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Resume Introduction Il s’agit d’un cas clinique illustrant une toxicite aux antipaludeens de synthese (APS) qu’il faut savoir systematiquement evoquer et rechercher. Observation Un homme de 59 ans avec antecedent de cardiopathie etiquetee ischemique revelee par des troubles de la conduction, et de lupus cutane traite par hydroxycholoroquine puis chloroquine, consultait pour une alteration de l’etat general. A l’examen clinique, il presentait une amyotrophie, un deficit moteur et une abolition des reflexes osteo-tendineux aux membres inferieurs. Une toxicite musculaire et cardiaque aux APS etait evoquee. Le diagnostic etait confirme par une biopsie musculaire montrant une myopathie vacuolaire floride typique. L’arret du medicament incrimine permettait une regression lente des atteintes. Conclusion La toxicite cardiaque et musculaire peripherique des APS, rare et parfois fatale, doit etre systematiquement evoquee et recherchee chez un patient expose plusieurs annees. La biopsie musculaire peut permettre le diagnostic en evitant la biopsie cardiaque.

Background The immune-checkpoint inhibitors (ICIs) announced a new era in cancer treatment allowing long-term survival in advanced cancers. However, immune related adverse events impose treatment limitations being one of the main challenges when dealing with ICI treated patients. Neurologic toxicities have unique presentations and can progress rapidly, requiring prompt recognition. Among them, ICI-related peripheral nerve disorders are highly heterogeneous, profoundly debilitating, and insufficiently explored. Material and Methods We reviewed the clinical and electrodiagnostic features of a retrospective cohort of patients hospitalized in our centre for ICI related neuropathies. We applied the EFNS 2021 electrodiagnostic criteria for neuropathies and we researched the outcome according to the treatment received. Results We included 16 patients: 4 men and 12 women, median age 61 years (31-72) treated by anti-PD1 monotherapy (10) or antiCTLA4-antiPD1 combination (6). Median delay from ICIs initiation to neuropathy symptoms was 58,5 days (4 cycles), it seemed lower in combination group (median 33,5 days vs 81,5 days in monotherapy patients p=0,02). Half of patients presented with concurrent non-neurological irAE. CSF was inflammatory in 56% of cases, pleocytosis was seen in 57% of these. Cranial nerve involvement was rare (3/16) the most frequent phenotype was demyelinating polyneuropathy fulfilling EFNS 2021 EMG criteria in 10 cases. The other 6 presented with non-length dependent sensory neuropathy, (3) dysautonomic neuropathy (1) or sensory motor neuropathy with incomplete EFNS 2021 EMG criteria (2). ICI treatment was stopped, and steroids were the first line of treatment for all patients. However, 12/16 patients received additional iv immunoglobulin. Supplementary immunomodulation (cyclophosphamide, tocilizumab) was required in 2 cases. 75% of patients improved within a median of 4.5 months, median decrease in mRS was 2 points. Noteworthy, the rechallenge by antiPD1 monotherapy was proposed in 4 patients with a single neuropathy relapse. Conclusion Our series expand the knowledge on the clinical and electrophysiological phenotype of ICI related neuropathies improving their recognition in clinical practice. Moreover, our findings argue for the benefit of adding iv immunoglobulin to steroids as a first line treatment for different phenotypes of ICI related neuropathies.

BackgroundThe cause of the motor neuron (MN) death that drives terminal pathology in Amyotrophic Lateral Sclerosis (ALS) remains unknown, and it is thought that the cellular environment of the MN may play a key role in MN survival. Several lines of evidence implicate vesicles in ALS, including that extracellular vesicles may carry toxic elements from astrocytes towards motor neurons, and that pathological proteins have been identified in circulating extracellular vesicles of sporadic ALS patients. Since MN degeneration at the neuromuscular junction is a feature of ALS, and muscle is a vesicle-secretory tissue, we hypothesized that muscle vesicles may be involved in ALS pathology.MethodsSporadic ALS patients were confirmed to be ALS according to El Escorial criteria, were genotyped to test for classic gene mutations associated with ALS, and physical function was assessed using the ALSFRS-R score. Muscle biopsies of either mildly affected deltoids of ALS patients (n=27) or deltoids of aged-matched healthy subjects (n=30) were used for extraction of muscle stem cells, to perform immunohistology, or for electron microscopy. Muscle stem cells were characterized by immunostaining, RTqPCR and transcriptomic analysis. Secreted muscle vesicles were characterized by proteomic analysis, Western blot, NanoSight, and electron microscopy. The effects of muscle vesicles isolated from the culture medium of ALS and healthy myotubes were tested on healthy human-derived iPSC motor neurons and on healthy human myotubes, with untreated cells used as controls.ResultsAn accumulation of multivesicular bodies was observed in muscle biopsies of sporadic ALS patients by immunostaining and electron microscopy. Study of muscle biopsies and biopsy-derived denervation-naïve differentiated muscle stem cells (myotubes) revealed a consistent disease signature in ALS myotubes, including intracellular accumulation of exosome-like vesicles and disruption of RNA-processing. Compared to vesicles from healthy control myotubes, when administered to healthy motor neurons the vesicles of ALS myotubes induced shortened, less branched neurites, cell death, and disrupted localization of RNA and RNA-processing proteins. The RNA-processing protein FUS and a majority of its binding partners were present in ALS muscle vesicles, and toxicity was dependent on the expression level of FUS in recipient cells. Toxicity to recipient motor neurons was abolished by anti-CD63 immuno-blocking of vesicle uptake.ConclusionALS muscle vesicles are shown to be toxic to motor neurons, which establishes the skeletal muscle as a potential source of vesicle-mediated toxicity in ALS.One Sentence SummaryMuscle cells of ALS patients secrete vesicles that are toxic to motor neurons

ObjectiveTo describe the spectrum of neurological and psychiatric complications in patients with Covid-19 seen in a multidisciplinary center over six months.MethodsWe conducted a retrospective, observational study on all patients showing neurological or psychiatric symptoms in the context of Covid-19 seen in the Department of Neurology and Psychiatry of the APHP-Sorbonne University. We collected demographic data, medical and treatment history, comorbidities, symptoms, date of onset, and severity of Covid-19 infection, neurological and psychiatric symptoms, neurological and psychiatric examination data and, when available, results from cerebrospinal fluid (CSF) analysis, brain magnetic resonance (MRI) imaging, 18-fluorodesoxyglucose-position emission computed tomography (FDG-PET/CT)), electroencephalography (EEG) and electroneuromyography (ENMG).Results245 patients were included in the analysis. One-hundred fourteen patients (47%) were admitted to the intensive care unit (ICU) and 10 (4%) died. The most frequently reported neuropsychiatric symptoms were motor deficit (41%), cognitive disturbance (35%), impaired consciousness (26%), psychiatric disturbance (24%), headache (20%) and behavioral disturbance (18%). The most frequent syndromes diagnosed were encephalopathy (43%), critical illness polyneuropathy and myopathy (26%), isolated psychiatric disturbance (18%), and cerebrovascular disorders (16%). No patients showed evidence of SARS-CoV-2 in their CSF. Encephalopathy was associated with greater age and higher risk of death. Critical illness neuromyopathy was associated with an extended stay in the ICU.ConclusionsThe majority of the neuropsychiatric complications recorded could be imputed to critical illness, intensive care and systemic inflammation, which contrasts with the paucity of more direct SARS-CoV-2-related complications or post-infection disorders.

To address the frequency of complex V defects, we systematically sequenced MT-ATP6/8 genes in 512 consecutive patients. We performed functional analysis in muscle or fibroblasts for 12 out of 27 putative homoplasmic mutations and in cybrids for four. Fibroblasts, muscle and cybrids with known deleterious mutations underwent parallel analysis. It included oxidative phosphorylation spectrophotometric assays, western blots, structural analysis, ATP production, glycolysis and cell proliferation evaluation. We demonstrated the deleterious nature of three original mutations. Striking gradation in severity of the mutations consequences and differences between muscle, fibroblasts and cybrids implied a likely under-diagnosis of human complex V defects.

Resume Les paranodopathies sont caracterisees par le dysfonctionnement des regions paranodales (adjacentes aux nœuds de Ranvier) sur les fibres myelinisees. Elles peuvent concerner le systeme nerveux central et/ou peripherique. La paranodopathie a anticorps anti-neurofascine (NF) 155 s’exprime typiquement par une polyradiculoneuropathie inflammatoire demyelinisante chronique (PIDC) a predominance distale, particulierement ataxiante et parfois associee a un tremblement postural. Des signes evocateurs d’une atteinte centrale peuvent egalement etre rapportes. Le diagnostic est soutenu par l’existence d’une hyperproteinorachie marquee, une atteinte demyelinisante severe a l’electroneuromyogramme (ENMG), d’eventuelles anomalies sur les IRM cerebrale et rachidienne et surtout par la presence dans le serum d’anticorps anti-neurofascine (NF) 155 de sous-type IgG4. Les immunoglobulines intraveineuses et echanges plasmatiques peuvent etre transitoirement efficaces. En cas de resistance a ces therapeutiques, une reponse peut etre obtenue sous rituximab. Nous rapportons le cas d’un homme de 52 ans souffrant d’une PIDC secondairement associee a une dysarthrie pseudo-bulbaire et un syndrome dysexecutif en rapport avec une paranodopathie a anticorps anti-NF155, et decrivons les principales caracteristiques de cette entite.

This case report signifies the need to systemically assess antimalarial toxicity in those undergoing long-term treatment.A 59-year-old man with a history of ischemic-labeled heart disease revealed by conduction disorders and cutaneous lupus treated initially with hydroxychloroquine followed by chloroquine consulted for asthenia and weight loss. Clinically, he had a muscular atrophy, a motor deficit, and an abolition of the osteo-tendinous reflexes in the lower limbs. Adverse drug effects of the antimalarial therapy were suspected-specifically, muscular and cardiac toxicity. The diagnosis was confirmed with a muscle biopsy, which showed typical and florid vacuolar myopathy. Cessation of the drug resulted in a slow regression of symptoms.Cardiac and muscular toxicity related to antimalarials are rare and sometimes fatal; thus, they must be systematically assessed in a patient with several years of exposure. A muscle biopsy could be sufficient to allow for the diagnosis.

Introduction Mitochondrial trifunctional protein deficiency (MTPD) is a long-chain fatty acid oxidation disorder characterized by co-existence of rhabdomyolysis episodes and peripheral neuropathy. Two phenotypes are described: generalized mitochondrial trifunctional protein deficiency (gMTPD) and isolated long-chain-3-hydroxyacyl-CoA dehydrogenase deficiency (iLCHADD) that is always associated with the c.1528G>C mutation. Peripheral neuropathy of MTPD is commonly described in children as axonal, length-dependent and sensorimotor. Objectives To report clinical and electrophysiological features of four independent adult MTPD patients with peripheral neuropathy. Results Onset of the disease was characterized in all patients by rhabdomyolysis episodes occurring during childhood preceded by severe hypoglycemic episodes in three patients. Peripheral nerve involvement manifesting as sensory ataxia appeared later, during adolescence or adulthood. In all cases, electroneuromyogram showed no length-dependent sensory potentials decrease characteristic of sensory neuronopathy (“ganglionopathy”). All patients harbored at least one c.1528G>C mutation. Discussion We describe MTPD as a newly hereditary etiology of sensory neuronopathy in adults, specifically in patients with c.1528G>C mutation. MTPD should be screened for by performing plasma acylcarnitines in patients with chronic sensory neuronopathy and additional suggestive features such as exercise intolerance or retinopathy .

Background and purpose Charcot-Marie-Tooth (CMT) 1C due to mutations in LITAF/SIMPLE is a rare subtype amongst the autosomal dominant demyelinating forms of CMT. Our objective was to report the clinical and electrophysiological characteristics of 18 CMT1C patients and compare them to 20 patients with PMP22 mutations: 10 CMT1A patients and 10 patients with hereditary neuropathy with liability to pressure palsies (HNPP). Methods Charcot-Marie-Tooth 1C patients were followed-up in referral centres for neuromuscular diseases or were identified by familial survey. All CMT1A and HNPP patients were recruited at the referral centre for neuromuscular diseases of Pitie-Salpetriere Hospital. Results Two phenotypes were identified amongst 18 CMT1C patients: the classical CMT form ('CMT-like', 11 cases) and a predominantly sensory form ('sensory form', seven cases). The mean CMT neuropathy score was 4.45 in CMT1C patients. Motor nerve conduction velocities in the upper limbs were significantly more reduced in CMT1A than in CMT1C patients. On the other hand, the motor nerve conduction velocity of the median nerve was significantly lower in CMT1C compared to the HNPP group. Distal motor latency was significantly more prolonged in CMT1A patients compared to the CMT1C and HNPP groups, the latter two groups having similar distal motor latency values. Molecular analysis revealed five new LITAF/SIMPLE mutations (Ala111Thr, Gly112Ala, Trp116Arg, Pro135Leu, Arg160Cys). Conclusions Our study delineates CMT1C as mostly a mild form of neuropathy, and gives clinical and electrophysiological clues differentiating CMT1C from CMT1A and HNPP. Delineating phenotypes in CMT subtypes is important to orient molecular diagnosis and to help to interpret complex molecular findings.

Neurological localizations of sarcoidosis are heterogeneous and may affect virtually every part of the central or peripheral nervous system. They are often the inaugural manifestation of sarcoidosis. The diagnosis may be difficult due to the lack of extra-neurological localization. Diagnosis may be discussed in the presence of an inflammatory neurological disease, in particular in case of suggestive radiological or biological pattern. Cerebrospinal fluid analysis shows lymphocytic pleiocytosis, often with low glucose level. The diagnosis relies on a clinical, biological and radiological presentation consistent with neurosarcoidosis, the presence of non-caseating granuloma and exclusion of differential diagnoses. Screening for other localizations of sarcoidosis, in particular cardiac disease may be obtained during neurosarcoidosis. The treatment of neurosarcoidosis relies on corticosteroids although immunosuppressive drugs are usually added because of the chronic course of this condition and to limit the side effects of steroids. Treatments and follow-up may be prolonged because of the high rate of relapses.

Resume Introduction Les syndromes neurologiques paraneoplasiques (SNP) avec presence d’anticorps anti-CV2/CRMP5 sont exceptionnels. Ils associent essentiellement une ataxie cerebelleuse, une neuropathie peripherique, des signes ophtalmologiques evocateurs dans ce contexte, avec atteinte uveo retinienne, nevrite optique retrobulbaire. Le cancer bronchique a petites cellules (CBPC) en est le principal pourvoyeur. Observation Un homme de 64 ans, fumeur, vit s’installer des troubles visuels avec œdeme papillaire bilateral, de discrets signes cerebelleux, des symptomes en faveur d’une ganglionopathie confirmee par l’electromyogramme. Des anticorps anti-neuronaux anti-CV2/CRMP5 etaient presents. Un CBPC etait responsable de ce syndrome paraneoplasique revelateur du cancer. Il regressa grâce au traitement du CBPC par radiochimiotherapie. Conclusion Un SNP merite d’etre evoque devant une symptomatologie neurologique atypique, diagnostic pouvant etre appuye par la presence d’anticorps anti-neuronaux, imposant de rechercher alors un CBPC pourvoyeur le plus frequent de ce type de syndromes.

Background and purpose: Some patients within the spectrum of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) have distal acquired demyelinating symmetric (DADS) neuropathy, usually associated with anti-myelin-associated-glycoprotein (MAG) IgM monoclonal gammopathy. The aim of this retrospective study was to investigate patients with DADS neuropathy without anti-MAG antibodies, and study their response to immunotherapy. Methods: Patients were selected on the basis of (i) ‘Definite CIDP’ according to the EFNS/PNS Guideline criteria, (ii) The presence of disproportionately prolonged motor latencies resulting in a terminal latency index (TLI) ≤0.25 in at least two motor nerves and (iii) The absence of anti-MAG antibodies on ELISA. Response to immunotherapy was defined as persistent improvement by at least one point on the INCAT disability score. Results: Data from 146 CIDP patients were analysed, and 10 patients were included. Six had clinically pure sensory neuropathy, and four had sensorimotor neuropathy. Ataxia was present in nine patients, generalized areflexia in seven and postural tremor in two. Five of the 10 patients had abnormal sensory potentials only in the upper limbs. An associated condition was found in nine patients: two chronic lymphocytic leukaemias, four IgG monoclonal gammopathies (one associated with non-Hodgkin’s lymphoma) and two IgM monoclonal gammopathies of unknown significance. Patients were mostly improved with intravenous immunoglobulin (IVIg), corticosteroids, plasma exchanges, or a combination thereof. Conclusion: DADS neuropathy without anti-MAG antibodies is more likely to be considered a variant of CIDP. In addition, such patients should be systematically investigated for an associated haematological or immunological condition.

Resume Introduction Les neuropathies cryoglobulinemiques secondaires a l’hepatite C sont frequentes et peuvent engager le pronostic fonctionnel. Le but de cette etude est de preciser les correlations anatomocliniques de ces neuropathies. Methodes Nous rapportons une serie retrospective de 22 cas de neuropathies cryoglobulinemiques secondaires a l’hepatite C. Ces cas ont ete colliges de 1992 a 2007 dans le service des explorations fonctionnelles neurologiques de l’hopital La Pitie-Salpetriere. Chaque patient a beneficie d’un examen clinique, electromyographique et d’une biopsie neuromusculaire. Le groupe des patients presentant une vascularite sur la biopsie nerveuse a ete compare a celui sans vascularite. Resultats Toutes les neuropathies etaient de mecanisme axonal, avec 11 polyneuropathies et 11 multinevrites. Les sept patients ayant une vascularite de moyen calibre sur la biopsie neuromusculaire presentaient pour six d’entre eux une multinevrite sensitivomotrice aigue (85 %), avec bloc de conduction ischemique dans trois cas (42 %) et une degenerescence wallerienne dans quatre cas (57 %). Parmi les quatre patients avec vascularite de petit calibre, deux avaient une multinevrite (50 %) sans bloc de conduction ischemique (0 %), avec dans un cas une degenerescence wallerienne (25 %). Chez les 11 patients sans vascularite (neuf infiltrats lymphocytaires perivasculaires et deux biopsies non inflammatoires), huit presentaient une polyneuropathie (72 %) sans bloc de conduction ischemique (0 %) ni degenerescence wallerienne (0 %). Les neuropathies du groupe vascularite etaient significativement differentes de celles du groupe non vascularite sur leur topographie (multinevrite versus polyneuropathie, p p p p = 0,01). Conclusion Chez un patient porteur d’une hepatite C avec cryoglobulinemie, le profil des neuropathies associees a une vascularite de petit calibre sur la biopsie nerveuse se place entre les formes severes de multinevrites avec vascularite de moyen calibre et les formes moderees de polyneuropathies associees a un infiltrat lymphocytaire perivasculaire. Le degre de severite depend du type d’inflammation et du diametre du vaisseau concerne par le processus inflammatoire.

If a sensory neuropathy appear from an autoimmune disease, it was important to precise the type with clinical and electrophysiological characteristic features (distal symmetric polyneuropathy, chronic inflammatory demyelinating polyneuropathy, Sensory mononeuritis multiplex, sensory neuronopathy, small-fiber neuropathy). The type of neuropathy have an influence on the complementary explorations. It was very important to determine the mechanism between the neuropathy and the autoimmune disease for the treatment. We present a young patient with systemic lupus erythemathosus and sensory neuropathy. This case illustrates this diagnosis strategy.

Resume Introduction La neuropathie motrice multifocale (NMM) est communement definie comme une maladie affectant exclusivement les nerfs moteurs aux quatre membres. Pour exemple, l’existence d’un deficit sensitif objectif et d’anomalies de la conduction sensitive constituent des criteres d’exclusion dans le guideline publie en 2006 par un groupe d’experts sous l’autorite de l’European Federation of Neurological Societies et de la Peripheral Nerve Society. Methode L’objectif de cette etude retrospective chez 21 patients, atteints de NMM et inclus selon des criteres internationaux [Workshop Report, 2001. 79th ENMC International Workshop. Multifocal motor neuropathy 14–15 April 2000, Hilversum. The Netherlands. Muscle Nerve 11, 309–314], a ete de rechercher une diminution significative de l’amplitude d’au moins un potentiel sensitif (PS) pendant une periode de suivi de sept ans en moyenne. Resultats Treize patients (62 %) (groupe 1) presentaient une anomalie d’au moins un PS, dont quatre patients avaient une atteinte d’au moins deux PS versus huit patients (groupe 2) sans anomalie. Aucun patient du groupe 1 n’avait de deficit sensitif clinique objectif. Aucune difference significative concernant l’âge de debut, le sexe, le nombre de nerfs moteurs atteints, la proteinorachie, la presence d’anticorps seriques anti-GM1 de classe IgM et la reponse aux immunoglobulines polyvalentes intraveineuses n’a ete decelee entre les deux groupes. Conclusion Cette etude souligne les difficultes persistantes de la definition de la NMM, et donc de sa distinction d’avec les formes frontieres des polyradiculonevrites inflammatoires demyelinisantes chroniques (PIDC) en general, et du syndrome de Lewis-Sumner (SLS) en particulier.

Chronic inflammatory demyelinating polyneuropathy (CIDP) was proposed by Dyck et al. in 1975. Diagnosis was based mainly on nerve biopsy features with segmental demyelination, onion bulb formation and inflammatory infiltrates. In many pathological studies, frequencies of these features of CIDP were not observed in the same percentages. Limitations on the nerve biopsy were explained by the study of small, distal, only sensory nerve specimens in the lower limb. In recent years, the usefulness of nerve biopsy has been reconsidered. If electron microscopy and teased-fiber studies are used, the examination can recognize CIDP erroneously classified as chronic idiopathic axonal polyneuropathy. Therapeutic options should be guided by suggestive abnormalities of demyelination and or inflammation on nerve biopsy even in the presence of a electrophysiologic axonal pattern.

Resume Introduction. – L’atteinte du systeme nerveux peripherique est frequente au cours des vascularites systemiques comme la periarterite noueuse ou l’angeite de Churg et Strauss. Des vascularites necrosantes affectant uniquement le nerf peripherique ont ete decrites recemment. Exegese. – Une femme âgee de 74 ans aux antecedents de nevrite optique retrobulbaire droite, de gammapathie monoclonale benigne et d’hypercholesterolemie traitee par fenofibrate, consulta pour des douleurs des membres inferieurs. L’examen clinique mettait en evidence un deficit moteur proximal des membres inferieurs associe a une amyotrophie des quadriceps. Les reflexes osteotendineux etaient abolis. La sensibilite superficielle etait normale, mais il existait une atteinte de la sensibilite profonde. L’electromyogramme mit en evidence une atteinte myogene diffuse de type inflammatoire et evolutive. L’amplitude des potentiels sensitifs aux membres inferieurs etait diminuee. Le bilan biologique a la recherche d’une maladie inflammatoire resta negatif. Le fenofibrate fut arrete mais l’aggravation neurologique se poursuivit. Un nouvel electromyogramme revela une accentuation de la baisse des amplitudes sensitives aux membres inferieurs. Une biopsie nerveuse mit en evidence des lesions inflammatoires vasculaires avec presence de necrose fibrinoide faisant porter le diagnostic de vascularite necrosante. Un traitement par corticotherapie fut institue. L’evolution fut favorable avec, six mois plus tard, une amelioration spectaculaire tant sur le plan clinique qu’electrophysiologique. Conclusion. – Les lesions histologiques des vascularites restreintes au systeme nerveux peripherique sont comparables a celles des periarterites noueuses classiques. Le syndrome inflammatoire biologique est souvent absent et elles ne s’accompagnent pas de signes generaux, ce qui renforce l’importance diagnostique de la biopsie neuromusculaire. Leur pronostic est generalement favorable apres corticotherapie, contrairement aux vascularites systemiques.

Resume Introduction. – Les dermatomyosites de lˈenfant nˈont pas, contrairement aux formes de lˈadulte, de caractere paraneoplasique. Exegese. – Nous rapportons lˈobservation dˈune jeune fille de 12 ans qui presente une dermatomyosite typique qui va se compliquer par lˈapparition de lesions tres agressives de panniculite lobulaire predominant aux membres inferieurs. Leur caractere refractaire a differents traitements (en particulier les corticoides, la chloroquine, la dapsone, le methotrexate, lˈazathioprine, les immunoglobulines par voie intraveineuse et la ciclosporine) va finalement conduire au diagnostic de lymphome T sous-cutane. Celui-ci va se compliquer dˈun syndrome dˈactivation macrophagique conduisant au deces malgre la chimiotherapie. Conclusions. – La survenue dˈune panniculite au cours dˈune dermatomyosite doit faire rechercher un lymphome T sous-cutane, et ce dˈautant que les lesions sont localement agressives et refractaires aux traitements habituels, afin de mettre en route precocement une chimiotherapie adaptee.

Introduction En 5 annees, la mediane de survie du melanome metastatique a ete multipliee par trois grâce aux therapies ciblees et aux immunotherapies. La mutation NRAS constitue une cible therapeutique prometteuse des inhibiteurs de MEK (MEKi) et les perspectives therapeutiques orientent vers des associations entre immunotherapie et therapies ciblees. L’augmentation asymptomatique du taux de CPK a ete decrite sous MEKi. Nous decrivons un cas de myopathie necrosante focale (MNF) avec syndrome de la tete tombante (STT) induite par un MEKi, le cobimetinib. Observations Un homme de 72 ans souffrant d’une maladie de Parkinson controlee etait traite en 3e ligne par nivolumab 3 mg/kg toutes les deux semaines apres echec de la dacarbazine et de l’ipilimumab, pour un melanome metastatique mute NRAS. Apres 10 mois de traitement, nous observions un echappement modere motivant l’introduction, validee en RCP, du cobimetinib 60 mg/jour 21 sur 28 jours associe au nivolumab. A 1 mois de l’introduction du MEKi, il presentait une douleur interscapulaire, une fatigabilite axiale a la marche avec anteflexion de la nuque et difficulte a relever la tete. Resultats Il existait un deficit moteur isole aux muscles extenseurs cervicaux a 4/5, hypermetaboliques sur la TEP/TDM sans metastase associee (Fig. 1) et une augmentation des CPK a 1011 U/l (N Discussion Le STT, caracterise par une faiblesse des muscles extenseurs de la nuque responsable d’une cyphose cervicale et l’impossibilite de relever la tete, a pour principales etiologies les myopathies, la myasthenie et la maladie de Parkinson. Des cas de myopathie necrosante sous anti-PD1 ont ete rapportes mais du fait des donnees anatomocliniques le nivolumab ne pouvait pas etre impute. Trois cas similaires de STT ont ete decrits sous un MEKi, le selumetinib. Via le mode d’action du MEKi, cette necrose serait plutot de mecanisme toxique qu’immunomediee (comme pour les statines), MEK jouant aussi bien un role dans la proliferation cellulaire que dans la consommation des acides gras par la cellule musculaire. Le STT est retrouve chez 6 % des Parkinsoniens, ce qui constitue un biais. La cinetique d’evolution clinicobiologique et les donnees de la litterature suggerent que le terrain du patient peut avoir joue un role favorisant mais n’est pas la cause de la MNF. Conclusion Il s’agit du premier cas de MNF avec STT sous cobimetinib. Cette toxicite merite une attention particuliere en raison de la clinique stereotypee et de l’augmentation de prescription des therapies ciblees.

Paraneoplastic neurological syndrome associated with anti-CV2/CRMP5 antibodies are rare. Various clinical manifestations can occur, cerebellar ataxia, polyneuropathy, optic neuritis with NORB or uveitis. Small cell lung carcinoma is generally responsible.We report the case of a 64-year-old man who developed visual symptoms with papilledema, cerebellar signs, polyneuropathy confirmed with a neurophysiological studies. Anti-CV2/CRMP5 antibodies were present. A small cell lung carcinoma was responsible for this paraneoplastic syndrome revealing the cancer. The paraneoplastic syndrome improved with radio chemotherapy of the cancer alone.A paraneoplastic neurological syndrome must be evoked in case of an atypic neurological syndrome. This diagnostic can be confirmed by the presence of anti-neuronal antibodies. In this case, a small cells cancer of the lung must be research.

Some patients within the spectrum of chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) have distal acquired demyelinating symmetric (DADS) neuropathy, usually associated with anti-myelin-associated-glycoprotein (MAG) IgM monoclonal gammopathy. The aim of this retrospective study was to investigate patients with DADS neuropathy without anti-MAG antibodies, and study their response to immunotherapy.Patients were selected on the basis of (i) 'Definite CIDP' according to the EFNS/PNS Guideline criteria, (ii) The presence of disproportionately prolonged motor latencies resulting in a terminal latency index (TLI) ≤ 0.25 in at least two motor nerves and (iii) The absence of anti-MAG antibodies on ELISA. Response to immunotherapy was defined as persistent improvement by at least one point on the INCAT disability score.Data from 146 CIDP patients were analysed, and 10 patients were included. Six had clinically pure sensory neuropathy, and four had sensorimotor neuropathy. Ataxia was present in nine patients, generalized areflexia in seven and postural tremor in two. Five of the 10 patients had abnormal sensory potentials only in the upper limbs. An associated condition was found in nine patients: two chronic lymphocytic leukaemias, four IgG monoclonal gammopathies (one associated with non-Hodgkin's lymphoma) and two IgM monoclonal gammopathies of unknown significance. Patients were mostly improved with intravenous immunoglobulin (IVIg), corticosteroids, plasma exchanges, or a combination thereof.DADS neuropathy without anti-MAG antibodies is more likely to be considered a variant of CIDP. In addition, such patients should be systematically investigated for an associated haematological or immunological condition.

Cryoglobulinemic neuropathies caused by hepatitis C virus are frequent and may have severe clinical outcomes. The aim of this study was to clarify the clinical and anatomical correlations of these neuropathies.Between 1992 and 2007, 22 consecutive patients with cryoglobulinemic neuropathies caused by hepatitis C virus were retrospectively included. Patients were evaluated clinically, electrophysiologically and underwent a neuromuscular biopsy. The group of patients with vasculitis on nerve biopsy was compared with the group without vasculitis.All the neuropathies were axonal with 11 polyneuropathies and 11 mononeuropathies multiplex. The seven patients with medium-sized vasculitis on the nerve biopsy presented an acute sensorimotor mononeuropathy multiplex in six cases (85%), with ischemic conduction block in three cases (42%) and wallerian degeneration in four cases (57%). Among the four patients with small-sized vasculitis, two had a mononeuropathy multiplex (50%) without conduction block (0%) and with wallerian degeneration in one case (25%). The 11 patients without vasculitis (nine lymphocytic perivascular infiltrates and two non inflammatory biopsies) had a polyneuropathy in eight cases (72%) without conduction block and wallerian degeneration (0%). The type of neuropathy was different in the group of patients with vasculitis compared with the group without vasculitis. The neuropathies with vasculitis were significantly different with more frequent mononeuropathies multiplex (p0.05), acute early stage (p0.01), disability (p0.05) and wallerian degeneration (p=0.01).Among hepatitis C patients with cryoglobulinemia, neuropathies with small-sized vasculitis show a pattern between severe mononeuropathies multiplex with medium-sized vasculitis and moderate polyneuropathies with lymphocytic perivascular infiltrates. In cryoglobulinemic vasculitis with hepatitis C, the severity of the neuropathy depends on the nature of the cellular inflammation and the size of the vessel involvement.

If a sensory neuropathy appear from an autoimmune disease, it was important to precise the type with clinical and electrophysiological characteristic features (distal symmetric polyneuropathy, chronic inflammatory demyelinating polyneuropathy, Sensory mononeuritis multiplex, sensory neuronopathy, small-fiber neuropathy). The type of neuropathy have an influence on the complementary explorations. It was very important to determine the mechanism between the neuropathy and the autoimmune disease for the treatment. We present a young patient with systemic lupus erythemathosus and sensory neuropathy. This case illustrates this diagnosis strategy.

Although the diagnosis of spondyloenchondrodysplasia (SPENCD) can only be made in the presence of characteristic metaphyseal and vertebral lesions, a recent report has highlighted the pleiotropic manifestations of this disorder which include significant neurological involvement and variable immune dysfunction. Here we present two patients, one of whom was born to consanguineous parents, further illustrating the remarkable clinical spectrum of this disease. Although both patients demonstrated intracranial calcification, they were discordant for the presence of mental retardation, spasticity and white matter abnormalities. And whilst one patient had features consistent with diagnoses of Sjogren syndrome, polymyositis, hypothyroidism and severe scleroderma, the other patient had clinical manifestations and an autoantibody profile of systemic lupus erythematosus. These cases further illustrate the association of SPENCD with immune dysregulation and highlight the differential diagnosis with Aicardi-Goutieres syndrome and other disorders associated with the presence of intracranial calcification. Undoubtedly, identification of the underlying molecular and pathological basis of SPENCD will provide important insights into immune and skeletal regulation.

Multifocal motor neuropathy is a well described condition characterized by slowly progressive, predominantly distal, asymmetric limb weakness and wasting, predominantly in the arms within an anatomical distribution of individual motor nerves, with minimal or no sensory involvement.The aim of this retrospective study was to look for a significant reduction of the amplitude of sensory potentials in a cohort of 21 patients with defined multifocal motor neuropathy according to the Workshop Report criteria [Workshop Report, 2001. 79th ENMC International Workshop. Multifocal motor neuropathy 14-15 April 2000, Hilversum. The Netherlands. Muscle Nerve 11, 309-314], within a follow-up of at least 3 years.Thirteen patients (62%) (Group 1) had a reduction of the amplitude of at least one sensory potential, of whom four patients had abnormalities of two or more sensory potentials, while eight patients (Group 2) had no abnormality. No significant differences were found for gender, age at onset, number of involved motor nerves, CSF protein count, presence/absence of anti-GM1 serum antibodies and response to IgIV between the two groups.This study underlines the difficulty in defining criteria for multifocal motor neuropathies capable of distinguishing them from other chronic acquired demyelinating polyneuropathies, and mainly from multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy, also called Lewis-Sumner's syndrome.

Hypohidrosis is a classic feature of Fabry disease; in contrast, hyperhidrosis has only been rarely described. The aim of the study is to characterise the baseline descriptive data on hyperhidrosis (frequency, age at onset, sex ratio and outcome with and without enzyme replacement therapy) in hemizygous male and heterozygous female patients with Fabry disease. We describe case histories of five patients with Fabry disease and hyperhidrosis seen at three different centres. We have also analysed a cohort of 21 paediatric patients in the UK and a large European cohort of patients enrolled in the Fabry Outcome Survey (FOS). Five patients (three female, two male) with hyperhidrosis were originally identified, although each had additional symptoms related to Fabry disease. The age at onset of hyperhidrosis was less than 18 years in four cases. In the cohort of 21 paediatric patients (12 female, nine male), one female had hyperhidrosis; the age at onset of this symptom was 11 years. In the FOS cohort, 66 of 714 patients with Fabry disease had hyperhidrosis (44 of 369 females, 11.9%; 22 of 345 males, 6.4%). The female predominance was observed in seven of nine countries from which data were analysed. Hyperhidrosis is an increasingly recognised feature of the Fabry disease phenotype. It is more prevalent in females than in males and often appears in childhood or adolescence. The efficacy of enzyme replacement therapy on this recently recognised symptom should be assessed.

Chronic inflammatory demyelinating polyneuropathy (CIDP) was proposed by Dyck et al. in 1975. Diagnosis was based mainly on nerve biopsy features with segmental demyelination, onion bulb formation and inflammatory infiltrates. In many pathological studies, frequencies of these features of CIDP were not observed in the same percentages. Limitations on the nerve biopsy were explained by the study of small, distal, only sensory nerve specimens in the lower limb. In recent years, the usefulness of nerve biopsy has been reconsidered. If electron microscopy and teased-fiber studies are used, the examination can recognize CIDP erroneously classified as chronic idiopathic axonal polyneuropathy. Therapeutic options should be guided by suggestive abnormalities of demyelination and or inflammation on nerve biopsy even in the presence of a electrophysiologic axonal pattern.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) comprises a group of dysimmune neuropathies easily diagnosed in more than half of the patients. Diagnosis is based on clinical, electrophysiological and biological clues. In some patients, diagnosis is unclear because of the debated value of the available clues. In such circumstances, dysimmune neuropathies may not be diagnosed, leading to insufficient treatment. This is an important category of patients because immunomodulatory drugs have proven efficacy. The CIDP spectrum includes a relatively wide range of diseases. Besides the easily recognized classic forms, there are many clinical variants, sometimes with a paucisymptomatic presentation leading to uncertain diagnosis. The French CIDP study group has established guidelines for diagnostic strategy in CIDP patients. The first part of this paper is devoted to the clinical aspects of the disease, classical forms and variants. In the second part, the results of electrophysiological studies are reported. In a third chapter, complementary examinations useful for diagnosis are discussed. The fourth chapter deals with the diagnostic strategy, discussed in relation to the different situations which may be encountered in clinical practice. details the technical modalities of appropriate electrophysiological studies and presents normal results together with those indicating demyelinating neuropathy. Nerve biopsy technique and results are given in appendix II.

Lumbosacral plexopathy is the equivalent in the lower limbs of neuralgic amyotrophy (also known as Parsonage-Turner syndrome) in the upper limbs. It is well-known in patients with diabetes mellitus, when it is known as Bruns-Garland syndrome.We report the case of a 47-year-old woman who developed a unilateral neuropathy of the leg, neither radicular nor truncal in origin. The slow continuous improvement was not affected by any of the treatments administered.Lumbosacral plexopathy is characterized by intense pain in one or both legs, associated with motor and sensory deficits. Recovery is usually slow (6 to 36 months) and often incomplete. The electrodiagnostic examination shows important acute motor and sensory axonal loss, characterized by denervation and low-amplitude sensory action potential. Treatment generally combines analgesics with narcotic agents, neuropathic pain medication, short-term corticosteroids, and rehabilitation. In the most severe cases, long-term corticosteroids and other immunosuppressive agents may be required. This diagnosis cannot be reached until all other radicular, plexal and truncal origins have been ruled out.

Necrotizing autoimmune myopathy (NAM) is a group of severe acquired myopathies, characterized by prominent myofiber necrosis with little or no muscle inflammation. They can be misdiagnosed as muscular dystrophies, preventing initiation of appropriate therapy. Specific auto-antibody anti-Signal recognition protein is observed in 16% of cases. Recently, auto-antibodies against 3-hydroxy-3-methylglutaryl-coenzymeA reductase (HMGCR) were identified in NAM patients by one group, especially in statin exposed patients. Here we report the first European series of patients. We detected and quantified anti-HMGCR auto-antibodies using addressable laser bead immunoassay that we developed. Patients (n = 38) were 44 ± 19 years old (3 pediatric cases) and sex ratio male: female was 0.22. Statin exposure was recorded in 40% of patients. Patients suffered from myalgia (44%), and had a muscular deficit (92%). Subacute onset (less than 6 months) was noted for most of them (n = 18), nevertheless 10 patients had a slow progressive muscular deficit (10 months to years). Severe proximal weakness was observed (72%) and three patients were bedridden at the diagnosis. All patients had increase CK level (6630 ± 5990 UI/L). CK level correlated with muscular strength (r2 = −0.64, p = 0.005) and to anti-HMGR titer (r2 = −0.5, p = 0.04). None patients presented signs of pulmonary involvement. Mean duration of treatments (steroids, immunosupressant and/or IgIV) was 30.1 ± 36.1 [3–42] months, and to date it was not possible to stop the treatment for any patient. This the first study confirming the observation and the description of anti-HMGCR NAM. The majority of patients we detected was statin-naive, had a severe weakness and need prolonged treatments. Anti-HMGCR auto-antibodies testing may be warranted in dystrophic like patients. Anti-HMGR titer correlates with CK level suggesting their role in physiopathogenesis.

Hypoglossal-facial anastomosis (HFA) is a cross-over between the proximal stump of the hypoglossal nerve (XII) and the distal one of the facial nerve (VII). The hypoglossal axons regrow within the sheaths of facial fibres, allowing the progressive reinnervation of the facial muscles. This model is interesting to study some mechanisms of plasticity of the nervous system for several reasons: 1) It is a quite simple and reproducible model of pathophysiological state. It allows the study of 2) the modifications of the nervous system induced by the HFA, both upwards and downwards to the lesion and 3) the modifications of reflex activities involving intrapontine connections such as the blink reflex. The electrophysiological features of the trigemino-facial (TF) and trigemino-hypoglossal (TG) connections demonstrated that a central reorganisation of the blink reflex (BR) was induced by HFA: the afferent volleys of the TF and TH reflexes elicited by cutaneous and mucosal trigeminal afferents respectively have been shown to project onto common interneurones located within the trigeminal principal sensory nucleus. A long-term prospective study showed: 1) a reinnervation of the facial muscles by the hypoglossal axons is a necessary perequisite for the central reorganisation of BR, 2) a hyperinnervation of the facial muscles by the hypoglossal axons, 3) a transient and regressive cross-innervation of paralyzed face by the healthy contralateral facial nerve.

Neuropathies induced by Sjögren's syndrome (SS) are usually axonal. Nevertheless some demyelinating neuropathies have been described in patients with SS. To date, the relationship between demyelinating neuropathies and SS remains imprecise.A 75 year-old man presented with a chronic history of sensory disturbances linked to demyelinating neuropathy. Electroneuromyography revealed a demyelinating neuropathy and complementary tests revealed both Sjögren's syndrome (SS) and HMSN IA.We suggested that an inherited affection might be researched before considering that demyelinating neuropathy might be a form of peripheral nervous system involvement in SS.

We report the clinical features of two unrelated patients, a 51-year-old woman and a 54-year-old man, presenting proximal myopathy with lipomatosis. In both patients, muscle biopsies showed numerous ragged-red fibers. Molecular analysis were performed with denaturating gradient gel electrophoresis (DGGE) on muscle, blood, hair, buccal and urinary cells. The A8344G mutation of the tRNA-lysine gene of the mitochondrial DNA was detected in all tissues at high levels (more than 80 p cent). None of the patients had a contributive family history, and signs of central nervous system involvement were absent. These observations confirm that lipomatosis may be encountered in mitochondrial disorders and is tightly associated with the A8344G mutation.

Peripheral neuropathy has been widely reported in patients with monoclonal gammopathy (MG), more frequently immunoglobulin M (IgM) or IgG than IgA. Nevertheless, it remains unclear whether this association has clinical or pathogenic relevance. In order to clarify the possible role of IgG/IgA MG in neuropathy, we studied the clinical and electrophysiological features of 15 consecutive patients with polyneuropathy and IgG/IgA-MG, and compared them to those of 40 patients with polyneuropathy associated with IgM-MG, previously reported. Nine middle-aged patients (60%) had a chronic progressive or relapsing demyelinating polyneuropathy (DP) that was clinically and electrophysiologically indistinguishable from classic chronic inflammatory demyelinating polyneuropathy (CIDP) and frequently responded to immunosuppressive treatments, both characteristics supporting a dysimmune process. Six older patients (40%) had a chronic axonal distal polyneuropathy similar to the so-called chronic cryptogenic sensory polyneuropathy: there was no clear relationship with the MG in these patients and the response to immunosuppressive treatments was poor. Several features allowed us to distinguish between polyneuropathies associated with IgG/IgA-MG (IgG/IgA-PN) considered together and polyneuropathies associated with IgM-MG (IgM-PN). In the first group, the proportion of patients with a predominantly sensory clinical picture (27%) was less than that in the second group (75%), and there were fewer changes in nerve conduction studies. In addition, we found that the nine patients with DP associated with IgG/IgA-MG (IgG/IgA-DP) differed from the 31 with DP associated with IgM-MG (IgM-DP): clinical and electrophysiological studies clearly showed that the demyelinating pattern was more heterogeneous in IgG/IgA-DP than in IgM-DP. The spectrum of polyneuropathies associated with IgG/IgA-MG is heterogeneous, including DP, which is similar to classic CIDP, and axonal polyneuropathy, in which the pathogenic role of the MG remains elusive. In addition, IgG/IgA-DP differ from IgM-DP on clinical and electrophysiological grounds, suggesting probable different physiopathological mechanisms.