Observational study of subclinical diabetic macular edema.

PURPOSE: To determine the rate of progression of eyes with subclinical diabetic macular edema (DME) to clinically apparent DME or DME necessitating treatment during a 2-year period. METHODS: In all, 43 eyes from 39 study participants with subclinical DME, defined as absence of foveal center edema as determined with slit lamp biomicroscopy but a center point thickness (CPT) between 225 and 299 µm on time domain (Stratus, Carl Zeiss Meditec) optical coherence tomography (OCT) scan, were enrolled from 891 eyes of 582 subjects screened. Eyes were evaluated annually for up to 2 years for the primary outcome, which was an increase in OCT CPT of at least 50 µm from baseline and a CPT of at least 300 µm, or treatment for DME (performed at the discretion of the investigator). RESULTS: The cumulative probability of meeting an increase in OCT CPT of at least 50 µm from baseline and a CPT of at least 300 µm, or treatment for DME was 27% (95% confidence interval (CI): 14%, 38%) by 1 year and 38% (95% CI: 23%, 50%) by 2 years. CONCLUSIONS: Although subclinical DME may be uncommon, this study suggests that between approximately one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification.

Visual function at baseline and 1 month in acute optic neuritis: predictors of visual outcome.

OBJECTIVE: To identify cutpoints for visual measures at baseline and 1 month predictive of abnormal 6-month vision that could be used as eligibility criteria in a clinical trial to test potential neuroprotection or myelin repair agents in patients with optic neuritis. To determine whether moderate-to-severe dysfunction in one or more visual measures at baseline or 1 month correlates with having major vision loss at 6 months. METHODS: We used the Optic Neuritis Treatment Trial database to evaluate various cutpoints for baseline and 1-month vision levels that predicted abnormal 6-month vision. For selected cutpoints, we computed a 95% CI for positive predictive value and the required sample size if the cutpoint was to be used for clinical trial eligibility. We evaluated whether the degree of visual loss at baseline, 1 month, or change in visual function from baseline to 1 month correlated with 6-month visual acuity, contrast sensitivity, or threshold visual field. RESULTS: The best cutpoints for baseline and 1 month were visual acuity

Early retinopathy progression in four randomized trials comparing insulin glargine and NPH [corrected] insulin.

Early worsening of diabetic retinopathy, characterized by cotton wool spots, intraretinal microvascular abnormalities and/or macular edema, can occur following improvement of glycemic control. In four randomized 28- to 52-week clinical trials comparing insulin glargine and NPH insulin in regard to glycemic control and frequency of hypoglycemia, ophthalmologic examinations and fundus photographs were included to assess frequency of early worsening of retinopathy or other early adverse ocular effects. Retinopathy progression rates at 28 weeks were 7-12% by clinical examination and 3-8% by photographic grading; corresponding rates of clinically significant macular edema (CSME) were 1-8% and 1-4%, respectively. Optic disc swelling was not observed clinically or in photographs. Two of the 24 possible comparisons (four trials, three outcomes, two assessment methods), both of which were photographic assessments in type 2 diabetes, were in/near the nominally significant range and favored NPH insulin: 28-week rates of >or=3-step retinopathy progression (insulin glargine: 16/213, 7.5%; NPH insulin: 6/220, 2.7%; p=0.028) and 52-week CSME rates (26/233, 11.2% and 14/214, 6.5%, respectively; p=0.098). Because the between-treatment differences were small and inconsistent across trials and assessment methods, and because overall rates were consistent with the natural course of diabetic retinopathy, we conclude that it is unlikely that insulin glargine carries a higher risk of early worsening or other early adverse effect than NPH insulin. These trials tended to exclude a large early adverse effect, such as optic disc swelling, but cannot assess longer-term effects; a 5-year randomized trial of insulin glargine versus NPH insulin has been initiated. Data from this manuscript have been presented as posters and published in abstract form at the European Association for the Study of Diabetes 2001 ( DIABETOLOGIA 44(Suppl 1):I-IV(A287), 2001) and the Latin American Diabetes Association 2001 (11-15 November 2001, Punta del Este, Uruguay; Poster 180) congresses.

Computerized method of visual acuity testing: adaptation of the amblyopia treatment study visual acuity testing protocol.

PURPOSE: To report a computerized method for determining visual acuity in children using the Amblyopia Treatment Study visual acuity testing protocol. METHODS: A computerized visual acuity tester was developed that uses a programmed handheld device that uses the Palm operating system (Palm, Inc, Santa Clara, California). The handheld device communicates with a personal computer running a Linux operating system and 17-inch monitor. At a test distance of 3 m, single letters can be displayed from 20/800 to 20/12. A C program on the handheld device runs the Amblyopia Treatment Study visual acuity testing protocol. Using this method, visual acuity was tested in both the right and left eyes, and then the testing was repeated in 156 children age 3 to 7 years at four clinical sites. RESULTS: Test-retest reliability was high (r =.92 and 0.95 for and right and left eyes, respectively), with 88% of right eye retests and 94% of left eye retests within 0.1 logarithm of minimal angle of resolution (logMAR) units of the initial test. The 95% confidence interval for an acuity score was calculated to be the score +/- 0.13 logMAR units. For a change between two acuity scores, the 95% confidence interval was the difference +/- 0.19 logMAR units. CONCLUSIONS: We have developed a computerized method for measurement of visual acuity. Automation of the Amblyopia Treatment Study visual acuity testing protocol is an effective method of testing visual acuity in children 3 to 7 years of age.

Amblyopia. Current clinical studies.

Over the next two years, results from several multi-center amblyopia treatment studies will become available. These data may have a profound influence on our approach to treating this condition. This is indeed an exciting time to be taking care of children with amblyopia, as we anticipate the results of these studies.

The amblyopia treatment study visual acuity testing protocol.

OBJECTIVE: To evaluate the reliability of a new visual acuity testing protocol for children using isolated surrounded HOTV optotypes. METHODS: After initial pilot testing and modification, the protocol was evaluated using the Baylor-Video Acuity Tester (BVAT) to present isolated surrounded HOTV optotypes. At 6 sites, the protocol was evaluated for testability in 178 children aged 2 to 7 years and for reliability in a subset of 88 children. Twenty-eight percent of the 178 children were classified as having amblyopia. RESULTS: Using the modified protocol, testability ranged from 24% in 2-year-olds to 96% in 5- to 7-year-olds. Test-retest reliability was high (r = 0.82), with 93% of retest scores within 0.1 logMAR unit of the initial test score. The 95% confidence interval for an acuity score was calculated to be the score +/-0.125 logMAR unit. For a change between 2 acuity scores, the 95% confidence interval was the difference +/-0.18 logMAR unit. CONCLUSIONS: The visual acuity protocol had a high level of testability in 3- to 7-year-olds and excellent test-retest reliability. The protocol has been incorporated into the multicenter Amblyopia Treatment Study and has wide potential application for standardizing visual acuity testing in children.

The Amblyopia Treatment Index.

OBJECTIVE: To develop a questionnaire to assess the acceptability of amblyopia treatment and its effect on the child and family. METHODS: A 20-item parental survey was developed and pilot tested on 64 subjects, aged 3 to 6 years, participating in the Amblyopia Treatment Study, a randomized trial comparing patching and atropine as treatments for moderate amblyopia. The survey was administered after 4 weeks of treatment. A descriptive item analysis and an internal consistency reliability analysis were performed. RESULTS: Nineteen of the 20 items demonstrated adequate variability as evidenced by the frequency distributions for item responses. Only 4 (<1%) of 1280 possible item responses were missing, one each by 4 different respondents. Factor analysis identified 3 treatment-related factors--"adverse effects," "compliance," and "social stigma"--among 11 of the 20 items. The internal-consistency reliability alpha for the 5-item adverse effects subscale was 0.82, the 4-item compliance subscale alpha was 0.81, and the 2-item social stigma subscale alpha was 0.84. CONCLUSIONS: The Amblyopia Treatment Index appears to be a useful instrument for assessing the impact of amblyopia treatment in 3- to 6-year-old children.

The SKILL Card test in optic neuritis: experience of the Optic Neuritis Treatment Trial. Smith-Kettlewell Institute Low Luminance. Optic Neuritis Study Group.

OBJECTIVES: To assess the value of the Smith-Kettlewell Institute Low Luminance (SKILL) Card test, designed to measure vision at reduced contrast and luminance, among patients with previous optic neuritis. MATERIALS AND METHODS: The SKILL Card test was administered to 295 patients participating in the Optic Neuritis Treatment Trial (ONTT) follow-up study, concurrent with measurement of visual acuity, visual field, contrast sensitivity, and color vision. Health-related quality of life (HRQL) was also assessed in a subset of patients using the National Eye Institute Visual Function Questionnaire and an ONTT-developed questionnaire. RESULTS: The SKILL Card difference score (high-contrast acuity score minus low-contrast acuity score) was only weakly associated with the other measures of vision function (rs absolute range, 0.05-0.31) and with the HRQL measures (rs absolute range, 0.02-0.15). In contrast, the light and dark component scores of the SKILL Card test had higher associations with the other vision measures (rs absolute range, 0.27-0.54) and with the HRQL measures (rs absolute range, 0.10-0.40). CONCLUSIONS: The SKILL Card difference score is not a meaningful measure for patients with optic neuritis; however, the test appears to have clinical usefulness as a method to measure high-contrast and low-contrast acuity.

Predictors of nonrecovery in acute traumatic sixth nerve palsy and paresis.

PURPOSE: To evaluate whether nonrecovery from acute traumatic sixth nerve palsy could be predicted from demographic factors or palsy characteristics. DESIGN: Prospective, observational case series SETTING: Multicenter (academic and private practices). OUTCOME MEASURE: Nonrecovery, defined as the presence of diplopia in primary position or more than 10 prism diopters of distance esotropia in primary position at 6 months after onset. METHODS: Using data from a previously described cohort of 84 eligible patients with acute traumatic sixth nerve palsy, we performed multivariate analyses of demographic factors and palsy characteristics. RESULTS: Nonrecovery at 6 months after onset was associated with a complete palsy (adjusted risk ratio, 9.11; 95% confidence interval [CI], 2.77-14.84) and with a bilateral palsy or paresis (adjusted risk ratio, 2.53; 95% CI, 0.98-4.29). The choice of conservative management (observation, prism, or patch) versus acute injection of Botulinum toxin (within 3 months of injury) did not influence final recovery. CONCLUSIONS: In acute traumatic sixth nerve palsy or paresis, failure to recover by 6 months after onset was associated independently with inability to abduct past midline at presentation and bilaterality. Although the overall recovery rate is high in acute traumatic sixth nerve palsy or paresis, a complete or bilateral case has a poor prognosis and is more likely to need strabismus surgery.

Recall bias in a prospective cohort study of acute time-varying exposures: example from the herpetic eye disease study.

Recall bias is possible in a prospective cohort study when exposure status is transient and must be periodically recalled, and ascertainment occurs after symptom onset. We know of no published demonstration of such bias at play in a prospective cohort study. In a substudy of a randomized clinical trial, 308 participants were prospectively followed to investigate potential acute triggers of ocular herpes simplex virus (HSV) recurrences. Participants reported on the presence of systemic infection or high psychological stress (exposures) on a home log that was completed weekly for up to 15 months and mailed to the study's coordinating centers. By protocol, exposure reporting was to occur on the last day of the week (Sunday) so that a prospective 1-week lag period between exposure and outcome in the following week could be assessed. The study outcome was development of a recurrence of ocular HSV disease documented by clinical examination. Using 35 weekly reports of exposure properly completed before the week of an outcome, there was no evidence of higher risk of HSV recurrence associated with systemic infection (rate ratio = 0.62, 95% confidence interval [CI]: 0.19-2.02) or high psychological stress rate (ratio = 0.0, 95% CI: 0.0-undefined). In contrast, when the analysis was based on 26 weekly reports of exposure improperly completed on or after the date of outcome, the risk of recurrence associated with systemic infection was estimated to be 4-fold (rate ratio = 4.07, 95% CI: 1.84-8.98), and there was a suggestion of a 2-fold risk associated with high psychological stress (rate ratio = 2.02, 95% CI: 0.69-5.91). Without real-time monitoring of exposure reporting, preservation of the temporal exposure-disease relationship-an implicit assumption of the prospective cohort study design-may be particularly tenuous when transient exposures are investigated longitudinally.

Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group.

BACKGROUND: Treatment with interferon beta has been shown to help patients with established multiple sclerosis, but it is not known whether initiating treatment at the time of a first clinical demyelinating event is of value. METHODS: We conducted a randomized, double-blind trial of 383 patients who had a first acute clinical demyelinating event (optic neuritis, incomplete transverse myelitis, or brain-stem or cerebellar syndrome) and evidence of prior subclinical demyelination on magnetic resonance imaging (MRI) of the brain. After initial treatment with corticosteroids, 193 patients were randomly assigned to receive weekly intramuscular injections of 30 microg of interferon beta-1a and 190 were assigned to receive weekly injections of placebo. The study end points were the development of clinically definite multiple sclerosis and changes in findings on MRI of the brain. The trial was stopped after a preplanned interim efficacy analysis. RESULTS: During three years of follow-up, the cumulative probability of the development of clinically definite multiple sclerosis was significantly lower in the interferon beta-1a group than in the placebo group (rate ratio, 0.56; 95 percent confidence interval, 0.38 to 0.81; P=0.002). As compared with the patients in the placebo group, patients in the interferon beta-1a group had a relative reduction in the volume of brain lesions (P<0.001), fewer new or enlarging lesions (P<0.001), and fewer gadolinium-enhancing lesions (P<0.001) at 18 months. CONCLUSIONS: Initiating treatment with interferon beta-1a at the time of a first demyelinating event is beneficial for patients with brain lesions on MRI that indicate a high risk of clinically definite multiple sclerosis.

Botulinum toxin treatment versus conservative management in acute traumatic sixth nerve palsy or paresis.

PURPOSE: Botulinum toxin (BTX), injected into the ipsilateral medial rectus muscle, has been advocated for the management of acute traumatic sixth nerve palsy or paresis. We conducted a multicenter, nonrandomized, data collection study to evaluate recovery rates of patients treated with either conservative measures or BTX. METHODS: All members of the American Association for Pediatric Ophthalmology and Strabismus and the North American Neuro-Ophthalmology Society were invited to enroll patients with acute traumatic sixth nerve palsy or paresis during a 2-year period (between March 1996 and February 1998). The BTX group was defined as patients who received a BTX injection within 3 months of injury. Recovery at 6 months from injury was defined as absence of diplopia in the primary position and a distance esotropia of no more than 10 PD in the primary position. Nonrecovered patients with less than 6 months of follow-up (n = 15) were excluded. RESULTS: Eighty-four eligible patients were enrolled by 46 investigators. Sixty-two patients (74%) were treated conservatively and 22 (26%) with BTX. Sixty-two patients (74%) had unilateral palsy, and 22 (26%) had bilateral palsy. Recovery rates were similar between BTX and conservatively treated patients (overall: 73% vs 71%, P = 1.0; unilateral: 81% vs 83%, P = 1.0; bilateral: 50% vs 38%, P = 0.66, respectively). CONCLUSIONS: In this prospective multicenter study of acute traumatic sixth nerve palsy or paresis, patients treated with either BTX or conservative measures had similar high recovery rates.

Interaction between HLA-DR2 and abnormal brain MRI in optic neuritis and early MS. Optic Neuritis Study Group.

The association of the human leukocyte antigen (HLA)-DR2 allele with brain MRI signal abnormalities and with the development of MS was assessed in 178 patients enrolled in the Optic Neuritis Treatment Trial. HLA haplotype DR2 was present in 85 (48%) of the 178 patients. Its presence was associated with increased odds of probable or definite MS at 5 years (odds ratio, 1.92; 95% confidence interval, 1.01 to 3.67; p = 0.04). The association was most apparent among patients with signal abnormalities on baseline brain MRI.

The National Eye Institute Visual Function Questionnaire: experience of the ONTT. Optic Neuritis Treatment Trial.

PURPOSE: To describe the health-related quality of life, measured with the National Eye Institute Visual Function Questionnaire (NEI-VFQ), of patients several years after the onset of optic neuritis, according to their neurologic and visual status; to assess the relationship between the NEI-VFQ subscales and clinical measures of visual function; and to assess the internal consistency reliability of the NEI-VFQ subscales. METHODS: The NEI-VFQ was administered to 244 patients 5 to 8 years after treatment for an episode of acute optic neuritis as part of the Optic Neuritis Treatment Trial. Visual acuity, visual field, contrast sensitivity, and color vision were measured at the same time as questionnaire completion. RESULTS: The NEI-VFQ scores generally were lower than those reported for a disease-free group. Reported dysfunction was greater when multiple sclerosis was present and when visual acuity was abnormal, supporting the construct validity of the NEI-VFQ. Rank correlations between the NEI-VFQ subscales and clinical measures of visual function were moderate at best. Internal consistency reliability was generally high for most of the NEI-VFQ subscales. CONCLUSIONS: These findings add support to the use of the NEI-VFQ as a valuable measure of self-reported visual impairment.

Comparison of central and peripheral visual field properties in the optic neuritis treatment trial.

PURPOSE: To compare the results of peripheral kinetic visual field testing and central static perimetry for patients enrolled in the Optic Neuritis Treatment Trial to determine (1) whether loss and recovery of visual field sensitivity in the far periphery was different from that observed in the central visual field and (2) whether the far peripheral visual field provided additional useful information that was not available in the central visual field results. METHODS: Both affected and fellow eyes of 448 patients with optic neuritis in the Optic Neuritis Treatment Trial were evaluated according to the trial protocol during the patients' first 3 years in the study. Central static visual field tests were performed with program 30-2 on the Humphrey Field Analyzer, and peripheral kinetic testing consisted of plotting the I3e and II4e isopters on the Goldmann perimeter. Both test procedures were conducted according to the trial protocols, and quality control assessments and clinical evaluations were performed on all the visual fields. RESULTS: For both affected and fellow eyes at all 11 visits, there was a greater number of abnormal visual fields in the central static perimetry results than in the peripheral kinetic data. Only 2.9% of affected eyes had an abnormal peripheral visual field with a normal Humphrey mean deviation during year 1. At baseline, 97.1% of affected eyes had an abnormal Humphrey mean deviation on central static testing, whereas only 69.9% had abnormal peripheral kinetic visual fields. Approximately 80% of the I3e and II4e isopters for affected eyes that were abnormal at baseline were within normal limits at 30 days, but it took until week 19 for even 70% of the Humphrey mean deviations to return to normal. In addition, the II4e isopters (more peripheral than the I3e isopters) that were abnormal at baseline showed a somewhat greater percentage of improvement from baseline through day 30 than the abnormal I3e isopters. Although this difference is statistically significant, it is probably not clinically significant. For visits after week 19, approximately 25% to 30% of affected eyes had an abnormal Humphrey mean deviation, whereas only 10% to 15% of peripheral kinetic fields were abnormal. CONCLUSIONS: For the affected eye in optic neuritis, the central visual field shows greater abnormalities than the far peripheral visual field. When the results obtained through Humphrey automated central static visual fields and Goldmann peripheral kinetic isopters are compared, the far periphery appears to recover more rapidly and more completely than the central field, at least in more severe cases of optic neuritis. In most cases, recovery in optic neuritis can probably be monitored effectively with automated perimetry of the central visual field alone. However, in cases of severe loss of the central visual field, a peripheral kinetic visual field obtained with a Goldmann perimeter may provide additional information about the patient's vision in the far periphery.