Emilien Delmont

Regional difference and similarity of familial amyloidosis with polyneuropathy in France.

Familial amyloidosis with polyneuropathy (FAP) in France have a large genetic heterogeneity with 29 transthyretin (TTR) gene mutations; Met30-TTR is the most frequent one (62%); followed by Tyr77-TTR (11.8%) and Phe77-TTR (6.2%). Analysis of 60 FAP patients diagnosed during the period 2008–2010 showed amyloid polyneuropathy was initially suspected in only 38% patients. TTR Met30 of Portuguese ancestry is different from TTR Met30 of non Portuguese ancestry and other non Met30 variants in geographical distribution and clinical presentation. There are three additional phenotypes of the neuropathy including multifocal upper limbs neuropathy, ataxic polyneuropathy and motor neuropathy. Patients with Tyr77-TTR are characterized by a late onset (>50 years), frequent ataxic phenotype; they are localized mainly in north of France. The more frequent use of the TTR genetic tests and the French network for FAP will help in the future to improve diagnosis and care.

Autoantibodies to nodal isoforms of neurofascin in chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelination polyneuropathy is a heterogeneous and treatable immune-mediated disorder that lacks biomarkers to support diagnosis. Recent evidence indicates that paranodal proteins (contactin 1, contactin-associated protein 1, and neurofascin-155) are the targets of autoantibodies in subsets of patients showing distinct clinical presentations. Here, we identified neurofascin-186 and neurofascin-140 as the main targets of autoantibodies in five patients presenting IgG reactivity against the nodes of Ranvier. Four patients displayed predominantly IgG4 antibodies, and one patient presented IgG3 antibodies that activated the complement pathway in vitro. These patients present distinct clinical features compared to those with anti-neurofascin-155 IgG4. Most patients had a severe phenotype associated with conduction block or decreased distal motor amplitude. Four patients had a subacute-onset and sensory ataxia. Two patients presented with nephrotic syndromes and one patient with an IgG4-related retroperitoneal fibrosis. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Clinical remission was associated with autoantibody depletion and with recovery of conduction block and distal motor amplitude suggesting a nodo-paranodopathy. Our data demonstrate that the pathogenic mechanisms responsible for chronic inflammatory demyelination polyneuropathy are broad and may include dysfunctions at the nodes of Ranvier in a subgroup of patients.

A clinical pattern-based etiological diagnostic strategy for sensory neuronopathies: a French collaborative study.

Sensory neuronopathies (SNNs) encompass paraneoplastic, infectious, dysimmune, toxic, inherited, and idiopathic disorders. Recently described diagnostic criteria allow SNN to be differentiated from other forms of sensory neuropathy, but there is no validated strategy based on routine clinical investigations for the etiological diagnosis of SNN. In a multicenter study, the clinical, biological, and electrophysiological characteristics of 148 patients with SNN were analyzed. Multiple correspondence analysis and logistic regression were used to identify patterns differentiating between forms of SNNs with different etiologies. Models were constructed using a study population of 88 patients and checked using a test population of 60 cases. Four patterns were identified. Pattern A, with an acute or subacute onset in the four limbs or arms, early pain, and frequently affecting males over 60 years of age, identified mainly paraneoplastic, toxic, and infectious SNN. Pattern B identified patients with progressive SNN and was divided into patterns C and D, the former corresponding to patients with inherited or slowly progressive idiopathic SNN with severe ataxia and electrophysiological abnormalities and the latter to patients with idiopathic, dysimmune, and sometimes paraneoplastic SNN with a more rapid course than in pattern C. The diagnostic strategy based on these patterns correctly identified 84/88 and 58/60 patients in the study and test populations, respectively.

Motor unit number index (MUNIX): Is it relevant in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)?

OBJECTIVE To determine the test-retest reliability of motor unit number index (MUNIX) technique and to explore if the MUNIX sumscore could be related with disability in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS The MUNIX technique was unilaterally assessed in the abductor digiti mini (ADM), the abductor pollicis brevi (APB) and the tibialis anterior (TA) muscles two different times by two blinded examiners. The MUNIX sumscore was calculated by adding the results of the ADM, APB and TA muscles. RESULTS 14 CIDP patients were enrolled. The intraclass correlation coefficient (ICC) was great for inter and intra variability for ADM muscles (0.8 and 0.81), TA muscles (0.86 and 0.89) and MUNIX sumscore (0.76 and 0.83). The MUNIX sumscores from the first and second evaluations were strongly correlated (r=0.83, p<0.001). The MUNIX sumscore was significantly correlated with MRC testing (r=0.71, p<0.01), overall neuropathy limitation scale (ONLS) (r=-0.70, p<0.001), rasch-built overall disability scale (R-ODS) (r=0.71, p<0.001). CONCLUSIONS The MUNIX technique has a good reproducibility and the MUNIX sumscore is related to the disability. SIGNIFICANCE The MUNIX technique estimates the axonal loss and the number of functional motor units. The MUNIX sumscore may be a good instrument to evaluate the CIDP patients during their follow-up.

Predictive factors of efficacy of rituximab in patients with anti-MAG neuropathy

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 6months 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 6months after RTX and 6/20 (30%) at the last follow-up (mean 42months). 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.

Determinants of Health‐Related Quality of life in anti‐MAG neuropathy: a cross‐sectional multicentre European study

Our objective was to assess determinants of quality of life (QoL) in anti‐myelin associated glycoprotein antibody (MAG) neuropathy. The SF‐36 questionnaire was assessed in 55 patients, from Marseille, Angers (France) and Birmingham (UK). Routine clinical evaluations included Medical Research Council (MRC) sum score, inflammatory neuropathy cause and treatment (INCAT) sensory score, inflammatory Rasch‐built overall disability score (I‐RODS), ataxia score, Jamar grip dynamometry, timed 10‐m walk, neuropathic pain symptom inventory (NPSI) score, and fatigue severity score (FSS). Physical component summary (PCS) and mental component summary (MCS) of the SF36 questionnaire were significantly lower than in reported normal subjects of both countries (p < 0.001). All SF‐36 domains correlated with I‐RODS, except MCS for which significance was, however, approached (p = 0.056). PCS correlated with MRC sum score, ataxia score, timed 10‐m walk, tremor, Jamar grip dynamometry, NPSI pain score, FSS and level of social support. MCS correlated exclusively with FSS and level of social support. In multivariate regression, PCS was associated independently with I‐RODS (p < 0.001) and NPSI pain score (p = 0.011), whereas MCS was associated independently with FSS (p = 0.022). QoL is accurately predicted in anti‐MAG neuropathy by the I‐RODS and FSS, lending support to their use in clinical and research settings. Effective measures to improve QoL should include tremor and neuropathic pain treatment, fatigue management, and improved social support.

Anti-NF155 chronic inflammatory demyelinating polyradiculoneuropathy strongly associates to HLA-DRB15

BackgroundThe aim of the research is to study the human leukocyte antigen (HLA) class II allele frequencies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with anti-neurofascin 155 (NF155) antibodies.MethodsThirteen anti-NF155+ and 35 anti-NF155 negative (anti-NF155neg) CIDP patients were included in a case-control study. The frequencies of the DRB1 HLA allele were analyzed in all patients while DQ frequencies were only studied in patients sharing the DRB1*15 allele. In silico HLA-peptide binding and NF155 antigenicity, predictions were performed to analyze overlap between presented peptides and antigenic regions.ResultsDRB1*15 alleles (DRB1*15:01 and DRB1*15:02) were present in 10 out of 13 anti-NF155+ CIDP patients and in only 5 out of 35 anti-NF155neg CIDP patients (77 vs 14%; OR = 20, CI = 4.035 to 99.13). DRB1*15 alleles appeared also in significantly higher proportions in anti-NF155+ CIDP than in normal population (77 vs 17%; OR = 16.9, CI = 4.434 to 57.30). Seven anti-NF155+ CIDP patients (53%) and 5 anti-NF155neg CIDP patients had the DRB1*15:01 allele (OR = 7, p = 0.009), while 3 anti-NF155+ CIDP patients and none of the anti-NF155neg CIDP patients had the DRB1*15:02 allele (OR = 23.6, p = 0.016). In silico analysis of the NF155 peptides binding to DRB1*15 alleles showed significant overlap in the peptides presented by the 15:01 and 15:02 alleles, suggesting functional homology.ConclusionsDRB1*15 alleles are the first strong risk factor associated to a CIDP subset, providing additional evidence that anti-NF155+ CIDP patients constitute a differentiated disease within the CIDP syndrome.

Prevalence, correlates and impact of pain and cramps in anti-MAG neuropathy: a multicentre European study

The frequency of pain and cramps is uncertain in anti‐myelin associated glycoprotein antibody (anti‐MAG) neuropathy. Whether these symptoms may affect function/quality of life is unknown.

Monitoring the short-term effect of intravenous immunoglobulins in multifocal motor neuropathy using motor unit number index

OBJECTIVE To determine whether motor unit number index (MUNIX) is pertinent to monitor the effect of intravenous immunoglobulins (IVIg) in multifocal motor neuropathy (MMN). METHODS MUNIX was assessed longitudinally in 7 MMN patients and 17 healthy controls in the abductor pollicis brevis (APB) and abductor digiti minimi (ADM) muscles. A MUNIX sum-score and a compound muscle action potential (CMAP) sum-score were calculated by summing up the scores of APB and ADM. MMN patients were evaluated on the first day of IVIg infusion, 5 MMN patients were evaluated 22days after IVIg infusion, and 3 MMN patients were evaluated 1month after two IVIg infusions. RESULTS Intraclass correlation coefficient of the MUNIX sum-score in healthy controls was 0.85, showing good test-retest reproducibility. MUNIX and CMAP sum-scores were lower in MMN patients than in healthy controls (p<0.01 and 0.02, respectively). MUNIX sum-score improved in three of the five patients 22days after IVIg infusion and in two of the three patients 1month after 2 IVIg infusions, whereas CMAP sum-score improved in only one patient in both evaluations. CONCLUSIONS In this preliminary study, MUNIX seems to be a reliable and sensitive tool to monitor the short-term efficiency of IVIg in MMN. SIGNIFICANCE MUNIX can help monitor IVIg treatment in MMN.

Motor unit number index correlates with disability in Charcot-Marie-Tooth disease

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.