Human gestational N-methyl-d-aspartate receptor autoantibodies impair neonatal murine brain function.

OBJECTIVE: Maternal autoantibodies are a risk factor for impaired brain development in offspring. Antibodies (ABs) against the NR1 (GluN1) subunit of the N-methyl-d-aspartate receptor (NMDAR) are among the most frequently diagnosed anti-neuronal surface ABs, yet little is known about effects on fetal development during pregnancy. METHODS: We established a murine model of in utero exposure to human recombinant NR1 and isotype-matched nonreactive control ABs. Pregnant C57BL/6J mice were intraperitoneally injected on embryonic days 13 and 17 each with 240µg of human monoclonal ABs. Offspring were investigated for acute and chronic effects on NMDAR function, brain development, and behavior. RESULTS: Transferred NR1 ABs enriched in the fetus and bound to synaptic structures in the fetal brain. Density of NMDAR was considerably reduced (up to -49.2%) and electrophysiological properties were altered, reflected by decreased amplitudes of spontaneous excitatory postsynaptic currents in young neonates (-34.4%). NR1 AB-treated animals displayed increased early postnatal mortality (+27.2%), impaired neurodevelopmental reflexes, altered blood pH, and reduced bodyweight. During adolescence and adulthood, animals showed hyperactivity (+27.8% median activity over 14 days), lower anxiety, and impaired sensorimotor gating. NR1 ABs caused long-lasting neuropathological effects also in aged mice (10 months), such as reduced volumes of cerebellum, midbrain, and brainstem. INTERPRETATION: The data collectively support a model in which asymptomatic mothers can harbor low-level pathogenic human NR1 ABs that are diaplacentally transferred, causing neurotoxic effects on neonatal development. Thus, AB-mediated network changes may represent a potentially treatable neurodevelopmental congenital brain disorder contributing to lifelong neuropsychiatric morbidity in affected children. ANN NEUROL 2019;86:656-670.

Normal gut microbiome in NMDA receptor encephalitis.

OBJECTIVE: To determine whether the gut microbiota shows overabundance of commensal bacteria species in patients with anti-NMDA receptor (NMDAR) encephalitis, similar to patients with MS or neuromyelitis optica where they potentially balance pro- and anti-inflammatory immune responses or participate in disease pathogenesis by molecular mimicry. METHODS: Intestinal microbiota was characterized in patients with NMDAR encephalitis (n = 23, mean age: 34 ± 12.7 years; 21 females) and age/sex/environment-matched healthy controls (n = 24, 40 ± 14.2 years; 22 females) using stool bacteria 16S rDNA sequencing and classification in operational taxonomic units (OTUs). Statistical analyses focused on intraindividual and interindividual bacterial diversity and identification of differentially abundant taxa. RESULTS: Patients with NMDAR encephalitis and controls had similar microbiome profiles of the gut microbiota regarding intraindividual bacterial diversity, OTU distribution, ratio between regional and local species diversity when testing all OTUs, and genera with a relative abundance greater than 0.5%. Similarly, the subgroup of NMDAR encephalitis patients with an ovarian teratoma (n = 3) showed no differences in microbiome variation compared with controls. Patients in the acute encephalitis stage (n = 8) showed significant differences in the numbers of Clostridium XVIII, Clostridium IV, Oscillibacter, Prevotella, and Blautia; however, significance was lost after correction for multiple testing. CONCLUSION: Patients with NMDAR encephalitis and controls both had a normal gut microbiome. The lack of overabundance of certain bacterial species in patients suggests that microbiome changes are no major contributors to the pathogenesis, disease course, or prognosis in NMDAR encephalitis. Despite the small sample size and heterogeneous groups, findings indicate differences to other neuroimmunologic diseases.

Red Flags: Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients.

Autoimmune mechanisms causing diverse psychiatric symptoms are increasingly recognized and brought about a paradigm shift in neuropsychiatry. Identification of underlying antibodies against neuronal ion channels or receptors led to the speculation that a number of patients go misdiagnosed with a primary psychiatric disease. However, there is no clear consensus which clinical signs in psychiatric patients should prompt further investigations including measurement of anti-neuronal autoantibodies. We therefore aimed to analyze the presenting symptoms in patients with autoimmune encephalitis and the time between symptom onset and initiation of antibody diagnostics. For this, we recruited 100 patients from the Charité Center for Autoimmune Encephalitis between May and October 2016, including all types of autoimmune encephalitides. Psychiatric abnormalities were the most common clinical symptoms and were the presenting sign in 60%. One-third of patients were initially hospitalized in a psychiatric ward. All patients positive for antibodies against the N-methyl-d-aspartate receptor showed behavioral changes, hallucinations, memory deficits, catatonia, or delusions. Patients positive for antibodies against other cell surface or intracellular antigens were often hospitalized with a psychosomatic diagnosis. The time between occurrence of first symptoms and antibody testing was often alarmingly prolonged. In patients with symptom onset between 2013 and 2016, the mean delay was 74 days, in cases diagnosed between 2007 and 2012 even 483 days, suggesting though that increased awareness of this novel disease group helped to expedite proper diagnosis and treatment. By analyzing the medical records in detail, we identified clinical signs that may help to assist in earlier diagnosis, including seizures, catatonia, autonomic instability, or hyperkinesia. Indeed, reanalyzing the whole cohort using these "red flags" led to a 58% reduction of time between symptom onset and diagnosis. We conclude that the timely diagnosis of an autoimmune psychiatric disease can be facilitated by use of the described clinical warning signs, likely enabling earlier immunotherapy and better prognosis. Also, the threshold for cerebrospinal fluid analysis and autoantibody testing should be low.