CASPR2 autoimmunity in children expanding to mild encephalopathy with hypertension

Abstract

ObjectiveTo delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies.MethodsRetrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease.ResultsTen children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy.ConclusionHigh-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.

Combining clinical and molecular heterogeneity within CASPR2-antibody mediated diseases: towards the underlying disease biology

“…Such absence of detectable CSF CASPR2-antibodies in patients with CNS-localisable features may represent an emerging theme in the field. 3 A similar trend was observed for serum CASPR2antibody levels: these were highest in both LE groups>PNH/+>PNH/-. Co-existent LGI1-antibodies were only detected in the PNH/+ patients with a malignant thymoma, a finding which may usefully help accurately identify a paraneoplastic subgroup.…”

“… 2–4 This clinical diversity has intensified with the interweaving of increasingly broad observations regarding patient demographics and tumour status. 3 One method to deconvolute clinical boundaries is to use the fundamental biology as a gold standard for classification. In the paper by Muñiz-Castrillo, the authors explain the complexity underlying the CASPR2-antibody diseases using a data-driven approach to phenotyping, in parallel with immunological and genetic markers integral to disease pathogenesis.…”

“…Today, cramps, neuropathic pain, hyperhidrosis, hypertension, seizures, cognitive impairment, psychiatric features and cerebellar ataxia are all recognised associations. [2][3][4] This clinical diversity has intensified with the interweaving of increasingly broad observations regarding patient demographics and tumour status. 3 One method to deconvolute clinical boundaries is to use the fundamental biology as a gold standard for classification.…”

Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions

“…At 3 years of age, he was diagnosed with autism spectrum disorder. The patient's clinical and serological findings were reported within a series of children with CASPR2 autoimmunity (Syrbe et al, 2020).…”

Autoimmune encephalitis in children and adolescents

“…This useful definition developed within adult neurology can usually be applicated to adolescents but is not always fully adequate in children < 5 years of age, because their presentation may differ: Some young cases present without the full spectrum of symptoms (so that the aspect of the abovementioned "uncommon symptom combination" is not evident); in other instances, the dominant features are not observed to adults (e.g. the massive arterial hypertension in young children with Morvan syndrome and CASPR2 antibodies [13]). It therefore remains a challenge to clinical experience whom to further evaluate for suspected autoimmune encephalitis.…”