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.

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.

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.

Colour vision impairment is associated with disease severity in multiple sclerosis.

BACKGROUND: Colour vision assessment correlates with damage of the visual pathway and might be informative of overall brain damage in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to investigate the association between impaired colour vision and disease severity. METHODS: We performed neurological and ophthalmic examinations, as well as magnetic resonance imaging (MRI) and optical coherence tomography (OCT) analyses, on 108 MS patients, both at baseline and after a follow-up of one year. Colour vision was evaluated by Hardy, Rand and Rittler plates. Dyschromatopsia was defined if colour vision was impaired in either eye, except for participants with optic neuritis (ON), for whom only the unaffected eye was considered. We used general linear models adjusted for sex, age, disease duration and MS treatment for comparing presence of dyschromatopsia and disease severity. RESULTS: Impaired colour vision in non-ON eyes was detected in 21 out of 108 patients at baseline. At baseline, patients with dyschromatopsia had lower Multiple Sclerosis Functional Composite (MSFC) scores and Brief Repeatable Battery-Neuropsychology executive function scores than those participants with normal colour vision. In addition, these patients had thinner retinal nerve fiber layer (RNFL), and smaller macular volume, normalized brain volume and normalized gray matter volume (NGMV) at baseline. Moreover, participants with incident dyschromatopsia after one-year follow-up had a greater disability measured by the Expanded Disability Status Scale and MSFC-20 and a greater decrease in NGMV than participants with normal colour vision. CONCLUSIONS: Colour vision impairment is associated with greater MS severity.

Trans-synaptic axonal degeneration in the visual pathway in multiple sclerosis.

OBJECTIVE: To evaluate the association between the damage to the anterior and posterior visual pathway as evidence of the presence of retrograde and anterograde trans-synaptic degeneration in multiple sclerosis (MS). METHODS: We performed a longitudinal evaluation on a cohort of 100 patients with MS, acquiring retinal optical coherence tomography to measure anterior visual pathway damage (peripapillary retinal nerve fiber layer [RNFL] thickness and macular volume) and 3T brain magnetic resonance imaging (MRI) for posterior visual pathway damage (volumetry and spectroscopy of visual cortex, lesion volume within optic radiations) at inclusion and after 1 year. Freesurfer and SPM8 software was used for MRI analysis. We evaluated the relationships between the damage in the anterior and posterior visual pathway by voxel-based morphometry (VBM), multiple linear regressions, and general linear models. RESULTS: VBM analysis showed that RNFL thinning was specifically associated with atrophy of the visual cortex and with lesions in optic radiations at study inclusion (p < 0.05). Visual cortex volume (ß = +0.601, 95% confidence interval [CI] = +0.04 to +1.16), N-acetyl aspartate in visual cortex (ß = +1.075, 95% CI = +0.190 to +1.961), and lesion volume within optic radiations (ß = -2.551, 95% CI = -3.910 to -1.192) significantly influenced average RNFL thinning at study inclusion independently of other confounders, especially optic neuritis (ON). The model indicates that a decrease of 1cm(3) in visual cortex volume predicts a reduction of 0.6µm in RNFL thickness. This association was also observed after 1 year of follow-up. Patients with severe prior ON (adjusted difference = -3.01, 95% CI = -5.08 to -0.95) and mild prior ON (adjusted difference = -1.03, 95% CI = -3.02 to +0.95) had a lower adjusted mean visual cortex volume than patients without ON. INTERPRETATION: Our results suggest the presence of trans-synaptic degeneration as a contributor to chronic axon damage in MS.

Retinal periphlebitis is associated with multiple sclerosis severity.

OBJECTIVES: To assess the association of primary retinal inflammation, namely retinal periphlebitis (RP) and microcystic macular edema, with clinical, brain, and retinal imaging biomarkers of multiple sclerosis (MS) severity. METHODS: One hundred patients with MS underwent a neurologic and ophthalmic examination, MRI, and optical coherence tomography. Disability was assessed using the Expanded Disability Status Scale at baseline and after a 1-year follow-up. The normalized brain volume, the normal-appearing gray matter volume, and T1 lesion volume were assessed at baseline as radiologic biomarkers of disease severity. Retinal nerve fiber layer thickness and macular volume at baseline were used as surrogate markers of axonal damage. We used general linear models adjusted for sex, age, disease duration, and MS treatment to compared adjusted means of these parameters among patients with RP and patients without primary retinal inflammation. RESULTS: Five patients showed RP, 2 showed microcystic macular edema, and the retina was normal in the remaining 93. Patients with RP had a tendency toward a higher adjusted-mean Expanded Disability Status Scale score at baseline and disability progression after a 1-year follow-up compared with patients without primary retinal inflammation. These patients also had a higher adjusted-mean T1 lesion volume (adjusted differences: 10.4, 95% confidence interval [CI]: 0.6 to 20.2; p = 0.038) and lower T1 brain volume (adjusted differences: -68, 95% CI: -139 to 2; p = 0.059). Patients with RP had a lower adjusted-mean retinal nerve fiber layer thickness (adjusted differences: -13.4, 95% CI: -24.4 to -2.3; p = 0.018) and a trend toward lower macular volume. CONCLUSIONS: These results support the role of RP as a biomarker of MS severity.