Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis.

Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia.

Real-world experience of assessing antibodies against the N-methyl-D-aspartate receptor (NMDAR-IgG) in psychiatric patients. A retrospective single-centre study.

OBJECTIVE: To evaluate the frequency of anti-NMDAR encephalitis in a secondary mental health service and investigate the challenges of its diagnosis in routine clinical practice. METHODS: Patients whose electronic health records registered an indication for NMDAR-IgG assessment were selected and seropositive patients were reviewed. RESULTS: In 1661 patients assessed for NMDAR-IgG over 12 years, the positivity rate was 3.79% (95% confidence interval [CI]: 2.87-4.70%). The working diagnosis at assessment was new onset psychosis in 38.7% and a chronic psychotic syndrome in 34.0%. Among seropositive patients, 30 (47.6%, 95%CI: 35.8-59.7%) had a final alternative diagnosis different from encephalitis after a median period of 49 months from onset. Patients with a final diagnosis of encephalitis were more frequently female (27/35 vs 13/30, p = 0.011) than other seropositive patients and had more frequently an acute (34/35 vs 11/30, p < 0.001), fluctuating (21/23 vs 4/27, p < 0.001) or agitated (32/32 vs 10/26, p < 0.001) presentation. Nine encephalitic patients received specialized follow-up for chronic neuropsychiatric problems including learning disabilities, organic personality disorder, anxiety, fatigue, obsessive-compulsive and autism-like disorder. CONCLUSIONS: In a psychiatric setting, NMDAR-IgG seropositivity rates were low with a positive predictive value for encephalitis around 50% when screened patients had chronic presentations and absence of other diagnostic criteria for encephalitis or psychosis of autoimmune origin. Chronic neuropsychiatric problems in anti-NMDAR encephalitis are not uncommon, so better diagnostic and treatment strategies are still needed.

Paraneoplastic neurological syndromes in Hodgkin and non-Hodgkin lymphomas.

Paraneoplastic neurological syndromes (PNSs) rarely associate with Hodgkin lymphoma (HL) and non-HLs (NHLs). Except for paraneoplastic cerebellar degeneration (PCD) in HL and dermato/ polymyositis in both HL and NHL, other PNSs are uncommon and have only been reported as isolated case reports or short series. There are several important differences in PNSs when occurring in association with HL and NHL compared with those associated with solid tumors. First, some PNSs such as sensory neuronopathy or Lambert-Eaton myasthenic syndrome rarely occur in lymphomas, whereas others, such as granulomatous angiitis, are only described in HL. Second, onconeural antibodies are absent in most PNSs associated with lymphomas with the exceptions of Tr (δ/notch-like epidermal growth factor-related receptor) in PCD and mGluR5 in limbic encephalitis (LE). The antigens recognized by these antibodies are not expressed in lymphoma cells, suggesting the tumor itself does not trigger the PNS. Third, unlike patients with solid tumors in patients with lymphoma, the PNSs often develops at advanced stages of the disease. Furthermore, the type and frequency of PNSs are different between HL and NHL; whereas LE and PCD occur almost exclusively in patients with HL, sensorimotor neuropathies and dermatomyositis are more frequent in NHL.

Long latency between GAD-antibody detection and development of limbic encephalitis--a case report.

BACKGROUND: In the pathogenesis of limbic encephalitis other promoting factors besides the pure existence of autoantibodies are increasingly discussed to play a significant role. This is to our knowledge the first described patient in whom the presence of autoantibodies precedes the manifestation of limbic encephalitis for many years. CASE PRESENTATION: At the age of 38 years, in the serum of a patient with polyendocrine autoimmunity high titers of cytoplasmic islet cell antibodies and of anti-glutamate decarboxylase (GAD) 65 antibodies were observed as an incidential finding, GAD67 antibodies were negative at that time. After a latency of 18 years, she manifested with refractory temporal lobe epilepsy most likely due to autoimmune limbic encephalitis. After epilepsy onset, the patient underwent magnetic resonance imaging (MRI), electroencephalography, cerebrospinal fluid (CSF), serum and neuropsychological investigations during a follow-up period of 8 years. A pharmacoresistent epilepsy with seizure onset from the right temporal lobe and declarative memory deficits were observed affecting primarily the recall of verbal informations. MRI showed a slightly increased signal in the right amygdala without progression. GAD antibodies could be detected in serum (titre 1: 1000) and CSF (titre 1:1) by immunofluorescence. Both, GAD65 and GAD67 antibodies were observed in cell-based assays. CONCLUSIONS: It can be assumed that in addition to a pre-existing systemic T-cell response associated with the longstanding polyendocrine autoimmunity, a delayed intrathecal autoimmunity developed leading to limbic encephalitis. This change might be reflected by the development of GAD67 antibodies in our patient. Besides the contribution of this case report to a better understandig of the pathomechanisms for the development of central nervous system (CNS) autoimmunity, it also has a clinical impact as early treatment of GAD antibody-associated CNS disorders has a better prognosis. Therefore, vigilance for symptoms indicating GAD antibody-associated CNS autoimmunity is mandatory in patients with GAD antibody-associated endocrine dysfunction.

Identifying encephalopathy in patients admitted to an intensive care unit: Going beyond structured information using natural language processing.

Background: Encephalopathy is a severe co-morbid condition in critically ill patients that includes different clinical constellation of neurological symptoms. However, even for the most recognised form, delirium, this medical condition is rarely recorded in structured fields of electronic health records precluding large and unbiased retrospective studies. We aimed to identify patients with encephalopathy using a machine learning-based approach over clinical notes in electronic health records. Methods: We used a list of ICD-9 codes and clinical concepts related to encephalopathy to define a cohort of patients from the MIMIC-III dataset. Clinical notes were annotated with MedCAT and vectorized with a bag-of-word approach or word embedding using clinical concepts normalised to standard nomenclatures as features. Machine learning algorithms (support vector machines and random forest) trained with clinical notes from patients who had a diagnosis of encephalopathy (defined by ICD-9 codes) were used to classify patients with clinical concepts related to encephalopathy in their clinical notes but without any ICD-9 relevant code. A random selection of 50 patients were reviewed by a clinical expert for model validation. Results: Among 46,520 different patients, 7.5% had encephalopathy related ICD-9 codes in all their admissions (group 1, definite encephalopathy), 45% clinical concepts related to encephalopathy only in their clinical notes (group 2, possible encephalopathy) and 38% did not have encephalopathy related concepts neither in structured nor in clinical notes (group 3, non-encephalopathy). Length of stay, mortality rate or number of co-morbid conditions were higher in groups 1 and 2 compared to group 3. The best model to classify patients from group 2 as patients with encephalopathy (SVM using embeddings) had F1 of 85% and predicted 31% patients from group 2 as having encephalopathy with a probability >90%. Validation on new cases found a precision ranging from 92% to 98% depending on the criteria considered. Conclusions: Natural language processing techniques can leverage relevant clinical information that might help to identify patients with under-recognised clinical disorders such as encephalopathy. In the MIMIC dataset, this approach identifies with high probability thousands of patients that did not have a formal diagnosis in the structured information of the EHR.

Frequency and Referral Patterns of Neural Antibody Studies During the COVID-19 Pandemic: Experience From an Autoimmune Neurology Center.

OBJECTIVE: To determine whether the frequency of paraneoplastic or autoimmune encephalitis antibodies examined in a referral center changed during the COVID-19 pandemic. METHODS: The number of patients who tested positive for neuronal or glial (neural) antibodies during pre-COVID-19 (2017-2019) and COVID-19 (2020-2021) periods was compared. The techniques used for antibody testing did not change during these periods and included a comprehensive evaluation of cell-surface and intracellular neural antibodies. The chi-square test, Spearman correlation, and Python programming language v3 were used for statistical analysis. RESULTS: Serum or CSF from 15,390 patients with suspected autoimmune or paraneoplastic encephalitis was examined. The overall positivity rate for antibodies against neural-surface antigens was similar in the prepandemic and pandemic periods (neuronal 3.2% vs 3.5%; glial 6.1 vs 5.2) with a mild single-disease increase in the pandemic period (anti-NMDAR encephalitis). By contrast, the positivity rate for antibodies against intracellular antigens was significantly increased during the pandemic period (2.8% vs 3.9%, p = 0.01), particularly Hu and GFAP. DISCUSSION: Our findings do not support that the COVID-19 pandemic led to a substantial increase of known or novel encephalitis mediated by antibodies against neural-surface antigens. The increase in Hu and GFAP antibodies likely reflects the progressive increased recognition of the corresponding disorders.

Neuroimmune disorders in COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the aetiologic agent of the coronavirus disease 2019 (COVID-19), is now rapidly disseminating throughout the world with 147,443,848 cases reported so far. Around 30-80% of cases (depending on COVID-19 severity) are reported to have neurological manifestations including anosmia, stroke, and encephalopathy. In addition, some patients have recognised autoimmune neurological disorders, including both central (limbic and brainstem encephalitis, acute disseminated encephalomyelitis [ADEM], and myelitis) and peripheral diseases (Guillain-Barré and Miller Fisher syndrome). We systematically describe data from 133 reported series on the Neurology and Neuropsychiatry of COVID-19 blog ( https://blogs.bmj.com/jnnp/2020/05/01/the-neurology-and-neuropsychiatry-of-covid-19/ ) providing a comprehensive overview concerning the diagnosis, and treatment of patients with neurological immune-mediated complications of SARS-CoV-2. In most cases the latency to neurological disorder was highly variable and the immunological or other mechanisms involved were unclear. Despite specific neuronal or ganglioside antibodies only being identified in 10, many had apparent responses to immunotherapies. Although the proportion of patients experiencing immune-mediated neurological disorders is small, the total number is likely to be underestimated. The early recognition and improvement seen with use of immunomodulatory treatment, even in those without identified autoantibodies, makes delayed or missed diagnoses risk the potential for long-term disability, including the emerging challenge of post-acute COVID-19 sequelae (PACS). Finally, potential issues regarding the use of immunotherapies in patients with pre-existent neuro-immunological disorders are also discussed.

Clinical characterisation of patients in the post-acute stage of anti-NMDA receptor encephalitis: a prospective cohort study and comparison with patients with schizophrenia spectrum disorders.

BACKGROUND: Anti-NMDA receptor (NMDAR) encephalitis is associated with a post-acute stage that is not well known. We aimed to describe the clinical features of this stage, similarities with schizophrenia spectrum disorders, and the factors that predict cognitive-psychiatric outcomes and could serve as prognostic biomarkers. METHODS: In this prospective cohort study, participants (aged 12-60 years) with anti-NMDAR encephalitis during the post-acute stage visited Hospital Clínic de Barcelona (Barcelona, Spain) on three occasions (at study entry [V1], at 6 months [V2], and at 12 months [V3]) and underwent comprehensive neuropsychiatric evaluations. Similar evaluations were done in a group of age-matched participants with schizophrenia spectrum disorders and a group of age-matched and sex-matched healthy participants also recruited from Hospital Clínic de Barcelona. We analysed differences between and within groups in the longitudinal follow-up using multilevel linear mixed-effect models, adjusting for group, age, sex, and socioeconomic status to control for possible confounding. FINDINGS: Between Jan 1, 2017, and Sept 30, 2020, 82 participants were recruited, 28 (34%) with anti-NMDAR encephalitis, 27 (33%) with schizophrenia spectrum disorders, and 27 (33%) healthy participants. Although, by V1 (median 4 months [IQR 3-7] from disease onset), many acute-stage symptoms in participants with anti-NMDAR encephalitis had resolved (acute stage median modified Rankin Scale [mRS] score 5 [IQR 4-5] vs V1 mRS score 2 [1-2]; p<0·0001), 25 (89%) participants showed deficits in at least one cognitive domain. In this group, 15 (68%) of 22 cognitive domain variables were impaired at V1, whereas only eight (36%) were altered at V3 (p=0·016). In participants with schizophrenia spectrum disorders, 11 (50%) of 22 variables (all shared with participants with anti-NMDAR encephalitis) were impaired at V1, without changes at V3. Two acute-stage features of anti-NMDAR encephalitis (ie, decreased consciousness and no improvement within the first 4 weeks of treatment) predicted cognitive domain outcomes, and a visuospatial task (ie, serial biases) at V1 showed potential in predicting learning and memory outcomes. At V1, all psychiatric symptom clusters were similarly altered in participants with anti-NMDAR encephalitis and in those with schizophrenia spectrum disorders, but only those in individuals with anti-NMDAR encephalitis subsequently improved (p=0·031). The greatest cognitive-psychiatric improvement in participants with anti-NMDAR encephalitis occurred between V1 and V2. During this interval, four (14%) participants with anti-NMDAR encephalitis would have met the diagnostic criteria of schizophrenia if CSF antibody findings had not been investigated. INTERPRETATION: The cognitive-psychiatric symptoms of anti-NMDAR encephalitis in the post-acute stage resembled those of stabilised schizophrenia, but only those in participants with anti-NMDAR encephalitis progressively improved, predominantly during V1-V2. These findings are important for clinical trials on anti-NMDAR encephalitis and suggest that prompt cognitive-psychosocial rehabilitation might be a valuable intervention. FUNDING: Instituto Salud Carlos III, NEURON Network of European Funding for Neuroscience Research, National Alliance for Research in Schizophrenia and Affective Disorders, and la Caixa Health-Research Foundation.

Placental transfer of NMDAR antibodies causes reversible alterations in mice.

OBJECTIVE: To determine whether maternofetal transfer of NMDA receptor (NMDAR) antibodies has pathogenic effects on the fetus and offspring, we developed a model of placental transfer of antibodies. METHODS: Pregnant C57BL/6J mice were administered via tail vein patients' or controls' immunoglobulin G (IgG) on days 14-16 of gestation, when the placenta is able to transport IgG and the immature fetal blood-brain barrier is less restrictive to IgG crossing. Immunohistochemical and DiOlistic (gene gun delivery of fluorescent dye) staining, confocal microscopy, standardized developmental and behavioral tasks, and hippocampal long-term potentiation were used to determine the antibody effects. RESULTS: In brains of fetuses, patients' IgG, but not controls' IgG, bound to NMDAR, causing a decrease in NMDAR clusters and cortical plate thickness. No increase in neonatal mortality was observed, but offspring exposed in utero to patients' IgG had reduced levels of cell-surface and synaptic NMDAR, increased dendritic arborization, decreased density of mature (mushroom-shaped) spines, microglial activation, and thinning of brain cortical layers II-IV with cellular compaction. These animals also had a delay in innate reflexes and eye opening and during follow-up showed depressive-like behavior, deficits in nest building, poor motor coordination, and impaired social-spatial memory and hippocampal plasticity. Remarkably, all these paradigms progressively improved (becoming similar to those of controls) during follow-up until adulthood. CONCLUSIONS: In this model, placental transfer of patients' NMDAR antibodies caused severe but reversible synaptic and neurodevelopmental alterations. Reversible antibody effects may contribute to the infrequent and limited number of complications described in children of patients who develop anti-NMDAR encephalitis during pregnancy.

Reduced serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia.

A mechanistic understanding of core cognitive processes, such as working memory, is crucial to addressing psychiatric symptoms in brain disorders. We propose a combined psychophysical and biophysical account of two symptomatologically related diseases, both linked to hypofunctional NMDARs: schizophrenia and autoimmune anti-NMDAR encephalitis. We first quantified shared working memory alterations in a delayed-response task. In both patient groups, we report a markedly reduced influence of previous stimuli on working memory contents, despite preserved memory precision. We then simulated this finding with NMDAR-dependent synaptic alterations in a microcircuit model of prefrontal cortex. Changes in cortical excitation destabilized within-trial memory maintenance and could not account for disrupted serial dependence in working memory. Rather, a quantitative fit between data and simulations supports alterations of an NMDAR-dependent memory mechanism operating on longer timescales, such as short-term potentiation.

Clinical significance of anti-NMDAR concurrent with glial or neuronal surface antibodies.

OBJECTIVE: To determine the frequency and significance of concurrent glial (glial-Ab) or neuronal-surface (NS-Ab) antibodies in patients with anti-NMDA receptor (NMDAR) encephalitis. METHODS: Patients were identified during initial routine screening of a cohort (C1) of 646 patients consecutively diagnosed with anti-NMDAR encephalitis and another cohort (C2) of 200 patients systematically rescreened. Antibodies were determined with rat brain immunostaining and cell-based assays. RESULTS: Concurrent antibodies were identified in 42 patients (4% from C1 and 7.5% from C2): 30 (71%) with glial-Ab and 12 (29%) with NS-Ab. Glial-Ab included myelin oligodendrocyte glycoprotein (MOG) (57%), glial fibrillary acidic protein (GFAP) (33%), and aquaporin 4 (AQP4) (10%). NS-Ab included AMPA receptor (AMPAR) (50%), GABAa receptor (GABAaR) (42%), and GABAb receptor (8%). In 39 (95%) of 41 patients, concurrent antibodies were detected in CSF, and in 17 (41%), concurrent antibodies were undetectable in serum. On routine clinical-immunologic studies, the presence of MOG-Ab and AQP4-Ab was suggested by previous episodes of encephalitis or demyelinating disorders (8, 27%), current clinical-radiologic features (e.g., optic neuritis, white matter changes), or standard rat brain immunohistochemistry (e.g., AQP4 reactivity). GFAP-Ab did not associate with distinct clinical-radiologic features. NS-Ab were suggested by MRI findings (e.g., medial temporal lobe changes [AMPAR-Ab], or multifocal cortico-subcortical abnormalities [GABAaR-Ab]), uncommon comorbid conditions (e.g., recent herpesvirus encephalitis), atypical tumors (e.g., breast cancer, neuroblastoma), or rat brain immunostaining. Patients with NS-Ab were less likely to have substantial recovery than those with glial-Ab (5 of 10 [50%] vs 17 of 19 [89%], p = 0.03). CONCLUSIONS: Between 4% and 7.5% of patients with anti-NMDAR encephalitis have concurrent glial-Ab or NS-Ab. Some of these antibodies (MOG-Ab, AQP4-Ab, NS-Ab) confer additional clinical-radiologic features and may influence prognosis.

Sleep disorders in anti-NMDAR encephalitis.

OBJECTIVE: To describe the sleep disorders in anti-NMDA receptor encephalitis (anti-NMDARe). METHODS: Patients recovering from anti-NMDARe were invited to participate in a prospective observational single-center study including comprehensive clinical, video-polysomnography (V-PSG) sleep assessment, and neuropsychological evaluation. Age- and sex-matched healthy participants served as controls. RESULTS: Eighteen patients (89% female, median age 26 years, interquartile range [IQR] 21-29 years) and 21 controls (81% female, median age 23 years, IQR 18-26 years) were included. In the acute stage, 16 (89%) patients reported insomnia and 2 hypersomnia; nightmares occurred in 7. After the acute stage, 14 (78%) had hypersomnia. At study admission (median 183 days after disease onset, IQR 110-242 days), 8 patients still had hypersomnia, 1 had insomnia, and 9 had normal sleep duration. Patients had more daytime sleepiness than controls (higher Barcelona Sleepiness Index, p = 0.02, and Epworth Sleepiness Score, p = 0.04). On V-PSG, sleep efficiency was similar in both groups, but patients more frequently had multiple and longer confusional arousals in non-REM (NREM) sleep (videos provided). In addition, 13 (72%) patients had cognitive deficits; 12 (67%) had psychological, social, or occupational disability; and 33% had depression or mania. Compared with controls, patients had a higher body mass index (median 23.5 [IQR 22.3-30.2] vs 20.5 [19.1-21.1] kg/m2; p = 0.007). Between disease onset and last follow-up, 14 (78%) patients developed hyperphagia, and 6 (33%) developed hypersexuality (2 requiring hospitalization), all associated with sleep dysfunction. CONCLUSIONS: Sleep disturbances are frequent in anti-NMDARe. They show a temporal pattern (predominantly insomnia at onset; hypersomnia during recovery), are associated with behavioral and cognitive changes, and can occur with confusional arousals during NREM sleep.

Hashimoto encephalopathy in the 21st century.

OBJECTIVE: To report the presenting syndromes and to determine whether pretreatment criteria of Hashimoto encephalopathy (HE) predict response to steroids. METHODS: We assessed symptoms and steroid responsiveness in 24 patients with pretreatment criteria of HE, including (1) subacute onset of cognitive impairment, psychiatric symptoms, or seizures; (2) euthyroid status or mild hypothyroidism; (3) serum thyroid peroxidase antibodies (TPOAb) >200 IU/mL; (4) absent neuronal antibodies in serum/CSF; and (5) no other etiologies. Additional studies included determination of TPOAb (>200 IU/mL) in 74 patients with criteria of possible autoimmune encephalitis (AE) without neuronal antibodies and 205 patients with different neuroimmunologic diseases, psychosis, or new-onset refractory status epilepticus (NORSE). Serum antibodies to the amino (ΝΗ2)-terminal of α-enolase (NH2-α-enolaseAb) were examined in the indicated 24 patients and 13 controls. RESULTS: The 24 patients (14 women) with suspected HE had a median age of 48 years (range 8-79 years). Four syndromes were identified: psychiatric (7, 29%), encephalopathy (7, 29%), NORSE-like (6, 25%), and limbic encephalitis (4, 17%). Only 6 of 19 (31.6%) patients completely responded to steroids. The frequency of TPOAb in the 74 patients with possible AE (6 of 74, 8.1%) was similar to that of the 205 controls (17 of 205, 8.2%; p = 0.84). NH2-α-enolaseAb were identified in 1 of 24 suspected HE cases and 1 of 13 controls. CONCLUSION: Current pretreatment criteria of HE do not predict steroid responsiveness. The detection of TPOAb across all control groups reveals their poor disease-specificity. NH2-α-enolaseAb did not help in the diagnosis of HE. These findings imply a redefinition of HE that requires a systematic exclusion of antibody-mediated encephalitis.

Telemedicine assessment of long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 encephalitis.

OBJECTIVE: To assess the feasibility of a structured telephone interview examining the long-term cognitive and functional status in anti-leucine-rich, glioma-inactivated 1 (LGI1) encephalitis. METHODS: Telephone interviews were conducted with 37 patients after a median follow-up of 87 months from disease onset and 23 healthy controls matched for age and sex. Cognitive status was assessed with the telephone Mini-Mental State Examination (t-MMSE) and 3 tests exploring verbal memory, fluency, and executive function. Functional status was evaluated with the Functional Activities Questionnaire and the modified Rankin Scale (mRS). Patients were classified as normal, with mild cognitive impairment (MCI), or with dementia based on cognitive and functional status. Assessment of the cognitive reserve was performed with a structured questionnaire. Logistic regression analysis was applied to identify predictors of cognitive impairment. RESULTS: Telephone interviews were successful in 36/37 (97%) patients. Cognitive impairment was detected in 27 (75%) including 17 with MCI and 10 with dementia. Eight (29%) patients would have been misclassified using only the t-MMSE. Twenty-six (72%) patients were functionally independent according to the mRS, but only 9 (35%) were cognitively normal. Independent predictors for long-term cognitive impairment were a low cognitive reserve (OR = 1.36, 95% CI: 1.05-1.76; p = 0.02) and bilateral hippocampal hyperintensity at initial MRI (OR = 27.03, 95% CI: 1.87-390; p = 0.02). CONCLUSIONS: Telemedicine is a feasible tool to assess the cognitive and functional outcome in patients with anti-LGI1 encephalitis. Cognitive impairment is often missed if only functional scales are used. Premorbid cognitive reserve and MRI with bilateral hippocampal hyperintensity were predictors for long-term cognitive impairment.

Rebound of multiple sclerosis activity after fingolimod withdrawal due to planning pregnancy: Analysis of predisposing factors.

BACKGROUND: Rebound of multiple sclerosis (MS) activity has been described after the withdrawal of high-efficacy drugs, but its impact during pregnancy is less known. We describe a series of cases of rebound syndrome after the cessation of fingolimod due to pregnancy planning. METHODS: The clinical and radiological data of 7 MS patients who discontinued fingolimod therapy between May 2012 and March 2018 to plan a pregnancy was analysed. RESULTS: Three (42.8%) of the 7 patients experienced a rebound effect, all of whom became pregnant. During pregnancy, the 3 patients had a mean (SD) of 5.3 (1.3) relapses, and 13 of the 15 relapses were treated with intravenous steroids and/or immunoglobulin. These patients experienced a median increase of 3 points in the Expanded Disability Status Scale (range, 2-4), as well as a median increase of 27 new gadolinium-enhancing lesions (range, 9-40) and 38 new T2 lesions in a post-partum MRI (range, 21-70). The 3 pregnancies resulted in the delivery of healthy babies. A strong correlation was found between the lymphocyte count at fingolimod onset and the annual relapse rate in the period without therapy (r= -0.84, p = 0.005). The time to first relapse was shorter in patients who had <300/µl lymphocytes at fingolimod onset (median time 46 vs 426 days, p = 0.010). CONCLUSION: Rebound activity after fingolimod suspension represents a severe long-lasting inflammatory syndrome that may affect up to 40% of female MS patient who discontinue therapy due to pregnancy planning. Lymphopenia (<300/µl) in the first 3 months of fingolimod onset may predispose patients to suffer earlier and higher disease activity upon cessation.

Associations of paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte glycoprotein antibodies: a multicentre observational study.

BACKGROUND: Investigations of myelin oligodendrocyte glycoprotein (MOG) antibodies are usually focused on demyelinating syndromes, but the entire spectrum of MOG antibody-associated syndromes in children is unknown. In this study, we aimed to determine the frequency and distribution of paediatric demyelinating and encephalitic syndromes with MOG antibodies, their response to treatment, and the phenotypes associated with poor prognosis. METHODS: In this prospective observational study, children with demyelinating syndromes and with encephalitis other than acute disseminated encephalomyelitis (ADEM) recruited from 40 secondary and tertiary centres in Spain were investigated for MOG antibodies. All MOG antibody-positive cases were included in our study, which assessed syndromes, treatment and response to treatment (ie, number of relapses), outcomes (measured with the modified Rankin scale [mRS]), and phenotypes associated with poor prognosis. We used Fisher's exact and Wilcoxon rank sum tests to analyse clinical features, and survival Cox regression to analyse time to antibody negativity. FINDINGS: Between June 1, 2013, and Dec 31, 2018, 239 children with demyelinating syndromes (cohort A) and 296 with encephalitis other than ADEM (cohort B) were recruited. 116 patients had MOG antibodies, including 94 (39%) from cohort A and 22 (7%) from cohort B; 57 (49%) were female, with a median age of 6·2 years (IQR 3·7-10·0). Presenting syndromes in these 116 patients included ADEM (46 [68%]), encephalitis other than ADEM (22 [19%]), optic neuritis (20 [17%]), myelitis (13 [11%]), neuromyelitis optica spectrum disorders (six [5%]), and other disorders (nine [8%]). Among the patients with autoimmune encephalitis in cohort B (n=64), MOG antibodies were more common than all neuronal antibodies combined (22 [34%] vs 21 [33%]). After a median follow-up of 42 months (IQR 22-67), 33 (28%) of the 116 patients had relapses, including 17 (17%) of 100 diagnosed at first episode. Steroids, intravenous immunoglobulin, or plasma exchange were used in 100 (86%) patients at diagnosis, and 32 (97%) of 33 at relapses. Rituximab was mainly used at relapses (11 [33%]). 99 (85%) of 116 patients had substantial recovery (mRS <2) and 17 (15%) moderate to severe deficits (mRS >2; one died). Phenotypes of poor prognosis included ADEM-like relapses progressing to leukodystrophy-like features, and extensive cortical encephalitis evolving to atrophy. Time to antibody negativity was longer in patients with relapses (HR 0·18, 95% CI 0·05-0·59). INTERPRETATION: The spectrum of paediatric MOG antibody-associated syndromes is wider than previously reported and includes demyelinating syndromes and encephalitis. Recognition of these disorders has important clinical and prognostic implications. FUNDING: Mutua Madrileña Foundation; ISCIII-Subdirección General de Evaluación y Fomento de la Investigación Sanitaria; Fondo Europeo de Desarrollo Regional; Pediatrics Spanish Society; Departament de Salut, Generalitat de Catalunya; Marato TV3 Foundation; Red Española de Esclerosis Múltiple; La Caixa Foundation; and Fundació CELLEX.

Late-onset neuromyelitis optica spectrum disorder: The importance of autoantibody serostatus.

OBJECTIVE: To describe the clinical features of late-onset (≥50 years) neuromyelitis optica spectrum disorder (LO-NMOSD), to compare the outcome with that of early-onset (EO-NMOSD), and to identify predictors of disability. METHODS: A retrospective, multicenter study of 238 patients with NMOSD identified by the 2015 criteria. Clinical and immunologic features of patients with LO-NMOSD were compared with those with EO-NMOSD. All patients were evaluated for aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) antibodies. RESULTS: Sixty-nine (29%) patients had LO-NMOSD. Demographic features, initial disease presentation, annualized relapse rate, and frequency of AQP4-IgG and MOG-IgG did not differ between patients with LO-NMOSD and EO-NMOSD. Among patients with AQP4-IgG or double seronegativity, those with LO-NMOSD had a higher risk to require a cane to walk (hazard ratio [HR], 2.10, 95% CI 1.3-3.54, p = 0.003 for AQP4-IgG, and HR, 13.0, 95% CI 2.8-59.7, p = 0.001, for double seronegative). No differences in outcome were observed between patients with MOG-IgG and LO-NMOSD or EO-NMOSD. Older age at onset (for every 10-year increase, HR 1.63, 95% CI 1.35-1.92 p < 0.001) in NMOSD, and higher disability after the first attack (HR 1.68, 95% CI 1.32-2.14, p < 0.001), and double seronegativity (HR 3.74, 95% CI 1.03-13.6, p = 0.045) in LO-NMOSD were the main independent predictors of worse outcome. CONCLUSIONS: Patients with LO-NMOSD have similar clinical presentation but worse outcome than EO-NMOSD when they are double seronegative or AQP4-IgG positive. Serostatus and residual disability after first attack are the main predictors of LO-NMOSD outcome.

Clinical and pathogenic significance of IgG, IgA, and IgM antibodies against the NMDA receptor.

OBJECTIVE: To determine the frequency and clinical relevance of immunoglobulin (Ig)G, IgA, and IgM N-methyl-d-aspartate receptor (NMDAR) antibodies in several diseases, and whether the IgG antibodies occur in disorders other than anti-NMDAR encephalitis. METHODS: Evaluation of IgG, IgA, and IgM NMDAR antibodies in serum of 300 patients with anti-NMDAR encephalitis, stroke, dementia, schizophrenia, or seronegative autoimmune encephalitis. Antibodies and their effect on cultured neurons were examined with cell-based assays and brain and live neuronal immunostaining. Retrospective analysis of the clinical diagnoses of a cohort of 1,147 patients with IgG NMDAR antibodies identified since 2005. RESULTS: Among the 300 patients studied, IgG NMDAR antibodies were only identified in those with anti-NMDAR encephalitis and all reacted with brain and live neurons. By cell-based assay, IgA or IgM antibodies were detected in 22 of 300 patients (7%) with different diseases, but only 10 (3%) reacted with brain and 7 (2%) with live neurons. In cultured neurons, IgG but not IgA or IgM antibodies caused a decrease of synaptic and extrasynaptic NMDAR. Among the cohort of 1,147 patients with IgG NMDAR antibodies, 1,015 (88.5%) had anti-NMDAR encephalitis, 45 (3.9%) a limited form of the disease, 41 (3.6%) autoimmune post-herpes simplex encephalitis, 37 (3.2%) overlapping syndromes (anti-NMDAR encephalitis and demyelinating disease), and 9 (0.8%) atypical encephalitic syndromes; none had schizophrenia. CONCLUSIONS: IgG NMDAR antibodies are highly specific for anti-NMDAR encephalitis and cause a decrease of the levels of NMDAR. In contrast, IgA or IgM antibodies occur infrequently and nonspecifically in other diseases and do not alter the receptor levels.

Frequency, symptoms, risk factors, and outcomes of autoimmune encephalitis after herpes simplex encephalitis: a prospective observational study and retrospective analysis.

BACKGROUND: Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication. METHODS: We did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis. FINDINGS: Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years [IQR 5-68]). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine [64%] had NMDA receptor [NMDAR] antibodies and five [36%] had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio [OR] 11·5, 95% CI 2·7-48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years [IQR 1·1-44·2]; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 [58%] of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days [IQR 24-32] vs 43 days [25-54]; p=0·0073), choreoathetosis (27 [100%] of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 [96%] of 27 vs seven [23%] of 31; p<0·001), NMDAR antibodies (24 [89%] of 27 vs 19 [61%] of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 [IQR 4-4] vs 2 [2-3]; p<0·0010; seizures 12 [63%] of 19 vs three [13%] of 23; p=0·001). INTERPRETATION: The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy. FUNDING: Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.

Antibody-associated CNS syndromes without signs of inflammation in the elderly.

OBJECTIVE: To report the CNS syndromes of patients ≥60 years of age with antibodies against neuronal surface antigens but no evidence of brain MRI and CSF inflammatory changes. METHODS: This was a retrospective clinical analysis of patients with antibodies against neuronal surface antigens who fulfilled 3 criteria: age ≥60 years, no inflammatory abnormalities in brain MRI, and no CSF pleocytosis. Antibodies were determined with reported techniques. RESULTS: Among 155 patients ≥60 years of age with neurologic syndromes related to antibodies against neuronal surface antigens, 35 (22.6%) fulfilled the indicated criteria. The median age of these 35 patients was 68 years (range 60-88 years). Clinical manifestations included faciobrachial dystonic seizures (FBDS) in 11 of 35 (31.4%) patients, all with LGI1 antibodies; a combination of gait instability, brainstem dysfunction, and sleep disorder associated with IgLON5 antibodies in 10 (28.6%); acute confusion, memory loss, and behavioral changes suggesting autoimmune encephalitis (AE) in 9 (25.7%; 2 patients with AMPAR, 2 with NMDAR, 2 with GABAbR, 2 with LGI1, and 1 with CASPR2 antibodies); and rapidly progressive cognitive deterioration in 5 (14.3%; 3 patients with IgLON5 antibodies, 1 with chorea; 1 with DPPX antibody-associated cerebellar ataxia and arm rigidity; and 1 with CASPR2 antibodies). CONCLUSIONS: In patients ≥60 years of age, the correct identification of characteristic CNS syndromes (FBDS, anti-IgLON5 syndrome, AE) should prompt antibody testing even without evidence of inflammation in MRI and CSF studies. Up to 15% of the patients developed rapidly progressive cognitive deterioration, which further complicated the differential diagnosis with a neurodegenerative disorder.