Expanding the clinical, radiological and neuropathological phenotype of 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 recently described inflammatory disease of the CNS with a predilection for the hindbrain and responsive to immunotherapy. Five further cases are described with detailed pathology and long term evaluation. CLIPPERS does not represent a benign condition, and without chronic immunosuppression the disease may relapse. The radiological distribution is focused not only in the pons but also in the brachium ponti and cerebellum. Pontocerebellar atrophy occurred early, even in cases treated promptly. Significant cognitive impairment was seen in some cases and was associated with additional cerebral atrophy. The pathology included distinctive histiocytic as well as lymphocytic components and evidence of neuro-axonal injury. Additional subclinical systemic findings on investigation were identified. Relapse was associated with withdrawal of corticosteroids, and disability was least marked in cases where both the presentation and relapses were treated promptly. We propose that the title of the syndrome be amended to chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids to more accurately reflect the distribution of the radiological findings.

Long-term Outcomes of CLIPPERS (Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids) in a Consecutive Series of 12 Patients

“…Staining for CD4, CD8, and granzyme B showed increased CD4 T cells in 5 of 7 samples, similar to findings by Simon and colleagues 10 in their recent publication reporting 5 cases of CLIPPERS.…”

“…However, one of these (patient 4) experienced a new relapse at 16 months after pulse cyclophosphamide therapy, suggesting that cyclophosphamide only suspends the symptoms. The efficacy of other immunomodulatoryorimmunosuppressivetherapies(ie,hydroxychloroquine sulfate, mitoxantrone hydrochloride, immune globulin intravenous pentetate, azathioprine, and mycophenolate mofetil 1,5,10 ) has not been proven. The pathogenesis of CLIPPERS is unknown.…”

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

“…On the other hand, this patient presented with a number of features compatible with PACNS, several of them previously not reported in CLIPPERS patients: 1) bout-associated severe headache of pressing quality (one patient of the Simon series developed headache as first symptom [2]), 2) a single, unprovoked secondarily generalized tonic-clonic seizure (followed by ongoing antiepileptic treatment), 3) an intracerebral haemorrhage, possibly indicating vasculitic damage to a vessel wall, 4) focal DSA findings resembling vasculitis, and 5) histopathological detection of single vessels showing transmural lymphocytic infiltration (also described by Simon et al [2]) or inflammatory vessel occlusion on brain biopsy. Of note, granulomas within vessel walls, fibrinoid vessel necrosis, giant cells or leukocytoclasia to histologically further support a diagnosis of vasculitis were not evident.…”

“…Its key features are: 1) episodic, subacutely progressive cerebellar ataxia as a cardinal symptom as well as diplopia and dysarthria in the majority of cases [1][2][3], 2) characteristic bilateral, multifocal punctate or curvilinear gadoliniumenhancing MRI lesions, predominantly affecting the pons and extending into adjacent brain regions, 3) white matter perivascular lymphohistiocytic infiltrates, dominated by CD4+ T cells and macrophages, with a variable extent of parenchymal inflammation, 4) steroid responsiveness of the symptoms, and 5) the absence of evidence for alternative diagnoses. In their recent series of five patients, Simon et al expanded the clinical and paraclinical phenotype of CLIPPERS [2]. They described progressive cognitive impairment, diffuse cerebral atrophy, MRI lesions predominantly affecting the cerebellum, and significant axonal damage in biopsy specimens as novel facultative findings in CLIPPERS patients.…”

Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS

“…Cervical cord inflammation is described in CLIPPERS, with lesions decreasing in frequency with increasing distance from the pons. 3,4 Longitudinally extensive thoracolumbar cord lesions have not been previously reported, hence this substantially altered our differential diagnosis, prompting anti-MOG antibody testing.…”