Therapeutic Approaches in CLIPPERS

Multiple Sclerosis and Related Disorders (P Villoslada, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Multiple Sclerosis and Related Disorders

Opinion statement

CLIPPERS for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, is a steroid-sensitive and steroid-dependent brainstem inflammatory disease of unknown origin. Since its first description in 2010, about 60 cases have been reported throughout the world. The mean age at onset is 50 years and men seem to be more frequently affected. In patients without chronic corticosteroid therapy or immunosuppressive agents, the disease had a relapsing remitting course, and the mean annualized relapse rate was 0.5. During attacks, although clinical and radiological improvement after high doses of corticosteroids was systematically observed, patients could display subsequent disability and hindbrain atrophy. Since no progressive course was observed, clinical and radiological sequelae were correlated with previous severe attacks. Therefore, maintaining the disease in remission may prevent the accumulation of disability. In the literature, no relapse occurred when chronic corticosteroid therapy was maintained above 20 mg per day. However, steroids side effects led to propose corticosteroid-sparing therapies. Unfortunately, no controlled therapy studies for CLIPPERS have been performed yet, and no therapeutic recommendations exist. Using the PubMed database, all articles having the following keywords “chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids” and “CLIPPERS” have been analysed. Considering that the mean annual relapse rate was 0.5, and that no relapse occurred when corticosteroid therapy was maintained above 20 mg per day, the therapeutic efficiency of corticosteroid-sparing agents was considered as “probable” when patients had a relapse-free period ≥24 months, in the absence of concomitant corticosteroid therapy. Corticosteroid-sparing agents whose efficiency is “probable” are methotrexate in two cases, cyclophosphamide in one case and hydroxychloroquine in one case. Considering the risk benefit ratio of corticosteroid-sparing agents, methotrexate seems to be the most suitable. Nevertheless, randomized controlled trials testing the different corticosteroid-sparing agents in CLIPPERS are necessary.

Keywords

Clippers CLIPPERS mimics Immunosuppressive therapy Corticosteroid-sparing therapy Th17-mediated disease 

Abbreviations

CLIPPERS

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

ARR

Annualized relapse rate

PPERS

Pontine perivascular enhancement responsive to steroids

LIPPERS

Lymphocytic inflammation with pontine perivascular enhancement responsive to steroids

CPPERS

Chronic pontine perivascular enhancement responsive to steroids

Notes

Acknowledgments

The authors would like to thank all members of the International CLIPPERS Consortium Meeting.

Compliance with Ethical Standards

Conflict of Interest

The authors 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.

References and Recommended Reading

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

  1. 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. 2010;133:2626–34. This is the first case series including 8 patients that describes CLIPPERSCrossRefPubMedGoogle Scholar
  2. 2.
    • 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;258:2140–6. This is the second case series including 3 CLIPPERS patientsCrossRefPubMedGoogle Scholar
  3. 3.
    •• 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;83:15–22. This case series including 5 CLIPPERS patients describes for the first time axonal injuries on histological findings, clinical sequelae and atrophyCrossRefPubMedGoogle Scholar
  4. 4.
    •• 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;69:847–55. This case series including 12 patients describes for the first time the course of CLIPPERS with and wihout chronic corticosteroidsCrossRefPubMedGoogle Scholar
  5. 5.
    Gabilondo I, Saiz A, Graus F, Villoslada P. Response to immunotherapy in CLIPPERS syndrome. J Neurol. 2011;258:2090–2.CrossRefPubMedGoogle Scholar
  6. 6.
    Sempere AP, Mola S, Martin-Medina P, Bernabeu A, Khabbaz E, Lopez-Celada S. Response to immunotherapy in CLIPPERS: clinical, MRI, and MRS follow-up. J Neuroimaging. 2013;23:254–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Suer D, Yusifova L, Arsava EM, Ekinci G, Us O, Uluc K. A case report of CLIPPERS (chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids) syndrome. Clin Neuroradiol. 2015;25:61–3.CrossRefPubMedGoogle Scholar
  8. 8.
    Kleinschmidt-DeMasters BK, West M. CLIPPERS with chronic small vessel damage: more overlap with small vessel vasculitis? J Neuropathol Exp Neurol. 2014;73:262–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Mélé N, Guiraud V, Labauge P, Oppenheim C, Mas JL, Taieb G. Effective antituberculous therapy in a patient with CLIPPERS: new insights into CLIPPERS pathogenesis. Neurol Neuroimmunol Neuroinflamm. 2014;1:e6.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Moreira I, Cruto C, Correia C, Alves JE, Taipa R, Pires MM. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): postmortem findings. J Neuropathol Exp Neurol. 2015;74:186–90.CrossRefPubMedGoogle Scholar
  11. 11.
    Tan BL, Agzarian M, Schultz DW. CLIPPERS: induction and maintenance of remission using hydroxychloroquine. Neurol Neuroimmunol Neuroinflamm. 2015;2:e56.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mashima K, Suzuki S, Mori T, Shimizu T, Yamada S, Hirose S, Okamoto S, Suzuki N. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) after treatment for Hodgkin's lymphoma. Int J Hematol. 2015;102:709–12.CrossRefPubMedGoogle Scholar
  13. 13.
    Reddy SM, Lath R, Swain M, Ranjan A. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): a case report and review of literature. Ann Indian Acad Neurol. 2015;18:345–7.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    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;86:103–5.CrossRefPubMedGoogle Scholar
  15. 15.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rico M, Villafani J, Tuñón A, Mateos V, Oliva-Nacarino P. IFN beta 1a as glucocorticoids-sparing therapy in a patient with CLIPPERS. Am J Case Rep. 2016;17:47–50.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    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;107:223–4.CrossRefGoogle Scholar
  18. 18.
    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. Can J Neurol Sci. 2014;41:528–9.CrossRefPubMedGoogle Scholar
  19. 19.
    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;344:224–6.CrossRefPubMedGoogle Scholar
  20. 20.
    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 Neurol. 2013;70:915–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Taieb G, Duran-Peña 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;58:221–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Buttmann M, Metz I, Brecht I, Brück W, Warmuth-Metz M. 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. J Neurol Sci. 2013;324:183–6.CrossRefPubMedGoogle Scholar
  23. 23.
    Ferreira RM, Machado G, Souza AS, Lin K, Corrêa-Neto Y. CLIPPERS-like MRI findings in a patient with multiple sclerosis. J Neurol Sci. 2013;327:61–2.CrossRefPubMedGoogle Scholar
  24. 24.
    Ortega MR, Usmani N, Parra-Herran C, Adams DJ, Steingo B, Rammohan KW. CLIPPERS complicating multiple sclerosis causing concerns of CNS lymphoma. Neurology. 2012;79:715–6.CrossRefPubMedGoogle Scholar
  25. 25.
    Symmonds M, Waters PJ, Küker W, Leite MI, Schulz UG. Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS. Neurology. 2015;84:1177–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Jones JL, Dean AF, Antoun N, Scoffings DJ, Burnet NG, Coles AJ. 'Radiologically compatible CLIPPERS' may conceal a number of pathologies. Brain. 2011;134:e187.CrossRefPubMedGoogle Scholar
  27. 27.
    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. Neurol Neuroimmunol Neuroinflamm. 2016;3:e226.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Guillaume Taieb
    • 1
  • Thibaut Allou
    • 1
  • Pierre Labauge
    • 1
  1. 1.Department of Neurology, CHU MontpellierHopital Guy de ChauliacMontpellier Cedex 5France

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