Serum and CSF Anti-NMDAR Antibody Testing in Psychiatry

Ethical approval for this study was granted from Metro South Addiction and Mental Health Services Human Research and Ethics Committee. A retrospective chart review of a statewide cohort of anti-NMDAR-Ab-positive cases was performed in Queensland, Australia, up to and including December 2018. Since 2010, all NMDAR Ab testing for the state has been performed in a single laboratory (Pathology Queensland, Brisbane, Queensland, Australia), which is a diagnostic referral laboratory offering specialized neuroimmunology testing. Anti-NMDA Abs are detected through a two-person blinded reading of a commercial fixed-cell assay containing four biochips of primate hippocampus, primate cerebellum, NR1-transfected human embryonic kidney 293 (HEK293) cells, and nontransfected control HEK293 cells (Euroimmun, Lübeck, Germany). Two neuroimmunology clinics in the public health care system are responsible for the population studied. Cases were identified by the laboratory records and review of clinic records. Adult patients were included if there was a positive IgG NMDAR Ab in either serum or CSF and the first presentation of illness was to psychiatric services. Equivocal or indeterminate NMDAR Ab cases, on the basis of weak immunofluorescence staining, which are typically repeated for accuracy, were also included but compared separately. Individuals were excluded if they were <18 years old, residing out of state, or tested by a private physician.

Case identification and data collection were performed separately by two authors (N.W. and A.S.). Variables collected included demographic characteristics, medical and psychiatric history, clinical features of presentation, course of illness and recovery, results of investigations, and treatment received. These variables were preselected and based on previous review of published cases (5). The timing of each major symptom type, investigations, and treatment commencement was noted. Initial and peak Bush-Francis Catatonia Rating Scale scores were recorded, but catatonia was noted if DSM-5 criteria were met (15, 16).

Symptoms were categorized into the following clusters for analysis: psychiatric, movement, seizures, autonomic, and cognitive. For clinical features, missing data were recorded as absence of that feature. For investigations, missing data were recorded as not tested. Treatment response and outcome were categorized as resolved, improved, no improvement, or deterioration/death, with posttreatment symptoms recorded.

Descriptive statistics were used for the initial analysis of the data. The CSF NMDAR-Ab-positive and CSF NMDAR-Ab-negative cases were compared by using Fisher’s exact test or t test as appropriate. The prespecified variables for comparison were chosen to aid psychiatric decision making in the acute phase (prodromal features: flu-like symptoms, insomnia, and cognitive deficit; psychiatric symptoms: severe agitation, odd/unusual behavior, affective lability, catatonia, and speech disturbance). The presence of neurological symptoms (e.g., seizures or movement disorder), autonomic disturbance, or loss of consciousness should prompt further investigation and thus not included in the comparison. Correction for multiple comparisons was performed with the Benjamini-Hochberg procedure, with a false discovery rate of 5% (17).

Twenty-four case patients, who presented to psychiatric services from 2011 to 2018, were identified with positive serum or CSF NMDAR Ab. This represents 60% (N=24/40 cases) of all positive NMDAR Ab results tested by the laboratory, with the remaining case patients presenting to neurology or general medicine. An additional three case patients with equivocal serum NMDAR Ab, who presented to psychiatry, were identified. All subjects had both serum and CSF antibody testing, except for one equivocal NMDAR Ab case in which repeated lumbar puncture was unsuccessful. The mean time to notify the treating clinician after a positive test was 2.8 days (SD=1.5).

Testing for the NMDAR Ab is increasingly performed in psychiatric settings. It is a sensitive and specific test, and false-positive results are thought to be rare when standard transfected cell-based assays are used in experienced laboratories (9, 18, 19). However, antibody presence does not necessarily confirm disease, and the ongoing clinical management of patients with atypical features can be challenging for psychiatrists. This study illustrates a detailed clinical profile that may differentiate patients with anti-NMDAR encephalitis from those with primary psychiatric disorders.

The clinical presentation, progression of illness, response to antipsychotics, and proportion of abnormal investigations of the CSF NMDAR Ab cases reflect previously described cohorts and case series of anti-NMDAR encephalitis (2, 5, 20). The majority responded to immunomodulatory therapy and/or tumor removal with a recurrence rate and recovery symptom profile that were, again, consistent with those for anti-NMDAR encephalitis. There was a higher proportion of patients with an isolated psychiatric presentation, likely attributable to case selection and the smaller numbers of this cohort (3). This may also explain the higher rates of psychosis (5). This study demonstrated that the majority of psychiatric symptoms—such as psychosis, agitation, mood disturbance, and anxiety—occurred on presentation to hospital, with only peak catatonic features developing later in the second week of admission. The psychiatric symptoms did not change until immunomodulation commenced, and over this time, there was high psychiatric risk, with half of the patients reporting thoughts or intent to harm themselves or others. Even with improvement after appropriate treatment, many patients still had behavioral disturbance or cognitive deficits in the extended recovery and rehabilitation phase.

The CSF NMDAR-Ab-negative cases appeared to cluster into two distinct symptom profiles. There were two patients with a clinical syndrome consistent with a classical anti-NMDAR encephalitis presentation with neurological symptoms and autonomic disturbance, responding to immunological therapy after unsuccessful psychiatric treatment. It is possible that for these patients, there may have been later CSF NMDAR Ab positivity that was not assessed, similar to the delayed CSF-positive case described in this cohort. The previously present CSF antibodies may have diminished with preserved serum antibodies, which has been rarely seen in long-term follow-up of patients with anti-NMDAR encephalitis (2). Alternatively, immunoprecipitation of the antibody at the blood-brain barrier has been hypothesized to account for this situation (21). The remaining patients, including those with equivocal NMDAR Ab results, did not develop any further neurological symptoms. It is noteworthy that only one of these patients was trialed, without effect, on immunological therapy, but all of these patients showed improvement with traditional psychiatric care. It is possible that patients with serum NMDAR Ab may be at risk of developing anti-NMDAR encephalitis if there is future disruption of the blood-brain barrier or some other “second hit” phenomena. Additionally, it is possible that these patients may have been tested too early, given the difference in initial timing of the antibody testing between CSF-positive and CSF-negative cases. However, reassuringly, the majority of CSF-negative cases have had subsequent antibody testing.

Interestingly, patients who later developed an encephalitic profile and responded to immunomodulatory therapy, independent of the CSF NMDAR Ab result, were older and had higher rates of prodromal cognitive deficits, catatonia, speech disturbance, and antipsychotic sensitivity, all evident before neurological deterioration. Other features—such as a viral prodrome, insomnia, severe agitation, pathological laughter/crying, unusual behavior, an atypical pattern of psychosis, and imaging—did not discriminate. Although further prospective confirmation is required, this suggests reassurance that, in the setting of a positive serum but negative CSF NMDAR Ab result, if there are no key features of catatonia, speech disturbance, cognitive deficits, or antipsychotic sensitivity, traditional psychiatric care can proceed without delay. Remaining alert to changes in the clinical presentation and repeated antibody testing are important. There may also be a role for EEG evidence of encephalopathy in assisting decision making (2). This is of consequence, as increased duration of untreated or partially treated psychosis and other psychiatric conditions are associated with higher psychiatric morbidity and poorer long-term outcomes (22). Confusion, stigmatization, and fracture of the therapeutic relationship can occur with repeated questioning of a diagnosis. Additionally, trialing immunomodulatory therapy, such as IVIg, in significantly suggestive cases, even without CSF-antibody presence, is a reasonable and appropriate management option (23).

The psychiatric symptom profile in the encephalitic cases likely represents the direct pathological effect of the NMDAR Ab and its impact on other neurotransmitters and neuronal networks, which can be extrapolated from the known effects of ketamine, a noncompetitive NMDAR antagonist. At lower doses, ketamine increases the release of excitatory neurotransmitters such as glutamate and dopamine, which causes agitation, positive psychotic symptoms, impairment of executive function, and repetitive or stereotyped motor behaviors in animal models (10, 24, 25). This represents NMDAR Ab titer in the initial phases of illness and postimmunomodulatory treatment. Higher ketamine doses result in catatonia, sedation, and unresponsiveness (10, 25). Rapidly fluctuating catatonia, between hyperactive and withdrawn/hypoactive states, is an unusual feature and could be pathognomonic for anti-NMDAR encephalitis, potentially representing a fluctuating state of NMDAR dysfunction or associated instability of the inhibitory and excitatory networks normally controlled by NMDA (26).

A number of limitations to the study should be considered. The majority of patients with anti-NMDAR encephalitis were tested in response to severe symptoms or rapid clinical deterioration. In addition, a previous local first-episode psychosis study as well as Royal Australia and New Zealand College of Psychiatrists 2016 guidelines recommending first-episode psychosis neuronal antibody testing may have increased the frequency of testing in this population (6, 27). Therefore, there may be a bias against testing psychogeriatric, chronic psychosis, and mood-predominant presentations. It is important to consider that more than 10% of patients demonstrate a positive CSF/negative serum pattern (5). There was one patient in the present cohort in which rapid and severe deterioration prompted CSF testing, despite a negative serum NMDAR-Ab result. However, in general, patients with negative serum tests are not subjected to lumbar puncture; potentially, this may lead to an underestimation of the prevalence of this disorder and an incomplete understanding of the psychiatric phenotype.

The clinical data were recorded retrospectively, and although we were involved in the care of the majority of patients, missing or inaccurately recorded data may have occurred. The methodology of recording absence of a feature when not documented will potentially underestimate the proportion of that feature, which is particularly significant for cognitive deficits and specific catatonic signs that are often poorly documented. No children were included in this study, which is an important consideration given that around a third of anti-NMDAR encephalitis cases occur in individuals <18 years of age, who may have a different clinical presentation (5, 28). Finally, the uncommon nature of anti-NMDAR encephalitis limits the size of this study cohort, which may affect its clinical application.

This study highlights the importance of careful psychiatric clinical assessment and formulation in determining the ongoing management after NMDAR-Ab testing. We suggest that traditional psychiatric care is appropriate for patients with isolated psychiatric symptoms who have positive serum NMDAR testing when CSF testing is negative and there are no key clinical features suggesting encephalitis. Further larger cohorts are required for confirmation, and we emphasize the importance of ongoing follow-up of the untreated CSF NMDAR-Ab-negative patients. Criteria established to clinically diagnose anti-NMDAR encephalitis independent of antibody status may be beneficial in this situation; however, the applicability of these criteria in a psychiatric setting has not yet been determined (23). Clinicians should remain alert for any clinical changes that are an indication for repeated CSF testing but should not otherwise delay psychiatric care.