The clinical spectrum of Caspr2 antibody-associated disease

Abstract

Objective: To report a large cohort of patients with antibodies against contactin-associated protein-like 2 (Caspr2) and provide the clinical spectrum of this disorder.

Methods: Serum and CSF samples were assessed at 2 neuroimmunology centers in Barcelona and Rotterdam. Patients were included if Caspr2 antibodies were confirmed with 2 independent techniques, including brain immunohistochemistry and cell-based assay. Clinical information was obtained by the authors or provided by treating physicians after patients' informed consent.

Results: Median age at symptom onset was 66 years. Of 38 patients, 34 were male. Median time to nadir of disease was 4 months (in 30% >1 year). The most frequent syndromes included limbic encephalitis (42%) and Morvan syndrome (29%). Seventy-seven percent of the patients had ≥3 of the following symptoms: encephalopathy (cognitive deficits/seizures), cerebellar dysfunction, peripheral nervous system hyperexcitability, dysautonomia, insomnia, neuropathic pain, or weight loss. A tumor, mostly thymoma, occurred in 19% of the patients. Immunoglobulin G4 subclass antibodies were present in all patients; 63% also had immunoglobulin G1 antibodies. Treatment response occurred in 93% of the patients and 25% had clinical relapses.

Conclusions: Caspr2 antibodies associate with a treatable disorder that predominantly affects elderly men. The resulting syndrome may vary among patients but it usually includes a set of well-established symptoms. Recognition of this spectrum of symptoms and consideration of the protracted clinical course are important for early diagnosis of this disorder. Prompt immunotherapy and tumor therapy (if needed) often result in improvement.

Figure 1. Immunoglobulin G (IgG) subtyping by cell-based immunofluorescence assay

Serum from patient 1 shows IgG1 and IgG4 reactivity with HEK cells expressing contactin-associated protein-like 2 (Caspr2). Serum from patient 2 shows only IgG4 reactivity. The control serum is from a healthy participant showing absence of IgG1 and IgG4 reactivity with Caspr2.

Figure 2. Treatment effect and outcome

(A) Effect of treatment in 27 patients (23 without and 4 with tumor). (B) Modified Rankin Scale (mRS) at follow-up in 33 patients. 0, no symptoms; 1, no significant disability, able to carry out all usual activities, despite some symptoms; 2, slight disability, able to look after own affairs without assistance, but unable to carry out all previous activities; 3, moderate disability, requires some help, but able to walk unassisted; 4, moderately severe disability, unable to attend to own bodily needs without assistance, and unable to walk unassisted; 5, severe disability, requires constant nursing care and attention, bedridden, incontinent; 6, dead.