Comparative Study of Paraneoplastic and Nonparaneoplastic Autoimmune Encephalitis With GABABR Antibodies.

BACKGROUND AND OBJECTIVES: While patients with paraneoplastic autoimmune encephalitis (AE) with gamma-aminobutyric-acid B receptor antibodies (GABABR-AE) have poor functional outcomes and high mortality, the prognosis of nonparaneoplastic cases has not been well studied. METHODS: Patients with GABABR-AE from the French and the Dutch Paraneoplastic Neurologic Syndromes Reference Centers databases were retrospectively included and their data collected; the neurologic outcomes of paraneoplastic and nonparaneoplastic cases were compared. Immunoglobulin G (IgG) isotyping and human leukocyte antigen (HLA) genotyping were performed in patients with available samples. RESULTS: A total of 111 patients (44/111 [40%] women) were enrolled, including 84 of 111 (76%) paraneoplastic and 18 of 111 (16%) nonparaneoplastic cases (cancer status was undetermined for 9 patients). Patients presented with seizures (88/111 [79%]), cognitive impairment (54/111 [49%]), and/or behavioral disorders (34/111 [31%]), and 54 of 111 (50%) were admitted in intensive care unit (ICU). Nonparaneoplastic patients were significantly younger (median age 54 years [range 19-88] vs 67 years [range 50-85] for paraneoplastic cases, p < 0.001) and showed a different demographic distribution. Nonparaneoplastic patients more often had CSF pleocytosis (17/17 [100%] vs 58/78 [74%], p = 0.02), were almost never associated with KTCD16-abs (1/16 [6%] vs 61/70 [87%], p < 0.001), and were more frequently treated with second-line immunotherapy (11/18 [61%] vs 18/82 [22%], p = 0.003). However, no difference of IgG subclass or HLA association was observed, although sample size was small (10 and 26 patients, respectively). After treatment, neurologic outcome was favorable (mRS ≤2) for 13 of 16 (81%) nonparaneoplastic and 37 of 84 (48%) paraneoplastic cases (p = 0.03), while 3 of 18 (17%) and 42 of 83 (51%) patients had died at last follow-up (p = 0.008), respectively. Neurologic outcome no longer differed after adjustment for confounding factors but seemed to be negatively associated with increased age and ICU admission. A better survival was associated with nonparaneoplastic cases, a younger age, and the use of immunosuppressive drugs. DISCUSSION: Nonparaneoplastic GABABR-AE involved younger patients without associated KCTD16-abs and carried better neurologic and vital prognoses than paraneoplastic GABABR-AE, which might be due to a more intensive treatment strategy. A better understanding of immunologic mechanisms underlying both forms is needed.

Sensory neuronopathies, diagnostic criteria and causes.

PURPOSE OF REVIEW: To stress on the diagnostic strategy of sensory neuronopathies (SNN), including new genes and antibodies. RECENT FINDING: SNN involve paraneoplastic, dysimmune, toxic, viral and genetic mechanisms. About one-third remains idiopathic. Recently, new antibodies and genes have reduced this proportion. Anti-FGFR3 and anti-AGO antibodies are not specific of SNN, although SNN is predominant and may occur with systemic autoimmune diseases. These antibodies are the only marker of an underlying dysimmune context in two-thirds (anti-FGFR3 antibodies) and one-third of the cases (anti-AGO antibodies), respectively. Patients with anti-AGO antibodies may improve with treatment, which is less clear with anti-FGFR3 antibodies. A biallelic expansion in the RFC1 gene is responsible for the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) in which SNN is a predominant manifestation. Most of the patients have an adult onset and are sporadic. The RFC1 mutation may represent one-third of idiopathic sensory neuropathies. Finally, the criteria for the diagnosis of paraneoplastic SNN have recently been updated. SUMMARY: The diagnostic of SNN relies on criteria distinguishing SNN from other neuropathies. The strategy in search of their cause now needs to include these recent findings.

Usefulness and prognostic value of diagnostic tests in patients with possible chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION/AIMS: Recent guidelines define chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and possible CIDP. The aims of our study were to evaluate the value of diagnostic tests to support the diagnosis of CIDP in patients with possible CIDP and to identify prognostic factors of therapeutic success. METHODS: We conducted an observational retrospective two-center study between 2014 and 2019. We selected patients with a clinical presentation suggesting CIDP, but whose electrodiagnostic (EDX) test results did not meet the EFNS/PNS 2021 criteria. We analyzed epidemiologic and clinical features, axonal loss on EDX, cerebrospinal fluid (CSF), somatosensory evoked potentials (SSEPs), plexus magnetic resonance imaging (MRI), nerve biopsy, and therapeutic response. RESULTS: We selected 75 patients, among whom 30 (40%) responded to treatment. The positivity rates of CSF analysis, MRI and SSEPs were not influenced by the clinical presentation or by the delay between symptom onset and medical assessment. A high protein level in CSF, female gender, and a relapsing-remitting course predicted the therapeutic response. DISCUSSION: It is important to properly diagnose suspected CIDP not meeting EFNS/PNS 2021 EDX criteria by using supportive criteria. Specific epidemiological factors and a raised CSF protein level predict a response to treatment. Further prospective studies are needed to improve diagnosis and the prognostic value of diagnostic tests in CIDP.

Prognostic Factors and Treatment Efficacy in Spinal Cord Sarcoidosis: An Observational Cohort With Long-term Follow-up.

BACKGROUND AND OBJECTIVES: Spinal cord sarcoidosis is a rare manifestation of sarcoidosis with a consequent risk of neurologic sequelae for the patient. We investigated prognostic factors and efficacy of immunosuppressive treatments in a longitudinal cohort. METHODS: We retrospectively studied patients with spinal cord sarcoidosis followed between 1995 and 2021 in 7 centers in France. Patients with definite, probable, or possible spinal cord sarcoidosis according to the Neurosarcoidosis Consortium Consensus Group criteria and with spinal cord involvement confirmed by MRI were included. We analyzed relapse or progression rate with a Poisson model, initial Rankin score with a linear model, and change in the Rankin score during follow-up with a logistic model. RESULTS: A total of 97 patients were followed for a median of 7.8 years. Overall mean relapse or progression rate was 0.17 per person-year and decreased over time. At last visit, 46 (47.4%) patients had a loss of autonomy (Rankin score ≥2). The main prognostic factors significantly associated with relapse or progression rate were gadolinium enhancement (relative rate [95% CI] 0.61 [0.4, 0.95]) or meningeal involvement (relative rate [95% CI] 2.05 [1.31, 3.19]) on spinal cord MRI and cell count (relative rate [95% CI] per 1 log increase 1.16 [1.01, 1.33]) on CSF analysis. Relapse or progression rate was not significantly associated with initial Rankin score or Expanded Disability Status Scale. Tumor necrosis factor-α (TNF-α) antagonists significantly decreased relapse or progression rate compared with corticosteroids alone (relative rate [95% CI] 0.33 [0.11, 0.98]). Azathioprine was significantly less effective than methotrexate on relapse or progression rate (relative rate [95% CI] 2.83 [1.04, 7.75]) and change in Rankin score (mean difference [95% CI] 0.65 [0.23, 1.08]). DISCUSSION: Regarding the relapse or progression rate, meningeal localization of sarcoidosis was associated with a worse prognosis, TNF-α antagonists resulted in a significant decrease compared to corticosteroids alone, and methotrexate was more effective than azathioprine. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in individuals with spinal cord neurosarcoidosis, TNF-α antagonists were associated with decreased relapse or progression rate compared to corticosteroids alone, but other therapies showed no significant benefit.

Argonaute Autoantibodies as Biomarkers in Autoimmune Neurologic Diseases.

OBJECTIVE: To identify and characterize autoantibodies (Abs) as novel biomarkers for an autoimmune context in patients with central and peripheral neurologic diseases. METHODS: Two distinct approaches (immunoprecipitation/mass spectrometry-based proteomics and protein microarrays) and patients' sera and CSF were used. The specificity of the identified target was confirmed by cell-based assay (CBA) in 856 control samples. RESULTS: Using the 2 methods as well as sera and CSF of patients with central and peripheral neurologic involvement, we identified Abs against the family of Argonaute proteins (mainly AGO1 and AGO2), which were already reported in systemic autoimmunity. AGO-Abs were mostly of immunoglobulin G 1 subclass and conformation dependent. Using CBA, AGO-Abs were detected in 21 patients with a high suspicion of autoimmune neurologic diseases (71.4% were women; median age 57 years) and only in 4/856 (0.5%) controls analyzed by CBA (1 diagnosed with small-cell lung cancer and the other 3 with Sjögren syndrome). Among the 21 neurologic patients identified, the main clinical presentations were sensory neuronopathy (8/21, 38.1%) and limbic encephalitis (6/21, 28.6%). Fourteen patients (66.7%) had autoimmune comorbidities and/or co-occurring Abs, whereas AGO-Abs were the only autoimmune biomarker for the remaining 7/21 (33.3%). Thirteen (61.9%) patients were treated with immunotherapy; 8/13 (61.5%) improved, and 3/13 (23.1%) remained stable, suggesting an efficacy of these treatments. CONCLUSIONS: AGO-Abs might be potential biomarkers of autoimmunity in patients with central and peripheral nonparaneoplastic neurologic diseases. In 7 patients, AGO-Abs were the only biomarkers; thus, their identification may be useful to suspect the autoimmune character of the neurologic disorder. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that AGO-Abs are more frequent in patients with autoimmune neurologic diseases than controls.

Updated Diagnostic Criteria for Paraneoplastic Neurologic Syndromes.

OBJECTIVE: The contemporary diagnosis of paraneoplastic neurologic syndromes (PNSs) requires an increasing understanding of their clinical, immunologic, and oncologic heterogeneity. The 2004 PNS criteria are partially outdated due to advances in PNS research in the last 16 years leading to the identification of new phenotypes and antibodies that have transformed the diagnostic approach to PNS. Here, we propose updated diagnostic criteria for PNS. METHODS: A panel of experts developed by consensus a modified set of diagnostic PNS criteria for clinical decision making and research purposes. The panel reappraised the 2004 criteria alongside new knowledge on PNS obtained from published and unpublished data generated by the different laboratories involved in the project. RESULTS: The panel proposed to substitute "classical syndromes" with the term "high-risk phenotypes" for cancer and introduce the concept of "intermediate-risk phenotypes." The term "onconeural antibody" was replaced by "high risk" (>70% associated with cancer) and "intermediate risk" (30%-70% associated with cancer) antibodies. The panel classified 3 levels of evidence for PNS: definite, probable, and possible. Each level can be reached by using the PNS-Care Score, which combines clinical phenotype, antibody type, the presence or absence of cancer, and time of follow-up. With the exception of opsoclonus-myoclonus, the diagnosis of definite PNS requires the presence of high- or intermediate-risk antibodies. Specific recommendations for similar syndromes triggered by immune checkpoint inhibitors are also provided. CONCLUSIONS: The proposed criteria and recommendations should be used to enhance the clinical care of patients with PNS and to encourage standardization of research initiatives addressing PNS.

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

OBJECTIVE: To describe the clinical characteristics and outcomes of coronavirus disease 2019 (COVID-19) among patients with myasthenia gravis (MG) and identify factors associated with COVID-19 severity in patients with MG. METHODS: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS (Filière Neuromusculaire) network (between March 1, 2020, and June 8, 2020), including patients with MG with a confirmed or highly suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a PCR test from a nasopharyngeal swab or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) serology, thoracic CT scan, or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes. RESULTS: Among 3,558 patients with MG registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ± 19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p = 0.004); factors that were not associated included sex, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity. CONCLUSIONS: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes (odds ratio, 102.6 [4.4-2,371.9]). These results are important for establishing evidence-based guidelines for the management of patients with MG during the COVID-19 pandemic.

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

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

Clinical spectrum and diagnostic pitfalls of neurologic syndromes with Ri antibodies.

OBJECTIVE: To describe the main syndrome and clinical course in a large cohort of patients with anti-Ri-associated paraneoplastic neurologic syndrome (Ri-PNS). METHODS: Twenty-year retrospective nationwide study and systematic review of the literature. RESULTS: Thirty-six patients with complete clinical information were identified (median age 66 years, range: 47-87 years). In this French cohort, the majority were women (78%). At onset, 4 main patterns were observed: cerebellar syndrome (39%), isolated tremor (24%), oculomotor disturbances (17%), and other symptoms (19%). Course was multistep for 78% of cases. At the time the disease reached the plateau phase (median 12 weeks, range: 1-64 weeks; 28% >3 months), 24 (67%) showed an overt cerebellar syndrome, which was isolated in 3 patients, and was most frequently (21/24 cases) part of a multisystem neurologic disease. Patients manifested a variety of movement disorders, including myoclonus (33%), dystonia (17%), either cervical or oromandibular, and parkinsonism (17%). Most patients had cancer (92%), mainly breast cancer (n = 22). Misdiagnoses concerned 22% of patients (n = 8) and included atypical parkinsonism (n = 2), MS (n = 2), Bickerstaff encephalitis (n = 1), hyperekplexia (n = 1), vestibular neuritis (n = 1), and functional neurologic disorder (n = 1). Survival at 12 months was 73% (95% CI [0.54-0.85]), at 24 months 62% (95% CI [0.41-0.78]), and at 36 months 47% (95% CI [0.25-0.65]). There was no major clinical difference between cases retrieved from the systematic review of the literature (n = 55) and the French cohort. CONCLUSIONS: Ri-PNS is a multisystem neurologic syndrome with prominent cerebellum/brainstem involvement. Opsoclonus-myoclonus is less common than expected, and the disorder can mimic neurodegenerative diseases.

Biallelic MYORG mutation carriers exhibit primary brain calcification with a distinct phenotype.

Primary familial brain calcification (PFBC) is a rare neurogenetic disorder with diverse neuropsychiatric expression. Mutations in four genes cause autosomal dominant PFBC: SLC20A2, XPR1, PDGFB and PDGFRB. Recently, biallelic mutations in the MYORG gene have been reported to cause PFBC with an autosomal recessive pattern of inheritance. We screened MYORG in 29 unrelated probands negatively screened for the autosomal dominant PFBC genes and identified 11 families with a biallelic rare or novel predicted damaging variant. We studied the clinical and radiological features of 16 patients of these 11 families and compared them to that of 102 autosomal dominant PFBC patients carrying a mutation in one of the four known autosomal dominant PFBC genes. We found that MYORG patients exhibited a high clinical penetrance with a median age of onset of 52 years (range: 21-62) with motor impairment at the forefront. In particular, dysarthria was the presenting sign in 11/16 patients. In contrast to patients with autosomal dominant PFBC, 12/15 (80%) symptomatic patients eventually presented at least four of the following five symptoms: dysarthria, cerebellar syndrome, gait disorder of any origin, akinetic-hypertonic syndrome and pyramidal signs. In addition to the most severe clinical pattern, MYORG patients exhibited the most severe pattern of calcifications as compared to the patients from the four autosomal dominant PFBC gene categories. Strikingly, 12/15 presented with brainstem calcifications in addition to extensive calcifications in other brain areas (lenticular nuclei, thalamus, cerebellar hemispheres, vermis, ±cortex). Among them, eight patients exhibited pontine calcifications, which were observed in none of the autosomal dominant PFBC patients and hence appeared to be highly specific. Finally, all patients exhibited cerebellar atrophy with diverse degrees of severity on CT scans. We confirmed the existence of cerebellar atrophy by performing MRI voxel-based morphometry analyses of MYORG patients with autosomal dominant PFBC mutation carriers as a comparison group. Of note, in three families, the father carried small pallido-dentate calcifications while carrying the mutation at the heterozygous state, suggesting a putative phenotypic expression in some heterozygous carriers. In conclusion, we confirm that MYORG is a novel major PFBC causative gene and that the phenotype associated with such mutations may be recognized based on pedigree, clinical and radiological features.

Isolated seizures are a common early feature of paraneoplastic anti-GABAB receptor encephalitis.

OBJECTIVE: To report the clinical features and long-term outcome of 22 newly diagnosed paraneoplastic patients with GABAB receptor antibodies (GABABR-Abs). METHODS: Retrospective clinical study of CSF-confirmed cases of GABABR-Abs encephalitis. RESULTS: We identified 22 patients (4 female) with GABABR-Abs, with a median age of 64 years (range 55-85). All were paraneoplastic: 20 small-cell lung cancer, one malignant thymoma, and one uncharacterized lung mass. The most frequent first symptom was the isolated recurrent seizures without cognitive inter-ictal impairment in 17 patients (77%). In the other, three presented the first behavioral disorders and two presented de novo status epilepticus (SE). After a median delay of 10 days (range 1-30), the recurrent seizures' phase was followed by an encephalitic phase characterized by confusion in 100% of cases and SE in 81% (n = 17), with 53% (n = 9) non-convulsive SE. Dysautonomic episodes were frequent (36%, n = 8, bradycardia and central apnea) and killed three patients. CSF study was abnormal in 95% of the cases (n = 21). At the encephalitic phase, MRI showed a temporal FLAIR hypersignal in 73% (n = 16) of the cases. First-line immunotherapy was initiated after a median delay of 26 days (range 6-65) from disease onset, and a partial response was observed in 10 out of 20 patients (50%). There was no complete response. Two years after onset, a massive anterograde amnesia affected all still alive patients. Nine patients died from cancer progression (median survival: 1.2 years). CONCLUSION: Paraneoplastic GABABR-Abs encephalitis is characterized by a stereotype presentation with an epilepsy phase before an encephalitic phase with dysautonomia. The functional prognosis is poor.

Malignant tumors in autoimmune encephalitis with anti-NMDA receptor antibodies.

OBJECTIVE: The aim of this study was to describe specificities of patients with NMDA receptor antibody (NMDAR-Ab) encephalitis associated with a malignant tumor. METHODS: Retrospective observational study of 252 patients with NMDAR-Ab encephalitis of the French Paraneoplastic Neurological Syndrome Reference Center. Patients were classified in three groups: (1) non-malignant ovarian teratomas, (2) malignant ovarian teratomas (immature), and (3) other malignant tumors. RESULTS: Sixty patients (23.8%) had an associated tumor and 15 (6%) were malignant. No particular neurological symptom was observed in these patients. Ovarian teratomas were the most frequent (51 cases) with 6 of them immature (11.8% of teratomas). Nine patients (3.6%) developed other malignant tumors (3 small cell lung carcinomas, 1 uterine adenocarcinoma, 1 prostate adenocarcinoma, 1 Hodgkin lymphoma, 1 pineal dysgerminoma, 1 neuroblastoma and 1 pancreatic neuroendocrine tumor). Among patients with a cancer other than teratoma, 6/9 were elderly patients (median age 65 years, representing 30% of elderly patients with such encephalitis) compared to a median age of 26 years in adult patients included herein. The clinical course was similar in the three groups, other than a higher death rate among patients with malignant tumors (86 versus 2%; p < 0.001) mainly due to tumor progression (5/7 deaths). CONCLUSION: Immature ovarian teratomas represent 11.8% of all teratomas in patients with NDMAR-Ab encephalitis. The other malignant tumors are mainly observed in elderly patients. The presence of a malignant tumor does not impact the neurological presentation but is directly associated with a higher risk of death.

Encephalitis with mGluR5 antibodies: Symptoms and antibody effects.

OBJECTIVE: To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. METHODS: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. RESULTS: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95. CONCLUSIONS: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.

Initial clinical presentation of young children with N-methyl-d-aspartate receptor encephalitis.

Autoimmune encephalitis with anti-N-methyl-d-aspartate receptor autoantibodies (NMDA-R-Abs) is a recently described disease affecting adult and pediatric patients. Symptoms of the disease are now perfectly described in the adult population but the clinical presentation is less known in young children. The aim of the present study was to describe the clinical presentation and the specificities of symptoms presented by young children with NMDA-R-Abs encephalitis to improve diagnosis of this disease, and to compare these to a series of previously published female adult patients. Fifty cases of children younger than twelve years of age diagnosed with NMDA-R-Abs encephalitis between January 1, 2007 and December 31, 2016 (27 females and 23 males) were retrospectively studied. The first neurological symptoms observed in young children with NMDA-R-Abs encephalitis were characterized by seizure (72%), especially focal seizure (42%), within a median of 15 days before other encephalitis symptoms; other patients mostly had behavioral disorders (26%). The seizures were frequently difficult to diagnose because of the transient unilateral dystonic or tonic posturing presentation or sudden unilateral pain in the absence of clonic movements. A post-ictal motor deficit was also frequently observed. This clinical presentation is different from that observed in adult females with NMDA-R-Abs encephalitis who initially present mainly psychiatric disorders (67%) or cognitive impairment (19%), and less frequently seizures (14%). The diagnosis of NMDA-R-Abs encephalitis should be systematically considered in young children of both sexes who present neurological symptoms suggesting recent seizures (focal or generalized) without obvious other etiology.

Paraneoplastic neuropathies.

PURPOSE OF REVIEW: To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. RECENT FINDINGS: A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. SUMMARY: A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Characteristics in limbic encephalitis with anti-adenylate kinase 5 autoantibodies.

OBJECTIVE: To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs). METHODS: We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay. RESULTS: AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57-80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aß42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs. CONCLUSIONS: AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.

Anti-N-methyl-D-aspartate receptor encephalitis after Herpes simplex virus-associated encephalitis: an emerging disease with diagnosis and therapeutic challenges.

INTRODUCTION: Morbidity and mortality of Herpes simplex virus encephalitis (HSE) remain high. Relapses of neurological signs may occur after initial clinical improvement under acyclovir treatment. METHODS: We report here a case of post-HSE anti-N-methyl-d-aspartate receptor-mediated encephalitis in an adult and perform a systematic search on PubMed to identify other cases in adults. RESULTS: We identified 11 previously published cases, to discuss diagnostic and therapeutic management. Symptoms in adults are often inappropriate behaviors, confusion and agitation. Diagnosis of anti-NMDA-R encephalitis after HSE is often delayed. Treatment consists in steroids, plasma exchange, and rituximab. Prognosis is often favorable. CONCLUSION: Anti-NMDA-R antibodies should be searched in cerebrospinal fluid of patients with unexpected evolution of HSE. This emerging entity reopens the hot debate about steroids in HSE.

Safety and efficacy of a 6-month home-based exercise program in patients with facioscapulohumeral muscular dystrophy: A randomized controlled trial.

BACKGROUND: Previous randomized controlled trials investigating exercise training programs in facioscapulohumeral muscular dystrophy (FSHD) patients are scarce and of short duration only. This study assessed the safety and efficacy of a 6-month home-based exercise training program on fitness, muscle, and motor function in FSHD patients. METHODS: Sixteen FSHD patients were randomly assigned to training (TG) and control (CG) groups (both n = 8) in a home-based exercise intervention. Training consisted of cycling 3 times weekly for 35 minutes (combination of strength, high-intensity interval, and low-intensity aerobic) at home for 24 weeks. Patients in CG also performed an identical training program (CTG) after 24 weeks. The primary outcome was change in peak oxygen uptake (VO2 peak) measured every 6 weeks. The principal secondary outcomes were maximal quadriceps strength (MVC) and local quadriceps endurance every 12 weeks. Other outcome measures included maximal aerobic power (MAP) and experienced fatigue every 6 weeks, 6-minute walking distance every 12 weeks, and muscle characteristics from vastus lateralis biopsies taken pre- and postintervention. RESULTS: The compliance rate was 91% in TG. Significant improvements with training were observed in the VO2 peak (+19%, P = 0.002) and MAP by week 6 and further to week 24. Muscle endurance, MVC, and 6-minute walking distance increased and experienced fatigue decreased. Muscle fiber cross-sectional area and citrate synthase activity increased by 34% (P = 0.008) and 46% (P = 0.003), respectively. Dystrophic pathophysiologic patterns were not exacerbated. Similar improvements were experienced by TG and CTG. CONCLUSIONS: A combined strength and interval cycling exercise-training program compatible with patients' daily professional and social activities leads to significant functional benefits without compromising muscle tissue.

Characterization of a Subtype of Autoimmune Encephalitis With Anti-Contactin-Associated Protein-like 2 Antibodies in the Cerebrospinal Fluid, Prominent Limbic Symptoms, and Seizures.

IMPORTANCE: Autoantibodies against contactin-associated protein-like 2 (CASPR2) are observed in several neurological syndromes, including neuromyotonia (NMT), Morvan syndrome (MoS), and limbic encephalitis. OBJECTIVE: To characterize the clinical and biological presentations of patients with anti-CASPR2 antibodies in the cerebrospinal fluid (CSF). DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective cohort analysis of 18 patients who had anti-CASPR2 antibodies in their CSF between March 2009 and November 2015 at the Centre National de Référence pour les Syndromes Neurologiques Paranéoplasiques in Lyon, France. Additionally, we analyzed 15 patients who were diagnosed as having NMT or MoS as a comparative group. MAIN OUTCOMES AND MEASURES: Clinical presentations, anti-CASPR2 antibodies specificities, brain magnetic resonance imaging, and CSF analyses, cancer prevalence, and evolution. RESULTS: In this cohort of 18 patients with anti-CASPR2 antibodies in their CSF, 17 (94.4%) were male and had a median (range) age of 64.5 (53-75) years; in the second group, 9 of 15 patients (60.0%) with NMT or MoS were male and had a median (range) age of 51 years (1 month to 75 years). Only 3 patients (16.7%) in this cohort had a previous or concomitant history of cancer (prostate, hematological, or thyroid), whereas 9 patients (60.0%) in the second group had a malignant thymoma. Symptoms of limbic encephalitis were observed in all patients, including temporal lobe seizures in 16 patients (88.9%) and memory disorders in 17 patients (94.4%) from the cohort. Extralimbic signs were also evident in 12 of 18 patients (66.7%), including cerebellar ataxia in 6 patients (33.3%). Only 2 patients (11.1%) from the cohort were diagnosed as having NMT. Brain magnetic resonance imaging displayed T2-weighted temporolimbic abnormalities in 14 of 15 patients (93.3%) in the second group. Cerebrospinal fluid analysis was abnormal in 9 of 12 patients (75.0%). For 16 of 18 patients (88.9%), follow-up was performed for at least a 6-month period (median [range], 34 [11-114] months). Of these, 15 (93.8%) improved and 6 (37.5%) relapsed. In all patients in this cohort, IgG4 autoantibodies were detected in the CSF. Anti-CASPR2 antibodies in the CSF targeted the laminin G1 and discoidin domains of CASPR2 in all patients. Importantly, anti-CASPR2 antibodies were detected in the serum but not in the CSF of all patients with NMT or MoS. CONCLUSIONS AND RELEVANCE: In this cohort study, anti-CASPR2 antibodies in the CSF are associated with a subtype of autoimmune encephalitis with prominent limbic involvement and seizures that is rarely associated with cancer. Conversely, patients with NMT and MoS have anti-CASPR2 antibodies only in the serum but not in the CSF and frequently present with a malignant thymoma. The anti-CASPR2 antibodies found in these patients targeted the discoidin and laminin G1 domains of CASPR2 and always included IgG4 autoantibodies.