Gary S. Rubin

Effect of Gene Therapy on Visual Function in Leber's Congenital Amaurosis

Early-onset, severe retinal dystrophy caused by mutations in the gene encoding retinal pigment epithelium-specific 65-kD protein (RPE65) is associated with poor vision at birth and complete loss of vision in early adulthood. We administered to three young adult patients subretinal injections of recombinant adeno-associated virus vector 2/2 expressing RPE65 complementary DNA (cDNA) under the control of a human RPE65 promoter. There were no serious adverse events. There was no clinically significant change in visual acuity or in peripheral visual fields on Goldmann perimetry in any of the three patients. We detected no change in retinal responses on electroretinography. One patient had significant improvement in visual function on microperimetry and on dark-adapted perimetry. This patient also showed improvement in a subjective test of visual mobility. These findings provide support for further clinical studies of this experimental approach in other patients with mutant RPE65. (ClinicalTrials.gov number, NCT00643747 [ClinicalTrials.gov].).

Falls and Fear of Falling: Which Comes First? A Longitudinal Prediction Model Suggests Strategies for Primary and Secondary Prevention

OBJECTIVES: Previous cross‐sectional studies have shown a correlation between falls and fear of falling, but it is unclear which comes first. Our objectives were to determine the temporal relationship between falls and fear of falling, and to see whether these two outcomes share predictors.

Psychophysics of reading-I. Normal vision

This paper is about the visual requirements for reading with normal vision. It is the first in a series devoted to the psychophysics of reading with normal and low vision. We have measured reading rates for text scanned across the face of a TV monitor while varying parameters that are important in current theories of pattern vision. Our results provide estimates of the stimulus parameters required for optimal reading of scanned text. We have found that maximum reading rates are achieved for characters subtending 0.3 degree to 2 degrees. Contrast polarity (black-on-white vs white-on-black text) has no effect. Reading rate increases with field size, but only up to 4 characters, independent of character size. When text is low-pass spatial-frequency filtered, reading rate increases with bandwidth, but only up to two cycles/character, independent of character size. When text is matrix sampled, reading rate increases with sample density, but only up to a critical sample density which depends on character size. The critical sample density increases from about 4 X 4 samples/character for 0.1 degree characters to more than 20 X 20 samples/character for 24 degrees characters. We suggest that one spatial-frequency channel suffices for reading.

Psychophysics of reading--II. Low vision.

Very little is known about the effects of visual impairment on reading. We used psychophysical methods to study reading by 16 low-vision observers. Reading rates were measured for text scanned across the face of a TV monitor while varying parameters that are likely to be important in low vision: angular character size, number of characters in the field, number of dots composing each character, contrast polarity (white-on-black vs black-on-white text), and character spacing. Despite diverse pathologies and degrees of vision loss in our sample, several major generalizations emerged. There is a wide variation in peak reading rates among low-vision observers, but 64% of the variance can be accounted for by two major distinctions: intact central fields vs central-field loss and cloudy vs clear ocular media. Peak reading rates for observers with central-field loss were very low (median 25 words/minute), while peak reading rates for observers with intact central fields were at least 90 words/minute (median 130 words/minute). Most low-vision readers require magnification to obtain characters of optimal size. Sloan M acuity was a better predictor of optimal character size than Snellen acuity, accounting for 72% of the variance. Low-vision reading is similar to normal reading in several respects. For example, both show the same dependence on the number of characters in the field. Our results provide estimates of the best reading performance to be expected from low-vision observers with characteristic forms of vision loss, and the stimulus parameters necessary for optimal performance. These results will be useful in the development of clinical tests of low vision, and in the design of low-vision reading aids.

Psychophysics of reading—V. The role of contrast in normal vision

How does contrast affect reading rate? What is the role of contrast sensitivity? We measured reading rate as a function of the contrast and character size of text for subjects with normal vision. Reading rates were highest (about 350 words/min) for letters ranging in size from 0.25 degree to 2 degrees. Within this range, reading was very tolerant to contrast reduction--for 1 degree letters, reading rate decreased by less than a factor of two for a tenfold reduction in contrast. The results were very similar for white-on-black and black-on-white text. Reading rate declined more rapidly for very small (less than 0.25 degree) and very large (greater than 2 degrees) letters. People with low vision usually require large characters to read, so high contrast is particularly important for them. Taking 35 words/min to be a threshold for reading, we constructed a contrast-sensitivity function (CSF) for reading. We were able to relate the shape of this CSF to the shape of sine-wave grating CSFs.

VISUAL IMPAIRMENT AND DISABILITY IN OLDER ADULTS

Background. Previous studies have reported that reduced visual acuity is associated with functional dependence in older persons. The purpose of this study was to determine whether components of vision impairment besides reduced acuity contribute to reduced functional independence. Methods. Community dwelling adults aged 65 years and older were administered a battery of vision tests including distance acuity, letter contrast sensitivity, disability glare, and stereoacuity. A physical function questionnaire assessed self-reported difficulty with activities of daily living (ADLs), Instrumental activities of daily living (lADLs), and mobility activities. A visual function questionnaire assessed self-reported difficulty with a wide variety of everyday visual activities. Results. Multiple logistic regression analysis showed that reduced acuity and reduced contrast sensitivity were independently associated with an overall vision disability score. Acuity was associated with difficulty in tasks requiring good resolution and adaption to changing light conditions, whereas contrast sensitivity was associated with difficulty in tasks requiring distance judgments, night driving, and mobility. Glare and stereoacuity were not associated with self-reported disability. Conclusions. Reduced acuity and contrast sensitivity are significant risk factors for selfreported disability.

Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease

PURPOSE To study fixation patterns and reading rates in eyes with central scotomas from geographic atrophy (GA) of age-related macular degeneration and to compare fixation patterns with those of patients with Stargardt disease. METHODS Scanning laser ophthalmoscope analysis of fixation patterns in eyes with 20/80 to 20/200 visual acuity. Included were 41 eyes of 35 patients with GA and 10 eyes of 5 patients with Stargardt disease. The patients with GA also were tested for maximum reading rate, and the size of the areas of atrophy were measured by fundus photograph analysis. RESULTS Sixty-three percent of GA eyes fixating outside the atrophy placed the scotoma to the right of fixation in visual field space, 22% placed the scotoma above fixation, and 15% placed it to the left, regardless of the laterality of the GA eye. Fixation was stable in subsequent years of testing for scotoma placement to the right of or above fixation. All GA eyes fixated immediately adjacent to the atrophy. In contrast, seven of ten eyes with Stargardt disease fixated at a considerable distance from the scotoma border, with the dense scotoma far above the fixation site in visual field space. For the patients with GA, the maximum reading rate was highly correlated with size of the atrophic area, but not with age or visual acuity within the limited visual acuity range tested. There was a trend to more rapid reading with the scotoma above fixation and slower reading with the scotoma to the left. CONCLUSION There is a preference for fixation with the scotoma to the right in eyes with GA. Patients with Stargardt disease use different strategies for fixation, perhaps due to subclinical pathology adjacent to the atrophic regions. The size of the atrophic area in GA plays the predominant role in reading rate for eyes that have already lost foveal vision.

Long-term effect of gene therapy on Leber's congenital amaurosis.

BACKGROUND Mutations in RPE65 cause Lebers congenital amaurosis, a progressive retinal degenerative disease that severely impairs sight in children. Gene therapy can result in modest improvements in night vision, but knowledge of its efficacy in humans is limited. METHODS We performed a phase 1-2 open-label trial involving 12 participants to evaluate the safety and efficacy of gene therapy with a recombinant adeno-associated virus 2/2 (rAAV2/2) vector carrying the RPE65 complementary DNA, and measured visual function over the course of 3 years. Four participants were administered a lower dose of the vector, and 8 were administered a higher dose. In a parallel study in dogs, we investigated the relationship among vector dose, visual function, and electroretinography (ERG) findings. RESULTS Improvements in retinal sensitivity were evident, to varying extents, in six participants for up to 3 years, peaking at 6 to 12 months after treatment and then declining. No associated improvement in retinal function was detected by means of ERG. Three participants had intraocular inflammation, and two had clinically significant deterioration of visual acuity. The reduction in central retinal thickness varied among participants. In dogs, RPE65 gene therapy with the same vector at lower doses improved vision-guided behavior, but only higher doses resulted in improvements in retinal function that were detectable with the use of ERG. CONCLUSIONS Gene therapy with rAAV2/2 RPE65 vector improved retinal sensitivity, albeit modestly and temporarily. Comparison with the results obtained in the dog model indicates that there is a species difference in the amount of RPE65 required to drive the visual cycle and that the demand for RPE65 in affected persons was not met to the extent required for a durable, robust effect. (Funded by the National Institute for Health Research and others; ClinicalTrials.gov number, NCT00643747.).

Visual Function Assessment Questionnaires

With increased emphasis on functional outcomes in ophthalmology, third-party health care payers and research funding agencies have turned their attention to the development and use of visual function questionnaires. Since 1980, more than a dozen such self-report visual function questionnaires have been developed. All of these instruments include items that ask about specific daily activities; patients must respond with a rating that represents the level of difficulty that they experience with the activity described. This article reviews all of the known instruments, with special attention paid to their validity and reliability. Most validation studies have reported high response consistency across items and significant correlations of instrument scores with visual impairment measures. Only two studies have measured test-retest reliability. The developers of visual function questionnaires typically divide the items into several different subscales, suggesting that different variables are being measured. Although the items are very similar for the different instruments, there is little agreement among instruments on the definition of subscales. All instruments are scored as the average of the ordinal patient ratings across items for each subscale and/or for the total instrument. Measurement issues underlying the scoring of ordinal patient ratings are discussed. It is argued that unless the instruments can be converted to interval scales, the averaging of patient ratings does not yield true measurements. The three visual function questionnaires that were calibrated with a statistical item response model, which estimates interval scales, are reviewed. It is concluded that future research and development should devote additional attention to the measurement properties of functional assessment instruments.

Self-reported preclinical disability identifies older women with early declines in performance and early disease

There appears to be a preclinical stage of physical disability which precedes onset of task difficulty (disability) in those who develop disability progressively as a result of chronic disease. Such a stage provides a basis for identifying older adults at risk of becoming disabled. This cross-sectional study evaluated whether a preclinical stage of physical function identified by self-report is associated with decrements in objective physical performance measures or increases in disease; that is, whether these measures, in those with preclinical disability, are intermediate between individuals who report no difficulty and no preclinical changes and those who report difficulty. The Womens Health and Aging Study II, an observational study of 436 women 70-80 years of age who were among the two-thirds least disabled living in the community. Participants were sampled from the HCFA Medicare eligibility lists and were determined eligible if they reported no difficulty, or difficulty in only one of four domains of physical function: mobility, upper extremity, IADL and ADL tasks. At the first follow-up (18 months after baseline), participants completed questionnaires on physical functioning for tasks in each of these domains, with possible answer options for each task: they had (1) difficulty (disabled); (2) no difficulty and no modification of task performance (High Function); or (3) no difficulty but reported modification and/or change in frequency of task performance (a self-report measure of preclinical disability predictive of incident difficulty). At the same visit, standardized, objective measures of function and disease were obtained, including measured walk; chair stands; strength: hip flexion, knee extension, ankle dorsiflexion, and grip; balance: function reach, single leg stand, tandem stand; joint exam: hip pain on passive motion and knee pain or tenderness; spirometry; ankle:arm blood pressure ratio; visual function: acuity, contrast sensitivity, stereopsis; and graded treadmill exercise test. Data were analyzed from the first follow-up examination. Physical performance decreased, and disease frequency increased, in association with decreasing self-reported mobility function (in walking one-half mile and climbing 10 steps), across three self-report categories: High Function, Preclinical Disability (Task Modification but No Difficulty) and Disability (Difficulty). These findings pertained for measures of walking speed, balance, strength, and knee and hip osteoarthritis. Self-reported level of function predicted differences in ranges as well as means for walking speed, balance and strength. These findings indicate a physiologic basis for self-reported function, including preclinical disability, specifically that different levels of disease severity, impairments and physical performance are concurrently associated with different categories of self-reported function. They also suggest new avenues for screening and intervention to prevent disability.