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The expanding phenotype of CLIPPERS: is it a disease or a syndrome?
  1. Jun-ichi Kira
  1. Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Japan
  1. Correspondence to Professor Jun-ichi Kira, Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; kira{at}neuro.med.kyushu-u.ac.jp

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Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a newly named pontine-centric inflammatory disorder.1 The cardinal feature of the disease is punctate gadolinium enhancement ‘peppering’ the pons on MRI. The unique MRI features of this disorder have attracted many neurologists' attention leading to the publication of several case reports recently.2–5 The biopsied pontine pathology from the original study revealed a marked perivascular and parenchymal CD3-postive T-cell inflammation without any specific pathology.1 However, because of the lack of a specific biomarker and long-term follow-up, the nosological position of CLIPPERS is still to be established.

The paper by Simon and colleagues6 (see page 15) reports five additional cases of CLIPPERS with detailed pathology and long-term evaluation, expanding the clinical, neuroimaging and pathological phenotype of this disorder: (1) cognitive impairment was seen in four of five cases along with cerebral atrophy in three of them; (2) MRI lesions were distributed not only in the pons but also in the brachium ponti and cerebellum, which later culminated in severe atrophy of the cerebellum and brachium ponti; (3) prominent CD4-positive T lymphocytic as well as histiocytic infiltrates were observed, involving both small arteries and veins but with few B cells. Neuroaxonal injury was also found but there was no evidence of vasculitis (destruction of the vessel wall with fibrinoid necrosis).6 Based on the distribution of MRI lesions, Simon and colleagues propose an amendment of the disorder to chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids (CLIPPERS).6 Lesions may occur in the spinal cord, basal ganglia or cerebral white matter. The perivascular gadolinium enhancement pattern and steroid-responsiveness indicate the autoimmune/inflammatory nature of this condition. These authors6 and others1 carried out extensive laboratory and pathological surveys to exclude specific causes for the condition, such as sarcoidosis, histiocytosis, lymphoma, granulomatosis, multiple sclerosis, isolated angiitis of the central nervous system, Lyme disease, Whipple disease, Bickerstaff brainstem encephalitis, Behcet's disease and Sjögren's syndrome, suggesting that CLIPPERS is an independent disease entity.

However, there appears to be some overlap with other autoimmune/inflammatory brainstem-predominant encephalitis, especially brainstem type of neuro-Behcet's disease and Sjögren's syndrome. Pittock and colleagues1 found no evidence of systemic illness; however, Simon and colleagues6 reported additional subclinical systemic findings in some cases, namely antinuclear antibody SS-A, lymphocytic conjunctival infiltrate, lymphocytic sialadenitis and parotid uptake on gallium scan. Neuro-Behcet's disease is well known and frequently affects the pons and cerebellum. This disease occasionally presents without apparent mucocutaneo-ocular manifestations,7 8 showing progressive cerebellar ataxia and prominent pontine and cerebellar atrophy. Such patients can also benefit from early steroid therapy. Cognitive impairment, first described by Simon and colleagues6 in CLIPPERS, is also frequently encountered in Behcet's disease. On MRI, enhancement of lesions in the pons and middle cerebellar peduncles frequently shows a mottled non-confluent pattern similar to that of CLIPPERS.9–11 At the chronic stage, severe atrophy of the basis pontis and cerebellum is common. Pathologically, Behcet's disease shows perivascular infiltration of T cells and macrophages/monocytes with few B cells, mainly involving venules but also occasionally small arteries.12 Examinations of needle reaction, HLA-DR51 and interleukin 6 in the cerebrospinal fluid are essential to differentiate brainstem type of neuro-Behcet's disease from CLIPPERS. So far, all cases with CLIPPERS have been reported from Western countries. Behcet's disease is prevalent in Mediterranean countries, the Middle East and Japan. It is interesting to know whether there is any racial preponderance for this condition.

Cerebellar and brainstem involvement has also been repeatedly reported in Sjögren's syndrome,13–15 while sicca symptoms may not be clinically overt. MRI features of brainstem involvement in primary Sjögren's syndrome occasionally presents punctate gadolinium-enhancing foci peppering the pons, middle cerebellar peduncles, cerebellar hemispheres and vermis, and mesencephalon, which are quite similar to those of CLIPPERS.15 The subclinical involvement of exocrine glands found in some CLIPPERS cases6 suggests a possibility that pontocerebellar involvement of CLIPPERS could be the first manifestation of certain systemic diseases, such as Sjögren's syndrome. Since sicca symptoms are frequently subclinical, and SS-A or SS-B could be negative in Sjögren's syndrome, minor salivary gland biopsy may be recommended. Thus, CLIPPERS could be a syndrome with heterogeneous aetiologies.

One peculiar finding is that T2-high lesions did not significantly extend beyond the boundaries of the contrast enhancement of individual lesions.6 This suggests vasogenic oedema is scarce while marked gadolinium enhancement of the lesions indicates disruption of the blood–brain barrier. A better explanation for this discrepancy is a topic for future investigations. On the other hand, the pontine and cerebellar atrophy that emerge later is prominent, suggesting severe neuroaxonal loss in this condition. Diffuse cerebral atrophy also developed in some cases along with cognitive dysfunction. So neurons are likely to be targeted by CLIPPERS. Since antineuronal autoantibodies were not detected in this condition, CD4-positive T cells and histiocytes may play unique roles in causing such MRI features and late parenchymatous atrophy. Cerebrospinal fluid assays on cytokines and chemokines may provide an insight into the nature of inflammation in this condition.

Due to the absence of a specific biomarker, it would require careful exclusion of other conditions to diagnose CLIPPERS. Nevertheless, clinical neurologists should be aware of this condition so that the benefits of early introduction of steroids are not lost, regardless of whether CLIPPERS is a disease or a syndrome.

References

Footnotes

  • Linked article 301054.

  • Competing interests None.

  • Provenance and peer review Commissioned; internally peer reviewed.

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