Title | Long-Term Stability of Neuroaxonal Structure in Alemtuzumab-Treated Relapsing-Remitting Multiple Sclerosis Patients |
Creator | Jillian K Chan; Elena Hernandez Martínez de Lapiscina; Carolyn Taylor; Ai-Lan Nguyen; Salut Alba-Arbalat; Virginia Devonshire; Ana-Luiza Sayao; Robert Carruthers; Fiona Costello; Anthony Traboulsee |
Affiliation | Department of Medicine (Neurology) (JKC, VD, A-LS, RC, AT), University of British Columbia, Vancouver, Canada; Department of Neurology (EHMdL, SA-A), Center of Neuroimmunology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Department of Statistics (CT), University of British Columbia, Vancouver, Canada; Department of Neruology (A-LN), University of Melbourne, Melbourne, Australia; Royal Melbourne Hospital (A-LN), Melbourne, Australia; and Departments of Clinical Neurosciences and Surgery (Ophthalmology) (FC), University of Calgary, Clinician Scientist with the Hotchkiss Brain Institute (HBI), Calgary, Canada. Department of Neurology and Neurotherapeutics (SCB), University of Texas Southwestern Medical Center, Dallas, Texas |
Abstract | Background: Patients with multiple sclerosis (MS) experience progressive thinning in optical coherence tomography (OCT) measures of neuroaxonal structure regardless of optic neuritis history. Few prospective studies have investigated the effects of disease-modifying therapies on neuroaxonal degeneration in the retina. Alemtuzumab is a monoclonal antibody shown to be superior to interferon β-1a in treating relapsing-remitting MS (RRMS). The purpose of this study was to assess the effects of alemtuzumab and first-line injectable treatments on OCT measures of neuroaxonal structure including peripapillary retinal nerve fiber layer (RNFL) thickness and combined ganglion cell-inner plexiform (GCIP) layer volume in RRMS patients followed up over 5 years. Methods: In this retrospective pilot study with prospectively collected double cohort data, spectral domain OCT measures of RNFL thickness and GCIP volume were compared between alemtuzumab-treated RRMS patients (N = 24) and RRMS patients treated with either interferon-β or glatiramer acetate (N = 21). Results: Over a median of 60 months (range 42-60 months), the alemtuzumab cohort demonstrated a change in the mean RNFL thickness (thinning from baseline) of -0.88 μm (95% confidence interval [CI] -2.63 to 0.86; P = 0.32) and mean GCIP volume of +0.013 mm (95% CI -0.006 to 0.032; P = 0.18). Over the same time period, the first-line therapy-treated cohort demonstrated greater degrees of RNFL thinning (mean change in RNFL thickness was -3.65 μm [95% CI -5.40 to -1.89; P = 0.0001]). There was also more prominent GCIP volume loss relative to baseline in the first-line therapy group (-0.052 mm [95% CI -0.070 to -0.034; P < 0.0001]). Conclusions: Alemtuzumab-treated patients with RRMS demonstrated relative stability of OCT-measured neuroaxonal structure compared with RRMS patients treated with either interferon-β or glatiramer acetate over a 5-year period. These findings, along with previous demonstration of improved brain atrophy rates, suggest that alemtuzumab may offer long-term preservation of neuroaxonal structure in patients with RRMS. |
Subject | Adult; Alemtuzumab / therapeutic use; Axons / pathology; Female; Humans; Immunosuppressive Agents / therapeutic use; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting / diagnostic imaging; Multiple Sclerosis, Relapsing-Remitting / drug therapy; Multiple Sclerosis, Relapsing-Remitting / pathology; Retina / diagnostic imaging; Retina / pathology; Retinal Neurons / pathology; Retrospective Studies; Tomography, Optical Coherence; Young Adult |
OCR Text | Show Original Contribution Long-Term Stability of Neuroaxonal Structure in Alemtuzumab-Treated Relapsing-Remitting Multiple Sclerosis Patients Jillian K. Chan, MD, Elena Hernandez Martínez de Lapiscina, MD, Carolyn Taylor, MSc, Ai-Lan Nguyen, MD, Salut Alba-Arbalat, OD, Virginia Devonshire, MD, Ana-Luiza Sayao, MD, Robert Carruthers, MD, Fiona Costello, MD, Anthony Traboulsee, MD Background: Patients with multiple sclerosis (MS) experience progressive thinning in optical coherence tomography (OCT) measures of neuroaxonal structure regardless of Department of Medicine (Neurology) (JKC, VD, A-LS, RC, AT), University of British Columbia, Vancouver, Canada; Department of Neurology (EHMdL, SA-A), Center of Neuroimmunology, Hospital Clinic of Barcelona, Institut d'Investigacions Biomèdiques August Pi Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Department of Statistics (CT), University of British Columbia, Vancouver, Canada; Department of Neruology (A-LN), University of Melbourne, Melbourne, Australia; Royal Melbourne Hospital (A-LN), Melbourne, Australia; and Departments of Clinical Neurosciences and Surgery (Ophthalmology) (FC), University of Calgary, Clinician Scientist with the Hotchkiss Brain Institute (HBI), Calgary, Canada.; and Department of Neurology and Neurotherapeutics (SCB), University of Texas Southwestern Medical Center, Dallas, Texas. Investigator add-on study to a Sanofi Genzyme-supported, investigator-sponsored open-label treatment trial at the University of British Columbia Hospital. The study was supported by the Instituto de Salud Carlos III, Spain (JR16/0006) and Fondo Europeo de Desarrollo Regional (FEDER) to E. Hernandez Martínez de Lapiscina. J. K. Chan received grant support from Biogen and consulted for Roche. E. Hernandez Martínez de Lapiscina received grant support from Merck (Grant for MS Innovation); consulting from Genzyme. Travel and accommodation support from Roche and Genzyme. She is a member of the IMSVISUAL consortium. A. L. Nguyen received research grants from Novartis, Biogen, Merck-Serono, and MS Research Australia; speaker honoraria and consulting fees from EMD Serono and Teva; and conference travel support from Genzyme-Sanofi, Biogen, and Roche. V. Devonshire received honorarium for speaking from the following companies: Sanofi, Biogen, Serono, Roche, and Novartis. A. L Sayao received speaker honoraria from Merck-Serono, consulted for Merck-Serono, Novartis, Biogen, Roche, and Genzyme. R. Carruthers is the site investigator for studies funded by Novartis, MedImmune, and Roche and receives research support from Teva Innovation Canada, Roche Canada, and Vancouver Coastal Health Research Institute. He has done consulting work and has received honoraria from Roche, EMD Serono, Sanofi, Biogen, Novartis, and Teva. A. Traboulsee received research funding from Biogen, Chugai, Novartis, Roche, and Sanofi Genzyme and consultancy honoraria from Biogen, Roche, Sanofi Genzyme, and Teva Neuroscience. The remaining authors report no conflicts of interest. Address correspondence to Jillian K. Chan, MD, Division of Neurology, UBC Hospital S213, 2211 Wesbrook Mall, Vancouver, Canada V6T 2B5; E-mail: jillian.chan@ubc.ca Chan et al: J Neuro-Ophthalmol 2020; 40: 37-43 optic neuritis history. Few prospective studies have investigated the effects of disease-modifying therapies on neuroaxonal degeneration in the retina. Alemtuzumab is a monoclonal antibody shown to be superior to interferon b-1a in treating relapsing-remitting MS (RRMS). The purpose of this study was to assess the effects of alemtuzumab and first-line injectable treatments on OCT measures of neuroaxonal structure including peripapillary retinal nerve fiber layer (RNFL) thickness and combined ganglion cell- inner plexiform (GCIP) layer volume in RRMS patients followed up over 5 years. Methods: In this retrospective pilot study with prospectively collected double cohort data, spectral domain OCT measures of RNFL thickness and GCIP volume were compared between alemtuzumab-treated RRMS patients (N = 24) and RRMS patients treated with either interferon-b or glatiramer acetate (N = 21). Results: Over a median of 60 months (range 42-60 months), the alemtuzumab cohort demonstrated a change in the mean RNFL thickness (thinning from baseline) of 20.88 mm (95% confidence interval [CI] 22.63 to 0.86; P = 0.32) and mean GCIP volume of +0.013 mm3 (95% CI 20.006 to 0.032; P = 0.18). Over the same time period, the first-line therapy-treated cohort demonstrated greater degrees of RNFL thinning (mean change in RNFL thickness was 23.65 mm [95% CI 25.40 to 21.89; P = 0.0001]). There was also more prominent GCIP volume loss relative to baseline in the first-line therapy group (20.052 mm3 [95% CI 20.070 to 20.034; P , 0.0001]). Conclusions: Alemtuzumab-treated patients with RRMS demonstrated relative stability of OCT-measured neuroaxonal structure compared with RRMS patients treated with either interferon-b or glatiramer acetate over a 5-year period. These findings, along with previous demonstration of improved brain atrophy rates, suggest that alemtuzumab may offer long-term preservation of neuroaxonal structure in patients with RRMS. Journal of Neuro-Ophthalmology 2020;40:37-43 doi: 10.1097/WNO.0000000000000802 © 2019 by North American Neuro-Ophthalmology Society 37 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution M ultiple sclerosis (MS) is a chronic, immune-mediated disease that affects the central nervous system (CNS) and causes inflammation and neurodegeneration. Neuronal loss (for the purposes of this study, defined as thinning of the ganglion cell-inner plexiform [GCIP] layer) and axonal injury (defined as retinal nerve fiber layer [RNFL] thinning) in the afferent visual pathway of the CNS can be quantified noninvasively in vivo with optical coherence tomography (OCT). As an endpoint, OCT has been validated as a reproducible measure of "neuroaxonal" (referring to GCIP and RNFL values) structure in MS for both clinical and research purposes (1,2). Reduced RNFL and GCIP measures, as evidence of neuroaxonal injury captured in the retinas of MS patients, correlate with worse visual outcomes, reduced quality of life, MRI measures of brain atrophy, and global disability. RNFL and GCIP loss are early phenomena in MS and that retinal thinning may occur independent of clinically overt episodes of optic neuritis (ON) (3-10). The annual atrophy rates in RNFL thickness ranged from no significant changes to 21.49 mm/year in MS patients (11). Yearly, GCIP decreases from 20.34 to 20.55 mm (5,12,13), a rate that was 46% faster compared with healthy controls (3,8). Disease-modifying therapies may have differential effects on OCT-determined rates of retinal atrophy, supporting a potential utility for OCT as a surrogate endpoint to investigate the neuroprotective benefits of MS treatments (4). Natalizumab-treated patients exhibited the lowest rate of GCIP thinning (20.17 mm/year) over approximately 3 years compared with patients receiving glatiramer acetate (GA) and interferon (IFN)-b-1a (14), whereas a prospective study by Zivadinov et al (15) showed that GA-treated patients had no significant change in RNFL thickness and total macular volume over 24 months compared with healthy controls. Alemtuzumab, an anti-CD52 monoclonal antibody used to treat relapsing-remitting MS (RRMS), has been shown to be superior to IFN-b-1a in clinical trials at reducing relapse rate, disability progression, and radiological disease activity including slowing of brain volume loss over 5 years (16-18). OCT measures demonstrating neurostability have been proposed as an additional criterion for no evidence of disease activity, in treating MS (19). The aim of this study was to compare OCT measures of neuroaxonal structure in alemtuzumab-treated RRMS patients followed up over 5 years vs a convenience sample, independent, parallel, prospective RRMS cohort treated with first-line injectable MS therapies. METHODS Study Design This retrospective (with prospectively collected parallel data), pilot study comparing OCT-measured rates of RNFL 38 and GCIP thinning between 2 independent RRMS cohorts followed up over a median of 60 months (range 42-60 months). The alemtuzumab cohort was recruited from the University of British Columbia MS Clinic in Vancouver, Canada, and included 24 RRMS participants who received at least 2 courses of alemtuzumab. The second cohort included 21 age- and sex-matched patients treated with first-line agents for at least 2 years from the MS Visual Pathway cohort at the Hospital Clinic in Barcelona, Spain (20). Informed, written consent was obtained from all participants. Inclusion Criteria Patients (aged 18-55 years; disease duration up to 20 years) fulfilled 2005 McDonald criteria for MS (21) and had Expanded Disability Status Scale scores of 5.0 or less. Exclusion criteria included a comorbid ophthalmological disorder. The alemtuzumab cohort could not have had exposure to corticosteroids, IFN, or GA within 28 days. Eyes affected by ON #6 months before baseline or during the study were excluded. Optical Coherence Tomography Testing was performed at both sites at baseline and at Month 60 (±18 months). The alemtuzumab cohort was assessed with Heidelberg Spectralis-OCT (software version 5.6.4; Heidelberg Engineering, Heidelberg, Germany) in accordance with OSCAR-1B criteria (22). Peripapillary RNFL thickness was measured with ring scan of 12°/ 3.5-mm diameter centered on the optic nerve head with 1,536 A scans per B-scan high-resolution mode, quality $15. Macular volume was measured with a raster scan of 6-mm diameter centered on the fovea with automatic real time (ART) $9 using matrix size 30 · 25, 61 high-speed B scans, 768 A scans per B scan, vertical acquisition. Macular layer segmentation was performed automatically using the algorithm included in the Viewer Mode (version 6.3.2.0). The first-line treatment cohort was tested with Heidelberg Spectralis-OCT (software version 5.3.0; Heidelberg Engineering) following OSCAR-1B criteria. Peripapillary RNFL measures were obtained with ring scan 12°/3.5-mm diameter centered on the optic nerve head with 1,536 A scans per B scan with an activated eyetracker, ART = 100. Macular volume was measured with a raster scan of 6-mm diameter centered on the fovea with ART $9 and a matrix size 20 · 20, 25 high-resolution B scans, 512 A scans per B scan, horizontal acquisition. Macular segmentation was performed automatically using Viewer Mode (version 6.0c). Statistical Analysis A mixed-effects linear regression model was fit to each of the OCT-measured rates (RNFL and GCIP) that included fixed effects for the three 2-level categorical variables of time (baseline and long-term follow-up), cohort (alemtuzumab and first-line therapy), and history of ON (ON and no ON [NON]) along Chan et al: J Neuro-Ophthalmol 2020; 40: 37-43 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Baseline demographics for alemtuzumab-treated and first-line-treated cohorts Characteristic Alemtuzumab-Treated Cohort (N = 24) Age (yrs) Female gender (%) Disease duration (yrs) Eyes with a history of ON (%) ARR Mean EDSS score 34.89 20 5.21 19 1.44 2.8 First-Line-Treated Cohort (N = 21) (±9.24) (83%) (±3.89) (41%) (±0.61) (±1.1) 35.23 18 4.96 14 0.74 1.6 (±8.24) (86%) (±4.50) (36%) (±0.38) (±0.9) P value 0.89* 1.00† 0.84* 0.38‡ ,0.0001* 0.0003* Plus-minus values are SD. *The 2-sample t test for quantitative data. † The Fisher exact test for proportions. ‡ The 2-sample x 2 test for equality of proportions with continuity correction. ARR, annualized relapse rate in 2 years before study entry; EDSS, Expanded Disability Status Scale; ON, optic neuritis. with 2 random intercept effects for patients and eyes within patients. The 2 random effects allow for separate effects to be estimated for each patient and for each eye within a patient; therefore, differences between patients and eyes within patients were taken into account along with the dependency of the repeated measures that were taken on each eye over time. Of all the interactions included, only the interaction between time and cohort was found to be significant and was therefore kept in the final model. The effect of each eye, baseline age, gender, and disease duration were added to the model separately but were not strongly significant and were therefore not included in the final model. The final model was used to calculate the least square means and 95% confidence intervals [CIs] for each cohort at each time period (averaged over the ON and NON eyes) as well as the difference between long-term follow-up and baseline. Similarly, mixed-effects models and estimates were done for the ON and NON eyes separately. Models were fit to all the available data, and the estimates for change over time from these models were based on those subjects who had results at both baseline and long-term follow-up. It was assumed that missing data occurred at random in that those subjects with missing data were no different from those with full data. Given the exploratory nature of this study, all significant P values based on a significance level of 0.05 are viewed as possibly indicating significance and were not adjusted for multiple testing. All analyses were conducted using R version 3.4.3 (201711-30). RESULTS Alemtuzumab Cohort There were 24 participants in the alemtuzumab cohort, with baseline demographics displayed in Table 1. The FIG. 1. Alemtuzumab-treated cohort RNFL and GCIP change over 60 months: The mean change in RNFL thickness and GCIP volume is shown for all eyes (N = 48), ON eyes (N = 19), and NON eyes (N = 29) in the alemtuzumab-treated cohort. Each data point is the value for an individual patient at baseline with a line tracking to his/her mean value at 60 months. The horizontal line is the mean value for the cohort at baseline and at 60 months. GCIP, ganglion cell-inner plexiform layer; LTF, long term follow-up; NON, no optic neuritis; ON, optic neuritis; RNFL, retinal nerve fiber layer. Chan et al: J Neuro-Ophthalmol 2020; 40: 37-43 39 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 40 ,0.0001 0.040 ,0.0001 annualized relapse rate (ARR) 2 years before treatment was 1.44 (±0.61). Before study entry, 9 (38%) participants were treatment-naive and 14 participants were treated with first-line injectable therapies. Follow-up OCT occurred at a median of 60 months (mean 57.6, range 42-60 months). There were 48 eyes scanned in total, and 2 eyes were excluded because of ON within 6 months of baseline. Thirteen participants received an additional course, and 1 participant received 2 additional courses of alemtuzumab. ,0.0001 0.020 ,0.0001 First-Line-Treated Cohort *P: comparison between alemtuzumab-treated and first-line-treated cohorts. CI, confidence interval; GCIP, ganglion cell-inner plexiform layer; NON, no optic neuritis; ON, optic neuritis; RNFL, retinal nerve fiber layer. All significant P values based on a significance level of 0.05 are in italics. 1.77 1.62 1.87 0.18 0.53 0.25 1.78 1.69 1.86 1.77 1.68 1.85 0.013 (20.0061 to 0.032) 0.010 (20.023, 0.043) 0.014 (20.010 to 0.038) 1.82 1.66 1.93 20.05 (20.070, 20.034) 20.037 (20.068 to 20.0064) 20.060 (20.083 to 20.037) 0.029 0.96 0.0021 0.0001 0.20 ,0.0001 23.65 (25.40 to 21.89) 22.23 (25.68 to 1.21) 24.43 (26.42 to 22.44) 89.48 81.13 95.10 0.32 0.20 0.89 87.99 81.66 94.40 RNFL (mm) All eyes ON eyes NON eyes GCIP (mm3) All eyes ON eyes NON eyes 88.88 83.77 94.26 20.88 (22.63 to 0.86) 22.11 (25.42 to 1.20) 0.14 (21.87 to 2.16) 93.13 83.37 99.54 Change (95% CI) 5 yrs Baseline Baseline 5 yrs Change (95% CI) P First-Line-Treated Cohort (N = 21) Alemtuzumab-Treated Cohort (N = 24) TABLE 2. Change in RNFL thickness and GCIP volume over 60 months in alemtuzumab-treated cohort and first-line-treated cohort P value P value* Original Contribution The convenience sample, parallel cohort included 21 patients (Table 1). The ARR 2 years before treatment was 0.74 ± 0.37. There were a total of 39 eyes after excluding 3 because of an episode of ON during the study. These patients received first-line injectable medications including IFN b-1b, IFN b-1a (subcutaneous and intramuscular), and GA for at least 24 months. Thirteen patients remained on first-line therapy. Three patients discontinued disease-modifying therapies; 2 patients switched to teriflunomide, and 1 each to dimethyl fumarate, fingolimod, natalizumab, and rituximab. Longitudinal Optical Coherence Tomography Analysis: Alemtuzumab Cohort ON and NON eyes of MS patients were grouped together; the mean RNFL thickness was 88.88 mm at baseline and 87.99 mm at long-term follow-up (median 60 months, mean 57.6 months), corresponding to a total mean change of 20.88 mm (95% CI 22.63 to 0.86; P = 0.32). The mean GCIP volume at baseline was 1.77 and 1.78 mm3 at long-term follow-up with a total mean change of +0.013 mm3 (95% CI 20.006 to 0.032; P = 0.18). Both the RNFL and GCIP were not significantly decreased over this longitudinal follow-up period (Fig. 1). Analyzing ON and NON eyes separately in individual groups did not show any significant change over this same time period (Table 2). Longitudinal Optical Coherence Tomography Analysis: First-Line Therapy Cohort All eyes were included; the RNFL thickness at baseline was 93.13 and 89.48 mm at 60 months of follow-up. The estimated mean change in RNFL thickness for all eyes was 23.65 mm (95% CI 25.40 to 21.89; P = 0.0001). The GCIP volume was 1.82 mm 3 at baseline and 1.77 mm 3 at 60 months of follow-up. The estimated mean change in GCIP volume was 20.052 mm 3 (95% CI 20.070 to 20.034; P , 0.0001). Both the RNFL thickness and GCIP volume in the first-line therapy cohort showed a significant decrease from baseline to follow-up at 60 months. Chan et al: J Neuro-Ophthalmol 2020; 40: 37-43 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Change in RNFL thickness and GCIP volume over 60 months in alemtuzumab-treated and first-line-treated cohorts: Boxplot whiskers present minimum and maximum values. The dark line represents median change, and the top and bottom plots represent the first and third quartile changes. All eyes, optic neuritis (ON) eyes, and no ON (NON) eyes are displayed for the first-line-treated group (N = 21) and alemtuzumab-treated group (N = 24). GCIP, ganglion cell-inner plexiform layer; RNFL, retinal nerve fiber layer. DISCUSSION The results of this exploratory study support the hypothesis that alemtuzumab facilitates neurostability in MS. Over a 5year period, alemtuzumab-treated MS patients demonstrated no significant loss of RNFL thickness or GCIP volume in contrast to a comparative cohort of MS patients receiving first-line therapies (Fig. 2). The latter demonstrated significant RNFL thinning and GCIP volume loss (Table 2), indicating accrued neuroaxonal damage in the afferent visual pathway. In addition, the first-line therapy cohort showed 2.76 mm more thinning in RNFL thickness and 0.065 mm3 more loss of GCIP volume for all eyes included in the study, relative to MS patients treated with alemtuzumab. These observations were noteworthy because alemtuzumab-treated patients had worse measures of MS disease activity and disability at study entry and would have been expected to demonstrate more severe neuroaxonal injury, compared with their MS counterparts receiving first-line therapies over 5 years. Clinically, earlier and greater loss of neuroaxonal substrate translates to poorer neurological outcomes (4,23). OCT measures need to be interpreted with caution in MS because they may reflect underlying mechanisms of disease pathobiology or, alternatively, drug effects. In a previous study by Nolan et al (24), comparing fingolimod-treated MS patients with MS patients receiving other therapies, OCT measures were compared between groups over a follow-up period of 5-6 months. There was a mean increase of 0.025 mm3 in macular volume in the fingolimod group, whereas no Chan et al: J Neuro-Ophthalmol 2020; 40: 37-43 change in macular volume was noted for non- fingolimod-treated patients. Although increased macular volume could be viewed as "neuroprotective" (24), these findings could alternatively be interpreted to demonstrate an increased propensity to develop microcystic macular edema, which is known to affect MS patients treated with fingolimod. This confounder limits the utility of total macular volume as a surrogate marker for neuroprotection in MS patients using this therapy (24,25). In the current study, the follow-up interval of 5 years allowed a sufficient period to capture significant decreases in OCT measures of neuroaxonal structure in MS patients. Moreover, patients with a history of nonMS-related optic nerve pathology and previous treatment with fingolimod were excluded. OCT measures observed were confined to the RNFL and GCIP, and eyes with an acute ON within 6 months of OCT were excluded. The latter exclusion criterion aimed to eliminate eyes with transient axoplasmic stasis as a result of acute ON leading to edema in the RNFL that could falsely elevate these measurements (26). Neuroaxonal injury occurs in MS patients, with or without a history of ON, and is believed to be due to both anterograde and retrograde transsynaptic neurodegeneration (27). This irreversible process occurs early in the disease course of MS patients (12). Monitoring peripapillary RNFL- and macular GCIP-segmented retinal layers in MS has previously been shown to be robust in detecting neurodegeneration longitudinally (11). Based on 6 longitudinal studies, RNFL atrophy is at least 1 mm every 1-2 41 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution years in MS patients with active disease and GCIP measurement further improves detection of early atrophy following ON (11). The RNFL thickness in the alemtuzumab cohort changed by 22.11 mm in ON eyes and +0.14 mm in NON eyes after 5 years. This may suggest that treatment has less of an effect on RNFL neurodegeneration after an episode of ON compared with eyes without a history of ON, supporting earlier initiation of higher efficacy treatment. GCIP measures have been shown to provide better reproducibility and reliability, improved structure-function relationships (with visual outcomes), and more robust correlations with brain atrophy over RNFL measures in addition to having less confounding elements, such as edema during acute inflammation (5,8). The GCIP volume change in the alemtuzumab cohort was +0.010 mm3 in ON eyes and +0.014 mm3 in NON eyes. Treatment with a highly effective immune therapy may be necessary to halt progressive neuronal loss and axonal damage. Limitations in this study include small cohort sizes, lack of serial OCT monitoring over time with clinical visual outcomes, and the absence of a direct comparison cohort to the alemtuzumab-treated group. Furthermore, baseline measurements of RNFL thickness and GCIP volume in the ON and NON eyes were not matched between cohorts. The use of an independent, parallel cohort receiving first-line therapies for at least 2 years was implemented for indirect comparison. Both cohorts in this study were scanned on different devices at separate sites, which may account for measurement changes. However, the same OCT device without adjustments was used consistently at each site over time. Although the cohorts did have differing OCT retinal layer thickness segmentation measures (vertical vs horizontal), it has been shown that these protocols compare well at a cohort level (28). New MRI T2 lesions and clinical relapses were not available longitudinally for both cohorts to better represent disease activity beyond baseline comparison data. To better investigate treatment effect on neuroaxonal integrity in MS, future studies should ideally include a prospective, longitudinal study comparing alemtuzumab with firstline injectable medications using serial OCT, and MRI measures of brain volume would help provide potential support for neurostability. OCT RNFL thickness and GCIP volume are measures that reflect neuroaxonal health in the afferent visual pathway, a functionally eloquent region of the CNS that is frequently affected in MS. Degeneration of these structures occurs in most MS patients, at varying rates. Treatment with alemtuzumab demonstrated relative neurostability of RNFL and GCIP measures over approximately 5 years, whereas treatment with first-line injectable therapies was associated with significant RNFL thinning and GCIP volume loss over a similar time period. The extent to which induction-based, high-efficacy immune 42 therapies protect neuroaxonal structure in MS awaits further study. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: A. Traboulsee, E. Hernandez Martínez de Lapiscina, and A. L. Nguyen; b. Acquisition of data: A. L. Nguyen, J. K. Chan, S. Alba-Arbalat, A. Traboulsee, E. Hernandez Martínez de Lapiscina, R. Carruthers, V. Devonshire, and A. L. Sayao; c. Analysis and interpretation of data: A. Traboulsee, E. Hernandez Martínez de Lapiscina, J. K. Chan, C. Taylor, and F. Costello. Category 2: a. Drafting the manuscript: J. K. Chan, A. Traboulsee, C. Taylor, and F. Costello; b. Revising it for intellectual content: A. Traboulsee, E. 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Date | 2020-03 |
Language | eng |
Format | application/pdf |
Type | Text |
Publication Type | Journal Article |
Source | Journal of Neuro-Ophthalmology, March 2020, Volume 40, Issue 1 |
Collection | Neuro-Ophthalmology Virtual Education Library: Journal of Neuro-Ophthalmology Archives: https://novel.utah.edu/jno/ |
Publisher | Lippincott, Williams & Wilkins |
Holding Institution | Spencer S. Eccles Health Sciences Library, University of Utah |
Rights Management | © North American Neuro-Ophthalmology Society |
ARK | ark:/87278/s6z952ts |
Setname | ehsl_novel_jno |
ID | 1592849 |
Reference URL | https://collections.lib.utah.edu/ark:/87278/s6z952ts |