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Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness.

ABSTRACT: Patients with anti-N-methyl-D-aspartate-glutamic-receptors (NMDAR) encephalitis often develop complex abnormal movements that may manifest early in the course of illness.A 17-year-old boy developed paroxysmal exercise-induced right foot weakness, without behavioral change. Two weeks later, he had hyperthermia and convulsive status epilepticus. Intravenous valproate resolved the status, but the paroxysmal episodes of right foot weakness persisted. They recurred any time he began running, without any refractory period or other triggering factors. Neurological examination between attacks was normal. Ictal video-polygraphy showed transient loss of lower limb muscle activity without any EEG changes. Results of brain MRI and extensive laboratory tests were normal. NMDAR antibodies were present in liquor and serum. No tumor was found. He was treated with intravenous methylprednisolone plus immunoglobulins with resolution of his symptoms that have not recurred at 8-month follow-up.Our case enlarges the spectrum of abnormal movements as presentation of oligosymptomatic anti-NMDAR encephalitis.

SUBMITTER: Labate A

PROVIDER: S-EPMC4176685 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness.

Labate Angelo A Quattrone Aldo A Dalmau Josep J Gambardella Antonio A

Movement disorders : official journal of the Movement Disorder Society 20130529 6

<h4>Background</h4>Patients with anti-N-methyl-D-aspartate-glutamic-receptors (NMDAR) encephalitis often develop complex abnormal movements that may manifest early in the course of illness.<h4>Methods/results</h4>A 17-year-old boy developed paroxysmal exercise-induced right foot weakness, without behavioral change. Two weeks later, he had hyperthermia and convulsive status epilepticus. Intravenous valproate resolved the status, but the paroxysmal episodes of right foot weakness persisted. They r ...[more]

PMID: 23720271

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Project description:ObjectiveTo report the autoantigens of a new category of treatment-responsive paraneoplastic encephalitis.MethodsAnalysis 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).ResultsTwelve 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.InterpretationAntibodies 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.

Project description:ObjectiveSeizures develop in 80% of patients with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti-NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti-NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures.MethodsWe performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti-NMDAR encephalitis or polyclonal rabbit anti-NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2-week treatment was assessed with video-electroencephalography. We assessed memory, anxiety-related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole-cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures.ResultsProlonged exposure to rabbit anti-NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety-related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice.SignificanceOur findings indicate that autoantibodies can induce seizures in anti-NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.

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Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness.

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Anti-N-methyl-D-aspartate-glutamic-receptor encephalitis presenting as paroxysmal exercise-induced foot weakness.

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