Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens

Abstract

Objective: To report the clinical and investigative features of children with a clinical diagnosis of probable autoimmune encephalopathy, both with and without antibodies to central nervous system antigens.

Method: Patients with encephalopathy plus one or more of neuropsychiatric symptoms, seizures, movement disorder or cognitive dysfunction, were identified from 111 paediatric serum samples referred from five tertiary paediatric neurology centres to Oxford for antibody testing in 2007-2010. A blinded clinical review panel identified 48 patients with a diagnosis of probable autoimmune encephalitis whose features are described. All samples were tested/retested for antibodies to N-methyl-D-aspartate receptor (NMDAR), VGKC-complex, LGI1, CASPR2 and contactin-2, GlyR, D1R, D2R, AMPAR, GABA(B)R and glutamic acid decarboxylase.

Results: Seizures (83%), behavioural change (63%), confusion (50%), movement disorder (38%) and hallucinations (25%) were common. 52% required intensive care support for seizure control or profound encephalopathy. An acute infective organism (15%) or abnormal cerebrospinal fluid (32%), EEG (70%) or MRI (37%) abnormalities were found. One 14-year-old girl had an ovarian teratoma. Serum antibodies were detected in 21/48 (44%) patients: NMDAR 13/48 (27%), VGKC-complex 7/48(15%) and GlyR 1/48(2%). Antibody negative patients shared similar clinical features to those who had specific antibodies detected. 18/34 patients (52%) who received immunotherapy made a complete recovery compared to 4/14 (28%) who were not treated; reductions in modified Rankin Scale for children scores were more common following immunotherapies. Antibody status did not appear to influence the treatment effect.

Conclusions: Our study outlines the common clinical and paraclinical features of children and adolescents with probable autoimmune encephalopathies. These patients, irrespective of positivity for the known antibody targets, appeared to benefit from immunotherapies and further antibody targets may be defined in the future.

Keywords: Amnesia; Epilepsy; Limbic System; Movement Disorders; Paediatric Neurology.

Figure 1

Study flow chart showing expert review and record linkage outcome. Four patients who were excluded from the study because they were not encephalopathic were positive for autoantibodies in the serum; two had VGKC-complex antibodies (one Guillain–Barré syndrome and one myositis) and two had N-methyl-D-aspartate receptor antibodies (one movement disorder, one optic neuritis). Patients with demyelinating conditions, Rasmussen encephalitis, or with neurological symptoms secondary to systemic diseases could have an autoimmune mechanism for their disorder but were excluded from this study.

Figure 2

Demographics of patients with autoimmune encephalopathy. (A) Age at disease onset of the 48 paediatric patients with autoimmune encephalopathy divided between antibody positive and antibody negative, male and female patients. (B) Ethnicity of the 48 paediatric patients with autoimmune encephalopathy; 24 patients (50%) were non-Caucasian: Asian (13), Black (5) and Other (6).

Figure 3

Outcome of all patients with autoimmune encephalopathy. The problems encountered in children at follow-up of 1–5 years (mean=24 months). Twenty patients recovered completely. Cognitive problems were still present in 23, seizures in 16, behavioural problems in 17 and two patients had additional motor problems.

Figure 4

Modified Rankin Scale (mRS) for children score reduction in total cohort and in the antibody positive and negative groups, stratified according to immunotherapies. A significant improvement of the mRS score between nadir and final follow-up, as measured by the χ² test, was seen in the patients who received immunotherapies (p=0.04) (A), with a similar trend in the antibody positive (B) and antibody negative (C) groups.