Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents

Abstract

Objective: To report the clinical features of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in patients < or = 18 years old.

Methods: Information was obtained by the authors or referring physicians. Antibodies were determined by immunocytochemistry and enzyme-linked immunosorbent assay (ELISA) using HEK293 cells ectopically expressing NR1.

Results: Over an 8-month period, 81 patients (12 male) with anti-NMDAR encephalitis were identified. Thirty-two (40%) were < or =18 years old (youngest 23 months, median 14 years); 6 were male. The frequency of ovarian teratomas was 56% in women >18 years old, 31% in girls < or =18 years old (p = 0.05), and 9% in girls < or =14 years old (p = 0.008). None of the male patients had tumors. Of 32 patients < or =18 years old, 87.5% presented with behavioral or personality change, sometimes associated with seizures and frequent sleep dysfunction; 9.5% with dyskinesias or dystonia; and 3% with speech reduction. On admission, 53% had severe speech deficits. Eventually, 77% developed seizures, 84% stereotyped movements, 86% autonomic instability, and 23% hypoventilation. Responses to immunotherapy were slow and variable. Overall, 74% had full or substantial recovery after immunotherapy or tumor removal. Neurological relapses occurred in 25%. At the last follow-up, full recovery occurred more frequently in patients who had a teratoma that was removed (5/8) than in those without a teratoma (4/23; p = 0.03).

Interpretation: Anti-NMDAR encephalitis is increasingly recognized in children, comprising 40% of all cases. Younger patients are less likely to have tumors. Behavioral and speech problems, seizures, and abnormal movements are common early symptoms. The phenotype resembles that of the adults, although dysautonomia and hypoventilation are less frequent or severe in children. Ann Neurol 2009;66:11-18.

Fig 1

Criteria of anti-NR1 antibodies. (A) The reactivity of a patient's CSF antibodies with neuronal cell surface antigens. (B–D) HEK293 cells transfected with the NR1 subunit of the NMDAR. (B) The reactivity of a patient's CSF is similar to the reactivity of a rabbit polyclonal antibody to NR1 (D); (C) merges both types of immunolabeling. Technical details previously reported. (A) Immunofluorescence method using nonpermeabilized rat hippocampal neurons and patient's CSF diluted 1:10; ×800 oil lens. (B–D) Immunofluorescence method using permeabilized HEK293 cells transfected with NR1 and colabeled with patient's CSF (diluted 1:10) and a rabbit polyclonal antibody to NR1 (1:1,000, AB9864; Chemicon, Temecula, CA); ×400.

Fig 2

Distribution of age and tumors in 81 patients with anti-NMDA receptor encephalitis. Black bars indicate the number of patients with tumors (in all instances ovarian teratomas). White bars indicate the number of patients without tumors. Younger patients were less likely to have a tumor.

Fig 3

Abnormal postures in patients with anti-NMDAR encephalitis. Patient #5 developed periods of agitation with opisthotonic posturing (as shown), purposeless opening of the mouth, choreic movements with hands and arms, pressured speech, and tachycardia alternating with periods of calm. The inset corresponds to an abnormal hand posture of patient #6; this posture and associated movements were described as pill-rolling.

Fig 4

EEG activity in a patient with anti-NMDAR encephalitis. The EEG from patient #4 demonstrates continuous activity with bilateral, left predominant, frontal-central-temporal rhythmic 2–3Hz delta activity. No correlate was found between the EEG activity and patient's abnormal movements, including shoulder writhing, dystonic neck extension, tongue thrusting, drooling, chewing, and “kissing” mouth movements. The EEG findings did not change after administration of levetiracetam.