Med/Psych Update

Is it psychosis, or an autoimmune encephalitis?

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How to differentiate anti-NMDA receptor encephalitis from first-episode psychosis.



Hidden within routine presentations of first-episode psychosis is a rare subpopulation whose symptoms are mediated by an autoimmune process for which proper treatment differs significantly from standard care for typical psychotic illness. In this article, we present a hypothetical case and describe how to assess if a patient has an elevated probability of autoimmune encephalitis, determine what diagnostics or medication-induced effects to consider, and identify unresolved questions about best practices.


Bizarre behavior and isolation

Ms. L, age 21, is brought to the emergency department (ED) by her college roommate after exhibiting out-of-character behavior and gradual self-isolation over the last 2 months. Her roommate noticed that she had been spending more time isolated in her dorm room and remaining in bed into the early afternoon, though she does not appear to be asleep. Ms. L’s mother is concerned about her daughter’s uncharacteristic refusal to travel home for a family event. Ms. L expresses concern about the intentions of her research preceptor, and recalls messages from the association of colleges telling her to “change her future.” Ms. L hears voices telling her who she can and cannot trust. In the ED, she says she has a headache, experiences mild dizziness while standing, and reports having a brief upper respiratory illness at the end of last semester. Otherwise, a medical review of systems is negative.

Although the etiology of first-episode psychosis can be numerous or unknown, many psychiatrists feel comfortable with the initial diagnostic for this type of clinical presentation. However, for some clinicians, it may be challenging to feel confident in making a diagnosis of autoimmune encephalitis.

Autoimmune encephalitis is a family of syndromes caused by autoantibodies targeting either intracellular or extracellular neuronal antigens. Anti-N-methyl-d-aspartate (NMDA) receptor encephalitis is one of the most common forms of autoimmune encephalitis that can present with symptoms of psychosis.1

In this article, we focus on anti-NMDA receptor encephalitis and use the term interchangeably with autoimmune encephalitis for 2 reasons. First, anti-NMDA receptor encephalitis can present with psychotic symptoms as the only symptoms (prior to cognitive or neurologic manifestations) or can present with psychotic symptoms as the main indicator (with other symptoms that are more subtle and possibly missed). Second, anti-NMDA receptor encephalitis often occurs in young adults, which is when it is common to see the onset of a primary psychotic illness. These 2 factors make it likely that these cases will come into the evaluative sphere of psychiatrists. We give special attention to features of cases of anti-NMDA receptor encephalitis confirmed with antineuronal antibodies in the CSF, as it has emerged that antibodies in the serum can be nonspecific and nonpathogenic.2,3

What does anti-NMDA receptor encephalitis look like?

Symptoms of anti-NMDA receptor encephalitis resemble those of a primary psychotic disorder, which can make it challenging to differentiate between the 2 conditions, and might cause the correct diagnosis to be missed. Pollak et al4 proposed that psychiatrically confusing presentations that don’t clearly match an identifiable psychotic disorder should raise a red flag for an autoimmune etiology. However, studies often fail to describe the specific psychiatric features of anti-NMDA receptor encephalitis, and thus provide little practical evidence to guide diagnosis. In some of the largest studies of patients with anti-NMDA receptor encephalitis, psychiatric clinical findings are often combined into nonspecific headings such as “abnormal behavior” or “behavioral and cognitive” symptoms.5 Such groupings make this the most common clinical finding (95%)5 but make it difficult to discern particular clinical characteristics. Where available, specific symptoms identified across studies include agitation, aggression, changes in mood and/or irritability, insomnia, delusions, hallucinations, and occasionally catatonic features.6,7 Attempts to identify specific psychiatric phenotypes distinct from primary psychotic illnesses have fallen short due to contradictory findings and lack of clinical practicality.8 One exception is the presence of catatonic features, which have been found in CSF-confirmed studies.2 In contrast to the typical teaching that the hallucination modality (eg, visual or tactile) can be helpful in estimating the likelihood of a secondary psychosis (ie, drug-induced, neurodegenerative, or autoimmune), there does not appear to be a difference in hallucination modality between encephalitis and primary psychotic disorders.9

History and review of systems

Another red flag to consider is the rapidity of symptom presentation. Symptoms that progress within 3 months increase the likelihood that the patient has autoimmune encephalitis.10 Cases where collateral information indicates the psychotic episode was preceded by a long, subtle decline in school performance, social withdrawal, and attenuated psychotic symptoms typical of a schizophrenia prodrome are less likely to be an autoimmune psychosis.11 A more delayed presentation does not entirely exclude autoimmune encephalitis; however, a viral-like prodrome before the onset of psychosis increases the likelihood of autoimmune encephalitis. Such a prodrome may include fever, headache, nausea, vomiting, and diarrhea.7

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