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CLIPPERS

  • Demyelinating Disorders (J Bernard and M Cameron, Section Editors)
  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described treatable, inflammatory, brainstem predominant encephalomyelitis. The diagnosis of CLIPPERS is challenging without a specific biomarker, and thus it is important to consider if both the clinical and radiographic features are consistent with the diagnosis, or rather a disease mimicker.

Recent Findings

Many patients with CLIPPERS-like lesions have been described in the literature with follow-up revealing a range of alternative diagnoses, such as malignancies, vasculitis, and other specific inflammatory diseases. As a result, some have proposed that CLIPPERS might represent a pre-malignancy state or simply an initial clinical syndrome of a variety of possible etiologies.

Summary

We describe the typical clinical, radiographic, and pathological features of CLIPPERS and emphasize consideration for alternative diagnoses when findings are not classic. A recommended diagnostic evaluation and initial treatment plan is provided.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Pittock SJ, Debruyne J, Krecke KN, Giannini C, van den Ameele J, De Herdt V, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain : a journal of neurology. 2010;133(9):2626–34.

    Article  Google Scholar 

  2. Taieb G, Duflos C, Renard D, Audoin B, Kaphan E, Pelletier J, et al. Long-term outcomes of CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) in a consecutive series of 12 patients. Arch Neurol. 2012;69(7):847–55.

    Article  PubMed  Google Scholar 

  3. Kastrup O, van de Nes J, Gasser T, Keyvani K. Three cases of CLIPPERS: a serial clinical, laboratory and MRI follow-up study. J Neurol. 2011;258(12):2140–6.

    Article  CAS  PubMed  Google Scholar 

  4. Jones JL, Dean AF, Antoun N, Scoffings DJ, Burnet NG, Coles AJ. ‘Radiologically compatible CLIPPERS’ may conceal a number of pathologies. Brain : a journal of neurology. 2011;134(Pt 8):e187.

    Article  Google Scholar 

  5. • De Graaff HJ, Wattjes MP, Rozemuller-Kwakkel AJ, Petzold A, Killestein J. Fatal B-cell lymphoma following chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. JAMA neurology. 2013;70(7):915–8. This case is one of several demonstrating that inflammatory brainstem lesions on MRI are not unique to CLIPPERS, and can be seen in several alternative etiologies including lymphoma, and thus a patient should be assessed for all of the typical neuroimaging and clinical findings of CLIPPERS before establishing the diagnosis.

    Article  PubMed  Google Scholar 

  6. Limousin N, Praline J, Motica O, Cottier JP, Rousselot-Denis C, Mokhtari K, et al. Brain biopsy is required in steroid-resistant patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neuro-Oncol. 2012;107(1):223–4.

    Article  Google Scholar 

  7. Lin AW, Das S, Fraser JA, Ang LC, Florendo-Cumbermack A, Jenkins ME, et al. Emergence of primary CNS lymphoma in a patient with findings of CLIPPERS. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 2014;41(4):528–9.

    Article  PubMed  Google Scholar 

  8. Taieb G, Uro-Coste E, Clanet M, Lassmann H, Benouaich-Amiel A, Laurent C, et al. A central nervous system B-cell lymphoma arising two years after initial diagnosis of CLIPPERS. J Neurol Sci. 2014;344(1–2):224–6.

    Article  PubMed  Google Scholar 

  9. Nakamura R, Ueno Y, Ando J, Matsuda H, Masuda A, Iiduka K, et al. Clinical and radiological CLIPPERS features after complete remission of peripheral T-cell lymphoma, not otherwise specified. J Neurol Sci. 2016;364:6–8.

    Article  PubMed  Google Scholar 

  10. Mashima K, Suzuki S, Mori T, Shimizu T, Yamada S, Hirose S, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after treatment for Hodgkin’s lymphoma. Int J Hematol. 2015;102(6):709–12.

    Article  CAS  PubMed  Google Scholar 

  11. Weng CF, Chan DC, Chen YF, Liu FC, Liou HH. Chronic hepatitis B infection presenting with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a case report. J Med Case Rep. 2015;9:266.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Symmonds M, Waters PJ, Kuker W, Leite MI, Schulz UG. Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS. Neurology. 2015;84(11):1177–9.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Wang X, Huang D, Huang X, Zhang J, Ran Y, Lou X, et al. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a lymphocytic reactive response of the central nervous system? A case report. J Neuroimmunol. 2017;305:68–71.

    Article  CAS  PubMed  Google Scholar 

  14. Ferreira RM, Machado G, Souza AS, Lin K, Correa-Neto Y. CLIPPERS-like MRI findings in a patient with multiple sclerosis. J Neurol Sci. 2013;327(1–2):61–2.

    Article  CAS  PubMed  Google Scholar 

  15. Ortega MR, Usmani N, Parra-Herran C, Adams DJ, Steingo B, Rammohan KW. CLIPPERS complicating multiple sclerosis causing concerns of CNS lymphoma. Neurology. 2012;79(7):715–6.

    Article  PubMed  Google Scholar 

  16. •• Blaabjerg M, Ruprecht K, Sinnecker T, Kondziella D, Niendorf T, Kerrn-Jespersen BM, et al. Widespread inflammation in CLIPPERS syndrome indicated by autopsy and ultra-high-field 7T MRI. Neurology(R) neuroimmunology & neuroinflammation. 2016;3(3):e226. This paper demonstrates the presence of inflammatory pathology outside of the originally described areas centered in the pons and cerebellum in CLIPPERS.

    Article  Google Scholar 

  17. Simon NG, Parratt JD, Barnett MH, Buckland ME, Gupta R, Hayes MW, et al. Expanding the clinical, radiological and neuropathological phenotype of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). J Neurol Neurosurg Psychiatry. 2012;83(1):15–22.

    Article  PubMed  Google Scholar 

  18. Biotti D, Deschamps R, Shotar E, Maillart E, Obadia M, Mari I, et al. CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Pract Neurol. 2011;11(6):349–51.

    Article  PubMed  Google Scholar 

  19. Tohge R, Nagao M, Yagishita A, Matsubara S. A case of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) in East Asia. Internal medicine (Tokyo, Japan). 2012;51(9):1115–9.

    Article  Google Scholar 

  20. Fang B, McKeon A, Hinson SR, Kryzer TJ, Pittock SJ, Aksamit AJ, et al. Autoimmune glial fibrillary acidic protein astrocytopathy: a novel meningoencephalomyelitis. JAMA neurology. 2016;73(11):1297–307.

    Article  PubMed  Google Scholar 

  21. Kleinschmidt-DeMasters BK, West M. CLIPPERS with chronic small vessel damage: more overlap with small vessel vasculitis? J Neuropathol Exp Neurol. 2014;73(3):262–7.

    Article  PubMed  Google Scholar 

  22. Tan BL, Agzarian M, Schultz DW. CLIPPERS: induction and maintenance of remission using hydroxychloroquine. Neurology(R) neuroimmunology & neuroinflammation. 2015;2(1):e56.

    Article  Google Scholar 

  23. Alsherbini K, Beinlich B, Salamat MS. Diffusely infiltrating central nervous system lymphoma involving the brainstem in an immune-competent patient. JAMA neurology. 2014;71(1):110–1.

    Article  PubMed  Google Scholar 

  24. Gabilondo I, Saiz A, Graus F, Villoslada P. Response to immunotherapy in CLIPPERS syndrome. J Neurol. 2011;258(11):2090–2.

    Article  PubMed  Google Scholar 

  25. Gul M, Chaudhry AA, Chaudhry AA, Sheikh MA, Carsons S. Atypical presentation of CLIPPERS syndrome: a new entity in the differential diagnosis of central nervous system rheumatologic diseases. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2015;21(3):144–8.

    Article  Google Scholar 

  26. Zhang YX, Hu HT, Ding XY, Chen LH, Du Y, Shen CH, et al. CLIPPERS with diffuse white matter and longitudinally extensive spinal cord involvement. Neurology. 2016;86(1):103–5.

    Article  PubMed  Google Scholar 

  27. Keegan BM, Pittock SJ. Cutting-edge questions about CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids). Arch Neurol. 2012;69(7):819–20.

    Article  PubMed  Google Scholar 

  28. • Tobin WO, Meyer FB, Keegan BM. Diagnostic yield and safety of cerebellar and brainstem parenchymal biopsy. World neurosurgery. 2015;84(6):1973–6. This paper provides the safety and yield of posterior fossa biopsy in patients with presumed non-malignant brain disease, as is typical in patients with CLIPPERS.

    Article  PubMed  Google Scholar 

  29. Taieb G, Renard D, Labauge P. Should CLIPPERS be considered a prelymphoma state or a new inflammatory disease? JAMA neurology. 2013;70(9):1200–1.

    Article  PubMed  Google Scholar 

  30. Binnahil M, Au K, Lu JQ, Wheatley BM, Sankar T. The influence of corticosteroids on diagnostic accuracy of biopsy for primary central nervous system lymphoma. The Canadian journal of neurological sciences Le journal canadien des sciences neurologiques. 2016;43(5):721–5.

    Article  PubMed  Google Scholar 

  31. Porter AB, Giannini C, Kaufmann T, Lucchinetti CF, Wu W, Decker PA, et al. Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: a pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma. Ann Neurol. 2008;63(5):662–7.

    Article  CAS  PubMed  Google Scholar 

  32. • Smith A, Matthews Y, Kossard S, Turner J, Buckland ME, Parratt J. Neurotropic T-cell lymphocytosis: a cutaneous expression of CLIPPERS. J Cutan Pathol. 2014;41(8):657–62. This case raises the important awareness of the non-specific pathological findings of perivascular lymphocytic predominant inflammation in CLIPPERS, which can also be seen in systemic inflammatory and neoplastic diseases.

    Article  PubMed  Google Scholar 

  33. •• Taieb G, Duran-Pena A, de Chamfleur NM, Moulignier A, Thouvenot E, Allou T, et al. Punctate and curvilinear gadolinium enhancing lesions in the brain: a practical approach. Neuroradiology. 2016;58(3):221–35. The authors review the important concept that punctate and curvilinear gadolinium enhancement is not unique to CLIPPERS, but rather there is a broad differential for these neuroimaging findings which depends heavily on the clinical context.

    Article  PubMed  Google Scholar 

  34. Taieb G, Renard D, Joujoux JM, Labauge P. Cutaneous lesions in a CLIPPERS patient: further confusion between CLIPPERS and grade I lymphomatoid granulomatosis. J Cutan Pathol. 2014;41(9):759–60.

    Article  PubMed  Google Scholar 

  35. Hillesheim PB, Parker JR, Parker JC Jr, Escott E, Berger JR. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids following influenza vaccination. Archives of pathology & laboratory medicine. 2012;136(6):681–5.

    Article  Google Scholar 

  36. Wang L, Holthaus EA, Jimenez XF, Tavee J, Li Y. MRI evolution of CLIPPERS syndrome following herpes zoster infection. J Neurol Sci. 2015;348(1–2):277–8.

    Article  PubMed  Google Scholar 

  37. Dudesek A, Rimmele F, Tesar S, Kolbaske S, Rommer PS, Benecke R, et al. CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. Review of an increasingly recognized entity within the spectrum of inflammatory central nervous system disorders. Clin Exp Immunol. 2014;175(3):385–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kira J. The expanding phenotype of CLIPPERS: is it a disease or a syndrome? J Neurol Neurosurg Psychiatry. 2012;83(1):2–3.

    Article  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Nicholas L. Zalewski & W. Oliver Tobin

  2. Mayo Clinic College of Medicine, Rochester, MN, USA

    W. Oliver Tobin

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  1. Nicholas L. Zalewski
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  2. W. Oliver Tobin
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Correspondence to W. Oliver Tobin.

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Conflict of Interest

Nicholas L. Zalewski and W. Oliver Tobin declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Demyelinating Disorders

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Zalewski, N.L., Tobin, W.O. CLIPPERS. Curr Neurol Neurosci Rep 17, 65 (2017). https://doi.org/10.1007/s11910-017-0773-7

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  • DOI: https://doi.org/10.1007/s11910-017-0773-7

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