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A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

ABSTRACT: Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range?=?12-41), 91% were women, and 74% had full recovery after therapy and tumor resection. These findings uncover a novel phenotype of paraneoplastic opsoclonus that until recently was likely considered idiopathic or postinfectious. The triad of young age (teenager to young adult), systemic teratoma, and high response to treatment characterize this novel brainstem-cerebellar syndrome.

SUBMITTER: Armangue T

PROVIDER: S-EPMC4819999 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

Armangue Thaís T Titulaer Maarten J MJ Sabater Lidia L Pardo-Moreno Javier J Gresa-Arribas Nuria N Barbero-Bordallo Natalia N Kelley Gordon R GR Kyung-Ha Noh N Takeda Akitoshi A Nagao Takahiro T Takahashi Yukitoshi Y Lizcano Angélica A Carr Aisling S AS Graus Francesc F Dalmau Josep J

Annals of neurology 20130910 3

Among 249 patients with teratoma-associated encephalitis, 211 had N-methyl-D-aspartate receptor antibodies and 38 were negative for these antibodies. Whereas antibody-positive patients rarely developed prominent brainstem-cerebellar symptoms, 22 (58%) antibody-negative patients developed a brainstem-cerebellar syndrome, which in 45% occurred with opsoclonus. The median age of these patients was 28.5 years (range = 12-41), 91% were women, and 74% had full recovery after therapy and tumor resectio ...[more]

PMID: 23613036

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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:We report seven patients, six from a single institution, who developed subacute limbic encephalitis initially considered of uncertain aetiology. Four patients presented with symptoms of hippocampal dysfunction (i.e. severe short-term memory loss) and three with extensive limbic dysfunction (i.e. confusion, seizures and suspected psychosis). Brain MRI and [(18)F]fluorodeoxyglucose (FDG)-PET complemented each other but did not overlap in 50% of the patients. Combining both tests, all patients had temporal lobe abnormalities, five with additional areas involved. In one patient, FDG hyperactivity in the brainstem that was normal on MRI correlated with central hypoventilation; in another case, hyperactivity in the cerebellum anticipated ataxia. All patients had abnormal CSF: six pleocytosis, six had increased protein concentration, and three of five examined had oligoclonal bands. A tumour was identified and removed in four patients (mediastinal teratoma, thymoma, thymic carcinoma and thyroid cancer) and not treated in one (ovarian teratoma). An immunohistochemical technique that facilitates the detection of antibodies to cell surface or synaptic proteins demonstrated that six patients had antibodies to the neuropil of hippocampus or cerebellum, and one to intraneuronal antigens. Only one of the neuropil antibodies corresponded to voltage-gated potassium channel (VGKC) antibodies; the other five (two with identical specificity) reacted with antigens concentrated in areas of high dendritic density or synaptic-enriched regions of the hippocampus or cerebellum. Preliminary characterization of these antigens indicates that they are diverse and expressed on the neuronal cell membrane and dendrites; they do not co-localize with VGKCs, but partially co-localize with spinophilin. A target autoantigen in one of the patients co-localizes with a cell surface protein involved in hippocampal dendritic development. All patients except the one with antibodies to intracellular antigens had dramatic clinical and neuroimaging responses to immunotherapy or tumour resection; two patients had neurological relapse and improved with immunotherapy. Overall, the phenotype associated with the novel neuropil antibodies includes dominant behavioural and psychiatric symptoms and seizures that often interfere with the evaluation of cognition and memory, and brain MRI or FDG-PET abnormalities less frequently restricted to the medial temporal lobes than in patients with classical paraneoplastic or VGKC antibodies. When compared with patients with VGKC antibodies, patients with these novel antibodies are more likely to have CSF inflammatory abnormalities and systemic tumours (teratoma and thymoma), and they do not develop SIADH-like hyponatraemia. Although most autoantigens await characterization, all share intense expression by the neuropil of hippocampus, with patterns of immunolabelling characteristic enough to suggest the diagnosis of these disorders and predict response to treatment.

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A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

Publications

A novel treatment-responsive encephalitis with frequent opsoclonus and teratoma.

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