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Clinical Trial of Docosahexaenoic Acid in Patients With Retinitis Pigmentosa Receiving Vitamin A Treatment
Eliot L. Berson, MD;
Bernard Rosner, PhD;
Michael A. Sandberg, PhD;
Carol Weigel-DiFranco, MA;
Ann Moser, BA;
Robert J. Brockhurst, MD;
K. C. Hayes, DVM, PhD;
Chris A. Johnson, PhD;
Ellen J. Anderson, RD;
Alexander R. Gaudio, MD;
Walter C. Willett, MD;
Ernst J. Schaefer, MD
Arch Ophthalmol. 2004;122:1297-1305.
ABSTRACT
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Objective To determine whether a therapeutic dose of docosahexaenoic acid (DHA), an  -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 -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 -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.
INTRODUCTION
Retinitis pigmentosa has a worldwide prevalence of about 1 in 4000 persons.1-10 Affected patients typically show elevated dark-adaptation thresholds,11-12 constricted visual fields, retinal arteriolar attenuation, intraretinal pigment around the midperiphery, and reduced and delayed electroretinograms (ERGs).13-14 Histological studies have shown that visual loss occurs owing to degeneration of rod and cone photoreceptors.15-16 A prior randomized, controlled trial showed that patients treated with vitamin A palmitate, 15 000 IU/d, had, on average, a slower rate of decline of retinal function as monitored by the ERG compared with those not receiving this dose.17
We and others have found that some patients with retinitis pigmentosa have decreased mean plasma and red blood cell (RBC) docosahexaenoic acid (DHA) concentrations.18-24 Rod outer segment membranes contain exceptionally large amounts of polyunsaturated fatty acids, especially DHA. In fact, they compose almost half of the esterified fatty acids in the outer segment phospholipids.25-27 Docosahexaenoic acid is a long chain -3 fatty acid found particularly in some fish (eg, salmon and tuna). The RBC DHA levels have been strongly correlated with DHA levels in the retina (r = 0.88).28 The proportion of DHA in outer segment phosphatidylethanolamine (PE) relative to other fatty acids is typically 10- to 15-fold higher than in nonneural tissue such as RBC membranes.25, 27 The special lipid composition of rod outer segments is thought to be necessary to maintain cellular membrane disc fluidity for the normal functioning of rhodopsin as it changes conformation in the initial stages of phototransduction.26, 29-33 Furthermore, it has been proposed that a concentration gradient of DHA normally exists in the subretinal space between the rod outer segments (higher concentration) and the retinal pigment epithelium (lower concentration) and that the release of 11-cis retinal from interphotoreceptor retinoid-binding protein is facilitated when interphotoreceptor retinoid-binding protein is exposed to a sufficient DHA concentration in the subretinal space.34-37
Because RBC membrane phospholipid levels are similar in composition to, and change in parallel with, retinal phospholipid levels with dietary manipulation,38-41 we evaluated the DHA content of RBC PE in patients with retinitis pigmentosa. We found that RBC PE DHA levels in our patients were significantly lower, on average, than in subjects with normal vision.24 In an analysis of longitudinal data from participants in our previous trial of vitamin A and/or vitamin E for whom we had RBCs available for analysis at year 3 or 4 of follow-up (n = 61), we found that the decline in 30-Hz ERG amplitude in these patients over a 4-year interval was inversely related to the RBC PE DHA concentration (P = .03) for all genetic types combined. These results persisted after controlling for age, sex, genetic type, baseline ERG amplitude, and treatment group assignment in a multiple regression model (P = .05).
The significant positive relationship between RBC PE DHA concentration and the preservation of ERG amplitude, the known role of DHA in maintaining normal photoreceptor function, and the evidence that vitamin A slows the average decline in ERG amplitude in patients with retinitis pigmentosa prompted us to conduct this randomized, controlled clinical trial to determine whether orally administered docosahexaenoic acid can halt or slow the course of the typical forms of retinitis pigmentosa among patients receiving vitamin A (given as retinyl palmitate) therapy.
METHODS
PROTOCOL
We first conducted a pilot study on 35 patients with the typical forms of retinitis pigmentosa who received 600 mg/d (n = 9) of docosahexaenoic acid, 1200 mg/d (n = 9) of docosahexaenoic acid, or a placebo control (n = 17) over 3 months to determine to what extent these dosages raised the concentration of RBC PE DHA in the short-term. All participants were also treated with 15 000 IU/d of vitamin A. Both dosages of docosahexaenoic acid at least doubled the RBC PE DHA concentration and were safely tolerated in this population. We chose the higher dosage of docosahexaenoic acid for this trial assuming that any therapeutic effect would be more readily detected with the higher dosage.
We screened patients with retinitis pigmentosa for eligibility according to ocular, dietary, and medical criteria (Table 1). We performed a baseline examination on eligible patients within 8 weeks of the screening examination. At baseline, patients were randomly assigned to 1 of 2 groups—those who received a supplement of 6 capsules per day each containing 500 mg of fatty acids of which 200 mg was docosahexaenoic acid for a total of 1200 mg/d of docosahexaenoic acid or those who received 6 placebo capsules per day containing 500 mg of fatty acids with no docosahexaenoic acid. The docosahexaenoic acid–enriched capsules, provided by Martek Biosciences Corporation, Columbia, Md, contained a vegetable oil from microalgae with ascorbyl palmitate (<0.001 mg) and tocopherols (<0.001 mg) as antioxidants. The fatty acid composition was as follows: capric, 0 to 10 mg; lauric, 0 to 30 mg; myristic, 50 to 100 mg; palmitic, 50 to 100 mg; palmitoleic, 0 to 10 mg; stearic, 0 to 10 mg; oleic, 50 to 150 mg; linoleic, 0 to 25 mg; docosahexaenoic, 190 to 210 mg; nervonic, 0 to 10 mg; and others, 0 to 15 mg. The control capsules, also provided by Martek Biosciences Corporation, contained a mixture of 50% corn and 50% soybean oil with ascorbyl palmitate (<0.001 mg) and tocopherols (<0.001 mg) as antioxidants. Their fatty acid composition was as follows: palmitic, 45 to 55 mg; stearic, 10 to 20 mg; oleic, 110 to 125 mg; and  -linolenic, 15 to 25 mg. Patients were instructed to take 3 capsules in the morning and 3 capsules in the evening. Both the docosahexaenoic acid plus vitamin A (DHA + A)–supplemented group and the control plus vitamin A (control + A) group received 3 g of fatty acids from these capsules; on a 2000-calorie diet this constituted 1.4% of calories as fat or an increase of 27 cal/d. All patients were given vitamin A as 15 000 IU of retinyl palmitate in tablets (Akorn Ophthalmics, Buffalo Grove, Ill) and instructed to take 1 tablet daily with breakfast. Patients completed a food frequency questionnaire42-43 and medical questionnaire at each visit with the aid of a clinical coordinator; they were followed up annually over 4 years (Table 2). Plasma and RBC PE DHA levels were monitored as measures of compliance,44 and serum retinol and retinyl ester levels as well as serum liver function test results were evaluated to help exclude any toxic effects of vitamin A therapy.45
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Table 1. Eligibility Criteria
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Table 2. Data Collected at Each Visit
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We used the measurement of static perimetric sensitivities (ie, total point score) with the 30-2 program size V target in the Humphrey Field Analyzer (HFA) (Carl Zeiss Ophthalmic Systems, Inc, Dublin, Calif) as the primary outcome measure. The size V target was used to minimize the number of locations with floor effects (sensitivity  0 dB). The FASTPAC test strategy was used to test both central (30-2) and peripheral (30/60-1) visual fields in as short a time as possible.46-48 Because the area of the visual field is statistically related to ERG amplitude49 and because our preliminary data derived from the 30-Hz ERG amplitude, we used the full-field 30-Hz ERG amplitude as a secondary outcome measure. Visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS])50 and the total point score to a size V target with the HFA 30-2 and 30/60-1 programs combined were also followed up as secondary outcome measures.
We estimated that 220 patients were needed to provide sufficient power (ie, = .05,  = .10) to observe a statistically significant difference (29 dB) between mean change in the DHA + A and control + A groups with respect to HFA 30-2 total point score over a 4-year interval and allowing for 5% attrition. The project was approved by the institutional review boards of the Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston, and the study conformed to the Declaration of Helsinki. All patients signed an informed consent form prior to the screening examination and, if eligible, prior to the baseline examination as well. The trial was funded by the National Eye Institute as a single-center study. A Data and Safety Monitoring Committee selected by the National Eye Institute met with the investigators prior to the onset of the study to approve the protocol and annually thereafter in closed session to review the results for both patient safety and efficacy. The study was planned to allow 4 years of follow-up for each patient. The Lan-DeMets -spending approach with an O'Brien-Fleming boundary with 5 looks was prespecified51 as the stopping rule. However, this stopping rule was just a guideline as the Data and Safety Monitoring Committee needed to consider all information from several measures of efficacy and safety in making informed decisions about stopping the study.
ASSIGNMENT
The procedure for randomization considered the estimated dietary intake and genetic type at the screening examination. A method of block randomization was used within 2 groups of -3 fatty acid intake (above and below the median of 0.16 g/d determined from a food frequency questionnaire administered to patients in our previous therapeutic trial of vitamin A) and 6 genetic types (dominant without known mutation, dominant with known rhodopsin or rhodopsin/peripherin mutation, recessive, X-linked, isolate, or undetermined [eg, adopted]) or 12 strata. Within each stratum, patients were randomized in equal numbers to the DHA + A group and control + A group in blocks of size 4. A separate set of randomization assignments was maintained for each stratum based on a computer-generated set of random numbers that was available only to a programmer who provided assignment information to the data manager (C.W.D.) on a case-by-case basis. Group assignment was implemented by the data manager.
MASKING
All members of the staff in contact with the patients, including the principal investigator (E.L.B.), were masked with regard to each patient's treatment group assignment. Each ocular examination was performed without review of previous records. All serum samples were analyzed without knowledge of treatment group assignment. Patients did not know the contents of the supplement under study or their treatment group assignment and also agreed not to know the course of their retinal degeneration until the end of the study. Treatment group assignments and plasma DHA and RBC PE DHA levels were placed in records separate from that used for ocular examinations as part of masking those in contact with the patients.
DATA ANALYSIS
Outcome data for a given patient for each visit represented the average of test results from both eyes or for a single eye if data for the other eye were unavailable. Visual field data (total point scores) were analyzed separately for the central field (HFA 30-2 program) and for total field (HFA 30-2 and 30/60-1 programs combined) when both were available. If an eye became pseudophakic after the baseline visit, visual field data for that eye were analyzed only for those visits prior to cataract surgery. If the total point score for a visual field became zero, the visit at which the zero score was first obtained was included in the analyses but subsequent visits were censored. Slopes and changes from baseline were computed for each patient, and average slopes and mean changes were evaluated for each parameter of ocular function by treatment group. Comparisons by assigned treatment group were also performed within genetic type and within category (ie, above and below the intake of 0.16 g/d) at baseline of dietary -3 fatty acid intake. Longitudinal regression analyses were then performed based on PROC MIXED of SAS version 6.12.52
The regression models that we used in this clinical trial generally have the following form:
(1) Yit = a + b1Gi + b2t + b3tGi + eit,
where Yit indicates outcome variable (eg, HFA 30-2 total point score) for the ith subject at time t; Gi, indicator variable for treatment group, equals 1 if patient i is in group 1, equals 0 if patient i is in group 2; t, time in years from the screening visit, t equals 0, 1, 2, . . . , 4; eit, error term that represents within-person variation for the ith patient at time t; and Corr (eit1, eit2) = r. We used PROC MIXED to fit model 1 where both a and b = (b1, b2, b3) are assumed to be random.
Although the baseline value is not explicitly specified as a covariate in equation 1, it is implicitly adjusted for because of the correlation between the error terms for the baseline visit and each follow-up visit. In particular, the marginal model in equation 1 can be rewritten in conditional form as follows:
(2) Yit = [a(1 – R)] + RYi0 + [b1(1 – R)Gi] + b2t + b3tGi + uit,
where Corr(uit1, uit2) equals [R/(1 + R)].
Equation 2 is a conditional model. Thus, b2 can be interpreted as the slope in the control + A group (ie, group 2), b2 + b3 can be interpreted as the slope in the DHA + A group (ie, group 1), and b3 is the difference in slope between the DHA + A group and the control + A group after controlling for baseline values.53
Two hundred eight patients were seen for all 4 years of follow-up and the results will focus on these patients. Sensitivity analyses were performed on all 221 patients randomized (1) for all available data and (2) after using multiple imputation methods to account for missing data.54
RESULTS
PARTICIPANT FLOW AND FOLLOW-UP
From May 13, 1996, to September 26, 1997, we examined 456 patients from across the United States to identify 221 patients (1 per family) with retinitis pigmentosa who met the preset list of eligibility criteria. Two hundred eight of these patients completed all 4 annual follow-up visits. Baseline characteristics of these 208 patients for factors used in the stratification of the randomization (ie, genetic type and dietary -3 fatty acid intake) are given in Table 3 by assigned treatment group. Also given is baseline information concerning the distribution of demographic factors, ocular function, and laboratory measures of DHA and retinol concentrations. Ninety-seven percent of the eligible patients had intraretinal bone spicule pigmentation around the midperipheral fundus. Eleven percent of patients reported partial hearing loss. Six percent of the study population were minorities. With the exception of RBC PE DHA levels, no significant differences in any of the above patient characteristics were noted between the DHA + A and control + A groups. Fifty percent of patients in the DHA + A group and 64% of patients in the control + A group had cataracts in at least 1 eye at baseline (P = .05).
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Table 3. Baseline Demographic and Ocular Characteristics of 208 Patients With Retinitis Pigmentosa*
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SAFETY AND COMPLIANCE
Capsule counts indicated that 92% of the docosahexaenoic acid capsules, 92% of the control capsules, and 94% of the vitamin A tablets were consumed over all 4 years. Similar results were seen with returned monthly calendars. One patient in the control + A group diagnosed as having breast cancer just before her year 4 visit died 4 months after the year 4 visit. No other patient reported the development of cancer to us during the study. No patient experienced a complete loss of vision in an eye over the course of the study. Furthermore, there was no evidence of systemic illness or a toxic effect that was attributable to the study capsules or to vitamin A during the course of this study based on complete blood cell counts, liver function assessments, patient responses to a symptom questionnaire, and on the serum retinol and serum retinyl ester levels. Two patients were examined by the consulting internist, 1 for gastrointestinal distress thought subsequently to be due to anxiety and the other for discoloration of the skin that proved subsequently to be related to Cushing syndrome.
Prior to treatment, the DHA + A and control + A groups showed comparable levels of plasma DHA (Table 3). At follow-up, mean ± SE plasma DHA percentages (mean of all follow-up measurements) of total plasma fatty acids were 5.12% ± 0.12% and 1.61% ± 0.07% for the DHA + A group vs the control + A group, respectively; mean change from baseline for the DHA + A group was significantly different from the mean change from baseline for the control + A group (P<.001). By year 1 the mean plasma DHA percentage of total fatty acids was 3-fold higher in the DHA + A group than in the control + A group and remained at that level for the 4 years of follow-up; no significant increase in plasma DHA percentage was noted in the control + A group.
Prior to treatment, the mean ± SE RBC PE DHA percentage of total RBC PE fatty acids was significantly higher in the DHA + A group (4.77% ± 0.18%) vs the control + A group (4.27% ± 0.14%) (P = .03) (Table 3). At year 1 of follow-up the mean ± SE RBC PE DHA percentages of total RBC PE fatty acids for the DHA + A group vs the control + A group were 12.62% ± 0.28% and 4.90% ± 0.18%; at year 4 the mean RBC PE DHA percentages of total fatty acids were 12.83% ± 0.05% and 4.66% ± 0.18% for the 2 groups, respectively. Averaging years 1 and 4, the mean ± SE change from baseline for the DHA + A group (7.95 ± 0.30) and mean change from baseline for the control + A group (0.51 ± 0.11) were both significantly different from zero (P<.001) and were significantly different from each other (P<.001). The RBC PE DHA values ranged from 2% to 18% of the total RBC PE fatty acids prior to treatment in both groups and at follow-up from 3% to 17% of the total RBC PE fatty acids in the DHA + A group and from 2% to 10% in the control + A group (Figure 1).
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Figure 1. Red blood cell phosphatidylethanolamine docosahexaenoic acid (RBC PE DHA) levels as a percentage of total RBC PE fatty acids in patients with retinitis pigmentosa supplemented with docosahexaenoic acid plus vitamin A (vitamin A given as retinyl palmitate) (DHA + A) or control plus vitamin A (control + A) measured prior to randomization (baseline) or as the mean of measurements at 1 year and 4 years subsequent to randomization (follow-up) among all patients in the 208 patient cohort for whom measurements were available. Sample sizes were 104 and 100 at baseline and 102 and 100 at follow-up for the DHA + A and control + A groups, respectively. Values have been displaced horizontally to facilitate visualization.
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Table 4 lists serum triglyceride and cholesterol levels at screening and year 4 for the 2 groups. The difference in slopes for the 2 groups was significant for the levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol.
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Table 4. Serum Triglyceride and Cholesterol Levels by Treatment Group*
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ANALYSIS OF OUTCOME MEASURES
Figure 2 shows mean ± SE values by year and treatment group for central field (HFA 30-2 program) sensitivity, total field (HFA 30-2 and 30/60-1 programs combined) sensitivity, 30-Hz ERG amplitude, and ETDRS visual acuity. Similar declines can be seen in all outcome measures in the DHA + A group vs the control + A group. Mean change analyses from time zero (mean of screening and baseline values) did not reveal statistically significant differences between the 2 treatment groups for any of these 4 measures.
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Figure 2. The mean central visual field sensitivity (Humphrey Field Analyzer [HFA] 30-2 program, size V target), the mean total visual field sensitivity (HFA 30-2 and 30/60-1 programs combined, size V target), the mean full-field, 30-Hz ERG amplitude, and the mean Early Treatment Diabetic Retinopathy Study visual acuity by year and treatment assignment (control plus vitamin A [vitamin A given as retinyl palmitate] [control + A] group vs docosahexaenoic acid plus vitamin A [DHA + A] group) for patients seen at all 4 years of follow-up. Symbols and error bars designate mean ± SE, respectively. Numbers of patients for the control + A group and the DHA + A group, respectively, are 102 and 103 (upper left panel), 102 and 102 (upper right panel), 100 and 101 (lower left panel), and 102 and 104 (lower right panel).
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Table 5 summarizes the mean annual rates of decline of visual field sensitivity to the HFA 30-2 program and the HFA 30-2 and 30/60-1 programs combined, of 30-Hz ERG amplitude, and of ETDRS visual acuity for the DHA + A group vs the control + A group among the 208 patients followed up for each of 4 annual visits. No significant differences in rates of change were observed between these 2 groups. Both groups lost, on average, about 37 to 38 dB per year to the HFA 30-2 program condition and 57 to 60 dB to the HFA 30-2 and 30/60-1 programs combined. These total point score declines correspond to losses of approximately 0.5 dB and 0.4 dB per year, respectively, for an average location in the visual field. Over 4 years, analysis of 30-Hz ERGs showed that the mean annual rates of decline of remaining function were 9.92% in the DHA + A group and 10.49% in the control + A group, which was not statistically significantly different (P = .64). These analyses were also performed on all available data, including patients with partial follow-up, but with missing values left as missing and after using multiple imputation methods to account for missing data among patients with incomplete follow-up. No substantive differences were noted between results obtained with these additional approaches compared with those in Table 5. A similar analysis as in Table 5 was performed for 0.5-Hz ERG amplitudes based on the 55% of patients with quantifiable responses; mean rate of decline for the DHA + A group (11.8%) was not significantly different from that for the control + A group (10.4%) (P = .54).
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Table 5. Annual Rate of Decline Over 4 Years for Measures of Ocular Function by Treatment Group*
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We also performed randomized comparisons by genetic type and by dietary intake of -3 fatty acids. No significant differences by treatment group assignment were observed for either the primary or the secondary outcome measures within the dominant, recessive, X-linked, or isolate forms of retinitis pigmentosa or within the category of baseline dietary -3 fatty acid intake (above and below intake of 0.16 g/d) (data not shown).
COMMENT
The present trial shows that in adult patients with retinitis pigmentosa, assigned to 15 000 IU/d of vitamin A, a daily supplement of 1200 mg of docosahexaenoic acid over a 4-year interval does not, on average, slow the course of retinal degeneration. Both the DHA + A and control + A groups lost 37 to 38 dB of visual field sensitivity to the HFA 30-2 program (size V target), 58 to 60 dB of visual field sensitivity to the HFA 30-2 and 30/60-1 programs combined (size V target), 10% of remaining 30-Hz cone ERG amplitude, and 0.7 letter of ETDRS visual acuity per year. No significant toxic adverse effects were noted over the course of this trial both for docosahexaenoic acid or vitamin A supplementation. Similarly, docosahexaenoic acid supplementation (400 mg/d) was associated with no identifiable safety risks over 4 years among 23 males with X-linked retinitis pigmentosa.55 No significant treatment effect was noted within any of the genetic types. Serum triglyceride levels increased by about 25% in the control + A group as described previously.45 In both groups the high-density lipoprotein cholesterol level increased and the low-density lipoprotein cholesterol level decreased or remained stable. On balance, changes in these values would not increase the risk for heart disease.
Good separation as monitored by mean RBC PE DHA levels was achieved between the DHA + A group vs the control + A group. The DHA + A group had a mean RBC PE DHA level 2- to 3-fold greater than the control + A group at 1 year and 4 years. At follow-up, averaging years 1 and 4, the mean RBC PE DHA level increased by 0.51% from baseline for the control + A group (significantly different from zero, P<.001) and increased 7.95% for the DHA + A group. How this RBC PE DHA change in the control + A group may have influenced their results and, thus, the comparison of results to the DHA + A group is unclear.
The lack of a significant difference in rate of loss of ocular function between the DHA + A and control + A groups precludes any general recommendation of DHA supplementation for patients with retinitis pigmentosa receiving vitamin A. Further investigation of these data from this trial or other trials may help to clarify whether any subgroups of patients with retinitis pigmentosa will benefit from a combination of docosahexaenoic acid plus vitamin A supplementation.
AUTHOR INFORMATION
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Correspondence: Eliot L. Berson, MD, Berman-Gund Laboratory for the Study of Retinal Degenerations, 243 Charles St, Boston, MA 02114.
Submitted for publication July 11, 2003; final revision received January 8, 2004; accepted April 19, 2004.
This study was supported by grant U10EY11030 from the National Eye Institute, Bethesda, Md, and in part by the Foundation Fighting Blindness, Owings Mills, Md.
We thank the study patients and their families and gratefully acknowledge the following individuals who contributed to the conduct of this trial: Tina Skop-Chaput, Michele Berry, Melissa Stillberger, Peggy Rodriguez, Kevin McDermott, Linda Berard, Heather Lee, Susana Chung, Shyana Harper, Anna Maria Baglieri, Ciara Rice, Cathy Lonergan, Suzanne Dalton, Marion McPhee, Martin Van Denburgh, Anita Liu, David Jones, and Sherrie Kaplan, PhD.
Members of the Data and Safety Monitoring Committee were Marian Fisher, PhD (chair); George Bresnick, MD; Baruch A. Brody, PhD; Barry Davis, MD, PhD; Natalie Kurinij, PhD (ex officio); Carol M. Mangione, MD; James Olson, PhD (1996-1999); Peter R. Pavan, MD (2000-2003); Sander J. Robins, MD; Pamela Sample, PhD; and Barbara A. Underwood, PhD (2001-2003).
From the Berman-Gund Laboratory for the Study of Retinal Degenerations, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston (Drs Berson, Rosner, Sandberg, Brockhurst, and Gaudio and Mss Weigel-DiFranco and Anderson); Kennedy Krieger Institute, Peroxisomal Diseases Laboratory, Baltimore, Md (Ms Moser); Foster Biomedical Research Laboratory, Brandeis University, Waltham, Mass (Dr Hayes); Devers Eye Institute, Portland, Ore (Dr Johnson); the Department of Nutrition, Harvard School of Public Health, Boston (Dr Willett); and the Lipid Metabolism Laboratory, Jean Mayer US Department of Agriculture Human Nutrition Research, Center on Aging at Tufts University, Boston (Dr Schaefer). The authors have no relevant financial interest in this article.
REFERENCES
1. Leber T. Die Pigmentdegeneration der Netzhaut und mit ihr verwandte Erkränkungen In: Graefe A, Saemisch-Hess T, eds. Handbuch der gesammten Augenheilkunde. Vol 7. 2nd ed. Leipzig, Germany: W Engelmann; 1916:1076-1225.
2. Bell J. Retinitis pigmentosa and allied diseases of the eye. In: Pearson K, ed. Treasury of Human Inheritance. Vol 2. London, England: Cambridge University Press; 1922:1-28.
3. Ammann F, Klein D, Franceschetti A. Genetic and epidemiological investigation of pigmentary degeneration of the retina and allied disorders in Switzerland. J Neurol Sci. 1965;2:183-196.
FULL TEXT
| PUBMED
4. Boughman JA, Conneally PM, Nance WE. Population genetic studies of retinitis pigmentosa. Am J Hum Genet. 1980;32:223-235.
ISI
| PUBMED
5. Bundy S, Crews SJ. Wishes of patients with retinitis pigmentosa concerning genetic counseling. J Med Genet. 1982;19:317-318.
FREE FULL TEXT
6. Hu DN. Genetic aspects of retinitis pigmentosa in China. Am J Med Genet. 1982;12:51-56.
FULL TEXT
|
ISI
| PUBMED
7. Bunker CH, Berson EL, Bromley WC, Hayes RB, Roderick TH. Prevalence of retinitis pigmentosa in Maine. Am J Ophthalmol. 1984;97:357-365.
ISI
| PUBMED
8. Heckenlively JR. Retinitis Pigmentosa. Philadelphia, Pa: JB Lippincott Co; 1988.
9. Haim M, Holm NV, Rosenberg T. Prevalence of retinitis pigmentosa and allied disorders in Denmark. Acta Ophthalmol (Copenh). 1992;70:178-186.
10. Berson EL. Retinitis pigmentosa: the Friedenwald Lecture. Invest Ophthalmol Vis Sci. 1993;34:1659-1676.
FREE FULL TEXT
11. Mandelbaum J. Dark adaptation: some physiologic and clinical considerations. Arch Ophthalmol. 1941;26:203-239.
FREE FULL TEXT
12. Sloan LL. Light sense in pigmentary degeneration of the retina. Arch Ophthalmol. 1942;28:613-631.
FREE FULL TEXT
13. Karpe G. Basis of clinical electroretinography. Acta Ophthalmol (Copenh). 1945;24(suppl):84.
14. Bjork A, Karpe G. The electroretinogram in retinitis pigmentosa. Acta Ophthalmol (Copenh). 1951;29:361-376.
15. Verhoeff FH. Microscopic observations in a case of retinitis pigmentosa. Arch Ophthalmol. 1931;5:392-407.
FREE FULL TEXT
16. Cogan DG. Symposium: primary chorioretinal aberrations with night blindness: pathology. Trans Am Acad Ophthalmol Otolaryngol. 1950;54:629-661.
17. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111:761-772.
FREE FULL TEXT
18. Converse CA, Hammer HM, Packard CJ, Shepherd J. Plasma lipid abnormalities in retinitis pigmentosa and related conditions. Trans Ophthalmol Soc U K. 1983;103:508-512.
19. Bazan NG, Scott BL, Reddy TS, Pelias MZ. Decreased content of docosahexaenoate and arachidonate in plasma phospholipids in Usher's syndrome. Biochem Biophys Res Comm. 1986;141:600-604.
FULL TEXT
|
ISI
| PUBMED
20. Anderson RE, Maude MB, Lewis RA, Newsome DA, Fishman GA. Fatty acid levels in retinitis pigmentosa [letter]. Exp Eye Res. 1987;44:155-159.
FULL TEXT
|
ISI
| PUBMED
21. Gong J, Rosner B, Rees DG, Berson EL, Weigel-DiFranco CA, Schaefer EJ. Plasma docosahexaenoic acid levels in various genetic forms of retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1992;33:2596-2602.
FREE FULL TEXT
22. McColl AJ, Converse CA. Lipid studies in retinitis pigmentosa. Prog Lipid Res. 1995;34:1-16.
FULL TEXT
|
ISI
| PUBMED
23. Hoffman DR, Birch DG. Docosahexaenoic acid in red blood cells of patients with X-linked retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1995;36:1009-1018.
FREE FULL TEXT
24. Schaefer EJ, Robins SJ, Patton GM, et al. Red blood cell membrane phosphatidylethanolamine fatty acid content in various forms of retinitis pigmentosa. J Lipid Res. 1995;36:1427-1433.
ABSTRACT
25. Anderson RE, Andrews LD. Biochemistry of retinal photoreceptor membranes in vertebrates and invertebrates. In: Westfall J, ed. Visual Cells in Evolution. New York, NY: Raven Press; 1975:1-22.
26. Fliesler SJ, Anderson RE. Chemistry and metabolism of lipids in the vertebrate retina. Prog Lipid Res. 1983;22:79-131.
FULL TEXT
|
ISI
| PUBMED
27. Anderson RE, Benolken RM, Dudley PA, Landis DJ, Wheeler TG. Polyunsaturated fatty acids of the photoreceptor membrane. Exp Eye Res. 1982;18:205-213.
28. Sarkadi-Nagy E, Wijendran V, Diau G, et al. The influence of prematurity and long chain polyunsaturate supplementation in 4-week adjusted age baboon neonate brain and related tissues. Pediatr Res. 2003;54:244-252.
FULL TEXT
|
ISI
| PUBMED
29. Roelofson B, Op den Kamp JA. Introduction to membrane phospholipids: structure, organization, and function. In: Zwaal RFA, ed. Coagulation and Lipids. Boca Raton, Fla; CRC Press; 1988:14-40.
30. Benga G, Holmes RP. Interactions between components in biological membranes and their implications for membrane function. Prog Biophys Mol Biol. 1984;43:195-257.
FULL TEXT
|
ISI
| PUBMED
31. Bazan NG, Burton SL. Docosahexaenoic acid and inherited retinal degenerations. In: Hollyfield JG, Anderson RE, LaVail MM, eds. Progress in Clinical Biological Research. New York, NY: Alan R Liss Inc; 1987:103-118.
32. Treen M, Uauy R, Jameson DM, Thomas VL, Hoffman DR. Effect of docosahexaenoic acid on membrane fluidity and function in intact cultured Y-79 retinoblastoma cells. Arch Biochem Biophys. 1992;294:564-570.
FULL TEXT
|
ISI
| PUBMED
33. Mitchell DC, Straume M, Litman BJ. Role of sn-1-saturated, sn-2-polyunsaturated phospholipids in control of membrane receptor conformational equilibrium: effects of cholesterol and acyl chain unsaturation on the metarhodopsin in equilibrium with metarhodopsin II equilibrium. Biochemistry. 1992;31:662-670.
FULL TEXT
| PUBMED
34. Chen Y, Noy N. Retinoid specificity of interphotoreceptor retinoid-binding protein. Biochemistry. 1994;33:10658-65.
FULL TEXT
| PUBMED
35. Chen Y, Houghton LA, Brenna JT, Noy N. Docosahexaenoic acid modulates the interactions of the interphotoreceptor retinoid-binding protein with 11-cis-retinal. J Biol Chem. 1996;271:20507-20515.
FREE FULL TEXT
36. Chen Y, Saari JC, Noy N. Interactions of all-trans-retinol and long-chain fatty acids with interphotoreceptor retinoid-binding protein. Biochemistry. 1993;32:11311-11318.
FULL TEXT
| PUBMED
37. Wolf G. Transport of retinoids by the interphotoreceptor retinoid-binding protein. Nutr Rev. 1998;56:156-158.
ISI
| PUBMED
38. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n–3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med. 1989;320:265-271.
ABSTRACT
39. Neuringer M, Connor WE, Van Petten C, Barstad L. Dietary omega-3 fatty acid deficiency and visual loss in infant rhesus monkeys. J Clin Invest. 1984;73:272-276.
40. Neuringer M, Anderson GJ, Connor WE. The essentiality of -3 fatty acids for the development and function of the retina and brain. Annu Rev Nutr. 1988;8:517-541.
FULL TEXT
|
ISI
| PUBMED
41. Birch DG, Birch EE, Hoffman DR, Uauy RD. Retinal development in very low-birth-weight infants fed diets differing in omega-3 fatty acids. Invest Ophthalmol Vis Sci. 1992;33:2365-2376.
FREE FULL TEXT
42. Willett WC, Sampson L, Browne ML, et al. The use of a self-administered questionnaire to assess diet four years in the past. Am J Epidemiol. 1988;127:188-199.
FREE FULL TEXT
43. London SJ, Sacks FM, Caesar J, Stampfer MJ, Siguel E, Willett WC. Fatty acid composition of subcutaneous adipose tissue and diet in postmenopausal US women. Am J Clin Nutr. 1991;54:340-345.
FREE FULL TEXT
44. Moser AB, Jones DS, Raymond GV, Moser HW. Plasma and red blood cell fatty acids in peroxisomal disorders. Neurochem Res. 1999;24:187-197.
FULL TEXT
|
ISI
| PUBMED
45. Sibulesky L, Hayes KC, Pronczuk A, Weigel-DiFranco C, Rosner B, Berson EL. Safety of less than 7,500 RE/day (25,000 IU/day) of vitamin A in adults with retinitis pigmentosa. Am J Clin Nutr. 1999;69:656-663.
FREE FULL TEXT
46. Mills RP, Barnebey HS, Migliazzo CV, Li Y. Does saving time using FASTPAC or suprathreshold testing reduce quality of visual fields? Ophthalmology. 1994;101:1596-1603.
ISI
| PUBMED
47. Schaumberger M, Schafer B, Lachenmayr BJ. Glaucomatous visual fields: FASTPAC versus full threshold strategy of the Hymphrey field analyzer. Invest Ophthalmol Vis Sci. 1995;36:1390-1397.
FREE FULL TEXT
48. Flanagan JG, Moss ID, Wild JM, et al. Evaluation of FASTPAC: a new strategy for threshold estimation with the Humphrey field analyzer. Graefes Arch Clin Exp Ophthalmol. 1993;231:465-469.
FULL TEXT
|
ISI
| PUBMED
49. Sandberg MA, Weigel-DiFranco C, Rosner B, Berson EL. The relationship between visual field size and electroretinogram amplitude in retinitis pigmentosa. Invest Ophthalmol Vis Sci. 1996;37:1693-1698.
FREE FULL TEXT
50. Ferris FL, Kassoff A, Bresnick GH, Bailey I. New visual acuity charts for clinical research. Am J Ophthalmol. 1982;94:91-96.
ISI
| PUBMED
51. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 1979;35:549-556.
FULL TEXT
|
ISI
| PUBMED
52. SAS Institute Inc. SAS Version 6.12. Cary, NC: SAS Institute; 1996.
53. Diggle P, editor, Heagerty P, editor, Liang K-Y, editor, Zeger S, editor. Analysis of Longitudinal Data. Oxford, England: Oxford University Press; 2002.
54. Little RJ, Rubin DB. Statistical Analysis With Missing Data. New York, NY: John Wiley & Sons; 1987.
55. Wheaton DH, Hoffman DR, Locke KG, Watkins RB, Birch DG. Biological safety assessment of docosahexaenoic acid supplementation in a randomized clinical trial for X-linked retinitis pigmentosa. Arch Ophthalmol. 2003;121:1269-1278.
FREE FULL TEXT
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