Faculty Bibliography

Introduction: Natalizumab treatment early in the relapsingremitting multiple sclerosis (RRMS) disease course may improve clinical outcomes. STRIVE is a multicentre, observational, openlabel, single-arm study of anti-JC virus antibody negative patients starting natalizumab < 3 years after RRMS diagnosis.
Objective(s): To examine no evidence of disease activity (NEDA) status, cognitive function, and health-related quality of life (HRQoL) over 3 years of natalizumab treatment in patients with early RRMS.
Method(s): NEDA was defined as no Expanded Disability Status Scale (EDSS) worsening (a score increase of >=1.5 from a baseline [BL] of 0, >=1.0 from a BL of 1.0-5.5, or >=0.5 from a BL >=6.0, confirmed over >=24 weeks), relapses, gadolinium-enhancing lesions, or new/enlarging T2-hyperintense lesions. Clinical NEDA was defined as no 24-week-confirmed EDSS worsening or relapses. The Kaplan-Meier method was used to estimate time to 24-week-confirmed EDSS worsening and improvement (a score decrease of >=1.0 from a BL >=2.0). The Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Impact Scale-29 (MSIS- 29) were assessed at BL and yearly thereafter. Changes from BL (CFBs) to year 3 were analysed via Wilcoxon signed-rank tests.
Result(s): At BL, the intent-to-treat population (N=222) had early RRMS with a mean (standard deviation [SD]) time since diagnosis of 1.6 (0.8) years, a mean (SD) EDSS score of 2.0 (1.1), and a mean (SD) of 1.4 (1.2) relapses in the prior year. A total of 50% of the patients had not used prior disease-modifying therapies. At year 3, 55 of 164 patients (33.5%) maintained NEDA (95% CI: 26.3%, 40.8%) and 107 of 171 patients (62.6%) maintained clinical NEDA (95% CI: 55.3%, 69.8%). At year 3, the cumulative probabilities of 24-week-confirmed EDSS worsening and improvement were 19.5% and 36.2%, respectively. From BL to year 3, patients exhibited significant improvements in SDMT score (n=153; mean CFB [95% CI]: 3.6 [2.0, 5.2]; P< 0.001) and in MSIS-29 (n=147) physical score (mean CFB [95% CI]: -4.8 [-7.1, -2.5]; P< 0.001), psychological score (mean CFB [95% CI]: -2.2 [-3.5, -0.9]; P=0.001), and quality-of-life score (mean CFB [95% CI]: -7.0 [-10.3, -3.7]; P< 0.001).
Conclusion(s): In patients with early RRMS, natalizumab treatment over 3 years was associated with NEDA maintenance and improved cognitive and HRQoL outcomes. These results are consistent with previous work showing natalizumab's effectiveness when initiated early in the RRMS disease course

Objective: To determine optimal thresholds for inter-eye differences in retinal nerve fiber (RNFL) and ganglion cell+inner plexiform (GCIP) layer thicknesses that are predictive of a unilateral optic nerve lesion in multiple sclerosis (MS).
Background(s): The optic nerve is a frequent site for involvement in MS. Current international diagnostic criteria for MS do not include the optic nerve as a lesion site despite the high prevalence of acute optic neuritis (ON). Spectral-domain optical coherence tomography (SD-OCT) detects thinning of RNFL and GCIP in MS.
Method(s): In this multi-center international study at 9 sites, SD-OCT, high-contrast visual acuity (VA), low-contrast letter acuity (LCLA), and vision-specific quality of life (QOL) were measured for MS patients and healthy controls as part of the International Multiple Sclerosis Visual System Consortium (IMSVISUAL). QOL was measured using the NEI-VFQ-25 and 10-item Neuro-Ophthalmic Supplement (NOS). Presence of an optic nerve lesion was defined as history of acute unilateral ON.
Result(s): Among healthy controls (n=348), the 95th percentile value for inter-eye difference (upper boundary of expected) was 7.0 microns; for GCIP, the 95th percentile was 3.0 microns. These values were applied to the MS cohort (n=1,346), and were associated with worse vision-specific QOL for inter-eye differences above the threshold values (P<=0.04, linear regression, accounting for age). Greater inter-eye differences in VA and LCLA were associated with greater inter-eye RNFL differences (P< 0.001) and GCIP (P<=0.002). Receiver operating characteristic (ROC) curve analysis demonstrated an optimal RNFL inter-eye difference threshold of 5 microns for identifying patients with unilateral ON (n=404) in the MS cohort (point on ROC curve where sensitivity and specificity are both optimized). For GCIP, the threshold was 4 microns.
Conclusion(s): Optimal inter-eye differences of 5 microns for peripapillary RNFL and 4 microns for macular GCIP thickness are robust thresholds for identifying unilateral optic nerve lesions based on analyses of an international MS cohort