Faculty Bibliography

PURPOSE: To examine the relation of visual function to retinal nerve fiber layer (RNFL) thickness as a structural biomarker for axonal loss in multiple sclerosis (MS), and to compare RNFL thickness among MS eyes with a history of acute optic neuritis (MS ON eyes), MS eyes without an optic neuritis history (MS non-ON eyes), and disease-free control eyes. DESIGN: Cross-sectional study. PARTICIPANTS: Patients with MS (n = 90; 180 eyes) and disease-free controls (n = 36; 72 eyes). METHODS: Retinal never fiber layer thickness was measured using optical coherence tomography (OCT; fast RNFL thickness software protocol). Vision testing was performed for each eye and binocularly before OCT scanning using measures previously shown to capture dysfunction in MS patients: (1) low-contrast letter acuity (Sloan charts, 2.5% and 1.25% contrast levels at 2 m) and (2) contrast sensitivity (Pelli-Robson chart at 1 m). Visual acuity (retroilluminated Early Treatment Diabetic Retinopathy charts at 3.2 m) was also measured, and protocol refractions were performed. MAIN OUTCOME MEASURES: Retinal nerve fiber layer thickness measured by OCT, and visual function test results. RESULTS: Although median Snellen acuity equivalents were better than 20/20 in both groups, RNFL thickness was reduced significantly among eyes of MS patients (92 mum) versus controls (105 mum) (P<0.001) and particularly was reduced in MS ON eyes (85 mum; P<0.001; accounting for age and adjusting for within-patient intereye correlations). Lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 mum. CONCLUSIONS: Scores for low-contrast letter acuity and contrast sensitivity correlate well with RNFL thickness as a structural biomarker, supporting validity for these visual function tests as secondary clinical outcome measures for MS trials. These results also suggest a role for ocular imaging techniques such as OCT in trials that examine neuroprotective and other disease-modifying therapies. Although eyes with a history of acute optic neuritis demonstrate the greatest reductions in RNFL thickness, MS non-ON eyes have less RNFL thickness than controls, suggesting the occurrence of chronic axonal loss separate from acute attacks in MS patients.

Although several neuroprotective agents have been proposed as potential therapies in Friedreich ataxia (FA), clinical trials of their efficacy are limited by a lack of sensitive outcome measures. We assessed whether performance measures (nine-hole peg test, the timed 25-foot walk, and low-contrast letter acuity) provide valid measures of disease status in FA. Scores for each measure correlated significantly with neurologic disability and disease duration. Rank correlations between scores for performance measures were moderate in magnitude, suggesting that the each test captures separate yet related dimensions of neurological function in FA. Linear regression models demonstrated that scores from the nine-hole peg test and the timed 25-foot walk (after reciprocal transformation) were predicted by age and triplet repeat length in patients with FA. In addition, comparison of the temporal courses of change for each performance measure demonstrated that scores from the timed 25-foot walk change early in the course of FA, nine-hole peg test scores change slowly over the full course of the disorder, and low-contrast letter acuity scores change in the later stages of the disease. Thus, a composite scale derived from these performance measures may provide the best overall measure for assessing disease progression throughout the illness.

OBJECTIVE: To evaluate concurrent and predictive validity for low-contrast letter acuity (L-CLA) testing as a candidate visual component for the Multiple Sclerosis Functional Composite (MSFC). METHODS: L-CLA testing was conducted in two MS patient cohorts. In the MSFC Validation Study, 137 participants from a Phase III trial of inteferon beta-1a (Avonex) for relapsing-remitting MS were followed. A second cohort included 65 patients with secondary progressive MS who participated in a substudy of the International MS Secondary Progressive Avonex Controlled Trial (IMPACT). The total number of letters read correctly at four contrast levels (100, 5, 1.25, and 0.6%) was correlated with Expanded Disability Status Scale (EDSS), MSFC, Sickness Impact Profile, Multiple Sclerosis Quality of Life Inventory, and brain parenchymal fraction (BPF), as determined by MRI. RESULTS: Low- and high-contrast letter acuity scores correlated with BPF at follow-up in the MSFC Validation Study (5%: r = 0.40, p < 0.0001; 100%: r = 0.31, p = 0.0002). L-CLA also correlated with EDSS (5%: r = -0.35, p < 0.0001; 1.25%: r = -0.26, p = 0.0003) and MSFC (5%: r = 0.47, p < 0.0001; 1.25%: r = 0.45, p < 0.0001). In the IMPACT Substudy, change in L-CLA scores from baseline to year 1 predicted subsequent change in the EDSS from year 1 to 2 at the 5% (p = 0.0142) and the 1.25% (p = 0.0038) contrast levels, after adjusting for change in MSFC scores from baseline to year 1. CONCLUSIONS: Low-contrast letter acuity (L-CLA) scores demonstrate concurrent and predictive validity in patients with relapsing-remitting and secondary progressive multiple sclerosis (MS). L-CLA testing provides additional information relevant to the MS disease process that is not entirely captured by the Multiple Sclerosis Functional Composite.

Endocrine and metabolic disorders that cause neuro-ophthalmologic manifestations are frequently encountered by ophthalmologists in clinical practice. This review focuses on three of the most common entities for which neuro-ophthalmologic signs and symptoms are a prominent feature. These entities include pituitary disorders (adenoma, apoplexy, and hypophysitis), thyroid-associated ophthalmopathy, and neuro-ophthalmologic complications of diabetes mellitus, such as ischemic ocular motor mononeuropathies and diabetic papillopathy.

The role for immediate neuroimaging in patients 50 years of age or older with acute isolated third, fourth, and sixth nerve palsies is controversial. We prospectively evaluated 66 patients, aged 50 years and older (median 67 years, range 50-85), with acute isolated ocular motor mononeuropathies. Our purpose was to evaluate both the role of neuroimaging and the role of clinical assessment in determining etiology. We found that clinical features, including time to maximal diplopic symptoms, were not predictive of etiology (median 2 days to maximal diplopic symptoms for both peripheral microvascular and other etiologies). The presence of any common vascular risk factor, including diabetes mellitus, hypertension, hypercholesterolemia, or coronary artery disease, was significantly associated with peripheral microvascular etiology in this cohort (p=0.0004, Fisher's exact test). Despite the high prevalence of peripheral microvascular ischemia as an etiology in this age group, other causes were identified by magnetic resonance imaging (MRI) or computed tomography (CT) scanning in 14% of patients. Diagnoses included brainstem and skull base neoplasms, brainstem infarcts, aneurysms, demyelinating disease, and pituitary apoplexy. Neuroimaging procedures may have a role in the initial evaluation of patients 50 years of age or older with acute ocular motor mononeuropathies.

Patients with a suspected diagnosis of giant cell arteritis (GCA) should be started on high-dose corticosteroid therapy without delay. A temporal artery biopsy should be performed after initiation of therapy to confirm the diagnosis. Patients with acute visual or neurologic symptoms present a neuro-ophthalmic emergency. Therapy should be initiated immediately with high-dose intravenous methylprednisolone sodium succinate and followed by high-dose oral prednisone. Treatment may begin with high-dose oral prednisone in patients without visual or neurologic symptoms. Calcium, vitamin D, and peptic ulcer prophylaxis should accompany steroid therapy, as indicated. The following treatments should be considered for patients with suspected GCA and acute visual or neurologic signs or symptoms: intravenous methylprednisolone sodium succinate (250 mg intravenously every 6 hours) should be given for 3 days, followed by oral prednisone (80 mg per day or 1 mg/kg) for 4 to 6 weeks. Prednisone should then be tapered by 10 mg per day every month. Most patients require 1 year of therapy to avoid relapse. Taper and duration should be modified according to erythrocyte sedimentation rate, C-reactive protein, and signs and symptoms of GCA. Rheumatologic consultation and follow-up is often helpful for these patients. For patients with suspected GCA and no acute visual or neurologic signs or symptoms, therapy may begin directly with oral prednisone (80 mg per day or 1 mg/kg) with same taper and duration based on laboratory values and clinical signs and symptoms.

BACKGROUND: Sensitivity of confrontation visual field (CVF) screening is low unless defects are significant. We compared the sensitivity of laser pointer visual field screening (LVF) with conventional CVF for identifying eyes with abnormal automated perimetry. METHODS: Ninety consecutive patients presenting for HVF prospectively underwent a masked comparison of CVF and LVF testing (175 eyes) from April to May 2000. LVF was performed using a laser pointer target projected onto a tangent screen. Points were tested in random fashion on either side of the vertical and horizontal meridians, near central fixation, around the blind spot, and in each quadrant. Single and double simultaneous finger counting was used to test CVF. RESULTS: LVF demonstrated significantly greater sensitivity as compared with CVF (73% versus 31%, P = 0.001) in identifying field defects found on HVF. Specificities for LVF and CVF were 82% and 99%, respectively. The average testing times per eye were 0.5 minute for CVF, 1.5 minutes for LVF, and 8.0 minutes for HVF. CONCLUSIONS: In this cohort, laser visual field testing was significantly more sensitive than confrontation testing. It may represent an effective, time-efficient tool for visual field screening.