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CLIPPERS Syndrome (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids): A Rare of Rare Neurological Entity
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Vaibhav O P Pandey, Priyanka V Kashyap, P. Monika Rao Department of Neurology, All India Institute of Medical Sciences (AIIMS) Bhopal, Madhya Pradesh, India. |
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Corresponding Author:
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Dr Priyanka V Kashyap Email: priyanka.tem@aiimsbhopal.edu.in |
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Received:
15-DEC-2025 |
Accepted:
07-MAR-2026 |
Published Online:
05-MAY-2026 |
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Abstract
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Background: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder of the central nervous system characterized by distinctive punctate and curvilinear pontine gadolinium-enhancing lesions on magnetic resonance imaging (MRI) and a marked response to corticosteroid therapy. Owing to its rarity and overlap with several neurological disorders, diagnosis is often challenging. Case Report: A 45-year-old man presented with recurrent brief episodes of right-sided hemisensory paresthesia involving the face, upper limb, and lower limb without altered consciousness or post-event neurological deficits. Neurological examination was unremarkable. MRI brain revealed characteristic punctate enhancing lesions involving the pons and midbrain with additional supratentorial white matter involvement. Cerebrospinal fluid analysis and autoimmune, vasculitic, and demyelinating workup, including aquaporin-4 and myelin oligodendrocyte glycoprotein antibodies were negative. Based on clinico-radiological findings and a dramatic response to corticosteroids, a diagnosis of CLIPPERS was established. Conclusion: CLIPPERS should be considered in patients with atypical recurrent brainstem-related symptoms and characteristic MRI findings after exclusion of close mimics. Early recognition is essential, as prompt corticosteroid therapy can result in favourable outcomes. |
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Keywords :
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Brain Stem Diseases, Central Nervous System Inflammatory Disorders, Magnetic Resonance Imaging, Paroxysmal Disorders, Pontine Diseases.
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Introduction
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare inflammatory disorder of the central nervous system characterized by a distinctive clinico-radiological pattern involving punctate and curvilinear gadolinium-enhancing lesions predominantly affecting the pons and adjacent brainstem structures, along with a marked responsiveness to corticosteroid therapy [ 1]. CLIPPERS remains an underrecognized entity with an uncertain pathophysiological basis, often posing a diagnostic challenge because of its overlap with demyelinating, neoplastic, infectious, and vasculitic disorders of the brainstem. Patients commonly present with symptoms related to brainstem and cerebellar dysfunction, including gait ataxia, diplopia, dysarthria, vertigo, and cranial nerve deficits [ 2]. However, atypical or limited clinical manifestations may occur, contributing to delays in diagnosis and inappropriate management. Recognition of the characteristic magnetic resonance imaging (MRI) findings and steroid responsiveness is essential for distinguishing CLIPPERS from important mimics, particularly central nervous system lymphoma and inflammatory demyelinating diseases. We report an unusual case of CLIPPERS presenting predominantly with paroxysmal hemisensory symptoms, highlighting the variable clinical spectrum of this rare steroid-responsive neuroinflammatory disorder and emphasizing the importance of early recognition to facilitate timely diagnosis and treatment.
Case Report
A 45-year-old man presented with recurrent episodes of self-limiting right-sided hemisensory paresthesia characterized by brief paroxysmal tingling involving the right half of the face, right upper limb, and right lower limb. Each episode lasted for a few seconds and was not associated with altered consciousness, motor weakness, or any post-event neurological deficits. There was no history suggestive of brainstem dysfunction. General physical and neurological examination were unremarkable, with no focal neurological deficits, long tract signs, or altered sensorium. Based on the transient nature of symptoms, clinical differentials of transient ischemic attack (TIA) and focal seizures with preserved awareness were initially considered. Magnetic resonance imaging (MRI) of the brain with contrast and MR angiography was performed. While no evidence of acute ischemic stroke was identified, MRI revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities involving the left perisylvian region, external capsule, posterior limb of the internal capsule, and subcortical left temporoparietal white matter. In addition, multiple non-contiguous punctate T2/FLAIR hyperintense lesions were noted in the left midbrain and pons, showing mild heterogeneous enhancement on post-contrast T1-weighted images [Fig.1,2].
Cerebrospinal fluid (CSF) examination was unremarkable. Considering the radiological findings, demyelinating disorders were evaluated; however, serum aquaporin-4 immunoglobulin G (AQP4-IgG) and myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibodies were negative. Further investigations, including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and C-reactive protein (CRP), did not reveal evidence of autoimmune, vasculitic, or infective etiologies. In view of the characteristic clinico-radiological features and a dramatic response to corticosteroid therapy, a diagnosis of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) was established following multidisciplinary clinico-radiological correlation.
Discussion
CLIPPERS is a rare inflammatory disorder of the central nervous system with a broad clinical spectrum, most commonly presenting with subacute symptoms related to brainstem, cranial nerve, and cerebellar dysfunction. Our patient had an unusual presentation in the form of recurrent paroxysmal hemisensory symptoms involving the face and limbs, suggestive of a brainstem sensory manifestation, without classical brainstem or cerebellar signs [ 1]. Although CLIPPERS has been reported across a wide age range, from childhood to advanced age, it predominantly affects middle-aged adults and demonstrates a slight male preponderance [ 1]. Preserved cognition and the absence of fever or meningeal signs may help distinguish it from infective or encephalitic processes. Neuroimaging remains central to diagnosis. The characteristic MRI appearance consists of punctate and curvilinear gadolinium-enhancing lesions predominantly centered in the pons, often extending to adjacent structures including the cerebellar peduncles, medulla, midbrain, spinal cord, and occasionally supratentorial regions such as the thalami, internal capsule, basal ganglia, and cerebral white matter [2]. Consistent with these observations, our patient demonstrated punctate pontine and midbrain lesions with supratentorial involvement and contrast enhancement in the absence of edema or mass effect, a feature favoring CLIPPERS over neoplastic conditions. Normal MR angiography further reduced the likelihood of vasculitis [1]. The pathogenesis of CLIPPERS remains uncertain, although histopathological studies have demonstrated dense perivascular lymphocytic infiltrates, predominantly involving the pons [1,3]. Cerebrospinal fluid findings are generally nonspecific, with mild protein elevation or pleocytosis reported in some patients, while oligoclonal bands are usually absent [5]. In our case, cerebrospinal fluid examination was normal, and an extensive workup excluded demyelinating, autoimmune, vasculitic, and infective etiologies. Negative aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) antibodies helped exclude closely related demyelinating disorders such as neuromyelitis optica spectrum disorder (NMOSD) and MOG-associated disease (MOGAD). CLIPPERS remains a diagnosis of exclusion, and careful differentiation from mimics is essential. Important differentials include central nervous system lymphoma, brainstem glioma, histiocytosis, neurosarcoidosis, infective rhombencephalitis (including tuberculosis and Listeria), primary CNS vasculitis, Bickerstaff brainstem encephalitis, and other inflammatory or demyelinating disorders [4]. Emerging evidence also suggests an association with systemic malignancies in a minority of patients, emphasizing the need for thorough clinical evaluation and longitudinal follow-up [5]. A striking response to corticosteroid therapy remains one of the defining features of CLIPPERS and supports the diagnosis. Our patient demonstrated marked clinical and radiological improvement following steroid treatment. Long-term immunosuppressive therapy, including azathioprine, may be required in recurrent or chronic cases to prevent relapse. Given the rarity of this recently recognized entity and its potential to mimic serious neurological disorders, awareness of atypical presentations is essential for timely diagnosis and appropriate management.
Conclusion
CLIPPERS should be considered in patients with atypical, recurrent brainstem-related neurological symptoms and characteristic punctate pontine MRI lesions after exclusion of close mimics. Early recognition of this rare steroid-responsive condition is crucial, as timely corticosteroid therapy can lead to excellent clinical and radiological outcomes.
Contributors: VOP: manuscript writing, patient management; PVK: manuscript editing, patient management; MR: Images, literature review. PVK will act as a study guarantor. All authors approved the final version of this manuscript and are responsible for all aspects of this study. Funding: None; Competing interests: None stated.
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Article Statistics |
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Pandey V O P, Kashyap P V, Rao P MCLIPPERS Syndrome (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids): A Rare of Rare Neurological Entity.JCR 2026;16:38-41 |
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Pandey V O P, Kashyap P V, Rao P MCLIPPERS Syndrome (Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids): A Rare of Rare Neurological Entity.JCR [serial online] 2026[cited 2026 May 28];16:38-41. Available from: http://www.casereports.in/articles/16/2/CLIPPERS-Syndrome-Chronic-Lymphocytic-Inflammation-with-Pontine-Perivascular-Enhancement-Responsive-to-Steroids.html |
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