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Research paper
Brain microstructural injury occurs in patients with RRMS despite ‘no evidence of disease activity’
  1. Asaff Harel1,2,
  2. Dylan Sperling1,
  3. Maria Petracca1,
  4. Achillefs Ntranos1,
  5. Ilana Katz-Sand1,
  6. Stephen Krieger1,
  7. Fred Lublin1,
  8. Zichen Wang3,
  9. Yangbo Liu4,
  10. Matilde Inglese1,5
  1. 1 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  2. 2 Department of Neurology, Lenox Hill Hospital, New York, USA
  3. 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, USA
  4. 4 Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, USA
  5. 5 Departmentof Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Perinatal Sciences, University of Genoa andIRCCS Azienda Ospedale Università San Martino-IST, Genoa, Italy
  1. Correspondence to Miss Matilde Inglese, Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; matilde.inglese{at}


Objectives The accuracy of ‘no evidence of disease activity’ (NEDA) in predicting long-term clinical outcome in patients with relapsing remitting multiple sclerosis (RRMS) is unproven, and there is growing evidence that NEDA does not rule out disease worsening. We used diffusion tensor imaging (DTI) to investigate whether ongoing brain microstructural injury occurs in patients with RRMS meeting NEDA criteria.

Methods We performed a retrospective study to identify patients with RRMS visiting our centre over a 3-month period who had undergone prior longitudinal DTI evaluation at our facility spanning ≥2 years. Patients meeting NEDA criteria throughout the evaluation period were included in the NEDA group, and those not meeting NEDA criteria were included in an ‘evidence of disease activity’ (EDA) group. Fractional anisotropy (FA) and mean diffusivity (MD) maps were created, and annual rates of change were calculated.

Results We enrolled 85 patients, 39 meeting NEDA criteria. Both NEDA and EDA groups showed longitudinal DTI worsening. Yearly FA decrease was lower in the NEDA group (0.5%, p<0.0001) than in the EDA group (1.2%, p=0.003), while yearly MD increase was similar in both groups (0.8% for NEDA and EDA, both p<0.01). There was no statistical difference in deterioration within and outside of T2 lesions. DTI parameters correlated with disability scores and fatigue complaints.

Conclusions White matter microstructural deterioration occurs in patients with RRMS over short-term follow-up in patients with NEDA, providing further evidence of the limitations of conventional measures and arguing for DTI in monitoring of the disease process.

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  • AH and DS contributed equally.

  • Contributors AH, DS, IK-S and MI contributed to the study design. AH, DS, MP and AN were responsible for the acquisition of data. AH, DS and MI were responsible for the writing of the article. MI supervised the study. AH, DS, MP, SK, FL, ZW, YL and MI participated in the analysis and interpretation of data. All authors contributed to the critical review of the manuscript for important intellectual content.

  • Funding This study was funded by National Multiple Sclerosis Society (NMSS RG 5120-A-3).

  • Competing interests AH has received consulting funds from TEVA pharmaceuticals. SK has received compensation for consulting and advisory board work with Acorda Therapeutics, Bayer, Biogen, EMD Serono (Merck & Co.), Genentech, Genzyme, Mallinckrodt, Novartis and Teva Pharmaceutical Industries and has given non-promotional lectures with Biogen. FL has received funding for research from Acorda Therapeutics, Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Genzyme, Sanofi, Celgene, NIH, NMSS and funding for consulting from Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Novartis, Teva Neuroscience, Actelion, Sanofi-Aventis, Acorda, Questcor, Roche, Genentech, Celgene, Johnson & Johnson, Revalesio, Coronado Bioscience, Genzyme, MedImmune, Bristol-Myers Squibb, Xenoport, Receptos and Forward Pharma. He serves as Co-Chief Editor for Multiple Sclerosis and Related Diseases and has stock ownership in Cognition Pharmaceuticals. MI has received research grants from NIH, NMSS, Novartis Pharmaceuticals Corp. and she is a consultant for Vaccinex.

  • Patient consent Not required.

  • Ethics approval Mount Sinai Hospital Institutional Review Board.

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