Immunomodulatory effects of targeted radionuclide therapy.

It is now clear that conventional radiation therapy can reinstate cell death immunogenicity. Recent preclinical data indicate that targeted radionuclide therapy that irradiate tumors at continuous low dose rate also can elicit immunostimulatory effects and represents a promising strategy to circumvent immune checkpoint inhibitor resistance. In this perspective, we discuss the accumulating preclinical and clinical data suggesting that activation of the immune system through the cGAS-STING axis and the release of extracellular vesicles by irradiated cells, participate to this antitumor immunity. This should need to be considered for adapting clinical practices to state of the art of the radiobiology and to increase targeted radionuclide therapy effectiveness.

Novel CAPN3 variant associated with an autosomal dominant calpainopathy.

AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.

Genetic risk scores and family history as predictors of schizophrenia in Nordic registers.

BACKGROUND: Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other. METHODS: We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes. RESULTS: Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility. CONCLUSIONS: Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

Peripheral nerve involvement in Fabry's disease: Which investigations? A case series and review of the literature.

BACKGROUND: Peripheral nerve system (PNS) involvement is common in Fabry's disease (FD), predominantly affecting the small nerve fibers that are difficult to investigate with conventional electrophysiological methods. PATIENTS AND METHODS: Eighteen patients followed for Fabry's disease underwent a prospective series of electroneurophysiological explorations, including a study of the cardiac parasympathetic autonomic nervous system (ANS) and electrochemical skin conductance (ESC) tests. Data were compared with those obtained in 18 matched healthy controls. RESULTS: All patients had at least one clinical sign suggestive of neuropathy: 16 reported an acrosyndrome and 12 had dyshidrosis. Cold hypoesthesia was found in 15 patients and heat hypoesthesia in 13. Electroneurophysiological investigations and study of the cardiac parasympathetic ANS were normal in all patients. The ESC was significantly lower in FD patients compared with controls. CONCLUSION: PNS involvement is common in FD and should be suspected in patients exhibiting an acrosyndrome, dyshidrosis and/or cold hypoesthesia. Conventional electrophysiological investigations are normal. New techniques, such as ESC, provide early diagnosis of small fiber involvement that currently requires more sophisticated tests difficult to apply in routine practice.

Motor-evoked potential gain is a helpful test for the detection of corticospinal tract dysfunction in amyotrophic lateral sclerosis.

OBJECTIVE: The detection of upper motor neuron (UMN) dysfunction is necessary for the diagnosis of amyotrophic lateral sclerosis (ALS). However, signs of UMN dysfunction may be difficult to establish. This study aimed to determine whether motor-evoked potential (MEP) gain (MEP area/background electromyographic activity) represents an efficient alternative to assess UMN dysfunction. METHODS: MEP area, MEP/compound muscle action potential (CMAP) area ratio, and MEP gain were tested at different force levels in healthy control subjects and ALS patients. Receiver operating characteristic (ROC) curve analyses was used to determine the diagnostic utility of MEP gain and compare it to alternative techniques, namely, diffusion tensor imaging (DTI) and the triple stimulation technique (TST). RESULTS: MEP gain revealed a significant difference between the patients and healthy control subjects in contrast to MEP area and MEP/CMAP area ratio. The diagnostic utility of MEP gain was comparable with that of TST and superior to that of DTI. CONCLUSION: MEP gain can distinguish ALS patients from control subjects and may be helpful for the diagnosis of ALS. SIGNIFICANCE: MEP gain appears to be a useful adjunct test and noninvasive method for the assessment of corticospinal dysfunction.

Near-Edge X-ray Absorption Fine Structure Investigation of the Quasi-One-Dimensional Organic Conductor (TMTSF)2PF6.

We present high-resolution near-edge X-ray absorption fine structure (NEXAFS) measurements at the P L2/3 edges, F K edge, C K edge, and Se M2/3 edges of the quasi-one-dimensional (1D) conductor and superconductor (TMTSF)2PF6. NEXAFS allows probing the donor and acceptor moieties separately; spectra were recorded between room temperature (RT) and 30 K at normal incidence. Spectra taken around RT were also studied as a function of the angle (θ) between the electric field of the X-ray beam and the 1D conducting direction. In contrast with a previous study of the S L2/3-edges spectra in (TMTTF)2AsF6, the Se M2/3 edges of (TMTSF)2PF6 do not exhibit a well-resolved spectrum. Surprisingly, the C K-edge spectra contain three well-defined peaks exhibiting strong and nontrivial θ and temperature dependence. The nature of these peaks as well as those of the F K-edge spectra could be rationalized on the basis of first-principles DFT calculations. Despite the structural similarity, the NEXAFS spectra of (TMTSF)2PF6 and (TMTTF)2AsF6 exhibit important differences. In contrast with the case of (TMTTF)2AsF6, the F K-edge spectra of (TMTSF)2PF6 do not change with temperature despite stronger donor-anion interactions. All these features reveal subtle differences in the electronic structure of the TMTSF and TMTTF families of salts.

Realistic multi-cellular dosimetry for 177Lu-labelled antibodies: model and application.

Current preclinical dosimetric models often fail to take account of the complex nature of absorbed dose distribution typical of in vitro clonogenic experiments in targeted radionuclide therapy. For this reason, clonogenic survival is often expressed as a function of added activity rather than the absorbed dose delivered to cells/cell nuclei. We designed a multi-cellular dosimetry model that takes into account the realistic distributions of cells in the Petri dish, for the establishment of survival curves as a function of the absorbed dose. General-purpose software tools were used for the generation of realistic, randomised 3D cell culture geometries based on experimentally determined parameters (cell size, cell density, cluster density, average cluster size, cell cumulated activity). A mixture of Monte Carlo and analytical approaches was implemented in order to achieve as accurate as possible results while reducing calculation time. The model was here applied to clonogenic survival experiments carried out to compare the efficacy of Betalutin®, a novel 177Lu-labelled antibody radionuclide conjugate for the treatment of non-Hodgkin lymphoma, to that of 177Lu-labelled CD20-specific (rituximab) and non-specific antibodies (Erbitux) on lymphocyte B cells. The 3D cellular model developed allowed a better understanding of the radiative and non-radiative processes associated with cellular death. Our approach is generic and can also be applied to other radiopharmaceuticals and cell distributions.

Multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of late-onset treatable metabolic disease.

INTRODUCTION: Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare, treatable, beta-oxidation disorder responsible for neuromuscular symptoms in adults. This case series describes the clinical and biochemical features of 13 French patients with late-onset MADD. METHODS AND RESULTS: Thirteen ambulant patients (eight women, five men), with a median age at onset of 27 years, initially experienced exercise intolerance (n=9), isolated muscle weakness (n=1) and a multisystemic pattern with either central nervous system or hepatic dysfunction (n=3). During the worsening period, moderate rhabdomyolysis (n=5), a pseudomyasthenic pattern (n=5) and acute respiratory failure (n=1) have been observed. Weakness typically affected the proximal limbs and axial muscles, and there was sometimes facial asymmetry (n=3). Moderate respiratory insufficiency was noted in one case. Median baseline creatine kinase was 190IU/L. Lactacidemia was sometimes moderately increased at rest (3/10) and after exercise (1/3). The acylcarnitine profile was characteristic, with increases in all chain-length acylcarnitine species. Electromyography revealed a myogenic pattern, while muscle biopsy showed lipidosis, sometimes with COX-negative fibers (n=2). The mitochondrial respiratory chain was impaired in five cases, with coenzyme Q10 decreased in two cases. All patients harbored mutations in the ETFDH gene (four homozygous, seven compound heterozygous, two single heterozygous), with nine previously unidentified mutations. All patients were good responders to medical treatment, but exercise intolerance and/or muscular weakness persisted in 11 of them. CONCLUSION: Late-onset forms of MADD may present as atypical beta-oxidation disorders. Acylcarnitine profiling and muscle biopsy remain the most decisive investigations for assessing the diagnosis. These tests should thus probably be performed more widely, particularly in unexplained cases of neuromuscular and multisystemic disorders.

Myofibrillar myopathies: State of the art, present and future challenges.

Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.

Donor-anion interactions at the charge localization and charge ordering transitions of (TMTTF)2AsF6 probed by NEXAFS.

High-resolution near-edge X-ray absorption fine structure (NEXAFS) measurements at the As M-edge, F K-edge and S L-edge of the Fabre salt (TMTTF)2AsF6 were performed from room temperature (RT) to 90 K, allowing to reach the charge localization regime below Tρ ≈ 230 K and to cross the charge ordering (CO) transition at TCO ≈ 102 K. The F K-edge and S L-edge spectra exhibit several transitions which have been indexed on the basis of first-principles DFT calculations. Upon cooling from RT significant energy shifts up to +0.8 eV and -0.4 eV were observed in transitions exhibited by the F 1s and S 2p spectra respectively, while the As 3p doublet does not show a significant shift. Opposite energy shifts found in the F 1s and S 2p spectra reflect substantial thermal changes in the electronic environment of F atoms of the anion and S atoms of TMTTF. The changes found around the charge localization crossover suggest an increase of the participation of the S d orbitals in the empty states of TMTTF as well as an increase of the strength of donoranion interactions. A new F 1s pre-edge signal detected upon entry into the CO phase is a clear fingerprint of the symmetry breaking occurring at TCO. We propose that this new transition is caused by a substantial mixing between the HOMO of the AsF6(-) anion and the unoccupied part of the TMTTF HOMO conduction band. Analysis of the whole spectra also suggests that the loss of the inversion symmetry associated with the CO is due to an anion displacement increasing the strength of SF interactions. Our data show unambiguously that anions are not, as previously assumed, innocent spectators during the electronic modifications experienced by the Fabre salts upon cooling. In particular the interpretation of the spectra pointing out a thermally dependent mixing of anion wave functions with those of the TMTTF chains demonstrates for the first time the importance of anion-donor interactions.

Somatosensory evoked potentials in the assessment of peripheral neuropathies: Commented results of a survey among French-speaking practitioners and recommendations for practice.

BACKGROUND: Somatosensory evoked potentials (SSEPs) are increasingly performed for the assessment of peripheral neuropathies, but no practical guidelines have yet been established in this specific application. STUDY AIM: To determine the relevant indication criteria and optimal technical parameters for SSEP recording in peripheral neuropathy investigation. METHODS: A survey was conducted among the French-speaking practitioners with experience of SSEP recording in the context of peripheral neuropathies. The results of the survey were analyzed and discussed to provide recommendations for practice. RESULTS: SSEPs appear to be a second-line test when electroneuromyographic investigation is not sufficiently conclusive, providing complementary and valuable information on central and proximal peripheral conduction in the somatosensory pathways. CONCLUSIONS: Guidelines for a standardized recording protocol, including the various parameters to be measured, are proposed. CLINICAL RELEVANCE: We hope that these proposals will help to recognize the value of this technique in peripheral neuropathy assessment in clinical practice.

²°¹Tl⁺-labelled Prussian blue nanoparticles as contrast agents for SPECT scintigraphy.

Prussian blue (PB) and its analogues on the nanometric scale are exciting nano-objects that combine the advantages of molecular-based materials and nanochemistry. Herein, we demonstrate that ultra-small PB nanoparticles of 2-3 nm can be easily labelled with radioactive (201)Tl(+) to obtain new nanoprobes as radiotracers for 201-thallium-based imaging.

Revisiting the spectrum of lower motor neuron diseases with snake eyes appearance on magnetic resonance imaging.

BACKGROUND AND PURPOSE: The 'snake eyes' sign refers to bilateral hyperintensities of the anterior horns on axial spinal cord imaging. Based on sporadic reports, it has been associated with a range of lower motor neuron (LMN) syndromes, such as spondylotic amyotrophy and Hirayama disease, as well as spinal cord infarction. The objective of our study was to comprehensively characterize the full diagnostic spectrum of LMN syndromes with this radiological clue and discuss potential aetiological factors. METHODS: A large patient cohort with snake eyes sign and upper limb LMN degeneration was recruited from three French neuromuscular units. Patients underwent detailed electrophysiological, radiological, clinical and anamnestic profiling. RESULTS: Twenty-nine patients were ascertained and followed up for 9.5 ± 8.6 years. The majority of the patients were male (86.2%) with a mean age of 37.3 ± 14.4 years. Symptoms were bilateral in most cases (86.2%). Patients with predominantly proximal and distal deficits were equally represented (44.8% and 55.2%, respectively). A history of preceding trauma or intense physical activity was confirmed in 58.6% of the cases; 27.6% of the patients were given an initial clinical diagnosis of amyotrophic lateral sclerosis (ALS), and 51.7% were originally suspected to have multifocal motor neuropathy. None of the patients developed ALS on longitudinal follow-up. CONCLUSION: The snake eyes sign on magnetic resonance imaging is associated with a wide spectrum of neurological conditions and is more common in young men with a history of strenuous activity or antecedent trauma. The recognition of this syndrome is crucial as many of these patients are initially misdiagnosed with ALS.

Primary neurolymphomatosis diagnosis and treatment: a retrospective study.

BACKGROUND: To discuss the therapeutic approach for primary neurolymphomatosis. METHODS: We report all primary neurolymphomatosis cases referred to our institution, with descriptions of clinical, radiological, electrophysiological, histological features and long-term follow-up. We treated all patients with a combination of high-dose methotrexate and alkylating agents. RESULTS: Five patients were diagnosed with histologically confirmed primary neurolymphomatosis. The majority of them presented with painful asymmetric sensory-motor neuropathy. Magnetic resonance imaging was abnormal in 4 of 5 patients, as shown with gadolinium enhancements. Electroneuromyography revealed denervation in all 4 cases with contributive examinations. All our patients received a chemotherapy combination of high-dose methotrexate and alkylating agent. Median progression-free survival was 8 months (2 complete responses and 2 partial responses), and overall survival was 24 months. CONCLUSIONS: Primary neurolymphomatosis is rare and polymorphic; it represents a difficult diagnosis of neuropathy. In our cohort, treatment with a chemotherapy combination with high-dose methotrexate showed encouraging results.

[Necrotizing myopathies: From genetic to acquired forms]. / Myopathies nécrosantes : des formes héréditaires aux formes acquises.

Necrotizing myopathies (NM) are defined by histological features. Muscle biopsy demonstrates marked muscle necrosis with regeneration, with little or an absence of inflammatory infiltrate. Histological pattern of NM is unspecific and can be encountered in diverse conditions as acquired myopathies and muscular dystrophies. Among acquired forms of NM, necrotizing autoimmune myopathy (NAM) is a recently recognized sub-group of the idiopathic inflammatory myopathies. Classically, patients present with a subacute severe proximal myopathy, associated with a markedly elevated creatine kinase level, usually greater than 10 times the upper limit of normal. Nevertheless, the clinical presentation can be misleading, with chronic course mimicking muscular dystrophy. Different forms of NAM can be distinguished with various underlying inciting conditions, including autoantibodies to the SRP, autoantibodies to the HMG-CoA reductase, association to connective tissue disease or underlying malignancy. Other associated conditions need yet to be identified. To confirm a diagnosis of NAM, other causes of NM should be excluded as toxic myopathies, muscular dystrophies and other inflammatory myopathies with a misleading histological pattern. NAM is a rare condition but is probably underdiagnosed. Both clinicoserologic and pathologic data must be taken into account to improve this diagnosis. We propose guidelines for diagnosis of NAM according to clinical course, to be used in clinical practice.

[Clinical and molecular diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) in 2012]. / Diagnostic clinique et moléculaire de la myopathie facioscapulo-humérale de type 1 (FSHD1) en 2012.

INTRODUCTION: Diagnosis of facioscapulohumeral dystrophy type 1 (FSHD1) is supported by a suggestive clinical presentation and associated with a heterozygous contraction of the D4Z4 repeat array on chromosome 4q35. STATE OF THE ART: The FSHD1 phenotype has a widely variable course with great inter- and intrafamilial heterogeneity. Three clinical forms can be distinguished: the classical phenotype associated with four to seven repeat units (RU) and a variable course, a severe infantile form with one to three RU, and a mild phenotype associated with borderline UR (8 to 10 RU). At the molecular level, for D4Z4 contraction to be pathogenic, it needs to occur on a specific chromosomal background, namely on the 4qA allelic variant of chromosome 4. In most cases, once FSHD is clinically suspected, the diagnosis can be genetically confirmed with a DNA test using Southern Blotting and hybridization to a set of probes. However, diagnosis of FSHD1 remains challenging. Firstly, some patients may present with an atypical phenotype with highly focal or unusual symptoms. Secondly, there are potential pitfalls in the genetic diagnosis of FSHD resulting in false positive or false negative results. In the absence of genetic confirmation, other investigations, mainly EMG and muscle biopsy, are needed to rule out another diagnosis. In cases with no clear diagnosis and a permissive chromosome without contraction, FSHD2 may be suspected. PERSPECTIVES: Molecular combing is a new technique which permits visualization and sizing of the D4Z4 repeat array on its genetic background on stretched single DNA fibers by fluorescence microscopy. This tool will improve genetic diagnosis in FSHD patients. CONCLUSION: Diagnosis of FSHD1 is mainly supported by clinical features. Clinicians need to be aware of unusual presentations of this disease. The wide spectrum of intrafamilial variability and the lack of good correlation between genotype and phenotype present challenges for genetic counseling and prognostication. More studies are needed concerning penetrance and genotype-phenotype correlation.

The French Pompe registry. Baseline characteristics of a cohort of 126 patients with adult Pompe disease.

Pompe disease is a rare autosomal recessive muscle lysosomal glycogenosis, characterised by limb-girdle muscle weakness and frequent respiratory involvement. The French Pompe registry was created in 2004 with the initial aim of studying the natural history of French patients with adult Pompe disease. Since the marketing in 2006 of enzyme replacement therapy (alglucosidase alfa, Myozyme(®)), the French Pompe registry has also been used to prospectively gather the biological and clinical follow-up data of all adult patients currently treated in France. This report describes the main clinical and molecular features, at the time of inclusion in the French registry, of 126 patients followed up in 21 hospital-based neuromuscular or metabolic centres. Sixty-five men and 61 women have been included in the registry. Median age at inclusion was 49 years, and the median age at onset of progressive limb weakness was 35 years. Fifty-five percent of the patients were walking without assistance, 24% were using a stick or a walking frame, and 21% were using a wheelchair. Forty-six percent of the patients needed ventilatory assistance, which was non-invasive in 35% of the cases. When performed, muscle biopsies showed specific features of Pompe disease in less than two-thirds of the cases, confirming the importance of acid alpha-glucosidase enzymatic assessment to establish the diagnosis. Molecular analysis detected the common c.-32-13T>G mutation, in at least one allele, in 90% of patients. The French Pompe registry is so far the largest country-based prospective study of patients with Pompe disease, and further analysis will be performed to study the impact of enzyme replacement therapy on the progression of the disease.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

[Favourable outcome after treatment with rituximab in a case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome]. / Efficacité du rituximab dans un cas de syndrome de Lambert-Eaton non paranéoplasique séronégatif.

INTRODUCTION: Lambert-Eaton myasthenic syndrome is a rare and autoimmune presynaptic disorder of the neuromuscular junction, due in 85% of cases to autoantibodies directed against voltage-gated calcium channels. It is a paraneoplastic disorder in 50 to 60% of cases. Diagnosis involves a proximal muscle weakness and areflexia, associated with a significant increment after post-exercise stimulation in electrophysiological study. Symptomatic treatment is based on 3,4-diaminopyridine. No etiological treatment has proven its efficacy in both paraneoplastic and non-paraneoplastic Lambert-Eaton myasthenic syndrome. CASE REPORT: We report a 41-year-old man who presented with a seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome in whom conventional immunosuppressive treatments (corticosteroids, azathioprine) failed, and who eventually improved after treatment with rituximab. CONCLUSION: Rituximab was an effective and well-tolerated treatment in this case of seronegative non-paraneoplastic Lambert-Eaton myasthenic syndrome. Its indication should be discussed when conventional immunosuppressive therapy fails in both seropositive and seronegative patients.