For clinicians, a patient’s early days of psychosis can be littered with diagnostic landmines. It can be challenging to parse the first signs of a primary psychiatric disorder from the earliest alarm bells of a life-threatening neurological disease?
Now, new data from a large international study in The Lancet Psychiatry makes the case that, in N-methyl-D-aspartate receptor (NMDAR) antibody encephalitis, the mind often gives the game away. Psychiatric symptoms can be a telling clue. But only if clinicians know what to look for.
“NMDAR-antibody encephalitis is a very serious illness and outcomes are linked to timeliness of treatment, with immunological therapies and neurological monitoring. So whether it is A&E doctors, psychiatrists, or neurologists, we all have a part to play in ensuring we consider this condition as a cause of new changes in mental state,” lead author and senior clinical researcher in the Oxford University’s Department of Psychiatry Adam Al-Diwan said in a press release. “However, this is not easy, particularly since psychotic disorders are far more common than NMDAR-antibody encephalitis. There is evidence of both over-suspicion, where people undergo unnecessary tests; but also under-diagnosis, where the condition is not picked up quickly enough, or at all.”
Methodology
In a bid to parse the differences, a team of European and U.S. researchers launched a multicenter, retrospective analysis of 100 illness episodes of NMDAR-antibody encephalitis. They compared those cases with 145 real-world psychosis episodes seen in early-intervention psychiatric services – including 10 cases of postpartum psychosis. The differences stood out immediately.
Psychiatric symptoms in NMDAR-antibody encephalitis showed up suddenly. Symptoms progressed to a full psychiatric presentation in a median of just one day.
Conversely, unselected first-episode psychosis normally took months to fully present themselves, with a median onset time of about six months. Even “rapid onset” psychosis cases appeared much slower than encephalitis.
In practical terms, a psychiatric syndrome that explodes over days rather than gradually emerging over weeks or months should raise immediate suspicion of an underlying medical cause.
“This study suggests that NMDAR-antibody encephalitis drives changes in mental state that are generally very rapid,” Al-Diwan added. “This should complement existing approaches anchored in recognising the combination of these psychiatric features with neurological features such as seizures and abnormal movements. While our score is simple to action, it now needs to be evaluated in future prospective studies in diverse settings.”
More Than an Issue of Timing
The symptoms themselves told their own story. While patients with NMDAR-antibody encephalitis displayed a wide range of psychiatric features, they rarely followed the classic patterns of schizophrenia or bipolar disorder. Hallmark symptoms of primary psychosis appeared less frequently. Core manic features proved to be similarly uncommon.
Instead, encephalitis arrived with a dense mix of atypical and fluctuating features. Catatonic signs stood out. Mutism, posturing, echolalia, stupor, and dramatic sleep–wake reversal all seemed to be far more common than in psychiatric comparison groups. And, in some cases, they remained exclusive to encephalitis. Visual hallucinations without an auditory counterpart were also disproportionately represented.
The evolution (or deterioration) of these symptoms seemed to be just as important.
Working with meticulous timelines, the researchers showed that NMDAR-antibody encephalitis follows a recognizable sequence. Mood and anxiety symptoms normally crop up first, within a day or two. Psychotic features soon follow. Within one to two weeks, many patients devolve into increasingly disorganized and catatonic states, plagued by agitation, repetitive or incoherent speech, altered consciousness, and abnormal motor behavior.
This rapid, shifting clinical picture – what the authors dub a kind of “young-onset delirium” – might explain why the disorder is misdiagnosed so often. In nearly 80% of cases, clinicians initially leaned toward diagnoses other than encephalitis. And, more often than not, they suspected a primary psychiatric disorder or a seizure condition.
More than a third of patients admitted to psychiatric wards ended up being transfered to medical care.
The stakes are obviously high. NMDAR-antibody encephalitis is certainly treatable. But outcomes depend heavily on timely immunotherapy and, when relevant, tumor removal. Blood tests for NMDAR antibodies can be notoriously prone to false negatives. And lumbar puncture – a diagnostic gold standard – remains difficult to access in most psychiatric settings.
Looking at Remedies
To help close that gap, the authors looked at whether clinical features alone could help flag high-risk cases sooner. They found that simple combinations – such as psychiatric onset within days and the presence of catatonic or delirium-like features – distinguished encephalitis from primary psychosis quite accurately. When these patterns were absent, clinicians could more confidently rule out encephalitis. When they were present, they helped justify urgent medical investigation.
The authors warn that no straightforward clinical approach can diagnose such a rare condition conclusively. But they argue that psychiatry has a critical, time-limited diagnostic window – usually only days – before neurological deterioration settles in.
When psychosis arrives fast, evolves unpredictably, and refuses traditional psychiatric classification, clinicians might want to think about the brain before exploring the mind.
