CLIPPERS: Is it for Real?
Abstract & Commentary
By Joseph E. Safdieh, MD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Safdieh reports no financial relationships relevant to this field of study.
Synopsis: CLIPPERS is a recently described steroid- responsive neurological syndrome manifested by subacute progressive cerebellar and brainstem inflammation with characteristic MRI appearance.
Sources: Simon NG, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry 2012 83:15-22. Kira J. The expanding phenotype of CLIPPERS: Is it a disease or a syndrome? J Neurol Neurosurg Psychiatry 2012 83:2-3.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, known by the acronym CLIPPERS, is a recently described neurological entity manifested by steroid-responsive cerebellar dysfunction. The etiology of the entity is unknown and may be an independent clinical entity (a disease) or a syndrome caused by an underlying medical disorder. The authors of this paper add five new cases to the literature, all of which include neuropathology.
All five cases manifested gait ataxia. In three cases, this was the presenting symptom. In one case, headaches and fatigue were the presenting symptoms and in another, right facial nerve palsy was the presenting symptom. Most patients developed dysarthria and limb ataxia, and four of five patients developed cognitive dysfunction. The mean age of onset was 43 (range 20-65), affecting four men and one woman. All patients had characteristic MRI features including numerous punctate or nodular gadolinium enhancing lesions bilaterally in the pons, cerebellum, and/or brachium pontis without mass effect, and with minimal or no vasogenic edema and no restricted diffusion on diffusion-weighted MRI. Patients with cognitive impairment also demonstrated cerebral atrophy. Cerebrospinal fluid (CSF) had mild lymphocytic pleocytosis and/or elevated protein in some cases. Two patients had parotid gland uptake on body PET scan; parotid biopsies were either normal or demonstrated nonspecific inflammation. One patient's CSF demonstrated oligoclonal banding. Two patients had positive ANA, one with positive SS-A.
All five patients eventually underwent brain biopsy and all cases demonstrated a predominantly white matter-based perivascular and parenchymal lymphohistiocytic inflammatory infiltrate with accompanying reactive gliosis. There were no neutrophils or eosinophils in any of the specimens. The perivascular inflammation centered around both small arteries and veins. All cases demonstrated axonal injury, and some elements of demyelination (not focal) were seen in three cases. There was no evidence of vasculitis. The majority of white blood cells were CD4+ lymphocytes and monocytes. There was no evidence of atypical lymphocytosis, EB virus infection, or viral inclusions.
All patients demonstrated a marked improvement with corticosteroid therapy, although it was often incomplete and relapse was common upon withdrawal of the steroids. In follow-up imaging, all patients had resolution of the gadolinium enhancing lesions, but they all developed cerebellar atrophy and three of five developed cortical atrophy. Clinical relapses were associated with recurrence of the gadolinium enhancement.
Commentary
In neurology there are a number of poorly understood clinical entities that respond to steroids. The most famous one is variably known as Hashimoto encephalopathy or SREAT (steroid-responsive encephalopathy with associated anti-thyroid antibodies). Experts debate whether this syndrome is a disease in its own right. For the time being, CLIPPERS can be added to that list as well. That said, one feature that distinguishes CLIPPERS from SREAT is the typical MRI appearance, which does suggest that there may be some underlying disease. The difficulty in diagnosis is that there are other neurological disorders, notably neuro-Behcet disease which can manifest without systemic symptoms and can cause a relapsing posterior fossa lymphocytic inflammatory disorder. It is not yet clear that CLIPPERS is merely describing cases of Behcet disease isolated to the CNS. Since there is no diagnostic biomarker for CLIPPERS, neurologists who encounter cases of suspected CLIPPERS, should make sure to investigate for all other potential causes, including Behcet, sarcoidosis, lymphoma, and systemic connective tissue diseases, to name a few. It is important to note that patients do respond to intravenous corticosteroids, and a steroid trial should be administered, once lymphoma has been excluded.
CLIPPERS is a recently described steroid- responsive neurological syndrome manifested by subacute progressive cerebellar and brainstem inflammation with characteristic MRI appearance.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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