NMDA Receptor Encephalitis: Structural Brain Changes and Clinical Outcomes

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune disease that affects the brain, causing cognitive dysfunction, psychiatric symptoms, seizures, and impaired consciousness. Despite advances in managing the acute disease phase, long-term recovery is often protracted, and many patients experience residual symptoms for years after disease onset. A recent study in Germany aimed to characterise morphological brain complexity, symptom trajectories, and the relationship between structural brain changes and post-acute outcomes in patients with NMDAR encephalitis.

## Introduction to NMDAR Encephalitis NMDAR encephalitis was first discovered in 2007 and is caused by autoantibodies against the GluN1 subunit of the NMDA receptor, which plays a key role in glutamatergic signalling, long-term potentiation, and synaptic plasticity across the brain. The disease is characterised by a severe acute syndrome, including cognitive dysfunction, psychiatric symptoms, seizures, autonomic dysregulation, and impaired consciousness, which can be life-threatening and frequently requires intensive care.

## Study Design and Methods The study included 70 patients with post-acute NMDAR encephalitis and 70 age-matched and sex-matched healthy control participants. Patients were referred to Charité-Universitätsmedizin Berlin, Germany, and data were collected between July 18, 2011, and March 17, 2021. The study used morphological complexity analysis with fractal dimensionality to quantify brain morphology from T1-weighted structural MRI. Patient outcomes were assessed using the modified Rankin Scale (mRS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), psychiatric phenotyping, and neuropsychological testing.

## Results and Discussion The study found that patients with NMDAR encephalitis showed significant clinical improvement in both mRS and CASE in the post-acute stage, but 47 (67%) patients continued to show residual CASE symptoms, most commonly memory dysfunction and psychiatric symptoms. Brain imaging revealed a characteristic pattern of reduced morphological complexity, including the hippocampus bilaterally and a fronto-cingulo-temporal cluster in grey and white matter. The study also found that patients with persistent symptoms showed stronger alterations of brain morphology than those without, and that stronger morphological alterations were associated with lower visuospatial and verbal memory performance.

The study's findings highlight the importance of fractal dimensionality as a new imaging marker of long-term outcomes in patients with NMDAR encephalitis. The results also emphasize the need for structured post-acute care to address long-term affective and cognitive morbidity in patients with NMDAR encephalitis. The following table summarizes the patient characteristics and outcomes: | Characteristic | Patients | Healthy Controls | | --- | --- | --- | | Sex (female/male) | 60/10 | 60/10 | | Age (mean/SD) | 28.1/10.2 | 29.0/9.3 | | mRS (median) | 5 vs 1 | - | | CASE (median) | 11 vs 1 | - | | Residual symptoms | 47 (67%) | - | | Memory dysfunction | 43 (61%) | - | | Psychiatric symptoms | 25 (36%) | - |