Anti-N-Methyl-Aspartate Receptor Encephalitis in Identical Twin Sisters
ABSTRACT Anti-N-methyl-aspartate receptor encephalitis is a potentially fatal form of encephalitis and frequently associated with ovarian teratomas. Surgical removal of ovarian teratomas improves clinical outcome, but it is unclear whether bilateral salpingo-oophorectomy for normal-appearing ovaries is of clinical benefit.
Our report describes a unique clinical scenario of identical twin sisters with anti-N-methyl-aspartate receptor encephalitis. Neither patient responded to immunosuppressive therapy. Imaging studies showed normal-appearing ovaries. The first twin continued on medical therapy only and died of the disease. The second twin underwent a bilateral salpingo-oophorectomy followed by gradual recovery.
Based on our experience in two genetically identical individuals, we suggest considering the removal of normal-appearing ovaries in patients with anti-N-methyl-aspartate receptor encephalitis who fail to respond to medical treatment.
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ABSTRACT: This introductory article to the special edition on glutamate neurotransmission in neuropsychiatric disorders provides an overview of glutamate neurotransmitter system physiology and pharmacology. Glutamate was only relatively recently recognized as the major excitatory neurotransmitter in the mammalian brain, in part due to its ubiquitous nature and diverse metabolic roles within the CNS. The extremely high concentration of glutamate in brain tissue paired with its excitotoxic potential requires tight physiological regulation of extracellular glutamate levels and receptor signaling in order to assure optimal excitatory neurotransmission but limits excitotoxic damage. In order to achieve this high level of control, the system has developed a complex physiology with multiple regulatory processes modulating glutamate metabolism, release, receptor signaling, and uptake. The basic physiology of the various regulatory components of the system including the rich receptor pharmacology is briefly reviewed. Potential contributions from each of the system's components to the pathophysiology of neuropsychiatric illnesses are briefly discussed, as are the many new pharmacological targets for drug development provided by the system, especially as they pertain to the proceeding preclinical and clinical articles in this issue.Pharmacology Biochemistry and Behavior 08/2011; 100(4):656-64. DOI:10.1016/j.pbb.2011.08.008 · 2.82 Impact Factor
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ABSTRACT: To report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis. 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). 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. 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 suggest a model of autoimmune NMDAR-related encephalitis with broad implications for other immune-mediated disorders of memory, behavior, and cognition.Annals of Neurology 01/2007; 61(1):25-36. DOI:10.1002/ana.21050 · 11.91 Impact Factor
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ABSTRACT: A severe form of encephalitis associated with antibodies against NR1-NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. We describe the clinical characteristics of 100 patients with encephalitis and NR1-NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1-NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Median age of patients was 23 years (range 5-76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased consciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0.004) and fewer neurological relapses (p=0.009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies.The Lancet Neurology 11/2008; 7(12):1091-8. DOI:10.1016/S1474-4422(08)70224-2 · 21.82 Impact Factor