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Neuro-inflammation
Research paper
Retinal ganglion cell loss in neuromyelitis optica: a longitudinal study
  1. Frederike C Oertel1,
  2. Joachim Havla2,
  3. Adriana Roca-Fernández3,
  4. Nathaniel Lizak1,4,
  5. Hanna Zimmermann1,
  6. Seyedamirhosein Motamedi1,
  7. Nadja Borisow1,
  8. Owen B White5,
  9. Judith Bellmann-Strobl1,6,
  10. Philipp Albrecht7,
  11. Klemens Ruprecht8,
  12. Sven Jarius9,
  13. Jacqueline Palace3,
  14. Maria Isabel Leite3,
  15. Tania Kuempfel2,
  16. Friedemann Paul1,6,8,
  17. Alexander U Brandt1,10
  1. 1 NeuroCure Clinical Research Center, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
  2. 2 Institute of Clinical Neuroimmunology, Ludwig Maximilians University, Munich, Germany
  3. 3 Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  4. 4 Monash School of Medicine, Monash University & The Alfred Hospital, Melbourne, Victoria, Australia
  5. 5 Central Clinical School, Department of Neurosciences, Monash University, Melbourne, Victoria, Australia
  6. 6 Experimental and Clinical Research Center, Max Delbrueck Center for Molecular Medicine and Charité—Universitätsmedizin Berlin, Berlin, Germany
  7. 7 Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
  8. 8 Department of Neurology, Charité—Universitätsmedizin Berlin, Berlin, Germany
  9. 9 Molecular Neuroimmunology Group, Department of Neurology, University of Heidelberg, Heidelberg, Germany
  10. 10 Department of Neurology, University of California, Irvine, Irvine, CA, United States
  1. Correspondence to Professor Friedemann Paul, NeuroCure Clinical Research Center, Charité, Charitéplatz 1, Berlin, 10117, Germany; friedemann.paul{at}charite.de

Abstract

Objectives Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory conditions of the central nervous system and an important differential diagnosis of multiple sclerosis (MS). Unlike MS, the course is usually relapsing, and it is unclear, if progressive neurodegeneration contributes to disability. Therefore, we aimed to investigate if progressive retinal neuroaxonal damage occurs in aquaporin4-antibody-seropositive NMOSD.

Methods Out of 157 patients with NMOSD screened, 94 eyes of 51 patients without optic neuritis (ON) during follow-up (F/U) and 56 eyes of 28 age-matched and sex-matched healthy controls (HC) were included (median F/U 2.3 years). The NMOSD cohort included 60 eyes without (EyeON −) and 34 eyes with a history of ON prior to enrolment (EyeON+). Peripapillary retinal nerve fibre layer thickness (pRNFL), fovea thickness (FT), volumes of the combined ganglion cell and inner plexiform layer (GCIP) and the inner nuclear layer (INL) and total macular volume (TMV) were acquired by optical coherence tomography (OCT).

Results At baseline, GCIP, FT and TMV were reduced in EyeON+ (GCIP p<2e−16; FT p=3.7e−4; TMV p=3.7e−12) and in EyeON − (GCIP p=0.002; FT p=0.040; TMV p=6.1e−6) compared with HC. Longitudinally, we observed GCIP thinning in EyeON− (p=0.044) but not in EyeON+. Seven patients had attacks during F/U; they presented pRNFL thickening compared with patients without attacks (p=0.003).

Conclusion This study clearly shows GCIP loss independent of ON attacks in aquaporin4-antibody-seropositive NMOSD. Potential explanations for progressive GCIP thinning include primary retinopathy, drug-induced neurodegeneration and retrograde neuroaxonal degeneration from lesions or optic neuropathy. pRNFL thickening in the patients presenting with attacks during F/U might be indicative of pRNFL susceptibility to inflammation.

https://doi.org/10.1136/jnnp-2018-318382

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    Footnotes

    • FP and AUB are joint senior authors.

    • FCO and JH are joint first authors.

    • Contributors FCO: data collection, OCT data processing, data analysis, writing of the manuscript. JH: data acquisition and collection, study coordination. ARF: data collection. NL: data collection, data analysis. HZ: data acquisition, study coordination, supervision of OCT data processing. SM: data analysis. NB/JBS/JP/MIL/TK: data acquisition, study coordination. OBW/PA/KR: study coordination. SJ: data acquisition. FP: data acquisition, study coordination, study concept. AUB: study concept, design, study coordination, data analysis, writing of the manuscript. All authors revised the manuscript for intellectual content and read and approved the final manuscript.

    • Funding The project was supported with grants from the German Ministry for Education and Research (BMBF/KKNMS; Competence Network Multiple Sclerosis (to FP, KR), from the Deutsche Forschungsgemeinschaft (DFG, grant Exc. 257 to FP, AUB), from the German Federal Ministry of Economic Affairs and Energy (EXIST 03EFEBE079 to AUB), from the German Ministry of Education and Research (N2-ADVISIMS 16GW0079 to FP and AUB), from the National Multiple Sclerosis Society (to FP), from the Guthy-Jackson Charitable Foundation (to FP, AUB) and from Novartis (to HZ). MIL and JP were funded for highly specialised service for neuromyelitis optica—NHS, UK, grants. JP also received research support from the MS society and Guthy-Jackson Charitable Foundation. FCO received financial support by the MD student research stipend from the Berlin Institute of Health (BIH). 

    • Competing interests FCO has nothing to disclose. JH reports personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, personal fees from Roche, non-financial support from Bayer Healthcare, personal fees from Santhera, personal fees and non-financial support from Biogen, personal fees and non-financial support from Sanofi Genzyme, all outside the submitted work. ARF is sponsored by Abide Therapeutic outside of the submitted work and reports no potential conflicts of interest. NL has nothing to disclose. HZ reports grants from Novartis, during the conduct of the study. SM has nothing to disclose; he is named as inventor on a patent application describing OCT image analysis. NB has nothing to disclose. JBS received speaking fees and travel grants from Bayer Healthcare, Sanofi-Aventis/Genzyme, Biogen and Teva Pharmaceuticals, unrelated to the present scientific work. PA reports grants, personal fees and non-financial support from Allergan, personal fees and non-financial support from Bayer Healthcare, grants, personal fees and non-financial support from Biogen, grants, personal fees and non-financial support from Ipsen, grants, personal fees and non-financial support from Merz Pharmaceuticals, personal fees and non-financial support from Merck, grants, personal fees and non-financial support from Novartis, non-financial support from Sanofi-Aventis/Genzyme, personal fees and non-financial support from Teva Pharmaceuticals, grants, personal fees and non-financial support from Roche, outside the submitted work. KR reports research support from Novartis and Merck Serono as well as speaking fees or travel grants from Bayer Healthcare, Biogen Idec, Merck Serono, Sanofi-Aventis/Genzyme, Teva Pharmaceuticals, Roche, Novartis and the Guthy-Jackson Charitable Foundation, all unrelated to this work. TK received travel expenses and personal compensations from Bayer Healthcare, Teva Pharmaceuticals, Merck, Novartis Pharma, Sanofi-Aventis/Genzyme, Roche and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma, unrelated to this work. OW has nothing to disclose. SJ has nothing to disclose. MIL reports personal fees from Biogen Idec and grants from Novartis, outside the submitted work. JP reports grants Journal of Neurology, Neurosurgery and Psychiatry and personal fees from Merck Serono, grants and personal fees from Biogen Idec, personal fees from Teva Pharmaceuticals, grants from Chugai, grants and personal fees from MedImmun, grants and personal fees from Alexion, grants and personal fees from Novartis, personal fees from Roche, grants from Genzyme, grants and personal fees from ABIDE, personal fees from TG Therapeutics, outside the submitted work. In addition, JP has a patent Isis: Diagnosing Multiple Sclerosis. FP reports research grants and speaker honoraria from Bayer, Teva, Genzyme, Merck, Novartis, MedImmune and is member of the steering committee of the OCTIMS study (Novartis), all unrelated to this work. AUB is cofounder and holds shares of commercial entities Motognosis and Nocturne. He is named as inventor on several patent applications describing serum biomarkers for MS, perceptive visual computing for tracking of motor dysfunction and OCT image analysis.

    • Patient consent Not required.

    • Ethics approval NeuroCure Clinical Research Center (NCRC) at Charité — Universitätsmedizin Berlin, Germany (EA1/131/09), the Ludwig Maximilians Universität Munich, Germany (Z427-

      14) and the Nuffield Center for Clinical Neurosciences at Oxford University, UK (REC 16/SC/0224).

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