CLIPPERS Syndrome

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Dear Editor, Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was first described in 2010 by Pittock et al., but the incidence and etiology have yet to be discovered. Since then, approximately 140 cases have been identified from 100 studies worldwide. From a clinical point of view, it may present with various symptoms, but the most common are diplopia, dysarthria, ataxia, and motor and sensory findings.[1] Other conditions must be excluded before the diagnosis of CLIPPERS can be made. We present a 56-year-old male patient without any disease other than hypertension. In addition to the symptoms of dizziness, nausea, and vomiting that started 1 month before the admission to our institution, the patient had a bilateral, occipital localized, and throbbing headache for 1 week. Physical examination revealed mild left peripheral facial paralysis, right 4/5 hemiparesis, right hemihypesthesia that did not involve half of the face, increased pathologic tendon reflex response in the right extremities, and a positive ataxic gait with Romberg sign. Brain and spinal cord T2-weighted fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging magnetic resonance imaging (MRI) revealed marked hyperintense edema with nondiffusion-restricting enlargement that thoroughly homogenized the pons and extended toward the pontobulbar region on T2W images and linear punctate and heterogeneous contrast enhancement on contrast images [Figure 1]. No bleeding or increased vascularity was observed in the susceptibility-weighted imaging sequence lesion. No pathology was detected in arterial magnetic resonance (MR) angiography. Hypoperfusion was detected in the cerebral blood volume values of the lesion on perfusion MRI. The choline peak slightly increased in MR spectroscopy.Figure 1: Baseline magnetic resonance imaging scans at admission. Salt-and-pepper appearance pontine and cerebellar enhancing lesionsThe blood test gave expected results: serology tests for HIV, syphilis, Borrelia, Brucella, Cytomegalovirus, rubella, Toxoplasma, chlamydia, varicella zoster, parvovirus, herpesvirus family and hepatitis A, B, and C viruses, as well as antineutrophil antibodies, were negative. Cerebrospinal fluid (CSF) analysis revealed 12/mm3 leukocyte cells and mild pleocytosis with high protein levels (83.4 mg/dL). No tumor cells were detected. CSF and serum results were negative for onconeuronal and viral serologic antibodies. Anti-aquaporin-4 immunoglobulin G (IgG) antibody and myelin oligodendrocyte glycoprotein IgG antibody were found negative in both cell-based assay and immunofluorescence assay methods. Contrast-enhanced computerized tomography scans of the neck, thorax, abdomen, and pelvis revealed no signs of malignancy. Treatment was started with intravenous methylprednisolone of 1 g/day for 10 days. Gait instability, motor deficit, and facial paralysis improved 48 h after the start of treatment. Then, 0.2 mg/kg/day oral methylprednisolone and 0.5 mg/kg/day azathioprine, targeting dose titration up to an additional 1 mg/kg, were continued. The patient was re-evaluated 2 and 6 weeks later. Neurologic examinations were normal at both visits. In the 2nd week brain MRI study, T2-weighted FLAIR sequences revealed that punctate hyperintensities and gadolinium-retaining lesions were highly reduced and disappeared in the 6th week [Figure 2]. CLIPPERS syndrome was diagnosed with characteristic radiologic images of perivascular involvement of the pons, which responded very well to steroids and exclusion of other systemic diseases.Figure 2: Second week (left) and 6th week (right) magnetic resonance imaging T2 and magnetic resonance imaging with gadoliniumCLIPPERS syndrome affects men more often than women, and the median age at onset is 46 years. Clinically, it may present with various symptoms, but the most common are diplopia, dysarthria, ataxia, and motor and sensory findings.[1] Other conditions must be excluded before CLIPPERS can be diagnosed. In the differential diagnosis, primary malignancies (primary central nervous system lymphoma and brain stem glioma), paraneoplastic syndromes (Bickerstaff encephalitis), neurosarcoidosis, infective diseases (listeria or tuberculosis rhombencephalitis), and demyelinating diseases (multiple sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorder), in particular, should be evaluated. Therefore, detailed systemic examination, blood and CSF examination, malignancy screening, and infection exclusion are essential. Typically, on T2-weighted FLAIR sequences on MRI, punctate hyperintensities with small diameters, no mass effect, and gadolinium uptake, designated as the “salt and pepper sign,” occur bilaterally in the pons, cerebellum, or less frequently in cerebral white matter.[1,2] Recently, it has been stated that diagnosis can be obtained more specifically with different quantitative MRI techniques.[3] Diagnosis is made with complete radiologic resolution after high-dose corticosteroid therapy and the absence of an alternative diagnosis. Pathogenic mechanisms are unknown. It is hypothesized that this syndrome may be an autoimmune inflammatory response or constitutes a variant of hematologic malignancies (most commonly lymphoma). In a study in which all cases diagnosed with CLIPPERS syndrome were evaluated, hematologic or solid malignancies and paraneoplastic syndrome were detected in 15.7% of the patients during follow-up after diagnosis.[1] A rapid response to corticosteroid treatment is expected. Maintenance with oral therapy after boluses of high-dose methylprednisolone is generally preferred. Chronic immunosuppressives are often added to treatment to prevent relapses that may exacerbate the disease.[1,4] Although it is stated in the literature that relapse may occur in patients after the prednisone dosage is reduced to below 20 mg/day, there is no difference in terms of relapse between dosages below and above 20 mg/day when additional chronic immunosuppressives are used.[4,5] Clinical trials reported good responses to maintenance therapy with methotrexate, azathioprine, mycophenolate, cyclophosphamide, and rituximab without disease progression.[5] Mortality is higher in cases associated with malignancy. On the other hand, increased CSF protein is more common in cases without malignancy. In relapsed cases, acute steroid treatment is shorter (10 days vs. 6 days), and malignancy and mortality are more frequent. In follow-ups, the recurrence rate is reported as approximately 59% and mortality as 10%.[1] Although a limited number of cases have been reported to date, we state that a slightly longer duration of steroid treatment in the acute period, careful evaluations in this regard in the follow-ups, even if there is no sign of malignancy in the early period, and the use of oral steroids and chronic immunosuppressive treatments together would be appropriate. However, more case series and clinical trials are needed to optimize diagnosis, treatment, and follow-up. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.