Using Acute Optic Neuritis Trials to Assess Neuroprotective and Remyelinating Therapies in Multiple Sclerosis.

Importance: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments. Objective: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS. Design, Setting, and Participants: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019. Exposures: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials. Main Outcomes and Measures: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials. Results: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 µm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, -0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R2, 0.57), GCIPL thinning (adjusted R2, 0.50), and changes in mfVEP latency (adjusted R2, 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] µm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R2, 0.20; 0.86 [95% CI, 0.35-1.37] µm less GCIPL thinning; P = .001; adjusted R2, 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05). Conclusions and Relevance: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.

Early retinal atrophy predicts long-term visual impairment after acute optic neuritis.

BACKGROUND: Visual recovery after optic neuritis (ON) used to be defined as good, although patients frequently complain of poor vision. METHODS: We carried out a prospective study on 38 consecutive patients with acute ON followed monthly for 6 months and evaluated high- and low-contrast visual acuity (HCVA and LCVA, respectively), quality of vision (National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25)), visual fields, and retinal thickness by spectral domain optical coherence tomography (OCT). RESULTS: We found significant impaired LCVA and color vision in ON eyes 6 months after acute ON, which impact on quality of life. LCVA and color vision were correlated with the thicknesses of the ganglion cell and inner plexiform layer (GCIPL; 2.5% LCVA r = 0.65 and p = 0.0001; color vision r = 0.75 and p < 0.0001) and that of the peripapillary retinal nerve fiber layer (pRNFL; LCVA r = 0.43 and p = 0.0098; color vision r = 0.62 and p < 0.0001). Linear regression models that included the change in the GCIPL and pRNFL thicknesses from baseline to month 1 after onset explained 47% of the change in 2.5% LCVA and 67% of the change of color vision acuity. When adjusting for the value of visual acuity at baseline, predictors of the change in vision from baseline to month 6 achieved similar performance for all three types of vision (HCVA, LCVA, and color vision). CONCLUSION: Monitoring retinal atrophy by OCT within the first month after ON onset allows individuals at a high risk of residual visual impairment to be identified.

Visual field impairment captures disease burden in multiple sclerosis.

Monitoring disease burden is an unmeet need in multiple sclerosis (MS). Identifying patients at high risk of disability progression will be useful for improving clinical-therapeutic decisions in clinical routine. To evaluate the role of visual field testing in non-optic neuritis eyes (non-ON eyes) as a biomarker of disability progression in MS. In 109 patients of the MS-VisualPath cohort, we evaluated the association between visual field abnormalities and global and cognitive disability markers and brain and retinal imaging markers of neuroaxonal injury using linear regression models adjusted for sex, age, disease duration and use of disease-modifying therapies. We evaluated the risk of disability progression associated to have baseline impaired visual field after 3 years of follow-up. Sixty-two percent of patients showed visual field defects in non-ON eyes. Visual field mean deviation was statistically associated with global disability; brain (normalized brain parenchymal, gray matter volume and lesion load) and retinal (peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex thickness) markers of neuroaxonal damage. Patients with impaired visual field had statistically significative greater disability, lower normalized brain parenchymal volume and higher lesion volume than patients with normal visual field testing. MS patients with baseline impaired VF tripled the risk of disability progression during follow-up [OR = 3.35; 95 % CI (1.10-10.19); p = 0.033]. The association of visual field impairment with greater disability and neuroaxonal injury and higher risk of disability progression suggest that VF could be used to monitor MS disease burden.

Dynamics of retinal injury after acute optic neuritis.

OBJECTIVE: We set out to assess the dynamics of retinal injury after acute optic neuritis (ON) and their association with clinical visual outcomes. METHODS: Thirty-one consecutive patients with acute ON were prospectively analyzed over a 6-month follow-up period. Each month, we used optical coherence tomography (OCT) to assess the thickness of peripapillary retinal nerve fiber layer (pRNFL) and segmented macular layers, as well as high-contrast visual acuity, low-contrast visual acuity (LCVA), color visual acuity (CVA), and visual fields (VF). RESULTS: In this prospective study, we found that 6 months after clinical onset, ON eyes suffered a reduction in pRNFL (-45.3 µm) and macular thickness (-17.3 µm). Macular atrophy was due to the decrease of macular RNFL thickness (-7.8 µm) and that of the ganglion cell layer and inner plexiform layer (GCIP, -11.3 µm), whereas the thickness of the outer retinal layers increased slightly. The macular RNFL and GCIP thickness decreased in parallel, yet it always occurred more rapidly and more severely for the GCIP. The change in the GCIP thickness in the first month predicted the visual impairment by month 6; a decrease ≥ of 4.5 µm predicted poor LCVA (sensitivity of 93% and specificity of 88%), and a decrease of ≥ 7 µm predicted poor VF and CVA (sensitivity of 78% and 100% and specificity of 63% and 66%, respectively). INTERPRETATION: Retinal axonal and neuronal damage develops quickly after ON onset. Assessment of ganglion cell layer thickness by OCT after ON onset can be used as an imaging marker of persistent visual disability.

Treatment of acute optic neuritis and vision complaints in multiple sclerosis.

OPINION STATEMENT: Multiple sclerosis is an autoimmune demyelinating disorder of the nervous system, in which almost all patients develop some degree of visual impairment during the disease. Optic neuritis is the most common and known visual affection and may be the initial clinical disease manifestation, but visual complaints can have a wide variety of presentations and some of them can lead to clinical confusion. Most symptoms are the result of acute injury and subsequent axonal loss in the afferent and efferent visual pathway, but others may be consequences of treatments. Currently, we can tell the functional and anatomical damage caused by multiple sclerosis by visual function test, measurement of eye movements, electrophysiological testing, optical coherence tomography, and magnetic resonance imaging. The purpose of this review is to describe the afferent and efferent visual symptoms associated with multiple sclerosis or multiple sclerosis treatment, and review the current and future therapeutic options available for them.

The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS.

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. FINDINGS: The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-aged MS population in Barcelona, Spain. We started the recruitment of patients in the early phase of MS in 2010 and it remains permanently open. All patients undergo a complete neurological and ophthalmological examination including measurements of physical and disability (Expanded Disability Status Scale; Multiple Sclerosis Functional Composite and neuropsychological tests), disease activity (relapses) and visual function testing (visual acuity, color vision and visual field). The MS-VisualPath protocol also assesses the presence of anxiety and depressive symptoms (Hospital Anxiety and Depression Scale), general quality of life (SF-36) and visual quality of life (25-Item National Eye Institute Visual Function Questionnaire with the 10-Item Neuro-Ophthalmic Supplement). In addition, the imaging protocol includes both retinal (Optical Coherence Tomography and Wide-Field Fundus Imaging) and brain imaging (Magnetic Resonance Imaging). Finally, multifocal Visual Evoked Potentials are used to perform neurophysiological assessment of the visual pathway. DISCUSSION: The analysis of the visual pathway with advance imaging and electrophysilogical tools in parallel with clinical information will provide significant and new knowledge regarding neurodegeneration in MS and provide new clinical and imaging biomarkers to help monitor disease progression in these patients.