CASPR2 antibody associated neurological syndromes in children

Abstract

To strengthen the understanding of the clinical features for CASPR2 neurological autoimmunity in children. A multicenter retrospective and prospective analysis of CASPR2 autoimmunity was conducted. Twenty-six patients were enrolled, including 25 with serum positivity and 3 with cerebrospinal fluid (CSF) positivity; 5 patients were co-positive with anti-NMDAR or anti-GABABR antibodies. Eleven patients (who manifested with refractory epilepsy, psychobehavioral abnormalities or 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 autoimmune encephalitis/ encephalopathy/ cerebellitis (including 1 whose condition was secondary to Japanese encephalitis). 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). Brain MRI revealed abnormalities in 10 patients (66.7%). Electroencephalography (EEG) recordings revealed a slow wave background in 13 patients (86.7%). Five patients showed elevated WBCs in CSF, and 4 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. Autoimmune encephalitis is the most common clinical phenotype; it can be secondary to Japanese encephalitis. 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.

Figure 1

CASPR2-IgG in serum tested by a cell-based assay (CBA) using HEK293T cells transiently cotransfected with full-length human CASPR2 and pcDNA3.1-EGFP (Scale bar: 20 µm). The patient’s IgG bound to CASPR2-transfected cells and showed red fluorescence as a positive control.

Figure 2

Brain MRI features of patients N.3, N.5, N.6, N.8 and N.10. Patient N.3, a 6-year-old boy, had a clinical-radiological presentation of Morvan syndrome including multifocal lesions in the occipital and parietal cortex and thalamus (A1, A2). Patient N.5, a 5-month-old boy, presented with encephalopathy and bilateral MRI abnormalities in the globus pallidus, corpus callosum and cerebral peduncle (B1, B2). Patient N.6, a 2-year-old girl, had a clinical-radiological presentation of autoimmune encephalitis, including cortical lesions in the frontal, parietal, occipital and temporal lobes and thalamus and cortical lesions showing enhancement with gadolinium administration (C1, C2). Patient N.8, a 5-year-old girl, presented with two episodes of fever and seizures within a week. Brain MRI showed extensive cortical lesions in the frontal, parietal, occipital and temporal lobes (D1, D2). Patient N.10, a 6-year-old boy, presented with fever, ataxia, slow responses. Brain MRI (E1–E8) showed a series of changes including lesions in the thalamus, caudate nucleus and cerebral peduncle (E1/E5, E2/E6, E3/E7, E4/E8, representing D4, D16, D30, and D50 after onset, respectively). Fluid-attenuated inversion recovery sequences were used in (A1, A2, C1, E1–E4, and C2, which show enhancement with gadolinium administration. T2 sequences were used in (E5–E8). Diffusion weighted imaging was used in (B1, B2, D1 and D2). Red arrows represent multiple cortical lesions, yellow arrows: thalamus, blue arrows: cerebral peduncle, green arrows: caudate nucleus, brown arrows: globus pallidus, white arrow: corpus callosum, black arrow: meningeal enhancement.

Figure 3

EEG features of patient N4, boy, aged 6 years, who presented with refractory epilepsy. (A) diffuse delta rhythm during awake period; (B) periodic waves from right frontal and temporal area during sleep.