Structural brain changes and clinical outcomes of patients with NMDA receptor encephalitis in Germany: a...

Many patients with N-methyl-D-aspartate receptor (NMDAR) encephalitis show persistent neurological or psychiatric symptoms, despite immunotherapy. The neuroanatomical basis of these symptoms remains uncertain. Morphological complexity analysis with fractal dimensionality has emerged as a sensitive neuroimaging method in related conditions, but remains unexplored in autoimmune encephalitis. We aimed to characterise morphological brain complexity, symptom trajectories from peak illness to the post-acute stage, and the relationship between structural brain changes and post-acute outcomes in patients with NMDAR encephalitis.

In this cross-sectional study, we included patients with post-acute NMDAR encephalitis referred to Charité-Universitätsmedizin Berlin, Germany. Patients were matched (1:1) to healthy control participants for sex and age by use of logistic regression propensity scores and nearest-neighbour matching. Data were collected between July 18, 2011, and March 17, 2021. Patient outcomes were assessed with the modified Rankin Scale (mRS), Clinical Assessment Scale for Autoimmune Encephalitis (CASE), psychiatric phenotyping, and neuropsychological testing. Morphological brain complexity was quantified from T1-weighted structural MRI. Normative modelling was used to evaluate the relationship between structural brain changes and post-acute outcomes. Self-reports on post-acute symptoms by individuals with lived experience informed the study design.

We included 70 patients (60 [86%] female and ten [14%] male; mean age 28·1 years [SD 10·2; range 15·0-67·0]) and 70 age-matched and sex-matched healthy control participants (60 [86%] female and ten [14%] male; 29·0 [9·3; 16·0-65·2]; ethnicity data unavailable). Study visits occurred at a median of 22·2 months from disease onset (IQR 8·5-42·5). Patients were severely affected at peak illness, but showed significant clinical improvement in both mRS (median 5 vs 1, Z -7·2, p<0·0001) and CASE (median 11 vs 1, Z -7·2, p<0·0001) in the post-acute stage. Nevertheless, 47 (67%) patients continued to show residual CASE symptoms, most commonly memory dysfunction (43 [61%]) and psychiatric symptoms (25 [36%]). In patients with persistent symptoms, psychiatric manifestations shifted from a psychosis-dominant phenotype at peak illness to an affective-dominant phenotype in the post-acute stage. Brain imaging showed a characteristic pattern of reduced morphological complexity, including the hippocampus bilaterally and a fronto-cingulo-temporal cluster in grey and white matter. Normative modelling revealed that patients with persistent symptoms showed stronger alterations of brain morphology than those without (psychiatric symptoms: t -2·65, p=0·0100; memory dysfunction: t -3·98, p=0·0002; both vs no symptoms t -5·46, p<0·0001). Similarly, stronger morphological alterations were associated with lower visuospatial and verbal memory performance (all p_FDR<0·015).

Post-acute NMDAR encephalitis is characterised by systematic alterations of brain morphology. These changes are associated with persistent psychiatric symptoms and memory dysfunction after immunotherapy, highlighting fractal dimensionality as a promising new imaging marker of long-term outcomes. The phenotypic shift in psychiatric symptoms and the persistence of memory dysfunction highlight the importance of structured post-acute care to address long-term affective and cognitive morbidity in patients with NMDAR encephalitis.

German Research Foundation and German Ministry of Education and Research.