Rand Spencer

Long-Term Results from an Epiretinal Prosthesis to Restore Sight to the Blind

PURPOSE Retinitis pigmentosa (RP) is a group of inherited retinal degenerations leading to blindness due to photoreceptor loss. Retinitis pigmentosa is a rare disease, affecting only approximately 100 000 people in the United States. There is no cure and no approved medical therapy to slow or reverse RP. The purpose of this clinical trial was to evaluate the safety, reliability, and benefit of the Argus II Retinal Prosthesis System (Second Sight Medical Products, Inc, Sylmar, CA) in restoring some visual function to subjects completely blind from RP. We report clinical trial results at 1 and 3 years after implantation. DESIGN The study is a multicenter, single-arm, prospective clinical trial. PARTICIPANTS There were 30 subjects in 10 centers in the United States and Europe. Subjects served as their own controls, that is, implanted eye versus fellow eye, and system on versus system off (native residual vision). METHODS The Argus II System was implanted on and in a single eye (typically the worse-seeing eye) of blind subjects. Subjects wore glasses mounted with a small camera and a video processor that converted images into stimulation patterns sent to the electrode array on the retina. MAIN OUTCOME MEASURES The primary outcome measures were safety (the number, seriousness, and relatedness of adverse events) and visual function, as measured by 3 computer-based, objective tests. RESULTS A total of 29 of 30 subjects had functioning Argus II Systems implants 3 years after implantation. Eleven subjects experienced a total of 23 serious device- or surgery-related adverse events. All were treated with standard ophthalmic care. As a group, subjects performed significantly better with the system on than off on all visual function tests and functional vision assessments. CONCLUSIONS The 3-year results of the Argus II trial support the long-term safety profile and benefit of the Argus II System for patients blind from RP. Earlier results from this trial were used to gain approval of the Argus II by the Food and Drug Administration and a CE mark in Europe. The Argus II System is the first and only retinal implant to have both approvals.

Vitrectomy in Eyes at Risk for Macular Hole Formation

Fifteen eyes believed to be at increased risk for macular hole formation underwent vitrectomy in an attempt to prevent macular hole formation. Full-thickness macular holes have not developed in 10 of 11 eyes with stage 1 macular holes. Four eyes were noted to have small full-thickness foveal defects (stage 2 macular holes) at the time of vitrectomy. Two of the four eyes have not progressed to macular hole formation and have 20/25 visual acuity. All patients have been followed for a minimum of 13 months (median, 18 months). The 12 eyes that have not experienced macular hole formation have had a significant (P less than 0.001) improvement in vision with seven (58%) attaining visual acuity of 20/25 or better. The postoperative foveal electroretinogram (ERG) amplitude was higher than the preoperative amplitude in five of the six eyes tested.

Foveal avascular zone and foveal pit formation after preterm birth

Background Vascularisation of the macula takes place between 24 and 27 weeks post-conception. Preterm birth may affect the formation of the foveal avascular zone (FAZ) and foveal depression, and displacement of inner retinal layers away from the incipient fovea. Objective To examine whether vascular abnormalities accompany an inner retinal abnormality, and whether they are coincident. Methods High-density spectral domain optical coherence tomography volume scans were obtained from 24 preterm children and 34 full-term controls (5–16 years). Matlab programs were used to quantify total retinal thickness, thickness of individual retinal layers and metrics of foveal morphology. Summed voxel projections for the ganglion cell layer–inner nuclear layer were used to identify the FAZ. Results Preterm children had significantly smaller FAZ diameters than controls (p<0.0001). The foveal pits of preterm children were significantly shallower and less steep (p<0.0001) and total retinal thickness at the fovea was significantly increased (p<0.0001) compared to controls. The ganglion cell layer–inner plexiform layer and outer nuclear layer were significantly (p≤0.0001) thicker in preterm children than in controls. Conclusions Preterm birth results in abnormal foveal vascularisation, a failure of the inner retinal neurons to migrate away from the fovea, and an elevated outer nuclear layer ratio. The spatial coincidence of inner retinal and vascular abnormalities in preterm children supports the hypothesis that aspects of foveal development are interdependent.

Critical Period For Foveal Fine Structure In Children With Regressed Retinopathy Of Prematurity

Purpose Midgestation is a critical period in the formation of the foveal avascular zone. The authors evaluated the effects of preterm birth on foveal structure in children with regressed retinopathy of prematurity. Methods Children with regressed retinopathy of prematurity with normal-appearing posterior poles (n = 26) and full-term control children (n = 56) were investigated. Frequency-domain optical coherence tomography 9-mm line scans across the fovea were obtained from right eyes. Using a customized segmentation program in MATLAB, total retinal thickness and the thickness of individual retinal layer regions were measured at the fovea (0°) and throughout ±8°. Results Total thickness of the fovea in the retinopathy of prematurity group (287.7 ± 47.6 &mgr;m) was greater than that in the control group (230.1 ± 18.2 &mgr;m). Bilinear fitting was performed to examine the relationship between total thickness and gestational age. Before 28 weeks, foveal thickness decreased with gestational age (14.3 &mgr;m/week); after 28 weeks, foveal thickness decreased only slightly (2.73 &mgr;m/week). Inner retinal layers contributed to the difference in thickness between groups more than outer layers. Foveal thickness was correlated with gestational age at birth but not with visual acuity or refractive error. Conclusion Preterm birth before 28 weeks of gestational age was associated with a failure of the inner retinal layers to migrate away from the fovea, resulting in increased foveal thickness.

Four-Year Placebo-Controlled Trial of Docosahexaenoic Acid in X-Linked Retinitis Pigmentosa (DHAX Trial): A Randomized Clinical Trial

IMPORTANCE X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100,000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. CONCLUSIONS AND RELEVANCE Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00100230.

Current concepts in retinopathy of prematurity

Significant advances regarding understanding the etiology and treatment of retinopathy of prematurity have occurred in the 50 years since its discovery. Nevertheless, there is still a great deal to be learned. In spite of major technological advances in neonatal care, retinopathy of prematurity is a multi-factorial disease and probably cannot be completely prevented. Early intervention in the diagnosis and management of these infants has greatly improved their visual prognosis. Further studies may help pediatricians and neonatologists to understand and control associated risk factors. Ophthalmologists must continue to examine these patients early and follow them closely to control the associated treatable aspects of the disease, such as strabismus and amblyopia.

Delayed presentation of cytomegalovirus retinitis in an infant with severe congenital cytomegalovirus infection.

Purpose: The purpose was to study the congenital cytomegalovirus (CMV), which is the most common cause for congenital infection in the United States, affecting nearly 40,000 infants per year. There is no widely accepted treatment protocol for congenital CMV infection despite recent clinical trials with antiviral medications ganciclovir and valganciclovir. Methods: We present a case report of an infant with severe congenital CMV infection with presentation of chorioretinitis in both eyes at 5 months of age. Results: The child did not receive treatment with ganciclovir during hospitalization after birth despite severe manifestations of CMV infection. Treatment was again withheld after diagnosis of retinitis because of immunocompetent status, potential side effects of ganciclovir treatment, and location of retinitis in the retinal periphery of both eyes. The retinitis resolved during a period of 3 months. Conclusion: This case shows that CMV retinitis in infants with congenital CMV infection can be delayed in presentation and can resolve without treatment. It shows the need for more consistent monitoring for chorioretinitis in infants with congenital CMV infection.

Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial.

PURPOSE Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. METHODS Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. RESULTS Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to <0.0001). CONCLUSIONS Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity. From the relationship between RBC-DHA and the rate of field sensitivity loss, we can extrapolate that an RBC-DHA level of 17% could minimize the decline in field sensitivity. (ClinicalTrials.gov number, NCT00100230.)

Factors Affecting Development of Motor Skills in Extremely Low Birth Weight Children

Purpose: The aim of this study is to analyze the impact of ophthalmic and neonatal factors on motor development in extremely low birth weight (ELBW) children. Methods: Sixty-four ELBW children at least 3 years of age were recruited. Visual acuity (VA) was assessed using the Teller acuity cards (TACs) and a letter test, if possible. A validated questionnaire assessing 25 fine (part A) and 20 gross motor (part B) skills was administered to the parents. Data were collected on retinopathy of prematurity (ROP) zone, intraventricular haemorrhage (IVH), length of stay in hospital, and number of days on oxygen. Results: Abnormal TAC acuity was associated with significantly lower scores on both parts A and B (part A: 21.5 versus 11.8, p < 0.001; part B: 17.5 versus 13.2, p < 0.001). Linear regression demonstrates a significant direct relationship between letter acuity and score A only (p = 0.03, r2 = 0.179). Neither length of hospital stay, number of days ventilated, nor a history of IVH were associated with score A or B. However, the presence of ROP zone 1 was associated with a lower score A (p = 0.03). Conclusion: In this ELBW cohort VA and ophthalmic factors were the only factors associated with scores of development, particularly fine motor development.

Safety assessment of docosahexaenoic acid in X-linked retinitis pigmentosa: the 4-year DHAX trial.

PURPOSE Docosahexaenoic acid (DHA) continues to be evaluated and recommended as treatment and prophylaxis for various diseases. We recently assessed efficacy of high-dose DHA supplementation to slow vision loss in patients with X-linked retinitis pigmentosa (XLRP) in a randomized clinical trial. Because DHA is a highly unsaturated fatty acid, it could serve as a target for free-radical induced oxidation, resulting in increased oxidative stress. Biosafety was monitored during the 4-year trial to determine whether DHA supplementation was associated with identifiable risks. METHODS Males (n = 78; 7-31 years) meeting entry criteria were enrolled. The modified intent-to-treat cohort (DHA = 33; placebo = 27) adhered to the protocol ≥ 1 year. Participants were randomized to an oral dose of 30 mg/kg/d DHA or placebo plus a daily multivitamin. Comprehensive metabolic analyses were assessed for group differences. Treatment-emergent adverse events including blood chemistry metabolites were recorded. RESULTS By year 4, supplementation elevated plasma and red blood cell-DHA 4.4- and 3.6-fold, respectively, compared with the placebo group (P < 0.00001). Over the trial duration, no significant differences between DHA and placebo groups were found for vitamin A, vitamin E, platelet aggregation, antioxidant activity, lipoprotein cholesterol, or oxidized LDL levels (all P > 0.14). Adverse events were transient and not considered severe (e.g., gastrointestinal [GI] irritability, blood chemistry alterations). One participant was unable to tolerate persistent GI discomfort. CONCLUSIONS Long-term, high-dose DHA supplementation to patients with XLRP was associated with limited safety risks in this 4-year trial. Nevertheless, GI symptoms should be monitored in all patients taking high dose DHA especially those with personal or family history of GI disturbances. (ClinicalTrials.gov number, NCT00100230.).