|Home | About | Journals | Submit | Contact Us | Français|
We evaluated whether a diet high in long chain omega-3 fatty acids can slow the rate of visual acuity loss among patients with retinitis pigmentosa on vitamin A palmitate.
We calculated dietary intake from questionnaires completed annually by 357 adult patients who were all receiving vitamin A 15,000 IU/day for 4–6 years. Rates of visual acuity decline were compared between those with high (≥ 0.20 g/day) versus low (<0.20 g/day) omega-3 intake. Analyses took age into account.
Mean rates of decline of acuity were slower among those with high omega-3 intake; ETDRS distance acuity: high =0.59 letter/year, low=1.00 letter/year, p=0.001; Snellen retinal acuity: high = 1.5%/year; low = 2.8%/year, p=0.030.
We conclude that mean annual rates of decline in distance and retinal visual acuities in adults with retinitis pigmentosa taking vitamin A 15,000 IU/day are slower over 4–6 years among those consuming a diet rich in omega-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.
Retinitis pigmentosa has a prevalence of about 1 in 4000; about 2 million people are affected worldwide.1–8 Patients typically report night blindness in adolescence and loss of side vision in young adulthood. As the condition advances they develop tunnel vision and some become virtually blind by age 60. Ocular findings include waxy pallor of the optic discs, attenuated retinal vessels, and intraretinal pigment around the mid-periphery. The majority develop central posterior subcapsular cataracts. Patients have elevated final dark-adaptation thresholds and reduced and delayed electroretinograms.9–13 Measures of visual function9–13 and histopathologic studies14,15 have established that visual loss occurs because of loss of function and degeneration of rod and cone photoreceptors across the retina.
Three clinical trials conducted by us in adults with typical retinitis pigmentosa from 1984–1991,16 from 1996–2001,17,18 and from 2003–200819 provided evidence that oral vitamin A as retinyl palmitate (15,000 IU/day) alone or in combination with an omega-3 rich diet (≥0.20 g/day), on average, slowed the rate of decline of retinal function in this condition without toxic side effects. In these trials of 4–6 year duration, treatment effects were observed on the rate of decline of the electroretinogram16 or visual field18,19 but no significant effects on decline in distance or retinal acuity were reported.
Visual acuity declines, on average, very slowly in patients with retinitis pigmentosa.20–22 Since eligibility criteria for the three trials were comparable and testing methods were the same for measuring acuity and estimating dietary omega-3 intake, we hypothesized that by combining data from all three clinical trials we would have sufficient statistical power to clarify whether any treatment effect on acuity occurred over a 4–6 year period.
We analyzed visual acuity data from three clinical trials conducted by us among patients with typical retinitis pigmentosa from 1984–1991 (clinical trial I), from 1996–2001 (clinical trial II), and from 2003–2008 (clinical trial III). Each had been approved by the Institutional Review Boards of the Massachusetts Eye and Ear Infirmary and Harvard Medical School and each had been conducted in accord with the guidelines of the Declaration of Helsinki. In each trial informed consent had been obtained from the patients after explanation of the nature and possible consequences of the trial. We included nearly all available patients (ages 18–60) in these analyses. We identified 7 patients (3 from trial I, 3 from trial II, and 1 from trial III) as outliers for decline in ETDRS acuity based on the Generalized Extreme Studentized Deviate Test (GESD)23 and excluded their data from analyses. In addition, for 9 patients who participated in two of the trials and 1 patient who participated in all three trials, data used in the present analyses were restricted to the first trial in which they participated. From trial I we included data from 143 of the 146 patients ages 18–49 on vitamin A as retinyl palmitate 15,000 IU/day for 4–6 years,16 from trial II we included data from 101 of the 108 patients ages 18 to 56 on this dose of vitamin A for 4–5 years,18 and from trial III we included data from 113 of the 121 patients ages 18–60 on this dose of vitamin A for 4–5 years for a total sample of 357 patients. 19 In each trial patients were screened according to comparable preset eligibility criteria. These eligibility criteria included a best corrected Snellen distance visual acuity of 20/100 or better in at least one eye. In each trial patients agreed not to know their group assignment or the course of their condition until the end of the study. Eligible patients had been reexamined 6–8 weeks after the screening examination before treatment and then annually thereafter during treatment. In each trial all staff in contact with the patients had been masked to treatment group assignment and each examination had been conducted without prior information on results of previous examinations. In each trial the data had been monitored by an independent Data and Safety Monitoring Committee selected by the National Eye Institute.
In all three trials patients were evaluated under the same test conditions. They completed the Willett food frequency questionnaire24 at screening and at annual follow-up visits with a clinical coordinator. They then had an ocular examination including a measure of Early Treatment Diabetic Retinopathy Study (ETDRS) distance acuity at 3.2 meters25 and, after dilation, Snellen retinal acuity with a Guyton-Minkowski retinal potential acuity meter (PAM) which projected a numerical acuity chart on the retina in a narrow beam that can bypass a central cataract. 26,27 The ETDRS chart, the standard method for measuring visual acuity in clinical trials, contained 5 letters of comparable difficulty on each line; adjacent lines differed in letter size by 0.23 loge unit. A different chart was used for each eye to reduce the likelihood of memorization. The ETDRS visual acuity was scored as the total number of letters identified. A numerical chart was used for measuring retinal acuity also to minimize memorization; retinal acuities were then transformed to the natural log scale. We performed a slit-lamp examination to quantify area of posterior subcapsular cataracts, if present, with a slit-lamp beam, and then a fundus examination with an ophthalmoscope.
From the responses to the food frequency questionnaire, we calculated intake of long chain omega-3 fatty acids (primarily docosahexaenoic acid [DHA]), total energy intake, and other nutrients as described elsewhere.28 The validity of long chain omega-3 fatty acid intake calculated from this questionnaire has been documented by comparison with levels in adipose tissue.29 In trial II, the validity of this questionnaire for estimating omega-3 intake was confirmed by the moderate correlation between dietary omega-3 intake and red blood cell phosphatidylethanolamine docosahexaenoic acid (RBC PE DHA) levels (r=0.53, p<0.01). A level of RBC PE DHA ≥5% of total RBC PE fatty acids corresponded to an estimated dietary omega-3 intake of ≥ 0.20 g/day.18
Using the food frequency questionnaire, we estimated omega-3 intake for each patient by averaging the data from all examination visits to minimize measurement error. Using these values the entire study population (n=357) was divided into those with high (≥0.20 g/d, n=215) or low (<0.20 g/d, n=142) omega-3 intake. The value of 0.20 g/d represents the median intake observed during the course of trial II. Furthermore, in trial II, patients with ≥ 0.20 g/d of omega-3 intake were found to have a slower loss of visual field than those with omega-3 intake < 0.20 g/d. 18
Eyes with a Snellen distance acuity <20/100 at baseline were excluded from analysis of ETDRS or PAM data to reduce the likelihood of a floor effect. If patients became pseudophakic (n = 6), or if ETDRS acuity declined to 0 letters (n = 8) (comparable to ≤ 20/300), data from these eyes at subsequent visits were censored to eliminate any effect of cataract surgery on acuity or any possible floor effect. Visual acuity testing at 1 meter was not performed. Longitudinal regression analyses30,31 using PROC MIXED of SAS 9.1.332 were performed to compare rates of decline in distance acuity and retinal acuity by high (≥0.20 g/d) versus low (<0.20 g/d) omega-3 intake. Since there were significant differences in baseline visual acuity among the 3 clinical trials, we included indicator variables for trial in the models used for analyses.33 In addition, since patients in the high omega group were slightly older than those in the low omega group (see Table 1), we also included a term for age at baseline. These analyses also took into account variable lengths of follow-up and intraclass correlations of visual acuity between fellow eyes of individual patients at a single visit and between the same eye over time.
Since Goldmann fields were performed in trial I and Humphrey fields in trials II and III, we could not combine data from the three trials for field analyses. With respect to full-field cone ERGs, among the 375 patients taking vitamin A, 10 participated in more than one trial and data from the first trial only were included. In addition, 99 patients had initial values <0.68 μV and could not be followed due to a floor effect which would be expected to occur when they reached 0.34 μV. Thus the sample for ERG analysis included 266 patients with pretreatment amplitudes ≥0.68 μV and analysis of the combined data was performed; annual rate of decline of 163 patients with high omega-3 intake was compared with rate of decline of 103 patients with low omega-3 intake.
Table 1 shows baseline demographic and ocular findings for the study population divided into those above and below the median intake of 0.20 g/day of omega-3 fatty acids averaged over all visits derived from the food frequency questionnaire. All patients were receiving vitamin A palmitate 15,000 IU/d, and no significant differences in serum retinol levels were seen among those with high versus those with low dietary omega-3 intake. No significant differences were seen in any of the parameters noted in the table beyond age and the anticipated difference in omega-3 intake.
The mean annual rates of change of distance and retinal acuity were slower among those with high omega-3 intake (≥0.20 g/day) than among those with low intake (< 0.20 g/day). The mean rates of change in distance acuity were −0.59 letter per year (high omega-3 intake) versus −1.00 letter per year (low omega-3 intake), p=0.001. For retinal acuity mean rates of change were −0.015 loge-unit (1.5% decline) per year for high intake versus −0.028 loge-unit (2.8% decline) per year for low intake, p = 0.030. In separate analyses there was no significant effect of age on rate of visual acuity decline for either distance or retinal acuity (data not shown).
Figure 1 shows mean loge annual rates of decline of visual acuity by omega-3 intake for both distance and retinal acuity. Sample sizes were 357 for distance acuity and 342 for retinal acuity. The latter sample excluded patients with pseudophakia at baseline because potential media obstruction would not be relevant in following these patients. In figures 1 and and2,2, values for distance (ETDRS) acuity were obtained by multiplying the number of letters identified by 0.046 (i.e. 0.02 log10-unit per letter × 2.303 loge-unit per log10-unit) so that the slopes for distance and retinal acuity were on the same (loge) scale.
Figure 2 shows mean loge annual rates of visual acuity decline by quartile of omega-3 intake. Quartiles 1 and 2 combined (low omega-3 intake) have a faster rate of decline than quartiles 3 and 4 combined (high omega-3 intake) for both distance acuity (p=0.003) and retinal acuity (p=0.035), supporting the division of this population into those with intake ≥0.20 g/d and those with intake <0.20 g/d.
Only slight changes in cataract frequency and cataract size were observed in both groups over the course of these trials. The frequency of cataract increased by 11% among those with high omega-3 intake and by 10% among those with low omega-3 intake over 4–6 years. Among patients with cataracts, average cataract diameter increased by 0.07 mm over the course of these trials among those with omega-3 intake ≥0.20 g/day, while cataract diameter increased by 0.14 mm for those with omega-3 intake < 0.20 g/day. These increases were not significantly different by omega-3 intake group. Annual rate of decline of remaining cone ERG amplitude for those with high omega-3 intake was 9.8% and for those with low omega-3 intake was 9.6%; the difference in rates of decline was not significant.
In this cohort of 357 patients with typical retinitis pigmentosa taking 15,000 IU/day of vitamin A as retinyl palmitate for 4–6 years, those with a diet high in long chain omega-3 fatty acids (≥0.20 g/day) had a 40% slower mean annual rate of decline in distance visual acuity than those with a diet low in these fatty acids. The groups defined by high and low dietary omega-3 intake were balanced with respect to other dietary factors and anthropometric variables except for age differences which were controlled for in the statistical analyses. Both groups showed comparable change in posterior subcapsular cataract diameter, further suggesting that this effect of omega-3 intake on distance acuity was not due to cataract enlargement in these patients. Since vitamin A plus an omega-3 rich diet slowed the rate of decline of distance and retinal acuity by about the same extent, we conclude that the benefit of this combination was due to an effect on preserving central retinal function.
Although annual rates of decline in distance and retinal acuities were significantly different when comparing patients with high vs low omega-3 intake (p=0.001 and p=0.030, respectively), we could not detect a significant difference in annual rates of decline for full-field cone ERGs. Since the full-field cone ERG is generated predominantly by mid- and far-peripheral cones and since no effect of omega-3 intake could be detected in this measure, this observation suggests that the benefit of omega-3 intake is limited to acuity and central field preservation (see below).
The mean rate of decline in letters per year on ETDRS testing was 0.59 letter for patients on vitamin A with high omega-3 intake versus 1.00 letter for patients on vitamin A with low omega-3 intake over a 4- to 6-year duration. If these rates are sustained over the long-term, we estimate that a representative patient who starts vitamin A by age 35 and eats an omega-3 rich diet (i.e. one to two 3-ounce servings of oily fish per week) with an ETDRS acuity of 50 letters (equivalent to 20/30 on the Snellen chart) would, on average, be expected to decline to an ETDRS acuity of 24 letters (equivalent to 20/100 on the Snellen chart) at age 79, whereas this patient taking vitamin A with a low dietary omega-3 intake (e.g. less than one 3-ounce serving of oily fish per week) would decline to this level at age 61.
We have previously reported an effect of dietary omega-3 intake on retaining central visual field sensitivity as measured with the Humphrey Field Analyzer 30-2 program (size V white test light). 18 Patients on vitamin A palmitate 15,000 IU per day with omega-3 intake of at least 0.20 grams per day had almost a 50% slower rate of decline in central visual field sensitivity as measured by the HFA 30-2 program than those on this dose of vitamin A with lower omega-3 intake (p = 0.02). We concluded that for the average patient in trial II (age 37 with 869 db of field sensitivity at baseline) intake of ≥ 0.20 g/d of dietary omega-3 would result in an additional 19 years of central visual field preservation.18 In the present study we find virtually the same benefit for visual acuity preservation (i.e., 18 years of additional vision). Therefore, the treatment regimen of vitamin A combined with an omega-3 rich diet (≥ 0.20 g/d) should make it possible for many patients with typical retinitis pigmentosa to retain both visual acuity and central visual field for most of their lives.
This research was supported by NEI grants U10 EY02014, U10 EY011030, and U10 EY013945 and by the Foundation Fighting Blindness, Columbia, Maryland. The principal investigator (ELB) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.