N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes

Abstract

Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

“…We performed blinded testing of serum for autoantibodies in all patients, almost exclusively using previously described live cell‐based assay methodologies (Table 1),6, 7 and flow cytometry from whole blood in patient 1. Written informed consent was obtained with ethical approval (REC16/YH/0013).…”

Neuronal antibodies in pediatric epilepsy: Clinical features and long‐term outcomes of a historical cohort not treated with immunotherapy

“…Cell‐based assays (CBAs) were used to detect antibodies to the NMDAR, alpha amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR), LGI1, CASPR2, and contactin‐2. These tests were scored on a visual scale: 0, no binding; 1, low but specific binding; to 4, strong binding to all transfected cells by two independent observers as previously described3, 5 and in use for routine diagnostics. All positive samples were confirmed, and then tested blind by LW as part of a routine antibody service, with dilutions to assess the titer; the positives samples were also tested for binding to the surface of live hippocampal neurons in culture, prepared from P0 Sprague‐Dawley rat pups as described previously 23, 24…”

Botulinum toxin treatment for hypersalivation in anti‐NMDA receptor encephalitis

“…Within the first 4 weeks of symptom onset, more than 40% of the patients with anti‐NMDAR encephalitis experience autonomic symptoms including hyperthermia, tachycardia, hypersalivation, bradycardia, hypertension, and hypotension 1, 3, 5. Although hypersalivation is one of the main autonomic dysfunctions in anti‐NMDAR encephalitis, there has been no clear consensus regarding which treatment is better for controlling hypersalivation.…”

“…Anti‐ N ‐methyl‐ d ‐aspartate receptor (NMDAR) encephalitis is an autoimmune synaptic disorder caused by autoantibodies directed against GluN1 subunit of the anti‐NMDAR, resulting in psychosis, loss of consciousness, memory deficits, seizure, speech problems, dyskinesia, autonomic dysfunction, and central hypoventilation 1, 2, 3, 4. By the first‐line immunotherapy (steroids, immunoglobulins, or plasma exchange) and second‐line immunotherapy (rituximab or cyclophosphamide), about 80% of patients with anti‐NMDAR encephalitis recovers favorably to be able to look after own affairs without assistance 5.…”

“…Hypersalivation is one of the main autonomic dysfunctions in anti‐NMDAR encephalitis where its prevalence was estimated between 4 and 18% 1, 3. Patients with anti‐NMDAR encephalitis can show excessive production of saliva, the inability to retain saliva within the mouth, and profound drooling, thus sometimes requiring constant suction of saliva.…”