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Background: Vitamin B12 (B12) has a fundamental role in both central and peripheral nervous system function at all ages. Neurologic manifestations may be the earliest and often the only manifestation of B12 deficiency. Mostly because of the poor sensitivity of methods of determination for B12 levels, peripheral neuropathy remains a classical but underdiagnosed complication of B12 deficiency. So the clinical and electrophysiological characteristics of B12-responsive neuropathy are not well known. Methods: A retrospective study of patients with B12-responsive neuropathy was conducted at our hospital on a 3-year period. The criteria for inclusion were: (a) neuropathy confirmed by the electrophysiological study (nerve conduction study); and (b) improvement of at least 1 point of the total Overall Neuropathy Limitations Scale score after vitamin B12 treatment. Results: Nine patients were identified. Serum B12 level was low in only four. Four patients had sensorimotor (predominantly sensory) axonal polyneuropathy while five had only sensory neuronopathy. Six improved in less than 1 month after B12 supplementation. Conclusion: B12-responsive neuropathy is a more heterogeneous group of neuropathy than previously described. B12 deficiency is a cause of peripheral neuropathy and should systematically be ruled out in the clinical setting of idiopathic neuropathy or sensory neuronopathy because of potential reversibility. Abbreviations: B12: vitamin B12; CMAP: compound muscle action potentials; DRG: dorsal root ganglia; ENMG: electroneuromyography; MCCT: motor central conduction time; MEP: motor evoked potentials; MMA: methylmalonic acid; MMCoAM: L-methylmalonyl–CoenzymeA mutase; ONLS: overall neuropathy limitations scale; SCV: sensory conduction velocities; SNAP: sensory nerve action potentials; SNN: sensory neuronopathy; SSS: SNAP sum score [ABSTRACT FROM AUTHOR]

Hypohidrosis is a frequent and early symptom in patients with Fabry disease. Studies have reported improved sweating in patients treated with enzyme-replacement therapy. A new method, Sudoscan, has been developed that is noninvasive, is quantitative, and can quickly evaluate sweat gland function. It is based on the electrochemical reaction between sweat chlorides and stainless-steel electrodes in contact with the palms and soles. The aim of our study was to evaluate the Sudoscan as a tool to assess sudomotor dysfunction in patients with Fabry disease. Consecutive patients were prospectively recruited who had a diagnosis of Fabry disease, which had been confirmed genetically and/or by measurement of α-galactosidase activity in leukocytes. Healthy controls, matched (1:1) for age and sex, were also enrolled. Test results were expressed immediately as electrochemical skin conductance (ESC, µS) for hands and feet. Sudomotor dysfunction was considered absent, moderate, or severe if the ESC measured on the feet was >60 µS, between 60 and 40 µS, or <40 µS, respectively. Among the 18 patients, 11 had hypohidrosis or anhidrosis. Hand and feet ESCs were significantly lower in patients compared to their controls (P=0.0015 and P=0.0047, respectively). Among patients, 8/18 (44.5%) had a sudomotor dysfunction, moderate in three and severe in five cases. Hand and feet ESCs were significantly lower in those with hypohidrosis/anhidrosis compared to those without (P=0.0014 and P=0.0056, respectively). This study showed that Sudoscan provided a quick, noninvasive, and quantitative measurement of sudomotor function in Fabry disease patients. [ABSTRACT FROM AUTHOR]

Background: Transthyretin-mediated amyloidosis is an inherited, progressively debilitating disease caused by mutations in the transthyretin gene. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of patisiran (ALN-TTR02), a small interfering RNA encapsulated within lipid nanoparticles, in patients with transthyretin-mediated familial amyloid polyneuropathy (FAP). Methods: In this phase II study, patients with FAP were administered 2 intravenous infusions of patisiran at one of the following doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W), or 0.3 mg/kg (n = 12) every 3 weeks (Q3W). Results: Of 29 patients in the intent-to-treat population, 26 completed the study. Administration of patisiran led to rapid, dose-dependent, and durable knockdown of transthyretin, with the maximum effect seen with patisiran 0.3 mg/kg; levels of mutant and wild-type transthyretin were reduced to a similar extent in Val30Met patients. A mean level of knockdown exceeding 85 % after the second dose, with maximum knockdown of 96 %, was observed for the Q3W dose. The most common treatment-related adverse event (AE) was mild-to-moderate infusion-related reactions in 10.3 % of patients. Four serious AEs (SAEs) were reported in 1 patient administered 0.3 mg/kg Q3W (urinary tract infection, sepsis, nausea, vomiting), and 1 patient administered 0.3 mg/kg Q4W had 1 SAE (extravasation-related cellulitis). Conclusions: Patisiran was generally well tolerated and resulted in significant dose-dependent knockdown of transthyretin protein in patients with FAP. Patisiran 0.3 mg/kg Q3W is currently in phase III development. [ABSTRACT FROM AUTHOR]

There are no validated criteria for the diagnosis of sensory neuronopathy (SNN) yet. In a preliminary monocenter study a set of criteria relying on clinical and electrophysiological data showed good sensitivity and specificity for a diagnosis of probable SNN. The aim of this study was to test these criteria on a French multicenter study. 210 patients with sensory neuropathies from 15 francophone reference centers for neuromuscular diseases were included in the study with an expert diagnosis of non-SNN, SNN or suspected SNN according to the investigations performed in these centers. Diagnosis was obtained independently from the set of criteria to be tested. The expert diagnosis was taken as the reference against which the proposed SNN criteria were tested. The set relied on clinical and electrophysiological data easily obtainable with routine investigations. 9/61 (16.4 %) of non-SNN patients, 23/36 (63.9 %) of suspected SNN, and 102/113 (90.3 %) of SNN patients according to the expert diagnosis were classified as SNN by the criteria. The SNN criteria tested against the expert diagnosis in the SNN and non-SNN groups had 90.3 % (102/113) sensitivity, 85.2 % (52/61) specificity, 91.9 % (102/111) positive predictive value, and 82.5 % (52/63) negative predictive value. Discordance between the expert diagnosis and the SNN criteria occurred in 20 cases. After analysis of these cases, 11 could be reallocated to a correct diagnosis in accordance with the SNN criteria. The proposed criteria may be useful for the diagnosis of probable SNN in patients with sensory neuropathy. They can be reached with simple clinical and paraclinical investigations. [ABSTRACT FROM AUTHOR]

Triple-A or Allgrove syndrome is a rare multisystem disease classically associated with esophageal achalasia, adrenal insufficiency and alacrima. Here, we describe the poorly understood neurological characteristics often associated with this condition, through the clinical and electrophysiological analysis of eight patients. All patients were genetically confirmed and had a mutation in the ALADIN gene. They all displayed a classical picture of Triple-A syndrome: all suffered from achalasia and alacrima and half of them from adrenal insufficiency. However, all harbored a neurological picture characterized by a recognizable pattern of peripheral neuropathy. Other neurological features included cognitive deficits, pyramidal syndrome, cerebellar dysfunction, dysautonomia, neuro-ophthalmological signs and bulbar and facial symptoms. This neurological picture was prominent in all patients and misled the initial diagnosis in six of them, which had a late onset. We then review the previous neurological reports of this disease, to improve the understanding of this rare condition. Diagnosis of late-onset Triple-A syndrome is difficult when the clinical picture is mainly neurological and when endocrine or gastrointestinal signs are minor. The characteristics of the peripheral neuropathy, among other neurological signs, can be of help. [ABSTRACT FROM AUTHOR]

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot–Marie–Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy ‘plus’ phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with ‘mitochondrial DNA breakage’ syndrome. Contrary to previous studies in patients with Charcot–Marie–Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability. [ABSTRACT FROM PUBLISHER]

Since several years, the use of intravenous immunoglobulins (IVIg) has increased. This growth has encouraged some countries to publish guidelines. In parallel, some countries have conducted audits to know how IVIg are used in clinical practice in the light of the available guidelines. The objective of this study was to assess IVIg use in three French university hospitals in 2006. All IVIg administrations were evaluated during 6 months (12 September 2005-12 March 2006) in French university hospitals of Marseille. Different data were recorded for each administration: patient characteristics, indication, formulation and quantity. During the study period, 2802 administrations of IVIg (corresponding to a total quantity of 76 780 g) have been recorded. Four hundred and thirty-five patients received at least one of these administrations. The five most reported indications were multifocal motor neuropathy (11.0% of total quantity), chronic inflammatory demyelinating polyradiculoneuropathy (10.2%), corticoresistant dermatomyositis (10.2%), immune thrombocytopaenia (9.9%) and primary immune deficiency (9.1%). According to available French recommendations, 70% of the IVIg use was for 'acknowledged indications', 9% for 'indications to be assessed' and 18% for 'unwarranted indications'. The 10 most reported indications were 'acknowledged indications' according to available recommendations of the French expert group. Nevertheless, the two most reported indications were not approved by the French Health Products Agency (AFSSAPS) at the time of the study and were approved since. [ABSTRACT FROM AUTHOR]

Ataxia-ocular apraxia 2 (AOA2) was recently identified as a new autosomal recessive ataxia. We have now identified causative mutations in 15 families, which allows us to clinically define this entity by onset between 10 and 22 years, cerebellar atrophy, axonal sensorimotor neuropathy, oculomotor apraxia and elevated alpha-fetoprotein (AFP). Ten of the fifteen mutations cause premature termination of a large DEAxQ-box helicase, the human ortholog of yeast Sen1p, involved in RNA maturation and termination. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to assess the usefulness of motor unit number index (MUNIX) technique in Charcot-Marie-Tooth disease and test the correlation between MUNIX and clinical impairment. Methods MUNIX technique was performed in the abductor pollicis brevis (APB), the abductor digiti minimi (ADM) and the tibialis anterior (TA) muscles in the nondominant side. A MUNIX sum score was calculated by adding the MUNIX of these 3 muscles. Muscle strength was measured using the MRC (medical research council) scale. Disability was evaluated using several functional scales, including CMT neuropathy score version 2 (CMTNSv2) and overall neuropathy limitation scale (ONLS). Results A total of 56 CMT patients were enrolled. The MUNIX scores of the ADM, APB and TA muscles correlated with the MRC score of the corresponding muscle (p < 0.01). The MUNIX sum score correlated with the clinical scales CMTNSv2 ( r   =  −0.65, p < 0.01) and ONLS ( r   =  −0.57, p < 0.01). Conclusion MUNIX correlates with muscle strength and clinical measurements of disability in patients with CMT disease. Significance The MUNIX technique evaluates motor axonal loss and correlates with disability. The MUNIX sum score may be a useful outcome measure of disease progression in CMT. [ABSTRACT FROM AUTHOR]

Objective To identify factors associated with efficacy of rituximab (RTX) infusions in patients with anti-myelin associated glycoprotein (MAG) neuropathy. Methods 33 patients with anti-MAG neuropathy treated with RTX were retrospectively evaluated. All patients underwent neurological, biological, and electrophysiological examinations. Good response was defined as an improvement of at least one point of the Overall Neuropathy Limitation Scale (ONLS) at 6 months or at the last follow-up. Disease evolution was defined as sub-acute if the ONLS increased by at least 2 points the year before therapy. Results Ten patients (30%) were improved 6 months after RTX and 6/20 (30%) at the last follow-up (mean 42 months). Response to RTX was significantly associated with subacute evolution and proximal weakness of the lower limbs at the onset of disease. Improvement was not correlated with electrophysiological data and anti-MAG antibodies titers. Discussion This study suggests that RTX may be efficacious in a sub-population of patients with anti-MAG neuropathy, particularly in those with proximal weakness of the lower limbs or sub-acute evolution. [ABSTRACT FROM AUTHOR]

Abstract: A woman with Crohn''s disease developed acute neuropathy and concomitant encephalopathy while being treated with infliximab. The etiological investigations were negative. Infliximab was stopped and she was given four series of polyvalent immunoglobulin injections. Eighteen months later, the encephalitic symptoms had disappeared and the neuropathic symptoms were less severe. TNF-alpha antagonists have been previously blamed for triggering neurological disorders, but no cases of acute neuropathy concomitant with encephalopathy have been reported so far. [Copyright &y& Elsevier]

Summary: Background: Charcot–Marie–Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A. Methods: This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot–Marie–Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779. Findings: The median change in CMTNS from baseline to 12 months was 0·5 points (95% CI −0·3 to 1·4) for the placebo group (n=62), 0·7 points (0·0 to 1·4) for the 1 g ascorbic acid group (n=56), and −0·4 points (−1·2 to 0·4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0·14). The occurrence of adverse events did not differ between the groups (p=0·74). Interpretation: Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown. Funding: French Ministry of Health (National PHRC 2004) and Association Française Contre les Myopathies. [Copyright &y& Elsevier]

High-affinity anti-GM1 antibodies are frequently described in several nervous system diseases, mainly in multifocal motor neuropathy (MMN) and some acute neuropathies. These antibodies are currently detected using enzyme-linked immunosorbent assay (ELISA) and immuno-thin-layer-chromatography (immuno-TLC) methods. We report in this article a new method based on the incorporation of exogenous GM1 in a selected cell line to detect anti-GM1 antibodies using flow cytometry (FC). This method is evaluated on 80 sera from normal blood donors (NBD) and patients suffering various nervous system diseases. It appears to be as sensitive as our method ELISA for the diagnosis of some motor neuron syndromes. [Copyright &y& Elsevier]

We report meningitis with diffuse neuralgic pain or polyradiculoneuropathy associated with PCR-documented acute hepatitis E in 2 adults. These observations suggest that diagnostic testing for hepatitis E virus should be conducted for patients who have neurologic symptoms and liver cytolysis. [ABSTRACT FROM AUTHOR]