Inflammatory sensory neuronopathies.

Inflammatory sensory neuronopathies are rare disorders mediated by dysimmune mechanisms targeting sensory neurons in the dorsal root ganglia. They constitute a heterogeneous group of disorders with acute, subacute, or chronic courses, and occur with cancer, systemic autoimmune diseases, notably Sjögren syndrome, and viral infections but a noticeable proportion of them remains isolated. Identifying inflammatory sensory neuronopathies is crucial because they have the potential to be stabilized or even to improve with immunomodulatory or immunosuppressant treatments provided that the treatment is applied at an early stage of the disease, before a definitive degeneration of neurons. Biomarkers, and notably antibodies, are crucial for this early identification, which is the first step to develop therapeutic trials.

Transthyretin amyloid polyneuropathy in France: A cross-sectional study with 413 patients and real-world tafamidis meglumine use (2009-2019).

OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.

Intravenous immunoglobulin for treatment of chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy in France: are daily practices in accordance with guidelines?

BACKGROUND AND PURPOSE: Chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN) are rare autoimmune diseases. Guidelines were published in 2010 for their diagnosis and treatment. In France, intravenous immunoglobulins (IVIGs) are mainly used for the first-line treatment. The burden of healthcare costs is often underlined but rarely studied. The aim of this survey was to compare to guidelines, the daily practice of French neurologists with IVIGs for CIDP and MMN treatment. METHODS: This was a retrospective observational study consisting of an online questionnaire performed between March and May 2014. A total of 49 questionnaires were included, a quarter of which were from neurologists working in neuromuscular reference centers (NRCs). RESULTS: A total of 182 patient case reports were studied. Patients were referred to an NRC for initial diagnosis in approximately 30% of cases in CIDP and 50% of cases in MMN. The initial management of IVIG (frequency, dose and duration) was not different between NRCs and non-NRCs. Guidelines were followed and neurologists were relatively at ease in diagnosing and treating patients. CONCLUSIONS: This was the first national study to describe the implementation of the European Federation of Neurological Sciences/Peripheral Nerve Society guidelines in the daily management of IVIGs in patients with MMN and CIDP in France. Efforts are needed to improve long-term tailored treatment and home treatment to reduce economic costs.

A case of anti-NMDA receptor encephalitis in a woman with a NMDA-R(+) small cell lung carcinoma (SCLC).

The association of small cell lung cancer with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is rare. We report a 62 year old patient who developed psychiatric disorders followed by epilepsy, movement disorders, mutism and hypoventilation. Flair weighted brain MRI sequences showed diffuse high signals in the limbic system. Anti-NMDAR antibodies were detected in the serum and CSF. The patient's IgGs reacted with the patient's own tumor cells and with 2 out of 4 small cell lung cancers of patients without neurological syndrome.

Evaluation of the application of the European guidelines for the diagnosis and clinical care of amyotrophic lateral sclerosis (ALS) patients in six French ALS centres.

BACKGROUND AND PURPOSE: Our objective was to evaluate the extent to which the 2005 recommendations of the European Federation of Neurological Sciences (EFNS) on the multidisciplinary management of amyotrophic lateral sclerosis (ALS) are followed in clinical practice. METHODS: This was a multicentre observational study involving six French ALS referral centres receiving prevalent and incident cases. Recommendations were translated into ad hoc questions referring to key aspects of management, and their application was evaluated by a clinical research assistant who independently examined the medical charts (MCs). When necessary, an independent board-certified neurologist answered the questions based on examination of the MC and interview of the caring neurologist. Questions regarding diagnosis and communication were put to patients in a self-administered questionnaire. RESULTS: In all, 376 patients [176 incident, 200 prevalent cases; median age at diagnosis 62.8 years (interquartile range 55.7-72.3); sex ratio 1.37; 27.3% bulbar onset] were included. All the topics covered in the recommendations were evaluated: diagnostic delay (e.g. mean 13.6 months, associated with age and onset); breaking the news (e.g. criteria for communication quality were satisfactory in more than 90%); multidisciplinary and sustained support (e.g. clinic visits were scheduled every 2-3 months in 90%). Also considered were whether riluzole had been offered, symptom management, genetic testing, ventilation, communication defects, enteral nutrition, palliative and end-of-life care. Characteristics associated with poor compliance with some guidelines (schedule of visits, delayed riluzole initiation) were also identified. CONCLUSION: This is the first evaluation of the application of the EFNS recommendations for the management of ALS in a nationwide sample. The results allow us to highlight areas for improvement.

Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience.

BACKGROUND AND PURPOSE: To describe the characteristics of patients presenting a paraneoplastic cerebellar degeneration without classical onconeural antibodies (seronegative PCD). METHODS: Thirty-nine seronegative PCD patients from the Paraneoplastic Neurological Syndrome Euronetwork were retrospectively analyzed and compared with 180 patients with PCD associated with classical onconeural antibodies (seropositive PCD). RESULTS: No patient had anti-CASPR2 or anti-mGluR1 antibodies. No significant difference between the clinical characteristics of seronegative and seropositive PCD patients was observed. Yet the frequency of associated tumors was different. Lymphoma was more frequent in seronegative than in seropositive women (24% vs. 2%, P = 0.002) whilst gynecological cancer were less frequent (38% vs. 74%, P = 0.002). In comparison with seropositive men, seronegative men more frequently had a non-small-cell lung cancer (27% vs. 6%, P = 0.08) or a genitourinary cancer (22% vs. 0%, P = 0.04) but less frequently a small-cell lung cancer (23% vs. 74%, P = 0.002). Seronegative and seropositive PCD patients with similar tumors had a similar overall survival. CONCLUSION: The clinical characteristics of seronegative and seropositive PCD are similar but the spectrum of associated tumors is different. The immunological scenario of seronegative PCD seems to be different from that of limbic encephalitis with only few patients harboring anti-neuropile antibodies.

Peripheral neuropathies associated with antibodies directed to intracellular neural antigens.

Antibodies directed to intracellular neural antigens have been mainly described in paraneoplastic peripheral neuropathies and mostly includes anti-Hu and anti-CV2/CRMP5 antibodies. These antibodies occur with different patterns of neuropathy. With anti-Hu antibody, the most frequent manifestation is sensory neuronopathy with frequent autonomic involvement. With anti-CV2/CRMP5 the neuropathy is more frequently sensory and motor with an axonal or mixed demyelinating and axonal electrophysiological pattern. The clinical pattern of these neuropathies is in keeping with the cellular distribution of HuD and CRMP5 in the peripheral nervous system. Although present in high titer, these antibodies are probably not directly responsible for the neuropathy. Pathological and experimental studies indicate that cytotoxic T-cells are probably the main effectors of the immune response. These disorders contrast with those in which antibodies recognize a cell surface antigen and are probably responsible for the disease. The neuronal cell death and axonal degeneration which result from T-cell mediated immunity explains why treating these disorders remains challenging.

Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies.

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytesT CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP.

Brain immunohistopathological study in a patient with anti-NMDAR encephalitis.

BACKGROUND AND PURPOSE: Anti-N-methyl-D-asparate (NMDA) receptor encephalitis is thought to be antibody-mediated. To perform an immunohistopathological study of the inflammatory reaction in a brain biopsy performed before immunomodulatory treatments in a patient with anti-NMDA receptor encephalitis. METHODS: An immunohistochemical study was performed using CD3, CD68, CD20, CD138 and CD1a antibodies. RESULTS: Prominent B-cell cuffing was present around brain vessels accompanied by some plasma cells, while macrophages and T cells were scattered throughout the brain parenchyma. CONCLUSION: These findings suggest that the B cells interact with the T cells and are involved in antibody secretion by the plasma cells.

[Small fiber sensory neuropathies: contribution of laser evoked potentials]. / Neuropathies sensitives des petites fibres : intérêt des potentiels évoqués laser.

Standard neurophysiological techniques evaluate exclusively large myelinated fibers, but are not useful to explore sensory small fibers. Quantitative sensory tests have been developed to explore the thermal nociceptive function but this exploration is only subjective. Laser evoked potentials (LEPs) represent a noninvasive and objective test to explore thermal and nociceptive pathways. The clinical interest of LEPs have been assessed recently in the diagnosis of small fibers sensory neuropathies. In routine, the determination of detection and nociceptive thresholds, the analysis of N2P2 latencies and amplitudes enable demonstration of a dysfunction of A delta nerve fibers, to quantify these lesions and to determine whether the neuropathies are length-dependent or not. The LEP amplitude is negatively correlated to deafferentation. The interest of LEPs remained to be studied compared to skin biopsy.

[Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 24 cases]. / Histoire naturelle des leucodystrophies avec mutation EIF2B: étude rétrospective multicentrique de 24 cas adultes.

INTRODUCTION: The childhood ataxia with central nervous system hypomyelination-vanishing white matter syndrome (CACH-VWM) was first characterized in children (2-5 years) on clinical and MRI criteria: cerebellospastic signs associated with episodes of rapid deterioration following stress and extensive cavitatingleucoencephalopathy. Causative mutations were found in the five genes encoding the subunits of the eukaryotic initiation factor 2B (eIF2B), involved in protein synthesis and its regulation under cellular stresses. A broad clinical spectrum has been subsequently described from congenital to adult-onset forms leading to the concept of eIF2B-related disorders. Our aim was to describe clinical and brain magnetic resonance imaging characteristics, genetic findings and natural history of patients with adult-onset eIF2B-related disorders. METHODS: The inclusion criteria were based on the presence of EIF2B mutations and a disease onset after the age of 16 years. One patient with an asymptomatic diagnosis was also included. Clinical and MRI findings were retrospectively recorded in all patients. This multicentric study included 24 patients from 22 families. RESULTS: A sex-ratio imbalance was noted (male/female=5/19). The mean age of onset was 30 years (range 12-62). Initial symptoms were neurologic (n=20), psychiatric (n=3) and ovarian failure (n=6). During follow-up (mean: 11 years, range 2-35 years), two patients died. Of the 22 survivors, 67% showed a decline in their cognitive functions and mean EDSS was 5.6 (range=0-9.5). One case remained asymptomatic. Stress worsened clinical symptoms in 33% of the patients. Magnetic resonance imaging findings consisted of cerebral atrophy (92%), extensive cystic leucoencephalopathy (83%), corpus callosum involvement (92%) and cerebellar (37%) T2-weighted hyperintensities. Most patients (83%) showed mutations in the EIF2B5 gene. The recurrent p.Arg113His-eIF2Be mutation was found at a homozygous state in 58% of the 24 eIF2B-mutated patients. CONCLUSION: eIF2B-related disorder is probably underestimated as an adult-onset inherited leucoencephalopathy. Cerebral atrophy is constant, whereas the typical vanishing of the white matter can be absent. Functional and cognitive prognosis remains severe. Molecular diagnosis is facilitated for these forms by screening for the recurrent p.Arg113His-eIF2Be mutation.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

Emergence of a surface immunoglobulin recycling process during B lymphocyte differentiation.

Surface immunoglobulin (Ig)-mediated endocytosis has been investigated in rat B lymphocytes and plasma cells, using horseradish peroxidase (HRP)-labeled sheep anti-rat Ig Fab' fragment of antibody and HRP as monomeric ligands, respectively. Quantitative estimates of HRP activity associated either with plasma membrane or with endomembrane compartments were made in several experimental conditions. Binding of HRP-conjugate on B lymphocytes was followed by its endocytosis in combination with surface Ig, as shown by the progressive disappearance of plasma membrane-associated HRP activity. Between 1 and 6 h at 37 degrees C in presence of conjugate the total amount of cell-associated activity was constant. These results indicate that during this time no reappearance of surface Ig occurred by neosynthesis, by the expression of an intracellular pool or by the recycling in a free form of the previously internalized molecules. On the contrary, at saturating doses, internalization of HRP by anti-HRP plasma cells increased linearly with time at 37 degrees C in presence of antigen, when, during the same time, the plasma membrane HRP-binding capacity remained constant. Cycloheximide did not affect continuous HRP uptake. The existence of a large intracellular pool of receptors has been ruled out by experiments of removal of binding sites with pronase. In addition, monensin caused a progressive decrease in the number of surface receptors on plasma cells but not on B lymphocytes. Our data then indicate that, unlike B lymphocytes, plasma cells were able to recycle their surface Ig.

Quantitative ultrastructural autoradiographic studies of iodinated plasma membranes of lymphocytes during segregation and internalization of surface immunoglobulins.

Rat spleen lymphocytes were iodinated (125 I) with lactoperoxidase. Quantitative autoradiographic studies on cells fixed immediately after iodination showed 19-24% of intracytoplasmic grains at 3HD and over from the plasma membrane. Normalization of grain density distribution and comparison of resulting curves with the universal curve of grain scatter of 125 I showed that a significant percentage of intracytoplasmic grains (36%) originates from intracytoplasmic labeled sources rather than from scattering from the heavily labeled plasma membrane. Damaged cells had a threefold grain density than intact cells. Radioactivity counts in sliced polyacrylamide gels of iodinated cells revealed 65-72% of total radioactivity in five peaks of apparent mol wt of 44, 50, 57, 90 and 195 thousand daltons. Segregation and internalization of anti-immunoglobulin-Ig-horseradish peroxidase (HRP) complexes from the iodinated plasma membrane proteins of lymphocytes was studied with quantitative autoradiography (125 I) and peroxidase cytochemistry; 64% of grains at 1.5HD (1,500 A) from the plasma membrane were within the cap zone, and 36% of grains remained outside the capped immunoglobulins; 45-57% of grains internalized together with Fab-anti-Ig-Ig-HRP, and 68% of grains internalized together with anti-Ig-Ig-HRP. These studies indicate that (a) iodination of rat spleen lymphocytes results in a significant internal labeling and that (b) immunoglobulins segregate into caps and internalize together with other iodinated plasma membrane proteins while a significant percentage of iodinated proteins (36%) are excluded from the immunoglobulin caps or internalization sites (32-55%).

Plasma membrane and internalized immunoglobulins of lymph node cells studied with conjugates of antibody or its Fab fragments with horseradish peroxidase.

Normal rat and mouse lymphoid cells were incubated at 0 degrees -4 degrees C for 1 h with purified rabbit or sheep antirat (mouse) immunoglobulin (Ig)-horseradish peroxidase (PO) conjugates or with Fab fragments of antibody coupled with peroxidase. Cells were subsequently washed and incubated in fresh medium, without labeled antibody or Fab fragments for 5-30 min at 20 degrees or 37 degrees C. With the use of the diaminobenzidine (DAB) method, distribution of peroxidase was studied in the light and electron microscopes. Fab fragments of antirat Ig antibody were iodinated with (125)I and subsequently coupled with horseradish PO. Plasma membrane and internalized immunoglobulins were detected by electron microscope autoradiography and peroxidase cytochemistry. Single- (Fab-PO), and double- ([(125)I]Fab-PO) labeled lymphoid cells showed identical patterns of surface or internal distribution of immunoglobulins. In the electron microscope, Fab-PO conjugates at 0 degrees -4 degrees C resulted in a diffuse specific staining of the plasmalemma of lymphocytes and plasma cells. Most of the small dark lymphocytes (T cells?) did not show plasma membrane Ig. Macrophages did not show plasmalemma staining, but displayed nonspecific cytoplasmic staining after incubation at 20 degrees or 37 degrees C with antibody or Fab-PO conjugates. Lymphocytes and plasma cells, after incubation with antibody-PO conjugates at 0 degrees -4 degrees C, had patchy deposits of oxidized DAB on their plasma membranes. Macrophages, similarly treated, had no plasmalemmal staining. Patch and cap formation on the plasma membrane of lymphocytes and plasma cells was seen regularly after antibody-PO incubation at 37 degrees C. Internalization patterns were different in lymphocytes and plasma cells. In lymphocytes, peroxidase staining was observed in small round or oval vesicles clustered at one pole of the cell (30 min at 37 degrees C). In plasma cells, peroxidase staining was seen in clusters of tubules resembling the Golgi apparatus. Internalization of plasma membrane IgG was less pronounced after antibody-PO labeling as compared to Fab-PO labeling.

[Polyradiculopathy revealing an enteropathy associated T-cell lymphoma in a patient with celiac disease]. / Polyradiculopathie révélant un lymphome T associé à une entéropathie au cours de la maladie coeliaque.

INTRODUCTION: Celiac disease (CD) may be complicated by an enteropathy associated T-cell lymphoma (EATL), but lymphomatous dissemination outside the gastrointestinal tract is uncommon especially to the peripheral nervous sytem. OBSERVATION: We report a 54-year-old CD patient with EATL revealed by subacute polyradiculopathy. DISCUSSION: Peripheral neuropathies associated with CD are generally not polyradiculopathies, but sensorimotor neuropathies. Peripheral neurological complications of non-Hodgkin lymphoma are more frequent with B-lymphoma and a neurological presentation of EATL is very rare. CONCLUSION: This case illustrates the usefulness of searching for EATL in CD patients with polyradiculopathy.

[Metabolic rhabdomyolysis during statin therapy]. / Rhabdomyolyse métabolique au cours d'un traitement par statine.

The occurrence of rhabdomyolysis during statin treatment for dyslipidemia is a well-known side effect. However, the differential diagnosis of rhabdomyolysis is large. We report on a patient treated with statin who presented a rhabdomyolysis. The persistence of laboratory abnormalities allowed to discover a metabolic rhabdomyolysis, namely a carnitine palmitoyltransférase II deficiency. The diagnosis of the genetic abnormality allows to modify the therapeutic care.