The pathogenesis hypothesis and research progress of CLIPPERS: A literature review

**Background:** Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder primarily affecting the pons, midbrain, and cerebellum. First described by Pittock et al. in 2010, it is characterized by lymphocytic infiltration and responds well to corticosteroids. The disease typically presents between ages 30 and 60, with a male-to-female ratio of 3:1. This literature review aims to summarize the clinical manifestations, diagnostic criteria, pathogenesis hypotheses, and treatment approaches for CLIPPERS.

**Methods:** The authors conducted a comprehensive search of PubMed, Web of Science, Cochrane Library, China National Knowledge Infrastructure, Wanfang database, and Chinese Biomedical Literature Databases from inception to January 15, 2022, using the keywords "Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids" and "CLIPPERS." They reviewed effective treatment cases and related reports to summarize clinical features, diagnostic criteria, and pathogenesis hypotheses.

**Key Results:** The review identifies three main pathogenesis hypotheses: (1) Organ-specific autoimmunity, where target autoantigens are concentrated in the perivascular region, causing perivascular inflammation. (2) Viral infection affecting autoimmunity, with cases linked to hepatitis B virus (HBV), Epstein-Barr virus (EBV), varicella infection, and influenza vaccination. (3) Th17-mediated autoimmunity, supported by findings that rifampicin and hydroxychloroquine, which inhibit Th17 differentiation, can improve symptoms. Pathologically, CLIPPERS shows perivascular infiltration of CD3+ T and CD4+ lymphocytes, with occasional CD20+ B cells, without demyelination or vasculitis. Diagnostic criteria include subacute pontocerebellar impairment, sensitivity to steroids, and MRI findings of multiple homogenous enhancing nodules <3 mm in the pons and cerebellum, without ring enhancement or mass effect. Typical symptoms include gait ataxia, dysarthria, diplopia, and sensory abnormalities. Nonspecific symptoms may include vertigo, nausea, tinnitus, cognitive dysfunction, and epilepsy. MRI typically shows long T2 and FLAIR hyperintensities with nodular or "peppering-like" enhancement. CSF analysis may show mild abnormalities, with IL-6 as a potential biomarker. Oligoclonal bands are detected in 20-37.5% of patients. Differential diagnoses include multiple sclerosis, lymphomatoid granulomatosis, CNS vasculitis, primary CNS lymphoma, neuromyelitis optica, and autoimmune GFAP astrocytopathy. Treatment involves high-dose corticosteroid pulse therapy (e.g., methylprednisolone 1 g daily for 5 days), followed by oral prednisone tapering. A stepwise reduction scheme starting at 1 mg/kg/day for 4-8 weeks, then gradual reduction, is recommended. Immunosuppressants such as cyclophosphamide, azathioprine, rituximab, leflunomide, and hydroxychloroquine have been used in some cases. Anti-tuberculosis drugs (rifampicin, isoniazid, pyrazinamide) and anti-HBV therapy have also shown benefit in selected patients. Prognosis is generally good with continuous low-dose corticosteroid therapy, but relapses can occur with dose reduction or withdrawal. Some cases may evolve into other conditions such as lymphomatoid granulomatosis or anti-MOG-associated disorders.

**Clinical Implications:** Early recognition and treatment with high-dose corticosteroids are crucial for improving outcomes in CLIPPERS. The review emphasizes the importance of long-term maintenance therapy with slow tapering to prevent relapse. The pathogenesis hypotheses suggest potential targets for future therapies, such as Th17 pathway inhibitors. Clinicians should maintain a high index of suspicion for CLIPPERS in patients with subacute brainstem and cerebellar symptoms and characteristic MRI findings, and carefully exclude mimics through comprehensive evaluation.