Faculty Bibliography

OBJECTIVE To determine the relationships between conventional and segmentation-derived optical coherence tomography (OCT) retinal layer thickness measures with intracranial volume (a surrogate of head size) and brain substructure volumes in multiple sclerosis (MS). DESIGN Cross-sectional study. SETTING Johns Hopkins University, Baltimore, Maryland. PARTICIPANTS A total of 84 patients with MS and 24 healthy control subjects. MAIN OUTCOME MEASURES High-definition spectral-domain OCT conventional and automated segmentation-derived discrete retinal layer thicknesses and 3-T magnetic resonance imaging brain substructure volumes. RESULTS Peripapillary retinal nerve fiber layer as well as composite ganglion cell layer + inner plexiform layer thicknesses in the eyes of patients with MS without a history of optic neuritis were associated with cortical gray matter (P = .01 and P = .04, respectively) and caudate (P = .04 and P = .03, respectively) volumes. Inner nuclear layer thickness, also in eyes without a history of optic neuritis, was associated with fluid-attenuated inversion recovery lesion volume (P = .007) and inversely associated with normal-appearing white matter volume (P = .005) in relapsing-remitting MS. As intracranial volume was found to be related with several of the OCT measures in patients with MS and healthy control subjects and is already known to be associated with brain substructure volumes, all OCT-brain substructure relationships were adjusted for intracranial volume. CONCLUSIONS Retinal measures reflect global central nervous system pathology in multiple sclerosis, with thicknesses of discrete retinal layers each appearing to be associated with distinct central nervous system processes. Moreover, OCT measures appear to correlate with intracranial volume in patients with MS and healthy control subjects, an important unexpected factor unaccounted for in prior studies examining the relationships between peripapillary retinal nerve fiber layer thickness and brain substructure volumes.

OBJECTIVE: To develop an objective and precise neurophysiologic method from which to identify and characterize the presence and magnitude of relative afferent pupillary defects (RAPD) in patients with MS. METHODS: Binocular infrared pupillometry was performed in 40 control subjects and 32 MS patients with RAPDs, using two precisely defined sequences of alternating light flashes (right-left and left-right). We analyzed three distinct pupillary metrics in response to light stimulation. These included percent diameter change (DC), constriction curve area (CCA), which measures change in diameter over time, and the phase-plane curve area (PCA) which measures change in diameter with change in velocity. Direct and consensual response ratios (for each eye) were computed and analyzed for each metric in response to both the first flash (i.e. first phase) and second flash (i.e. second phase) of the 'swinging flashlight' test. RESULTS: Second flash pupillary response metric asymmetry ratios yielded the highest discriminatory power for RAPD detection. Receiver operating characteristic areas under the curve for each of the pupillary metric response asymmetry ratios were as follows: diameter change: 0.97; constriction curve area: 0.96; phase-plane curve area: 0.95 (p<0.0001 for all comparisons compared to normal subjects). The sum of these three squared ratios (SSR) yielded a combined metric with the greatest discriminatory power (receiver operator characteristic area under the curve=0.99). CONCLUSIONS: Second flash (i.e. the second phase of the swinging light test) pupillary metric response asymmetry ratios are highly sensitive and specific for the confirmation and characterization of an RAPD in patients with MS. This objective neurophysiologic method may be useful for studying the relationship between a stereotyped reflex, and nervous system architecture, with potential ramifications for detecting and monitoring neuroprotective and restorative effects of novel agents in MS treatment trials.

BACKGROUND:: In cases of progressive optic neuropathy, diagnostic uncertainty often persists despite extensive work-up. Optic nerve biopsy (ONB) can be considered, especially when visual decline of the affected or fellow eye ensues despite empiric therapy. We aimed to evaluate both diagnostic and therapeutic utilities of ONB based on the long-term experience at a tertiary care institution. METHODS:: This was a retrospective chart review of biopsies over 20 years at a single institution involving intrinsic or adherent optic nerve masses. Main outcome measures included the impact of tissue sampling on reaching a diagnosis and on guiding treatment. Secondary measures included vision in the eye of the ONB and the fellow eye. RESULTS:: Fifteen patients with a mean age of 51.7 +/- 17.4 years underwent biopsies. At the time of biopsy, visual acuity was no light perception in 8 (53%) eyes, light perception to counting fingers in 5 (33%), and 20/400 or better in 2 (13%). The fellow eye of 7 patients (47%) experienced some degree of sequential vision loss before biopsy. Seven specimens included en bloc biopsy of the nerve, 7 contained the dural sheath (usually with a portion of the optic nerve), and 1 only of the compressive mass. Six patients (40%) had tumors. Six of 8 inflammatory lesions biopsied required further clinical data to arrive at specific diagnoses. In one case, a clinical diagnosis could not be made. No patients experienced further vision loss in the fellow eye at last follow-up (median, 8 months). CONCLUSIONS:: In diverse circumstances of progressive optic neuropathy, ONB can be beneficial in establishing the diagnosis. ONB can help direct specific local or systemic treatment, particularly when infectious or inflammatory etiologies are identified. ONB, if considered early in the disease course, can potentially halt or prevent vision loss when the fellow eye is threatened.

BACKGROUND: Microcystic macular oedema (MMO) of the retinal inner nuclear layer (INL) has been identified in patients with multiple sclerosis (MS) by use of optical coherence tomography (OCT). We aimed to determine whether MMO of the INL, and increased thickness of the INL are associated with disease activity or disability progression. METHODS: This retrospective study was done at the Johns Hopkins Hospital (Baltimore, MD, USA), between September, 2008, and March, 2012. Patients with MS and healthy controls underwent serial OCT scans and clinical assessments including visual function. OCT scanning, including automated intraretinal layer segmentation, yielded thicknesses of the retinal nerve fibre layer, the ganglion cell layer plus inner plexiform layer, the INL plus outer plexiform layer (the combined thickness of these layers was used as a surrogate measure of INL thickness), and the outer nuclear layer. Patients with MS also underwent annual brain MRI scans. Disability scores were compared with the Wilcoxon rank-sum test. Mixed-effects linear regression was used to compare OCT measures and letter-acuity scores. Logistic regression was used to examine the relations of baseline OCT thicknesses with clinical and radiological parameters. FINDINGS: 164 patients with MS and 60 healthy controls were assessed. Mean follow-up was 25.8 months (SD 9.1) for patients with MS and 22.4 months (11.4) for healthy controls. Ten (6%) patients with MS had MMO during at least one study visit; MMO was visible at baseline in four of these patients. Healthy controls did not have MMO. Patients with MS and MMO had higher baseline MS severity scores (median 5.93 [range 2.44-8.91]) than those who did not have MMO at any time during the study (151 patients; 3.81 [0.13-9.47]; p=0.032), although expanded disability status scale (EDSS) scores were not significantly different (5.2 [1.0-6.5] for patients with MS and MMO vs 2.5 [0.0-8.0] for those without MMO; p=0.097). The eyes of patients with MS and MMO (12 eyes) versus those without MMO (302 eyes) had lower letter-acuity scores (100% contrast, p=0.017; 2.5% contrast, p=0.031; 1.25% contrast, p=0.014), and increased INL thicknesses (p=0.003) at baseline. Increased baseline INL thickness in patients with MS was associated with the development of contrast-enhancing lesions (p=0.007), new T2 lesions (p=0.015), EDSS progression (p=0.034), and relapses in patients with relapsing-remitting MS (p=0.008) during the study. MMO was not associated with disease activity during follow-up. INTERPRETATION: Increased INL thickness on OCT is associated with disease activity in MS. If this finding is confirmed, INL thickness could be a useful predictor of disease progression in patients with MS. FUNDING: National Multiple Sclerosis Society, National Eye Institute, Braxton Debbie Angela Dillon and Skip Donor Advisor Fund.

Due to the recent focus on concussion in sports, a number of tests have been developed to diagnose and manage concussion. While each test measures different brain functions, no single test has been shown to quickly and reliably assess concussion in all cases. In addition, most of the current concussion tests have not been validated by scientific investigation. This review identifies the pros and cons of the most commonly used noninvasive tests for concussion in order to provide a more complete picture of the resources that are available for concussion testing. The potential utility of research tools such as the head impact telemetry system, advanced magnetic resonance imaging protocols, and biomarkers are discussed in the context of the currently employed tools.

Macular optical coherence tomography (OCT) segmentation, enabling quantification of retinal axonal and neuronal subpopulations, may help elucidate the neuroretinal pathobiology of multiple sclerosis (MS). This study aimed to determine the agreement, reproducibility, and visual correlations of retinal layer thicknesses measured by different OCT segmentation techniques, on two spectral-domain OCT devices. Macular scans of 52 MS patients and 30 healthy controls from Spectralis OCT and Cirrus HD-OCT were segmented using fully manual (Spectralis), computer-aided manual (Spectralis and Cirrus), and fully automated (Cirrus) segmentation techniques. Letter acuity was recorded. Bland-Altman analyses revealed low mean differences across OCT segmentation techniques on both devices for ganglion cell + inner plexiform layers (GCIP; 0.76-2.43 mum), inner nuclear + outer plexiform layers (INL + OPL; 0.36-1.04 mum), and outer nuclear layers including photoreceptor segment (ONL + PR; 1.29-3.52 mum) thicknesses. Limits of agreement for GCIP and ONL + PR thicknesses were narrow. Results of fully manual and computer-aided manual segmentation were comparable to those of fully automated segmentation. MS patients demonstrated macular RNFL, GCIP, and ONL + PR thinning compared to healthy controls across OCT segmentation techniques, irrespective of device (p < 0.03 for all). Low-contrast letter acuity in MS correlated significantly and more strongly with GCIP than peripapillary RNFL thicknesses, regardless of the segmentation method or device. GCIP and ONL + PR thicknesses, measured by different OCT devices and segmentation techniques, are reproducible and agree at the individual and cohort levels. GCIP thinning in MS correlates with visual dysfunction. Significant ONL + PR thinning, detectable across OCT segmentation techniques and devices, strongly supports ONL pathology in MS. Fully automated, fully manual and computer-assisted manual OCT segmentation techniques compare closely, highlighting the utility of accurate and time-efficient automated segmentation outcomes in MS clinical trials.

OBJECTIVE:To test the hypothesis that patients with multiple sclerosis (MS) with intereye asymmetry on low contrast letter acuity, and thickness of the retinal nerve fiber layer (RNFL), would exhibit corresponding changes in cortical timing and amplitude responses on pattern reversal multifocal visual evoked potentials (mfVEP), contingent upon variable stimulus contrast. METHODS:In a cross-sectional study, we investigated a cohort of 11 normal subjects and 40 patients with MS, 21 of whom had a history of acute optic neuritis (MS-AON) with an intereye asymmetry with respect to RNFL thickness, and on low contrast letter acuity performance. Pattern reversal mfVEP was performed at high (100%), low (33.3%), and very low (14.2%) Michelson-contrast levels. RESULTS:Compared to baseline measures at 100% contrast, the mean amplitude of the mfVEP was reduced in MS-AON eyes, upon pattern-reversal stimulation at the 2 lower contrast levels (p < 0.0001). With respect to changes in timing responses, the intereye asymmetry was increased in the MS-AON patients upon lower contrast pattern-reversal stimulation (p < 0.0001 for 33.3% compared to 100%, and p < 0.001 for 14.2% compared to 100%). The fellow eye in 12 (57%; p < 0.001) of the patients with an abnormal eye, and a history of AON, revealed abnormal amplitude and timing responses upon low contrast stimulation (signifying unmasking of occult damage). CONCLUSIONS:Our findings support the hypothesis that mfVEP metric abnormalities are contingent upon contrast magnitude during pattern reversal stimulation. Further, this paradigm was capable of unmasking occult abnormalities in a significant number of apparently unaffected eyes.

OBJECTIVE: Low-contrast letter acuity has demonstrated treatment effects for sustained visual loss in trials of natalizumab for relapsing multiple sclerosis (MS). To test new therapies that may involve neuroprotection and repair, it will be essential for outcome measures to detect improvement as well as loss of visual function. We determined the effects of natalizumab on the frequency and cumulative probability of visual improvement using low-contrast letter acuity a prespecified tertiary outcome measure in AFFIRM. METHODS: AFFIRM was a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated efficacy and safety of natalizumab (n=627) vs. placebo (n=315) in relapsing-remitting MS. Binocular acuities were measured at low-contrast (1.25%, 2.5%) and high-contrast visual acuity (VA). Improvement was defined as 12-week sustained increases from baseline. Clinically meaningful change for primary analyses was pre-defined as 7-letter improvement for low-contrast acuity and 5-letter improvement for VA based upon previous studies. RESULTS: Compared to placebo, cumulative probabilities of sustained visual improvement were greater in the natalizumab group by 57% for 2.5% contrast (21.7% vs. 14.0%; HR=1.57; 95% CI: 1.11-2.22; P=0.012) and 39% for 1.25% contrast (32.5% vs. 25.0%; HR=1.39; 95% CI: 1.07-1.82; P=0.014). The 5- and 10-letter low-contrast assessments did not show treatment differences. High-contrast VA was insensitive to changes over time and treatment effects. CONCLUSION: Low-contrast letter acuity detected treatment effects on sustained visual improvement in patients with relapsing MS. The ability to detect visual improvement and loss makes low-contrast acuity an important measure for future trials assessing the impact of therapy on this outcome and the potential of a therapy for neuroprotection and repair.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.

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 (200x200 or 512x128) and ONH Cube 200x200 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