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Research paper
CLIPPERS and its mimics: evaluation of new criteria for the diagnosis of CLIPPERS
  1. Guillaume Taieb1,
  2. Patricia Mulero2,
  3. Dimitri Psimaras3,
  4. Bob W van Oosten4,
  5. Jörg D. Seebach5,
  6. Romain Marignier6,
  7. Fernando Pico7,8,
  8. Valérie Rigau9,
  9. Yuji Ueno10,
  10. Claire Duflos11,
  11. Vera Fominykh12,
  12. Vincent Guiraud13,
  13. Christine Lebrun-Frénay14,
  14. Jean-Philippe Camdessanché6,15,
  15. Philippe Kerschen16,
  16. Guido Ahle17,
  17. Nieves Téllez18,
  18. Alex Rovira2,
  19. Khe Hoang-Xuan3,
  20. Jean Pelletier19,
  21. Pierre Labauge1
  22. in cooperation with the French CLIPPERS group
    1. 1 Department of Neurology, University Hospital of Montpellier, Montpellier, France
    2. 2 Centre d'Esclerosi Mútiple de Catalunya, Hospital Universitari Vall d'Hebron, Barcelona, Spain
    3. 3 Department of Neurology, AP-HP Pitié-Salpêtrière, Service de Neurologie Mazarin, Paris, France
    4. 4 Department of Neurology, VU University Medical Center, Amsterdam, Netherlands
    5. 5 Department of Immunology and Allergology, University Hospital of Genève, Geneva, Switzerland
    6. 6 Centre de Recherche en Neurosciences de Lyon, INSERM U1028 and CNRS UMR5292, Equipe FLUID, Lyon, France
    7. 7 Department of Neurology, Centre Hospitalier de Versailles, Versailles, France
    8. 8 University of Versailles Saint Quentin en Yvelines et Paris Saclay, Versailles, France
    9. 9 Department of Neuropathology, University Hospital of Montpellier, Montpellier, France
    10. 10 Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan
    11. 11 Clinical Research and Epidemiology Unit, DIM, University Hospital of Montpellier, Montpellier, France
    12. 12 Department of Neurology, University Hospital of Moscow, Moscow, Russia
    13. 13 Department of Neurology, University Hospital of Saint-Etienne, Saint-Etienne, France
    14. 14 Department of Neurology, Hospital of Nice, Nice, France
    15. 15 Department of Neurology, University Hospital of Sainte Anne, Paris, France
    16. 16 Department of Neurology, University Hospital of Luxembourg, Luxembourg, Luxembourg
    17. 17 Department of Neurology, Hospital of Colmar, Colmar, France
    18. 18 Department of Neurology, Hospital Clinico de Valladolid, Valladolid, Spain
    19. 19 APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille, France
    1. Correspondence to Dr Guillaume Taieb, Department of Neurology, CHU Montpellier, Hôpital Guy de Chauliac, Montpellier 34295, France; taiebguillaume{at}gmail.com

    Abstract

    Objective To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).

    Methods We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria.

    Results After a median follow-up of 50 months (IQR 25–82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement ( ≥ 3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥ 30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma.

    Conclusions Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥ 30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.

    • CLIPPERS
    • primary central nervous system vasculitis
    • primary central nervous system lymphoma
    • lymphomatoid granulomatosis
    • anti-myelin oligodendrocyte glycoprotein related diseases
    • autoimmune glial fibrillary acidic protein astrocytopathy
    • diagnostic criteria
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    Footnotes

    • Collaborators Elsa Kaphan, Bertrand Audoin, MD (Department of Neurology, APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille, France, Site investigator); David Brassat, MD, PhD (Department of Neurology, University Hospital of Toulouse, France, Site investigator); Emmanuelle Uro-Coste, MD, PhD (Department of Neuropathology, University Hospital of Toulouse, Site investigator); Thibaut Allou, MD (Department of Neurology, Hospital of Perpignan, France, Site investigator); Jean-Christophe Ouallet, Patrice Desbordes, MD (Department of Neurology, University Hospital of Bordeaux, France, Site investigator); Giovanni Castelnovo, Eric Thouvenot, MD (Department of Neurology, University Hospital of Nîmes, France, Site investigator); Caroline Arquizan, Xavier Ayrignac, Nicolas Gaillard, MD (Department of Neurology, University Hospital of Montpellier, France, Site investigator); Nicolas Menjot de Chamfleur, MD (Department of Neuroradiology, University Hospital of Montpellier, France, Site investigator); Thierry Vincent, MD, PhD (Department of Immunology, University Hospital of Montpellier, France, Site investigator); Nadège Limousin, Cecilia Rousselot, MD (Department of Neurology, University Hospital of Tours, France, Site investigator); Delphine Loussouarn, MD (Department of Neurology, University Hospital of Nantes, France, Site investigator); Laurent Magy, MD, PhD (Department of Neurology, University Hospital of Limoges, France, Site investigator); Romain Lefaucheur, MD (Department of Neurology, University Hospital of Rouen, France, Site investigator); Jerome De Sèze, Christine Tranchant, MD, PhD (Department of Neurology, University Hospital of Strasbourg, France, Site investigator); Yannick Béjot, MD (Department of Neurology, University Hospital of Dijon, France, Site investigator).

    • Contributors GT and PL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: GT and PL. Acquisition, analysis or interpretation of data: all authors. Drafting the manuscript: GT, BWvO, FP, VG, CL, J-PC, GA, JP and PL. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: CD.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Patient consent for publication Parental/guardian consent obtained.

    • Ethics approval The Ethics Committee of Montpellier University Hospital Research approved the study, and individual consent was obtained from all patients.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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