Ava K. Bittner

Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial

BACKGROUND Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients. METHODS In our open-label, prospective, phase 1b trial, we enrolled patients (aged ≥6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill Universitys Montreal Childrens Hospital. Patients received 7 days of oral QLT091001 (10-40 mg/m(2) per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2·2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052. FINDINGS Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6-38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28-683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2-30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients). INTERPRETATION Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations. FUNDING QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision.

Vision Test Variability in Retinitis Pigmentosa and Psychosocial Factors

Purpose. We explored whether greater amounts of short-term variability in visual acuity (VA), contrast sensitivity (CS), or visual field (VF) in retinitis pigmentosa (RP) was related to disease severity or psychosocial factors. Methods. We obtained spectral domain-optical coherence tomography in 27 RP subjects and determined variability (SD) of VA, CS, and VF during a mean of 16 tests self-administered at home on a personal computer twice a week. Subjects completed the Positive and Negative Affect Schedules at each personal computer-test session, and SF-36 general health and Beck Depression Inventory questionnaires on one occasion. Results. There was a 0.10 log unit increase in VA variability for every 0.58 logMAR increase (worse mean VA) (p = 0.001). For subjects with reduced foveal thickness, mean VA explained more of the total VA variability than foveal thickness (R2 = 0.72 and 0.46, respectively, in simple linear regressions). There was a statistically significant 4.3% increased log VF area variability for every 50% mean log VF area decrease (p < 0.001); explaining most of the total variability in log VF area variability (R2 = 0.44). When controlling for mean log VF area, there was a statistically significant increase in log VF area variability for subjects with greater than minimal depressive symptoms (p = 0.015), with increased mean irritability scores (p = 0.02), decreased SF-36 physical functioning subscale scores (p = 0.03), or decreased mean score for feeling active, strong, and proud (p = 0.008) (adjusted R2 = 0.62). CS variability was low and not statistically significantly related to mean CS, macular thickness, or psychosocial factors. Conclusions. Increased VA and VF variability was predicted largely by increased RP severity. Greater VF variability occurred in subjects with reduced VF who reported less physical activity or increased negative psychosocial states. These associations should be considered during clinical examinations and trials for RP.

Safety and Proof-of-Concept Study of Oral QLT091001 in Retinitis Pigmentosa Due to Inherited Deficiencies of Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT)

Restoring vision in inherited retinal degenerations remains an unmet medical need. In mice exhibiting a genetically engineered block of the visual cycle, vision was recently successfully restored by oral administration of 9-cis-retinyl acetate (QLT091001). Safety and visual outcomes of a once-daily oral dose of 40 mg/m2/day QLT091001 for 7 consecutive days was investigated in an international, multi-center, open-label, proof-of-concept study in 18 patients with RPE65- or LRAT-related retinitis pigmentosa. Eight of 18 patients (44%) showed a ≥20% increase and 4 of 18 (22%) showed a ≥40% increase in functional retinal area determined from Goldmann visual fields; 12 (67%) and 5 (28%) of 18 patients showed a ≥5 and ≥10 ETDRS letter score increase of visual acuity, respectively, in one or both eyes at two or more visits within 2 months of treatment. In two patients who underwent fMRI, a significant positive response was measured to stimuli of medium contrast, moving, pattern targets in both left and right hemispheres of the occipital cortex. There were no serious adverse events. Treatment-related adverse events were transient and the most common included headache, photophobia, nausea, vomiting, and minor biochemical abnormalities. Measuring the outer segment length of the photoreceptor layer with high-definition optical coherence tomography was highly predictive of treatment responses with responders having a significantly larger baseline outer segment thickness (11.7 ± 4.8 μm, mean ± 95% CI) than non-responders (3.5 ± 1.2 μm). This structure-function relationship suggests that treatment with QLT091001 is more likely to be efficacious if there is sufficient photoreceptor integrity. Trial Registration ClinicalTrials.gov NCT01014052

A survey of photopsias in self-reported retinitis pigmentosa: location of photopsias is related to disease severity.

Purpose: To characterize photopsias or light shows in patients self-reporting retinitis pigmentosa and determine associations between their location and patient-reported visual function. Methods: One hundred and twenty-seven self-reported patients with retinitis pigmentosa with varying levels of vision completed an anonymous survey on an Internet web site. Results: One hundred and eighteen (93%) of the respondents reported photopsias. The majority (60%) who experience photopsias have them daily, 48% already had them before being diagnosed with retinitis pigmentosa, and 69% report interference with vision. The proportions noting photopsias mostly peripherally versus centrally were 53% of those reading normal or small print versus 35% requiring magnification (odds ratio, 2.3; 95% confidence interval, 1.0–5.5; P = 0.05); 61% of current drivers versus 41% who stopped or never drove (odds ratio, 2.6; 95% confidence interval, 1.0–6.7; P = 0.04); and 54% of individuals who easily navigate or have only minor difficulty in unfamiliar areas versus 29% of those with great difficulty or needing assistance with mobility (odds ratio, 3.0; 95% confidence interval, 1.2–6.7; P = 0.02). Conclusion: Contrary to common belief that photopsias are associated with end-stage retinal degeneration, they are also commonly reported in earlier stages. The location of photopsias appears to be related to residual photoreceptor function assessed by self-reported performance of daily activities. Clinicians and researchers should be aware of their frequent occurrence and offer reassurance to patients.

Orientation and mobility assessment in retinal prosthetic clinical trials.

Purpose. The purpose of this study was to develop an orientation and mobility (O&M) assessment protocol to implement in subjects who have been implanted with an artificial silicon retina (ASR), and to use this experience to propose a research agenda for O&M with prosthetic vision. Methods. A controlled and naturalistic assessment was developed that included walking a prescribed obstacle course and travel to and from a hospital cafeteria. Subjects were tested before and 3 and 6 months after being implanted with the ASR. Outcome measures were walking speed and number of contacts with obstacles. The experiences from this study led to a proposed research agenda in O&M. Results. Eight subjects with retinitis pigmentosa participated in this study. The vision status of the subjects ranged from <20/1600 to 20/80 visual acuity and visual fields of <5 to 40°. Using a repeated-measures analysis of variance, no differences were found in the primary outcome measures. Four subjects were observed to have reduced mobility after implantation. Three subjects self-reported enhancements of travel after implantation, but this enhancement was not observed. Conclusions. This study demonstrates that mobility might not be improved with prosthetic vision. The proposed research agenda emphasizes the importance of developing individualized assessments, identifying specific items of orientation rather than mobility for measuring the effect of prosthetic vision, and to develop and evaluate instructional programs that may be needed to obtain the full benefit of the technology.

Worse-than-usual visual fields measured in retinitis pigmentosa related to episodically decreased general health

Background/aims We examined whether retinitis pigmentosa (RP) subjects’ worse-than-usual vision measures were related to episodic changes in psychosocial factors and/or general health. Methods In a prospective, cohort study, 37 RP subjects self-administered personal computer (PC)-based visual acuity (VA), contrast sensitivity (CS) and visual field (VF) tests at home twice a week, for 16 sessions in 2–3 months. Subjects rated their general health prior to each vision test session, and completed the Perceived Stress Scale, Positive and Negative Affect Schedules, and Epworth and Stanford Sleepiness Scales immediately after each session. Results Nine subjects with reduced mean VA >0.5 log minimal angle of resolution (logMAR) on average had statistically significant 26% more sessions with measured deviations ≥0.1 logMAR from their mean (95% CI 20% to 32%; p<0.001), which were not significantly related to changes in psychosocial factors or general health. Measured deviations ≥0.1 logCS from mean CS were not statistically significantly related to any measured factors. We found a statistically significant increased frequency of sessions with ≥20% VF reduction from the mean (p<0.001) as mean log VF area was reduced. Subjects reporting reduced general health during a session had a statistically significant over twofold greater odds of having a VF reduction from the mean beyond 1 SD (95% CI 1.26 to 5.00; p=0.009). Conclusions Measured episodic VF reductions were more common in advanced RP and related to decreased general health at a session, which should be considered during clinical examinations and trials when determining true changes in vision. We did not find evidence that fluctuations in psychosocial factors were significantly correlated with vision reductions across subjects.

Variability and Errors of Manually Digitized Goldmann Visual Fields.

Purpose Goldmann visual fields (GVFs) are useful for tracking changes in areas of functional retina, including the periphery, in inherited retinal degeneration patients. Quantitative GVF analysis requires digitization of the chart coordinates for the main axes and isopter points marked by the GVF operator during testing. This study investigated inter- and intra-digitizer variability among users of a manual GVF digitization program. Methods Ten digitizers were trained for 1 hour, then digitized 23 different GVFs from inherited retinal degeneration patients in each of three testing blocks. Digitizers labeled each isopter as seeing or non-seeing, and its target size. Isopters with the same test target within each GVF were grouped to create isopter groups. Results The standard deviation of isopter group area showed an approximate square-root relationship with total isopter group area. Accordingly, the coefficient of variation for isopter group area decreased from 68% to 0.2% with increasing isopter group area. A bootstrap version of ANOVA did not reveal a significant effect of digitizers on isopter group area. Simulations involving random sampling of digitizers showed that five to seven digitizers would be required to catch 95% to 99% of labeling errors and isopter misses, on the basis of data discrepancies, with 99% probability. Conclusions These data suggest that any minimally trained digitizer would be capable of reliably determining any isopter area, regardless of size. Studies using this software could either use five to seven minimally trained digitizers for each GVF, three digitizers who demonstrate low frequencies of errors on a practice set of GVFs, or two digitizers with an expert reader to adjudicate discrepancies and catch errors.

Photopsias are related in part to perceived stress and positive mood in retinitis pigmentosa

PurposeWe measured the relationship between the occurrence of photopsias (spontaneous phosphenes), and retinitis pigmentosa (RP) subjects’ level of vision, light exposure, and psychosocial factors to attempt to confirm RP patients’ previous reports of these associations.MethodsA total of 36 RP subjects self-administered PC-based binocular visual acuity, contrast sensitivity, and visual field tests at home twice a week, for 16 sessions in 2–3 months. After each session, subjects reported photopsias during the vision tests and completed questionnaires: Epworth Sleepiness Scale, Stanford Sleepiness Scale, Perceived Stress Scale, and Positive and Negative Affect Schedules.ResultsAcross all subjects, photopsias occurred during 47% of sessions. Five (14%) subjects never noted photopsias, while five others noted photopsias at every session. Two-thirds of subjects experienced photopsias frequently (>20% of sessions). On average, the odds of noticing photopsias increased by 57% for every 1-point increase in mean perceived stress (OR=1.57; 95% CI: 1.04, 2.4; P=0.03) or reduced by 38% for every 1-point increase in positive mood (OR=0.62; 95% CI: 0.39, 0.98; P=0.04), after adjusting for age, gender, and vision. Similarly, the odds of experiencing photopsias during a session increased by 16% for every 3-point increase in perceived stress and decreased by 17% for every 3-point increase in positive mood, after adjusting for age and gender (OR=1.16; 95% CI: 1.01, 1.33; P=0.048)(OR=0.83; 95% CI: 0.73, 0.94; P=0.004), respectively. Frequency of photopsias was not statistically significantly related to other factors measured.ConclusionsIncreased photopsias appear to be related to times when subjects report increased perceived stress and/or decreased positive mood, rather than RP patients’ age, level of vision, reported light exposure, or sleepiness.

Improved Adherence to Vision Self-monitoring with the Vision and Memory Stimulating (VMS) Journal for Non-neovascular Age-related Macular Degeneration during a Randomized Controlled Trial

Objective An educational, interactive journal [Vision and Memory Stimulating (VMS) journal] was developed to boost patient confidence and promote long-term adherence with weekly vision self-monitoring in age-related macular degeneration (AMD) patients at risk for vision loss from new-onset neovascularization. Methods In a multicenter randomized controlled trial, 198 subjects with intermediate stage, non-neovascular AMD received the VMS journal or followed usual care (e.g. their doctor’s instructions for vision monitoring; Amsler grid). At 6 and/or 12 months post-enrollment, 157 subjects completed a questionnaire on vision self-monitoring. Results At 6 and 12 months, respectively, 85% and 80% of the VMS journal subjects reported vision monitoring at least weekly, which represent statistically significant 7.1 and 4.2 times greater odds than the 50% of controls who monitored weekly at both follow-up times (p<0.001). At 6 and 12 months, respectively, 29% and 25% of controls indicated that they had not checked their vision in the past 6 months, while only 1.5% and 5% of the VMS journal subjects reported no vision self-monitoring. At 6 and 12 months, respectively, only 15% and 13% of the VMS journal subjects vs. 53% and 44% of the controls reported that they did not feel confident that they were taking care of their sight by self-monitoring (p<0.001). Usual care controls had statistically significant 6.7 and 5.0 times greater odds of reporting non-confidence at 6 and 12 months, respectively. There was no statistically significant change in weekly vs. less frequent self-monitoring between the groups (p=0.68), with 81% of all subjects reporting no change in frequency between 6 and 12 months. Conclusions These findings support the efficacy of the VMS journal for increasing vision self-monitoring adherence and confidence, in addition to promoting persistence in weekly monitoring over the course of a year in AMD subjects at risk for exudative retinal changes.