9. Logroscino G, Traynor BJ, Hardiman O, et al.Incidence of amyotrophic lateral sclerosis inEurope. J Neurol Neurosurg Psychiatry2010;81:385e90.

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11. Ibarretxe-Bilbao N, Ramirez-Ruiz B, Junque C, et al.Differential progression of brain atrophy in Parkinson’s

disease with and without visual hallucinations.J Neurol Neurosurg Psychiatry 2010;81:650e7.

12. Uncini A, Manzoli C, Notturno F, et al. Pitfalls inelectrodiagnosis of Guillain-Barre syndrome subtypes.J Neurol Neurosurg Psychiatry 2010;81:1157e63.

13. Douglass CP, Kandler RH, Shaw PJ, et al. Anevaluation of neurophysiological criteria used in thediagnosis of motor neuron disease. J NeurolNeurosurg Psychiatry 2010;81:646e9.

14. Zampieri C, Salarian A, Carlson-Kuhta P, et al. Theinstrumented timed up and go test: potential

outcome measure for disease modifying therapies inParkinson’s disease. J Neurol Neurosurg Psychiatry2010;81:171e6.

15. Kagi G, Bhatia KP, Tolosa E. The role of DAT-SPECT inmovement disorders. J Neurol Neurosurg Psychiatry2010;81:5e12.

16. Charlton RA, Schiavone F, Barrick TR, et al. Diffusiontensor imaging detects age related white matterchange over a 2 year follow-up which is associatedwith working memory decline. J Neurol NeurosurgPsychiatry 2010;81:13e19.

The expanding phenotype ofCLIPPERS: is it a disease ora syndrome?Jun-ichi Kira

Chronic lymphocytic inflammation withpontine perivascular enhancementresponsive to steroids (CLIPPERS) isa newly named pontine-centric inflam-matory disorder.1 The cardinal feature ofthe disease is punctate gadoliniumenhancement ‘peppering’ the pons onMRI. The unique MRI features of thisdisorder have attracted many neurologists’attention leading to the publication ofseveral case reports recently.2e5 The biop-sied pontine pathology from the originalstudy revealed a marked perivascular andparenchymal CD3-postive T-cell inflam-mation without any specific pathology.1

However, because of the lack of a specificbiomarker and long-term follow-up, thenosological position of CLIPPERS is still tobe established.

The paper by Simon and colleagues6

(see page 15) reports five additional casesof CLIPPERS with detailed pathology andlong-term evaluation, expanding the clin-ical, neuroimaging and pathologicalphenotype of this disorder: (1) cognitiveimpairment was seen in four of five casesalong with cerebral atrophy in three ofthem; (2) MRI lesions were distributednot only in the pons but also in thebrachium ponti and cerebellum, which

later culminated in severe atrophy of thecerebellum and brachium ponti; (3)prominent CD4-positive T lymphocytic aswell as histiocytic infiltrates wereobserved, involving both small arteriesand veins but with few B cells. Neuro-axonal injury was also found but therewas no evidence of vasculitis (destructionof the vessel wall with fibrinoid necrosis).6

Based on the distribution of MRI lesions,Simon and colleagues propose an amend-ment of the disorder to chronic lympho-cytic inflammation with pontocerebellarperivascular enhancement responsiveto steroids (CLIPPERS).6 Lesions mayoccur in the spinal cord, basal ganglia orcerebral white matter. The perivasculargadolinium enhancement pattern andsteroid-responsiveness indicate the auto-immune/inflammatory nature of thiscondition. These authors6 and others1

carried out extensive laboratory andpathological surveys to exclude specificcauses for the condition, such as sarcoid-osis, histiocytosis, lymphoma, gran-ulomatosis, multiple sclerosis, isolatedangiitis of the central nervous system,Lyme disease, Whipple disease, Bickerstaffbrainstem encephalitis, Behcet’s diseaseand Sjögren’s syndrome, suggesting thatCLIPPERS is an independent diseaseentity.However, there appears to be some

overlap with other autoimmune/inflam-matory brainstem-predominant encepha-litis, especially brainstem type ofneuro-Behcet’s disease and Sjögren’ssyndrome. Pittock and colleagues1 foundno evidence of systemic illness; however,

Simon and colleagues6 reported additionalsubclinical systemic findings in somecases, namely antinuclear antibody SS-A,lymphocytic conjunctival infiltrate,lymphocytic sialadenitis and parotiduptake on gallium scan. Neuro-Behcet’sdisease is well known and frequentlyaffects the pons and cerebellum. Thisdisease occasionally presents withoutapparent mucocutaneo-ocular manifesta-tions,7 8 showing progressive cerebellarataxia and prominent pontine and cere-bellar atrophy. Such patients can alsobenefit from early steroid therapy. Cogni-tive impairment, first described by Simonand colleagues6 in CLIPPERS, is alsofrequently encountered in Behcet’sdisease. On MRI, enhancement of lesionsin the pons and middle cerebellar pedun-cles frequently shows a mottled non-confluent pattern similar to that ofCLIPPERS.9e11 At the chronic stage, severeatrophy of the basis pontis and cerebellumis common. Pathologically, Behcet’sdisease shows perivascular infiltration of Tcells and macrophages/monocytes withfew B cells, mainly involving venules butalso occasionally small arteries.12 Exami-nations of needle reaction, HLA-DR51 andinterleukin 6 in the cerebrospinal fluid areessential to differentiate brainstem type ofneuro-Behcet’s disease from CLIPPERS. Sofar, all cases with CLIPPERS have beenreported from Western countries. Behcet’sdisease is prevalent in Mediterraneancountries, the Middle East and Japan. It isinteresting to know whether there is anyracial preponderance for this condition.Cerebellar and brainstem involvement

has also been repeatedly reported in Sjög-ren’s syndrome,13e15 while sicca symp-toms may not be clinically overt. MRIfeatures of brainstem involvement inprimary Sjögren’s syndrome occasionallypresents punctate gadolinium-enhancingfoci peppering the pons, middle cerebellarpeduncles, cerebellar hemispheres andvermis, and mesencephalon, which arequite similar to those of CLIPPERS.15 Thesubclinical involvement of exocrine glandsfound in some CLIPPERS cases6 suggests

Department of Neurology, Neurological Institute,Graduate School of Medical Sciences, Kyushu University,Japan

Correspondence to Professor Jun-ichi Kira,Department of Neurology, Neurological Institute,Graduate School of Medical Sciences, Kyushu University,Fukuoka 812-8582, Japan;kira@neuro.med.kyushu-u.ac.jp

2 J Neurol Neurosurg Psychiatry January 2012 Vol 83 No 1

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a possibility that pontocerebellar involve-ment of CLIPPERS could be the firstmanifestation of certain systemic diseases,such as Sjögren’s syndrome. Since siccasymptoms are frequently subclinical, andSS-A or SS-B could be negative in Sjögren’ssyndrome, minor salivary gland biopsymay be recommended. Thus, CLIPPERScould be a syndrome with heterogeneousaetiologies.

One peculiar finding is that T2-highlesions did not significantly extend beyondthe boundaries of the contrast enhance-ment of individual lesions.6 This suggestsvasogenic oedema is scarce while markedgadolinium enhancement of the lesionsindicates disruption of the bloodebrainbarrier. A better explanation for thisdiscrepancy is a topic for future investi-gations. On the other hand, the pontineand cerebellar atrophy that emerge later isprominent, suggesting severe neuroaxonalloss in this condition. Diffuse cerebralatrophy also developed in some casesalong with cognitive dysfunction. Soneurons are likely to be targeted byCLIPPERS. Since antineuronal autoanti-bodies were not detected in this condition,CD4-positive T cells and histiocytes mayplay unique roles in causing such MRIfeatures and late parenchymatousatrophy. Cerebrospinal fluid assays oncytokines and chemokines may provide aninsight into the nature of inflammation inthis condition.

Due to the absence of a specificbiomarker, it would require careful exclu-sion of other conditions to diagnoseCLIPPERS. Nevertheless, clinical neurolo-gists should be aware of this condition sothat the benefits of early introduction ofsteroids are not lost, regardless of whetherCLIPPERS is a disease or a syndrome.

Competing interests None.

Contributors J-iK is the sole contributor.

Provenance and peer review Commissioned;internally peer reviewed.

Received 11 October 2011Revised 19 October 2011Accepted 20 October 2011

J Neurol Neurosurg Psychiatry 2012;83:2e3.doi:10.1136/jnnp-2011-301626

REFERENCES1. Pittock SJ, Debruyne J, Krecke KN, et al. Chronic

lymphocytic inflammation with pontine perivascularenhancement responsive to steroids (CLIPPERS).Brain 2010;133:2626e34.

2. Taieb G, Wacongne A, Renard D, et al. A new caseof chronic lymphocytic inflammation with pontineperivascular enhancement responsive to steroidswith initial normal magnetic resonance imaging. Brain2011;134(Pt 8):e182.

3. List J, Lesemann A, Wiener E, et al. A new case ofchronic lymphocytic inflammation with pontineperivascular enhancement responsive to steroids.Brain 2011;134(Pt 8):e185.

4. Kastrup O, van de Nes J, Gasser T, et al. Threecases of CLIPPERS: a serial clinical, laboratoryand MRI follow-up study. J Neurol. PublishedOnline First: 10 May 2011. doi:10.1007/s00415-011-6071-4.

5. Gabilondo I, Saiz A, Graus F, et al. Response toimmunotherapy in CLIPPERS syndrome. J Neurol2011;258:2090e2.

6. Simon N, Parratt J, Barnett M, et al. Expandingthe clinical, radiological and neuropathologicalphenotype of chronic lymphocytic Inflammation withPontine Perivascular Enhancement Responsive toSteroids (CLIPPERS). J Neurol Neurosurg Psychiatr2012;83:16e23.

7. Hirose M, Ikeuchi T, Hayashi S, et al. A possiblevariant of neuro-Behcet disease presenting chronicprogressive ataxia without mucocutaneo-ocularsymptoms. Rheumatol Int 2006;27:61e5.

8. Taskapilioglu O, Seferoglu M, Akkaya C, et al.Delayed diagnosis of a neuroBehcet patient with onlybrainstem and cerebellar atrophy: literature review. JNeurol Sci 2099;277:160e3.

9. Kazui S, Naritomi H, Imakita S, et al. Sequentialgadolinium-DTPA enhanced MRI studies in neuro-Behcet’s disease. Neuroradiology 1991;33:136e9.

10. Nakamura Y, Takahashi M, Ueyama K, et al.Magnetic resonance imaging and brain-stem auditoryevoked potentials in neuro-Behcet’s disease. J Neurol1994;241:481e6.

11. Lee SH, Yoon PH, Park SJ, et al. MRI findings inneuro-Behcet’s disease. Clin Radiol2001;56:485e94.

12. Hirohata S. Histopathology of central nervoussystem lesions in Behcet’s disease. J Neurol Sci2008;267:41e7.

13. Owada K, Uchihara T, Ishida K, et al. Motorweakness and cerebellar ataxia in Sjogrensyndromedidentification of antineuronal antibody:a case report. J Neurol Sci 2002;197:79e84.

14. Ichikawa H, Ishihara K, Fujimoto R, et al.An autopsied case of Sjogren syndrome withmassive necrosis and demyelinating lesions of thecerebellar white matter. J Neurol Sci2004;225:143e8.

15. Yerdelen D, Karatas M, Alkan O, et al. A new kind ofand reversible brainstem involvement in primarySjogren’s syndrome as an initial manifestation. Int JNeurosci 2010;120:155e8.

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a disease or a syndrome?The expanding phenotype of CLIPPERS: is it

Jun-ichi Kira

doi: 10.1136/jnnp-2011-3016262012 83: 2-3 J Neurol Neurosurg Psychiatry 

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