Disease modifying therapy management of multiple sclerosis after stem cell therapies: A retrospective case series.

BACKGROUND: Stem cell therapies (SCT) have not received formal regulatory approval for the treatment of people with multiple sclerosis (PwMS), but PwMS may seek various options on their own accord. The current literature largely focuses on the efficacy and safety of SCT in PwMS in clinical trials, in particular autologous hematopoietic stem cell transplantation (aHSCT), in carefully selected participants. There is little reported on the MS disease modifying therapy (DMT) management of PwMS who choose to undergo SCT outside of these trials. METHODS: We identified PwMS from two academic centers who had MS diagnosis fulfilling 2017 McDonald criteria and received SCT (methodologies permitted: aHSCT, umbilical-derived mesenchymal stem cells and/or adipose-derived mesenchymal stem cells (AdMSC)), with the goal to treat MS, between 1/1/2015 and 11/30/2021. RESULTS: Nine PwMS (five females; age range at SCT treatment 25-69 years old; MS disease duration 1-12 years; six relapsing-remitting, three secondary progressive, one primary progressive) underwent a total of eleven SCTs (nine aHSCT, two AdMSC, one umbilical-derived MSC) with the goal to treat MS. Two of six PwMS who underwent SCT <10 years from MS diagnosis, and one of three PwMS who underwent stem cell therapies >10 years from MS diagnosis were clinically stable thereafter. An MS DMT was resumed in five PwMS afterwards, including rituximab, ocrelizumab, siponimod, and glatiramer acetate: one remained clinically stable, whereas four clinically progressed. Four PwMS remained off of a DMT: three were clinically stable, whereas one clinically progressed. All nine patients demonstrated radiographic stability by MRI after SCT. Only one met formal criteria to consider aHSCT for MS. CONCLUSIONS: We demonstrate the heterogeneous real-world experience of treating MS after patient-chosen experimental SCTs, detailing the range of DMT management in various patient circumstances. Limitations of our study include its small sample size and the variety of stem cell therapies received.

Multiple Sclerosis and Autoimmune Neurology of the Central Nervous System.

Autoimmune disorders of the central nervous system are common and often affect people in the most productive years of their lives. Among primary autoimmune diseases of the central nervous system, multiple sclerosis is most prevalent in the United States. Many other autoantibody-mediated neurologic syndromes have been identified within the past 2 to 3 decades, including neuromyelitis optica and anti-N-methyl-D aspartate receptor encephalitis. Finally, the central nervous system can also be affected by systemic autoimmune diseases such as sarcoidosis. Many of these diseases are treatable when detected early.

Historical Trends in the Diagnosis of Peduncular Hallucinosis.

BACKGROUND: Peduncular hallucinosis (PH) describes the clinical syndrome of vivid, dream-like visual hallucinations that intrude on normal wakefulness. Additional clinical deficits, especially ophthalmoparesis, have historically been an important part of the diagnosis and localization of this syndrome. We examined how modern neuroimaging has impacted the diagnosis of PH. METHODS: We reviewed all available cases of PH, including 3 of ours and all previously reported in the literature. We determined whether other eye movement abnormalities were part of the clinical presentation and whether a neuroimaging study was performed to make the diagnosis. RESULTS: A total of 85 cases were identified and evaluated. Eye movement abnormalities were present in 12/15 (80%) without a neuroimaging study but in only 24/70 (34%) of cases in which a neuroimaging study was performed (P = 0.001). CONCLUSIONS: Although eye movement abnormalities historically have been considered a key localizing clinical feature supporting the diagnosis of PH, we found that in the era of modern neuroimaging, co-occurring eye movement abnormalities are far less frequent and are not a requisite feature of the diagnosis.

Screening Utility of the King-Devick Test in Mild Cognitive Impairment and Alzheimer Disease Dementia.

The King-Devick (K-D) test is a 1 to 2 minute, rapid number naming test, often used to assist with detection of concussion, but also has clinical utility in other neurological conditions (eg, Parkinson disease). The K-D involves saccadic eye and other eye movements, and abnormalities thereof may be an early indicator of Alzheimer disease (AD)-associated cognitive impairment. No study has tested the utility of the K-D in AD and we sought to do so. The sample included 206 [135 controls, 39 mild cognitive impairment (MCI), and 32 AD dementia] consecutive subjects from the Boston University Alzheimer's Disease Center registry undergoing their initial annual evaluation between March 2013 and July 2015. The K-D was administered during this period. Areas under the receiver operating characteristic curves generated from logistic regression models revealed the K-D test distinguished controls from subjects with cognitive impairment (MCI and AD dementia) [area under the curve (AUC)=0.72], MCI (AUC=0.71) and AD dementia (AUC=0.74). K-D time scores between 48 and 52 seconds were associated with high sensitivity (>90.0%) and negative predictive values (>85.0%) for each diagnostic group. The K-D correlated strongly with validated attention, processing speed, and visual scanning tests. The K-D test may be a rapid and simple effective screening tool to detect cognitive impairment associated with AD.

20/40 or Better Visual Acuity After Optic Neuritis: Not as Good as We Once Thought?

BACKGROUND: Although patients with acute optic neuritis (ON) recover high-contrast visual acuity (HCVA) to 20/40 or better in 95% of affected eyes, patients with a history of ON continue to note subjective abnormalities of vision. Furthermore, substantial and permanent thinning of the retinal nerve fiber layer (RNFL) and the ganglion cell layer (GCL) is now known to occur early in the course of ON. We measured vision-specific quality of life (QOL) in patients with a history of acute ON and recovery of VA to 20/40 or better in their affected eyes to determine how these QOL scores relate to RNFL and GCL thickness and low-contrast letter acuity (LCLA) across the spectrum of visual recovery. METHODS: Data from an ongoing collaborative study of visual outcomes in multiple sclerosis and ON were analyzed for this cross-sectional observational cohort. Patients and disease-free control participants completed the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, as well as VA and LCLA testing for each eye separately and binocularly. Optical coherence tomography measures for each eye included peripapillary RNFL thickness and macular GCL + inner plexiform layer (GCL + IPL) thickness. RESULTS: Patients with a history of acute ON and recovery to 20/40 or better VA (n = 113) had significantly reduced scores for the NEI-VFQ-25 (83.7 ± 15.4) and 10-Item Neuro-Ophthalmic Supplement (74.6 ± 17.4) compared with disease-free controls (98.2 ± 2.1 and 96.4 ± 5.2, P < 0.001, linear regression models, accounting for age and within-patient, intereye correlations). Most patients with 20/40 or better visual recovery (98/112, 88%) had monocular HCVA in their affected eye of 20/20 or better. Although patients with 20/50 or worse HCVA recovery demonstrated the worst performance on low-contrast acuity, affected eye RNFL and GCL + IPL thickness, and QOL scales, these measures were also significantly reduced among those with 20/40 or better HCVA recovery compared with controls. CONCLUSIONS: Patients with a history of ON and "good" visual recovery, defined in the literature as 20/40 or better HCVA, are left with clinically meaningful reductions in vision-specific QOL. Such patient-observed deficits reflect the underlying significant degrees of retinal axonal and neuronal loss and visual dysfunction that are now known to characterize ON even in the setting of maximal HCVA recovery. There remains an unmet therapeutic need for patients with ON.

Varicella Zoster Virus Infection in Granulomatous Arteritis of the Aorta.

Granulomatous arteritis characterizes the pathology of giant cell arteritis, granulomatous aortitis, and intracerebral varicella zoster virus (VZV) vasculopathy. Because intracerebral VZV vasculopathy and giant cell arteritis are strongly associated with productive VZV infection in cerebral and temporal arteries, respectively, we evaluated human aortas for VZV antigen and VZV DNA. Using 3 different anti-VZV antibodies, we identified VZV antigen in 11 of 11 aortas with pathologically verified granulomatous arteritis, in 1 of 1 cases of nongranulomatous arteritis, and in 5 of 18 control aortas (28%) obtained at autopsy. The presence of VZV antigen in granulomatous aortitis was highly significant (P = .0001) as compared to control aortas, in which VZV antigen was never associated with pathology, indicating subclinical reactivation. VZV DNA was found in most aortas containing VZV antigen. The frequent clinical, radiological, and pathological aortic involvement in patients with giant cell arteritis correlates with the significant detection of VZV in granulomatous aortitis.

The King-Devick test of rapid number naming for concussion detection: meta-analysis and systematic review of the literature.

BACKGROUND: Vision encompasses a large component of the brain's pathways, yet is not represented in current sideline testing. OBJECTIVES: We performed a meta-analysis of published data for a vision-based test of rapid number naming (King-Devick [K-D] test). STUDIES & METHODS: Pooled and meta-analysis of 15 studies estimated preseason baseline K-D scores and sensitivity/specificity for identifying concussed versus nonconcussed control athletes. RESULT: Baseline K-D (n = 1419) showed a weighted estimate of 43.8 s (95% CI: 40.2, 47.5; I2 = 0.0%; p=0.85 - indicating very little heterogeneity). Sensitivity was 86% (96/112 concussed athletes had K-D worsening; 95% CI: 78%, 92%); specificity was 90% (181/202 controls had no worsening; 95% CI: 85%, 93%). CONCLUSION: Rapid number naming adds to sideline assessment and contributes a critical dimension of vision to sports-related concussion testing.

Zeroing in on zoster: A tale of many disorders produced by one virus.

While herpes zoster infection has been recognized since antiquity, chickenpox (varicella) was confused with smallpox until the 1800s, when both illnesses became better understood. In the 20th century, varicella zoster virus (VZV) was shown to cause varicella upon primary (first-time) infection and herpes zoster (shingles) after reactivation of latent VZV. Scientific progress over the past 50 years has rapidly advanced the understanding and prevention of disease produced by VZV. Combined imaging and virological studies continue to reveal the protean neurological, ocular and visceral disorders produced by VZV.

Quality of life in idiopathic intracranial hypertension at diagnosis: IIH Treatment Trial results.

OBJECTIVE: The study purpose was to examine vision-specific and overall health-related quality of life (QOL) at baseline in Idiopathic Intracranial Hypertension Treatment Trial patients who were newly diagnosed and had mild visual loss. We also sought to determine the associations between vision-specific QOL scores and visual symptoms, visual function, pain, headache-related disability, and obesity. METHODS: We assessed QOL using the 36-Item Short Form Health Survey, National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), and 10-Item NEI-VFQ-25 Neuro-Ophthalmic Supplement. We compared these results with those of previously reported idiopathic intracranial hypertension (IIH) QOL studies. We assessed relationships between QOL and other clinical characteristics. RESULTS: Among 165 participants with IIH (161 women and 4 men with a mean age ± SD of 29.2 ± 7.5 years), vision-specific QOL scores were reduced compared with published values for disease-free controls. Scores of participants were comparable to published results for patients with multiple sclerosis and a history of optic neuritis. A multiple linear regression model for the NEI-VFQ-25 composite score found that perimetric mean deviation in the best eye, visual acuity in the worst eye, visual symptoms, and pain symptoms (headache, neck pain), but not obesity, were independently associated with QOL. CONCLUSIONS: IIH affects QOL at time of diagnosis even in patients with mild visual impairment. Vision-specific QOL in patients with newly diagnosed IIH may be as decreased as that for patients with other neuro-ophthalmic disorders. IIH treatment should target visual loss and other symptoms of increased intracranial pressure associated with reduced QOL. Reduced QOL does not simply reflect obesity, an underlying IIH risk factor.

Adding Vision to Concussion Testing: A Prospective Study of Sideline Testing in Youth and Collegiate Athletes.

BACKGROUND: Sports-related concussion commonly affects the visual pathways. Current sideline protocols test cognition and balance but do not include assessments of visual performance. We investigated how adding a vision-based test of rapid number naming could increase our ability to identify concussed athletes on the sideline at youth and collegiate levels. METHODS: Participants in this prospective study included members of a youth ice hockey and lacrosse league and collegiate athletes from New York University and Long Island University. Athletes underwent preseason baseline assessments using: 1) the King-Devick (K-D) test, a <2-minute visual performance measure of rapid number naming, 2) the Standardized Assessment of Concussion (SAC), a test of cognition, and 3) a timed tandem gait test of balance. The SAC and timed tandem gait are components of the currently used Sport Concussion Assessment Tool, 3rd Edition (SCAT3 and Child-SCAT3). In the event of a concussion during the athletic season, injured athletes were retested on the sideline/rink-side. Nonconcussed athletes were also assessed as control participants under the same testing conditions. RESULTS: Among 243 youth (mean age 11 ± 3 years, range 5-17) and 89 collegiate athletes (age 20 ± 1 years, range 18-23), baseline time scores for the K-D test were lower (better) with increasing participant age (P < 0.001, linear regression models). Among 12 athletes who sustained concussions during their athletic season, K-D scores worsened from baseline by an average of 5.2 seconds; improvement by 6.4 seconds was noted for the nonconcussed controls (n = 14). The vision-based K-D test showed the greatest capacity to distinguish concussed vs control athletes based on changes from preseason baseline to postinjury (receiver operating characteristic [ROC] curve areas from logistic regression models, accounting for age = 0.92 for K-D, 0.87 for timed tandem gait, and 0.68 for SAC; P = 0.0004 for comparison of ROC curve areas). CONCLUSIONS: Adding a vision-based performance measure to cognitive and balance testing enhances the detection capabilities of current sideline concussion assessment. This observation in patients with mild traumatic brain injury reflects the common involvement and widespread distribution of brain pathways dedicated to vision.

Vision testing is additive to the sideline assessment of sports-related concussion.

We examined the King-Devick (K-D) test, a vision-based test of rapid number naming, as a complement to components of the Sport Concussion Assessment Tool, 3rd edition (SCAT3) for diagnosis of concussion. Baseline and postconcussion data for the University of Florida men's football, women's soccer, and women's lacrosse teams were collected, including the K-D test, Standardized Assessment of Concussion (SAC), and Balance Error Scoring System (BESS). Among 30 athletes with first concussion during their athletic season (n = 217 total), differences from baseline to postinjury showed worsening of K-D time scores in 79%, while SAC showed a ≥2-point worsening in 52%. Combining K-D and SAC captured abnormalities in 89%; adding the BESS identified 100% of concussions. Adding a vision-based test may enhance the detection of athletes with concussion.

Sports-related concussion: Anonymous survey of a collegiate cohort.

Studies suggest that a lack of standardized knowledge may lead to underreporting and undertreatment of sports-related concussion. However, there has been little work done to establish how this knowledge may affect athletes' behaviors toward reporting their concussions and removing themselves from play. We conducted an anonymous online survey to assess athletes' knowledge of signs and symptoms of concussion, and also sought to estimate the potential frequency of underreporting in a collegiate athlete cohort. Among 262 athletes who responded to the survey, 43% of those with a history of concussion reported that they had knowingly hidden symptoms of a concussion to stay in a game, and 22% of athletes overall indicated that they would be unlikely or very unlikely to report concussion symptoms to a coach or athletic trainer in the future. These data suggest that there may be a substantial degree of underreporting of concussion among collegiate athletes, despite most acknowledging that they have been formally educated about the risks of concussion.

Saccades and memory: baseline associations of the King-Devick and SCAT2 SAC tests in professional ice hockey players.

OBJECTIVE: The Sports Concussion Assessment Tool 2 (SCAT2) and King-Devick (K-D) tests have both been proposed as sideline tools to detect sports-related concussion. We performed an exploratory analysis to determine the relation of SCAT2 components, particularly the Standardized Assessment of Concussion (SAC), to K-D test scores in a professional ice hockey team cohort during pre-season baseline testing. We also examined changes in scores for two athletes who developed concussion and had rinkside testing. METHODS: A modified SCAT2 (no balance testing) and the K-D test, a brief measure of rapid number naming, were administered to 27 members of a professional ice hockey team during the 2011-2012 pre-season. Athletes with concussion also underwent rinkside testing. RESULTS: Lower (worse) scores for the SCAT2 SAC Immediate Memory Score and the overall SAC score were associated with greater (worse) times required to complete the K-D test at baseline. On average, for every 1-point reduction in SAC Immediate Memory Score, we found a corresponding increase (worsening) of K-D time score of 7.3s (95% CI 4.9, 9.7, p<0.001, R(2)=0.62, linear regression, accounting for age). For the overall SAC score, 1-point reductions were associated with K-D score worsening of 2.2s (95% CI 0.6, 3.8, p=0.01, R(2)=0.25, linear regression). In two players tested rinkside immediately following concussion, K-D test scores worsened from baseline by 4.2 and 6.4s. These athletes had no differences found for SCAT2 SAC components, but reported symptoms of concussion. CONCLUSION: In this study of professional athletes, scores for the K-D test, a measure for which saccadic (fast) eye movements are required for the task of rapid number naming, were associated with reductions in Immediate Memory at a pre-season baseline. Both working memory and saccadic eye movements share closely related anatomical structures, including the dorsolateral prefrontal cortex (DLPFC). A composite of brief rapid sideline tests, including SAC and K-D (and balance testing for non-ice hockey sports), is likely to provide an effective clinical tool to assess the athlete with suspected concussion.

Measures of visual pathway structure and function in MS: Clinical usefulness and role for MS trials.

Over the past decade, the visual pathway in multiple sclerosis (MS) has become an important system for assessing both patient function and disease burden. Abnormalities of low-contrast acuity, long recognized as important correlates of driving, facial recognition, and other activities of daily living, are now noted to be common among patients with MS, even among those with no history of acute optic neuritis (ON). Low-contrast letter acuity scores correlate well with brain MRI lesion burden, visual-evoked potential (VEP) amplitudes, health-related quality of life (QOL), and retinal nerve fiber layer (RNFL) axonal and neuronal loss as measured by optical coherence tomography (OCT). Axonal and neuronal degeneration in MS is likely to be an important cause of visual impairment and disability, particularly among patients with progressive MS subtypes. With the advent of OCT and the use of low-contrast letter acuity charts in MS research and clinical trials, the structure-function correlations afforded by the anterior visual pathway can be assessed and potentially harnessed as a model for testing new therapies. Recent advances in OCT, such as high resolution spectral-domain techniques and computerized algorithms for image analysis, have allowed for measurement of specific retinal layers, including the ganglion cell (GCL) neuronal layer and its intimately associated, thin layer of interneurons, the inner plexiform layer (IPL). Longitudinal collaborative studies of GCL+IPL thinning and RNFL axonal loss are providing an in vivo view into neuroretinal pathology, and are providing new insights into how the visual pathway may reflect overall mechanisms of disease in MS.

Monocular and binocular low-contrast visual acuity and optical coherence tomography in pediatric multiple sclerosis.

BACKGROUND: Low-contrast letter acuity and optical coherence tomography (OCT) capture visual dysfunction and axonal loss in adult-onset multiple sclerosis (MS), and have been proposed as secondary outcome metrics for therapeutic trials. Clinical trials will soon be launched in pediatric MS, but such outcome metrics have not been well-validated in this population. OBJECTIVES: To determine whether MS onset during childhood and adolescence is associated with measurable loss of visual acuity and thinning of the retinal nerve fiber layer (RNFL), whether such features are noted only in the context of clinical optic nerve inflammation (optic neuritis, ON) or are a feature of MS even in the absence of optic nerve relapses, and to define the optimal methods for such detection. STUDY DESIGN: Cross-sectional study. METHODS: Monocular and binocular high- and low-contrast letter acuity and contrast sensitivity were assessed in a cross-sectional cohort of children (ages 5 to 17 years) with MS (N=22 patients, 44 eyes; 8 patients with a history of ON) and disease-free controls (N=29 patients; 58 eyes) from three academic centers. Binocular summation was determined by calculating the number of letters correctly identified using the binocular score minus the better eye score for each visual test. RNFL thickness was measured using OCT (Stratus OCT-3). Results were analyzed in terms of "eyes" as: MS ON+, MS ON-, and control eyes. Generalized estimating equation (GEE) regression models were used to compare patients to controls. RESULTS: Traditional high-contrast visual acuity scores did not differ between MS ON+, MS ON-, and controls eyes. MS ON+ eyes had decreased monocular (p<0.001) and decreased binocular (p=0.007) low-contrast letter acuity (Sloan 1.25% contrast charts) scores. Monocular visual acuity did not differ when comparing MS ON- and control eyes. The magnitude of binocular summation using low-contrast charts was similar for pediatric MS participants and controls and was not diminished in children with a history of ON. While the mean RNFL thickness for all MS eyes (103±17 µm) trended lower when compared to corresponding measures in control eyes (109±9 µm, p=0.085), we confirmed a highly significant reduction in mean RNFL thickness in MS eyes with a history of ON (86±22 µm, p<0.001). RNFL thickness of MS ON- eyes in pediatric MS patients (109±11 µm) did not differ from controls (p=0.994). CONCLUSIONS: Low-contrast letter acuity detects subtle visual loss in MS patients with prior ON, consistent with incomplete recovery, a finding further supported by RNFL loss in ON affected eyes. In MS patients with prior unilateral ON, binocular acuity is decreased; however, the magnitude of binocular summation is preserved, unlike adult-onset MS who exhibit a reduced capacity for visual compensation in the context of unilateral injury. Also unlike findings in adult-onset MS, we did not demonstrate RNFL thinning in ON- eyes of children and adolescents with MS. Further validation is required to confirm whether neurodegeneration of visual pathways occurs in the absence of relapse, and thus whether OCT will serve as a sensitive metric for such pathology in the pediatric and adolescent MS context.

Ganglion cell loss in relation to visual disability in multiple sclerosis.

PURPOSE: We used high-resolution spectral-domain optical coherence tomography (SD-OCT) with retinal segmentation to determine how ganglion cell loss relates to history of acute optic neuritis (ON), retinal nerve fiber layer (RNFL) thinning, visual function, and vision-related quality of life (QOL) in multiple sclerosis (MS). DESIGN: Cross-sectional study. PARTICIPANTS: A convenience sample of patients with MS (n = 122; 239 eyes) and disease-free controls (n = 31; 61 eyes). Among MS eyes, 87 had a history of ON before enrollment. METHODS: The SD-OCT images were captured using Macular Cube (200×200 or 512×128) and ONH Cube 200×200 protocols. Retinal layer segmentation was performed using algorithms established for glaucoma studies. Thicknesses of the ganglion cell layer/inner plexiform layer (GCL+IPL), RNFL, outer plexiform/inner nuclear layers (OPL+INL), and outer nuclear/photoreceptor layers (ONL+PRL) were measured and compared in MS versus control eyes and MS ON versus non-ON eyes. The relation between changes in macular thickness and visual disability was also examined. MAIN OUTCOME MEASURES: The OCT measurements of GCL+IPL and RNFL thickness; high contrast visual acuity (VA); low-contrast letter acuity (LCLA) at 2.5% and 1.25% contrast; on the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and 10-Item Neuro-Ophthalmic Supplement composite score. RESULTS: Macular RNFL and GCL+IPL were significantly decreased in MS versus control eyes (P<0.001 and P = 0.001) and in MS ON versus non-ON eyes (P<0.001 for both measures). Peripapillary RNFL, macular RNFL, GCL+IPL, and the combination of macular RNFL+GCL+IPL were significantly correlated with VA (P≤0.001), 2.5% LCLA (P<0.001), and 1.25% LCLA (P≤0.001). Among OCT measurements, reductions in GCL+IPL (P<0.001), macular RNFL (P = 0.006), and the combination (macular RNFL+GCL+IPL; P<0.001) were most strongly associated with lower (worse) NEI-VFQ-25 and 10-Item Supplement QOL scores; GCL+IPL thinning was significant even accounting for macular RNFL thickness (P = 0.03 for GCL+IPL, P = 0.39 for macular RNFL). CONCLUSIONS: We demonstrated that GCL+IPL thinning is most significantly correlated with both visual function and vision-specific QOL in MS, and may serve as a useful structural marker of disease. Our findings parallel those of magnetic resonance imaging studies that show gray matter disease is a marker of neurologic disability in MS. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Visual pathway axonal loss in benign multiple sclerosis: a longitudinal study.

BACKGROUND: Benign multiple sclerosis (MS), traditionally defined as Expanded Disability Status Scale (EDSS) score ≤3 and ≥15-year disease duration, is thought to follow a milder clinical course. We determined the extent of visual pathway axonal loss by optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) thickness in a benign MS cohort and examined the relation to vision and quality of life (QOL). METHODS: In this longitudinal study of vision in MS at 3 academic centers, a subset of patients with EDSS, visual function, OCT, and QOL assessments was analyzed. Low- and high-contrast letter acuity was performed to assess visual function. RNFL thickness was determined using time-domain OCT. QOL scales included the 25-Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Short Form-36 Health Survey. RESULTS: Among 68 patients (135 eyes) studied longitudinally, 13 (26 eyes) had benign MS using criteria of EDSS score ≤3 and ≥15-year disease duration. Benign MS eyes had as much RNFL thinning (-3.6 µm, P = 0.0008 vs baseline, paired t test) as typical MS eyes (-3.3 µm, P < 0.0001). Both groups had significant low-contrast acuity loss. History of optic neuritis (ON) was more frequent in benign MS (69% vs 33% of eyes). History of ON distinguished benign vs typical MS (P = 0.002) and correlated with RNFL thickness at baseline (P = 0.002) and disease duration (P = 0.03) but not EDSS (P = 0.32, logistic regression). NEI-VFQ-25 scores were also worse for benign MS, accounting for age (75 ± 21 vs 88 ± 11, P = 0.005). CONCLUSION: Patients with benign MS have RNFL axonal loss that is as marked as that of typical MS and have reduced vision and QOL. While overall neurologic impairment is mild, visual dysfunction, not well captured by the EDSS, accounts for a substantial degree of disability in benign MS.

Vision in multiple sclerosis: the story, structure-function correlations, and models for neuroprotection.

Visual dysfunction is one of the most common clinical manifestations of multiple sclerosis (MS). Just over a decade ago, MS clinical trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function. Low-contrast letter acuity emerged as the leading candidate to measure visual disability in MS, and subsequent studies found low-contrast acuity testing to correlate well with brain MRI lesion burden, visual-evoked potentials, quality of life (QOL), and retinal nerve fiber layer (RNFL) loss, as measured by optical coherence tomography (OCT). OCT in MS has allowed for assessment of structure-function correlations that make the anterior visual pathway and acute optic neuritis (ON) ideal models for testing novel agents for neuroprotection and repair. New therapies that reduce axonal loss by neuroprotective or myelin repair mechanisms can now be assessed noninvasively by OCT and coupled with visual function data. Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 µm) vs controls (105 µm) and is particularly reduced in MS eyes with a history of ON (85 µm). Worsening of visual function by a clinically significant ≥ 7 letters or approximately 1.5 lines for low-contrast acuity is associated with approximately 4.5 µm reductions in RNFL thickness in MS eyes. Longitudinal studies of OCT have also shown RNFL axonal loss over time that occurs even in the absence of acute ON and that correlates with clinically meaningful worsening of vision and QOL, even in patients with benign MS. The latest OCT investigations involve high-resolution spectral-domain (SD) OCT with segmentation and measurement of specific retinal layers using computerized algorithms. These methods allow quantitation of ganglion cell (neuronal) layer loss and axonal degeneration in MS in vivo. In this review, we examine the data from these studies and ongoing trials that highlight the entity of ON as a model to investigate neuroprotection and neurorepair. In doing so, we also present representative group data from studies that have examined visual function, OCT measures, and QOL scales in patients with MS and ON and disease-free controls. These data, and those from recent meta-analyses, may be used to provide reference values for the development of clinical trial protocols.