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Anti-leucine-rich glioma-inactivated protein 1 (LGI1) encephalitis is an autoimmune disorder that can be treated with immunotherapy, but the symptoms that remain after treatment have not been well described. We aimed to characterise the clinical features of patients with anti-LGI1 encephalitis for 1 year starting within the first year after initial immunotherapy. For this prospective cohort study, we recruited patients with anti-LGI1 encephalitis as soon as possible after they had received conventional immunotherapy for initial symptoms; patients were recruited from 21 hospitals in Spain. Patients were excluded if they had an interval of more than 1 year since initial immunotherapy, had pre-existing neurodegenerative or psychiatric disorders, or were unable to travel to Hospital Clínic de Barcelona (Barcelona, Spain). Patients visited Hospital Clínic de Barcelona on three occasions—the first at study entry (visit 1), the second 6 months later (visit 2), and the third 12 months after the initial visit (visit 3). They underwent neuropsychiatric and videopolysomnography assessments at each visit. Healthy participants who were matched for age and sex and recruited from Hospital Clínic de Barcelona underwent the same investigations at study entry and at 12 months. Cross-sectional comparisons of clinical features between groups were done with conditional logistic regression, and binary logistic regression was used to assess associations between cognitive outcomes at 12 months and clinical features before initial immunotherapy and at study entry. Between May 1, 2019, and Sept 30, 2022, 42 participants agreed to be included in this study. 24 (57%) participants had anti-LGI1 encephalitis (mean age 63 years [SD 12]; 13 [54%] were female and 11 [46%] were male) and 18 (43%) were healthy individuals (mean age 62 years [10]; 11 [61%] were female and seven [39%] were male). At visit 1 (median 88 days [IQR 67–155] from initiation of immunotherapy), all 24 patients had one or more symptoms; 20 (83%) patients had cognitive deficits, 20 (83%) had psychiatric symptoms, 14 (58%) had insomnia, 12 (50%) had rapid eye movement (REM)-sleep behaviour disorder, nine (38%) had faciobrachial dystonic seizures, and seven (29%) had focal onset seizures. Faciobrachial dystonic seizures were unnoticed in four (17%) of 24 patients and focal onset seizures were unnoticed in five (21%) patients. At visit 1, videopolysomnography showed that 19 (79%) patients, but no healthy participants, had disrupted sleep structure (p=0·013); 15 (63%) patients and four (22%) healthy participants had excessive fragmentary myoclonus (p=0·039), and nine (38%) patients, but no healthy participants, had myokymic discharges (p=0·0051). These clinical and videopolysomnographic features led to additional immunotherapy in 15 (63%) of 24 patients, which resulted in improvement of these features in all 15 individuals. However, at visit 3, 13 (65%) of 20 patients continued to have cognitive deficits. Persistent cognitive deficits at visit 3 were associated with no use of rituximab before visit 1 (odds ratio [OR] 4·0, 95% CI 1·5–10·7; p=0·0015), REM sleep without atonia at visit 1 (2·2, 1·2–4·2; p=0·043), and presence of LGI1 antibodies in serum at visit 1 (11·0, 1·1–106·4; p=0·038). Unsuspected but ongoing clinical and videopolysomnography alterations are common in patients with anti-LGI1 encephalitis during the first year or more after initial immunotherapy. Recognising these alterations is important as they are treatable, can be used as outcome measures in clinical trials, and might influence cognitive outcome. Fundació La Caixa.

Patients with coronavirus disease 2019 (COVID-19) frequently develop acute encephalopathy and encephalitis, but whether these complications are the result from viral-induced cytokine storm syndrome or anti-neural autoimmunity is still unclear. In this study, we aimed to evaluate the diagnostic and prognostic role of CSF and serum biomarkers of inflammation (a wide array of cytokines, antibodies against neural antigens, and IgG oligoclonal bands), and neuroaxonal damage (14-3-3 protein and neurofilament light [NfL]) in patients with acute COVID-19 and associated neurologic manifestations (neuro-COVID). We prospectively included 60 hospitalized neuro-COVID patients, 25 (42%) of them with encephalopathy and 14 (23%) with encephalitis, and followed them for 18 months. We found that, compared to healthy controls (HC), neuro-COVID patients presented elevated levels of IL-18, IL-6, and IL-8 in both serum and CSF. MCP1 was elevated only in CSF, while IL-10, IL-1RA, IP-10, MIG and NfL were increased only in serum. Patients with COVID-associated encephalitis or encephalopathy had distinct serum and CSF cytokine profiles compared with HC, but no differences were found when both clinical groups were compared to each other. Antibodies against neural antigens were negative in both groups. While the levels of neuroaxonal damage markers, 14-3-3 and NfL, and the proinflammatory cytokines IL-18, IL-1RA and IL-8 significantly associated with acute COVID-19 severity, only the levels of 14-3-3 and NfL in CSF significantly correlated with the degree of neurologic disability in the daily activities at 18 months follow-up. Thus, the inflammatory process promoted by SARS-CoV-2 infection might include blood-brain barrier disruption in patients with neurological involvement. In conclusion, the fact that the levels of pro-inflammatory cytokines do not predict the long-term functional outcome suggests that the prognosis is more related to neuronal damage than to the acute neuroinflammatory process.

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. 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. 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. 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. 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.

Neurological immune-related adverse events associated with immune checkpoint inhibitors can have several clinical manifestations, but the syndromes and prognostic factors are still not well known. We aimed to characterise and group the clinical features, with a special focus in patients presenting with encephalopathy, and to identify predictors of response to therapy and survival. This retrospective observational study included patients with neurological immune-related adverse events from 20 hospitals in Spain whose clinical information, serum samples, and CSF samples were studied at Hospital Clinic de Barcelona, Barcelona, Spain. Patients with pre-existing paraneoplastic syndromes or evidence of alternative causes for their neurological symptoms were excluded. We reviewed the clinical information, classified their clinical features, and determined the presence of neural antibodies. Neurological status was assessed by the treating physician one month after adverse event onset (as improvement vs no improvement) and at the last evaluation (complete recovery or modified Rankin Scale score decrease of at least 2 points, indicating good outcome, vs all other modified Rankin Scale scores, indicating poor outcome); if the participant had died, the date and cause of death were recorded. We used Fisher's exact tests and Mann-Whitney U tests to analyse clinical features, and multivariable logistic regression to analyse prognostic factors. From Jan 1, 2018, until Feb 1, 2023, 83 patients with suspected neurological immune-related adverse events after use of immune checkpoint inhibitors were identified, of whom 64 patients were included. These patients had a median age of 67 years (IQR 59–74); 42 (66%) were male and 22 (34%) were female. The predominant tumours were lung cancer (30 [47%] patients), melanoma (13 [21%] patients), and renal cell carcinoma (seven [11%] patients). Neural antibodies were detected in 14 (22%) patients; 52 (81%) patients had CNS involvement and 12 (19%) had peripheral nervous system involvement. Encephalopathy occurred in 45 (70%) patients, 12 (27%) of whom had antibodies or well defined syndromes consistent with definite paraneoplastic or autoimmune encephalitis, 24 (53%) of whom had encephalitis without antibodies or clinical features characteristic of a defined syndrome, and nine (20%) of whom had encephalopathy without antibodies or inflammatory changes in CSF or brain MRI. Nine (14%) of 64 patients had combined myasthenia and myositis, five of them with myocarditis. Even though 58 (91%) of 64 patients received steroids and 31 (48%) of 64 received additional therapies, 18 (28%) did not improve during the first month after adverse event onset, and 11 of these 18 people died. At the last follow-up for the 53 remaining patients (median 6 months, IQR 3–13), 20 (38%) had a poor outcome (16 deaths, one related to a neurological immune-related adverse event). Mortality risk was increased in patients with lung cancer (vs those with other cancers: HR 2·5, 95% CI 1·1–6·0) and in patients with encephalopathy without evidence of CNS inflammation or combined myocarditis, myasthenia, and myositis (vs those with the remaining syndromes: HR 5·0, 1·4–17·8 and HR 6·6, 1·4–31·0, respectively). Most neurological immune-related adverse events involved the CNS and were antibody negative. The presence of myocarditis, myasthenia, and myositis, of encephalopathy without inflammatory changes, or of lung cancer were independent predictors of death. Most deaths occurred during the first month of symptom onset. If our findings are replicated in additional cohorts, they could confirm that these patients need early and intensive treatment. The Instituto de Salud Carlos III and the European Union.

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABA B R (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABA B R or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABA B R antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABA B R or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

The usefulness of current diagnostic approaches in children with suspected autoimmune encephalitis is unknown. We aimed to assess the diagnosis of autoimmune encephalitis in clinical practice and to compare the performance of two international diagnostic algorithms (one intended for patients of any age [general], the other intended for paediatric patients), with particular emphasis on the evaluation of patients with probable antibody-negative autoimmune encephalitis because this diagnosis suggests that immunotherapy should be continued or escalated but is difficult to establish. We did a prospective cohort study that included all patients (<18 years of age) with suspected autoimmune encephalitis recruited at 40 hospitals in Spain whose physicians provided clinical information every 6 months for 2 years or more. Neural antibody testing to confirm diagnosis of antibody-positive autoimmune encephalitis was done at Institut d’Investigacions Biomèdiques August Pi i Sunyer-Hospital Clínic, Barcelona. Patients were classified according to the most probable diagnosis at last follow-up into four prespecified categories. We used multivariable logistic analysis to assess a potential association between immunotherapy and outcome in individuals with probable antibody-negative autoimmune encephalitis. We also did a retrospective analysis of agreement, assessed with the kappa index, between diagnoses made according to the general and paediatric diagnostic algorithms. Between June 1, 2013, and May 31, 2021, 729 children (mean age 7·1 years [SD 4·9]; 383 boys [53%], 346 girls [47%]) with suspected autoimmune encephalitis were recruited. After a median follow-up of 36 months (IQR 26–60), patients were classified according to their most probable diagnosis: definite autoimmune encephalitis or well defined inflammatory or autoimmune disorders (n=230 [32%]); CNS infections (n=112 [15%]); inflammatory CNS disorders of unknown cause (n=81 [11%], including three (4%) with a novel Klüver-Bucy-like syndrome; and non-inflammatory disorders (n=306 [42%]), which were predominantly epileptic or psychiatric disorders (177 [58%] of 306). Neural antibodies were detected in 150 (65%) of 230 patients who had definite autoimmune encephalitis; 127 (85%) of these 150 individuals had antibodies to the NMDA receptor or myelin oligodendrocyte glycoprotein (MOG). Agreement between algorithms was excellent (kappa index 0·99, 95% CI 0·97–1·00) for the diagnosis of children with antibody-positive autoimmune encephalitis, good (0·59, 0·54–0·65) for recommendations of empiric immunotherapy, and poor (0·29, 0·21–0·37) for the diagnosis of probable antibody-negative autoimmune encephalitis. Compared with the general algorithm, the paediatric algorithm included more patients in the probable antibody-negative autoimmune encephalitis category (173 vs 41). These patients included some of those who had a diagnosis of CNS inflammatory disorder of unknown cause at the last follow-up (80 of 81 with the paediatric algorithm vs 31 of 81 with the general algorithm), who might have benefitted from immunotherapy, and some of those diagnosed with a non-inflammatory disorder at the last follow-up (47 of 306 with the paediatric algorithm vs six of 306 with the general algorithm), who did not need immunotherapy. About a third of children with suspected autoimmune encephalitis eventually had confirmation of this diagnosis, or diagnosis of another well defined inflammatory disorder. Frequent mimics of autoimmune encephalitis were infectious, epileptic, and psychiatric disorders. Both algorithms performed well in the diagnosis of antibody-positive autoimmune encephalitis, but the paediatric algorithm under-recognised definite autoimmune encephalitis that can occur without autoantibodies and might have overdiagnosed patients with probable antibody-negative autoimmune encephalitis. By contrast, the general algorithm might have underdiagnosed patients with probable antibody-negative autoimmune encephalitis. Given that the diagnosis of probable antibody-negative autoimmune encephalitis has treatment implications, inaccuracies on this diagnostic category leads to overuse or underuse of immunotherapy. Instituto de Salud Carlos III, Fundació Clínic per la Recerca Biomèdica, The Edmond J Safra Foundation, and la Caixa Foundation. For the Spanish translation of the abstract see Supplementary Materials section.

Detection of Leucine-rich glioma inactivated 1 (LGI1) antibodies in patients with suspected autoimmune encephalitis is important for diagnostic confirmation and prompt implementation of immunomodulatory treatment. However, the clinical laboratory diagnosis can be challenging. Previous reports have suggested that the type of test and patient’s sample (serum or CSF) have different clinical performances, however, there are no studies comparing different diagnostic tests on paired serum/CSF samples of patients with anti-LGI1 encephalitis. Here, we assessed the clinical performance of a commercial and an in house indirect immunofluorescent cell based assays (IIF-CBA) using paired serum/CSF of 70 patients with suspected anti-LGI1 encephalitis and positive rat brain indirect immunohistochemistry (IIHC). We found that all (100%) patients had CSF antibodies when the in house IIF-CBA was used, but only 88 (83%) were positive if the commercial test was used. In contrast, sera positivity rate was higher with the commercial test (94%) than with the in house assay (86%). If both serum and CSF were examined with the commercial IIFA-CBA, 69/70 (98.5%) patients were positive in at least one of the samples. These findings are clinically important for centers in which rat brain IIHC and in house IIFA-CBA are not available. Moreover, the observation that all patients with anti-LGI1 encephalitis have antibodies in CSF is in line with the concept that these antibodies are pathogenic.

Objective We reviewed the psychotic symptoms of anti‐NMDA receptor encephalitis (NMDARE) to differentiate its presentation from those found in a primary psychiatric disorder. We hypothesized that the cycloid psychosis (CP) phenotype would be a frequent clinical presentation in the psychiatric phase of NMDARE. Method A systematic literature review in PubMed of all case reports published on NMDARE was performed from database inception to March 2020. We included all cases where psychotic symptoms were reported and whose diagnoses were confirmed by the presence of anti‐NMDAR antibodies in the cerebrospinal fluid (CSF). An email including a short test (CP phenotype, Perris and Brockington's criteria) was sent to all case report authors asking them to describe the psychotic symptoms. Results We identified 335 case reports fulfilling our criteria, and the authors of 200 replied. Our analyses were based exclusively on those answers and data extracted from the articles. Median patient age was 25 years (+‐11.4), 81% were female, and 39% had an ovarian teratoma. A complete CP phenotype was identified in 175 patients (87%). These were acute psychotic episodes with a sudden onset and a fluctuating clinical pattern mostly characterized by confusion (97%), delusions (75%), hallucinations (69%), motility disturbances (87%), and mood oscillations (80%). Conclusion The complete CP phenotype was frequently the expression of psychotic symptoms in NMDARE. We suggest that patients with a first psychotic episode who initially exhibit the CP phenotype should undergo CSF analysis to determine whether antibodies against neuronal cell surface or synaptic receptors are present to rule out a possible diagnosis of autoimmune encephalitis. It is of the utmost importance to precisely describe the initial psychiatric phenotype of anti‐NMDARE to perform an early diagnosis and to ameliorate prognosis. The complete cycloid psychosis phenotype was a frequent clinical presentation of anti‐NMDA receptor encephalitis cases with psychotic symptoms. This phenotype has an acute and sudden onset and a fluctuating course and is characterized by confusion, delusions, hallucinations, mood swings, and motility disturbances.

The increasing recognition of a new category of encephalitides that occur in association with antibodies against neuronal surface proteins has prompted the use of terms like “autoimmune psychosis” and “autoimmune psychiatric disorders.” However, although psychosis and other psychiatric symptoms can occur in autoimmune encephalitides and systemic autoimmune diseases, evidence for a distinct psychiatric entity beyond these conditions is lacking. A particularly defining condition is anti-NMDA receptor encephalitis, which has been central to promoting concepts such as autoimmune psychosis and autoimmune psychiatric disorders. While anti-NMDA receptor encephalitis can resemble primary psychiatric conditions, certain clinical features often suggest the specific diagnosis. This Review traces the development of the autoimmune psychosis concept and examines the implications of framing it as a separate entity. We discuss leading theories of psychosis and the convergence of the NMDA receptor hypofunction/glutamate hypothesis with anti-NMDA receptor encephalitis mechanisms. The interest generated by such disorders has driven uncontrolled antibody testing in psychiatric populations, often neglecting pretest probability and favoring prevalence over diagnostic specificity. Finally, we highlight the main limitations of current approaches and propose directions for future research.

We studied the relationship between the incidence of coronavirus disease 2019 (COVID-19), demographical, and climatological measurements in different regions across the world. Lower solar irradiance and higher population density were independent predictors of greater COVID-19 outbreaks. Further studies on the potential protective effect of sunlight over COVID-19 are warranted.