CLIPPERS

Eoin P Flanagan MBBch (Dr. Flanagan of the Department of Neurology at Mayo Clinic has no relevant financial relationships to disclose.)
Sean J Pittock MD (Dr. Pittock of the Department of Neurology at Mayo Clinic has no relevant financial relationships to disclose.)
Anthony T Reder MD, editor. (Dr. Reder of the University of Chicago served on advisory boards and as a consultant for Bayer, Biogen Idec, Caremark Rx, Genentech, Genzyme, Novartis, Malinkrodt, Serono, and Teva-Marion.)
Originally released September 12, 2012; last updated December 18, 2013; expires December 18, 2016

This article includes discussion of CLIPPERS and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

The authors describe the characteristics of a brainstem syndrome called chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Patients with CLIPPERS develop the subacute onset of brainstem dysfunction, including prominent ataxia and diplopia. MRI demonstrates the hallmark feature of punctate curvilinear perivascular enhancement “peppered” throughout the pons. Pathology reveals perivascular T-cell infiltrates. The differential diagnosis is broad, and alternative etiologies need to be excluded. Response to high-dose intravenous corticosteroids is uniform, and maintenance oral steroids and alternative immunosuppressants are often necessary to prevent relapse.

Key points

 

• The characteristic clinical presentation of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a subacute pontine-centric brainstem syndrome including ataxia, dysarthria, diplopia, and facial numbness.

 

• The hallmark feature on MRI is that of punctate curvilinear patchy gadolinium enhancement “peppering” the pons, which may involve adjacent brainstem structures, cerebellum, and spinal cord.

 

• Extensive investigations are necessary to exclude alternative causes of brainstem syndromes prior to the diagnosis of CLIPPERS.

 

• Pathology reveals a perivascular, predominantly CD3-positive Tcell infiltrate. Although brainstem or cerebellar biopsy may be necessary in cases where alternative etiologies remain a distinct possibility despite rigorous other investigations, in some cases it may be diagnosed and treated without pathological confirmation.

 

• High-dose intravenous methylprednisolone is the initial treatment of choice. Improvements are notable with this regimen in all patients, but relapses are the rule, and maintenance immunosuppression is necessary.

Historical note and terminology

A case series of 8 patients with an inflammatory brainstem syndrome associated with characteristic neuroimaging findings and response to corticosteroids was first described by Drs. Pittock and Keegan at Mayo Clinic in Minnesota (USA) in collaboration with Dr. Debruyne and colleagues from Ghent University Hospital in Belgium. The syndrome was named chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) to reflect the characteristic clinical and neuroimaging features and treatment response. This seminal article was published in Brain in 2010 (Pittock et al 2010). This has been followed by additional case series (Kastrup et al 2011; Simon et al 2012; Taieb et al 2012) and many other case reports (Biotti et al 2011; Gabilondo et al 2011; Jones et al 2011; List et al 2011; Sempere et al 2011; Tohge et al 2012). As of our writing this review, there have been to our knowledge approximately 34 cases of CLIPPERS described in the literature. Given the recent recognition of this disorder, this number is expected to increase substantially over the coming years. There have been 4 patients described in the literature with some similar features to CLIPPERS but without all of the characteristic features (Duprez and Sindic 2011; Jones et al 2011; Hillesheim et al 2012; Limousin et al 2012). In particular, these patients seemed to have more homogenous confluent lesions in the pons and often did not respond to high-dose intravenous corticosteroids. Alternative diagnoses in 2 of these patients included low-grade brainstem glioma and B-cell lymphoma (Jones et al 2011; Limousin et al 2012). This highlights the need to consider pathological sampling of the lesions in atypical cases of CLIPPERS to exclude alternative causes.

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