The role of immunoglobulin in cerebrospinal fluid on the differential diagnosis of autoimmune encephalitis and viral encephalitis in children.

BACKGROUND: A case-control study was conducted to analyze the role of cerebrospinal fluid immunoglobulin in the differential diagnosis of autoimmune encephalitis and viral encephalitis in children. METHODS: One hundred and twenty patients with autoimmune encephalitis (AE) treated in our hospital from February 2021 to February 2022 were included as the observation group (AE group). 100 patients with viral encephalitis (VE group) were selected as the control group. The clinical data of all patients were collected and analyzed retrospectively. Immunoglobulin G (IgG) and immunoglobulin A (IgA)in cerebrospinal fluid of the two patients were measured by immune turbidimetry. Immunoglobulin M (IgM), and the diagnostic value of immunoglobulin in cerebrospinal fluid (CSF) in patients with AE was analyzed by receiver working curve (ROC). RESULTS: The level of IgG in the cerebrospinal fluid of the AE group was higher than that of the VE group, and the level of IgM was lower than that of the VE group, and the difference was statistically significant (P < 0.05). There was no significant difference in IgA levels between the two groups (P > 0.05). In terms of Magnetic Resonance (MR) features, the paraventricular, hippocampal, occipital and parietal lobes were more involved in AE patients, frontal and temporal lobes were more involved in VE patients, and paraventricular and occipital lobes were involved in MS. The proportion of bilateral extensive lesions in both groups was significantly higher than 50%. The proportions of patients in the AE group involving the lateral ventricle, insula, and parietal lobes were significantly higher than those in the VE group, and the proportions involving the basal ganglia, temporal lobes, and frontal lobes were significantly lower than those in the VE group, and the differences were statistically significant (All P < 0.05). The Area Under Curve (AUC) of IgG, IgA and IgM alone in the diagnosis of AE were 0.795(0.587-0.762), 0.602(0.502-0.631) and 0.627(0.534-0.708), respectively with the sensitivity values of 81.24% and 65.608, respectively and the specificity values of 65.08%, 57.54% and 75.01% respectively. The AUC of IgA + IgM in the diagnosis of AE was 0.733(0.617-0.849), and the sensitivity and specificity are 62.58% and 75.07% respectively. The AUC of IgA + IgG in the diagnosis of AE was 0.823(0.730-0.917), and the sensitivity and specificity were 81.24% and 67.54% respectively. The AUC of IgG + IgM in the diagnosis of AE was 0.886(0.814 ~ 0.958), and the sensitivity and specificity were 84.48% and 77.59% respectively. The AUC of IgA + IgM + IgG in the diagnosis of AE was 0.924 (0.868-0.981) with the sensitivity of 93.82%, and the specificity of 77.56%. CONCLUSION: The level of immunoglobulin in cerebrospinal fluid can be used as an effective reference index for the diagnosis of AE. The combined detection of IgA, IgM and IgG can improve the accuracy, sensitivity and specificity of AE.

Paraneoplastic Calmodulin Kinase-Like Vesicle-Associated Protein (CAMKV) Autoimmune Encephalitis.

OBJECTIVES: To report an autoimmune paraneoplastic encephalitis characterized by immunoglobulin G (IgG) antibody targeting synaptic protein calmodulin kinase-like vesicle-associated (CAMKV). METHODS: Serum and cerebrospinal fluid (CSF) samples harboring unclassified antibodies on murine brain-based indirect immunofluorescence assay (IFA) were screened by human protein microarray. In 5 patients with identical cerebral IFA staining, CAMKV was identified as top-ranking candidate antigen. Western blots, confocal microscopy, immune-absorption, and mass spectrometry were performed to substantiate CAMKV specificity. Recombinant CAMKV-specific assays (cell-based [fixed and live] and Western blot) provided additional confirmation. RESULTS: Of 5 CAMKV-IgG positive patients, 3 were women (median symptom-onset age was 59 years; range, 53-74). Encephalitis-onset was subacute (4) or acute (1) and manifested with: altered mental status (all), seizures (4), hyperkinetic movements (4), psychiatric features (3), memory loss (2), and insomnia (2). Paraclinical testing revealed CSF lymphocytic pleocytosis (all 4 tested), electrographic seizures (3 of 4 tested), and striking MRI abnormalities in all (mesial temporal lobe T2 hyperintensities [all patients], caudate head T2 hyperintensities [3], and cortical diffusion weighted hyperintensities [2]). None had post-gadolinium enhancement. Cancers were uterine adenocarcinoma (3 patients: poorly differentiated or neuroendocrine-differentiated in 2, both demonstrated CAMKV immunoreactivity), bladder urothelial carcinoma (1), and non-Hodgkin lymphoma (1). Two patients developed encephalitis following immune checkpoint inhibitor cancer therapy (atezolizumab [1], pembrolizumab [1]). All treated patients (4) demonstrated an initial response to immunotherapy (corticosteroids [4], IVIG [2]), though 3 died from cancer. INTERPRETATION: CAMKV-IgG is a biomarker of immunotherapy-responsive paraneoplastic encephalitis with temporal and extratemporal features and uterine cancer as a prominent oncologic association. ANN NEUROL 2024;96:21-33.

Limitations of a Commercial Assay as Diagnostic Test of Autoimmune Encephalitis.

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 GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR 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, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

Prozone phenomenon observed in indirect immunofluorescence assay by antibodies against neuronal antigens.

A marked prozone effect was observed in indirect immunofluorescence with human sera and human cerebrospinal fluid in two clinical cases involving breast carcinoma with paraneoplastic neuronal antibodies, and anti- N-methyl-D-aspartic acid (NMDA) receptor antibodies. Anti-Yo antibodies and anti-NMDA antibodies were not detectable under high concentrations (1:10 serum dilution and neat CSF respectively) but showed a true effect when sufficiently diluted at 1:80 and 1:5 respectively. This paper demonstrates that prozone effects have their occurrences in indirect immunofluorescence, and clinicians and laboratory technicians should be wary of its implications during screening of autoantibody markers in neurological diseases.

Searching for autoimmune encephalitis: Beware of normal CSF.

OBJECTIVE: To determine the prevalence of cerebrospinal fluid (CSF) markers associated with inflammation (i.e., elevated white blood cell count, protein concentration, and CSF-specific oligoclonal bands) in patients with early active autoimmune encephalitis (AE). METHODS: CSF characteristics, including WBC count, protein concentration, and oligoclonal banding, were analyzed in patients diagnosed with AE at two tertiary care centers. RESULTS: Ninety-five patients were included in the study. CSF white blood cell counts and protein levels were within normal limits for 27% (CI95%: 19-37) of patients with AE. When results of oligoclonal banding were added, 14% (CI95%: 6-16) of patients with AE had "normal" CSF. The median CSF white blood cell count was 8 cells/mm3 (range: 0-544) and the median CSF protein concentration was 0.42 g/L (range: 0.15-3.92). CONCLUSIONS: White blood cell counts and protein levels were within normal limits in the CSF of a substantial proportion of patients with early active AE. Inclusion of CSF oligoclonal banding identified a higher proportion of patients with an inflammatory CSF profile, especially when CSF was sampled early in the disease process.

Glial fibrillary acidic protein (GFAP) associated autoimmune meningoencephalitis in a patient receiving nivolumab.

Immune checkpoint inhibitors (ICIs) represent a major development in cancer treatment, allowing for improved survival and disease control in an expanding number of cancer types. Due to their mechanism of disrupting immunologic homeostasis, ICIs are frequently associated with adverse effects, termed immune related adverse effects (irAE). These side effects can affect any organ system, including the central and peripheral nervous systems. We present a case of a 47 year old man with stage IIIc metastatic melanoma who received 3 cycles of nivolumab (a monoclonal antibody inhibitor of programmed cell death protein 1 (PD-1)). After completing the third cycle, he presented with a meningoencephalitis clinical picture with an inflammatory cerebrospinal fluid (CSF) and normal MRI. He was found to have a positive anti-glial fibrillary acidic protein (GFAP) autoantibody in his CSF by immunofluorescent assay (IFA) and cell based assay (CBA) which confirmed a diagnosis of anti-GFAP autoimmune encephalitis. He was treated with immunotherapy and made a full recovery. In this report, we present the first reported case of anti-GFAP autoimmune encephalitis associated with ICI therapy and provide a brief review of the literature.

Human Cerebrospinal Fluid Monoclonal LGI1 Autoantibodies Increase Neuronal Excitability.

OBJECTIVE: Leucine-rich glioma-inactivated 1 (LGI1) encephalitis is the second most common antibody-mediated encephalopathy, but insight into the intrathecal B-cell autoimmune response, including clonal relationships, isotype distribution, frequency, and pathogenic effects of single LGI1 antibodies, has remained limited. METHODS: We cloned, expressed, and tested antibodies from 90 antibody-secreting cells (ASCs) and B cells from the cerebrospinal fluid (CSF) of several patients with LGI1 encephalitis. RESULTS: Eighty-four percent of the ASCs and 21% of the memory B cells encoded LGI1-reactive antibodies, whereas reactivities to other brain epitopes were rare. All LGI1 antibodies were of IgG1, IgG2, or IgG4 isotype and had undergone affinity maturation. Seven of the overall 26 LGI1 antibodies efficiently blocked the interaction of LGI1 with its receptor ADAM22 in vitro, and their mean LGI1 signal on mouse brain sections was weak compared to the remaining, non-ADAM22-competing antibodies. Nevertheless, both types of LGI1 antibodies increased the intrinsic cellular excitability and glutamatergic synaptic transmission of hippocampal CA3 neurons in slice cultures. INTERPRETATION: Our data show that the patients' intrathecal B-cell autoimmune response is dominated by LGI1 antibodies and that LGI1 antibodies alone are sufficient to promote neuronal excitability, a basis of seizure generation. Fundamental differences in target specificity and antibody hypermutations compared to the CSF autoantibody repertoire in N-methyl-D-aspartate receptor encephalitis underline the clinical concept that autoimmune encephalitides are very distinct entities. Ann Neurol 2020;87:405-418.

Autoimmune encephalitis with psychosis: Warning signs, step-by-step diagnostics and treatment.

Objectives: Despite intensive research, schizophrenia and schizoaffective disorders continue to be theoretical constructs that describe clinical syndromes and no pathophysiologically defined diseases. Moreover, there are no clear biomarkers at hand. Therefore, these diagnoses are still set up based on clinical ICD-10/DSM-5 criteria and the exclusion of alcohol-/drug-associated, systemic or other brain organic causes.Methods: Recently, autoimmune encephalitis with psychotic symptoms caused by specific antineuronal antibodies has been identified as a rare, but potentially treatable differential diagnosis. However, these inflammatory brain diseases are not reliably detected by our current routine diagnostic workup in psychiatry. This qualitative review provides structured diagnostic and therapeutic support for clinical practice.Results: Disturbances of consciousness and orientation, catatonia, speech dysfunction, focal neurological signs, epileptic seizures/EEG abnormalities or autonomic dysfunction are warning signs in psychiatric patients which should always induce cerebrospinal fluid analysis with determination of antineuronal autoantibodies. Currently established immunotherapy strategies are summarised, taking into account international expert advice.Conclusions: Guided by clinical warning signs, our qualitative review enables rapid and reliable diagnosis of definite autoimmune encephalitis. This is of high relevance for the affected individuals, since early and sufficiently intense immunotherapy often leads to a good prognosis despite severe illness.

Differential Diagnosis of Autoimmune Encephalitis from Infectious Lymphocytic Encephalitis by Analysing the Lymphocyte Subsets of Cerebrospinal Fluid.

This study is aimed at investigating the lymphocyte subsets of cerebrospinal fluid (CSF) to provide possible differential diagnostic values and better understand the pathophysiological mechanism underlying autoimmune encephalitis (AE) and infectious lymphocytic encephalitis. A series of CD markers, including CD3/4/8/20 representing different types and developmental stages of lymphocytes, were used to count the corresponding subpopulations of CSF from clinical and laboratory confirmed cases of anti-N-methyl-D-aspartate receptor AE (NMDAR-AE), herpes simplex virus encephalitis (HSVE), and tuberculous meningitis (TBM). The percentages of lymphocytes observed and the CD4 : CD8 ratios were compared between the three groups. There were no significant differences of the percentage of total lymphocytes, CD3 cells, and CD4 cells of CSF among each group. However, there were strongly statistical differences of the CD4 : CD8 ratio in CSF of each group with 0.6 : 1 in NMDAR-AE, 0.9 : 1 in HSVE, and 3.2 : 1 in TBM. The percentage of CD20 B lymphocytes in NMDAR-AE was statistically higher than that of other groups. The distinct percentages of lymphocyte subpopulations of CSF appeared to be characteristic and could potentially serve as diagnostic indicators. Further verification and research will be necessary to clarify the significance and nature of CD4 : CD8 ratios and B lymphocytes in CSF between AE and the infectious lymphocytic encephalitis.

Differences and diversity of autoimmune encephalitis in 77 cases from a single tertiary care center.

BACKGROUND: The incidence of autoimmune encephalitis has risen globally. There are two general categories of disease-associated antibodies that can be tested for: neuronal surface and intracellular. However, testing both groups of autoantibodies are costly. This study aims to identify differences between groups by comparing clinical presentations, radiological findings and CSF profile of patients, and determine if any parameters are indicative of one group of autoantibodies over another. Additionally, we aim to report the local incidence of less common groups of disease-associated antibodies as well. METHODS: Seventy-seven records of autoimmune encephalitis/encephalomyelitis patients admitted to King Chulalongkorn Memorial Hospital, Bangkok, Thailand, between October 2010 and February 2017 were reviewed. Patients with infections or those with classic central nervous system demyelinating features were excluded. RESULTS: Of 77 patients, 40% presented with neuronal surface antibodies and 33% had intracellular antibodies. The most common autoantibody detected in each group was anti-NMDAr antibody (25/31, 81%) and anti-Ri antibody (7/25, 28%) respectively. In the neuronal surface antibody group, behavioral change was the most common complaint (45%), followed by seizures (39%) and abnormal movements (29%). In the latter group, seizure was the most common presenting symptom (32%), followed by motor weakness (20%), behavioural change (16%) and abnormal movements (16%). Patients with neuronal surface antibodies were younger (35 vs 48 years old, p = 0.04) and more likely to present with behavioral change (45% vs 16%, p = 0.02). Mortality rate was higher in the intracellular group (16% vs 3.2%, p = 0.09). No differences were detected in magnetic resonance imaging (MRI) and CSF profile. CONCLUSIONS: In the early stages of the disease, both groups have comparable clinical outcomes. Although there were significant differences in age and percentage of patients with behavioral change, both groups of autoimmune encephalitis still shared many clinical features and could not be distinguished based on MRI and CSF profiles. Therefore, we recommend that patients with features of autoimmune encephalitis should be screened for both the neuronal surface and intracellular antibodies regardless of clinical presentation.

Neuronal damage and neuroinflammation markers in patients with autoimmune encephalitis and multiple sclerosis.

Inflammatory diseases of the central nervous system (CNS) are a diagnostic challenge to clinicians. Autoimmune encephalitis (AE) is an important diagnostic consideration in patients with CNS inflammatory disorders; despite of a wide range of neuropsychiatric symptoms it should be diagnosed as soon as possible and the patient transferred to the neurologist. We studied a group of AE patients (n = 24) as compared to multiple sclerosis (MS, n = 61) and control (n = 19) groups. Detailed clinical pictures of patients are presented. We focused on relevant cerebrospinal fluid (CSF) tests like protein levels, cytosis and oligoclonal bands, neuroinflammation indices (interleukin-6, soluble receptor of IL-6, neopterin, anti-ribosomal proteins antibodies) and markers of neurodegeneration (phosphorylated neurofilament heavy chain, pNfh). Elevated neopterin level was found in AE group as compared to the MS and control groups, while protein and pNfh were increased in both AE and MS groups. In the MS group, the cytosis and soluble receptor of IL-6 were higher as compared to the control group. Anti-ribosomal proteins antibodies were increased in a single patient with AE. High levels of protein were predictive of mortality in AE patients, while IL-6 and pNfh were elevated in severe AE patients. AE patients with paraneoplastic etiology demonstrated oligoclonal bands positivity. Taken together, our results suggest the neopterin as an additional marker of autoimmune brain inflammation. Though higher levels of protein, IL-6 and pNfh were found in patients with severe disease progression and death, prognostic values of these markers should be validated in larger cohorts of patients.

Elevated Adenosine Deaminase Levels in the Cerebrospinal Fluid in Immune Checkpoint Inhibitor-induced Autoimmune Encephalitis.

Immune checkpoint inhibitors (ICIs) are promising drugs for various cancers. However, immune activation by ICIs can lead to immune-related adverse events (irAEs). Autoimmune encephalitis is a rare irAE, and its clinical features remain unknown. We herein report two patients with ICI-associated autoimmune encephalitis who, saliently, showed elevated adenosine deaminase (ADA) levels in the cerebrospinal fluid (CSF). This is the first report of increased ADA levels in the CSF of patients with ICI-induced autoimmune encephalitis. Although the mechanism of the ADA increase is poorly understood, elevated ADA in the CSF may be informative in the diagnosis of this rare disorder.

Serum and CSF neurofilament light chain levels in antibody-mediated encephalitis.

Circulating and cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels represent a reliable indicator of disease activity and axonal damage in different neuroinflammatory conditions. Recently, high CSF NfL levels have been detected in active autoimmune encephalitis, as opposed to significant lower levels after clinical improvement. The aim of the present study was to evaluate serum and CSF NfL concentration in patients with autoimmune encephalitis and to analyse the association between NfL levels and clinical, MRI, and CSF data. We retrospectively included 25 patients with neurological syndromes associated with autoantibodies to neuronal cell surface antigens and we collected clinical, MRI, CSF, and follow-up data. Using an ultrasensitive method (Simoa, Quanterix), we measured NfL levels in serum and CSF samples of all patients and in 25 sera of healthy controls. Serum NfL levels were higher in all cases, including 20 patients with inflammatory MRI/CSF features and 5 non-inflammatory cases (median 16.9 pg/ml, range 4.5-90) than in controls (median 6.9 pg/ml, range 2.7-12.8; p < 0.001). A correlation between serum and CSF NfL levels was found (r = 0.461, p = 0.023), whereas no significant association was observed between NfL levels and clinical, MRI/CSF inflammatory burden, and antibody type. In the 13 available follow-up samples, correlation between disease activity and NfL values was also observed. In conclusion, NfL levels are significantly increased in the serum of patients with antibody-mediated encephalitis, independently of the MRI/CSF inflammatory profile. These findings support the presence of ongoing axonal damage and suggest the co-occurrence of different mechanisms for neuronal/axonal involvement in antibody-associated CNS syndromes.

Diagnostic tools for immune causes of encephalitis.

BACKGROUND: Autoimmune encephalitis (AE) refers to a central nervous system (CNS) antibody-mediated entity characterized by a rapid onset behavioural and cognitive decline that can be associated with movement disorders, epileptic and dysautonomic features. Interestingly, it is thought to be as common as its infectious disease counterpart and can share some clinical, radiological, and laboratory findings. OBJECTIVES: The aim is to describe the main clinical features of AE caused by antibodies targeting cell-surface neuronal agents and the diagnostic means to identify them. Paraneoplastic syndromes, associated with intracellular antibodies, will not be tackled in this review. SOURCES: PubMed/MEDLINE were the sources. CONTENT: According to a recent population-based study, autoimmunity is one of the most frequent cause of encephalitis after infectious agents. Its diagnosis lies upon 'classic' clinical features, which are dominated by neuropsychiatric symptoms and epileptic seizures. Cerebral spinal fluid (CSF) and serum autoantibody testing can confirm AE. Complementary examination with magnetic resonance imaging (MRI) and electroencephalogram (EEG) may be helpful for excluding other causes and managing seizures. In addition, exclusion of infectious and other origins must be considered. IMPLICATIONS: AE misdiagnosis can lead to a delay in treatment onset and, thus, clinical worsening. In this sense, identifying the causative agent is of utmost importance. However, the absence of CSF or serum antibody detection does not exclude the diagnosis of AE. Despite extensive testing, many encephalitis cases remain of unknown origin. It is obvious that some autoantibodies have not yet been identified in AE. Since radiological and biological examinations are not always contributive, early symptom recognition might help to hasten the diagnostic process.

Encephalitis Associated to Metabotropic Glutamate Receptor 5 (mGluR5) Antibodies in Cerebrospinal Fluid.

A 68-years-old Hispanic man, complained of night sweats, low grade fewer, unexplained weight loss, and memory problems over 3 months. Abdominal tomography showed multiple intra-abdominal adenopathy and biopsy confirmed classic Hodgkin's lymphoma. He commenced treatment with chemotherapy. Three months later, he had acute onset of inattention, auditory hallucinations and alterations of anterograde memory. The patient developed psychomotor agitation, unresponsive to a combination of neuroleptics and benzodiazepines. Brain MRI showed a small established cerebellar infarction. Electroencephalogram was normal. Tests for toxic metabolic encephalopathy were negative. One oligoclonal IgG bands was found in the Cerebrospinal fluid (CSF), which was not observed in corresponding serum, but cell count and protein were normal. Extensive testing for infectious encephalitis was unremarkable. CSF testing for commercially available neural and non-neural autoantibodies was negative. The patient fulfilled the Gultekin diagnostic criteria for paraneoplastic limbic encephalitis and methylprednisolone IV 1g/d for 5 days was given. He recovered rapidly, with progressive improvement in memory and psychomotor agitation. After treatment commenced, results for antibodies to mGluR5 in CSF taken prior to treatment were returned as positive. mGluR5 is found on post-synaptic terminals of neurons and microglia and is expressed primarily in the hippocampus and amygdala. This case highlights the difficulties in diagnosing this type of encephalitis: the CSF did not show pleocytosis, the MRI showed only chronic change and the electroencephalogram was normal. The dramatic recovery after methylprednisolone help to better characterized the clinical spectrum of auto-immune encephalitis. Diagnosing anti mGlutR5 encephalitis may lead to potentially highly effective treatment option and may anticipate the diagnostic of a cancer. A high index of suspicion is needed to avoid missed diagnosis. In patients with unexplained encephalitis, testing for antibodies to mGluR5 in CSF and serum should be considered. When there is a reasonable index of suspicion of auto-immune encephalitis, treatment should not be delayed for the antibody results.

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.

Positive Allosteric Modulation as a Potential Therapeutic Strategy in Anti-NMDA Receptor Encephalitis.

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENT Anti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.

Anti-N-Methyl-D-aspartate Receptor Encephalitis: A Severe, Potentially Reversible Autoimmune Encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is potentially lethal, but it is also a treatable autoimmune disorder characterized by prominent psychiatric and neurologic symptoms. It is often accompanied with teratoma or other neoplasm, especially in female patients. Anti-NMDAR antibodies in cerebrospinal fluid (CSF) and serum are characteristic features of the disease, thereby suggesting a pathogenic role in the disease. Here, we summarize recent studies that have clearly documented that both clinical manifestations and the antibodies may contribute to early diagnosis and multidisciplinary care. The clinical course of the disorder is reversible and the relapse could occur in some patients. Anti-NMDAR encephalitis coexisting with demyelinating disorders makes the diagnosis more complex; thus, clinicians should be aware of the overlapping diseases.