Brain biopsy is required in steroid-resistant patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)

Abstract

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a treatable brainstem encephalitis recently described by Pittock et al. [1]. We report a case with clinical, radiological, and pathological signs of CLIPPERS but with final diagnosis of type B primary central nervous system lymphoma (PCNSL).In March 2010, a 33-year-old man with unremarkable personal history was first seen in the internal medicine unit for isolated vomiting with weight loss of 5 kg. The clinical and paraclinical examinations were unremarkable. In June, he was admitted to our unit for subacute gait ataxia, dysphagia, and binocular diplopia. Clinical examination revealed bilateral sixth nerve palsy and gait ataxia with pyramidal signs. Brain magnetic resonance imaging (MRI) showed hyperintense lesions on T2-weighted and fluidattenuated inversion recovery (FLAIR) sequences within the pons, medulla, and upper cervical cord, with enhancement after gadolinium administration. Cerebrospinal fluid (CSF) analysis showed elevated levels of proteins (1.10 g/l) with normal electrophoretic pattern and without abnormal cell count (2/mm 3 ). Extensive laboratory investigations were normal. Whole-body fluorodeoxyglucose positron emission tomography (FDG-PET), and labial salivary gland biopsies were negative, including aquaporin-4 water channel and onconeural antibodies. Biopsy of pons revealed perivascular lymphocyte infiltrates without any findings of sarcoidosis, lymphoma, glioma, or lymphomatoid granulomatosis (Fig. 1d). CLIPPERS syndrome was suspected, and the patient was treated for five consecutive days with 1,000 mg intravenous methylprednisolone followed by oral prednisone 60 mg (1 mg/kg/day) every day, with dramatic recovery except for persistence of moderate gait ataxia. In August 2010, a second brain MRI showed a reduction in the number and size of brainstem lesions. Localized proton magnetic resonance spectroscopy (MRS) examination showed a slight decrease of N-acetyl-aspartate/creatine (NAA/Cr) ratio (1:52) and an increase in choline/creatine (Cho/Cr) ratio (1:58) in the brain and medulla (Fig. 1a). The dose of steroids was reduced by 10 mg/week until 30 mg/ day was reached. In September 2010, he complained of numbness in all four limbs with worsening gait ataxia. A third brain MRI showed enlargement of the pontine lesions with necrosis. The MRS showed a slightly elevated Cho/ NAA ratio, as well as strong resonance of lipids and lactates (Fig. 1b). The patient was then treated with 1,000 mg intravenous methylprednisolone for 5 days; this was followed by double-filtration plasmapheresis. Because no further clinical improvement was observed, monthly intravenous cyclophosphamide was added. In October, the fourth brain MRI revealed radiological progression of brainstem lesions with the appearance of gadoliniumenhanced lesions localized close to the left lateral ventricle.

Atypical chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids (CLIPPERS), primary angiitis of the CNS mimicking CLIPPERS or overlap syndrome? A case report

“…A careful diagnostic workup is required in every patient with a suspected diagnosis of CLIPPERS. Although not specific for CLIPPERS, brain biopsy will help to rule out important differential diagnoses, in particular in steroid-unresponsive cases, as a number of conditions, including brain tumours, may radiologically mimic CLIPPERS [6,7]. Of note, our patient who required chronic immunosuppressive treatment for disease stabilisation responded well to methotrexate without concomitant steroid treatment, while she had experienced an intracranial haemorrhage while on pulsed intravenous cyclophosphamide and myelotoxicity on azathioprine.…”

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after treatment for Hodgkin’s lymphoma

“…We believe that the pathogenesis of CLIPPERS is not tightly associated with CNS lymphoma, although there were several patients with CLIPPERS progressed to CNS lymphoma in the literature [2][3][4][5]. The underlying pathogenesis of CLIPPERS may also include some autoimmune or hematological disorders.…”

“…Characteristics of four patients in the previous reports who presented initially with CLIPPERS features and progressed eventually to CNS lymphoma are summarized in Table 1 [2][3][4][5]. They were all male and aged from 33 to 74 years.…”

“…No underlying diseases or conditions were initially identified in CLIPPERS. However, there have been several case reports in which CLIPPERS was diagnosed by an initial brain biopsy, but the immunosuppressive therapy was ineffective, and CNS lymphoma was finally confirmed by a second brain biopsy [2][3][4][5]. These case reports suggest that CLIPPERS could occur as a herald of CNS lymphoma.…”

Horizontal eyeball akinesia as an initial manifestation of CLIPPERS

“…Differential diagnoses of CLIPPERS include CNS lymphoma, lymphomatoid granulomatosis, CNS infections, neurosarcoidosis, neuro-Behçet's disease, Sjögren's syndrome, MS, NMO, primary angiitis of the CNS, CNS histiocytosis, acute disseminated encephalomyelitis, Bickerstaff brainstem encephalitis, other inflammatory demyelinating CNS diseases, other autoimmune encephalitides, brainstem tumors, and paraneoplastic disorders. [1,2,10,11,7,31,39,40,41,32,42,43,6] …”