Naismith, RT

Toosy, AT

Villoslada, P

UCL Discovery

EDITORIALAhmed T. Toosy, FRCPRobert T. Naismith, MDPablo Villoslada, MDCorrespondence toDr. Toosy:a.toosy@ucl.ac.ukNeurology® 2017;89:1–2See page 2469OCT as a window to the MS brainThe view becomes slightly clearerOptical coherence tomography (OCT) has beenapplied to multiple sclerosis (MS) to investigate reti-nal neuroaxonal loss. Reductions in peripapillary ret-inal nerve fiber layer (pRNFL) thickness have beenreported in different MS-related subtypes from clini-cally isolated syndromes1 to secondary progressiveMS.2 A recent meta-analysis additionally confirmedatrophy of the ganglion cell–inner plexiform (GCIP)layer in MS.3 Associations between OCT-derived ret-inal thicknesses (pRNFL and GCIP) and cerebralatrophy quantified by MRI have also been reported,4,5leading to the suggestion of usingOCT as a biomarkerof MS disease progression in the clinic. Despite chal-lenges and lingering questions, several recent studiessuggest potential for clinical value. For example,a recent retrospective study provided evidence fordifferential rates of GCIP atrophy according toDMT usage. Natalizumab-treated patients with MSexhibited the lowest atrophy rates (20.16 mm/y),similar to healthy controls (20.14 mm/y), whereasthose treated with interferon-b and glatiramer acetatehad more atrophy (20.28 to 20.54 mm/y).6 An ear-lier study found faster GCIP annualized thinningrates associated with clinical or radiologic MS activityin 161 patients.7 In addition, a recent cohort studyidentified a cutoff of 88 mm for the pRNFL to predicttwice the risk of disability worsening at 2 years and 4times higher risk at 5 years for the patients (manybeing treated) below this cutoff.8 This literature im-plies a potential role for OCT in the clinical moni-toring of MS in the future.In this issue of Neurology®, Pisa et al.9 extend thiswork by determining OCT associations with no evi-dence of disease activity (NEDA) in MS. NEDA hasbeen suggested as a long-term treatment goal in MS.Conventionally applied to active MS amenable todisease-modifying treatments (DMTs), it relies upon3 criteria being concurrently met: no clinical relapse,no disability worsening, and no new MRI activity (nonew/enlarging T2 lesions and no gadolinium-enhancing lesions). Pisa et al. performed a longitudi-nal investigation of 72 patients with MS, performingMRI, OCT, visual evoked potentials, and ExpandedDisability Status Scale (EDSS) assessments, 2 yearsapart. Patients with MS with NEDA at follow-up(31.7%) had mean binocular RNFL thinning of20.93 mm 6 1.35 SD, whereas patients with evi-dence of disease activity (EDA) demonstrated greaterRNFL thinning at 22.83 mm 6 2 SD (t test p ,0.001). There was no interaction between NEDA/EDA and disease subtype (relapsing vs progressive).Further analyses showed RNFL loss when MRI activ-ity or relapse activity were considered separately.Greater RNFL loss over 2 years was also associatedwith worsening EDSS scores. After receiver operatingcharacteristic curve calculation, a value of 21.25 mmwas obtained as the optimal cutoff value associatedwith NEDA status, with specificity 81.4% and sen-sitivity 80%. A history of optic neuritis did not appearto alter the longitudinal changes in RNFL thinning.In the clinic, how would recording serial changesin OCT add value to clinical assessment and MRI?Certain challenges remain for OCT (e.g., determin-ing its contribution to clinical monitoring over a real-istic time frame, its value in the presence of opticnerve or radiation lesions). Therefore, large prospec-tive studies are required, in which OCT metrics areused as risk factors for disease worsening. For exam-ple, the Rio criteria established that in the first yearof starting a new therapy, a higher composite score,which includes relapses, disability worsening, and.2 T2 lesions, is associated with higher risk of dis-ability worsening over the next 2 years.10 Analo-gously, OCT could be validated within a compositescore of several predictors of MS clinical progression.However, we first need to understand the criticalthreshold for OCT metrics, and how this interactswith our other markers for disability worsening.Multicenter, international clinical repositories withlong-term follow-up could be leveraged to deriveand validate thresholds and interactions for OCTand other early disease markers. Once we understandhow OCT fits with our established predictors, onewould next need to know the effectiveness of treat-ment escalation upon long-term MS outcomes fordisability. As an example, if a patient was stable fromFrom Queen Square MS Centre (A.T.T.), Department of Neuroinflammation, UCL Institute of Neurology, University College London, UK; JohnL. Trotter Multiple Sclerosis Center (R.T.N.), Department of Neurology, School of Medicine, Washington University in St. Louis, MO; andCenter of Neuroimmunology (P.V.), Institut D’Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the editorial.© 2017 American Academy of Neurology 1ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Published Ahead of Print on November 15, 2017 as 10.1212/WNL.0000000000004755a clinical and imaging perspective, what would be thelong-term benefit of a more effective therapy if thepatient demonstrated a sustained annual retinal thin-ning of some validated threshold?Overall, this study provides interesting insightsinto the potential utility of OCT for monitoringMS disease activity. Some limitations to this studyexist, such as the requirement to validate in an inde-pendent cohort, the limited sample size and follow-up, and lack of a normative reference population fordefining the spontaneous decline of retinal thicknesswith age. Moreover, the cutoff proposed is based onthe change in RNFL and not on a specific absolutevalue such as in previous studies and for this reasonthese results cannot be considered a validation of pre-vious biomarkers. Nevertheless, the findings of thisstudy lend support to the notion that OCT is relatedto inflammatory activity, presumably through anindirect mechanism that affects neuroaxonal loss.Future studies should be able to address the outstand-ing issues related to its potential utility in MS formonitoring disease progression and even, perhaps,guide therapy decision-making. However, these stud-ies will require multicenter collaborations with largeenough patient numbers and data of sufficient dura-tion to inform long-term, accurate predictions. Thiswill be a large research endeavor; nevertheless, thefindings from this current study provide us withimpetus and encouragement to pursue this goal.STUDY FUNDINGNo targeted funding reported.DISCLOSUREA.T. Toosy has received speaker honoraria from Biomedia, Serono Sym-posia International Foundation, and Bayer, and meeting expenses fromBiogen Idec. He is the UK PI for 2 clinical trials sponsored by MEDDAYPharmaceutical Company (MD1003 in optic neuropathy [MS-ON] andprogressive MS [MS-SPI2]). Robert T. Naismith has received honorariafor consulting from Acorda, Alkermes, Bayer, Biogen, EMD Serono,Genzyme, Genentech, Novartis, and Teva. P. Villoslada has receivedresearch grants from the European Commission, the Instituto de SaludCarlos III (Spain), GAEM Foundation, and Fundacio Marato TV3.He is currently an employee at Genentech. Go to Neurology.org for fulldisclosures.REFERENCES1. Oberwahrenbrock T, Ringelstein M, Jentschke S, et al.Retinal ganglion cell and inner plexiform layer thinningin clinically isolated syndrome. Mult Scler 2013;19:1887–1895.2. Henderson APD, Trip SA, Schlottmann PG, et al. Aninvestigation of the retinal nerve fibre layer in progressivemultiple sclerosis using optical coherence tomography.Brain 2007;131:277–287.3. Petzold A, Balcer LJ, Calabresi PA, et al. Retinal layersegmentation in multiple sclerosis: a systematic reviewand meta-analysis. Lancet Neurol 2017;16:797–812.4. Sepulcre J, Murie-Fernandez M, Salinas-Alaman A,Garcia-Layana A, Bejarano B, Villoslada P. Diagnosticaccuracy of retinal abnormalities in predicting diseaseactivity in MS. Neurology 2007;68:1488–1494.5. Saidha S, Al-Louzi O, Ratchford JN, et al. Optical coher-ence tomography reflects brain atrophy in multiple sclero-sis: a four-year study. Ann Neurol 2015;78:801–813.6. Button J, Al-Louzi O, Lang A, et al. Disease-modifyingtherapies modulate retinal atrophy in multiple sclerosis:a retrospective study. Neurology 2017;88:525–532.7. Ratchford JN, Saidha S, Sotirchos ES, et al. Active MS isassociated with accelerated retinal ganglion cell/inner plex-iform layer thinning. Neurology 2013;80:47–54.8. Martinez-Lapiscina EH, Arnow S, Wilson JA, et al.Retinal thickness measured with optical coherencetomography and risk of disability worsening in multiplesclerosis: a cohort study. Lancet Neurol 2016;15:574–584.9. Pisa M, Guerrieri S, Di Maggio G, et al. No evidence ofdisease activity is associated with reduced rate of axonalretinal atrophy in MS. Neurology 2017;89:2469–2475.10. Río J, Castilló J, Rovira A, et al. Measures in the first yearof therapy predict the response to interferon b in MS.Mult Scler J 2009;15:848–853.2 Neurology 89 December 12, 2017ª 2017 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

OCT as a window to the MS brain: The view becomes slightly clearer

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OCT as a window to the MS brain: The view becomes slightly clearer

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