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Original research
Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study
  1. Cathérine Dekeyser1,
  2. Matthias Hautekeete1,
  3. Melissa Cambron2,3,
  4. Vincent Van Pesch4,5,
  5. Francesco Patti6,7,
  6. Jens Kuhle8,9,
  7. Samia Khoury10,
  8. Jeanette Lechner Scott11,12,
  9. Oliver Gerlach13,14,
  10. Alessandra Lugaresi15,16,
  11. Davide Maimone17,
  12. Andrea Surcinelli18,
  13. Pierre Grammond19,
  14. Tomas Kalincik20,21,
  15. Mario Habek22,23,
  16. Barbara Willekens24,25,
  17. Richard Macdonell26,
  18. Patrice Lalive27,
  19. Tunde Csepany28,
  20. Helmut Butzkueven29,30,
  21. Cavit Boz31,
  22. Valentina Tomassini32,33,
  23. Matteo Foschi34,35,
  24. José Luis Sánchez-Menoyo36,37,
  25. Ayse Altintas38,
  26. Saloua Mrabet39,40,
  27. Gerardo Iuliano41,
  28. Maria Jose Sa42,43,
  29. Raed Alroughani44,
  30. Rana Karabudak45,46,
  31. Eduardo Aguera-Morales47,48,
  32. Orla Gray49,
  33. Koen de Gans50,
  34. Anneke van der Walt51,52,
  35. Pamela A McCombe53,54,
  36. Norma Deri55,
  37. Justin Garber56,
  38. Abdullah Al-Asmi57,
  39. Olga Skibina58,59,
  40. Pierre Duquette60,
  41. Elisabetta Cartechini61,
  42. Daniele Spitaleri62,
  43. Riadh Gouider40,63,
  44. Aysun Soysal64,
  45. Liesbeth Van Hijfte65,
  46. Mark Slee66,
  47. Maria Pia Amato67,68,
  48. Katherine Buzzard69,70,
  49. Guy Laureys65
  1. 1Neurology, University Hospital Ghent, Gent, Belgium
  2. 2Neurology, Sint-Jan Bruges Hospital, Bruges, Belgium
  3. 3University of Ghent, Ghent, Belgium
  4. 4Neurology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
  5. 5Université Catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium
  6. 6Neuroscience, University of Catania Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', Catania, Italy
  7. 7Multiple Sclerosis Unit, AOU Policlinico G Rodolico-San Marco, Catania, Italy
  8. 8Neurology, University Hospital Basel, Basel, Switzerland
  9. 9Biomedicine and Clinical Research, Multiple Sclerosis Centre and Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Basel, Switzerland
  10. 10Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  11. 11Hunter Medical Research Institute, The University of Newcastle, Newcastle, New South Wales, Australia
  12. 12Hunter New England Health, John Hunter Hospital, New Lambton Heights, New South Wales, Australia
  13. 13Neurology, Zuyderland Medical Centre, Sittard-Geleen, The Netherlands
  14. 14Neurology, Universiteit Maastricht School for Mental Health and Neuroscience, Maastricht, The Netherlands
  15. 15UOSI Riabilitazione Sclerosi Multipla, IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna, Italy
  16. 16Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italy
  17. 17Centro Sclerosi Multipla, UOC Neurologia, Azienda Ospedaliera Cannizzaro, Catania, Italy
  18. 18Department of Neuroscience, MS Center, S Maria delle Croci Hospital, Ravenna, Italy
  19. 19CISSS Chaudière-Appalaches Research Center, Levis, Quebec, Canada
  20. 20Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  21. 21Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  22. 22University Hospital Centre Zagreb Department of Neurology, Zagreb, Croatia
  23. 23University of Zagreb School of Medicine, Zagreb, Zagreb, Croatia
  24. 24Neurology, Universitair Ziekenhuis Antwerpen, Edegem, Belgium
  25. 25Laboratory of Experimental Hematology, Universiteit Antwerpen Faculteit geneeskunde en gezondheidswetenschappen, Wilrijk, Belgium
  26. 26Austin Health, Melbourne, Victoria, Australia
  27. 27Clinical Neurosciences, Division of Neurology, Unit of Neuroimmunology, Geneva University Hospitals Department of Medicine, Geneve, Switzerland
  28. 28Department of Neurology, University of Debrecen, Debrecen, Hungary
  29. 29Department of Neuroscience, Monash University Central Clinical School, Melbourne, Victoria, Australia
  30. 30Neurology, The Alfred Hospital, Melbourne, Victoria, Australia
  31. 31Neurology, Karadeniz Technical University, Medical Faculty, Trabzon, Turkey
  32. 32Istituto di Tecnologie Avanzate Biomediche (ITAB), Dipartimento di Neuroscienze e Imaging e Scienze Cliniche; Centro Sclerosi Multipla, Clinica Neurologica, Ospedale SS Annunziata, Università degli Studi Gabriele d'Annunzio Chieti Pescara, Chieti, Italy
  33. 33University G. d’Annunzio of Chieti-Pescara, Chieti, Italy
  34. 34Department of Neuroscience, MS Center, Neurology Unit, S. Maria delle Croci Hospital, Ravenna, Italy
  35. 35Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, L'Aquila, Italy
  36. 36Neurology, Galdakao-Usansolo University Hospital, Osakidetza-Basque Health Service, Galdakao, Spain
  37. 37Biocruces Bizkaia Health Research Institute, Barakaldo, Spain
  38. 38Neurology, Koc University School of Medicine and Koc University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey
  39. 39Neurology, Razi University Hospital, Clinical Investigation Centre Neurosciences and Mental Health, Tunis, Tunisia
  40. 40University of Tunis El Manar Faculty of Medicine of Tunis, Tunis, Tunisia
  41. 41Ospedali Riuniti di Salerno, Salerno, Italy
  42. 42Neurology, Centro Hospitalar de São João, Porto, Portugal
  43. 43Fernando Pessoa University Faculty of Health Sciences, Porto, Portugal
  44. 44Neurology, Amiri Hospital, Kuwait City, Kuwait
  45. 45Neurological Sciences, Yeditepe Universitesi, Istanbul, Turkey
  46. 46Neuroimmunology, Koşuyolu Hospitals, Istanbul, Turkey
  47. 47Neurology, Hospital Universitario Reina Sofia, Cordoba, Spain
  48. 48GC28 Neuroplasticity and Oxidative Stress, IMIBIC, Cordoba, Spain
  49. 49South Eastern HSC Trust, Belfast, UK
  50. 50Groene Hart Ziekenhuis, Gouda, The Netherlands
  51. 51Monash University Central Clinical School, Melbourne, Victoria, Australia
  52. 52Alfred Hospital, Melbourne, Victoria, Australia
  53. 53UQCCR, Royal Brisbane and Woman's Hospital Health Service District, Herston, Queensland, Australia
  54. 54The University of Queensland, Brisbane, Queensland, Australia
  55. 55Hospital Fernandez, Buenos Aires, Argentina
  56. 56Westmead Hospital, Sydney, New South Wales, Australia
  57. 57Sultan Qaboos University College of Medicine and Health Science, Muscat, Muscat Governorate, Oman
  58. 58Neurosciences, The Alfred, Melbourne, Victoria, Australia
  59. 59Neurology, Box Hill Hospital, Box Hill, Victoria, Australia
  60. 60CHUM and Universite de Montreal, Montreal, Quebec, Canada
  61. 61UOC Neurologia, Azienda Sanitaria Unica Regionale Marche - AV3, Macerata, Italy
  62. 62Neurology, Azienda Ospedaliera di Rilievo Nazionale e di Alta Specialità San Giuseppe Moscati Neurologia e Stroke Unit, Avellino, Italy
  63. 63Department of Neurology, Razi Hospital, Faculty of Medicine of Tunis, University Tunis el Manar, Tunisia, Manouba, Tunisia
  64. 64Bakirkoy Education and Research Hospital for Psychiatric and Neurological Diseases, Istanbul, Turkey
  65. 65University Hospital Ghent, Gent, Belgium
  66. 66Neurology, Flinders Medical Centre, Adelaide, South Australia, Australia
  67. 67Department NEUROFARBA, University of Florence, Florence, Italy
  68. 68IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
  69. 69Department of Neurology, Box Hill Hospital, Melbourne, Victoria, Australia
  70. 70Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
  1. Correspondence to Dr Cathérine Dekeyser, Neurology, University Hospital Ghent, Gent, Belgium; catherine.dekeyser{at}uzgent.be

Abstract

Background It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course.

Methods This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis.

Results In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015).

Conclusions In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

  • MULTIPLE SCLEROSIS
  • NEUROIMMUNOLOGY
  • CLINICAL NEUROLOGY
  • CSF

Data availability statement

Data are available upon reasonable request. Data that support the findings of this study will be made available upon reasonable request directed to the corresponding author and the MSBase study group.

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Data availability statement

Data are available upon reasonable request. Data that support the findings of this study will be made available upon reasonable request directed to the corresponding author and the MSBase study group.

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Footnotes

  • Twitter @ALugaresi, @mattfos89, @doctoredu

  • Contributors CD: conceptualisation, methodology, data collection, formal analysis and investigation, and writing (original draft preparation), guarantor. MH: conceptualisation, methodology, data collection, formal analysis and investigation, and writing (review and editing). MC: conceptualisation, methodology, data collection and writing (review and editing). VVP: conceptualisation, methodology, data collection and writing (review and editing). FP: data collection and writing (review and editing). JK: data collection and writing (review and editing). SK: data collection and writing (review and editing). JLS: data collection and writing (review and editing). OG: data collection and writing (review and editing). AL: data collection and writing (review and editing). DM: data collection and writing (review and editing). AS: data collection and writing (review and editing). PG: data collection and writing (review and editing). TK: data collection and writing (review and editing). MH: data collection and writing (review and editing). BW: data collection and writing (review and editing). RM: data collection and writing (review and editing). PL: data collection and writing (review and editing). TC: data collection and writing (review and editing). HB: data collection and writing (review and editing). CB: data collection and writing (review and editing). VT: data collection and writing (review and editing). MF: data collection and writing (review and editing). JLS-M: data collection and writing (review and editing). AA: data collection and writing (review and editing). SM: data collection and writing (review and editing). GI: data collection and writing (review and editing). MJS: data collection and writing (review and editing). RA: data collection and writing (review and editing). RK: data collection and writing (review and editing). EA-M: data collection and writing (review and editing). OG: data collection and writing (review and editing). KdG: data collection and writing (review and editing). AvdW: data collection and writing (review and editing). PAMcC: data collection and writing (review and editing). ND: data collection and writing (review and editing). JG: data collection and writing (review and editing). AA-A: data collection and writing (review and editing). OS: data collection and writing (review and editing). PD: data collection and writing (review and editing). EC: data collection and writing (review and editing). DS: data collection and writing (review and editing). RG: data collection and writing (review and editing). AS: data collection and writing (review and editing). LVH: data collection and writing (review and editing). MS: data collection and writing (review and editing). MPA: data collection and writing (review and editing). KB: data collection and writing (review and editing). GL: conceptualisation, methodology, data collection, writing (review and editing) and supervision.

  • 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 CD: received travel compensation from Sanofi-Genzyme, Merck and Biogen. MH: none declared. CM: received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene, Biogen, Sandoz and Janssen. VVP: received travel grants from Merck Healthcare KGaA (Darmstadt, Germany), Biogen, Sanofi, Bristol Meyer Squibb (BMS), Almirall and Roche. His institution has received research grants and consultancy fees from Roche, Biogen, Sanofi, Merck Healthcare KGaA (Darmstadt, Germany), BMS, Janssen, Almirall, Novartis Pharma and Alexion. FP: received personal compensation for serving on advisory board by Almirall, Alexion, Biogen, Bristol, Janssen, Merck, Novartis and Roche. He further received research grants from Alexion, Almirall, Biogen, Bristol, Merck, Novartis and Roche and by FISM, Reload Association (Onlus), Italian Health Minister and University of Catania. JK: received speaker fees, research support and travel support and/or served on advisory boards by the Swiss MS Society, Swiss National Research Foundation (320030_189140/1), University of Basel, Progressive MS Alliance, Alnylam, Bayer, Biogen, BMS, Celgene, Immunic, Merck, Neurogenesis, Novartis, Octave Bioscience, Quanterix, Roche, Sanofi and Stata DX. SK: received compensation for scientific advisory board activity from Merck and Roche and received compensation for serving on the IDMC for Biogen. JLS: received travel compensation from Novartis, Biogen, Roche and Merck. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Biogen, Merck, Roche, TEVA and Novartis. OG: none declared. AL: has received personal compensation for consultation, serving on a scientific advisory board, speaking or other activities from Alexion, Biogen, BMS, Horizon, Janssen, Merck Serono, Novartis, and Sanofi/Genzyme, and her institutions have received research grants from Novartis and Sanofi/Genzyme. DM: received speaker honoraria for advisory board and travel grants from Alexion, Almirall, Bayer, Biogen, BMS, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. AS: received travel and meeting attendance support from Novartis, Biogen, Roche, Merck, Bristol, Sanofi-Genzyme, Almirall and Piam. PG: has served in advisory boards for Novartis, EMD Serono, Roche, Biogen Idec, Sanofi Genzyme and Pendopharm and has received grant support from Genzyme and Roche and has received research grants for his institution from Biogen Idec, Sanofi Genzyme and EMD Serono. TK: served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen and steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. MH: participated as a clinical investigator and/or received consultation and/or speaker fees from Biogen, Sanofi Genzyme, Merck, Bayer, Novartis, Pliva/Teva, Roche, Alvogen, Actelion, Alexion Pharmaceuticals and TG Pharmaceuticals. BW: received honoraria for acting as a member of Scientific Advisory Boards/Consultancy for Alexion, Almirall, Biogen, Celgene/BMS, Merck, Janssen, Novartis, Roche, Sandoz and Sanofi-Genzyme; speaker honoraria and travel support from Biogen, Celgene/BMS, Merck, Novartis, Roche and Sanofi-Genzyme; and research and/or patient support grants from Biogen, Janssen, Merck, Sanofi-Genzyme and Roche. Honoraria and grants were paid to UZA/UZA Foundation. Further, she received research funding from FWO-TBM, Belgian Charcot Foundation, Start2Cure Foundation, Queen Elisabeth Medical Foundation for Neurosciences and the National MS Society USA. RM: received remuneration for his speaking engagements, advisory board memberships, research and travel from Biogen, Merck, Genzyme, Bayer, Roche, Teva, Novartis, CSL, BMS, MedDay and NHMRC. PL: received honoraria for speaking and or travel expense from Biogen, Merck, Novartis and Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis and Roche; and research support from Biogen, Merck and Novartis. None were related to this work. TC: received speaker honoraria/conference travel support from Biogen, Merck, Novartis, Roche, Sanofi-Aventis and Teva. HB: received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; and has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. CB: received conference travel support from Biogen, Novartis, Bayer-Schering, Merck and Teva and has participated in clinical trials by Sanofi Aventis, Roche and Novartis. VT: participated as a clinical investigator and/or received consultation and/or speaker fees and/or travel grants and/or research support from Biogen, Sanofi Genzyme, Merck, Novartis, Roche, Alexion, Viatris, Janssen, BMS and Almirall. MF: received travel and meeting attendance support from Novartis, Biogen, Roche, Sanofi-Genzyme and Merck. JLS-M: accepted travel compensation from Novartis, Merck and Biogen and speaking honoraria from Biogen, Novartis, Sanofi, Merck, Almirall, Bayer and Teva and has participated in clinical trials by Biogen, Merck and Roche. AA: received speaker honoraria from Novartis and Alexion. SM: has received a MENACTRIMS clinical fellowship grant (2020). GI: had travel/accommodations/meeting expenses funded by Bayer Schering, Biogen, Merck, Novartis, Sanofi Aventis and Teva. MJS: received consulting fees, speaker honoraria and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, BMS, Celgene, Janssen, Merck-Serono, Novartis, Roche, Sanofi and Teva. RA: received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. RK: received consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events, support for attending meetings and travels, and participation on a data safety monitoring board or advisory board from Gen Turkey. EA-M: has received honoraria as a speaker from Biogen, Merck, Novartis and Sanofi-Genzyme and for serving on scientific advisory boards from Novartis. OG: received honoraria as consultant on scientific advisory boards for Genzyme, Biogen, Merck, Roche and Novartis; has received travel grants from Biogen, Merck, Roche, and Novartis; and has participated in clinical trials by Biogen and Merck. Her institution has received research grant support from Biogen. KDG: served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis and Merck; received conference fees and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, AbbVie and Merck; and received educational event support from Novartis. AvdW: served on advisory boards and received unrestricted research grants from Novartis, Biogen, Merck and Roche. She has received speaker’s honoraria and travel support from Novartis, Roche, and Merck. She received grant support from the National Health and Medical Research Council of Australia and MS Research Australia. PMcC: received honoraria and consulting fees from Novartis, Bayer Schering and Sanofi and travel grants from Novartis, Biogen and Bayer Schering. ND: received funding from Bayer, Merck, Biogen, Genzyme and Novartis. JG: received conference travel support from Roche, Merck and Novartis and received speaker honoraria from Biogen and research support from Roche. AA-A: received personal compensation for serving as a scientific advisory or speaker/moderator for Novartis, Biogen, Roche, Sanofi-Genzyme and Merck. OS: received honoraria and consulting fees from Bayer Schering, Novartis, Merck, Biogen and Genzyme. PD: served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis and Genzyme. EC: none declared. DS: received honoraria as a consultant on scientific advisory boards by Bayer-Schering, Novartis and Sanofi-Aventis and compensation for travel from Novartis, Biogen, Sanofi Aventis, Teva and Merck. RG: has received personal compensation for consultation, serving on a scientific advisory board, speaking or other activities from Biogen, Hikma, Merck, Roche and Sanofi/Genzyme. AS: none declared. LVH: received travel compensation from Merck. MS: none declared. MPA: received honoraria as consultant on scientific advisory boards by Biogen, Bayer-Schering, Merck, Teva and Sanofi-Aventis and has received research grants by Biogen, Bayer-Schering, Merck, Teva and Novartis. KB: received speaker honoraria and/or education support from Biogen, Teva, Novartis, Genzyme-Sanofi, Roche, Merck and Alexion and has been a member of advisory boards for Merck and Biogen. GL: received travel and/or consultancy compensation from Sanofi-Genzyme, Roche, Teva, Merck, Novartis, Celgene and Biogen.

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

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