Discriminative power of intra-retinal layers in early multiple sclerosis using 3D OCT imaging

Abstract

Objective

To evaluate volumetric changes and discriminative power of intra-retinal layers in early-stage multiple sclerosis (MS) using a 3D optical coherence tomography (OCT) imaging method based on an in-house segmentation algorithm.

Methods

3D analysis of intra-retinal layers was performed in 71 patients with early-stage MS (mean disease duration 2.2 ± 3.5 years) at baseline and 40 healthy controls (HCs). All patients underwent a follow-up OCT scan within 23 ± 9 months. Patients with a clinical episode of optic neuritis (ON) more than 6 months prior to study entrance were compared with patients who never experienced clinical symptoms of an ON episode (NON).

Results

Significantly decreased total retinal volume (TRV), macular retinal nerve fiber layer (mRNFL) and ganglion cell—inner plexiform layer (GCIPL) volumes were detected in ON patients compared to NON patients (all p values < 0.05) at baseline. Each parameter on its own allowed identification of prior clinical ON based on a discriminative model (ROC analysis). Over time, TRV decreased in both ON (p = 0.013) and NON patients (p = 0.002), whereas mRNFL volume (p = 0.028) decreased only in ON and GCIPL volume (p = 0.003) decreased only in NON patients.

Conclusion

Our 3D-OCT data demonstrated that TRV, mRNFL and GCIPL allow discrimination between ON and NON patients in a cross-sectional analysis. However, the subsequent retinal atrophy pattern diverges in the initial phase of MS: Prior ON promotes sustained axonal thinning over time indicated by mRNFL loss, whereas longitudinal measurement of GCIPL volume better depicts continuous retrograde neurodegeneration in NON patients in early-stage MS.

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References

  1. 1.

    Zipp F, Gold R, Wiendl H (2013) Identification of inflammatory neuronal injury and prevention of neuronal damage in multiple sclerosis: hope for novel therapies? JAMA Neurol 70(12):1569–1574

    PubMed  Google Scholar 

  2. 2.

    Balk LJ, Twisk JW, Steenwijk MD, Daams M, Tewarie P, Killestein J et al (2014) A dam for retrograde axonal degeneration in multiple sclerosis? J Neurol Neurosurg Psychiatry 85(7):782–789

    CAS  Article  Google Scholar 

  3. 3.

    Barkhof F, Calabresi PA, Miller DH, Reingold SC (2009) Imaging outcomes for neuroprotection and repair in multiple sclerosis trials. Nature Rev Neurol 5(5):256–266

    Article  Google Scholar 

  4. 4.

    Shams PN, Plant GT (2009) Optic neuritis: a review. Int MS J 16(3):82–89

    CAS  PubMed  Google Scholar 

  5. 5.

    Petzold A, de Boer JF, Schippling S, Vermersch P, Kardon R, Green A et al (2010) Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 9(9):921–932

    Article  Google Scholar 

  6. 6.

    Balk LJ, Petzold A (2014) Current and future potential of retinal optical coherence tomography in multiple sclerosis with and without optic neuritis. Neurodegener Dis Manag 4(2):165–176

    Article  Google Scholar 

  7. 7.

    Garcia-Martin E, Ara JR, Martin J, Almarcegui C, Dolz I, Vilades E et al (2017) Retinal and optic nerve degeneration in patients with multiple sclerosis followed up for 5 years. Ophthalmology 124:688–696

    Article  Google Scholar 

  8. 8.

    Green AJ, McQuaid S, Hauser SL, Allen IV, Lyness R (2010) Ocular pathology in multiple sclerosis: retinal atrophy and inflammation irrespective of disease duration. Brain 133(Pt 6):1591–1601

    Article  Google Scholar 

  9. 9.

    Sriram P, Graham SL, Wang C, Yiannikas C, Garrick R, Klistorner A (2012) Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study. Investig Ophthalmol Vis Sci 53(3):1271–1275

    Article  Google Scholar 

  10. 10.

    Ratchford JN, Saidha S, Sotirchos ES, Oh JA, Seigo MA, Eckstein C et al (2013) Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning. Neurology 80(1):47–54

    Article  Google Scholar 

  11. 11.

    Syc SB, Saidha S, Newsome SD, Ratchford JN, Levy M, Ford E et al (2012) Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain 135(Pt 2):521–533

    Article  Google Scholar 

  12. 12.

    Oberwahrenbrock T, Ringelstein M, Jentschke S, Deuschle K, Klumbies K, Bellmann-Strobl J et al (2013) Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler 19(14):1887–1895

    Article  Google Scholar 

  13. 13.

    Martinez-Lapiscina EH, Arnow S, Wilson JA, Saidha S, Preiningerova JL, Oberwahrenbrock T et al (2016) Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study. Lancet Neurol 15(6):574–584

    Article  Google Scholar 

  14. 14.

    Albrecht P, Frohlich R, Hartung HP, Kieseier BC, Methner A (2007) Optical coherence tomography measures axonal loss in multiple sclerosis independently of optic neuritis. J Neurol 254(11):1595–1596

    Article  Google Scholar 

  15. 15.

    Dorr J, Wernecke KD, Bock M, Gaede G, Wuerfel JT, Pfueller CF et al (2011) Association of retinal and macular damage with brain atrophy in multiple sclerosis. PloS One 6(4):e18132

    Article  Google Scholar 

  16. 16.

    Gracien RM, Jurcoane A, Wagner M, Reitz SC, Mayer C, Volz S et al (2016) Multimodal quantitative MRI assessment of cortical damage in relapsing-remitting multiple sclerosis. J Magn Resonance Imaging JMRI 44(6):1600–1607

    Article  Google Scholar 

  17. 17.

    Oberwahrenbrock T, Schippling S, Ringelstein M, Kaufhold F, Zimmermann H, Keser N et al (2012) Retinal damage in multiple sclerosis disease subtypes measured by high-resolution optical coherence tomography. Mult Scler Int 2012:530305

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Saidha S, Al-Louzi O, Ratchford JN, Bhargava P, Oh J, Newsome SD et al (2015) Optical coherence tomography reflects brain atrophy in multiple sclerosis: a four-year study. Ann Neurol 78(5):801–813

    Article  Google Scholar 

  19. 19.

    Saidha S, Sotirchos ES, Oh J, Syc SB, Seigo MA, Shiee N et al (2013) Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. JAMA Neurol 70(1):34–43

    Article  Google Scholar 

  20. 20.

    Balk LJ, Cruz-Herranz A, Albrecht P, Arnow S, Gelfand JM, Tewarie P et al (2016) Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study. J Neurol 263(7):1323–1331

    Article  Google Scholar 

  21. 21.

    Graham EC, You Y, Yiannikas C, Garrick R, Parratt J, Barnett MH et al (2016) Progressive loss of retinal ganglion cells and axons in nonoptic neuritis eyes in multiple sclerosis: a longitudinal optical coherence tomography study. Investig Ophthalmol Vis Sci 57(4):2311–2317

    Article  Google Scholar 

  22. 22.

    Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69(2):292–302

    Article  Google Scholar 

  23. 23.

    Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina EH, Lagreze WA et al (2016) The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology 86(24):2303–2309

    Article  Google Scholar 

  24. 24.

    Tewarie P, Balk L, Costello F, Green A, Martin R, Schippling S et al (2012) The OSCAR-IB consensus criteria for retinal OCT quality assessment. PloS One 7(4):e34823

    CAS  Article  Google Scholar 

  25. 25.

    Droby A, Panagoulias M, Albrecht P, Reuter E, Duning T, Hildebrandt A et al (2016) A novel automated segmentation method for retinal layers in OCT images proves retinal degeneration after optic neuritis. Br J Ophthalmol 100(4):484–490

    Article  Google Scholar 

  26. 26.

    Fan Q, Teo YY, Saw SM (2011) Application of advanced statistics in ophthalmology. Investig Ophthalmol Vis Sci 52(9):6059–6065

    Article  Google Scholar 

  27. 27.

    Youden WJ (1950) Index for rating diagnostic tests. Cancer 3(1):32–35

    CAS  Article  Google Scholar 

  28. 28.

    DeLong ER, DeLong DM, Clarke-Pearson DL (1988) Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 44(3):837–845

    CAS  Article  Google Scholar 

  29. 29.

    International Multiple Sclerosis Genetics Consortium, Beecham AH, Patsopoulos NA, Xifara DK, Davis MF, Kemppinen A et al (2013) Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nature Genet 45(11):1353–1360

    Article  Google Scholar 

  30. 30.

    Knier B, Berthele A, Buck D, Schmidt P, Zimmer C, Muhlau M et al (2016) Optical coherence tomography indicates disease activity prior to clinical onset of central nervous system demyelination. Mult Scler 22(7):893–900

    CAS  Article  Google Scholar 

  31. 31.

    Narayanan D, Cheng H, Bonem KN, Saenz R, Tang RA, Frishman LJ (2014) Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler 20(10):1331–1341

    Article  Google Scholar 

  32. 32.

    Gabilondo I, Martinez-Lapiscina EH, Fraga-Pumar E, Ortiz-Perez S, Torres-Torres R, Andorra M et al (2015) Dynamics of retinal injury after acute optic neuritis. Ann Neurol 77(3):517–528

    Article  Google Scholar 

  33. 33.

    Cerovski B, Kutija MB, Vidovic T, Popovic-Suic S, Jandrokovic S, Kordic R et al (2013) The role of optical coherence tomography (OCT) in optic neuritis (ON). Coll Antropol 37(Suppl 1):121–125

    PubMed  Google Scholar 

  34. 34.

    Lampert EJ, Andorra M, Torres-Torres R, Ortiz-Perez S, Llufriu S, Sepulveda M et al (2015) Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. J Neurol 262(11):2491–2497

    CAS  Article  Google Scholar 

  35. 35.

    Walter SD, Ishikawa H, Galetta KM, Sakai RE, Feller DJ, Henderson SB et al (2012) Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 119(6):1250–1257

    Article  Google Scholar 

  36. 36.

    Sanchez-Dalmau B, Martinez-Lapiscina EH, Torres-Torres R, Ortiz-Perez S, Zubizarreta I, Pulido-Valdeolivas IV et al (2018) Early retinal atrophy predicts long-term visual impairment after acute optic neuritis. Mult Scler 24(9):1196–1204

    Article  Google Scholar 

  37. 37.

    Balk LJ, Coric D, Nij Bijvank JA, Killestein J, Uitdehaag BM, Petzold A (2018) Retinal atrophy in relation to visual functioning and vision-related quality of life in patients with multiple sclerosis. Mult Scler 24(6):767–776

    Article  Google Scholar 

  38. 38.

    Pulicken M, Gordon-Lipkin E, Balcer LJ, Frohman E, Cutter G, Calabresi PA (2007) Optical coherence tomography and disease subtype in multiple sclerosis. Neurology 69(22):2085–2092

    CAS  Article  Google Scholar 

  39. 39.

    Gordon-Lipkin E, Chodkowski B, Reich DS, Smith SA, Pulicken M, Balcer LJ et al (2007) Retinal nerve fiber layer is associated with brain atrophy in multiple sclerosis. Neurology 69(16):1603–1609

    CAS  Article  Google Scholar 

  40. 40.

    Pietroboni AM, Dell’Arti L, Caprioli M, Scarioni M, Carandini T, Arighi A et al (2017) The loss of macular ganglion cells begins from the early stages of disease and correlates with brain atrophy in multiple sclerosis patients. Mult Scler. https://doi.org/10.1177/1352458517740214

    Article  PubMed  Google Scholar 

  41. 41.

    Huang-Link YM, Al-Hawasi A, Lindehammar H (2015) Acute optic neuritis: retinal ganglion cell loss precedes retinal nerve fiber thinning. Neurol Sci 36(4):617–620

    Article  Google Scholar 

  42. 42.

    Gabilondo I, Sepulveda M, Ortiz-Perez S, Fraga-Pumar E, Martinez-Lapiscina EH, Llufriu S et al (2013) Retrograde retinal damage after acute optic tract lesion in MS. J Neurol Neurosurg Psychiatry 84(7):824–826

    Article  Google Scholar 

  43. 43.

    Petzold A, Balcer LJ, Calabresi PA, Costello F, Frohman TC, Frohman EM et al (2017) Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 16(10):797–812

    Article  Google Scholar 

  44. 44.

    Knier B, Schmidt P, Aly L, Buck D, Berthele A, Muhlau M et al (2016) Retinal inner nuclear layer volume reflects response to immunotherapy in multiple sclerosis. Brain 139:2855–2863

    Article  Google Scholar 

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Acknowledgements

This study was funded by the German Ministry for Education and Research (BMBF) German Competence Network Multiple Sclerosis (KKNMS) to FZ, SG, SGM and HW. We would like to thank Dr. Cheryl Ernest for proofreading the manuscript. The results presented are part of the doctoral thesis of LZ.

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Authors

Contributions

CBS and AD analyzed and interpreted the data and wrote the manuscript. LZ collected and analyzed the data. MP developed the 3D expansion of the 2D automatic segmentation algorithm. LK, HW, JK and SGM organized patient recruitment and logistics and provided clinical information. SG helped to conceptualize the study, analyzed and interpreted the data. FZ and VF designed the project, were responsible for the concept, generated funding, organized patient recruitment, provided clinical information and wrote the manuscript.

Corresponding author

Correspondence to Vinzenz Fleischer.

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Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

This study was approved by the local ethics committees at the University Medical Centers in Mainz (Germany) and Münster (Germany) and performed in accordance with the Declaration of Helsinki. All participants gave their informed consent.

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Seitz, C.B., Droby, A., Zaubitzer, L. et al. Discriminative power of intra-retinal layers in early multiple sclerosis using 3D OCT imaging. J Neurol 265, 2284–2294 (2018). https://doi.org/10.1007/s00415-018-8988-3

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Keywords

  • Optical coherence tomography
  • Optic neuritis
  • MS
  • Neuroimmunology