Clinical, Radiologic, and Immunologic Features of Patients With CTLA4 Deficiency With Neurologic Involvement

Abstract

Background and Objectives:CTLA4 deficiency (CTLA4d) is a disease with multisystem auto-immune features, including neurological manifestations. We aimed to describe neurological involvement in these patients.Methods:We performed a cross-sectional observational study using the French Reference Centre for Primary Immunodeficiencies (CEREDIH) registry, plus a surveillance in national society networks. Participants with confirmed CTLA4d and neurological involvement were included. Clinical, laboratory and radiological features were collected, as well as treatments. Available MRI were double-reviewed.Results:Among 70 patients with CTLA4d, 13 patients (21%) had neurological involvement. Neurological symptoms began at a median age of 18 [15-45] years, mostly occurring after systemic manifestations (median delay: 8.5 [4.5-10.5] years). Main symptoms included headaches, focal deficit (54% each) and seizures (38%). MRI detected at least one large contrast-enhancing lesion in eight patients. Lesions reminiscent of multiple sclerosis lesions were found in six patients. Cerebellar (6 patients) and large spinal cord lesions (3 patients) were common. Ten patients were treated with Abatacept, of whom nine (90%) showed good clinical and radiological response.Discussion:Neurologic involvement is common among patients with CTLA4d. Despite its rarity, and considering the suspected efficacy of Abatacept, neurologists should be aware of the characteristics of CTLA4d neurological involvement.

Management of Autoimmune Encephalitis in a 7-Year-Old Child With CTLA-4 Haploinsufficiency and AMPA Receptor Antibodies

“…In the small number of previously reported cases of CTLA-4h–related CNS involvement, the majority had T2-hyperintense MRI brain lesions. 4,6-10 Only 3 cases had abnormal CSF analysis but normal brain MRI, 8,9 similar to our case. Notably, in the majority, the genetic diagnosis was not known at onset of symptoms.…”

“…As a result, the subsequent treatment initially did not prioritize CTLA-4 replacement therapy and only after its addition partial or even complete recovery has been reported. 4 , 6 - 11 In our case, despite the immediate initiation of abatacept, additional treatment was still required.…”

“…The CNS can be affected in one-third although this is usually seen years after the onset of systemic autoimmune or infectious manifestations, accompanied by inflammatory CNS lesions on brain MRI. 2 , 4 A diagnostic delay of months to years before a genetic diagnosis can result in late initiation of targeted treatment and delayed improvement. Involvement of antineuronal antibodies in a patient with CTLA-4h and its possible significance for the clinical picture and treatment has not been previously reported.…”