Stickler Syndrome (SS): Laser Prophylaxis for Retinal Detachment (Modified Ora Secunda Cerclage, OSC/SS).

PURPOSE: To introduce a novel technique of encircling laser prophylaxis (ora secunda cerclage Stickler syndrome, OSC/SS) to prevent rhegmatogenous retinal detachment (RRD) in Stickler syndrome eyes. PATIENTS AND METHODS: After first eye RRD at age 50 and at age 18, respectively, a 53-year-old father and his 22-year-old son with type 2 SS (STL2) gave informed consent and underwent OSC/SS prophylaxis, performed in each fellow eye. A 26-year-old STL2 daughter then suffered first eye retinal detachment and similarly chose fellow eye OSC/SS prophylaxis. A second son, 28 years of age with STL2, chose OSC/SS prophylaxis in both eyes. RESULTS: The three OSC/SS treated fellow eyes have gone 12 years, 11 years, and 8 years without RRD. STL1 and less common STL2 eyes are known to have a similar rate of RRD, and 80% of STL1 fellow eyes develop RRD at a median of 4 years in the absence of prophylaxis. Moreover, five of six (83%) known STL2 family members suffered RRD, only the STL2 son with bilateral OSC/SS remaining bilaterally attached. All five OSC/SS treated eyes (average 8.7 years post-prophylaxis) retained preoperative visual acuity of 20/20 to 20/30, with an average, asymptomatic reduction of meridional field in each eye to 50 degrees. In contrast, in the three eyes having suffered RRD prior to presentation, visual acuity ranged from 20/125 to 8/200 and average meridional field was 29 degrees. CONCLUSION: Encircling grid laser (OSC) modified in Stickler eyes to encompass the ora serrata and extend posteriorly to and between the vortex vein ampullae (OSC/SS) is a reasonable RRD prophylaxis option to offer STL1 and STL2 patients as an alternative to no treatment or less effective prophylaxis. Because of rarity and severity, the ultimate proof of safety and efficacy will likely come not from randomized trials, but from a non-randomized, prospective, cohort comparison study of such individual efforts.

Reliability of Semiautomated Kinetic Perimetry (SKP) and Goldmann Kinetic Perimetry in Children and Adults With Retinal Dystrophies.

PURPOSE: To investigate the precision of visual fields (VFs) from semiautomated kinetic perimetry (SKP) on Octopus 900 perimeters, for children and adults with inherited retinal degenerations (IRDs). Goldmann manual kinetic perimetry has long been used in the diagnosis and follow-up of these patients, but SKP is becoming increasingly common. Octopus VFs (OVFs) and Goldmann VFs (GVFs) were both mapped on two occasions. METHODS: Nineteen females and 10 males with IRDs were tested on OVFs and GVFs, with two targets per test (V4e and one smaller target). Tests were performed in the same (randomized) order at two visits about 1 week apart. The VFs were digitized to derive isopter solid angles. Comparisons, within and between visits, were performed with paired t-tests and Bland-Altman plots. RESULTS: Median age was 20 years (range, 7-70; 10 participants aged ≤17 years old). There were no significant differences in solid angles between OVFs and GVFs (P ≥ 0.06) or between the two visits' solid angles on either perimeter (P ≥ 0.30). Between-visit test-retest variability for GVFs and OVFs was similar (P ≥ 0.73), with median values of approximately 9% to 13%. Overall variability was lower for children than adults (medians of 7.5% and 12.8%, respectively). CONCLUSIONS: Octopus SKP and Goldmann perimetry produced VFs of similar size and variability. TRANSLATIONAL RELEVANCE: Our study indicates that SKP provides a viable alternative to traditional Goldmann perimetry in clinical trials or care involving both children and adults with IRDs.

Standing Balance and Spatiotemporal Aspects of Gait Are Impaired Upon Nocturnal Awakening in Healthy Late Middle-Aged and Older Adults.

STUDY OBJECTIVES: Nocturnal awakenings may constitute a unique risk for falls among older adults. We describe differences in gait and balance between presleep and midsleep testing, and whether changes in the lighting environment during the midsleep testing further affect gait and balance. METHODS: Twenty-one healthy, late middle-aged and older (64.7 ± 8.0 y) adults participated in this repeated-measures design consisting of four overnight laboratory stays. Each night, participants completed baseline visual acuity, gait, and balance testing. After a 2-h sleep opportunity, they were awakened for 13 min into one of four lighting conditions: very dim white light (< 0.5 lux); dim white light (∼28.0 lux); dim orange light (∼28.0 lux); and white room-level light (∼200 lux). During this awakening, participants completed the same sequence of testing as at baseline. RESULTS: Low-contrast visual acuity significantly decreased with decreasing illuminance conditions (F(3,45) = 98.26, p < 0.001). Our a priori hypothesis was confirmed in that variation in stride velocity and center of pressure path length were significantly worse during the mid-sleep awakening compared to presleep baseline. Lighting conditions during the awakening, however, did not influence these parameters. In exploratory analyses, we found that over one-third of the tested gait and balance parameters were significantly worse at the midsleep awakening as compared to baseline (p < 0.05), and nearly one-quarter had medium to large effect sizes (Cohen d ≥ 0.5; r ≥ 0.3). CONCLUSIONS: Balance and gait are impaired during midsleep awakenings among healthy, late middle-aged and older adults. This impairment is not ameliorated by exposure to room lighting, when compared to dim lights.

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).

UNLABELLED: 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.

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 University's Montreal Children's 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.

Evaluating Barten image metric for predicting character recognition in people with low vision.

Electronic devices with small visual displays (SVDs) are often inaccessible to the millions of Americans with vision loss. The Barten square root integral (SQRI) is an image quality metric that has been shown to predict whether people with normal vision can see images on a cathode ray tube monitor. The present proof-of-concept study begins to explore whether the same metric could predict the ability of users with low vision to see images on SVDs. In a sample population of 33 adults with low vision, the Barten SQRI was the best predictor of the ability to recognize low-contrast single digits on a screen (r(2) = 0.80, p < 0.01), followed by the Pelli-Robson Contrast Sensitivity Chart (r(2) = 0.69, p < 0.01). Visual acuity was not significantly predictive of the ability to read low-contrast characters on a display. Further work will explore whether the Barten SQRI remains predictive of the ability of people with low vision to use actual devices that have SVDs.

Patient awareness of binocular central scotoma in age-related macular degeneration.

PURPOSE: To assess whether age-related macular degeneration (AMD) patients are aware of binocular central visual field defects. METHODS: One hundred fifty-three consecutive AMD patients in their initial low-vision rehabilitation evaluation were immediately asked at the beginning of their visit (1) whether they were able to see any blind spots or defects in their field of vision and (2) whether they had any evidence or experiences that led them to believe that they had defects in their field of vision. They then had their vision assessed by binocular central visual field testing using the California Central Visual Field Test, binocular reading performance evaluated using the Smith-Kettlewell Reading Test (SK Read) and MN Read charts, and visual acuity measured using the ETDRS chart at 1 meter. Mean diameters of the scotomas with borders near fixation were noted. RESULTS: Visual acuity median was 20/253 (range 20/40 to hand movements). Binocular scotomas were present in 88% of patients (66% had dense scotoma). Of patients with binocular scotomas, 56% were totally unaware of their presence, even with dense scotomas measuring up to 30° in diameter; 1.5% could fleetingly see a defect in their visual field on waking; and 44% related experiences of things "disappearing" on them. The median and range of scotoma diameters for those unaware vs. those with some awareness of their scotomas were comparable. There was no significant relationship of awareness of the scotoma with age, acuity, scotoma size, density, or duration of onset. Awareness of scotoma was associated with fewer errors on the SK Read (p < 0.01). CONCLUSIONS: Low vision clinicians cannot depend on patients to report the presence of significant scotomas; thus, appropriate testing must be performed. Presence of scotomas decreased reading accuracy, but some awareness of the scotomas had a tendency to improve accuracy. The value of rehabilitation programs aimed at increasing patient awareness of their scotomas may be supported by this evidence.

A test of face discrimination ability in aging and vision loss.

PURPOSE: The ability to recognize faces is fundamental to social interactions but has not been studied extensively in visual disorders such as age-related macular degeneration (AMD). We report here the development of a face discrimination test, in which both response times (RTs) and accuracies are measured. Results are compared for young and older control subjects and older adults with AMD to determine the factors underlying performance on this test. METHODS: Subjects were 14 older controls, 11 young adult controls, and 34 individuals with binocular AMD. In the face discrimination test, colored reference photographs of eight people were presented continuously (male faces in the first half of the test, female faces in the second). On each trial, subjects reported which reference face matched the test face (shown with different poses and/or expressions). In addition, the older controls then identified the expression on the test face. RESULTS: The older controls showed generally small numbers of errors (0 to 9%) on the face identifications but more errors on expression identifications (up to 22%). They tended to show shorter RTs (but no changes in accuracy) with repeated presentations of the same face. The young controls responded more quickly, and they made almost no mistakes. Although performance varied, as a group, those with AMD were slower and showed more errors in identification than the older controls did. Across all subjects, both visual acuity and contrast sensitivity contributed significantly to the variances in RTs and accuracy. CONCLUSIONS: The group of older controls had poorer and more variable RTs and accuracies than the young controls. Difficulties in face matching, in terms of both accuracy and RT, were observed for subjects with AMD. Performance accuracy and RTs for this new test depended on both visual acuity and contrast sensitivity.

Incomplete cortical reorganization in macular degeneration.

PURPOSE: Activity in regions of the visual cortex corresponding to central scotomas in subjects with macular degeneration (MD) is considered evidence for functional reorganization in the brain. Three unresolved issues related to cortical activity in subjects with MD were addressed: Is the cortical response to stimuli presented to the preferred retinal locus (PRL) different from other retinal loci at the same eccentricity? What effect does the role of age of onset and etiology of MD have on cortical responses? How do functional responses in an MD subject's visual cortex vary for task and stimulus conditions? METHODS: Eight MD subjects-four with age-related onset (AMD) and four with juvenile onset (JMD)-and two age-matched normal vision controls, participated in three testing conditions while undergoing functional magnetic resonance imaging (fMRI). First, subjects viewed a small stimulus presented at the PRL compared with a non-PRL control location to investigate the role of the PRL. Second, they viewed a full-field flickering checkerboard compared with a small stimulus in the original fovea to investigate brain activation with passive viewing. Third, they performed a one-back task with scene images to investigate brain activation with active viewing. RESULTS: A small stimulus at the PRL generated more extensive cortical activation than at a non-PRL location, but neither yielded activation in the foveal cortical projection. Both passive and active viewing of full-field stimuli left a silent zone at the posterior pole of the occipital cortex, implying a lack of complete cortical reorganization. The silent zone was smaller in the task requiring active viewing compared with the task requiring passive viewing, especially in JMD subjects. CONCLUSIONS: The PRL for MD subjects has more extensive cortical representation than a retinal region with matched eccentricity. There is evidence for incomplete functional reorganization of early visual cortex in both JMD and AMD. Functional reorganization is more prominent in JMD. Feedback signals, possibly associated with attention, play an important role in the reorganization.

Age effects on visual-perceptual processing and confrontation naming.

The impact of age-related changes in visual-perceptual processing on naming ability has not been reported. The present study investigated the effects of 6 levels of spatial frequency and 6 levels of contrast on accuracy and latency to name objects in 14 young and 13 older neurologically normal adults with intact lexical-semantic functioning. Spatial frequency and contrast manipulations were made independently. Consistent with the hypotheses, variations in these two visual parameters impact naming ability in young and older subjects differently. The results from the spatial frequency-manipulations revealed that, in general, young vs. older subjects are faster and more accurate to name. However, this age-related difference is dependent on the spatial frequency on the image; differences were only seen for images presented at low (e.g., 0.25-1 c/deg) or high (e.g., 8-16 c/deg) spatial frequencies. Contrary to predictions, the results from the contrast manipulations revealed that overall older vs. young adults are more accurate to name. Again, however, differences were only seen for images presented at the lower levels of contrast (i.e., 1.25%). Both age groups had shorter latencies on the second exposure of the contrast-manipulated images, but this possible advantage of exposure was not seen for spatial frequency. Category analyses conducted on the data from this study indicate that older vs. young adults exhibit a stronger nonliving-object advantage for naming spatial frequency-manipulated images. Moreover, the findings suggest that bottom-up visual-perceptual variables integrate with top-down category information in different ways. Potential implications on the aging and naming (and recognition) literature are discussed.

Estimating cerebral blood volume with expanded vascular space occupancy slice coverage.

A model for quantifying cerebral blood volume (CBV) based on the vascular space occupancy (VASO) technique and varying the extent of blood nulling yielding task-related signal changes with various amounts of blood oxygenation level-dependent (BOLD) and VASO weightings was previously described. Challenges associated with VASO include limited slice coverage and the confounding inflow of fresh blood. In this work, an approach that extends the previous model to multiple slices and accounts for the inflow effect is described and applied to data from a multiecho sequence simultaneously acquiring VASO, cerebral blood flow (CBF), and BOLD images. This method led to CBV values (7.9 +/- 0.3 and 5.6 +/- 0.3 ml blood/100 ml brain during activation [CBV(ACT)] and rest [CBV(REST)], respectively) consistent with previous studies using similar visual stimuli. Furthermore, an increase in effective blood relaxation (0.65 +/- 0.01) compared to the published value (0.62) was detected, likely reflecting inflow of fresh blood. Finally, cerebral metabolic rate of oxygen (CMRO(2)) estimates using a multiple compartment model without assumption of CBV(REST) led to estimates (18.7 +/- 17.0%) that were within published ranges.

Eye and visual function in traumatic brain injury.

Combat blast is an important cause of traumatic brain injury (TBI) in the Department of Veterans Affairs polytrauma population, whereas common causes of TBI in the civilian sector include motor vehicle accidents and falls. Known visual consequences of civilian TBI include compromised visual acuity, visual fields, and oculomotor function. The visual consequences of TBI related to blast remain largely unknown. Blast injury may include open globe (eye) injury, which is usually detected and managed early in the rehabilitation journey. The incidence, locations, and types of ocular damage in eyes without open globe injury after exposure to powerful blast have not been systematically studied. Initial reports and preliminary data suggest that binocular function, visual fields, and other aspects of visual function may be impaired after blast-related TBI, despite relatively normal visual acuity. Damage to the ocular tissues may occur from blunt trauma without rupture or penetration (closed globe injury). Possible areas for research are development of common taxonomy and assessment tools across services, surgical management, and outcomes for blast-related eye injury; the incidence, locations, and natural history of closed globe injury; binocular and visual function impairment; quality of life in affected service members; pharmacological and visual therapies; and practice patterns for screening, management, and rehabilitation.

Models of reading performance in older adults with normal age-related vision.

Reading rate with print size (reading performance) was studied in a group of 132 older readers with normal age-related vision using the Minnesota Low Vision Reading Acuity (MNREAD) test. Regression by a monotonic Weibull model had greater convergence success with lower residual error than either Logistic or Gompertz models. Reading performance by Weibull model regression was characterized by inflexion slope, critical print size, and maximum reading rate. Successive shortening of the data set length before regression by the monotonic Weibull model gave decreased fitting error. This finding suggests that some individual reading rates, rather than asymptoting at the largest print size, may give nonsigmoidal responses. Shortening the data set length decreases regression error but significantly changes regression parameter values. A nonmonotonic Weibull model that was sensitive to declining reading rate at large print size improved regression on 22% of our data. This result indicates that a subgroup of subjects had response falloff at large print size and reading performance characteristics that included incremental and decremental reading rate slopes at different print sizes, which were separated by a reading rate plateau.

Visual function in patients with choroidal neovascularization resulting from age-related macular degeneration: the importance of looking beyond visual acuity.

PURPOSE: A detailed understanding of overall quality of vision may help primary care physicians, optometrists, and general ophthalmologists to improve the care of patients with choroidal neovascularization (CNV) resulting from age-related macular degeneration (AMD). METHODS: Published literature was reviewed using Medline searches and the authors' knowledge of the field. RESULTS: Both visual acuity and contrast sensitivity are strongly associated with the ability to perform vision-related activities of daily living. CNV resulting from AMD often leads to scotoma, which is also strongly associated with the ability to perform everyday activities such as reading and driving. Contrast sensitivity and visual field extent may be better predictors of many abilities than visual acuity. Laser photocoagulation, verteporfin therapy, and pegaptanib sodium have been proven to reduce the risk of visual acuity loss in patients with CNV resulting from AMD. Laser photocoagulation frequently causes scotoma, but data on its effects on other aspects of overall quality of vision are scarce. Verteporfin therapy has been shown to also reduce the risk of contrast sensitivity loss and has been associated with stabilization or reduction of scotoma size. Treatment effects beyond visual acuity have not been investigated for pegaptanib. Detailed assessment of overall quality of vision also aids the design of vision rehabilitation programs tailored to the needs of individual patients. CONCLUSIONS: Understanding the impact of vision loss on patients with CNV resulting from AMD and assessing treatment benefits requires assessment of overall quality of vision. Primary care physicians and optometrists have an important role in ensuring that patients receive the best possible care, which can be aided by prompt referral to an ophthalmologist or retina specialist and collaboration with low-vision specialists and optometrists who together can make detailed assessments of overall quality of vision, implement appropriate treatment, and design effective rehabilitation strategies.

Effects of preferred retinal locus placement on text navigation and development of advantageous trained retinal locus.

Sixty readers were evaluated for visual function and text-navigation ability. The visual field and preferred retinal locus (PRL) were measured with a scanning laser ophthalmoscope (SLO). We found significant differences in text-navigation ability based on scotoma and PRL placement. Readers with a PRL to the left of or above a scotoma had significantly less text-navigation abilities. Readers with a PRL to the left of a scotoma tended to misread words with similar beginnings and omit the last word on a line. Readers with a PRL above a scotoma tended to skip a line or reread the same line twice. In a follow-up study, seven subjects with a nonadvantageous PRL quickly developed a trained retinal locus (TRL) during instruction with an SLO. Although the readers developed the TRL in about 15 minutes, they read slower with the TRL than the PRL. This TRL research provides promising pilot data.

Preferred retinal loci and macular scotoma characteristics in patients with age-related macular degeneration.

Many patients with macular scotomas due to age-related macular degeneration do not perceive black spots in the visual field where the scotomas are located. Rather, they describe objects as "vanishing," "jumping out of nowhere" or "having blurry parts," or a combination of features. In addition, when the macular scotoma affects the fovea, the visual system uses 1 or more preferred retinal loci (PRLs) as a "pseudofovea" to perform visual tasks. Visual function testing with the scanning laser ophthalmoscope has provided a wealth of information regarding how patients perceive the visual world and how the oculomotor system directs eye movements. This article describes 2 specific functions of the oculomotor system, fixation stability and refixation precision, with data collected from normally sighted people and patients with visual field loss. The implications of the characteristics of PRLs and macular scotomas for clinical testing are discussed.