The differential diagnosis of first-episode psychosis (FEP) remains a central challenge in modern neuropsychiatry. Among the emerging entities reshaping our diagnostic frameworks is autoimmune psychosis (AP), most often associated with anti-NMDA receptor (NMDAR) encephalitis. This condition, while rare, exemplifies how immunological processes can masquerade as primary psychiatric illness, underscoring the need for rigorous investigation when patients present with atypical features.
The Central Role of CSF Antibody Testing
The most compelling finding for confirming suspected AP is the presence of NMDAR antibodies in cerebrospinal fluid (CSF). While ancillary tests such as abnormal EEG patterns, brain MRI changes, or subtle neurological findings can heighten suspicion, none carry the same weight as a positive CSF antibody result. Importantly, serum antibody testing has been shown to lack sensitivity; many true cases of autoimmune encephalitis may be missed if CSF testing is not pursued. This makes lumbar puncture not merely a supportive test, but the decisive diagnostic pivot in suspected cases.
The study highlighted here reinforces this principle by demonstrating that none of the screened FEP patients had detectable NMDAR antibodies in either serum or CSF. On the surface, this finding suggests that antibody-mediated psychosis is uncommon. Yet, the concurrent recognition of misdiagnosed cases—patients transferred after initial treatment elsewhere who were ultimately confirmed to have anti-NMDAR encephalitis—illustrates the danger of relying solely on clinical suspicion or serum testing. These patients uniformly tested positive for CSF antibodies, reaffirming the diagnostic specificity of CSF testing.
The Implications of Negative and Non-Specific Results
A negative CSF NMDAR antibody test effectively rules out antibody-mediated FEP, guiding clinicians to focus on alternative explanations for psychosis. However, the diagnostic process does not end there. Patients with serum positivity for non-NMDAR antibodies, or with CSF findings suggestive of inflammation without NMDAR antibodies, warrant further workup. In such instances, clinicians must consider systemic inflammatory disorders, including lupus psychosis, or other secondary autoimmune syndromes that can mimic primary psychotic illness.
A Proposed Diagnostic Algorithm
The authors propose a pragmatic diagnostic algorithm that centers CSF antibody testing within a stepwise, suspicion-driven framework. This algorithm recommends lumbar puncture in three principal contexts:
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Neurological Red Flags: Any FEP patient who presents with concurrent neurological symptoms or abnormal EEG/MRI findings should undergo CSF antibody testing.
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Paraclinical Abnormalities: Even in the absence of overt neurological signs, FEP patients with abnormal serum antibody screens, EEG, or MRI warrant CSF testing.
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Clinical Red Flags: Features suggestive of anti-NMDAR encephalitis—such as intolerance to antipsychotics, new neurological signs after psychosis onset, or association with a viral prodrome or tumor—demand CSF testing regardless of initial neurological exam findings.
By anchoring diagnostic certainty to CSF results while integrating clinical vigilance, this algorithm balances sensitivity with specificity and avoids the pitfalls of both over- and under-diagnosis.
Broader Clinical Relevance
This study’s contribution lies not only in its algorithmic clarity but also in its reminder to clinicians: autoimmune encephalitis should always remain within the differential when psychosis deviates from expected trajectories. Patients who fail to improve with antipsychotics, whose presentation includes unexplained neurological signs, or who have systemic clues to autoimmunity deserve further evaluation.
Ultimately, the diagnosis of autoimmune psychosis is less about the discovery of a common entity and more about avoiding catastrophic oversight. By integrating CSF antibody testing into the standard evaluation of atypical or treatment-resistant FEP, clinicians may improve early recognition, ensure timely immunotherapy, and dramatically alter the long-term outcomes of patients whose illness is, at its root, immunologically driven and potentially reversible.