Dataset Information

Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.

ABSTRACT:

Objective

To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.

Study design

Review of clinical data, long-term follow-up, and immunologic studies performed in a single center in Spain in the last 4 years.

Results

The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%), the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other 40% psychiatric. One month into the disease, all patients had involuntary movements and alterations of behavior and speech. All patients received steroids, intravenous immunoglobulin or plasma exchange, and 7 rituximab or cyclophosphamide. With a median follow up of 17.5 months, 85% had substantial recovery, 10% moderate or severe deficits, and 1 died. Three patients had previous episodes compatible with anti-NMDAR encephalitis, 2 of them with additional relapses after the diagnosis of the disorder. Ovarian teratoma was identified in 2 patients, 1 at onset of encephalitis and the other 1 year later. Two novel observations (1 patient each) include, the identification of an electroencephalographic pattern ("extreme delta brush") considered characteristic of this disorder, and the development of anti-NMDAR encephalitis as post herpes simplex encephalitis choreoathetosis.

Conclusions

The initial symptoms of pediatric anti-NMDAR encephalitis vary from those of the adults (more neurologic and less psychiatric in children), the development of a mono-symptomatic illness is extremely rare (except in relapses), and most patients respond to treatment. Our study suggests a link between post herpes simplex encephalitis choreoathetosis and anti-NMDAR encephalitis.

SUBMITTER: Armangue T

PROVIDER: S-EPMC3582718 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.

Armangue Thaís T Titulaer Maarten J MJ Málaga Ignacio I Málaga Ignacio I Bataller Luis L Gabilondo Iñigo I Graus Francesc F Dalmau Josep J

The Journal of pediatrics 20121116 4

<h4>Objective</h4>To report the clinical features of 20 pediatric patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.<h4>Study design</h4>Review of clinical data, long-term follow-up, and immunologic studies performed in a single center in Spain in the last 4 years.<h4>Results</h4>The median age of the patients was 13 years (range, 8 months-18 years), 70% were female. In 12 patients (60%), the initial symptoms were neurologic, usually dyskinesias or seizures, and in the other ...[more]

PMID: 23164315

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Project description:Background: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been discovered for more than a decade, but the establishment of standardized immunotherapy protocol for pediatric patients still needs more clinical evidence. Methods: A multicenter, retrospective study was conducted on pediatric patients diagnosed with anti-NMDAR encephalitis between November 2011 and December 2018. The clinical records including clinical manifestations, immunotherapy strategies, and outcomes were collected and analyzed. Results: A total of 386 patients were included in our study and the median onset age was 8.00 (IQR 4.83-10.90) years. All patients received first-line immunotherapy and the majority (341, 88.3%) used the standard combination of methylprednisolone pulses (MEP) and intravenous immunoglobulins (IVIG), but 211 patients did not show satisfactory improvement (mRS ≥ 3). Mainly three treatment strategies were applied after first-line immunotherapy: second-line immunotherapy, repetitive first-line immunotherapy, and maintaining oral prednisolone. For patients with mRS ≥ 4 after first-line immunotherapy, the incidence of poor outcome (mRS ≥ 3) in oral prednisolone group was higher than that in other treatment groups (p = 0.039). No difference in complete recovery rate (mRS = 0) was found between patients receiving second-line and repetitive first-line immunotherapy, or patients using long-term and short-term prednisolone. Out of 149 patients who received anti-myelin oligodendrocyte glycoprotein antibody (MOG-Ab) test, 27 (18.12%) were positive. Patients with concomitantly positive MOG-Ab showed milder conditions compared to patients with typical anti-NMDAR encephalitis and were more inclined to relapses. We also identified female, MOG-Ab positive, and not receiving second-line and/or repetitive first-line immunotherapy were risk factors for relapses. Conclusions: For patients with mRS ≥ 4 after first-line immunotherapy and patients with concomitantly positive MOG-Ab, second-line immunotherapy is recommended. When second-line immunotherapy is not applicable, repetitive first-line immunotherapy can be considered as an option. Both second-line and repetitive first-line immunotherapy are beneficial to reduce relapse rate. The duration of sequential oral prednisolone can be shortened after fully evaluating patients' conditions.

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.

Dataset Information

Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.

Objective

Study design

Results

Conclusions

Publications

Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients.

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