Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis

Acta Psychiatrica Scandinavica
Volume 138, Issue 5 p. 401-408

Review

Refining the psychiatric syndrome of anti-N-methyl-d-aspartate receptor encephalitis

N. Warren, D. Siskind, C. O'Gorman
First published: 10 July 2018

Abstract

Objective
To review the psychiatric symptoms of anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, in an attempt to differentiate the presentation from a primary psychiatric disorder.

Method
A systematic literature review of PubMed and EMBASE of all published cases of anti-NMDA receptor encephalitis was performed from inception to January 2018.

Results

There were 706 cases of anti-NMDA receptor encephalitis identified. Cases were typically young (mean age 22.6 years, SD 14.8), female (F : M ratio 3.5 : 1) and presented with significant behavioural disturbance. Reported behaviour was most commonly severe agitation and aggression, abnormal speech, and catatonia. Psychosis occurred in 45.8% of cases. Investigation results were inconsistent (MRI abnormal in 35.6%, EEG abnormal in 83.0%) and non-specific. Psychiatric treatment often required multiple psychotropics, and there may be increased risk of significant side-effects such as neuroleptic malignant syndrome. Prognosis was usually good; however, cognitive and behavioral symptoms remained prominent during recovery, and psychiatrist involvement was required in this period.

Conclusion
The presentation of anti-NMDA receptor encephalitis is variable. However, there are often psychiatric features which are atypical to a primary psychiatric illness, such as severe agitation, speech abnormalities, and catatonia, which may help early identification.

Summations

The most common psychiatric symptoms are agitation/aggression and speech disturbance, with psychosis occurring in less than half of presentations.
Catatonia, especially when fluctuating, is a key feature which may indicate anti-NMDA receptor encephalitis.
When clinically suspected, EEG and MRI can be useful supportive investigations, but lumbar puncture for CSF analysis is required to confirm the diagnosis.

Greater awareness, leading to earlier detection and treatment, may account for differences in results compared with initial descriptions of the disorder.
Future prospective studies which provide greater details of psychiatric symptoms (notably behavioural abnormalities, catatonia, sleep disturbance, and cognition) are required.

Introduction

Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis imbues great interest in psychiatrists, as it can present with symptoms reminiscent of a schizophreniform illness, but those symptoms may completely resolve with immunomodulatory therapy. First described in 2007, it is becoming increasingly recognized and is thought to be the most common autoimmune encephalitis causing psychiatric symptoms. The disorder occurs when the directly pathogenic anti-NMDA receptor antibody binds to the glycine subunit of the NMDA receptor, leading to receptor capping and internalization, causing neuronal dysfunction. Similar to non-competitive NMDA antagonists such as phencyclidine and ketamine, this neuronal dysfunction is thought to result in symptoms through disruption to frontostriatal connections and other neuronal networks.

The disorder most commonly presents acutely with psychiatric symptoms resulting in mental health service involvement. A viral prodrome is seen in around 70%, and there are high rates of concurrent cognitive disturbance such as short-term memory deficits and confusion. The majority of cases develop neurological deterioration, typically within one to 3 weeks of initial presentation. Purely psychiatric cases of anti-NMDA receptor encephalitis are thought to be rare. Movement disorders, seizures, and autonomic disturbance lead to involvement of other medical specialities, with a deterioration in consciousness often requiring intensive care support. Around 50% of cases are associated with tumors, such as ovarian teratoma. In addition to surgical treatment, management is primarily with immune suppression or plasmapheresis.

Large case series have been published that grouped the observed symptoms into broad clusters, such as ‘behavioural’ or ‘psychiatric’. It was later reported that psychiatric presentations were predominantly psychotic or manic in nature. More specific information has not been available to guide psychiatrists seeking to identify the condition early in the disease course, or to differentiate the psychiatric presentation of anti-NMDA receptor encephalitis from a primary psychiatric illness.

Early identification is important as it has been associated with more favorable outcomes. Reaching a diagnosis can be complicated by long turn around times for serum antibody testing, and other tests such as MRI brain and electroencephalogram (EEG), may be normal. These tests, as well as lumbar puncture to obtain CSF confirmation of antibodies, may be difficult to achieve in someone who is acutely psychiatrically unwell.

Aims of the study
We aimed to clarify the psychiatric presentation of anti-N-methyl-d-aspartate receptor encephalitis through a systematic review of all published cases. In particular, the timeline of psychiatric and neurological symptoms, the frequency of psychosis, and features of behavioural deterioration would be highlighted. We hypothesized that there may be specific features of the anti-N-methyl-d-aspartate receptor encephalitis that may differentiate this disorder from a primary psychiatric illness.

Methods
Cases were identified by search of PubMed and EMBASE (Inception to January 2018) with search terms: NMDA, NMDAR, NMDARE, and NMDA encephalitis. The search results were limited to case reports and series, including conference and poster abstracts. Search and screening of abstracts and articles were conducted independently by two authors (NW, CO), and references of selected articles were checked to identify other eligible studies. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations were followed (Fig. 1).

Figure 1. PRISMA 2009 flow diagram: published cases of anti-NMDA receptor encephalitis. From: Moher et al.

Broad inclusion criteria were used to capture all possible presentations of anti-NMDA receptor encephalitis. Cases were included if there was documentation of both a positive IgG NMDA receptor antibody result in either the serum or CSF, as well as any clinical symptoms; below this standard was considered insufficient information. Cases in which a positive result was later obtained from stored serum or CSF (taken at the time of clinical symptoms) were included. Suspected cases that were not confirmed with antibody testing were excluded. Aggregated data from case series were not included. When there was disputed eligibility for inclusion, the case was discussed with all authors and consensus reached.

Data collected included demographics, past medical and psychiatric history, and current comorbidities, suspected trigger and presence of viral prodrome symptoms, initial and subsequent clinical presentation of encephalitis, timing of symptoms, investigations, treatments, and outcomes. Catatonia was not recorded unless explicitly documented. Missing data were noted. Duplicated cases were screened and removed. At this stage, cases with significant active comorbid neurological diagnoses that could complicate the clinical picture were excluded from further analysis. These cases included the following: herpes simplex virus (HSV) encephalitis, Japanese encephalitis, neurosyphilis, demyelinating disorders, and glioblastoma. Additionally, one case receiving chemotherapy for non-Hodgkin's lymphoma was also excluded (Table S1). Four cases were removed that had negative CSF and positive serum antibody, considered to be false-positive results. There were four cases where >1 year elapsed between first presentation and next relevant symptoms. We considered this time period excessive, perhaps representing comorbid conditions or a relapse of anti-NMDA encephalitis that was initially undiagnosed, and these cases were excluded.

To review the type of initial presentation, the progression of symptoms, and overall clinical presentation, the symptoms were grouped as per recognized symptom clusters: behaviour, psychosis, cognition, neurology, seizures, and autonomic. As previous case series have described mood disturbance and anxiety within the behavioural cluster, this convention was maintained, without creating a separate ‘mood/anxiety’ cluster. Doing so also allowed isolation of the psychotic symptoms (delusions and hallucinations) for comparison. A ‘neurology’ cluster was used instead of movement disorders to capture other neurologic manifestations such as ataxia and weakness.

Descriptive statistics were employed for initial analysis of the data. The pre-specified subgroups (teratoma vs no teratoma) were compared by Student's t-test and Fisher's exact test for continuous and nominal variables respectively. P-values for comparison were adjusted by Bonferroni correction, giving P < 0.003 for significance.

Results
There were 882 full-text articles identified in the databases. Following screening at abstract and full-text level, 565 studies with 706 cases were identified between 2007 and 2018 (Fig. 1). The cases excluded from further analysis are summarized in Table S1, resulting in 633 cases for further analysis. There were 492 females and 141 males. The mean age of onset was 22.6 years (SD 14.8), with 253 cases under the age of 18 years and a range of age from 8 months to 84 years (Fig. 2).

A prior psychiatric history was documented in 38 cases (6.0%). In 26 cases, this was suspected to be an earlier presentation of limbic encephalitis either without antibody testing or prior to available testing. A viral prodrome was documented in 133 cases (21.0%). At the time of symptom onset, headache (75 cases) and fever (56 cases) were noted.

Presentation of anti-NMDA receptor encephalitis

The presenting symptom was behavioural in 309 cases (49.0%), seizures in 112 cases (17.8%), psychosis in 105 cases (16.7%), neurological in 65 cases (10.3%), cognitive in 38 cases (6%), and autonomic in one case. The time between the initial presenting symptom and next symptom from a different symptom cluster was mean 18.6 days (SD 31.5). Six cases were initially given a diagnosis of conversion disorder/dissociative seizures, and seven cases were diagnosed with schizophrenia.

During the course of the illness, symptoms in each cluster were present as follows: behaviour – 508 cases (80.3%), neurological – 478 cases (75.5%), seizures – 400 cases (63.2%), autonomic – 325 cases (51.3%), psychosis – 290 cases (45.8%), and cognition – 278 cases (43.9%). Twenty-six cases (4.1%) had isolated psychiatric (behaviour or psychosis clusters) with a female-to-male ratio of 2.7 : 1 and a mean age of 31.5 years (SD 18.2). In 176 cases, the initial presentation was with behavioural disturbance and there was no development of psychosis during the course of the illness (27.8%). The presence of symptoms from all clusters – psychiatric (behaviour or psychosis), neurological, seizures, and autonomic, as initially described in the literature, was seen in 153 cases (24.2%) 4.

The psychiatric symptoms are noted in Table 1. The most common behavioural disturbance was agitated or aggressive behaviour, which occurred in the absence of alcohol or drug intoxication. Abnormal speech was also noted in over half of the cases. Labile mood and anxiety were more frequently reported than mania. The majority of delusions were defined as paranoid. Auditory and visual hallucinations occurred in around the same proportion, yet when visual hallucinations were noted they were the only psychotic phenomena in 43 cases. Catatonia was recorded to be fluctuating in 38 of the 207 cases. There were 83 cases which did not record catatonia but did have either mutism, echolalia, or pathological laughter, suggestive of a catatonic syndrome.

Table 1. Psychiatric symptoms of Anti-NMDA receptor encephalitis
Symptom complex N % of total cases
Abnormal behaviour 80.3%
Agitated/aggressive 55.5%
Odd/bizarre 25.6%
Pathological laughter/crying 12.0%
Withdrawal/decreased 10.9%
Unspecified 9.2%
Impulsivity/hypersexuality 9.2%
Anorexia/weight loss 6.3%
Self-injury 3.3%
Hyperactive/increased 2.1%
Abnormal speech 50.4%
Mute 21.2%
Reduced output 13.9%
Abnormal content 12.6%
Dysarthria 8.8%
Echolalia 5.4%
Increased output 2.2%

Insomnia 23.4%
Hypersomnolence 1.7%
Psychosis 45.8%
Not specified 6.6%
Delusion 20.5%
Paranoid 11.4%
Not specified 5.1%
Grandiose 2.2%
Religious 2.1%
Bizarre 1.3%
Ideas of reference 0.6%
Nihilism 0.5%
Hallucinations 31.3%
Auditory 15.2%
Visual 13.7%
Not specified 8.1%
Other 1.3%
Mood 24.5%
Lability 11.2%
Depression 10.0%
Mania 4.7%
Suicidal ideation 3.5%
Apathy 0.8%
Anxiety 15.0%
Obsessive–compulsive disorder 0.9%
Catatonia 32.7%

Insomnia occurred in 148 cases (23.4%) and hypersomnia in 11 cases (1.7%). Cognitive disturbance was most commonly documented as confusion (117 cases, 18.5%) or sudden/rapid onset memory deficits (102 cases, 16.1%). A deterioration in consciousness occurred in 242 cases (38.2%). The most common movement disturbance was orofacial dyskinesia with other neurological symptoms reported in Table 2.

Table 2. Other features of anti-N-methyl-d-aspartate receptor encephalitis:
Neurological 75.5%
Orofacial dyskinesia 44.7%
Choreoathetoid movements 33.5%
Dystonic movements 15.6%
Ataxia 10.7%
Rigidity 8.2%
Weakness 6.5%
Sensory disturbance 3.9%
Opsoclonus–myoclonus 2.1%
Oculogyric crisis 1.9%
Tremor 1.9%
Seizures 63.2%
Autonomic 51.3%
Respiratory failure 22.0%
Hyperthermia 17.7%
Asystole 2.2%

Investigations
NMDAR antibody testing in both the CSF and serum was performed in 231 cases. For these cases, both CSF and serum were positive in 198 cases. There were 30 cases (13.0% of both tested) with positive CSF and negative serum. Other CSF abnormalities were found in 343 cases (of 449 tested, 76.4%) – documented as lymphocytic pleocytosis (309 cases), high protein (112 cases), and oligoclonal bands (77 cases). MRI brain imaging was abnormal in 182 cases, of 511 tested (35.6%), including T2/FLAIR hyperintensities (182 cases) and atrophy (26 cases). Interestingly, 46 cases with a normal initial MRI documented a subsequent abnormal MRI later in the illness course. EEG was abnormal in 370 cases of 446 tested (83.0%): diffuse slowing (278 cases), seizures (36 cases), and extreme delta brush (34 cases). In 401 cases, both EEG and MRI were performed, and in 340 of these cases (85.0%), at least one test (MRI, EEG, or both) was abnormal.

Psychiatric treatment and recovery
Antipsychotics were used in 159 cases including haloperidol (58 cases, 36.5%), risperidone (41 cases, 25.8%), olanzapine (37 cases, 23.3%), quetiapine (21 cases, 13.2%), and aripiprazole (11 cases, 6.9%). More than one antipsychotic was used in 62 cases (39.0%). Antipsychotics were ceased due to suspected neuroleptic malignant syndrome (NMS) in 42 cases (18 cases treated with multiple antipsychotics, 10 cases haloperidol monotherapy, seven cases risperidone monotherapy, and four cases olanzapine monotherapy). The use of anti-epileptics was inconsistently reported.

Complete recovery was documented in 264 cases (41.7%) and partial recovery in 189 cases (29.9%), with most reporting cognitive deficits (135 cases). This may underestimate the proportion who achieve complete recovery. 91.5% of those cases with partial recovery were followed up for <2 years. There was no recovery or further deterioration in 53 cases (8.4%), including death in 25 cases. The mean time to recovery was reported as 231.5 days (SD 248.4). Recurrence was noted in 43 cases (6.8%).

Teratoma-related anti-NMDA receptor encephalitis
Ovarian teratoma was documented in 178 cases (28.1%) and other malignancies in 28 cases (4.4%). Comparing the cases associated with a teratoma to those where no tumor was identified; the teratoma-associated cases were significantly more likely to present with psychiatric symptoms and have psychosis and autonomic symptoms at some stage during their illness. The time to recovery was shorter in teratoma-associated cases (184.2 days vs 253.3 days), but this finding did not reach statistical significance.

Discussion
The vast majority of anti-NMDA receptor encephalitis cases present with an acute onset of psychiatric symptoms, which have atypical features in comparison with primary psychiatric illness and occur in the absence of a prior identified psychiatric history. There was, however, considerable variability of symptoms between cases and during the disease course. Overall, the demographics and clinical features in these cases were similar to those reported in the large case series. However, fewer than a quarter of cases had the course initially described, involving symptoms from all clusters that of psychiatric, movement, seizures, and autonomic. Since that time, increased awareness may have led to earlier recognition and treatment, which might ameliorate or prevent development of all clinical manifestations.

Psychosis was seen in under half of the cases of anti-NMDA receptor encephalitis, with other symptoms such as agitation/aggression or speech disturbance being more common features. Psychosis was, however, seen at greater rates in the cases with associated ovarian teratoma, which may explain why this presentation, rather than behavioral disturbance, was emphasized in earlier descriptions of the disorder. The increasing recognition and understanding of anti-NMDA receptor encephalitis among psychiatrists have led to routine screening of populations with first-episode psychosis (FEP). The yield from these approaches has been small, possibly due to a narrow focus on psychosis alone. Over one-quarter of the cases identified in this study presented with behavioral disturbance and never developed psychotic symptoms.

Despite the variability in symptoms and the lack of a defining pathognomonic feature such as psychosis, certain characteristics of anti-NMDA receptor encephalitis can help differentiate this disorder from a primary psychiatric illness. Unlike FEP populations, the overwhelming majority of cases are female, even when excluding those associated with an ovarian teratoma. Additionally, over a third of cases were under the age of 18 years. Almost all cases who presented with psychiatric features progressed to having neurological symptoms or autonomic disturbance. It should be borne in mind that orofacial dyskinesia, the most common associated movement disorder, could be misinterpreted as an extrapyramidal side-effect of antipsychotic medication, especially as the average time for progression to further symptoms was at least 2 weeks.

When compared with FEP populations, the anti-NMDA receptor encephalitis cases demonstrated elevated rates of agitation, aggression, and catatonia. Other atypical features include pathological laughter or crying and a rapid onset of memory deficits, which are infrequently noted in primary psychiatric populations. There was a high proportion of cases with visual hallucinations, often in the absence of other psychotic phenomena. Disturbance of speech was more commonly described as reduced output or mutism, compared to abnormal content, that might be expected with a thought disorder. Mood lability and depression, rather than sustained elevated mood, were the most common affective disturbances, although depression may have been misidentified from catatonic withdrawal. Interestingly, catatonia was often noted to be fluctuating, changing from severe agitation to withdrawal and mutism repeatedly. Fluctuation can also be seen in other features of anti-NMDA receptor encephalitis, such as confusion and movement disorder. The phenomena of fluctuation are minimally highlighted in the literature, but potentially may be a useful diagnostic clue.

Psychiatric symptoms were often described as resistant to treatment and required multiple psychotropics. Antipsychotics were ceased in around a quarter of the cases due to concerns for developing NMS, particularly in patients treated with haloperidol or multiple agents. There were no cases of suspected NMS in patients treated with quetiapine. However, signs of NMS (rigidity, fever, and decreased consciousness) may also reflect the natural progression of anti-NMDA receptor encephalitis and were seen in many of cases not treated with psychotropics.

Investigations, such as MRI brain, EEG, and lumbar puncture, may be difficult to accomplish if there are significant aggression and agitation, and there is no current consensus to the utility of these investigations in FEP. However, in the majority of cases, EEG was abnormal. Diffuse slowing, extreme delta brush, and electroencephalographic seizures are not found in primary psychiatric illness and are not caused by treatment with atypical antipsychotics or benzodiazepines. Slowing, and less commonly seizures, is described following prolonged or high-dose treatment with typical antipsychotics or clozapine, but are unlikely findings if EEG is performed early. Without CSF antibody testing, anti-NMDA receptor encephalitis cases may be missed. It is important that lumbar puncture is performed in any suspected case, which may require use of sedation or anesthesia in agitated patients. This is especially relevant since early treatment has been associated with better long-term outcomes. The importance of recognizing an atypical pattern of psychiatric presentation and advocating for further investigations is again highlighted.

There are a number of limitations inherent in the methodology of this study that should be considered. Case reports and case series are subject to reporting and publication bias. Studies were found in journals covering the whole spectrum of health care, such as emergency medicine, gynecology, intensive care, neurology, oncology, psychiatry, and rehabilitation. This reflects the diverse group of physicians who are involved in the care of those with anti-NMDA receptor encephalitis but also may lead to difficulties describing psychiatric symptoms. Available clinical data may be incomplete or tainted by ‘what is already known’. Potentially new observations may be downplayed or omitted. For this analysis, omission was considered equivalent to absence. These simplifications were necessary given the source material, but potentially limit clinical application of our findings. For example, cases reporting some catatonic symptoms (such as mutism, echolalia, or pathological laughter) were not considered to have catatonia unless this was explicitly documented, which likely underemphasized the importance of catatonia to differentiation of anti-NMDA receptor encephalitis. Similarly, cognition and insomnia were poorly reported and potentially represent salient diagnostic features. Describing the evolution of clinical symptoms that occur with disease progression was not possible since accurate timelines were mostly unavailable.

This is the largest systematic review of cases of anti-NMDA receptor encephalitis. Similar to previous published case series, we find that the presentation is most commonly psychiatric (behavioral or psychosis). However, there is a diverse range of symptoms within the psychiatric clusters that may not have been previously appreciated. Suggestive features for anti-NMDA receptor encephalitis include rapid onset of psychiatric symptoms in a person without prior psychiatric history, agitation and aggression, mood lability, visual hallucinations, halting speech or mutism, and catatonia. Although not definitive, an abnormal EEG or MRI brain can assist the treating doctor, and when abnormal, CSF testing for NMDA receptor antibody should be obtained. Further prospective studies should include careful evaluation of psychiatric symptoms of the disorder.