Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking, and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years [standard deviation (SD) = 15.1]. Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE-LE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.

A mouse model of sensory neuropathy induced by a long course of monomethyl-auristatin E treatment.

Antibody-drug conjugates (ADCs) are anticancer drugs consisting of a monoclonal antibody, targeting selective tumor antigens, to which has been frequently associated a highly potent cytotoxic agent, the monomethyl auristatin E (MMAE) using a chemical linker. MMAE is a tubulin polymerization inhibitor derived from dolastin-10. These MMAE-ADCs are responsible for peripheral nerve toxicities. Our objective was to develop and characterize a mouse model of MMAE-induced peripheral neuropathy induced by free MMAE injections. MMAE was injected in Swiss mice at 50 µg/kg i.p. every other day for 7 weeks. Assessments of motor and sensory nerve functions were performed once a week on MMAE and Vehicle-treated mice. Sciatic nerve and paw skin were removed at the end of experiment for subsequent immunofluorescence and morphological analysis. MMAE did not affect motor coordination, muscular strength and heat nociception, but significantly induced tactile allodynia in MMAE-treated mice compared with Vehicle-treated mice from day 35 to day 49. MMAE significantly reduced myelinated and unmyelinated axon densities in sciatic nerves and led to a loss of intraepidermal nerve fiber in paw skin. In summary, long course of low dose of MMAE induced a peripheral sensory neuropathy associated with nerve degeneration, without general state alteration. This model may represent a ready accessible tool to screen neuroprotective strategies in the context of peripheral neuropathies induced by MMAE-ADCs.

Clinical and electrophysiological characteristics of women with X-linked Charcot-Marie-Tooth disease.

BACKGROUND: X-Linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by gender differences in clinical severity. Women are usually clinically affected later and less severely than men. However, their clinical presentation appears to be heterogenous. Our aim was to extend the phenotypic description in a large series of women with CMTX1. METHODS: We retrospectively evaluated 263 patients with CMTX1 from 11 French reference centers. Demographic, clinical, and nerve conduction data were collected. The severity was assessed by CMT Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) scores. We looked for asymmetrical strength, heterogeneous motor nerve conduction velocity (MNCV), and motor conduction blocks (CB). RESULTS: The study included 137 women and 126 men from 151 families. Women had significantly more asymmetric motor deficits and MNCV than men. Women with an age of onset after 19 years were milder. Two groups of women were identified after 48 years of age. The first group represented 55%, with women progressing as severely as men, however, with a later onset age. The second group had mild or no symptoms. Some 39% of women had motor CB. Four women received intravenous immunoglobulin before being diagnosed with CMTX1. CONCLUSIONS: We identified two subgroups of women with CMTX1 who were over 48 years of age. Additionally, we have demonstrated that women with CMTX can exhibit an atypical clinical presentation, which may result in misdiagnosis. Therefore, in women presenting with chronic neuropathy, the presence of clinical asymmetry, heterogeneous MNCV, and/or motor CB should raise suspicion for X-linked CMT, particularly CMTX1, and be included in the differential diagnosis.

CANOMAD: a neurological monoclonal gammopathy of clinical significance that benefits from B-cell-targeted therapies.

CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M [IgM] paraprotein, cold agglutinins, and disialosyl antibodies) is a rare syndrome characterized by chronic neuropathy with sensory ataxia, ocular, and/or bulbar motor weakness in the presence of a monoclonal IgM reacting against gangliosides containing disialosyl epitopes. Data regarding associated hematologic malignancies and effective therapies in CANOMAD are scarce. We conducted a French multicenter retrospective study that included 45 patients with serum IgM antibodies reacting against disialosyl epitopes in the context of evocating neurologic symptoms. The main clinical features were sensitive symptoms (ataxia, paresthesia, hypoesthesia; n = 45, 100%), motor weakness (n = 18, 40%), ophthalmoplegia (n = 20, 45%), and bulbar symptoms (n = 6, 13%). Forty-five percent of the cohort had moderate to severe disability (modified Rankin score, 3-5). Cold agglutinins were identified in 15 (34%) patients. Electrophysiologic studies showed a demyelinating or axonal pattern in, respectively, 60% and 27% of cases. All patients had serum monoclonal IgM gammopathy (median, 2.6 g/L; range, 0.1-40 g/L). Overt hematologic malignancies were diagnosed in 16 patients (36%), with the most frequent being Waldenström macroglobulinemia (n = 9, 20%). Forty-one patients (91%) required treatment of CANOMAD. Intravenous immunoglobulins (IVIg) and rituximab-based regimens were the most effective therapies with, respectively, 53% and 52% of partial or better clinical responses. Corticosteroids and immunosuppressive drugs were largely ineffective. Although more studies are warranted to better define the optimal therapeutic sequence, IVIg should be proposed as the standard of care for first-line treatment and rituximab-based regimens for second-line treatment. These compiled data argue for CANOMAD to be included in neurologic monoclonal gammopathy of clinical significance.

GM2 gangliosidosis AB variant: first case of late onset and review of the literature.

AB variant is the rarest form of GM2 gangliosidosis, neurodegenerative diseases caused by lysosomal accumulation of GM2 gangliosides. Less than thirty cases are referenced in the literature, and to date, no late-onset form has been described. Our proband is a 22-year-old male with spinocerebellar ataxia and lower limbs motor deficiency. His symptoms started at the age of 10. A genetic analysis revealed two mutations in the GM2A gene encoding the GM2 activator protein (GM2-AP), an essential co-factor of hexosaminidase A. Both mutations, GM2A:c.79A > T:p.Lys27* and GM2A:c.415C > T:p.Pro139Ser, were inherited respectively from his father and his mother. The nonsense mutation was predicted to be likely pathogenic, but the missense mutation was of unknown significance. To establish the pathogenicity of this variant, we studied GM2 accumulation and GM2A gene expression. Electron microscopy and immunofluorescence performed on patient's fibroblasts did not reveal any lysosomal accumulation of GM2. There was also no difference in GM2A gene expression using RT-qPCR, and both mutations were found on cDNA Sanger sequencing. Measurement of plasma gangliosides by liquid-phase chromatography-tandem mass spectrometry showed an accumulation of GM2 in our patient's plasma at 83.5 nmol/L, and a GM2/GM3 ratio at 0.066 (median of negative control at 30.2 nmol/L [19.7-46.8] and 0.019 respectively). Therefore, the association of both p.Lys27* and p.Pro169Ser mutations leads to a GM2-AP functional deficiency. Whereas the first mutation is more likely to be linked with infantile form of GM2 gangliosidosis, the hypomorphic p.Pro169Ser variant may be the first associated with a late-onset form of AB variant.

[Muscle cramps]. / Crampes musculaires.

Muscle cramps are very common and can reduce quality of life. There are multiple causes, including some physiological conditions, metabolic, endocrine, vascular disorders or neuromuscular diseases. Adequate management first requires differentiating cramps from other muscular phenomena. In most cases, the investigations are limited to a comprehensive history and clinical examination, but a biological, radiological and/or electrophysiological work-up may be useful. Treatment, when needed, is most often symptomatic and is unfortunately based on little evidence.

Les crampes musculaires sont fréquentes dans la population générale avec, dans certains cas, une altération importante de la qualité de vie. Leur cause est très variée, pouvant être en lien avec certaines conditions physiologiques ou avec des troubles métaboliques, endocriniens, vasculaires ou neuromusculaires. Une prise en charge adéquate nécessite dans un premier temps de différencier les crampes d'autres phénomènes musculaires. Dans la plupart des cas, les investigations se limitent à une anamnèse et un examen clinique, mais un bilan biologique, radiologique et/ou électrophysiologique peut être parfois indiqué. Le traitement, si nécessaire, est le plus souvent symptomatique et repose malheureusement sur peu d'évidences scientifiques.

[Cramps and fasciculations: is it amyotrophic lateral sclerosis?] / Crampes et fasciculations : est-ce une sclérose latérale amyotrophique ?

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease of the adult age. It is an aggressive condition with a mean disease duration of only 3 to 5 years, characterized by progressive weakness and atrophy of limb, bulbar, and respiratory muscles. In general, death is caused by chronic hypoventilation due to respiratory insufficiency. No causal treatment is known today, but the two therapeutic agents authorized in Switzerland for the treatment of ALS can slow disease progression significantly. Other important therapeutic strategies include invasive/non-invasive ventilation, pain therapy, as well as physio-, ergo- and speech therapy on a regular basis.

La sclérose latérale amyotrophique (SLA) est la maladie du motoneurone la plus fréquente de l'adulte. C'est une maladie sévère (la survie moyenne est d'environ 3 à 5 ans), caractérisée par une dégénérescence des premier et deuxième motoneurones. Elle se manifeste par un déficit moteur amyotrophiant progressif des membres, de la langue, des muscles bulbaires et respiratoires. En général, le décès est causé par une hypoventilation chronique. Il n'existe actuellement aucun traitement curatif. Les deux médicaments autorisés en Suisse peuvent ralentir significativement la progression de la maladie et plusieurs nouvelles molécules sont à l'essai. Les traitements non médicamenteux/symptomatiques constituent le deuxième pilier de la prise en charge : ventilation non invasive, traitement des symptômes bulbaires, stabilisation du poids, physio et ergothérapie.

[Muscle disease in the adults: when to suspect it?] / Maladies musculaires de l'adulte : quand évoquer le diagnostic ?

Muscle diseases or myopathies have heterogeneous clinical presentations and etiologies. The principal sign is muscular weakness, whose distribution can help diagnostic orientation. Exercise intolerance, even without weakness at rest, can indicate an underlying myopathy. An isolated CK elevation can have multiple causes, but its persistence after a period of rest can point towards a subclinical myopathy. Isolated myalgia, especially at rest, are usually not associated with muscle disease. If the suspicion of myopathy is high, the patient will be assessed by a neurologist trained in muscle disorders, with correlation of clinical and neurophysiological findings, muscle imaging and, if indicated, muscle biopsy and genetic analysis. Cardiac and respiratory assessments are mandatory if a myopathy is suspected.

Les myopathies sont d'étiologie et de présentation hétérogènes. Le signe principal est la faiblesse musculaire, dont la distribution peut orienter le diagnostic. L'intolérance à l'effort, même isolée, peut indiquer une myopathie, en particulier métabolique. Une élévation isolée des créatines kinases (CK) peut avoir des causes multiples mais la persistance d'une valeur anormalement élevée au repos peut être un indice de myopathie subclinique. Les myalgies isolées, notamment au repos, ne sont en général pas associées aux myopathies. Si la suspicion de myopathie est retenue, le patient sera évalué par un neurologue expert en pathologie musculaire, pour complément d'explorations par bilan neurophysiologique (ENMG (électroneuromyographique)), imagerie musculaire et biopsie musculaire ou analyse génétique. Les bilans cardiaque et respiratoire sont indispensables dans tous les cas.

[What have we learned about chronic inflammatory demyelinating polyradiculoneuropathyin the last twenty years ?] / Qu'avons-nous compris en 20 ans sur la polyradiculoneuropathie inflammatoire démyélinisante chronique ?

chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been widely described during the last quarter of the twentieth century. The last 20 years have seen decisive progress in its understanding. The diagnostic criteria have been simplified and the steps of the diagnostic process have been clarified. The phenotypic contours of the disease are now well known, as are the diagnostic pitfalls. From a pathophysiological point of view, the discovery of autoantibodies directed against nodal and paranodal proteins has been a major advance, although it concerns only a minority of patients. These discoveries have a major impact on the therapeutic management of these patients, often suffering from a very active form of the disease. The next 20 years will surely see a further deepening of knowledge about this fascinating disease.

La polyradiculoneuropathie inflammatoire démyélinisante chronique est une entité largement décrite au cours du dernier quart du 20e siècle. Les 20 dernières années ont vu s'accomplir des progrès décisifs dans sa compréhension. Les critères diagnostiques se sont simplifiés et les étapes de la démarche diagnostique se sont précisées. Les contours phénotypiques de l'affection sont désormais bien connus, de même que les pièges diagnostiques. Sur le plan physiopathologique, la découverte des autoanticorps dirigés contre les protéines nodales et paranodales a été une avancée majeure qui ne concerne toutefois qu'une minorité de patients. Ces découvertes ont un impact majeur sur la prise en charge thérapeutique de ces patients, souffrant souvent d'une forme très active de la maladie. Les 20 prochaines années verront sûrement s'approfondir encore les connaissances sur cette maladie fascinante.

[Treating hereditary neuropathies : a dream come true?] / Traiter les neuropathies héréditaires : un rêve qui devient réalité ?

Hereditary neuropathies have been the subject of recent major therapeutic advances. Treatments based on antisense oligonucleotides (ASO) and small interfering RNA (siRNA) have been developed and are now commercially available to treat hereditary transthyretin amyloidosis (hTTR) and porphyria. More recently, a CRISPR-Cas9 genomic editing treatment targeting the TTR gene has been developed and is being tested in patients with hTTR. Based on their success in hTTR and porphyria, innovative treatments targeting mRNA and DNA are being evaluated in other hereditary neuropathies, including Charcot-Marie-Tooth disease (CMT).

Les neuropathies héréditaires ont fait l'objet d'avancées thérapeu­tiques majeures. Ainsi, des traitements à base d'oligonucléotides antisens (ASO) et d'ARN interférentiels (ARNi) ont récemment été développés et sont maintenant disponibles pour traiter efficacement la neuropathie amyloïde familiale à transthyrétine (NAF-TTR) et la porphyrie. Encore plus récemment, des traitements d'édition génomique de type CRISPR-Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats-Cas9) ciblant le gène TTR ont été mis au point et sont testés chez des patients avec une NAF-TTR. Forts de leur succès dans la NAF-TTR et la porphyrie, ces traitements innovants ciblant l'ARNm et l'ADN sont en cours d'évaluation dans d'autres neuropathies héréditaires, dont la maladie de Charcot-Marie-Tooth (CMT).

[Neurological shoulder pain and weakness : practical attitudes]. / Douleurs et faiblesse de l'épaule neurologique : attitudes pratiques.

Shoulder pain or paresis should be assessed carefully, as there are many possible causes, which can be osteoarticular, degenerative, inflammatory, or neurological. Weakness or pain can be related to cervicobrachialgia, plexitis, or focal mononeuropathy. The clinical picture should identify any muscular or mechanical origin of paresis responsible for pseudo-paretic functional limitation. Neurogenic scapulalgia with functional deficit implies the compression or entrapment of a nerve trunk including the axillary, long thoracic, accessory, suprascapular, or dorsal scapular nerves. Nerve conduction study and myography together with medical imaging help to identify the relevant etiology. Treatment mostly includes pain relief and physiotherapy, but surgery is rarely necessary.

L'épaule douloureuse ou parétique est d'appréhension délicate et de causes variées : ostéoarticulaire, dégénérative, inflammatoire ou neurologique. La faiblesse ou la douleur peuvent être liées à une cervicobrachialgie, une plexite ou une mononeuropathie focale. Le tableau clinique doit distinguer une parésie d'origine musculaire ou mécanique responsable alors d'une limitation fonctionnelle pseudo-parétique. Une scapulalgie déficitaire neurogène implique la recherche d'une mononeuropathie d'enclavement ou compressive d'un tronc nerveux, axillaire, long thoracique, accessoire du XIe nerf crânien, suprascapulaire ou dorsal de la scapula. Au besoin l'ENMG (électroneuromyogramme)et l'imagerie débrouilleront les multiples étiologies. Le traitement requiert le plus souvent une antalgie et une rééducation, rarement une chirurgie.

[Small fiber neuropathy diagnosis]. / Diagnostiquer une neuropathie des petites fibres.

Small fiber neuropathies affect small, poorly myelinated sensory Aδ and amyelinated C autonomic fibers. Neuropathic pain is often the main symptom. Positive diagnosis is based on the presence of deficient thermo-algesic sensory signs and/or dysautonomic signs with normal neurography. Several tests help to confirm the involvement of small fibers, ranging from simple tests such as the sympathetic skin response to skin biopsy, which measures the density of intraepidermal nerve fibers. The availability of these different tests varies greatly from one center to another. There are multiple etiologies, from rare genetic causes to the more frequent acquired dysimmune or metabolic causes. However, in more than half of the cases, no etiology is identified.

Les neuropathies des petites fibres touchent les petites fibres peu myélinisées sensitives Aδ et amyéliniques C autonomes. La douleur neuropathique est souvent le symptôme principal. Le diagnostic positif repose sur la présence de signes sensitifs thermo-algiques déficitaires et/ou de signes dysautonomiques avec des neurographies normales. Plusieurs examens aident à confirmer l'atteinte des petites fibres, allant de tests simples comme la réponse cutanée sympathique à la biopsie de peau qui mesure la densité des fibres nerveuses intra-épidermiques. L'accessibilité de ces différents examens est très variable d'un centre à l'autre. Les étiologies sont variées, des causes génétiques rares aux causes acquises dysimmunes ou métaboliques plus fréquentes. Toutefois, dans plus de la moitié des cas, aucune étiologie n'est retrouvée.

Charcot-Marie-Tooth disease misdiagnosed as chronic inflammatory demyelinating polyradiculoneuropathy: An international multicentric retrospective study.

BACKGROUND AND PURPOSE: Charcot-Marie-Tooth (CMT) disease, an untreatable hereditary polyneuropathy, may mimic chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a treatable neuropathy. METHODS: In this retrospective study, we analyzed the characteristics of CMT patients misdiagnosed as CIDP at 16 university hospitals in three countries, compared these patients with a reference group of CIDP patients, and estimated the cost of misdiagnosis. RESULTS: Among 1104 CIDP cases, we identified 35 CMT patients misdiagnosed as CIDP (3.2%). All were initially diagnosed with definite or probable CIDP (European Federation of Neurological Societies/Peripheral Nerve Society criteria), and mutations in PMP22, MPZ, and 10 other CMT genes were found in 34%, 31%, and 35% of cases, respectively. In comparison with a reference group of 35 CIDP patients, CMT patients were younger (median age at disease onset = 39 vs. 56 years) and more frequently had motor weakness at disease onset (80% vs. 29%), hearing loss (14% vs. 0%), normal brachial plexus imaging (70% vs. 40%), lower cerebrospinal fluid protein content (median = 0.5 vs. 0.8 g/L), and lower treatment response (20% vs. 69%). Treatment cost in these 35 misdiagnosed patients was estimated at 4.6 million euros (M€), whereas the cost of CMT genetic analysis in 1104 patients was estimated at 2.7 M€. CONCLUSIONS: In this study, 35 of 1104 (3.2%) patients initially diagnosed with CIDP had CMT. Importantly, the cost of treating these 35 misdiagnosed patients was significantly higher than the cost of performing CMT genetic analysis in 1104 patients (4.6 M€ vs. 2.7 M€), suggesting that CMT genetic investigations should be more widely used before diagnosing CIDP.

Electrodiagnostic accuracy in polyneuropathies: supervised learning algorithms as a tool for practitioners.

OBJECTIVE: The interpretation of electrophysiological findings may lead to misdiagnosis in polyneuropathies. We investigated the electrodiagnostic accuracy of three supervised learning algorithms (SLAs): shrinkage discriminant analysis, multinomial logistic regression, and support vector machine (SVM), and three expert and three trainee neurophysiologists. METHODS: We enrolled 434 subjects with the following diagnoses: chronic inflammatory demyelinating polyneuropathy (99), Charcot-Marie-Tooth disease type 1A (124), hereditary neuropathy with liability to pressure palsy (46), diabetic polyneuropathy (67), and controls (98). In each diagnostic class, 90% of subjects were used as training set for SLAs to establish the best performing SLA by tenfold cross validation procedure and 10% of subjects were employed as test set. Performance indicators were accuracy, precision, sensitivity, and specificity. RESULTS: SVM showed the highest overall diagnostic accuracy both in training and test sets (90.5 and 93.2%) and ranked first in a multidimensional comparison analysis. Overall accuracy of neurophysiologists ranged from 54.5 to 81.8%. CONCLUSIONS: This proof of principle study shows that SVM provides a high electrodiagnostic accuracy in polyneuropathies. We suggest that the use of SLAs in electrodiagnosis should be exploited to possibly provide a diagnostic support system especially helpful for the less experienced practitioners.

Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.

OBJECTIVE: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. METHODS: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. RESULTS: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. CONCLUSION: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.

Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy.

BACKGROUND: Intravenous immunoglobulin (IVIG) is a polyspecific pooled immunoglobulin G preparation and one of the commonly used therapeutics for autoimmune diseases including those of neurological origin. A recent report in murine model proposed that IVIG expands regulatory T (Treg) cells via induction of interleukin 33 (IL-33). However, translational insight on these observations is lacking. METHODS: Ten newly diagnosed Guillain-Barré syndrome (GBS) patients were treated with IVIG at the rate of 0.4 g/kg for three to five consecutive days. Clinical evaluation for muscular weakness was performed by Medical Research Council (MRC) and modified Rankin scoring (MRS) system. Heparinized blood samples were collected before and 1, 2, and 4-5 weeks post-IVIG therapy. Peripheral blood mononuclear cells were stained for surface CD4 and intracellular Foxp3, IFN-γ, and tumor necrosis factor alpha (TNF-α) and were analyzed by flow cytometry. IL-33 and prostaglandin E2 in the plasma were measured by ELISA. RESULTS: The fold changes in plasma IL-33 at week 1 showed no correlation with the MRC and MRS scores at weeks 1, 2, and ≥4 post-IVIG therapy. Clinical recovery following IVIG therapy appears to be associated with Treg cell response. Contrary to murine study, there was no association between the fold changes in IL-33 at week 1 and Treg cell frequency at weeks 1, 2, and ≥4 post-IVIG therapy. Treg cell-mediated clinical response to IVIG therapy in GBS patients was associated with reciprocal regulation of effector T cells-expressing TNF-α. CONCLUSION: Treg cell expansion by IVIG in patients with autoimmune diseases lack correlation with IL-33. Treg cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to IVIG therapy.

OnabotulinumtoxinA injections in chronic migraine, targeted to sites of pericranial myofascial pain: an observational, open label, real-life cohort study.

BACKGROUND: OnabotulinumtoxinA has proven its efficacy in reducing the number of headache days in chronic migraine (CM) patients. The usual paradigm includes 31 pericranial injection sites with low dose (5 U) per site. The aim of this study is to present the results obtained using a simpler injection protocol of onabotulinumtoxinA, with injection sites targeted to pericranial myofascial sites of pain. METHODS: Observational, open label, real-life, cohort study. We enrolled 63 consecutive patients fulfilling the diagnostic criteria of CM, and refractory to conventional treatments. The patients were injected using a "follow-the-pain" pattern into the corrugator and/or temporalis and/or trapezius muscles. The doses per muscle were fixed. According to the number of muscles injected, the total dose could vary from 70 to 150 U per session. Patients were considered responders if they had a ≥ 50% decrease in number of headache days in at least two consecutive injection cycles. RESULTS: Forty one patients (65.1% in intention to treat analysis) responded to treatment. In 70.7% of responders, the effect size was even higher, with a reduction ≥70% in the number of headache days. The associated cervical pain and muscle tenderness, present in 33 patients, was reduced by ≥50% in 31 patients (94%). Triptan consumption dramatically decreased (81%) in responders. The trapezius was the most frequently injected muscle. We observed no serious adverse event. The mean patient satisfaction rate was 8.5/10. CONCLUSIONS: This study provides additional robust evidence supporting the efficacy of onabotulinumtoxinA injections in CM. Furthermore, the paradigm we used, with reduced number of injection sites targeted to pericranial myofascial sites of pain, may provide evidence in favor of the implication of myofascial trigger points in migraine chronicization. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Record I17022 ClinicalTrials.gov Identifier: NCT03175263 . Date of registration: June 7, 2017. Retrospectively registered.

Contribution of dot-blot assay to the diagnosis and management of myositis: a three-year practice at a university hospital centre.

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases with wide clinical spectrum that may lead to delayed diagnosis. The aim of this study was to examine the impact of IIM-specific dot-blot assay on diagnostic process of patients presenting with muscular or systemic symptoms evocating of IIM. METHODS: We collected all the prescriptions of an IIM specific dot-blot assay (8 autoantigens including Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, PM/Scl and Scl-70) over a 38-month period. RESULTS: 316 myositis dot-blot assays (MSD) were performed in 274 patients (156 women, mean age 53±10.6 years) referring for muscular and/or systemic symptoms suggesting IIM. The timing of dot prescription through the diagnostic process was highly variable: without (35%), concomitantly (16%) or after electromyographic studies (35%). Fifty-nine patients (22%) had IIM according to Bohan and Peter's criteria. Among them, 29 (49%) had positive dot (8 Jo-1, 6 PM-Scl, 5 PL-12, 5 SRP, 2 Mi-2, 2 PL-7 and 1 Ku). Various other diagnoses were performed including 35 autoimmune disease or granulomatosis (12%), 19 inflammatory rheumatic disease (7%), 16 non inflammatory muscular disorders (6%), 10 drug-induced myalgia (4%), 11 infectious myositis (4%). Except 11 borderline SRP results and one transient PM-Scl, MSD was positive only in one case of IIM. Dot allowed clinicians to correct diagnosis in 4 cases and improved the diagnosis of IIM subtypes in 4 cases. CONCLUSIONS: This study reflects the interest of myositis dot in the rapid diagnosis process of patients with non-specific muscular symptoms leading to various diagnoses including IIM.

Charcot-Marie-Tooth diseases: an update and some new proposals for the classification.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease, the most frequent form of inherited neuropathy, is a genetically heterogeneous group of disorders of the peripheral nervous system, but with a quite homogeneous clinical phenotype (progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss and usually decreased tendon reflexes). Our aim was to review the various CMT subtypes identified at the present time. METHODS: We have analysed the medical literature and performed a historical retrospective of the main steps from the individualisation of the disease (at the end of the nineteenth century) to the recent knowledge about CMT. RESULTS: To date, >60 genes (expressed in Schwann cells and neurons) have been implicated in CMT and related syndromes. The recent advances in molecular genetic techniques (such as next-generation sequencing) are promising in CMT, but it is still useful to recognise some specific clinical or pathological signs that enable us to validate genetic results. In this review, we discuss the diagnostic approaches and the underlying molecular pathogenesis. CONCLUSIONS: We suggest a modification of the current classification and explain why such a change is needed.