Faculty Bibliography

OBJECTIVE: To describe a novel neurophysiologic signature of the retinal ganglion cell and to elucidate its relationship to abnormalities in validated structural and functional measures of the visual system. METHODS: We used multifocal electroretinogram-generated optic nerve head component (ONHC) responses from normal subjects (n = 18), patients with multiple sclerosis (MS) (n = 18), and those with glaucoma (n = 3). We then characterized the relationship between ONHC response abnormalities and performance on low-contrast visual acuity, multifocal visual-evoked potential-induced cortical responses, and average and quadrant retinal nerve fiber layer (RNFL) thicknesses, as measured by spectral-domain optical coherence tomography. RESULTS: Compared with the eyes of normal subjects, the eyes of patients with MS exhibited an increased number of abnormal or absent ONHC responses (p < 0.0001). For every 7-letter reduction in low-contrast letter acuity, there were corresponding 4.6 abnormal ONHC responses at 2.5% contrast (p < 0.0001) and 6.6 abnormalities at the 1.25% contrast level (p < 0.0001). Regarding average RNFL thickness, for each 10-mum thickness reduction, we correspondingly observed 6.8 abnormal ONHC responses (p = 0.0002). The most robust association was between RNFL thinning in the temporal quadrant and ONHC response abnormalities (p < 0.0001). CONCLUSION: Further characterization of ONHC abnormalities (those that are reversible and irreversible) may contribute to the development of novel neurotherapeutic strategies aimed at achieving neuroprotective, and perhaps even neurorestorative, effects in disorders that target the CNS in general, and MS in particular.

IMPORTANCE Retrospective studies have demonstrated disparate outcomes following acute optic neuritis in individuals of African descent compared with individuals of white race/ethnicity. However, published analyses of the prospectively collected Optic Neuritis Treatment Trial (ONTT) data identified no association between worse visual outcomes and black race/ethnicity. OBJECTIVES To investigate the associations of age, sex, and race/ethnicity with visual outcomes following acute optic neuritis through application of longitudinal data analysis techniques to the ONTT data set. DESIGN Secondary analysis of the ONTT (a prospective randomized controlled trial) data set. Our models included effects of treatment (placebo, oral prednisone, or intravenous methylprednisolone), time, and treatment x time interaction, as well as demographic covariates of age, sex, and race/ethnicity. SETTING AND PARTICIPANTS The ONTT data were collected at multiple centers in the United States. Patients of black (n = 58) and white (n = 388) race/ethnicity with acute optic neuritis who enrolled in the ONTT within 8 days of symptom onset were included in analyses. MAIN OUTCOMES AND MEASURES The contrast sensitivity and visual acuity (logMAR) in the affected eye were modeled using 2-stage mixed-effects regression techniques. All available follow-up data from baseline to 15 to 18 years were included. RESULTS The data identified no relationship of age, sex, or treatment with contrast sensitivity or visual acuity outcomes. Race/ethnicity was significantly related to contrast sensitivity (P < .001) and visual acuity (P < .001) during a 15-year period following acute optic neuritis, with black race/ethnicity being associated with worse scores for both. CONCLUSIONS AND RELEVANCE Race/ethnicity seems to be associated with contrast sensitivity and visual acuity outcomes in affected eyes following acute optic neuritis. To our knowledge, this is the largest cohort of black race/ethnicity with acute optic neuritis to be studied and represents the first evidence from a prospectively collected data set to support a hypothesis of race/ethnicity-dependent visual outcomes of acute optic neuritis.

BACKGROUND: Sports-related concussion has received increasing awareness due to short- and long-term neurologic sequelae seen among athletes. The King-Devick (K-D) test captures impairment of eye movements and other correlates of suboptimal brain function. We investigated the K-D test as a screening for concussion when administered by layperson sports parents in a cohort of amateur boxers. METHODS: The K-D test was administered pre-fight and post-fight by laypersons masked to the head trauma status of each athlete. Matches were watched over by a ringside physician and boxing trainer. Athletes with suspected head trauma received testing with the Military Acute Concussion Evaluation (MACE) by the ringside physician to determine concussion status. Athletes sustaining concussion were compared to the athletes screened using the K-D test. RESULTS: Post-fight K-D scores were lower (better) than the best baseline score (41 vs. 39.3 s, P=0.34, Wilcoxon signed-rank test), in the absence of concussion. One boxer sustained a concussion as determined by the ringside physician. This boxer was accurately identified by the layperson K-D testers due to a worsening in K-D test compared to baseline (3.2 seconds) and an increased number of errors. High levels of test-retest reliability were observed (intraclass correlation coefficient 0.90 [95% CI 0.84-0.97]). Additionally, 6 boxers who participated in multiple bouts showed no worsening of their K-D times further supporting that scores are not affected by the fatigue associated with sparring. CONCLUSION: The K-D test is a rapid sideline screening tool for concussion that can be effectively administered by non-medically trained laypersons.

BACKGROUND: The King-Devick (KD) test measures the speed of rapid number naming, and is postulated to require fast eye movements, attention, language, and possibly other aspects of cognitive functions. While used in multiple sports concussion studies, it has not been applied to the field of movement disorders. METHODS: Forty-five Parkinson's disease (PD), 23 essential tremor (ET), and 65 control subjects were studied. Subjects performed two trials of reading out loud single-digit numbers separated by varying spacing on three test cards that were of different formats. The sum time of the faster trial was designated the KD score and compared across the three groups. RESULTS: PD patients had higher (worse) KD scores, with longer reading times compared to ET and control subjects (66 s vs. 49 s vs. 52 s, p < 0.001, adjusting for age and gender). No significant difference was found between ET and control (Delta = -3 s, 95% CI: -10 to 4). CONCLUSIONS: This is the first study of the King-Devick Test in Parkinson's disease. PD patients were found to have a slower rapid number naming speed compared to controls. This test may be a simple and rapid bedside tool for quantifying correlates of visual and cognitive function in Parkinson's disease.

BACKGROUND: The decision between conservative management and invasive treatment of juxtaorbital intracranial vascular anomalies can be challenging. Whereas arteriovenous malformations (AVMs) can lead to vision loss and are potentially life threatening if they rupture, invasive endovascular and surgical procedures also carry risks. CASE DESCRIPTIONS: Two patients developed blinding orbital congestion soon after successful treatment of cerebral vascular anomalies. The first patient, a 36 year-old man, underwent partial embolization followed by resection of a congenital frontal lobe AVM. The second patient, a 62 year-old woman, underwent embolization of a peri-orbital/skull base dural arteriovenous malformation. Following intervention, both patients developed unilateral vision loss proptosis, chemosis, complete ophthalmoplegia, and elevated intraocular pressure. The first patient suffered from acute orbital compartment syndrome in the absence of any acute localized hemorrhage or thrombosis. The second patient experienced refractory acute glaucoma from orbital congestion, secondary hyphema and angle closure due to superior ophthalmic vein and cavernous sinus thromboses. CONCULSIONS: These cases highlight the potential orbital congestion to worsen acutely after invasive treatment of juxtaorbital cerebral vascular anomalies, and suggest diverse mechanisms of resultant visual and orbital compromise. The first case represents the first report of orbital compartment syndrome following resection of a congenital AVM.

Purpose: The King-Devick (K-D) test, a rapid number naming test, captures impaired eye movements and saccades, findings correlated with suboptimal brain function. This test has been used to screen athletes for concussions, with worse time scores in athletes following concussion, consistent with widely distributed visual pathways. We examined the K-D test as a measure of vision and eye movements in multiple sclerosis (MS) and determined the relation of K-D scores to visual function, vision-specific quality of life (QoL), work disability, and history of optic neuritis (ON).
Method(s): Patients with MS and disease-free controls completed the test at a single visit. Scores represent time needed to read single-digit numbers on 3 test cards. Patients had testing of monocular and binocular low-contrast acuity (2.5%, 1.25%), high-contrast acuity (VA), spectral-domain OCT, NEI-VFQ-25, 10-Item Neuro-Ophthalmic Supplement, and MS Functional Composite.
Result(s): In the MS cohort (n=81), K-D scores were worse compared to controls (54.7+/-15.7 vs. 41.2+/-7.2 seconds, p=0.003, least squares means, adjusting for age). Higher scores in MS were associated with worse scores for vision-specific QoL (p<0.001 for NEI-VFQ-25, p<0.001 for 10-Item Supplement), binocular low-contrast acuity at 2.5%, 1.25% (p<0.001), binocular VA (p=0.003), timed 25-foot walk (p<0.001), 9-hole peg test (p=0.001), and 3- second PASAT3 (p=0.03, linear regression). Patients with history of acute ON (p=0.003) or binocular low-contrast acuities below the control group average (p=0.009 for 2.5%, logistic regression) had worse K-D scores. Correspondingly, monocular vision (p=0.001-0.009) and RNFL thickness (p=0.001) were reduced in eyes of patients with worse K-D (adjusting for age and within-patient, inter-eye correlations). Disabled patients (receiving disability pension) did worse on the K-D test compared to those working full-time, accounting for age (p<0.001).
Conclusion(s): The K-D test captures visual dysfunction, vision-specific quality of life and neurologic impairment in MS. Scores reffect work disability as well as structural changes as measured by OCT. History of ON and abnormal binocular acuities were associated with worse scores, suggesting that the K-D captures both a0erent and e0erent components of vision. The K-D test should be considered for future MS trials as a rapid global visual performance measure

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.

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 mum) trended lower when compared to corresponding measures in control eyes (109+/-9 mum, p=0.085), we confirmed a highly significant reduction in mean RNFL thickness in MS eyes with a history of ON (86+/-22 mum, p<0.001). RNFL thickness of MS ON- eyes in pediatric MS patients (109+/-11 mum) 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.