CASPR2 Neurological Autoimmunity in Children

Abstract Objective To identify the clinical features of CASPR2 neurological autoimmunity in children and to strengthen the understanding of the disease for developing diagnosis and treatment strategies. Methods A multicenter retrospective analysis and prospective observation of CASPR2 autoimmunity in the past 7 years was conducted. Results Twenty-six anti-CASPR2-positive patients were enrolled in this study, including 25 with serum positivity and 3 with cerebrospinal fluid (CSF) positivity (2 patients with both serum and CSF positivity); 3 patients were co-positive with anti-NMDAR antibody and 1 was copositive with anti-GABABR antibody. Eleven patients (6 manifesting with refractory epilepsy, 4 manifesting with psychobehavioral abnormalities and 1 accompanied with germinoma) presented with low antibody titers, relatively normal MRI/EEG/CSF examinations, and poor response to immunotherapy and were thus considered false positive (42.3%). Fifteen patients were diagnosed with anti-CASPR2-related neurological autoimmunity: 10 with autoimmune encephalitis (including 2 manifested as Morvan syndrome and 1 whose condition was secondary to Japanese encephalitis), 4 with typical clinical features of autoimmune encephalopathy, and 1 with autoimmune cerebellitis. The most common symptoms included disorders of consciousness (10/15), fever (8/15), psychological symptoms/abnormal behaviors (8/15), sleep disorders (8/15), seizures (7/15), movement disorders (5/15), autonomic symptoms (5/15), peripheral nerve hyperexcitability/neuromyotonia (5/14) and weakness/hemiplegia (4/15). Brain MRI revealed abnormalities in 10 patients (66.7%). The most common sites of lesions were the cerebral cortex (6/15, widely distributed across the frontal, parietal, occipital and temporal lobes) and thalamus (5/15). Electroencephalography (EEG) recordings revealed a slow wave background in 13 patients (86.7%). Five of 15 patients showed elevated WBCs in the CSF, and 4 of 15 patients showed elevated protein levels in the CSF. Thirteen patients received immunotherapy (rituximab was adopted in 2 cases) and recovered well. Two patients received symptomatic treatment, and the recovery was slow and accompanied by emotional abnormalities and developmental delay. Conclusions CASPR2 autoantibody disease is not very rare in children and can occur in infancy. The most common clinical phenotypes of CASPR2-related autoimmunity were encephalitis phenotype, including Morvan syndrome and cerebellar ataxia. We also first reported a case of autoimmune encephalitis secondary to Japanese encephalitis. The prognosis of this disease is good, and rituximab can be used in patients who respond poorly to conventional immunotherapy. The high false-positive rate of anti-CASPR2 in refractory epilepsy and the psychobehavioral abnormalities needs to be explored further.