CLIPPERS Syndrome: A Rare Inflammatory Disease of the Central Nervous System

By SWA

CLIPPERS syndrome (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids) is a rare, chronically inflammatory disease of the central nervous system (CNS) that primarily affects the brainstem—especially the pons—and the cerebellum. The condition was first described in 2010 by Pittock et al., and has since been diagnosed in only a small number of patients worldwide (Pittock et al., 2010).

What is CLIPPERS?

The acronym describes the core features of the disease:

  • Chronic: The course of the disease is long-lasting or relapsing.
  • Lymphocytic: The inflammation is characterized by infiltration of lymphocytes.
  • Pontine Perivascular Enhancement: MRI shows punctate or small patchy contrast enhancement around blood vessels in the pons.
  • Steroid-Responsive: Symptoms and MRI changes improve significantly under corticosteroid treatment.

Symptoms

The clinical presentation is variable and depends on the location of the inflammatory lesions. Common symptoms include:

  • Gait instability and balance disorders (ataxia)
  • Speech disturbances (dysarthria)
  • Double vision (diplopia)
  • Facial sensory disturbances (e.g., tingling or numbness)
  • Headaches
  • Cognitive impairments
  • Abnormal eye movements or other cranial nerve dysfunctions

Diagnosis

Diagnosis is based on a combination of clinical findings, characteristic MRI features, exclusion of other diseases, and a good clinical response to steroids.

1. Imaging (MRI):
MRI shows typical, multiple, punctate or linear contrast-enhancing lesions in the pons, cerebellum, and sometimes the midbrain. This imaging pattern is often referred to as the "peppered pons" (Zhou et al., 2014).

2. CSF Analysis (Lumbar Puncture):
Cerebrospinal fluid (CSF) typically shows mild lymphocytic pleocytosis and sometimes slightly elevated protein. Oligoclonal bands may be present but are not specific.

3. Biopsy:
In unclear cases or atypical presentations, a brain biopsy may be necessary. Histopathology usually shows perivascular infiltration dominated by T-lymphocytes, with no signs of malignancy (Kantarci et al., 2012).

4. Exclusion of Other Conditions:
Since similar MRI findings can occur in infectious, neoplastic, or vasculitic diseases, CLIPPERS is considered a diagnosis of exclusion. Differential diagnoses include:

Pathogenesis

The exact cause of CLIPPERS syndrome remains unclear. It is believed to involve a misdirected immune response, possibly triggered by viral infections (e.g., COVID-19, hepatitis B, varicella-zoster virus). To date, no genetic predisposition has been identified.

Treatment

First-line therapy involves the administration of high-dose corticosteroids (e.g., intravenous methylprednisolone). Most patients show significant clinical and radiological improvement within days.

Long-term immunosuppressive maintenance therapy is often required to prevent relapses. Medications such as methotrexate, azathioprine, or mycophenolate mofetil are commonly used. In some cases, rituximab or cyclophosphamide has been administered (Taieb et al., 2019).

Course and Prognosis

With appropriate therapy, the prognosis is generally favorable. However, relapses are common if maintenance therapy is discontinued. Early diagnosis and treatment are crucial to prevent permanent neurological deficits.

Long-term data are limited, but existing reports suggest that with stable immunosuppressive therapy, patients can maintain a good quality of life (Tobin et al., 2017).

Summary

CLIPPERS syndrome is a rare but important differential diagnosis among inflammatory CNS diseases with characteristic MRI findings. The combination of a "peppered" brainstem pattern on MRI, clinical symptoms, and a strong response to corticosteroids strongly suggests the diagnosis. Long-term immunomodulatory treatment is essential to prevent relapses and preserve neurological function.

References

  • Pittock, S. J., Debruyne, J., Krecke, K. N., Brown, P. D., McKeon, A., & Parisi, J. E. (2010). Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain, 133(9), 2626–2634. https://doi.org/10.1093/brain/awq164
  • Tobin, W. O., Pittock, S. J., & Weinshenker, B. G. (2017). CLIPPERS and other chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids mimics: Diagnostic and therapeutic challenges. Current Opinion in Neurology, 30(3), 312–319. https://doi.org/10.1097/WCO.0000000000000447

 

© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742

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