Skip to main content

Advertisement

SpringerLink
Log in

Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis

  • Review
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

The aim of this study was to summarise existing findings regarding optical coherence tomography (OCT) measurements of ganglion cell layer (GCL) alterations in optic neuritis (ON) and multiple sclerosis (MS). Peer-reviewed studies published prior to April 2016 were searched using PubMed, EMBASE, Web of Science and Scopus. Studies were included if they measured GCL thickness using OCT in patients with either ON, MS or clinically isolated syndrome. For the meta-analysis, we compared GCL thickness in MS patients with and without prior ON, to healthy controls. 42/252 studies were reviewed. In acute ON, studies showed significant thinning of the GCL within the first 5 weeks (n = 5), earlier than retinal nerve fibre layer (RNFL) thinning. GCL thinning at 1–2 months after acute ON predicted visual function at 6 months (n = 3). The meta-analysis showed that the thickness of the GCL was significantly reduced in MS patients both with and without previous ON compared to healthy controls. GCL thinning was associated with visual function in most studies (n = 10) and expanded disability status scale (EDSS) scores (n = 6). In acute ON, thinning of the GCL is measurable prior to RNFL thinning, and GCL thickness after 1–2 months may predict visual function after 6 months. Furthermore, GCL thinning occurs in MS both with and without prior ON, and may be associated with visual function and EDSS score. This suggests that the GCL is a promising biomarker, which may be used to examine in vivo neurodegeneration in ON and MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Petzold A, Wattjes MP, Costello F et al (2014) The investigation of acute optic neuritis: a review and proposed protocol. Nat Rev Neurol 10:447–458. doi:10.1038/nrneurol.2014.108

    Article  PubMed  Google Scholar 

  2. Optic Neuritis Study Group (2008) Multiple Sclerosis Risk After Optic Neuritis. Arch Neurol 65:727–732. doi:10.1001/archneur.65.6.727

    Google Scholar 

  3. Frohman EM, Fujimoto JG, Frohman TC et al (2008) Optical coherence tomography: a window into the mechanisms of multiple sclerosis. Nat Clin Pract Neurol 4:664–675. doi:10.1038/ncpneuro0950

    Article  PubMed  PubMed Central  Google Scholar 

  4. Perry VH, Lund RD (1990) Evidence that the lamina cribrosa prevents intraretinal myelination of retinal ganglion cell axons. J Neurocytol 19:265–272

    Article  CAS  PubMed  Google Scholar 

  5. Ikuta F, Zimmerman HM (1976) Distribution of plaques in seventy autopsy cases of multiple sclerosis in the United States. Neurology 26:26–28

    Article  CAS  PubMed  Google Scholar 

  6. Toussaint D, Périer O, Verstappen A, Bervoets S (1983) Clinicopathological study of the visual pathways, eyes, and cerebral hemispheres in 32 cases of disseminated sclerosis. J Clin Neuroophthalmol 3:211–220

    Article  CAS  PubMed  Google Scholar 

  7. Petzold A, de Boer JF, Schippling S et al (2010) Optical coherence tomography in multiple sclerosis: a systematic review and meta-analysis. Lancet Neurol 9:921–932. doi:10.1016/S1474-4422(10)70168-X

    Article  PubMed  Google Scholar 

  8. Kupersmith MJ, Mandel G, Anderson S et al (2011) Baseline, one and three month changes in the peripapillary retinal nerve fiber layer in acute optic neuritis: relation to baseline vision and MRI. J Neurol Sci 308:117–123. doi:10.1016/j.jns.2011.05.039

    Article  PubMed  Google Scholar 

  9. Kallenbach K, Simonsen H, Sander B et al (2010) Retinal nerve fiber layer thickness is associated with lesion length in acute optic neuritis. Neurology 74:252–258. doi:10.1212/WNL.0b013e3181ca0135

    Article  CAS  PubMed  Google Scholar 

  10. Wolf-Schnurrbusch UEK, Ceklic L, Brinkmann CK et al (2009) Macular thickness measurements in healthy eyes using six different optical coherence tomography instruments. Invest Ophthalmol Vis Sci 50:3432–3437. doi:10.1167/iovs.08-2970

    Article  PubMed  Google Scholar 

  11. Huang D, Swanson EA, Lin CP et al (1991) Optical coherence tomography. Science 254:1178–1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Balk LJ, Steenwijk MD, Tewarie P et al (2015) Bidirectional trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis. J Neurol Neurosurg Psychiatry 86:419–424. doi:10.1136/jnnp-2014-308189

    Article  CAS  PubMed  Google Scholar 

  13. Balk LJ, Twisk JWR, Steenwijk MD et al (2014) A dam for retrograde axonal degeneration in multiple sclerosis? J Neurol Neurosurg Psychiatry 85:782–789. doi:10.1136/jnnp-2013-306902

    Article  CAS  PubMed  Google Scholar 

  14. Balk L, Tewarie P, Killestein J et al (2014) Disease course heterogeneity and OCT in multiple sclerosis. Mult Scler 20:1198–1206. doi:10.1177/1352458513518626

    Article  CAS  PubMed  Google Scholar 

  15. Seigo MA, Sotirchos ES, Newsome S et al (2012) In vivo assessment of retinal neuronal layers in multiple sclerosis with manual and automated optical coherence tomography segmentation techniques. J Neurol 259:2119–2130. doi:10.1007/s00415-012-6466-x

    Article  PubMed  Google Scholar 

  16. Sotirchos ES, Seigo MA, Calabresi PA, Saidha S (2013) Comparison of point estimates and average thicknesses of retinal layers measured using manual optical coherence tomography segmentation for quantification of retinal neurodegeneration in multiple sclerosis. Curr Eye Res 38:224–228. doi:10.3109/02713683.2012.722243

    Article  PubMed  Google Scholar 

  17. Modvig S, Degn M, Sander B et al (2015) Cerebrospinal fluid neurofilament light chain levels predict visual outcome after optic neuritis. Mult Scler. doi:10.1177/1352458515599074

    Google Scholar 

  18. Gabilondo I, Martínez-Lapiscina EH, Fraga-Pumar E et al (2015) Dynamics of retinal injury after acute optic neuritis. Ann Neurol 77:517–528. doi:10.1002/ana.24351

    Article  PubMed  Google Scholar 

  19. Kupersmith MJ, Garvin MK, Wang J-K et al (2015) Retinal ganglion cell layer thinning within one month of presentation for optic neuritis. Mult Scler. doi:10.1177/1352458515598020

    PubMed  PubMed Central  Google Scholar 

  20. Behbehani R, Al-Moosa A, Sriraman D, Alroughani R (2016) Ganglion cell analysis in acute optic neuritis. Mult Scler Relat Disord 5:66–69. doi:10.1016/j.msard.2015.10.008

    Article  CAS  PubMed  Google Scholar 

  21. Syc SB, Saidha S, Newsome SD et al (2012) Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain 135:521–533. doi:10.1093/brain/awr264

    Article  PubMed  Google Scholar 

  22. Al-Louzi OA, Bhargava P, Newsome SD et al (2015) Outer retinal changes following acute optic neuritis. Mult Scler. doi:10.1177/1352458515590646

    PubMed  PubMed Central  Google Scholar 

  23. Costello F, Pan YI, Yeh EA et al (2015) The temporal evolution of structural and functional measures after acute optic neuritis. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp-2014-309704

    PubMed Central  Google Scholar 

  24. Schneider E, Zimmermann H, Oberwahrenbrock T et al (2013) Optical coherence tomography reveals distinct patterns of retinal damage in neuromyelitis optica and multiple sclerosis. PLoS One 8:e66151. doi:10.1371/journal.pone.0066151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Garcia-Martin E, Polo V, Larrosa JM et al (2014) Retinal layer segmentation in patients with multiple sclerosis using spectral domain optical coherence tomography. Ophthalmology 121:573–579. doi:10.1016/j.ophtha.2013.09.035

    Article  PubMed  Google Scholar 

  26. Tegetmeyer H, Kühn E (2011) Quantitative analysis of changes in macular layers following optic neuritis. Neuro-Ophthalmol 35:101–107

    Article  Google Scholar 

  27. Esen E, Sizmaz S, Balal M et al (2016) Evaluation of the innermost retinal layers and visual evoked potentials in patients with multiple sclerosis. Curr Eye Res. doi:10.3109/02713683.2015.1119283

    PubMed  Google Scholar 

  28. Fernandes DB, Raza AS, Nogueira RGF et al (2013) Evaluation of inner retinal layers in patients with multiple sclerosis or neuromyelitis optica using optical coherence tomography. Ophthalmology 120:387–394. doi:10.1016/j.ophtha.2012.07.066

    Article  PubMed  Google Scholar 

  29. González-López JJ, Rebolleda G, Leal M et al (2014) Comparative diagnostic accuracy of ganglion cell-inner plexiform and retinal nerve fiber layer thickness measures by Cirrus and Spectralis optical coherence tomography in relapsing–remitting multiple sclerosis. Biomed Res Int 2014:128517. doi:10.1155/2014/128517

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hokazono K, Raza AS, Oyamada MK et al (2013) Pattern electroretinogram in neuromyelitis optica and multiple sclerosis with or without optic neuritis and its correlation with FD-OCT and perimetry. Doc Ophthalmol 127:201–215. doi:10.1007/s10633-013-9401-2

    Article  PubMed  Google Scholar 

  31. Huang-Link YM, Fredrikson M, Link H (2015) Benign multiple sclerosis is associated with reduced thinning of the retinal nerve fiber and ganglion cell layers in non-optic-neuritis eyes. J Clin Neurol 11:241–247. doi:10.3988/jcn.2015.11.3.241

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kaushik M, Wang CY, Barnett MH et al (2013) Inner nuclear layer thickening is inversely proportional to retinal ganglion cell loss in optic neuritis. PLoS One 8:e78341. doi:10.1371/journal.pone.0078341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Klistorner A, Sriram P, Vootakuru N et al (2014) Axonal loss of retinal neurons in multiple sclerosis associated with optic radiation lesions. Neurology 82:2165–2172. doi:10.1212/WNL.0000000000000522

    Article  PubMed  PubMed Central  Google Scholar 

  34. Narayanan D, Cheng H, Bonem KN et al (2014) Tracking changes over time in retinal nerve fiber layer and ganglion cell-inner plexiform layer thickness in multiple sclerosis. Mult Scler 20:1331–1341. doi:10.1177/1352458514523498

    Article  PubMed  PubMed Central  Google Scholar 

  35. Oberwahrenbrock T, Ringelstein M, Jentschke S et al (2013) Retinal ganglion cell and inner plexiform layer thinning in clinically isolated syndrome. Mult Scler 19:1887–1895. doi:10.1177/1352458513489757

    Article  PubMed  Google Scholar 

  36. Petracca M, Cordano C, Cellerino M et al (2016) Retinal degeneration in primary-progressive multiple sclerosis: a role for cortical lesions? Mult Scler. doi:10.1177/1352458516637679

    PubMed  Google Scholar 

  37. Saidha S, Syc SB, Durbin MK et al (2011) Visual dysfunction in multiple sclerosis correlates better with optical coherence tomography derived estimates of macular ganglion cell layer thickness than peripapillary retinal nerve fiber layer thickness. Mult Scler 17:1449–1463. doi:10.1177/1352458511418630

    Article  PubMed  Google Scholar 

  38. Soufi G, AitBenhaddou E, Hajji Z et al (2015) Evaluation of retinal nerve fiber layer thickness measured by optical coherence tomography in Moroccan patients with multiple sclerosis. J Fr Ophtalmol 38:497–503. doi:10.1016/j.jfo.2014.11.008

    Article  CAS  PubMed  Google Scholar 

  39. Tátrai E, Simó M, Iljicsov A et al (2012) In vivo evaluation of retinal neurodegeneration in patients with multiple sclerosis. PLoS One 7:e30922. doi:10.1371/journal.pone.0030922

    Article  PubMed  PubMed Central  Google Scholar 

  40. Varga BE, Gao W, Laurik KL et al (2015) Investigating tissue optical properties and texture descriptors of the retina in patients with multiple sclerosis. PLoS One 10:e0143711. doi:10.1371/journal.pone.0143711

    Article  PubMed  PubMed Central  Google Scholar 

  41. Walter SD, Ishikawa H, Galetta KM et al (2012) Ganglion cell loss in relation to visual disability in multiple sclerosis. Ophthalmology 119:1250–1257. doi:10.1016/j.ophtha.2011.11.032

    Article  PubMed  PubMed Central  Google Scholar 

  42. Xu LT, Bermel RA, Nowacki AS, Kaiser PK (2016) Optical coherence tomography for the detection of remote optic neuritis in multiple sclerosis. J Neuroimaging. doi:10.1111/jon.12326

    Google Scholar 

  43. Zimmermann H, Freing A, Kaufhold F et al (2013) Optic neuritis interferes with optical coherence tomography and magnetic resonance imaging correlations. Mult Scler 19:443–450. doi:10.1177/1352458512457844

    Article  PubMed  Google Scholar 

  44. Sriram P, Wang C, Yiannikas C et al (2014) Relationship between optical coherence tomography and electrophysiology of the visual pathway in non-optic neuritis eyes of multiple sclerosis patients. PLoS One 9:e102546. doi:10.1371/journal.pone.0102546

    Article  PubMed  PubMed Central  Google Scholar 

  45. Davies EC, Galetta KM, Sackel DJ et al (2011) Retinal ganglion cell layer volumetric assessment by spectral-domain optical coherence tomography in multiple sclerosis: application of a high-precision manual estimation technique. J Neuroophthalmol 31:260–264. doi:10.1097/WNO.0b013e318221b434

    Article  PubMed  PubMed Central  Google Scholar 

  46. Outteryck O, Majed B, Defoort-Dhellemmes S et al (2015) A comparative optical coherence tomography study in neuromyelitis optica spectrum disorder and multiple sclerosis. Mult Scler. doi:10.1177/1352458515578888

    Google Scholar 

  47. Sriram P, Graham SL, Wang C et al (2012) Transsynaptic retinal degeneration in optic neuropathies: optical coherence tomography study. Invest Ophthalmol Vis Sci 53:1271–1275. doi:10.1167/iovs.11-8732

    Article  PubMed  Google Scholar 

  48. Albrecht P, Ringelstein M, Müller AK et al (2012) Degeneration of retinal layers in multiple sclerosis subtypes quantified by optical coherence tomography. Mult Scler 18:1422–1429. doi:10.1177/1352458512439237

    Article  CAS  PubMed  Google Scholar 

  49. Balk L, Mayer M, Uitdehaag BMJ, Petzold A (2013) Physiological variation of segmented OCT retinal layer thicknesses is short-lasting. J Neurol 260:3109–3114. doi:10.1007/s00415-013-7097-6

    Article  PubMed  Google Scholar 

  50. Garcia-Martin E, Calvo B, Malvè M et al (2013) Three-dimensional geometries representing the retinal nerve fiber layer in multiple sclerosis, optic neuritis, and healthy eyes. Ophthalmic Res 50:72–81. doi:10.1159/000350413

    Article  CAS  PubMed  Google Scholar 

  51. Droby A, Panagoulias M, Albrecht P et al (2015) A novel automated segmentation method for retinal layers in OCT images proves retinal degeneration after optic neuritis. Br J Ophthalmol. doi:10.1136/bjophthalmol-2014-306015

    PubMed  Google Scholar 

  52. Saidha S, Sotirchos ES, Oh J et al (2013) Relationships between retinal axonal and neuronal measures and global central nervous system pathology in multiple sclerosis. JAMA Neurol 70:34–43. doi:10.1001/jamaneurol.2013.573

    Article  PubMed  PubMed Central  Google Scholar 

  53. Ratchford JN, Saidha S, Sotirchos ES et al (2013) Active MS is associated with accelerated retinal ganglion cell/inner plexiform layer thinning. Neurology 80:47–54. doi:10.1212/WNL.0b013e31827b1a1c

    Article  PubMed  PubMed Central  Google Scholar 

  54. Saidha S, Al-Louzi O, Ratchford JN et al (2015) Optical coherence tomography reflects brain atrophy in multiple sclerosis: a four-year study. Ann Neurol 78:801–813. doi:10.1002/ana.24487

    Article  PubMed  PubMed Central  Google Scholar 

  55. Saidha S, Sotirchos ES, Ibrahim MA et al (2012) Microcystic macular oedema, Thickness of the inner nuclear layer of the retina, and disease characteristics in multiple sclerosis: a retrospective study. Lancet Neurol 11:963–972. doi:10.1016/S1474-4422(12)70213-2

    Article  PubMed  PubMed Central  Google Scholar 

  56. Lampert EJ, Andorra M, Torres-Torres R et al (2015) Color vision impairment in multiple sclerosis points to retinal ganglion cell damage. J Neurol 262:2491–2497. doi:10.1007/s00415-015-7876-3

    Article  CAS  PubMed  Google Scholar 

  57. Álvarez-Cermeño JC, Muñoz-Negrete FJ, Costa-Frossard L et al (2016) Intrathecal lipid-specific oligoclonal IgM synthesis associates with retinal axonal loss in multiple sclerosis. J Neurol Sci 360:41–44. doi:10.1016/j.jns.2015.11.030

    Article  PubMed  Google Scholar 

  58. Oberwahrenbrock T, Balk L, Petzold A et al (2014) Re: Garcia-Martin et al.: retinal layer segmentation in patients with multiple sclerosis using spectral domain optical coherence tomography (Ophthalmology 2014;121:573–9). Ophthalmology. doi:10.1016/j.ophtha.2014.06.018

    PubMed  Google Scholar 

  59. Kimbrough DJ, Sotirchos ES, Wilson JA et al (2015) Retinal damage and vision loss in African American multiple sclerosis patients. Ann Neurol 77:228–236. doi:10.1002/ana.24308

    Article  PubMed  PubMed Central  Google Scholar 

  60. Tewarie P, Balk L, Costello F et al (2012) The OSCAR-IB consensus criteria for retinal OCT quality assessment. PLoS One 7:e34823. doi:10.1371/journal.pone.0034823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Schippling S, Balk LJ, Costello F et al (2015) Quality control for retinal OCT in multiple sclerosis: validation of the OSCAR-IB criteria. Mult Scler 21:163–170. doi:10.1177/1352458514538110

    Article  CAS  PubMed  Google Scholar 

  62. Bhargava P, Lang A, Al-Louzi O et al (2015) Applying an open-source segmentation algorithm to different OCT devices in multiple sclerosis patients and healthy controls: implications for clinical trials. Mult Scler Int 136295. doi:10.1155/2015/136295

  63. Park K-A, Kim J, Oh SY (2014) Analysis of spectral domain optical coherence tomography measurements in optic neuritis: differences in neuromyelitis optica, multiple sclerosis, isolated optic neuritis and normal healthy controls. Acta Ophthalmol 92:e57–e65. doi:10.1111/aos.12215

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Anna Magnussen for illustrations and Jun He for translation from Chinese.

Author information

Authors and Affiliations

  1. Department of Neurology, Clinic of Optic Neuritis and Clinic of Multiple Sclerosis, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Nordre Ringvej 57, 2600, Glostrup, Denmark

    Josefine Britze, Gorm Pihl-Jensen & Jette Lautrup Frederiksen

Authors
  1. Josefine Britze
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gorm Pihl-Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jette Lautrup Frederiksen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JB carried out the literature search, systematic review and meta-analysis, and wrote the first draft of the manuscript. GPJ contributed with long-term experience with OCT, statistical guidance and thoroughly revised the manuscript. JLF conceived the idea for this review, made a structure for the manuscript and thoroughly revised the manuscript.

Corresponding author

Correspondence to Jette Lautrup Frederiksen.

Ethics declarations

Funding

None.

Conflicts of interest

The authors declare that they have no conflicts of interest relevant to this manuscript.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 163 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Britze, J., Pihl-Jensen, G. & Frederiksen, J.L. Retinal ganglion cell analysis in multiple sclerosis and optic neuritis: a systematic review and meta-analysis. J Neurol 264, 1837–1853 (2017). https://doi.org/10.1007/s00415-017-8531-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-017-8531-y

Keywords

Search

Navigation