Pediatric CLIPPERS: Expanding the Neuroimaging Spectrum of a Rare Steroid-Responsive Neuroinflammatory Syndrome—A Systematic Review

Abstract

Highlights What are the main findings? This systematic review summarizes the currently available evidence on the clinical, neuroradiological, cerebrospinal fluid, treatment, and outcome characteristics reported in pediatric CLIPPERS. The available evidence suggests that pediatric CLIPPERS may present with neuroimaging findings extending beyond the classic pontocerebellar pattern, including supratentorial and spinal cord involvement in selected cases, while generally maintaining a corticosteroid-responsive course. What are the implications of the main findings? Awareness of the reported clinical and neuroimaging manifestations may facilitate earlier recognition of pediatric CLIPPERS and support timely diagnostic evaluation and immunosuppressive treatment in selected patients. Further prospective multicenter studies are needed to validate the proposed clinical and neuroimaging spectrum, refine diagnostic criteria, optimize long-term immunosuppressive strategies, and better define outcomes in pediatric CLIPPERS. Abstract Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an uncommon inflammatory disorder of the central nervous system that is exceptionally rare during childhood. Although pontocerebellar punctate enhancement is considered its neuroradiological hallmark, the full spectrum of pediatric clinical and imaging manifestations remain poorly characterized because available evidence is limited to isolated case reports and small case series. We conducted a systematic review to characterize the clinical presentation, neuroimaging phenotype, diagnostic challenges, therapeutic strategies, and outcomes of pediatric CLIPPERS. Methods: A systematic literature search was conducted in PubMed/MEDLINE and Scopus from database inception to December 2025, following PRISMA guidelines. Studies reporting patients younger than 18 years with a diagnosis of CLIPPERS were eligible. Clinical, neuroradiological, laboratory, histopathological, therapeutic, and outcome data were extracted using a standardized form. Diagnostic certainty was assessed according to the Tobin criteria, and methodological quality was evaluated using the Joanna Briggs Institute (JBI) critical appraisal tools. Results: Ten studies comprising 13 pediatric patients fulfilled the inclusion criteria. Median age at presentation was 13 years (range 3–16 years), with a slight male predominance. Ataxia was the most common presenting manifestation (84.6%), followed by cranial nerve involvement (61.5%) and diplopia (46.2%). Magnetic Resonance Imaging (MRI) consistently demonstrated brainstem involvement, predominantly affecting the pons (84.6%) and cerebellum (76.9%), while supratentorial lesions (46.2%), midbrain involvement (46.2%), and spinal cord abnormalities (23.1%) suggest that the neuroradiological phenotype may extend beyond the classic pontocerebellar pattern, although these findings were observed in a limited number of patients. Cerebrospinal fluid (CSF) findings were nonspecific, typically showing normal results or mild lymphocytic pleocytosis. Histopathological examination, when available, demonstrated characteristic perivascular T-cell-predominant inflammatory infiltrates. All patients received high-dose corticosteroids with initial clinical improvement; however, relapses occurred in 61.5% of cases, frequently during corticosteroid tapering, often requiring steroid-sparing immunosuppressive therapy. Based on the available evidence, we suggest a practical clinic-radiological framework to facilitate the evaluation of children presenting with suspected CLIPPERS. Conclusions: Pediatric CLIPPERS represents a rare but increasingly recognized neuroinflammatory disorder characterized by marked corticosteroid responsiveness and a wide range of neuroradiological phenotypes. Although pontocerebellar involvement remains the defining imaging feature, supratentorial and spinal cord lesions are not uncommon and should not exclude the diagnosis after careful consideration of alternative inflammatory, autoimmune, infectious, and neoplastic disorders. Given the high relapse rate and the limited quality of available evidence, prolonged follow-up and collaborative multicenter studies are needed to refine pediatric diagnostic criteria and optimize long-term management.