| Summary: | <p>Autoimmune encephalopathies are immunotherapy-responsive brain diseases mediated by
autoantibodies against cell surface antigens. NMDAR-antibody encephalitis (NMDAR-Ab-E) is an
autoimmune encephalopathy mediated by IgG against the NR1 NMDA receptor subunit. The illness
has a psychiatric onset in most and an association with ovarian teratoma (OT) in a third. This thesis
explores the psychopathology and immunobiology of NMDAR-Ab-E; it focuses on the pattern and
evolution of mental state abnormalities and serological and cellular measures of autoimmunising
mechanisms.</p>
<p>A systematic review identified 464 individually reported patients with more detail than ‘psychiatric’
and/or ‘behavioural’. Granular lower-level phenomena were grouped into higher-level categories:
behaviour (68%), psychosis (67%), mood (47%), catatonia (30%), and sleep (21%). These had a
propensity to overlap within individual patients, most clearly in psychiatric-described reports (221/329,
67% vs 96/118, 81%). Network analysis suggested a complex pattern of disorganisation, disinhibition,
and affective instability rather than sub-groups of patients with simple syndromes (network density and
median closeness centrality of 1 in the psychiatric-described group). Further detailed interviews (n=5)
revealed temporal progression: complete insomnia and depressive mood develop early, possessionlike/
drugged-dissociative appearance during the psychosis, and developmental regression and
episodic amnesia as late features. Reductive framing as atypical/organic psychosis or delirium could
help focus clinical recognition. Lumbar puncture in acute psychiatric services needs to expand and
comparison with primary psychoses would help focus how far.</p>
<p>Using a live cell-based assay (CBA) with a 1:40 end-point dilution cut-off, 13/286 samples (5%) from
bipolar depression, 12/101 (12%) from acute mania, 5/57 (9%) from traumatic brain injury (TBI) and
3/55 (5%) from healthy volunteer cohorts were NR1-IgG positive. 31 cerebrospinal fluid (CSF) samples
from the TBI cohort were negative including two whose serum pair was positive. In contrast, 34/39
(87%) of NMDAR-Ab-E sera paired with CSF NR1-IgG positive samples were detectable at 1:40 and
39/39 at 1:20. Overlapping NR1-IgG levels meant that level could not fully discriminate between groups
and a N368Q NR1 mutation abrogated binding in 18/20 (90%) comparator group positive samples
suggesting that these were not false positives. However, no positive samples from the comparator
group bound neurons, unlike 70% of the selected NMDAR-Ab-E positive sera. Therefore, the NMDARAb-
E NR1-IgG were probably of greater affinity and/or polyclonality compared to the comparators,
consistent with a more fully realised autoimmunisation process.</p>
<p>Live CBAs for IgM and IgA NR1 autoantibodies were developed. NR1-IgM was common in NMDARAb-
E (121/285, 42% samples) and persistent (up to 2555 days post-onset). There was a timedependent
positive serum NR1-IgA association with OT (OR 6.32 P=0.005 <40 days post-onset). NR1-
IgG and NR1-IgA but not NR1-IgM were common in tumour fluid, cultured explants produced NR1-IgG
with and without activation cytokines, flow cytometry detected B cells from naïve through to classswitched
memory and antibody-secreting phenotypes, and GC-like structures with BCL6+AID+ B cells
and CD21+ sustentacular meshwork were found histologically. Ultrasound-guided fine needle
aspiration (FNA) of cervical lymph nodes (LN) in patients with and without OT successfully detected
distinct population frequencies in transitional B cells, T follicular helper cells (TfH), and CD83+ B cells.
Cultured LN cells from three patients with fully resected OTs did not produce NR1-IgG whereas those
from a patient with a partially treated OT and a relapsing patient without an OT did produce NR1-IgG.
LN cells from this relapsing patient also produced NR1-IgG during remission. These data consolidate
the status of NMDAR-Ab-E-associated OTs as tertiary lymphoid organs and provide direct evidence of
secondary lymphoid organ involvement in pathogenesis.</p>
<p>The two areas converge: the immunological findings suggest early autoimmunising events that can
propagate if left unchecked and a refined psychopathologic description could help better identify cases
during this window of opportunity.</p>
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