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Original research
Multiple sclerosis: structural and functional integrity of the visual system following alemtuzumab therapy
  1. Chenyu Wang1,2,
  2. Joshua Barton2,
  3. Kain Kyle1,2,
  4. Linda Ly1,
  5. Yael Barnett1,3,
  6. Hans-Peter Hartung2,4,
  7. Stephen W Reddel2,
  8. Heidi Beadnall2,5,
  9. Marinda Taha2,
  10. Alexander Klistorner1,6,
  11. Michael Harry Barnett1,2,5
  1. 1Sydney Neuroimaging Analysis Centre, Camperdown, New South Wales, Australia
  2. 2Brain and Mind Centre, The University of Sydney, Camperdown, New South Wales, Australia
  3. 3Radiology Department, St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia
  4. 4Clinic for Neurology, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
  5. 5Neurology Department, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  6. 6Save Sight Institute, The University of Sydney, Sydney, New South Wales, Australia
  1. Correspondence to Dr Michael Harry Barnett, Brain and Mind Centre, The University of Sydney, Camperdown, NSW 2050, Australia; michael{at}sydneyneurology.com.au

Abstract

Objective To investigate potential neuroprotective and pro-remyelinating effects of alemtuzumab in multiple sclerosis (MS), using the visual pathway as a model.

Methods We monitored clinical, multifocal visual evoked potential (mfVEP) and MRI outcomes in 30 patients commencing alemtuzumab for relapsing MS, and a reference group of 20 healthy controls (HCs), over 24 months. Change in mfVEP latency was the primary endpoint; change in optic radiation (OR) lesion diffusion metrics and Mars letter contrast sensitivity over the course of the study were secondary endpoints.

Results In patients, we observed a mean shortening of mfVEP latency of 1.21 ms over the course of the study (95% CI 0.21 to 2.21, p=0.013), not altered by correction for age, gender, disease duration or change in OR T2 lesion volume. Mean mfVEP latency in the HC group increased over the course of the study by 0.72 ms (not significant). Analysis of chronic OR T2 lesions (patients) showed an increase in normalised fractional anisotropy and axial diffusivity between baseline and 24 months (both p<0.01). Mean Mars letter contrast sensitivity was improved at 24 months vs baseline (p<0.001), and driven by an early improvement, in both patients and HC.

Conclusion We found evidence of partial lesion remyelination after alemtuzumab therapy, indicating either natural restoration in the context of a ‘permissive’ local milieu; or potentially an independent, pro-reparative mechanism of action. The visual system presents a unique opportunity to study function-structure specific effects of therapy and inform the design of future phase 2 MS remyelination trials.

  • multiple sclerosis

Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplemental information.

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Footnotes

  • CW and JB are joint first authors.

  • AK and MHB are joint senior authors.

  • Correction notice This article has been corrected since it appeared Online First. Equal and Senior authorship details have been added.

  • Contributors MHB, CW and AK conceived the study. CW and YB developed the imaging protocols. KK and LL performed MRI analysis. AK and JB developed the electrophysiological protocols and analysed the mfVEP and OCT data. MHB, SWR, JB, HB and MT collected and analysed all clinical data. CW performed statistical testing. H-PH and all authors made significant contributions to data analysis and interpretation, and drafting and revision of the manuscript.

  • Funding This study is funded by a Sanofi-Genzyme Research Grant: VisMS (Vision in MS: GZ-2015-11423). CW is supported by the Nerve Research Foundation, University of Sydney and Multiple Sclerosis Research Australia.

  • Competing interests CW has received research fellowship support from Multiple Sclerosis Research Australia, Nerve Research Foundation at the University of Sydney, and is an employee at Sydney Neuroimaging Analysis Centre (SNAC). JB has received honoraria for talks and advisory boards and support for scientific meetings from Sanofi-Genzyme, Novartis, Teva, Merck and Biogen. KK and LL are employees at SNAC. YB is a consulting neuroradiologist for SNAC. HB has received honoraria for presentations and advisory boards; and has received educational travel support from Biogen, Genzyme, Merck, Novartis and/or Roche. SWR has received institutional support from Baxter, Bayer Schering, Biogen Idec, CSL, Genzyme, Grifols, Octapharma, Merck, Novartis, Roche, Sanofi Aventis Genzyme, Servier and TEVA; and is a co-founder of Medical Safety Systems/RxMx. MHB reports grants from Genzyme-Sanofi, during the conduct of the study; grants from Genzyme-Sanofi, Novartis, Biogen and Merck outside the submitted work; and is a co-founder of RxMx, which provides automated laboratory monitoring for patients with MS prescribed immunotherapies; and research director of SNAC. H-PH has received fees for serving on steering and data monitoring committees from Bayer Healthcare, Biogen, Celgene BMS, CSL Behring, GeNeuro, MedImmune, Merck, Novartis, Octapharma, Roche, Sanofi Genzyme, TG Therapeutics and Viela Bio; fees for serving on advisory boards from Biogen, Sanofi Genzyme, Merck, Novartis, Octapharma and Roche; and lecture fees from Biogen, Celgene BMS, Merck, Novartis, Roche and Sanofi Genzyme. MT and AK have nothing to disclose.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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