Guillaume Nicolas

Proposed revised electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy

Electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were proposed by an Ad Hoc Subcommittee of the American Academy of Neurology (AAN) in 1991. Only 60% of CIDP patients fulfilled these criteria, which therefore appear poorly sensitive. We therefore sought to revise the electrophysiological criteria. We selected 40 CIDP patients and compared them with 35 patients with axonal polyneuropathy, 116 patients with Charcot‐Marie‐Tooth type 1A (CMT1A) disease, and 66 patients with immunoglobulin M (IgM) monoclonal gammopathy. The proposed electrophysiological criteria identified 90% of the CIDP patients, although 3% of patients with axonal polyneuropathy were falsely identified. For the CIDP patients, sensitivity and specificity were 90% and 97%, respectively. Of the patients with IgM monoclonal gammaglobulin of undetermined significance (MGUS) and CMT1A, 100% fulfilled these new criteria, whereas 90% and 97%, respectively, fulfilled the AAN criteria. These results suggest that the AAN criteria are more appropriate for IgM MGUS and CMT1A patients than for CIDP patients. We therefore propose new electrophysiological criteria for CIDP that appear to have better sensitivity.

Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease.

Mutations of the mitofusin 2 gene (MFN2) may account for at least a third of the cases of Charcot–Marie–Tooth disease type 2 (CMT2). This study investigates mitochondrial cellular bioenergetics in MFN2‐related CMT2A.

Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

Objective: To determine whether rituximab 375 mg/m2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months. Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form–36 questionnaire. Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.

Validity of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy: a multicentre European study

Background: Diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP) have variable sensitivity and specificity. Newly published criteria by Koski et al combine clinical and electrophysiological components, either of which suffices to establish the diagnosis. European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria require mandatory electrophysiology, as do other sets of criteria. Methods: The value of the two above-mentioned sets of criteria, on 151 patients with CIDP, and 162 controls with axonal neuropathy, from four European centres was assessed. Results were compared with Van den Bergh and Piéret’s criteria and those of the American Academy of Neurology (AAN). The utility of more extensive nerve-conduction studies was ascertained. Results: Koski et al’s criteria had a sensitivity of 63% and specificity of 99.3%. With unilateral, right-sided, forearm/foreleg, four-nerve studies, EFNS/PNS criteria offered a sensitivity of 81.3% and specificity of 96.2% for “definite/probable” CIDP. Van den Bergh and Piéret’s criteria had a sensitivity of 79.5% and specificity of 96.9%. AAN criteria were poorly sensitive (45.7%) but highly specific (100%). “Possible” electrophysiological CIDP as per EFNS/PNS criteria were poorly specific (69.2%). More extensive studies increased the diagnostic sensitivity of EFNS/PNS criteria (96.7%) but reduced the specificity (79.3%). Conclusions: In our patient populations, the EFNS/PNS criteria were the most sensitive and allowed identification of a highly significantly greater number of patients than Koski et al’s criteria. The latter were comparable in specificity with the “definite/probable” EFNS/PNS electrodiagnostic subcategories. More extensive nerve-conduction studies improved diagnostic yield but resulted in loss of specificity.

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K)

Mutations in GDAP1, an outer mitochondrial membrane protein responsible for recessive Charcot-Marie-Tooth disease (CMT4A), have also been associated with CMT2K, a dominant form of the disease. The three CMT2K patients we studied carried a novel dominant GDAP1 mutation, C240Y (c.719G > A). Mitochondrial respiratory chain complex I activity in fibroblasts from CMT2K patients was 40% lower than in controls, whereas the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. Thus, besides the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume.

Work increases the incidence of carpal tunnel syndrome in the general population

The purpose of this study was to estimate the incidence of carpal tunnel syndrome (CTS) in a general population according to employment status and to assess the proportion of cases attributable to work. CTS occurring in patients aged 20–59 years living in the French Maine and Loire region were included prospectively from 2002 to 2004. Medical and occupation history was gathered by mailed questionnaire. Incidence rates of CTS and relative risks (RRs) of CTS were computed in relation to employment status. The attributable fractions of risk of CTS to work among the exposed persons (AFEs) were calculated. A total of 1168 patients (819 women, 349 men) were included during the 3‐year period. The mean incidence rate of CTS per 1000 person‐years was higher in employed than unemployed persons (1.7 vs. 0.8 in women and 0.6 vs. 0.3 in men). The excess risk of CTS was statistically significant for male (RR 4.2) and female (RR 3.0) blue‐collar workers and female lower‐grade white‐collar workers (RR 2.5). The AFE to work in general was 47% (95% confidence interval: 39–54) in women. AFEs reached higher values in female blue‐collar workers [67% (65–68)] and lower‐grade services, sales, and clerical white‐collar workers [61% (57–64)]. The AFE in male blue‐collar workers was 76% (72–80). These data show a higher incidence of CTS in the working than the non‐working population and suggest that a substantial proportion of CTS cases diagnosed in lower‐grade white‐collar and blue‐collar workers are attributable to work. Muscle Nerve, 2008

Mitochondrial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involving GDAP1 mutations

Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics.

Genotype–phenotype correlation and course of transthyretin familial amyloid polyneuropathies in france

To compare the natural history of familial transthyretin amyloid polyneuropathies (FAP) due to the Val30Met, Ser77Tyr, and Ile107Val mutations in France with the classical Portuguese Val30Met FAP.

Electrophysiological diagnosis of Guillain–Barré syndrome subtype: could a single study suffice?

Background Serial electrophysiology has been suggested as essential for accurate diagnosis in Guillain–Barré syndrome (GBS). However, whether more adapted electrophysiological criteria may allow a single study to be sufficient is unknown. Methods We retrospectively reviewed records of 365 consecutive patients with GBS from Birmingham, UK, and Garches, France, admitted between 1998 and 2013. Electrophysiology was analysed using existing criteria as well as a set of modified criteria, developed using sensitive and specific cut-off values for demyelination and incorporating new knowledge on electrophysiology of axonal GBS. We compared diagnostic rates and classification changes using modified criteria with published literature relating to serial studies. Results With existing criteria, we found similar proportions of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) (71.5% vs 72%; p=1), axonal GBS (17.5% vs 14.7%; p=0.62) and equivocal forms (9.9% vs 13.3%; p=0.41) to the previous studies considered. With modified criteria, we identified comparable rates of AIDP (56.2% vs 58.7%; p=0.70), axonal GBS (35.1% vs 36%; p=0.89) and equivocal forms (7.7% vs 5.3%; p=0.63) with a single nerve conduction study as compared with when serial electrophysiology was used in previous analyses. We observed an identical diagnostic shift from AIDP to axonal GBS with modified criteria as that described with serial studies (21.5% vs 18.5%; p=0.72). Classification changes with modified criteria correlated significantly with performing of electrophysiology ≤7 days after symptom onset (p=0.045), indicating their greater usefulness in earlier disease stages. Conclusions A single electrophysiological study may suffice to establish the ultimate electrodiagnosis of GBS subtype if the proposed modified electrodiagnostic criteria are used.

Attributable risk of carpal tunnel syndrome according to industry and occupation in a general population.

OBJECTIVE An epidemiologic surveillance network for carpal tunnel syndrome (CTS) was set up in the general population of a French region to assess the proportion of CTS cases attributable to work in high-risk industries and occupations. METHODS Cases of CTS occurring among patients ages 20-59 years living in the Maine and Loire region were included prospectively from 2002 to 2004. Medical and occupation history was gathered by mailed questionnaire for 815 women and 320 men. Age-adjusted relative risks of CTS and the attributable risk fractions of CTS among exposed persons (AFEs) were computed in relation to industry sectors and occupation categories. RESULTS Twenty-one industry sectors and 8 occupational categories for women and 10 sectors and 6 occupational categories for men were characterized by a significant excess risk of CTS. High AFE values were observed in the manufacturing (42-93% for both sexes), construction (66% for men), and personal service industries (66% for women) and in the trade and commerce sectors (49% for women). High AFE values were observed in lower-grade white-collar occupations for women (43-67%) and blue-collar occupations for men (60-74%) and women (48-88%). CONCLUSION The attributable proportions of CTS cases among workers employed in industry sectors and occupation categories identified at high risk of CTS varied between 36% and 93%.