Paraneoplastic anti–N‐methyl‐D‐aspartate receptor encephalitis associated with ovarian teratoma

Abstract

Objective-To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.Methods-Analysis of clinical features, neuropathological findings, tumors, and serum/ cerebrospinal fluid antibodies using rat tissue, neuronal cultures, and HEK293 cells expressing subunits of the N-methyl-D-aspartate receptor (NMDAR).Results-Twelve women (14 -44 years) developed prominent psychiatric symptoms, amnesia, seizures, frequent dyskinesias, autonomic dysfunction, and decreased level of consciousness often requiring ventilatory support. All had serum/cerebrospinal fluid antibodies that predominantly immunolabeled the neuropil of hippocampus/forebrain, in particular the cell surface of hippocampal neurons, and reacted with NR2B (and to a lesser extent NR2A) subunits of the NMDAR. NR2B binds glutamate and forms heteromers (NR1/NR2B or NR1/NR2A/NR2B) that are preferentially expressed in the adult hippocampus/forebrain. Expression of functional heteromers (not single subunits) was required for antibody binding. Eleven patients had teratoma of the ovary (six mature) and one a mature teratoma in the mediastinum; five of five tumors examined contained nervous tissue that strongly expressed NR2 subunits and reacted with patients' antibodies. Tumor resection and immunotherapy resulted in improvement or full recovery of eight of nine patients (paralleled by decreased antibody titers); two of three patients without tumor resection died of neurological deterioration. Autopsies showed extensive microgliosis, rare T-cell infiltrates, and neuronal degeneration predominantly involving, but not restricted to, the hippocampus.Interpretation-Antibodies to NR2B-and NR2A-containing heteromers of the NMDAR associate with a severe but treatment-responsive encephalitis. Our findings provide a diagnostic test and Address correspondence to Dr Dalmau, Department of Neurology, 3 W. Gates, Division Neurooncology, 3400 Spruce Street, University of Pennsylvania, Philadelphia, PA 19104., E-mail: josep.dalmau@uphs.upenn In a previous study, we described a disorder that appeared to represent a new category of severe, potentially lethal, but treatmentresponsive paraneoplastic encephalitis. 4 The affected patients were women who developed prominent psychiatric symptoms, seizures, memory deficits, and decreased level of consciousness often requiring ventilatory support. Three salient features included the young age of the patients, the association with ovarian teratomas, and the detection of antibodies to unknown antigens predominantly expressed in the cell membrane of hippocampal neurons (also referred to as a subgroup of neuropil antigens). 5 Since then, we have studied eight additional patients and now report the identification of the target autoantigens, which are heteromers containing NR1 and NR2 subunits of the N-methyl-D-aspartate receptor (NMDAR), also expressed by the associated tumors. Patients and MethodsPatients include 12 women with paraneoplastic encephalitis associated with teratomas. ImmunocytochemistryRat h...

NMDAR encephalitis: passive transfer from man to mouse by a recombinant antibody

“…3A), but not the isotype control rhuMab 12D7 (Fig. 3B), produced an intense pattern of brain reactivity characteristic of NMDAR as previously reported using patients' sera or CSF,14 with a strong emphasis of the hippocampal region. Tissue reactivity of rhuMab SSM5 was clearly reduced by preincubation of tissue sections with sera from patients with anti‐NMDAR encephalitis (Fig.…”

“…To characterize the tissue reactivity of rhuMab SSM5, immunohistochemistry on mildly fixed sagittal rat brain sections was performed, as previously described 14. Patient‐derived rhuMab SSM5 (Fig.…”

“…Although anti‐NMDAR antibodies are mainly of the complement‐activating IgG1 and IgG3 subtypes, complement deposition was not detected in brain biopsy specimens from treatment‐naïve patients with anti‐NMDAR encephalitis, probably due to the low levels of complement present in CSF and relative preservation of the blood–brain barrier (BBB) 7, 13. Consistently, anti‐NMDAR IgG antibodies did not reduce the number of synapses, dendritic spines, dendritic complexity, or cell survival in cultured rat hippocampal neurons,9 and neuronal damage was sparse in brain biopsy specimens 13, 14. Passive infusion of patients' CSF into the cerebroventricular system of mice via osmotic minipumps induced reversible memory impairment and behavioral changes consistent with symptoms found in patients with anti‐NMDAR encephalitis in vivo 15…”

N‐methyl‐D‐aspartate receptor antibody production from germinal center reactions: Therapeutic implications

“…Immunoglobulin G (IgG) autoantibodies to the NR1 subunit of the N‐methyl‐D‐aspartate receptor (NMDAR) cause a severe and diffuse encephalitis characterized by psychosis, amnesia, and a complex movement disorder 1, 2. The autoantibodies are typically present in serum and cerebrospinal fluid (CSF) at disease onset and persist for several years despite various immunotherapies.…”

“…This finding, together with the higher concentrations of NR1‐IgG in serum than CSF,2, 5 suggest that the autoantibodies are initially generated in the periphery. Indeed, especially given the recent description of NR1‐specific B cells and antibody‐secreting cells (ASCs) in the CSF, the consistent observation of NR1‐IgG intrathecal synthesis is most likely secondary to the cells, and some autoantibodies, crossing the blood–brain barrier after the primary systemic immunization 1, 2, 6, 7…”