Frequency and Characteristics of Isolated Psychiatric Episodes in Anti-N-Methyl-D-Aspartate Receptor Encephalitis
TL;DR: In patients with new-onset psychosis, having a history of encephalitis, subtle neurological symptoms, and/or abnormal results on ancillary tests should prompt screening for NMDAR antibodies.
Abstract: IMPORTANCE: Patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis often develop prominent psychiatric manifestations. The frequency and type of isolated psychiatric episodes (pure psychiatric symptoms without neurological involvement) either as initial presentation of the disease or as relapse are unknown. OBJECTIVE: To determine the frequency, symptoms, and outcome of isolated psychiatric episodes in a cohort of patients with anti-NMDAR encephalitis. DESIGN, SETTING, AND PARTICIPANTS: Observational cohort of patients diagnosed during a 5-year period (median follow-up, 2 years). A total of 571 patients with IgG antibodies against the NR1 subunit of the NMDAR were included in the study. Antibody studies were performed at the University of Pennsylvania and the University of Barcelona, and clinical information was obtained by us or referring physicians. MAIN OUTCOMES AND MEASURES: Frequency, type of symptoms, and outcome of patients with anti-NMDAR encephalitis and isolated psychiatric manifestations. RESULTS: Of 571 patients, 23 (4%) developed isolated psychiatric episodes, 5 at disease onset and 18 during relapse. For all 23 patients, age (median, 20 years), sex (91%female), and tumor association (43%; ovarian teratoma in all cases) were similar to the population at large. Predominant symptoms included delusional thinking (74%), mood disturbances (70%, usually manic), and aggression (57%). Brain magnetic resonance imaging findings were abnormal in 10 of 22 patients (45%) and cerebrospinal fluid analysis showed pleocytosis in 17 of 22 patients (77%). Eighty-three percent of the patients had full or substantial recovery after immunotherapy and tumor resection when appropriate. After relapse, 17 of 18 patients (94%) returned to a similar or better prerelapse functional level. CONCLUSIONS AND RELEVANCE: Isolated psychiatric episodes are rare but can occur as initial onset or relapse of anti-NMDAR encephalitis. Recognition of these episodes is important because they respond to immunotherapy. In patients with new-onset psychosis, having a history of encephalitis, subtle neurological symptoms, and/or abnormal results on ancillary tests should prompt screening for NMDAR antibodies.
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TL;DR: The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum, and antibody titres were higher in patients with poor outcome than in those with good outcome, emphasising the importance of including CSF in antibody studies, and that antibody titre can complement clinical assessments.
Abstract: Summary Background Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is a severe but treatable autoimmune disorder which diagnosis depends on sensitive and specific antibody testing. We aimed to assess the sensitivity and specificity of serum and CSF antibody testing in patients with anti-NMDA receptor encephalitis, and the relation between titres, relapses, outcome, and epitope repertoire. Methods In this observational study, we used rat brain immunohistochemistry and cell-based assays (CBA) with fixed or live NMDA receptor-expressing cells to determine the sensitivity and specificity of antibody testing in paired serum and CSF samples. Samples were obtained at diagnosis from patients with anti-NMDA receptor encephalitis and from control participants worldwide. We deemed a patient to be antibody positive if their serum, their CSF, or both tested positive with both immunohistochemistry and CBA techniques; we determined titres with serial sample dilution using brain immunohistochemistry. We examined samples from 45 patients (25 with good outcome [modified Rankin Scale, mRS 0–2], ten with poor outcome [mRS 3–6], and ten with relapses) at three or more timepoints. We determined the epitope repertoire in the samples of 23 patients with CBA expressing GluN1-NMDA receptor mutants. Findings We analysed samples from 250 patients with anti-NMDA receptor encephalitis and 100 control participants. All 250 patients had NMDA receptor antibodies in CSF but only 214 had antibodies in serum (sensitivity 100·0% [98·5–100·0%] vs 85·6% [80·7–89·4%], p vs 129, difference 211, [95% CI 1–421], p=0·049; serum dilution 7370 vs 1243, difference 6127 [2369–9885], p=0·0025), and in patients with teratoma than in those without teratoma (CSF 395 vs 110, difference 285 [134–437], p=0·0079; serum 5515 vs 1644, difference 3870 [548–7193], p=0·024). Over time there was a decrease of antibody titres in the 35 patients with good or poor outcome and samples followed at three timepoints regardless of outcome (from diagnosis to last follow-up: CSF 614 to 76, difference 538 [288–788]; serum 5460 to 1564, difference 3896 [2428–5362]; both p vs seven of 16, p=0·037). After recovery, 24 of 28 CSF samples and 17 of 23 serum samples from patients remained antibody positive. Patients' antibodies targeted a main epitope region at GluN1 aminoacid 369; the epitope repertoire did not differ between patients with different outcomes, and did not change during relapses. Interpretation The sensitivity of NMDA receptor antibody testing is higher in CSF than in serum. Antibody titres in CSF and serum were higher in patients with poor outcome or teratoma than in patients with good outcome or no tumour. The titre change in CSF was more closely related with relapses than was that in serum. These findings emphasise the importance of including CSF in antibody studies, and that antibody titres can complement clinical assessments. Funding Dutch Cancer Society, National Institutes of Health, McKnight Neuroscience of Brain Disorders award, the Fondo de Investigaciones Sanitarias, ErasmusMC fellowship, and Fundacio la Marato de TV3.
710 citations
TL;DR: Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy, and future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
Abstract: The identification of anti-NMDA receptor (NMDAR) encephalitis about 12 years ago made it possible to recognise that some patients with rapidly progressive psychiatric symptoms or cognitive impairment, seizures, abnormal movements, or coma of unknown cause, had an autoimmune disease. In this disease, autoantibodies serve as a diagnostic marker and alter NMDAR-related synaptic transmission. At symptom onset, distinguishing the disease from a primary psychiatric disorder is challenging. The severity of symptoms often requires intensive care. Other than clinical assessment, no specific prognostic biomarkers exist. The disease is more prevalent in women (with a female to male ratio of around 8:2) and about 37% of patients are younger than 18 years at presentation of the disease. Tumours, usually ovarian teratoma, and herpes simplex encephalitis are known triggers of NMDAR autoimmunity. About 80% of patients improve with immunotherapy and, if needed, tumour removal, but the recovery is slow. Animal models have started to reveal the complexity of the underlying pathogenic mechanisms and will lead to novel treatments beyond immunotherapy. Future studies should aim at identifying prognostic biomarkers and treatments that accelerate recovery.
418 citations
TL;DR: The process of discovery of these diseases is traced, describing the triggers and symptoms related to each autoantigen, and the structural and functional alterations caused by the autoantibodies are reviewed with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals.
Abstract: Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all...
394 citations
Erasmus University Rotterdam1, University of Barcelona2, Medical University of Vienna3, Kitasato University4, University of Hamburg5, Hospital of the University of Pennsylvania6, McMaster Children's Hospital7, Boston Children's Hospital8, Harvard University9, Pali Momi Medical Center10, Kindai University11, University College London12, National Defense Medical College13, Pontifical Catholic University of Chile14, University of Tokyo15, Innsbruck Medical University16, Catalan Institution for Research and Advanced Studies17
TL;DR: In this paper, the authors report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.
Abstract: Objective
To report the clinical, radiological, and immunological association of demyelinating disorders with anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis.
Methods
Clinical and radiological analysis was done of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4), and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays.
Results
Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent magnetic resonance imaging (MRI) and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of neuromyelitis optica (NMO) spectrum disorder (5 cases, 4 anti-AQP4 positive) or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4 positive, 2 MOG positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis; NMDAR antibodies were detected only in the 50 anti-NMDAR patients, MOG antibodies in 3 of 50 anti-NMDAR and 1 of 56 NMO patients, and AQP4 antibodies in 48 of 56 NMO and 1 of 50 anti-NMDAR patients (p < 0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1 of 23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18 of 50 anti-NMDAR controls (p = 0.011).
Interpretation
Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (eg, dyskinesias, psychosis) may have anti-NMDAR encephalitis. Ann Neurol 2014;75:411–428
386 citations
TL;DR: Findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibodies-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
Abstract: Anti-N-methyl D-aspartate receptor (NMDAR) encephalitis is a severe neuropsychiatric disorder that associates with prominent memory and behavioural deficits. Patients’ antibodies react with the N-terminal domain of the GluN1 (previously known as NR1) subunit of NMDAR causing in cultured neurons a selective and reversible internalization of cell-surface receptors. These effects and the frequent response to immunotherapy have suggested an antibody-mediated pathogenesis, but to date there is no animal model showing that patients’ antibodies cause memory and behavioural deficits. To develop such a model, C57BL6/J mice underwent placement of ventricular catheters connected to osmotic pumps that delivered a continuous infusion of patients’ or control cerebrospinal fluid (flow rate 0.25 µl/h, 14 days). During and after the infusion period standardized tests were applied, including tasks to assess memory (novel object recognition in open field and V-maze paradigms), anhedonic behaviours (sucrose preference test), depressive-like behaviours (tail suspension, forced swimming tests), anxiety (black and white, elevated plus maze tests), aggressiveness (resident-intruder test), and locomotor activity (horizontal and vertical). Animals sacrificed at Days 5, 13, 18, 26 and 46 were examined for brain-bound antibodies and the antibody effects on total and synaptic NMDAR clusters and protein concentration using confocal microscopy and immunoblot analysis. These experiments showed that animals infused with patients’ cerebrospinal fluid, but not control cerebrospinal fluid, developed progressive memory deficits, and anhedonic and depressive-like behaviours, without affecting other behavioural or locomotor tasks. Memory deficits gradually worsened until Day 18 (4 days after the infusion stopped) and all symptoms resolved over the next week. Accompanying brain tissue studies showed progressive increase of brain-bound human antibodies, predominantly in the hippocampus (maximal on Days 13–18), that after acid extraction and characterization with GluN1-expressing human embryonic kidney cells were confirmed to be against the NMDAR. Confocal microscopy and immunoblot analysis of the hippocampus showed progressive decrease of the density of total and synaptic NMDAR clusters and total NMDAR protein concentration (maximal on Day 18), without affecting the post-synaptic density protein 95 (PSD95) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. These effects occurred in parallel with memory and other behavioural deficits and gradually improved after Day 18, with reversibility of symptoms accompanied by a decrease of brain-bound antibodies and restoration of NMDAR levels. Overall, these findings establish a link between memory and behavioural deficits and antibody-mediated reduction of NMDAR, provide the biological basis by which removal of antibodies and antibody-producing cells improve neurological function, and offer a model for testing experimental therapies in this and similar disorders.
357 citations
Cites background from "Frequency and Characteristics of Is..."
...Approximately 75% of patients with anti-NMDAR encephalitis present with mood and psychiatric alterations ranging from manic or depressive behaviour to psychosis, often followed by stereotyped movements, seizures, or decreased level of consciousness (Kayser et al., 2013; Titulaer et al., 2013)....
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References
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TL;DR: A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis and the pathogenesis of the disorder seems to be mediated by antibodies.
Abstract: Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.
2,604 citations
Hospital of the University of Pennsylvania1, University of Barcelona2, California Department of Public Health3, Kitasato University4, Columbia University5, University of Toronto6, Niigata University7, Autonomous University of Barcelona8, Children's Hospital of Philadelphia9, Catalan Institution for Research and Advanced Studies10
TL;DR: Most patients with anti-NMDAR encephalitis respond to immunotherapy; second-line immunotherapy is usually effective when first-line treatments fail, and outcomes continued to improve for up to 18 months after symptom onset.
Abstract: Summary Background Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder in which the use of immunotherapy and the long-term outcome have not been defined. We aimed to assess the presentation of the disease, the spectrum of symptoms, immunotherapies used, timing of improvement, and long-term outcome. Methods In this multi-institutional observational study, we tested for the presence of NMDAR antibodies in serum or CSF samples of patients with encephalitis between Jan 1, 2007, and Jan 1, 2012. All patients who tested positive for NMDAR antibodies were included in the study; patients were assessed at symptom onset and at months 4, 8, 12, 18, and 24, by use of the modified Rankin scale (mRS). Treatment included first-line immunotherapy (steroids, intravenous immunoglobulin, plasmapheresis), second-line immunotherapy (rituximab, cyclophosphamide), and tumour removal. Predictors of outcome were determined at the Universities of Pennsylvania (PA, USA) and Barcelona (Spain) by use of a generalised linear mixed model with binary distribution. Results We enrolled 577 patients (median age 21 years, range 8 months to 85 years), 211 of whom were children ( Interpretation Most patients with anti-NMDAR encephalitis respond to immunotherapy. Second-line immunotherapy is usually effective when first-line treatments fail. In this cohort, the recovery of some patients took up to 18 months. Funding The Dutch Cancer Society, the National Institutes of Health, the McKnight Neuroscience of Brain Disorders award, The Fondo de Investigaciones Sanitarias, and Fundacio la Marato de TV3.
2,226 citations
TL;DR: Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation, which reveals a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.
Abstract: Since its discovery in 2007, the encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) has entered the mainstream of neurology and other disciplines. Most patients with anti-NMDAR encephalitis develop a multistage illness that progresses from psychosis, memory deficits, seizures, and language disintegration into a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. The disorder predominantly affects children and young adults, occurs with or without tumour association, and responds to treatment but can relapse. The presence of a tumour (usually an ovarian teratoma) is dependent on age, sex, and ethnicity, being more frequent in women older than 18 years, and slightly more predominant in black women than it is in white women. Patients treated with tumour resection and immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) respond faster to treatment and less frequently need second-line immunotherapy (cyclophosphamide or rituximab, or both) than do patients without a tumour who receive similar initial immunotherapy. More than 75% of all patients have substantial recovery that occurs in inverse order of symptom development and is associated with a decline of antibody titres. Patients' antibodies cause a titre-dependent, reversible decrease of synaptic NMDAR by a mechanism of crosslinking and internalisation. On the basis of models of pharmacological or genetic disruption of NMDAR, these antibody effects reveal a probable pathogenic relation between the depletion of receptors and the clinical features of anti-NMDAR encephalitis.
1,966 citations
"Frequency and Characteristics of Is..." refers background in this paper
...F/20 X NA X + + Delusions, depression (1) Steroids, IVIg; (2) RTX; (3) MMF ....
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...F/16 X + + Aggression, catatonic mania (1) Steroids, IVIg Equal Substantial (>75%), 39...
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...F/13 X + + Aggression, AVH, delusions, suicidality (1) Steroids (initial); (2) steroids; (3) IVIg; (4) RTX, CTX; (5) MMF (relapses) Worse Substantial (>75%), 72...
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...F/12 X + − Aggression, delusions, disinhibition, echolalia (1) Steroids, IVIg (initial); (2) plasmapheresis, CTX, RTX, MMF (relapses) Equal Full, 46...
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...F/18 X X + + X Delusions, AVH, hyperphagia (1) Steroids, IVIg ....
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TL;DR: To report the clinical features of anti–N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis in patients ≤ 18 years old.
Abstract: Anti–N-methyl-D-aspartate receptor (NMDAR) encephalitis is a recently described disorder with a well defined set of clinical features.1 The associated syndrome has been characterized in adults, frequently young women with teratomas of the ovary who develop changes of mood, behavior, and personality, resembling acute psychosis. The clinical picture usually progresses to include seizures, decreased level of consciousness, dyskinesias, autonomic instability, and hypoventilation.2–5 Despite the severity of the disorder, patients often improve with immunotherapy and removal of the teratoma.1,3,6 These findings and the discovery that all patients have serum and cerebrospinal fluid (CSF) antibodies that react with the cell surface of neurons suggested an immune-mediated pathogenesis.1,7,8 Further studies demonstrated that the target antigen of patients’ antibodies was the NR1 subunit of the NMDAR. Additionally, application of antibodies into cultures of hippocampal neurons resulted in a significant decrease of postsynaptic NMDAR clusters that was reversed after antibody removal.9 A recent series of 100 patients showed that the disorder also occurs in patients without teratoma, and that men and children can be affected. Since then the number of pediatric cases diagnosed at our institution or whose serum and CSF were referred for immunological studies has steadily increased.9 Although this may suggest that in children the phenotype is as characteristic as that of the adults, there are in fact differences in tumor association, neurological presentation, and frequency of symptoms. To facilitate the recognition of this disorder in children, we report eight patients diagnosed over an 8-month period at the Children's Hospital of Philadelphia (CHOP) and review the general clinical features of 24 pediatric cases from other institutions.
943 citations
TL;DR: Overall, the data support a model in which the early features of N-methyl-d-aspartate receptor encephalopathy are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands, which is associated with restriction to the first stage.
Abstract: Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.
889 citations
"Frequency and Characteristics of Is..." refers background in this paper
...F/20 X NA X + + Delusions, depression (1) Steroids, IVIg; (2) RTX; (3) MMF ....
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...F/13 X + + Aggression, AVH, delusions, suicidality (1) Steroids (initial); (2) steroids; (3) IVIg; (4) RTX, CTX; (5) MMF (relapses) Worse Substantial (>75%), 72...
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...F/12 X + − Aggression, delusions, disinhibition, echolalia (1) Steroids, IVIg (initial); (2) plasmapheresis, CTX, RTX, MMF (relapses) Equal Full, 46...
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...F/24 X X + − X Aggression, delusions, mania (1) IVIg; (2) steroids, RTX Equal Full, 20...
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...M/19 X X X + NA Aggression, delusions, mania (1) Steroids; (2) AZA ....
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