymphocytic picture (50%) and the electrophysiology showed an axonal pattern (55%). Treatment was variable and often in combination. 11 cases received steroid therapy with only 1 death within this group, whereas of the 4 patients who did not receive steroid therapy there were 3 deaths. In conclusion checkpoint immunotherapy - induced acute neuropathies are distinct from and progress differently to Guillain-Barre syndrome. As with other immunotherapy related adverse events corticosteroid therapy should be initiated in addition to usual therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Diagnostic capability of retinal thickness measures in diabetic peripheral neuropathy.

PubMed

Srinivasan, Sangeetha; Pritchard, Nicola; Sampson, Geoff P; Edwards, Katie; Vagenas, Dimitrios; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

To examine the diagnostic capability of the full retinal and inner retinal thickness measures in differentiating individuals with diabetic peripheral neuropathy (DPN) from those without neuropathy and non-diabetic controls. Individuals with (n=44) and without (n=107) diabetic neuropathy and non-diabetic control (n=42) participants underwent spectral domain optical coherence tomography (SDOCT). Retinal thickness in the central 1mm zone (including the fovea), parafovea and perifovea was assessed in addition to ganglion cell complex (GCC) global loss volume (GCC GLV) and focal loss volume (GCC FLV), and retinal nerve fiber layer (RNFL) thickness. Diabetic neuropathy was defined using a modified neuropathy disability score (NDS) recorded on a 0-10 scale, wherein, NDS ≥3 indicated neuropathy and NDS indicated <3 no neuropathy. Diagnostic performance was assessed by areas under the receiver operating characteristic curves (AUCs), 95 per cent confidence intervals (CI), sensitivities at fixed specificities, positive likelihood ratio (+LR), negative likelihood ratio (-LR) and the cut-off points for the best AUCs obtained. The AUC for GCC FLV was 0.732 (95% CI: 0.624-0.840, p<0.001) with a sensitivity of 53% and specificity of 80% for differentiating DPN from controls. Evaluation of the LRs showed that GCC FLV was associated with only small effects on the post-test probability of the disease. The cut-off point calculated using the Youden index was 0.48% (67% sensitivity and 73% specificity) for GCC FLV. For distinguishing those with neuropathy from those without neuropathy, the AUCs of retinal parameters ranged from 0.508 for the central zone to 0.690 for the inferior RNFL thickness. For distinguishing those with moderate or advanced neuropathy from those with mild or no neuropathy, the inferior RNFL thickness demonstrated the highest AUC of 0.820, (95% CI: 0.731-0.909, p<0.001) with a sensitivity of 69% and 80% specificity. The cut-off-point for the inferior RNFL

Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy.

PubMed

Köşkderelioğlu, Aslı; Ortan, Pınar; Ari, Alpay; Gedizlioğlu, Muhteşem

2016-03-01

To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients with hepatitis C. The results were in

Screening for Electrophysiological Abnormalities in Chronic Hepatitis C Infection: Peripheral Neuropathy and Optic Neuropathy

PubMed Central

KÖŞKDERELİOĞLU, Aslı; ORTAN, Pınar; ARI, Alpay; GEDİZLİOĞLU, Muhteşem

2016-01-01

Introduction To investigate the existence of peripheral and optic neuropathies in asymptomatic individuals with hepatitis C infection. Methods Thirty consecutive patients who were followed in a hepatitis C outpatient clinic were recruited for electrophysiological evaluation together with 30 age- and gender-compatible healthy controls. All patients had a detailed neurological examination. The information regarding the disease duration and management with interferons were collected. Nerve conduction studies and visual evoked potentials (VEP) were recorded in all subjects. The results of the patient and control groups were statistically compared. Results Of the patients with hepatitis C infection, 16 were females and 14 males. The mean age was 57.5 years, and the average disease duration was 6.43 years. The P100 latencies in the patient group were within normal limits, while the amplitudes were meaningfully small by comparison with the controls. There were some abnormalities in the nerve conduction studies of 15 patients. Sensorial neuropathy was detected in two patients, sensorimotor polyneuropathy in four, carpal tunnel syndrome in seven, and carpal tunnel syndrome and sensorimotor polyneuropathy as comorbid states in another two patients. The nerve conduction studies and VEP parameters were entirely normal in the control group. Conclusion Hepatitis C-related neurological abnormalities may occur both in the central and peripheral nervous system. Mononeuritis multiplex, sensorial axonal neuropathy, and multiple mononeuropathies are some of the presentations of the peripheral nervous system involvement. The mode of infection is considered to be via vasculitic mechanisms. In addition, optic neuropathy is a known complication of interferon treatment. Autoantibodies, cytokines, chemokines, and cryoglobulins are accused to play roles in the pathogenesis. In this study, we investigated the involvement of the peripheral nervous system and optic nerves in a group of patients

Peripheral Neuropathy and Nerve Compression Syndromes in Burns.

PubMed

Strong, Amy L; Agarwal, Shailesh; Cederna, Paul S; Levi, Benjamin

2017-10-01

Peripheral neuropathy and nerve compression syndromes lead to substantial morbidity following burn injury. Patients present with pain, paresthesias, or weakness along a specific nerve distribution or experience generalized peripheral neuropathy. The symptoms manifest at various times from within one week of hospitalization to many months after wound closure. Peripheral neuropathy may be caused by vascular occlusion of vasa nervorum, inflammation, neurotoxin production leading to apoptosis, and direct destruction of nerves from the burn injury. This article discusses the natural history, diagnosis, current treatments, and future directions for potential interventions for peripheral neuropathy and nerve compression syndromes related to burn injury. Copyright © 2017 Elsevier Inc. All rights reserved.

Leber Hereditary Optic Neuropathy: Exemplar of an mtDNA Disease.

PubMed

Wallace, Douglas C; Lott, Marie T

2017-01-01

The report in 1988 that Leber Hereditary Optic Neuropathy (LHON) was the product of mitochondrial DNA (mtDNA) mutations provided the first demonstration of the clinical relevance of inherited mtDNA variation. From LHON studies, the medical importance was demonstrated for the mtDNA showing its coding for the most important energy genes, its maternal inheritance, its high mutation rate, its presence in hundreds to thousands of copies per cell, its quantitatively segregation of biallelic genotypes during both mitosis and meiosis, its preferential effect on the most energetic tissues including the eye and brain, its wide range of functional polymorphisms that predispose to common diseases, and its accumulation of mutations within somatic tissues providing the aging clock. These features of mtDNA genetics, in combination with the genetics of the 1-2000 nuclear DNA (nDNA) coded mitochondrial genes, is not only explaining the genetics of LHON but also providing a model for understanding the complexity of many common diseases. With the maturation of LHON biology and genetics, novel animal models for complex disease have been developed and new therapeutic targets and strategies envisioned, both pharmacological and genetic. Multiple somatic gene therapy approaches are being developed for LHON which are applicable to other mtDNA diseases. Moreover, the unique cytoplasmic genetics of the mtDNA has permitted the first successful human germline gene therapy via spindle nDNA transfer from mtDNA mutant oocytes to enucleated normal mtDNA oocytes. Such LHON lessons are actively being applied to common ophthalmological diseases like glaucoma and neurological diseases like Parkinsonism.

Approach to Peripheral Neuropathy for the Primary Care Clinician.

PubMed

Doughty, Christopher T; Seyedsadjadi, Reza

2018-02-02

Peripheral neuropathy is commonly encountered in the primary care setting and is associated with significant morbidity, including neuropathic pain, falls, and disability. The clinical presentation of neuropathy is diverse, with possible symptoms including weakness, sensory abnormalities, and autonomic dysfunction. Accordingly, the primary care clinician must be comfortable using the neurologic examination-including the assessment of motor function, multiple sensory modalities, and deep tendon reflexes-to recognize and characterize neuropathy. Although the causes of peripheral neuropathy are numerous and diverse, careful review of the medical and family history coupled with limited, select laboratory testing can often efficiently lead to an etiologic diagnosis. This review offers an approach for evaluating suspected neuropathy in the primary care setting. It will describe the most common causes, suggest an evidence-based workup to aid in diagnosis, and highlight recent evidence that allows for selection of symptomatic treatment of patients with neuropathy. Copyright © 2018 Elsevier Inc. All rights reserved.

Delayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy.

PubMed

Gottfried, J A; Mayer, S A; Shungu, D C; Chang, Y; Duyn, J H

1997-11-01

Delayed demyelination is a rare and poorly understood complication of hypoxic brain injury. A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma. MRI showed diffuse white matter signal changes, and brain biopsy demonstrated a noninflammatory demyelinating process. Proton magnetic resonance spectroscopy revealed elevated choline and lactate and reduced N-acetyl aspartate signal in the affected white matter, consistent with demyelination and a shift to anaerobic metabolism. Arylsulfatase A activity from peripheral leukocytes was approximately 50% of normal, consistent with a "pseudodeficiency" phenotype. These findings confirm the hypothesis that relative arylsulfatase A deficiency predisposes susceptible individuals to delayed posthypoxic leukoencephalopathy and implicates lactic acidosis in the pathogenesis of this disorder.

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

PubMed

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

2017-04-01

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

22q11.2q13 Duplication Including SOX10 causes Sex-reversal and Peripheral Demyelinating Neuropathy, Central Dysmyelinating Leukodystrophy, Waardenburg Syndrome and Hirschsprung Disease

PubMed Central

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

2017-01-01

Diagnosis of genetic syndromes may be difficult when specific components of a disorder manifest at a later age. We present a follow up of a previous report [Seeherunvong et al., 2004; Ajmga 127: 149–151], of an individual with 22q duplication and sex-reversal syndrome. The subject’s phenotype evolved to include peripheral and central demyelination, Waardenburg syndrome type IV, and Hirschsprung disease (PCWH; MIM 609136). DNA microarray analysis defined the duplication at 22q11.2q13, including SOX10. Sequencing of the coding region of SOX10 did not reveal any mutations. Our data suggest that SOX10 duplication can cause disorders of sex development and PCWH, supporting the hypothesis that SOX10 toxic gain-of-function rather than dominant negative activity underlies PCWH. PMID:28328136

Properties of pattern standard deviation in open-angle glaucoma patients with hemi-optic neuropathy and bi-optic neuropathy.

PubMed

Heo, Dong Won; Kim, Kyoung Nam; Lee, Min Woo; Lee, Sung Bok; Kim, Chang-Sik

2017-01-01

To evaluate the properties of pattern standard deviation (PSD) according to localization of the glaucomatous optic neuropathy. We enrolled 242 eyes of 242 patients with primary open-angle glaucoma, with a best-corrected visual acuity ≥ 20/25, and no media opacity. Patients were examined via dilated fundus photography, spectral-domain optical coherence tomography, and Humphrey visual field examination, and divided into those with hemi-optic neuropathy (superior or inferior) and bi-optic neuropathy (both superior and inferior). We assessed the relationship between mean deviation (MD) and PSD. Using broken stick regression analysis, the tipping point was identified, i.e., the point at which MD became significantly associated with a paradoxical reversal of PSD. In 91 patients with hemi-optic neuropathy, PSD showed a strong correlation with MD (r = -0.973, β = -0.965, p < 0.001). The difference between MD and PSD ("-MD-PSD") was constant (mean, -0.32 dB; 95% confidence interval, -2.48~1.84 dB) regardless of visual field defect severity. However, in 151 patients with bi-optic neuropathy, a negative correlation was evident between "-MD-PSD" and MD (r2 = 0.907, p < 0.001). Overall, the MD tipping point was -14.0 dB, which was close to approximately 50% damage of the entire visual field (p < 0.001). Although a false decrease of PSD usually begins at approximately 50% visual field damage, in patients with hemi-optic neuropathy, the PSD shows no paradoxical decrease and shows a linear correlation with MD.

Acute-onset chronic inflammatory demyelinating polyneuropathy: An electrodiagnostic study.

PubMed

Anadani, Mohammad; Katirji, Bashar

2015-11-01

Acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is an increasingly recognized CIDP subtype. Differentiating A-CIDP from Guillain-Barré syndrome (GBS) is challenging but important, because there are different treatment outcomes. We report 3 patients with A-CIDP who were initially diagnosed with severe GBS but were later confirmed to have CIDP based on their clinical course and electrodiagnostic (EDx) studies. We also report on the long-term treatment of these patients and review the literature on EDx studies in this syndrome. Three patients were initially diagnosed with GBS and responded to treatment. However, all 3 had arrest in improvement or deterioration during their rehabilitation phases. EDx studies showed prominent demyelinating changes many months after the initial presentation. All responded very well to immunotherapy. Although several features may suggest the diagnosis of A-CIDP at initial presentation, close follow-up of GBS patients during the recovery phase is also needed for accurate diagnosis. EDx studies may distinguish patients with A-CIDP from GBS patients. © 2015 Wiley Periodicals, Inc.

Massive nerve root enlargement in chronic inflammatory demyelinating polyneuropathy.

PubMed Central

Schady, W; Goulding, P J; Lecky, B R; King, R H; Smith, C M

1996-01-01

OBJECTIVE: To report three patients with chronic inflammatory demyelinating polyneuropathy (CIDP) presenting with symptoms suggestive of cervical (one patient) and lumbar root disease. METHODS: Nerve conduction studies, EMG, and nerve biopsy were carried out, having found the nerve roots to be very enlarged on MRI, CT myelography, and at surgery. RESULTS: Clinically, peripheral nerve thickening was slight or absent. Subsequently one patient developed facial nerve hypertrophy. This was mistaken for an inner ear tumour and biopsied, with consequent facial palsy. Neurophysiological tests suggested a demyelinating polyneuropathy. Sural nerve biopsy showed in all cases some loss of myelinated fibres, inflammatory cell infiltration, and a few onion bulbs. Hypertrophic changes were much more prominent on posterior nerve root biopsy in one patient: many fibres were surrounded by several layers of Schwann cell cytoplasm. There was an excellent response to steroids in two patients but not in the third (most advanced) patient, who has benefited only marginally from intravenous immunoglobulin therapy. CONCLUSIONS: MRI of the cauda equina may be a useful adjunct in the diagnosis of CIDP. Images PMID:8971116

Inherited and acquired disorders of myelin: the underling myelin pathology

PubMed Central

Duncan, Ian D.; Radcliff, Abigail B.

2016-01-01

Remyelination is a major therapeutic goal in human myelin disorders, serving to restore function to demyelinated axons and providing neuroprotection. The target disorders that might be amenable to the promotion of this repair process are diverse and increasing in number. They range primarily from those of genetic, inflammatory to toxic origin. In order to apply remyelinating strategies to these disorders, it is essential to know whether the myelin damage results from a primary attack on myelin or the oligodendrocyte or both, and whether indeed these lead to myelin breakdown and demyelination. In some disorders, myelin sheath abnormalities are prominent but demyelination does not occur. This review explores the range of human and animal disorders where myelin pathology exists and focusses on defining the myelin changes in each and their cause, to help define whether they are targets for myelin repair therapy. PMID:27068622

Diabetic neuropathy: Clinical manifestations and current treatments

PubMed Central

Callaghan, Brian C.; Cheng, Hsinlin; Stables, Catherine L.; Smith, Andrea L.; Feldman, Eva L.

2014-01-01

Diabetic peripheral neuropathy is a prevalent, disabling condition. The most common manifestation is a distal symmetric polyneuropathy (DSP), but many patterns of nerve injury can occur. Currently, the only effective treatments are glucose control and pain management. While glucose control dramatically decreases the development of neuropathy in those with type 1 diabetes, the effect is likely much smaller in those with type 2 diabetes. High levels of evidence support the use of certain anticonvulsants and antidepressants for pain management in diabetic peripheral neuropathy. However, the lack of disease modifying therapies for diabetic DSP makes the identification of new modifiable risk factors essential. Intriguingly, growing evidence supports an association between metabolic syndrome components, including pre-diabetes, and neuropathy. Future studies are needed to further explore this relationship with implications for new treatments for this common disease. PMID:22608666

Physical examination of upper extremity compressive neuropathies.

PubMed

Popinchalk, Samuel P; Schaffer, Alyssa A

2012-10-01

A thorough history and physical examination are vital to the assessment of upper extremity compressive neuropathies. This article summarizes relevant anatomy and physical examination findings associated with upper extremity compressive neuropathies. Copyright © 2012 Elsevier Inc. All rights reserved.

Cramp-fasciculation syndrome associated with monofocal motor neuropathy.

PubMed

Dubuisson, Nicolas J; Van Pesch, Vincent; Van Den Bergh, Peter Y K

2017-10-01

Cramp-fasciculation syndrome is a peripheral nerve hyperexcitability disorder, which could be caused by inflammatory neuropathy. We describe a 51-year-old woman who presented with a 4- to 5-year history of fasciculations and painful cramping of the right thenar eminence. Electrophysiological studies showed motor conduction block in the right median nerve between the axilla and the elbow with fasciculation potentials and cramp discharges on electromyography in the right abductor pollicis brevis muscle. High titers of serum anti-GM1 immunoglobulin M antibodies were detected. Monofocal motor neuropathy of the right median nerve was diagnosed. Intravenous immunoglobulin treatment led to significant improvement of symptoms and signs. Although fasciculations and cramps have been reported in multifocal motor neuropathy and are considered supporting criteria for the diagnosis, the occurrence of cramp-fasciculation syndrome as the presenting feature and predominant manifestation in monofocal motor neuropathy, a variant of multifocal motor neuropathy, is unique. Muscle Nerve 56: 828-832, 2017. © 2017 Wiley Periodicals, Inc.

Infectious optic neuropathies: a clinical update

PubMed Central

Kahloun, Rim; Abroug, Nesrine; Ksiaa, Imen; Mahmoud, Anis; Zeghidi, Hatem; Zaouali, Sonia; Khairallah, Moncef

2015-01-01

Different forms of optic neuropathy causing visual impairment of varying severity have been reported in association with a wide variety of infectious agents. Proper clinical diagnosis of any of these infectious conditions is based on epidemiological data, history, systemic symptoms and signs, and the pattern of ocular findings. Diagnosis is confirmed by serologic testing and polymerase chain reaction in selected cases. Treatment of infectious optic neuropathies involves the use of specific anti-infectious drugs and corticosteroids to suppress the associated inflammatory reaction. The visual prognosis is generally good, but persistent severe vision loss with optic atrophy can occur. This review presents optic neuropathies caused by specific viral, bacterial, parasitic, and fungal diseases. PMID:28539795

[A case of hereditary sensory and autonomic neuropathy type 1E with frontal lobe dysfunction as an initial symptom].

PubMed

Watanabe, Masashi; Matsumoto, Yushi; Okamoto, Kensho; Okuda, Bungo; Mizuta, Ikuko; Mizuno, Toshiki

2017-12-27

A 49-year-old man had developed gradually personality change, gait disturbance, and hearing loss for five years. On admission, he presented with frontal release signs, stuttering, vertical gaze palsy, sensorineural deafness, muscle rigidity, ataxia, and sensory disturbance with areflexia in the lower extremities. Brain MRI demonstrated atrophy in the cerebellum and midbrain tegmentum as well as cerebral atrophy, predominantly in the frontal lobe. He was tentatively diagnosed as progressive supranuclear palsy on the basis of clinical features and imagings. On nerve conduction study, no sensory nerve action potentials were elicited in the upper and lower extremities. Details of family history revealed a hereditary sensory neuropathy with autosomal dominant inheritance in his relatives. Because genetic analysis showed a rare missense mutation (c.1483T>C, p.Y495H) in DNA methyltransferase 1 gene, we diagnosed him as having hereditary sensory and autonomic neuropathy type 1E (HSAN1E). In addition, p.M232R mutation in prion protein gene was detected. It should be kept in mind that there are some patients with HSAN1E presenting with frontal lobe dysfunction as an initial symptom and with clinical features mimicking progressive supranuclear palsy.

Elusive inheritance: Transgenerational effects and epigenetic inheritance in human environmental disease.

PubMed

Martos, Suzanne N; Tang, Wan-Yee; Wang, Zhibin

2015-07-01

Epigenetic mechanisms involving DNA methylation, histone modification, histone variants and nucleosome positioning, and noncoding RNAs regulate cell-, tissue-, and developmental stage-specific gene expression by influencing chromatin structure and modulating interactions between proteins and DNA. Epigenetic marks are mitotically inherited in somatic cells and may be altered in response to internal and external stimuli. The idea that environment-induced epigenetic changes in mammals could be inherited through the germline, independent of genetic mechanisms, has stimulated much debate. Many experimental models have been designed to interrogate the possibility of transgenerational epigenetic inheritance and provide insight into how environmental exposures influence phenotypes over multiple generations in the absence of any apparent genetic mutation. Unexpected molecular evidence has forced us to reevaluate not only our understanding of the plasticity and heritability of epigenetic factors, but of the stability of the genome as well. Recent reviews have described the difference between transgenerational and intergenerational effects; the two major epigenetic reprogramming events in the mammalian lifecycle; these two events making transgenerational epigenetic inheritance of environment-induced perturbations rare, if at all possible, in mammals; and mechanisms of transgenerational epigenetic inheritance in non-mammalian eukaryotic organisms. This paper briefly introduces these topics and mainly focuses on (1) transgenerational phenotypes and epigenetic effects in mammals, (2) environment-induced intergenerational epigenetic effects, and (3) the inherent difficulties in establishing a role for epigenetic inheritance in human environmental disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gene Therapy for the Treatment of Diabetic Neuropathy

PubMed Central

Mata, Marina; Chattopadhyay, Munmun; Fink, David J

2009-01-01

Neuropathy is a common, untreatable complication of both type 1 and type 2 diabetes. In animal models peptide neurotrophic factors can be used to protect against the development of neuropathy, but the combination of short half-life and off-target effects of these potent pleiotropic peptides has limited translation to human therapy. Gene transfer is a promising strategy that might circumvent these limitations. In this essay we review the basic methods of gene transfer and the preclinical data in rodent models that support the utility of this approach in the treatment of diabetic neuropathy. The path to a clinical applications and potential pitfalls in developing gene therapy for the treatment of diabetic neuropathy are considered. PMID:18990298

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

PubMed Central

Padiath, Quasar S.

2016-01-01

ABSTRACT Autosomal Dominant Leukodystrophy (ADLD), a fatal adult onset demyelinating disorder, is the only human disease that has been linked to mutations of the nuclear lamina protein, lamin B1, and is primarily caused by duplications of the LMNB1 gene. Why CNS myelin is specifically targeted and the mechanisms underlying ADLD are unclear. Recent work from our group has demonstrated that over expression of lamin B1 in oligodendrocytes, the myelin producing cells in the CNS, resulted in age dependent epigenetic modifications, transcriptional down-regulation of lipogenic gene expression and significant reductions of myelin-enriched lipids. Given the high lipid content of meylin, we hypothesize that lipid loss is one of the primary drivers of the demyelination phenotype. These results can, at least partially, explain the age dependence and cell type specificity in ADLD and are discussed in the context of the existing literature, in an attempt to delineate potential pathways underlying the disease phenotype. PMID:27854160

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

PubMed

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

2010-12-15

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

[Peripheral neuropathy and blood-nerve barrier].

PubMed

Kanda, Takashi

2009-11-01

It is important to know the cellular properties of endoneurial microvascular endothelial cells (PnMECs) and microvascular pericytes which constitute blood-nerve barrier (BNB), since this barrier structure in the peripheral nervous system (PNS) may play pivotal pathophysiological roles in various disorders of the PNS including inflammatory neuropathies (i.e. Guillain-Barré syndrome), vasculitic neuropathies, hereditary neuropathies and diabetic neuropathy. However, in contrast to blood-brain barrier (BBB), very few studies have been directed to BNB and no adequate cell lines originating from BNB had been launched. In our laboratory, we successfully established human immortalized cell lines originating from BNB using temperature-sensitive SV40 large T antigen and the cellular properties of human cell lines are presented in this paper. Human PnMEC cell line showed high transendothelial electrical resistance and expressed tight junction components and various types of influx as well as efflux transporters that have been reported to function at BBB. Human pericyte cell line also possessed tight junction proteins except claudin-5 and secrete various cytokines and growth factors including bFGF, VEGF, GDNF, NGF, BDNF and angiopoietin-1. Co-culture with pericytes or pericyte-conditioned media strengthend barrier properties of PnMEC, suggesting that in the PNS, peripheral nerve pericytes support the BNB function and play the same role of astrocytes in the BBB. Future accumulation of the knowledge concerning the cellular properties of BNB-forming cells will open the door to novel therapeutic strategies for intractable peripheral neuropathies.

Genetics Home Reference: hereditary sensory and autonomic neuropathy type V

MedlinePlus

... links) National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy National Institutes of Health Rare Diseases Clinical Research ... neuropathy type 5 University of Chicago Center for Peripheral Neuropathy Patient Support and Advocacy Resources (1 link) The ...

Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia.

PubMed

Miura, Yumako; Devaux, Jérôme J; Fukami, Yuki; Manso, Constance; Belghazi, Maya; Wong, Anna Hiu Yi; Yuki, Nobuhiro

2015-06-01

A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Directional diffusivity as a magnetic resonance (MR) biomarker in demyelinating disease

NASA Astrophysics Data System (ADS)

Benzinger, Tammie L. S.; Cross, Anne H.; Xu, Junqian; Naismith, Robert; Sun, Shu-Wei; Song, Sheng-Kwei

2007-09-01

Directional diffusivities derived from diffusion tensor magnetic resonance imaging (DTI) measurements describe water movement parallel to (λ ||, axial diffusivity) and perpendicular to (λ⊥radial diffusivity) axonal tracts. λ || and λ⊥ have been shown to differentially detect axon and myelin abnormalities in several mouse models of central nervous system white matter pathology in our laboratory. These models include experimental autoimmune encephalomyelitis (EAE), (1) myelin basic protein mutant mice with dysmyelination and intact axons, (2) cuprizone-induced demyelination, and remyelination, with reversible axon injury (2, 3) and a model of retinal ischemia in which retinal ganglion cell death is followed by Wallerian degeneration of optic nerve, with axonal injury preceding demyelination. (4) Decreased λ|| correlates with acute axonal injury and increased λ⊥ indicates myelin damage. (4) More recently, we have translated this approach to human MR, investigating acute and chronic optic neuritis in adults with multiple sclerosis, brain lesions in adults with multiple sclerosis, and acute disseminated encephalomyelitis (ADEM) in children. We are also investigating the use of this technique to probe the underlying structural change of the cervical spinal cord in acute and chronic T2- hyperintense lesions in spinal stenosis, trauma, and transverse myelitis. In each of these demyelinating diseases, the discrimination between axonal and myelin injury which we can achieve has important prognostic and therapeutic implications. For those patients with myelin injury but intact axons, early, directed drug therapy has the potential to prevent progression to axonal loss and permanent disability.

Coexistence of Guillain-Barré syndrome and Behçet's disease.

PubMed

Shugaiv, Erkingul; Kiyat-Atamer, Asli; Tüzün, Erdem; Deymeer, Feza; Oflazer, Piraye; Parman, Yesim; Akman-Demir, Gulsen

2013-01-01

Behçet's disease (BD) is a multisystemic, recurrent and inflammatory disorder. Neurological involvement is rare and affects mainly the central nervous system (CNS) in the form of brainstem meningoencephalitis or dural sinus thrombosis. Peripheral neuropathy is usually not observed during the course of BD but some reports have shown electrophysiologic evidence of subclinical neuropathy, mononeuritis multiplex and cranial neuropathy in BD patients. The co-occurrence of Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating neuropathy, with other autoimmune or systemic diseases is rare. We present a case of BD with clinical and electrophysiological diagnosis of GBS. The findings of the patient were discussed with reference to literature.

Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis.

PubMed

Brenton, J Nicholas; Banwell, Brenda L

2016-01-01

Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination.

Demyelinating and ischemic brain diseases: detection algorithm through regular magnetic resonance images

NASA Astrophysics Data System (ADS)

Castillo, D.; Samaniego, René; Jiménez, Y.; Cuenca, L.; Vivanco, O.; Rodríguez-Álvarez, M. J.

2017-09-01

This work presents the advance to development of an algorithm for automatic detection of demyelinating lesions and cerebral ischemia through magnetic resonance images, which have contributed in paramount importance in the diagnosis of brain diseases. The sequences of images to be used are T1, T2, and FLAIR. Brain demyelination lesions occur due to damage of the myelin layer of nerve fibers; and therefore this deterioration is the cause of serious pathologies such as multiple sclerosis (MS), leukodystrophy, disseminated acute encephalomyelitis. Cerebral or cerebrovascular ischemia is the interruption of the blood supply to the brain, thus interrupting; the flow of oxygen and nutrients needed to maintain the functioning of brain cells. The algorithm allows the differentiation between these lesions.

[Risk factors in the epidemic neuropathy of Cuba].

PubMed

Molina-Esquivel, E; Pita-Rodríguez, G; Monterrey-Gutiérrez, P A; Clúa-Calderín, A M

1998-01-01

A case control study to find out if Cuba's epidemic neuropathy was a result of one of the following causes: (1) an infectious process, (2) exposure to one or more toxical agents, (3) low intake of one or more nutrients, or (4) more than one of such causes and their interactions. A total of 311 cases of epidemic neuropathy with optic and peripheral symptoms and 377 controls were studied. A questionnaire with 55 items was employed to document exposure to factors determined by the etiologic hypothesis. Data analysis was done separately for the optical and peripheral types of the disease. No association was found between illness and any deficiency of basic sanitation for both types of neuropathy. Acute stress, irregularities in food intake, body weight loss in the last 12 months and other indicators of nutritional deficiencies were associated to both clinical manifestations, although they were also high in the controls. Low frequency of illness was found for people living with diseased persons. Females had a significant high risk of illness in the peripheral manifestations whereas smoking was the only toxical risk factor in optical neuropathy. Nutritional deficiencies together with unidentified personal factors were the main associations for illness outcome; smoking increased significantly the risk of optical neuropathy. 1. The infection etiology was unsupported in the study. 2. Smoking appeared as a factor for the optical neuropathy. 3. Stress induced by vital events were significantly associated with the disease. 4. Both types of the neuropathy were associated to body weight loss and other indicators of nutritional deficit.

Quality assessment of online patient education resources for peripheral neuropathy.

PubMed

Hansberry, David R; Suresh, Ragha; Agarwal, Nitin; Heary, Robert F; Goldstein, Ira M

2013-03-01

Given its practicality, the internet is a primary resource for patients afflicted with diseases like peripheral neuropathy. Therefore, it is important that the readily available online resources on peripheral neuropathy are tailored to the general public, particularly concerning readability. Patient education resources were downloaded from the US National Library of Medicine, Mayo Clinic, National Institute of Neurological Disorders and Stroke, Neuropathy.org, GBS/CIDP Foundation International, Hereditary Neuropathy Foundation, Charcot-Marie-Tooth Association, Foundation for Peripheral Neuropathy, and Neuropathy Action Foundation websites. All patient education material related to peripheral neuropathy was evaluated for its level of readability using the Flesch Reading Ease (FRE) and Flesch-Kincaid Grade Level. The FRE scores averaged 43.4 with only the US National Library of Medicine scoring above 60 (76.5). The Flesch-Kincaid Grade Level scores averaged 11.0. All scores were above a seventh-grade level except the US National Library of Medicine, which had a score of a fifth-grade reading level. Most Americans may not fully benefit from patient education resources concerning peripheral neuropathy education on many of the websites. Only the US National Library of Medicine, which is written at a fifth-grade level, is likely to benefit the average American. © 2013 Peripheral Nerve Society.

Giant axonal neuropathy alters the structure of keratin intermediate filaments in human hair

PubMed Central

Soomro, Asfia; Alsop, Richard J.; Negishi, Atsuko; Kreplak, Laurent; Fudge, Douglas; Kuczmarski, Edward R.; Goldman, Robert D.

2017-01-01

Giant axonal neuropathy (GAN) follows an autosomal recessive genetic inheritance and impedes the peripheral and central nervous system due to axonal swellings that are packed with neurofilaments. The patients display a number of phenotypes, including hypotonia, muscle weakness, decreased reflexes, ataxia, seizures, intellectual disability, pale skin and often curled hair. We used X-ray diffraction and tensile testing to determine potential changes to the structure of keratin intermediate filaments (IFs) in the hair of patients with GAN. A statistically significant decrease in the 47 and the 27 Å diffraction signals were observed. Tensile tests determined that the hair was slightly stiffer, stronger and more extensible in GAN patients. These results suggest that the structure of keratin IFs in hair is altered in GAN, and the findings are compatible with an increased positional disorder of the keratin tetramers within the hair fibres. PMID:28424304

Giant axonal neuropathy alters the structure of keratin intermediate filaments in human hair.

PubMed

Soomro, Asfia; Alsop, Richard J; Negishi, Atsuko; Kreplak, Laurent; Fudge, Douglas; Kuczmarski, Edward R; Goldman, Robert D; Rheinstädter, Maikel C

2017-04-01

Giant axonal neuropathy (GAN) follows an autosomal recessive genetic inheritance and impedes the peripheral and central nervous system due to axonal swellings that are packed with neurofilaments. The patients display a number of phenotypes, including hypotonia, muscle weakness, decreased reflexes, ataxia, seizures, intellectual disability, pale skin and often curled hair. We used X-ray diffraction and tensile testing to determine potential changes to the structure of keratin intermediate filaments (IFs) in the hair of patients with GAN. A statistically significant decrease in the 47 and the 27 Å diffraction signals were observed. Tensile tests determined that the hair was slightly stiffer, stronger and more extensible in GAN patients. These results suggest that the structure of keratin IFs in hair is altered in GAN, and the findings are compatible with an increased positional disorder of the keratin tetramers within the hair fibres. © 2017 The Author(s).

Immunization-Safety Monitoring Systems for the 2009 H1N1 Monovalent Influenza Vaccination Program

DTIC Science & Technology

2011-01-01

central nervous system, optic neuritis, chronic inflammatory demyelinating polyneuropathy ) 340, 341.0, 341.8, 341.9, 377.30, 377.31, 377.32, 377.34...neuropathy, polyneuropathy due to drugs or other toxic agents, critical illness polyneuropathy , other inflammatory and toxic neuropathy) 337.0, 337.9, 354.1...Popula- tions at high risk, such as those with chronic diseases, are sometimes not well represented in clinical studies; however, additional efforts

Pitfalls in the molecular genetic diagnosis of Leber hereditary optic neuropathy (LHON)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johns, D.R.; Neufeld, M.J.

1993-10-01

Pathogenetic mutations in mtDNA are found in the majority of patients with Leber hereditary optic neuropathy (LHON), and molecular genetic techniques to detect them are important for diagnosis. A false-positive molecular genetic error has adverse consequences for the diagnosis of this maternally inherited disease. The authors found a number of mtDNA polymorphisms that occur adjacent to known LHON-associated mutations and that confound their molecular genetic detection. These transition mutations occur at mtDNA nt 11779 (SfaNI site loss, 11778 mutation), nt 3459 (BsaHI site loss, 3460 mutation), nt 15258 (AccI site loss, 15257 mutation), nt 14485 (mismatch primer Sau3AI site loss,more » 14484 mutation), and nt 13707 (BstNI site loss, 13708 mutation). Molecular genetic detection of the most common pathogenetic mtDNA mutations in LHON, using a single restriction enzyme, may be confounded by adjacent polymorphisms that occur with a false-positive rate of 2%-7%. 19 refs.« less

Gut commensalism, cytokines, and central nervous system demyelination.

PubMed

Telesford, Kiel; Ochoa-Repáraz, Javier; Kasper, Lloyd H

2014-08-01

There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination.

Gene therapy for inherited retinal and optic nerve degenerations.

PubMed

Moore, Nicholas A; Morral, Nuria; Ciulla, Thomas A; Bracha, Peter

2018-01-01

The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber's congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber's hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.

[A rare cause of optic neuropathy: Cassava].

PubMed

Zeboulon, P; Vignal-Clermont, C; Baudouin, C; Labbé, A

2016-06-01

Cassava root is a staple food for almost 500 million people worldwide. Excessive consumption of it is a rare cause of optic neuropathy. Ten patients diagnosed with cassava root related optic neuropathy were included in this retrospective study. Diagnostic criteria were a bilateral optic neuropathy preceded by significant cassava root consumption. Differential diagnoses were excluded through a neuro-ophthalmic examination, blood tests and a brain MRI. All patients had visual field examination and OCT retinal nerve fiber layer (RNFL) analysis as well as an evaluation of their cassava consumption. All patients had a bilateral optic nerve head atrophy or pallor predominantly located into the temporal sector. Visual field defects consisted of a central or cecocentral scotoma for all patients. RNFL showed lower values only in the temporal sector. Mean duration of cassava consumption prior to the appearance of visual symptoms was 22.7±11.2 years with a mean of 2.57±0.53 cassava-based meals per week. Cassava related optic neuropathy is possibly due to its high cyanide content and enabled by a specific amino-acid deficiency. Cassava root chronic consumption is a rare, underappreciated cause of optic neuropathy and its exact mechanism is still uncertain. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Peripheral neuropathy in HIV-infected and uninfected patients in Rakai, Uganda.

PubMed

Saylor, Deanna; Nakigozi, Gertrude; Nakasujja, Noeline; Robertson, Kevin; Gray, Ronald H; Wawer, Maria J; Sacktor, Ned

2017-08-01

To determine the prevalence, risk factors, and functional impairment associated with peripheral neuropathy in a prospective cohort of adults in rural Uganda. Eight hundred participants (400 HIV- and 400 antiretroviral-naive HIV+) in the Rakai Community Cohort Study underwent detailed neurologic evaluations including assessment of neuropathy symptoms, functional measures (Patient Assessment of Own Functioning Inventory and Karnofsky Performance Status scores), and neurologic evaluation by a trained medical officer. Neuropathy was defined as ≥1 subjective symptom and ≥1 sign of neuropathy on examination. Neuropathy risk factors were assessed using log binomial regression. Fifty-three percent of participants were men, with a mean (SD) age of 35 (8) years. Neuropathy was present in 13% of the cohort and was more common in HIV+ vs HIV- participants (19% vs 7%, p < 0.001). Older age (relative risk [RR] 1.04, 95% confidence interval [CI] 1.02-1.06), female sex (RR 1.49, 95% CI 1.04-2.15), HIV infection (RR 2.82, 95% CI 1.86-4.28), tobacco use (RR 1.59, 95% CI 1.02-2.48), and prior neurotoxic medication use (RR 2.08, 95% CI 1.07-4.05) were significant predictors of neuropathy in the overall cohort. Only older age was associated with neuropathy risk in the HIV+ (RR 1.03, 95% CI 1.01-1.05) and HIV- (RR 1.06, 95% CI 1.02-1.10) cohorts. Neuropathy was associated with impaired functional status on multiple measures across all participant groups. Peripheral neuropathy is relatively common and associated with impaired functional status among adults in rural Uganda. Older age, female sex, and HIV infection significantly increase the risk of neuropathy. Neuropathy may be an underrecognized but important condition in rural Uganda and warrants further study. © 2017 American Academy of Neurology.

Peripheral neuropathy in HIV-infected and uninfected patients in Rakai, Uganda

PubMed Central

Nakigozi, Gertrude; Nakasujja, Noeline; Robertson, Kevin; Gray, Ronald H.; Wawer, Maria J.; Sacktor, Ned

2017-01-01

Objective: To determine the prevalence, risk factors, and functional impairment associated with peripheral neuropathy in a prospective cohort of adults in rural Uganda. Methods: Eight hundred participants (400 HIV− and 400 antiretroviral-naive HIV+) in the Rakai Community Cohort Study underwent detailed neurologic evaluations including assessment of neuropathy symptoms, functional measures (Patient Assessment of Own Functioning Inventory and Karnofsky Performance Status scores), and neurologic evaluation by a trained medical officer. Neuropathy was defined as ≥1 subjective symptom and ≥1 sign of neuropathy on examination. Neuropathy risk factors were assessed using log binomial regression. Results: Fifty-three percent of participants were men, with a mean (SD) age of 35 (8) years. Neuropathy was present in 13% of the cohort and was more common in HIV+ vs HIV− participants (19% vs 7%, p < 0.001). Older age (relative risk [RR] 1.04, 95% confidence interval [CI] 1.02–1.06), female sex (RR 1.49, 95% CI 1.04–2.15), HIV infection (RR 2.82, 95% CI 1.86–4.28), tobacco use (RR 1.59, 95% CI 1.02–2.48), and prior neurotoxic medication use (RR 2.08, 95% CI 1.07–4.05) were significant predictors of neuropathy in the overall cohort. Only older age was associated with neuropathy risk in the HIV+ (RR 1.03, 95% CI 1.01–1.05) and HIV− (RR 1.06, 95% CI 1.02–1.10) cohorts. Neuropathy was associated with impaired functional status on multiple measures across all participant groups. Conclusions: Peripheral neuropathy is relatively common and associated with impaired functional status among adults in rural Uganda. Older age, female sex, and HIV infection significantly increase the risk of neuropathy. Neuropathy may be an underrecognized but important condition in rural Uganda and warrants further study. PMID:28679596

Leigh-like encephalopathy complicating Leber's hereditary optic neuropathy.

PubMed

Funalot, Benoît; Reynier, Pascal; Vighetto, Alain; Ranoux, Danièle; Bonnefont, Jean-Paul; Godinot, Catherine; Malthièry, Yves; Mas, Jean-Louis

2002-09-01

Leber's hereditary optic neuropathy is a mitochondrial disease caused by point mutations in mitochondrial DNA. It usually presents as severe bilateral visual loss in young adults. We report on a neurological disorder resembling Leigh syndrome, which complicated Leber's hereditary optic neuropathy in three unrelated male patients harboring mitochondrial DNA mutations at nucleotide positions 3460, 14459, and 14484, respectively. This Leigh-like encephalopathy appears to be associated with a much more severe outcome than isolated Leber's hereditary optic neuropathy.

[Toronto clinical scoring system in diabetic peripheral neuropathy].

PubMed

Liu, Feng; Mao, Ji-Ping; Yan, Xiang

2008-12-01

To evaluate the application value of Toronto clinical scoring system (TCSS) and its grading of neuropathy for diabetic peripheral neuropathy (DPN), and to explore the relationship between TCSS grading of neuropathy and the grading of diabetic nephropathy and diabetic retinopathy. A total of 209 patients of Type 2 diabtes (T2DM) underwent TCSS. Taking electrophysiological examination as a gold standard for diagnosing DPN, We compared the results of TCSS score > or = 6 with electrophysiological examination, and tried to select the optimal cut-off points of TCSS. The corresponding accuracy, sensitivity, and specificity of TCSS score > or = 6 were 76.6%, 77.2%, and 75.6%, respectively.The Youden index and Kappa were 0.53 and 0.52, which implied TCSS score > or = 6 had a moderate consistency with electrophysiological examination. There was a linear positive correlation between TCSS grading of neuropathy and the grading of diabetic nephropathy and diabetic retinopathy (P<0.05). The optimal cut-off point was 5 or 6 among these patients. TCSS is reliable in diagnosing DPN and its grading of neuropathy has clinical value.

Composite ganglioside autoantibodies and immune treatment response in MMN and MADSAM.

PubMed

Martinez-Thompson, Jennifer M; Snyder, Melissa R; Ettore, Michael; McKeon, Andrew; Pittock, Sean J; Roforth, Matthew M; Mandrekar, Jay; Mauermann, Michelle L; Taylor, Bruce V; Dyck, P James B; Windebank, Anthony J; Klein, Christopher J

2018-06-01

Multifocal motor neuropathy (MMN) is a motor only, asymmetric onset neuropathy that is relatively treatment-refractory compared with classic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. We reviewed 35 patients seropositive for GM1 (monosialo-asialo [immunoglobulin M, IgM; immunoglobulin G, IgG]) and/or GD1b (disialo [IgG, IgM]) autoantibodies having MMN, classic CIDP, or MADSAM. Immune-treatment responsiveness and clinical course was compared with antibody negative disease controls. Seventy-nine percent of seropositives with an initial diagnosis of MMN were immunotherapy responsive compared with 46% of seronegatives (P = 0.045). Eight ganglioside antibody positive MMN patients of 19 (42%) developed sensory findings consistent with MADSAM compared with 3 of 41 (7%) seronegative MMN patients (P = 0.003). MMN and MADSAM patients with ganglioside antibody positivity had more sustained treatment responses (P = 0.03). Patients initially diagnosed with MMN seropositive for diverse GM1 autoantibodies appear more likely to have sustained treatment response and evolution to MADSAM. Muscle Nerve 57: 1000-1005, 2018. © 2017 Wiley Periodicals, Inc.

Stressful life events and the risk of initial central nervous system demyelination.

PubMed

Saul, Alice; Ponsonby, Anne-Louise; Lucas, Robyn M; Taylor, Bruce V; Simpson, Steve; Valery, Patricia; Dwyer, Terence; Kilpatrick, Trevor J; Pender, Michael P; van der Mei, Ingrid Af

2017-06-01

There is substantial evidence that stress increases multiple sclerosis disease activity, but limited evidence on its association with the onset of multiple sclerosis. To examine the association between stressful life events and risk of first demyelinating event (FDE). This was a multicentre incident case-control study. Cases ( n = 282 with first diagnosis of central nervous system (CNS) demyelination, including n = 216 with 'classic FDE') were aged 18-59 years. Controls without CNS demyelination ( n = 558) were matched to cases on age, sex and study region. Stressful life events were assessed using a questionnaire based on the Social Readjustment Rating Scale. Those who suffered from a serious illness in the previous 12 months were more likely to have an FDE (odds ratio (OR) = 2.35 (1.36, 4.06), p = 0.002), and when we limited our reference group to those who had no stressful life events, the magnitude of effect became stronger (OR = 5.41 (1.80, 16.28)). The total stress number and stress load were not convincingly associated with the risk of an FDE. Cases were more likely to report a serious illness in the previous 12 months, which could suggest that a non-specific illness provides an additional strain to an already predisposed immune system.

Vitamin B supplementation for diabetic peripheral neuropathy.

PubMed

Jayabalan, Bhavani; Low, Lian Leng

2016-02-01

Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction. Copyright © Singapore Medical Association.

Vitamin B supplementation for diabetic peripheral neuropathy

PubMed Central

Jayabalan, Bhavani; Low, Lian Leng

2016-01-01

Vitamin B12 deficiency has been associated with significant neurological pathology, especially peripheral neuropathy. This review aims to examine the existing evidence on the effectiveness of vitamin B12 supplementation for the treatment of diabetic peripheral neuropathy. A search of PubMed and the Cochrane Central Register of Controlled Trials for all relevant randomised controlled trials was conducted in December 2014. Any type of therapy using vitamin B12 or its coenzyme forms was assessed for efficacy and safety in diabetics with peripheral neuropathy. Changes in vibration perception thresholds, neuropathic symptoms and nerve conduction velocities, as well as the adverse effects of vitamin B12 therapy, were assessed. Four studies comprising 363 patients met the inclusion criteria. This review found no evidence that the use of oral vitamin B12 supplements is associated with improvement in the clinical symptoms of diabetic neuropathy. Furthermore, the majority of studies reported no improvement in the electrophysiological markers of nerve conduction. PMID:26892473

Investigation of depression in Greek patients with diabetic peripheral neuropathy.

PubMed

Rekleiti, Maria; Sarafis, Pavlos; Saridi, Maria; Toska, Aikaterini; Melos, Chrysovaladis; Souliotis, Kyriakos; Tsironi, Maria

2013-06-16

Considerable studies directly connect the complications in diabetic patients, and especially peripheral neuropathy, with the emergence of depression. Neuropathetic pain may deteriorate the general health status of the diabetic patient and glycaemic regulation. The purpose of this study was to investigate the appearance and degree of diabetic peripheral neuropathy and its correlation with depression, with other parameters of the disease and also duration. 57 diabetic patients participated with diagnosed diabetic peripheral neuropathy (male n=27, female n= 30, mean of age 72.7±6.35 years). The first part of Michigan Neuropathy Screening Instrument and the Zung Depression Rating Scale were used as tools for our study. Data was analysed with the SPSS 18.0 statistic program. 57.9% of the patients were overweight, 35.1% were obese and only 7% were within normal weight range. The BMI findings between the two genders indicate that male participants are more often obese than females. Women surpassed men in the category of overweight patients (p < 0.05). The score based on MNSI was high and between 3 to 12 (mean average of 8.19±2.60 with 8 as intermediate rate). Almost 60% of patients had severe neuropathy, only 2 were found with mild symptoms and the rest had moderate neuropathtic symptoms, based on the score summary from the questionnaire. Investigating in detail the relation of diabetic neuropathy and depression, it derives that a high degree of diabetic neuropathy is related with high score of depression [F(3.160)=9.821, p=0.001]. Moderate and severe neuropathy was found with almost the same levels of depression. The correlation between diabetic neuropathy and depression is confirmed, while a very high depression rate was found in patients with severe neuropathy. The issue needs further study by using common instruments to obtain comparative results from the scientific community.

Acute optic neuropathy associated with a novel MFN2 mutation.

PubMed

Leonardi, Luca; Marcotulli, Christian; Storti, Eugenia; Tessa, Alessandra; Serrao, Mariano; Parisi, Vincenzo; Santorelli, F M; Pierelli, Francesco; Casali, Carlo

2015-07-01

Mutations in the mitofusin 2 (MFN2) gene cause CMT2A the most common form of autosomal dominant axonal Charcot-Marie-Tooth (CMT). In addition, mutations in MFN2 have been shown to be responsible for Hereditary Motor Sensory Neuropathy type VI (HSMN VI), a rare early-onset axonal CMT associated with optic neuropathy. Most reports of HMSN VI presented with a sub-acute form of optic neuropathy. Herein, we report a CMT2A patient, who developed very rapidly progressing severe optic neuropathy. A 40-year-old Caucasian man was evaluated for gait disturbance and lower limbs weakness, slowly progressed over the last 2 years. Due to clinical data and family history, a diagnosis of CMT2 was made. The novel heterozygous c.775C > T (p.Arg259Cys) mutation in MFN2 was detected in the patient and his clinical affected mother. Interestingly, the patient developed a severe sudden bilateral visual deterioration few years early, with clinical and instrumental picture suggestive of acute bilateral optic neuropathy. Our report expands the spectrum of MFN2-related manifestation because it indicates that visual symptoms of HMSN VI may enter in the differential with acquired or hereditary acute optic neuropathies, and that severe optic neuropathy is not invariably an early manifestation of the disease but may occur as disease progressed. This report could have an impact on clinicians who evaluate patients with otherwise unexplainable bilateral acute-onset optic neuropathy, especially if associated with a motor and sensory axonal neuropathy.

Comparison of oxaliplatin and paclitaxel-induced neuropathy (Alliance A151505).

PubMed

Pachman, Deirdre R; Qin, Rui; Seisler, Drew; Smith, Ellen M Lavoie; Kaggal, Suneetha; Novotny, Paul; Ruddy, Kathryn J; Lafky, Jacqueline M; Ta, Lauren E; Beutler, Andreas S; Wagner-Johnston, Nina D; Staff, Nathan P; Grothey, Axel; Dougherty, Patrick M; Cavaletti, Guido; Loprinzi, Charles L

2016-12-01

Oxaliplatin and paclitaxel are commonly used chemotherapies associated with acute and chronic neuropathies. There is a need to better understand the similarities and differences of these clinical syndromes. Neuropathy data were pooled from patients receiving adjuvant oxaliplatin and weekly paclitaxel or every 3 weeks of paclitaxel. Patients completed daily questionnaires after each chemotherapy dose and the European Organization for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy before each chemotherapy cycle and for 12 months post-treatment. Acute neuropathy symptoms from both drugs peaked around day 3. Acute symptoms experienced in cycle 1 predicted occurrence in subsequent cycles. Paclitaxel-induced acute symptoms were similar in intensity in each cycle and largely resolved between cycles. Oxaliplatin-induced acute symptoms were about half as severe in the first cycle as in later cycles and did not resolve completely between cycles. Both drugs caused a predominantly sensory chronic neuropathy (with numbness and tingling being more common than pain). Oxaliplatin-induced neuropathy worsened after the completion of treatment and began to improve 3 months post-treatment. In contrast, paclitaxel-induced neuropathy began improving immediately after chemotherapy cessation. During treatment, the incidence of paclitaxel sensory symptoms was similar in the hands and feet; with oxaliplatin, the hands were affected more than the feet. Both paclitaxel- and oxaliplatin-induced acute neurotoxicity appeared to predict the severity of chronic neuropathy, more prominently with oxaliplatin. Knowledge of the similarities and differences between neuropathy syndromes may provide insight into their underlying pathophysiology and inform future research to identify preventative treatment approaches.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

PubMed Central

Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

2015-01-01

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PMID:26198449

Diabetes and obesity are the main metabolic drivers of peripheral neuropathy.

PubMed

Callaghan, Brian C; Gao, LeiLi; Li, Yufeng; Zhou, Xianghai; Reynolds, Evan; Banerjee, Mousumi; Pop-Busui, Rodica; Feldman, Eva L; Ji, Linong

2018-04-01

To determine the associations between individual metabolic syndrome (MetS) components and peripheral neuropathy in a large population-based cohort from Pinggu, China. A cross-sectional, randomly selected, population-based survey of participants from Pinggu, China was performed. Metabolic phenotyping and neuropathy outcomes were performed by trained personnel. Glycemic status was defined according to the American Diabetes Association criteria, and the MetS using modified consensus criteria (body mass index instead of waist circumference). The primary peripheral neuropathy outcome was the Michigan Neuropathy Screening Instrument (MNSI) examination. Secondary outcomes were the MNSI questionnaire and monofilament testing. Multivariable models were used to assess for associations between individual MetS components and peripheral neuropathy. Tree-based methods were used to construct a classifier for peripheral neuropathy using demographics and MetS components. The mean (SD) age of the 4002 participants was 51.6 (11.8) and 51.0% were male; 37.2% of the population had normoglycemia, 44.0% prediabetes, and 18.9% diabetes. The prevalence of peripheral neuropathy increased with worsening glycemic status (3.25% in normoglycemia, 6.29% in prediabetes, and 15.12% in diabetes, P < 0.0001). Diabetes (odds ratio [OR] 2.60, 95% CI 1.77-3.80) and weight (OR 1.09, 95% CI 1.02-1.18) were significantly associated with peripheral neuropathy. Age, diabetes, and weight were the primary splitters in the classification tree for peripheral neuropathy. Similar to previous studies, diabetes and obesity are the main metabolic drivers of peripheral neuropathy. The consistency of these results reinforces the urgent need for effective interventions that target these metabolic factors to prevent and/or treat peripheral neuropathy.