Normal brain magnetic resonance imaging in anti–N-methyl-D-aspartate receptor encephalitis despite neuropsychiatric presentation

Introduction

Encephalitis associated with antibodies against the N-methyl-D-aspartate receptor is an autoimmune disorder mediated by antibodies targeting this glutamatergic receptor, a key regulator of synaptic transmission and neuronal plasticity. It is increasingly recognised as a cause of acute neuropsychiatric syndromes across a wide age range and is often underdiagnosed in early stages. The condition frequently presents with psychosis, behavioural change and cognitive dysfunction, often leading to initial psychiatric assessment and potential delays in neurological evaluation. Despite the severity of clinical manifestations, brain magnetic resonance imaging may remain normal, creating a clinico-radiological dissociation that can delay diagnosis—definitively established by the detection of antibodies in cerebrospinal fluid—and the initiation of appropriate treatment. This diagnostic challenge is particularly relevant in acute settings, where early recognition is essential to improve outcomes.

Objectives

To investigate the relationship between neuroimaging findings and clinical presentation in patients with anti–N-methyl-D-aspartate receptor encephalitis, with a focus on the prevalence and clinical implications of normal imaging.

Methods

A retrospective observational study was conducted including patients with anti–N-methyl-D-aspartate receptor encephalitis confirmed by serological positivity at a tertiary hospital between 2019 and 2024. Clinical data collected included age, sex, initial presentation, referral pathway and time to diagnosis. Brain magnetic resonance imaging studies were systematically reviewed to assess the presence, anatomical distribution and characteristics of abnormalities across T2-weighted, fluid-attenuated inversion recovery and diffusion-weighted sequences. Imaging findings were analysed in relation to clinical presentation and disease course. Descriptive statistical analysis was performed, including calculation of frequencies, ranges and mean time intervals.

Results

Six patients were included, aged 2–73 years. Neuropsychiatric symptoms were the predominant initial manifestation in all cases (6/6, 100%), including behavioural change, psychotic symptoms, movement disorders and rapidly progressive cognitive decline. Four patients (4/6, 67%) were initially referred for psychiatric assessment, reflecting early diagnostic uncertainty and overlap with primary psychiatric disorders. The mean time from symptom onset to diagnosis was approximately 7 days. Brain magnetic resonance imaging was normal in four cases (4/6, 67%), despite clinically significant presentations. One patient had pre-existing hydrocephalus without acute imaging changes. One patient (1/6, 17%) demonstrated extensive cortical and limbic involvement, including the temporal lobe, insular cortex and thalamus, with T2/fluid-attenuated inversion recovery hyperintensity, diffusion restriction and leptomeningeal enhancement, in the context of concomitant herpes simplex virus type 1 infection. No consistent association was observed between imaging findings and clinical severity.

Conclusions

This case series highlights a marked clinico-radiological dissociation in anti–N-methyl-D-aspartate receptor encephalitis, with brain magnetic resonance imaging frequently normal despite severe neuropsychiatric symptoms. This pattern may contribute to initial misdiagnosis and referral to psychiatric services, reflecting the absence of specific neuroradiological markers in this condition. Conversely, extensive imaging abnormalities may occur in complex presentations, particularly in the presence of concomitant infection. These findings underscore the need for a high index of clinical suspicion, integration of clinical and laboratory data, and early diagnostic testing in patients presenting with acute neuropsychiatric syndromes, in order to enable timely initiation of immunomodulatory therapy and improve clinical outcomes.

References

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