Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)

Abstract

The classification and pathological mechanisms of many central nervous system inflammatory diseases remain uncertain. In this article we report eight patients with a clinically and radiologically distinct pontine-predominant encephalomyelitis we have named 'chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids' (CLIPPERS). The patients were assessed clinically, radiologically and pathologically at Mayo Clinic, USA and Ghent University Hospital, Belgium from 1999 to 2009. Median follow-up duration from clinical onset was 22 months (range 7-144 months). Patients underwent extensive laboratory (serum and cerebrospinal fluid), radiological and pathological testing (conjunctival, transbronchial and brain biopsies) to search for causes of an inflammatory central nervous system disorder. All eight patients (five female, three male) presented with episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and had a favourable initial response to high dose glucocorticosteroids. All patients had symmetric curvilinear gadolinium enhancement peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally spinal cord. Radiological improvement accompanied clinical response to glucocorticosteroids. Patients routinely worsened following glucocorticosteroid taper and required chronic glucocorticosteroid or other immunosuppressive therapy. Neuropathology of biopsy material from four patients demonstrated white matter perivascular, predominantly T lymphocytic, infiltrate without granulomas, infection, lymphoma or vasculitis. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a definable, chronic inflammatory central nervous system disorder amenable to immunosuppressive treatment. The T cell predominant inflammatory pathology in affected central nervous system lesions and the clinical and radiological response to immunosuppressive therapies is consistent with an immune-mediated process.

Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids Following Influenza Vaccination

“…Whereas CLIPPERS has scattered punctate gadolinium enhancement of the pons, Bickerstaff brainstem encephalitis features a uniform nongadolinium enhancement that can be found in the upper brainstem, thalamus, and the pons on MRI. 1,4,7,8 The histopathologic findings of Bickerstaff brainstem encephalitis do show chronic perivascular inflammation with activated microglia similar to CLIPPERS, but it is usually accompanied by edema and occasional microglial nodules. 8 Common viral and fungal causes were excluded by histochemical and immunohistochemical stains, although rarer pathogens may be the causative agent.…”

“…Chronic pharmacologic therapy with immunosuppressive agents is typically required for remission of symptoms. [1][2][3][4] CLIPPERS, a diagnosis of exclusion, requires the discussion of more common entities. Restricted acute disseminated encephalomyelitis in the brainstem is a consideration given the patient's history of vaccination, but was not supported given the radiologic and pathologic appearance.…”

“…Central nervous system vasculitis and neurosarcoidosis were also considered in the differential of disease with similar radiologic findings, but were excluded owing to the lack of clinical and pathologic evidence for either condition. 1,4 Although the possibility of a paraneoplastic disease was entertained because the patient had a renal cell carcinoma, this syndrome has not been typically associated with this cancer. The possibility of central pontine myelinolysis was also entertained, but no history of hyponatremia was found.…”

“…1,4 Pontine inflammation requiring long-term immunosuppressive agents suggests an autoimmune disorder. The perivascular inflammation is the common histologic clue in the diagnosis and may be the consequence of the location of the antigen inciting the disorder.…”

“…2012;136:681-685; doi: 10.5858/ arpa.2011-0428-CR) C hronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIP-PERS) is a rare central nervous system (CNS) inflammatory disease involving the pons. The disorder was first described in 2010 by Pittock et al 1 and characterized as a T-lymphocyte predominant pontine encephalomyelitis that is responsive to immunosuppression with steroids. In the authors' case series of 8 patients, the condition often worsened after glucocorticosteroid tapering or responded incompletely and required additional immunosuppressive agents for effective treatment.…”