Natural history of retinitis pigmentosa based on genotype, vitamin A/E supplementation, and an electroretinogram biomarker.

BACKGROUNDA randomized clinical trial from 1984 to 1992 indicated that vitamin A supplementation had a beneficial effect on the progression of retinitis pigmentosa (RP), while vitamin E had an adverse effect.METHODSSequencing of banked DNA samples from that trial provided the opportunity to determine whether certain genotypes responded preferentially to vitamin supplementation.RESULTSThe genetic solution rate was 587 out of 765 (77%) of sequenced samples. Combining genetic solutions with electroretinogram outcomes showed that there were systematic differences in severity and progression seen among different genetic subtypes of RP, extending findings made for USH2A, RHO, RPGR, PRPF31, and EYS. Baseline electroretinogram 30-Hz flicker implicit time was an independent, strong predictor of progression rate. Using additional data and baseline implicit time as a predictor, the deleterious effect of vitamin E was still present. Surprisingly, the effect of vitamin A progression in the cohort as a whole was not detectable, with or without data from subsequent trials. Subgroup analyses are also discussed.CONCLUSIONOverall, genetic subtype and implicit time have significant predictive power for a patient's rate of progression, which is useful prognostically. While vitamin E supplementation should still be avoided, these data do not support a generalized neuroprotective effect of vitamin A for all types of RP.TRIAL REGISTRATIONClinicalTrials.gov NCT00000114, NCT00000116, and NCT00346333.FUNDINGFoundation Fighting Blindness and the National Eye Institute: R01 EY012910, R01 EY031036, R01 EY026904, and P30 EY014104.

Association of Vitamin A Supplementation With Disease Course in Children With Retinitis Pigmentosa.

Importance: While oral vitamin A supplementation is considered to potentially slow loss of retinal function in adults with retinitis pigmentosa and normal liver function, little data from children with this disease are available. Objective: To compare disease courses in children with retinitis pigmentosa taking or not taking vitamin A supplementation. Design, Setting, and Participants: Retrospective, nonrandomized comparison of vitamin A and control cohorts followed up for a mean of 4 to 5 years by the Electroretinography Service of the Massachusetts Eye and Ear Infirmary. The study included children with different genetic types of typical retinitis pigmentosa: 55 taking vitamin A and 25 not taking vitamin A. The dates for patient evaluations ranged from June 1976 to July 2016, and the data analysis occurred in October 2016. Interventions: Age-adjusted dose of oral vitamin A palmitate (≤15 000 IU/d). Main Outcomes and Measures: Mean exponential rates of change of full-field cone electroretinogram amplitude to 30-Hz flashes estimated by repeated-measures longitudinal regression without and with adjusting for potential confounders. Results: Of the 55 children in the vitamin A cohort, 38 (69%) were male; the mean [SD] age was 9.1 [1.9] years; and 48 (87%) were white , 6 (11%) were Asian, and 1 (2%) was black. Of the 25 members of the control cohort, 19 (76%) were male; the mean [SD] age was 9.2 [1.7] years; and 25 (100%) were white. The estimated mean rates of change with the unadjusted model were -0.0713 loge unit/y (-6.9% per year) for the vitamin A cohort and -0.1419 loge unit per year (-13.2% per year) for the control cohort (difference, 0.0706 loge unit per year; 95% CI for the difference, 0.0149-0.1263 loge unit per year; P = .01). The adjusted model confirmed a slower mean rate of decline in the vitamin A cohort (difference, 0.0771 loge-unit per year; 95% CI for the difference, 0.0191-0.1350 loge-unit per year; P = .009). With respect to ocular safety, the mean exponential rates of change of visual field area and visual acuity and the incidences of falling to a visual field diameter of 20° or less or a visual acuity of 20/200 or less in at least 1 eye did not differ by cohort. Conclusions and Relevance: A vitamin A palmitate supplement was associated with a slower loss of cone electroretinogram amplitude in children with retinitis pigmentosa. Although the relatively small-sample, retrospective, nonrandomized design does not allow a test of causation and is subject to possible biases, these findings support consideration of an age-adjusted dose of vitamin A in the management of most children with the common forms of retinitis pigmentosa.

The relationship of central foveal thickness to urinary iodine concentration in retinitis pigmentosa with or without cystoid macular edema.

IMPORTANCE: Current treatments for cystoid macular edema (CME) in retinitis pigmentosa (RP) are not always effective, may lead to adverse effects, and may not restore visual acuity. The present research lays the rationale for evaluating whether an iodine supplement could reduce CME in RP. OBJECTIVE: To determine whether central foveal thickness (CFT) in the presence of CME is related to dietary iodine intake inferred from urinary iodine concentration (UIC) in nonsmoking adults with RP. DESIGN, SETTING, AND PARTICIPANTS: We performed a cross-sectional observational study of 212 nonsmoking patients aged 18 to 69 years referred to our institution for RP with visual acuity of no worse than 20/200 in at least 1 eye. EXPOSURE: Retinitis pigmentosa with or without CME. MAIN OUTCOMES AND MEASURES: With the eye as the unit of analysis, the relationship of log CFT measured by optical coherence tomography to UIC measured from multiple spot samples and represented as a 3-level classification variable (<100, 100-199, and ≥200 µg/L), assigning greater weight to patients with more reliable UIC estimates. RESULTS: Analyses were limited to 199 patients after excluding 11 who failed to return urine samples for measuring UIC and 2 outliers for UIC. Of the 199 patients, 36.2% had CME in 1 or both eyes. Although log CFT was inversely related to UIC based on findings from all eyes (P = .02), regression of log CFT on UIC separately for eyes with and without CME showed a strong inverse significant relationship for the former group (P < .001) and no significant relationship for the latter group (P = .66) as tested. For the eyes with CME, CFT ranged from a geometric mean of 267 µm for a median UIC of less than 100 µg/L to a geometric mean of 172 µm for a median UIC of 200 µg/L or greater. In contrast, we found no significant association between CME prevalence and UIC based on the entire sample as tested (odds ratio, 1.01 [95% CI, 0.38-2.67]; P = .99). CONCLUSIONS AND RELEVANCE: A higher UIC in nonsmoking adults with RP was significantly associated with less central foveal swelling in eyes with CME. Additional study is required to determine whether an iodine supplement can limit or reduce the extent of CME in patients with RP.

ω-3 intake and visual acuity in patients with retinitis pigmentosa receiving vitamin A.

OBJECTIVE: To evaluate whether a diet high in long chain ω-3 fatty acids can slow the rate of visual acuity loss among patients with retinitis pigmentosa receiving vitamin A palmitate. METHODS: We calculated dietary intake from questionnaires completed annually by 357 adult patients from 3 randomized trials who were all receiving vitamin A, 15 000 IU/d, for 4 to 6 years. Rates of visual acuity decline were compared between those with high (≥0.20 g/d) vs low (<0.20 g/d) ω-3 intake. Analyses took age into account. RESULTS: Mean rates of decline of acuity were slower among those with high ω-3 intake: Early Treatment Diabetic Retinopathy Study distance acuity: high intake=0.59 letter per year, low intake=1.00 letter per year,P=.001; Snellen retinal acuity: high intake=1.5% per year, low intake=2.8% per year, P=.03. CONCLUSIONS: We conclude that mean annual rates of decline in distance and retinal visual acuities in adults with retinitis pigmentosa receiving vitamin A, 15 000 IU/d,are slower over 4 to 6 years among those consuming a diet rich in ω-3 fatty acids. To our knowledge, this is the first report that nutritional intake can modify the rate of decline of visual acuity in retinitis pigmentosa.

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A.

OBJECTIVE: To determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received 12 mg of lutein or a control tablet daily. All were given 15,000 IU/d of vitamin A palmitate. Randomization took into account genetic type and baseline serum lutein level. MAIN OUTCOME MEASURES: The primary outcome was the total point score for the Humphrey Field Analyzer (HFA) 30-2 program; prespecified secondary outcomes were the total point scores for the 60-4 program and for the 30-2 and 60-4 programs combined, 30-Hz electroretinogram amplitude, and Early Treatment Diabetic Retinopathy Study acuity. RESULTS: No significant difference in rate of decline was found between the lutein plus vitamin A and control plus vitamin A groups over a 4-year interval for the HFA 30-2 program. For the HFA 60-4 program, a decrease in mean rate of sensitivity loss was observed in the lutein plus vitamin A group (P = .05). Mean decline with the 60-4 program was slower among those with the highest serum lutein level or with the highest increase in macular pigment optical density at follow-up (P = .01 and P = .006, respectively). Those with the highest increase in macular pigment optical density also had the slowest decline in HFA 30-2 and 60-4 combined field sensitivity (P = .005). No significant toxic effects of lutein supplementation were observed. CONCLUSION: Lutein supplementation of 12 mg/d slowed loss of midperipheral visual field on average among nonsmoking adults with retinitis pigmentosa taking vitamin A. Application to Clinical Practice Data are presented that support use of 12 mg/d of lutein to slow visual field loss among nonsmoking adults with retinitis pigmentosa taking vitamin A. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00346333.

Further evaluation of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment: subgroup analyses.

OBJECTIVE: To determine whether docosahexaenoic acid will slow the course of retinal degeneration in subgroups of patients with retinitis pigmentosa who are receiving vitamin A. DESIGN: A cohort of 208 patients with retinitis pigmentosa, aged 18 to 55 years, were randomly assigned to 1200 mg of docosahexaenoic acid plus 15 000 IU/d of vitamin A given as retinyl palmitate (DHA + A group) or control fatty acid plus 15 000 IU/d of vitamin A (control + A group) and followed up over 4 years. Seventy percent of the patients in each group were taking vitamin A, 15 000 IU/d, prior to entry. We compared rates of decline in ocular function in the DHA + A vs control + A groups among the subgroups defined by use or nonuse of vitamin A prior to entry. We also determined whether decline in ocular function was related to red blood cell phosphatidylethanolamine docosahexaenoic acid level, dietary omega-3 fatty acid intake, or duration of vitamin A use. Main outcome measures were Humphrey Field Analyzer visual field sensitivity, 30-Hz electroretinogram amplitude, and visual acuity. RESULTS: Among patients not taking vitamin A prior to entry, those in the DHA + A group had a slower decline in field sensitivity and electroretinogram amplitude than those in the control + A group over the first 2 years (P =.01 and P =.03, respectively); these differences were not observed in years 3 and 4 of follow-up or among patients taking vitamin A prior to entry. In the entire cohort, red blood cell phosphatidylethanolamine docosahexaenoic acid level was inversely related to rate of decline in total field sensitivity over 4 years (test for trend, P =.05). This was particularly evident over the first 2 years among those not on vitamin A prior to entry (test for trend, P =.003). In the entire control + A group, dietary omega-3 fatty acid intake was inversely related to loss of total field sensitivity over 4 years (intake, <0.20 vs > or =0.20 g/d; P =.02). The duration of vitamin A supplementation prior to entry was inversely related to rate of decline in electroretinogram amplitude (P =.008). CONCLUSIONS: For patients with retinitis pigmentosa beginning vitamin A therapy, addition of docosahexaenoic acid, 1200 mg/d, slowed the course of disease for 2 years. Among patients on vitamin A for at least 2 years, a diet rich in omega-3 fatty acids (> or =0.20 g/d) slowed the decline in visual field sensitivity.

Clinical trial of docosahexaenoic acid in patients with retinitis pigmentosa receiving vitamin A treatment.

OBJECTIVE: To determine whether a therapeutic dose of docosahexaenoic acid (DHA), an omega-3 fatty acid, will slow the course of retinal degeneration in adult patients with retinitis pigmentosa who are also receiving vitamin A. DESIGN: Randomized, controlled, double-masked trial of 221 patients, aged 18 to 55 years, evaluated over a 4-year interval. Patients were given either 1200 mg/d of docosahexaenoic acid or control capsules. All were given 15 000 IU/d of vitamin A (given as retinyl palmitate). Randomization considered genetic type and baseline dietary omega-3 fatty acid intake. MAIN OUTCOME MEASURES: The primary outcome measure was the total point score for the 30-2 program of the Humphrey field analyzer; secondary outcome measures were the total point score for the 30-2 and 30/60-1 programs combined, 30-Hz electroretinogram amplitude, and Early Treatment Diabetic Rentinopathy Study visual acuity. RESULTS: No significant differences in decline in ocular function were found between the docosahexaenoic acid plus vitamin A (DHA + A) group and control plus vitamin A (control + A) group over a 4-year interval among all 221 randomized patients or among the 208 patients who completed all 4 follow-up visits. The mean annual rate of loss of sensitivity for the Humphrey Field Analyzer 30-2 program was 37 dB for the DHA + A group and 38 dB for the control + A group (P =.88). For the Humphrey Field Analyzer 30-2 and 30/60-1 programs combined, the mean annual rates of loss of field sensitivity were 57 dB for the DHA + A group and 60 dB (P =.73) for control + A group. No toxic adverse effects were observed. No significant differences by treatment group assignment were observed within genetic types or within the category of baseline omega-3 fatty acid intake. CONCLUSION: In patients assigned to receive 15 000 IU/d of vitamin A, this randomized trial showed that 1200 mg/d of docosahexaenoic acid supplementation over a 4-year interval did not, on average, slow the course of disease in patients with retinitis pigmentosa.