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Figure 1.
Visual field sensitivity by yearand treatment group (docosahexaenoic acid plus vitamin A [DHA + A group] vscontrol plus vitamin A [control + A group]) for patients not on vitamin Aprior to entry (A) and for patients on vitamin A prior to entry (B). Samplesizes for those not on vitamin A prior to entry were 28 for the DHA + A groupand 34 for the control + A group; and for those on vitamin A prior to entry,75 for the DHA + A group and 68 for the control + A group. Slopes of declinein total field sensitivity are shown for the DHA + A vs control + A groupsfor years 0 to 2 and 2 to 4 among those not on vitamin A prior to entry (C).Limit lines depict standard error values.

Visual field sensitivity by yearand treatment group (docosahexaenoic acid plus vitamin A [DHA + A group] vscontrol plus vitamin A [control + A group]) for patients not on vitamin Aprior to entry (A) and for patients on vitamin A prior to entry (B). Samplesizes for those not on vitamin A prior to entry were 28 for the DHA + A groupand 34 for the control + A group; and for those on vitamin A prior to entry,75 for the DHA + A group and 68 for the control + A group. Slopes of declinein total field sensitivity are shown for the DHA + A vs control + A groupsfor years 0 to 2 and 2 to 4 among those not on vitamin A prior to entry (C).Limit lines depict standard error values.

Figure 2.
Linear regression of red bloodcell phosphatidylethanolamine docosahexaenoic acid (RBC PE DHA) level on dietary ω-3fatty acid intake based on 103 patients in the control plus vitamin A–treated(control + A) group. Each point represents the mean of 3 measurements of RBCPE DHA level and 5 measurements of dietary ω-3 fatty acid intake overthe course of the study. The correlation (lower right) indicates that 28%(r2) of the variation in RBC PE DHA levelcan be explained by the variation in dietary ω-3 fatty acid intake.Based on the regression line, a dietary ω-3 fatty acid intake of 0.20g/d corresponds to an RBC PE DHA value of approximately 5% of total RBC PEfatty acids.

Linear regression of red bloodcell phosphatidylethanolamine docosahexaenoic acid (RBC PE DHA) level on dietary ω-3fatty acid intake based on 103 patients in the control plus vitamin A–treated(control + A) group. Each point represents the mean of 3 measurements of RBCPE DHA level and 5 measurements of dietary ω-3 fatty acid intake overthe course of the study. The correlation (lower right) indicates that 28%(r2) of the variation in RBC PE DHA levelcan be explained by the variation in dietary ω-3 fatty acid intake.Based on the regression line, a dietary ω-3 fatty acid intake of 0.20g/d corresponds to an RBC PE DHA value of approximately 5% of total RBC PEfatty acids.

Figure 3.
Model for interphotoreceptor retinoid-bindingprotein (IRBP)–mediated targeting of retinoids to their sites of actionin the eye. The model is based on the following 3 observations: (1) docosahexaenoicacid (DHA) is enriched in photoreceptor rather than retinal pigment epithelium(RPE); (2) this fatty acid constitutes a large fraction of fatty acids boundto IRBP endogenously; and (3) the addition of docosahexaenoic acid switchesIRBP retinoid-binding site 2 from a state in which it possesses a high affinityfor 11-cis retinal (RAL) to a state in which it isincapable of binding this ligand. It is proposed that when IRBP is localizednear RPE, its fatty acid–binding site is occupied with fatty acids thatare enriched in these cells, such as palmitate. Under these conditions, IRBPadopts a conformation (shaded) that confers a high affinity for RAL on retinoid-bindingsite 2 (bottom left corner of this scheme). When IRBP moves across the interphotoreceptormatrix (IPM) to the vicinity of the photoreceptors, its fatty acid contentis readjusted according to the fatty acids prevalent in these cells to containa large fraction of DHA. Binding of DHA switches the protein to a conformation(unshaded) in which site 2 has a very low affinity for RAL, resulting in rapidrelease of this ligand. Site 2 then becomes occupied with all-trans-retinol (ROL), the affinity for which remains high in the presenceof DHA. The process is reversed when IRBP moves back to the proximity of RPE.The overall outcomes of the cycle are that RAL moves to photoreceptors, ROLis transported to RPE, and the fatty acids transfer down their concentrationgradients. (The affinity of IRBP's retinoid-binding site 1 for ROL and RALis only marginally affected by fatty acids. This site may function simplyas a buffer that nonspecifically allows for elevated concentrations of retinoidsin the IPM.) ROS indicates rod outer segment. Reprinted with permission fromWolf. Used with permission from the InternationalLife Sciences Institute, Washington, DC.

Model for interphotoreceptor retinoid-bindingprotein (IRBP)–mediated targeting of retinoids to their sites of actionin the eye. The model is based on the following 3 observations: (1) docosahexaenoicacid (DHA) is enriched in photoreceptor rather than retinal pigment epithelium(RPE); (2) this fatty acid constitutes a large fraction of fatty acids boundto IRBP endogenously; and (3) the addition of docosahexaenoic acid switchesIRBP retinoid-binding site 2 from a state in which it possesses a high affinityfor 11-cis retinal (RAL) to a state in which it isincapable of binding this ligand. It is proposed that when IRBP is localizednear RPE, its fatty acid–binding site is occupied with fatty acids thatare enriched in these cells, such as palmitate. Under these conditions, IRBPadopts a conformation (shaded) that confers a high affinity for RAL on retinoid-bindingsite 2 (bottom left corner of this scheme). When IRBP moves across the interphotoreceptormatrix (IPM) to the vicinity of the photoreceptors, its fatty acid contentis readjusted according to the fatty acids prevalent in these cells to containa large fraction of DHA. Binding of DHA switches the protein to a conformation(unshaded) in which site 2 has a very low affinity for RAL, resulting in rapidrelease of this ligand. Site 2 then becomes occupied with all-trans-retinol (ROL), the affinity for which remains high in the presenceof DHA. The process is reversed when IRBP moves back to the proximity of RPE.The overall outcomes of the cycle are that RAL moves to photoreceptors, ROLis transported to RPE, and the fatty acids transfer down their concentrationgradients. (The affinity of IRBP's retinoid-binding site 1 for ROL and RALis only marginally affected by fatty acids. This site may function simplyas a buffer that nonspecifically allows for elevated concentrations of retinoidsin the IPM.) ROS indicates rod outer segment. Reprinted with permission fromWolf.10 Used with permission from the InternationalLife Sciences Institute, Washington, DC.

Table 1. 
Demographic and Ocular Characteristics at Entry of PatientsWith Retinitis Pigmentosa*
Demographic and Ocular Characteristics at Entry of PatientsWith Retinitis Pigmentosa*
Table 2. 
Annual Rate of Decline for Measures of Ocular Function byTreatment Group and Vitamin A Status Prior to Entry Over a 4-Year Interval*
Annual Rate of Decline for Measures of Ocular Function byTreatment Group and Vitamin A Status Prior to Entry Over a 4-Year Interval*
Table 3. 
Annual Decline in Total Visual Field Sensitivity as a Functionof RBC PE DHA Level*
Annual Decline in Total Visual Field Sensitivity as a Functionof RBC PE DHA Level*
Table 4. 
Annual Decline in Visual Field Sensitivity in the ControlGroup as a Function of Dietary ω-3 Fatty Acid Intake Among Patientson Vitamin A Prior to Entry*
Annual Decline in Visual Field Sensitivity in the ControlGroup as a Function of Dietary ω-3 Fatty Acid Intake Among Patientson Vitamin A Prior to Entry*
Table 5. 
Relationship Between Duration of Vitamin A Intake Prior toEntry and 30-Hz ERG Amplitude Decline in the Control Group*
Relationship Between Duration of Vitamin A Intake Prior toEntry and 30-Hz ERG Amplitude Decline in the Control Group*
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Neuringer  MAnderson  GJConnor  WE The essentiality of ω-3 fatty acids for the development and functionof the retina and brain. Annu Rev Nutr. 1988;8517- 541
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Birch  DGBirch  EEHoffman  DRUauy  RD Retinal development in very-low-birth-weight infants fed diets differingin omega-3 fatty acids. Invest Ophthalmol Vis Sci. 1992;332365- 2376
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Berson  ELRosner  BSandberg  MA  et al.  A randomized trial of vitamin A and vitamin E supplementation for retinitispigmentosa. Arch Ophthalmol. 1993;111761- 772
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Hoffman  DRLocke  KGWheaton  DHFish  GESpencer  RBirch  DG A randomized, placebo-controlled clinical trial of docosahexaenoicacid supplementation for X-linked retinitis pigmentosa. Am J Ophthalmol. 2004;137704- 718
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Chen  YHoughton  LABrenna  JTNoy  N Docosahexaenoic acid modulates the interactions of the interphotoreceptorretinoid-binding protein with 11-cis-retinal. J Biol Chem. 1996;27120507- 20515
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Chen  YSaari  JCNoy  N Interactions of all-trans-retinol and long-chainfatty acids with interphotoreceptor retinoid-binding protein. Biochemistry. 1993;3211311- 11318
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Wolf  G Transport of retinoids by the interphotoreceptor retinoid-binding protein. Nutr Rev. 1998;56156- 158
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Aguirre  GDAcland  GMMaude  MBAnderson  RE Diets enriched in docosahexaenoic acid fail to correct progressiverod-cone degeneration (prcd) phenotype. Invest Ophthalmol Vis Sci. 1997;382387- 2407
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Anderson  REMaude  MBBok  D Low docosahexaenoic acid levels in rod outer segment membranes of micewith rds/peripherin and P2 16L peripherin mutations. Invest Ophthalmol Vis Sci. 2001;421715- 1720
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Clinical Sciences
September 2004

Further Evaluation of Docosahexaenoic Acid in Patients With RetinitisPigmentosa Receiving Vitamin A TreatmentSubgroup Analyses

Author Affiliations

From the Berman-Gund Laboratory for the Study of Retinal Degenerations,Harvard Medical School, Massachusetts Eye and Ear Infirmary (Drs Berson, Rosner,Sandberg, Brockhurst, and Gaudio and Mss Weigel-DiFranco and Anderson), theDepartment of Nutrition, Harvard School of Public Health (Dr Willett), andthe Lipid Metabolism Laboratory, Jean Mayer US Department of Agriculture HumanNutrition Research, Center on Aging at Tufts University (Dr Schaefer), Boston,Mass; the Kennedy Krieger Institute, Peroxisomal Diseases Laboratory, Baltimore,Md (Ms Moser); the Foster Biomedical Research Laboratory, Brandeis University,Waltham, Mass (Dr Hayes); and the Devers Eye Institute, Portland, Ore (DrJohnson). The authors have no relevant financial interest in this article.

Arch Ophthalmol. 2004;122(9):1306-1314. doi:10.1001/archopht.122.9.1306
Abstract

Objective  To determine whether docosahexaenoic acid will slow the course of retinaldegeneration in subgroups of patients with retinitis pigmentosa who are receivingvitamin 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 000IU/d of vitamin A given as retinyl palmitate (DHA + A group) or control fattyacid plus 15 000 IU/d of vitamin A (control + A group) and followed upover 4 years. Seventy percent of the patients in each group were taking vitaminA, 15 000 IU/d, prior to entry. We compared rates of decline in ocularfunction in the DHA + A vs control + A groups among the subgroups definedby use or nonuse of vitamin A prior to entry. We also determined whether declinein ocular function was related to red blood cell phosphatidylethanolaminedocosahexaenoic acid level, dietary ω-3 fatty acid intake, or durationof vitamin A use. Main outcome measures were Humphrey Field Analyzer visualfield 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 electroretinogramamplitude 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 amongpatients taking vitamin A prior to entry. In the entire cohort, red bloodcell phosphatidylethanolamine docosahexaenoic acid level was inversely relatedto rate of decline in total field sensitivity over 4 years (test for trend, P = .05). This was particularly evident over the first2 years among those not on vitamin A prior to entry (test for trend, P = .003). In the entire control + A group, dietary ω-3fatty acid intake was inversely related to loss of total field sensitivityover 4 years (intake, <0.20 vs ≥0.20 g/d; P =.02). The duration of vitamin A supplementation prior to entry was inverselyrelated 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 diseasefor 2 years. Among patients on vitamin A for at least 2 years, a diet richin ω-3 fatty acids (≥0.20 g/d) slowed the decline in visual fieldsensitivity.

We have reported elsewhere in this issue that oral supplementation withdocosahexaenoic acid in a dosage of 1200 mg/d did not, on average, slow therate of decline in ocular function over a 4-year interval among 208 patientswith retinitis pigmentosa who concurrently received vitamin A, 15 000IU/d.1 Among these patients randomly assignedto docosahexaenoic acid plus vitamin A (DHA + A group) or control fatty acidcapsules plus vitamin A (control + A group), about 70% reported taking vitaminA, 15 000 IU/d, prior to entry, whereas 30% did not; approximately equalnumbers of patients on and not on vitamin A prior to entry were in the DHA+ A and control + A groups. After 1 year of follow-up, we unexpectedly noteda highly significant statistical interaction between the effect of docosahexaenoicacid supplementation and the status of vitamin A intake prior to entry onchange in visual field sensitivity (P<.01), suggestingthe need for subgroup analyses. Therefore, we followed change in ocular functionin these 4 subgroups over the 3 remaining years of this trial. The presentarticle compares rates of decline in ocular function over 4 years among thesubgroups within the DHA + A and control + A groups defined by use or nonuseof vitamin A prior to entry.

Data from our previous clinical trial of vitamin A for retinitis pigmentosashowed that the decline in 30-Hz electroretinogram (ERG) amplitude over a4-year interval was inversely related to red blood cell phosphatidylethanolaminedocosahexaenoic acid (RBC PE DHA) concentration (P =.03) among 61 patients for whom we had RBC levels available for analysis atyear 3 or 4.1 Because RBC DHA levels have beencorrelated with retinal DHA levels,2 and DHAconcentration is high in the PE fraction of retinal phospholipids,3 we evaluated the relationship of rate of loss of ocularfunction to RBC PE DHA levels in the present study population. Because RBCphospholipids vary with manipulation of dietary ω-3 fatty acids,4,5 we also evaluated in the control +A group alone whether rate of decline in ocular function could be relatedto dietary ω-3 fatty acid intake as a measure of docosahexaenoic acidintake.

In our previous trial of vitamin A supplementation for retinitis pigmentosa,we found a significantly slower rate of decline in retinal function in thosepatients randomized to 15 000 IU/d of vitamin A than in those not onthis dosage, but this difference became obvious only after 4 years of follow-up.6 In the present study, we therefore also evaluatedwhether the rate of decline in ocular function in the control + A group wasrelated to duration of vitamin A intake prior to entry.

METHODS

Patients with retinitis pigmentosa, aged 18 to 55 years, underwent screeningfor eligibility according to ocular, dietary, and medical criteria and wererandomly assigned to a DHA + A or a control + A group. All eligible patientshad typical forms of retinitis pigmentosa with elevated final dark-adaptationthresholds, retinal arteriolar narrowing, and reduced and delayed ERGs; mosthad intraretinal bone spicule pigment around the midperipheral fundus. Atypicalforms such as paravenous, unilateral, or sector retinitis pigmentosa wereexcluded. Patients with Bardet-Biedl syndrome, Refsum disease, retinitis punctataalbescens, or retinitis pigmentosa associated with profound congenital deafnesswere also excluded. Patients were subdivided according to whether or not theyreported taking 15 000 IU/d of vitamin A prior to entry. Study design,eligibility criteria, informed consent, techniques for evaluation, main outcomemeasures, method of randomization, procedures for masking, and methods ofdata analyses are described elsewhere.1 Within6 to 8 weeks after a screening examination, eligible patients were randomlyassigned at a baseline examination to 600 mg of oral docosahexaenoic acidtwice daily (DHA + A group) or control fatty acid capsules (control + A group).All were given 1 tablet per day containing 15 000 IU of vitamin A asretinyl palmitate. The study was approved by the institutional review boardsof the Massachusetts Eye and Ear Infirmary and Harvard Medical School, Boston,Mass. The study conformed to the Declaration of Helsinki.

Subgroup analyses are listed as follows. First, rates of decline inocular function were compared between the DHA + A and control + A groups amongthe subgroups taking vitamin A prior to entry and between the DHA + A andcontrol + A groups among the subgroups not taking vitamin A prior to entryover the 4-year study.

Second, analyses were performed relating rate of decline in ocular functionto category of RBC PE DHA level based on an equal-interval scale of percentageof total RBC PE fatty acids (<5.0%, 5.0%-9.9%, 10.0%-14.9%, and 15.0%-19.9%)in the entire study population and in the 2 subgroups defined by vitamin Astatus prior to entry.

Third, in the entire control + A group (ie, those receiving controlfatty acids plus 15 000 IU/d of vitamin A regardless of vitamin A statusprior to entry), analyses were performed relating rates of decline in ocularfunction to level of dietary ω-3 fatty acid intake (at or above andbelow the median intake of 0.20 g/d observed over the course of this study)over the 4-year period of this study and for the periods years 0 to 2 and2 to 4.

Fourth, in the entire control + A group, we subdivided patients on thebasis of duration of vitamin A intake (15 000 IU/d) prior to study entry(ie, not on vitamin A prior to entry, on vitamin A prior to entry for 1-23months, or on vitamin A prior to entry for ≥24 months) and compared ratesof decline in ocular function among these subgroups.

In addition, in the entire control + A group, we evaluated whether arelationship existed between dietary ω-3 fatty acid intake and RBC PEDHA levels and whether vitamin A intake was associated with a change in RBCPE DHA levels over the duration of the study.

RESULTS
PARTICIPANTS AND PATIENT FLOW

Table 1 gives demographicand ocular characteristics at baseline for the 208 patients seen annuallyfor all 4 years in the DHA + A vs control + A groups within the subgroupsdefined by status of vitamin A intake prior to entry. In accord with the criteriafor randomization, the subgroups defined by vitamin A status prior to entryhad no significant differences in percentages of patients by genetic typeof retinitis pigmentosa and no significant differences in dietary intake of ω-3fatty acids at baseline. The study population was about 50% male and 50% female,with a comparable distribution in the subgroups on or not on vitamin A priorto entry. Eleven percent reported partial hearing loss, with no significantdifference among the subgroups.

Baseline ocular function (ie, mean of screening and baseline examinationsprior to treatment) showed slightly less visual field sensitivity in the DHA+ A vs control + A groups within the subgroups, although the differences werenot statistically significant in either subgroup. Visual acuity accordingto the Early Treatment Diabetic Retinopathy Study (ETDRS acuity) and ERG amplitudesat baseline were also not significantly different between the DHA + A andcontrol + A groups in either subgroup (Table 1). Within the subgroups defined by vitamin A use prior toentry, the DHA + A and control + A groups showed comparable levels of RBCPE DHA, plasma DHA, serum retinol, and serum retinyl esters prior to treatment.The RBC PE DHA levels (expressed as the mean ± SE percentage of totalRBC PE fatty acids) were significantly higher among those on vitamin A (4.66%± 0.15%) vs those not on vitamin A prior to entry (4.22% ± 0.16%)(P = .05).

For those on vitamin A prior to entry, RBC PE DHA levels at follow-upwere 13.12% ± 0.26% (n = 73) in the DHA + A group and 5.02% ±0.21% (n = 66) in the control + A group. For those not on vitamin A priorto entry, RBC PE DHA levels at follow-up were 11.98% ± 0.68% (n = 29)in the DHA + A group and 4.31% ± 0.25% (n = 34) in the control + Agroup. These RBC levels were consistent with reported compliance, ie, 90%of patients reported taking the study capsules 90% of the time.

ANALYSES OF OUTCOME MEASURES
Effect of Docosahexaenoic Acid Supplementation as a Function of VitaminA Status Prior to Entry

Table 2 lists mean annualrates of decline of central and total visual field sensitivity, 30-Hz ERGamplitude, and ETDRS acuity over a 4-year interval among the 208 patientsin the DHA + A vs control + A groups for those on and not on vitamin A priorto entry. We found significant statistical interactions of treatment effectsaccording to vitamin A supplement use prior to entry for visual field sensitivityand 30-Hz ERG amplitude, suggesting that treatment group effects were differentfor those on vs not on vitamin A prior to entry. For those on vitamin A priorto entry, the mean annual rates of decline of central and total field sensitivityand 30-Hz ERG amplitude were not significantly different between the DHA +A and control + A groups. For those not on vitamin A prior to entry, meanrates of decline of central and total visual field sensitivity and 30-Hz ERGamplitude were significantly lower in the DHA + A vs control + A groups. Nosignificant statistical interaction effect was noted for ETDRS acuity, andno significant differences in rates of ETDRS acuity decline were noted insubgroup comparisons.

Figure 1A shows values (mean± SE) of total visual field sensitivity (total point score for HumphreyField Analyzer [HFA] 30-2 and 30/60-1 programs combined) by year among thosenot on vitamin A prior to entry in the DHA + A vs control + A groups. In thesesubgroups, the difference between the 2 curves was larger during years 1 and2 and smaller during years 3 and 4. In contrast, as seen in Figure 1B, among those on vitamin A prior to entry, the differencesbetween the curves for the DHA + A vs control + A groups were not significantlydifferent for either time period, although a slight divergence of the curveswas noted particularly in years 3 and 4. Figure 1C shows the annual rates (mean ± SE) among thosenot on vitamin A prior to entry for years 0 to 2 and 2 to 4 for rate of totalfield sensitivity decline when comparing the DHA + A vs control + A groups.The rate of decline was significantly slower in the DHA + A vs control + Agroups for years 0 to 2 (P = .006), but was not significantlydifferent for years 2 to 4 (P = .57).

Relationship of Change in Ocular Function to RBC PE DHA Level

Table 3 summarizes that,for the entire study cohort, a trend toward a significantly faster declinein visual field sensitivity was seen for those with lower compared with higherRBC PE DHA levels over 4 years (central field test for trend, P = .09; total field test for trend, P = .05).Patients with an RBC PE DHA level of less than 5% of total RBC PE fatty acidsshowed a significantly faster rate of loss of total field sensitivity vs thosewith a level of at least 5% (P = .02). Among thosenot on vitamin A prior to entry, a significantly faster decline was seen forthose with lower compared with higher RBC PE DHA levels from years 0 to 2(central field test for trend, P = .01; total fieldtest for trend, P = .003). These significant differenceswere not seen from years 2 to 4, although the trends were in the same directionas from years 0 to 2. Among those on vitamin A prior to entry, no significantdifferences in rate of loss of central or total HFA sensitivity by RBC PEDHA level were seen for years 0 to 2 or years 2 to 4 (Table 3).

Effect of Dietary ω-3 Fatty Acid Intake on Change in Ocular Function

Table 4 shows that amongpatients in the control + A group on vitamin A prior to entry, the rate ofdecline in visual field sensitivity over a 4-year interval for the central(30-2) condition was significantly related to the amount of dietary ω-3fatty acid intake; those with an intake of at least 0.20 g/d had a 40% to50% slower rate of decline compared with those with intake of less than 0.20g/d (P = .02). A similar result was seen for thetotal (HFA 30-2 and 30/60-1 combined) condition (P =.05). Similar trends were seen for years 0 to 2 and 2 to 4, although the differenceswere only significant for the latter period (P =.03). The same pattern was seen for the 30-2 and total conditions among thosenot on vitamin A prior to entry, but the differences were not significant(data not shown).

Effect of Duration of Vitamin A Intake on Change in Ocular Function

Table 5 lists data for patientsin the entire control + A group categorized by the number of years on vitaminA, 15 000 IU/d, prior to entry. Although their initial 30-Hz ERG amplitudesdid not differ significantly, those on vitamin A for 2 or more years priorto entry had the slowest rate of decline during the study, whereas those noton vitamin A prior to entry had the fastest rate of decline. Estimated annualrates of decline of remaining retinal function were 13.0% for those not onvitamin A prior to entry, 11.6% for those on vitamin A for 1 to 23 monthsprior to entry, and 7.9% for those on vitamin A for 24 or more months priorto entry. There was a significant linear trend with duration of intake ofvitamin A prior to entry (test for trend, P = .008).A similar trend was seen for central field and total field sensitivity decline.With respect to total field sensitivity, patients in the control + A groupshowed an 84-dB annual decline during the study for those not on vitamin Aprior to entry, a 42-dB decline during the study for those taking vitaminA for 1 to 23 months prior to entry, and a 62-dB decline for those takingvitamin A for 2 or more years prior to entry (test for trend, P = .08).

OTHER ANALYSES
Relationship of ω-3 Fatty Acid Intake to RBC PE DHA Levels

Figure 2 shows that a significantrelationship existed between dietary ω-3 fatty acid intake and RBC PEDHA level for the patients in the control + A group (P<.001).The analysis shows that a 0.20-g/d dietary intake of ω-3 fatty acidscorresponds to an RBC PE DHA level of approximately 5%.

Association Between Vitamin A Intake and RBC PE DHA Levels

In the control + A group (ie, those receiving control fatty acids plusvitamin A, 15 000 IU/d), irrespective of vitamin A status prior to entry,mean RBC PE DHA level increased significantly from 4.27% (weighted averageof 4.39% and 4.04%; Table 1) atbaseline to 4.78% at year 4 (mean ± SE increase, 0.51% ± 0.11%; P<.001). Although intake of dietary ω-3 fattyacids increased from 0.18 to 0.26 g/d in the control + A group, a significantrise from baseline in RBC PE DHA remained after adjusting for change in intakeof dietary ω-3 fatty acids as measured by the average intake of dietary ω-3fatty acids for all follow-up visits minus the intake of dietary ω-3fatty acids at baseline (P = .001).

COMMENT

The present study shows that among patients with retinitis pigmentosanot previously taking vitamin A, those who receive a new supplementation ofa combination of docosahexaenoic acid plus vitamin A have a significantlyslower rate of decline in visual field sensitivity and 30-Hz ERG amplitudethan those given vitamin A alone for 2 years. For this 2-year period, amongthose not already taking vitamin A prior to entry, those given docosahexaenoicacid along with vitamin A lost, on average, 25 dB of sensitivity, whereasthose given vitamin A alone lost, on average, 141 dB. Considering their totalvisual field sensitivity at baseline (Table1) and the amount of decline over the first 2 years (Figure 1A), the DHA + A group lost, on average, 2% (25 dB/1276 dB),whereas the control + A group lost, on average, 10% (ie, 141 dB/1436 dB);the saving was, therefore, about 8% over 2 years. This beneficial effect didnot persist beyond year 2. For those already taking 15 000 IU/d of vitaminA prior to the onset of the trial, docosahexaenoic acid supplementation didnot provide additional benefit.

Among the entire study population, those with lower RBC PE DHA levels(<5% of total RBC PE fatty acids) had a significantly faster rate of declinein visual field sensitivity than those with higher RBC PE DHA levels overthe 4 years of the study. Similarly, a significant inverse relationship hasbeen shown by others between rate of loss of cone ERG amplitude over 4 yearsand RBC DHA level among patients with X-linked retinitis pigmentosa.7 It has been proposed that a concentration gradientof 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 interphotoreceptorretinoid-binding protein (IRBP) is facilitated when IRBP is exposed to sufficientDHA in the subretinal space79 (Figure 3 ). It is known that the DHA concentrationis reduced in the outer retina in canine11 andmurine12 models of hereditary retinal degeneration.Whether degeneration leads to loss of DHA or vice versa is not established,but a lack of DHA may impair release of 11-cis retinal(ie, the active form of vitamin A) that is essential for photoreceptor survival.13,14 Because the RBC DHA level is thoughtto reflect the retinal level of DHA,2 we proposethat an RBC PE DHA fatty acid level less than 5% may indicate that the subretinallevel of DHA is insufficient to release 11-cis retinalfrom IRBP in patients with retinitis pigmentosa, thereby contributing to deathof photoreceptor cells. It follows that increasing the RBC PE DHA level to5% or higher through docosahexaenoic acid supplementation or eating foodsrich in ω-3 fatty acids may be necessary to increase the DHA level inthe subretinal space enough to allow release of 11-cis retinalfrom IRBP.

Alternatively, increasing the concentration of 11-cis retinal in the retina by supplementing with vitamin A may facilitateincorporation of DHA into the retina. In this regard, the control + A group(ie, patients receiving control fatty acids plus vitamin A) showed a significantrise in their RBC PE DHA level during the course of the study that was independentof change in dietary ω-3 fatty acid intake. This may partially explainwhy the treatment effect of docosahexaenoic acid was significant in the first2 years of the study only among those who were not taking vitamin A priorto entry. Those taking vitamin A prior to entry may have already elevatedtheir RBC PE DHA level sufficiently to modify the course of their disease.Indeed, the mean level of RBC PE DHA was significantly higher among patientson vs those not on vitamin A prior to entry.

A significant relationship was also observed between the level of dietary ω-3fatty acid intake and the rates of decline of central and total field sensitivityamong patients in the control + A group on vitamin A prior to entry (Table 4). A level of dietary intake of ω-3fatty acids of at least 0.20 g/d, which corresponds to an RBC PE DHA levelof about 5% or greater (Figure 2),was associated with a slower rate of decline in visual field sensitivity thana level of intake of less than 0.20 g/d. These findings support the hypothesisthat patients with retinitis pigmentosa taking vitamin A would benefit frommaintaining an average dietary intake of ω-3 fatty acids of at least0.20 g/d. This is equivalent to one to two 84- to 112-g (3- to 4-ounce) servingsper week of fish rich in ω-3 fatty acids, such as salmon, tuna, mackerel,sardines, or herring.15

The clinical significance of an average dietary intake of ω-3fatty acids of at least 0.20 g/d among patients with retinitis pigmentosawho receive vitamin A supplements can only be estimated. If the rates of declineof central visual field sensitivity observed during this study persist long-term,and if the average central field sensitivity of a patient aged 37 years isabout 869 dB (Table 1, control+ A group on vitamin A prior to entry), we propose that an average patienton vitamin A who maintains an intake of ω-3 fatty acids of 0.20 g/dafter 37 years of age would be expected to lose about 21 dB per year (Table 4) and, therefore, would lose virtuallyall central field sensitivity by 78 years of age (ie, [869/21] + 37). In contrast,an average patient receiving vitamin A with dietary intake of ω-3 fattyacids of less than 0.20 g/d after 37 years of age would be expected to lose39 dB per year (Table 4) and wouldlose virtually all central field sensitivity by 59 years of age (ie, [869/39]+ 37). Therefore, maintenance of a dietary intake of ω-3 fatty acidsof at least 0.20 g/d after 37 years of age could result in an estimated 19years of additional vision for the average patient with retinitis pigmentosawho combines vitamin A, 15 000 IU/d, with a diet rich in ω-3 fattyacids.

In a previous trial of vitamin A for retinitis pigmentosa, we reportedthat those receiving vitamin A palmitate, 15 000 IU/d, showed an 8.3%annual rate of decline in remaining 30-Hz ERG amplitude over 6 years comparedwith a 10.0% annual decline among those in the trace control group receivingvitamin A at a dosage of 75 IU/d.6 The beneficialeffect of 15 000 IU/d of vitamin A was best seen after patients had receivedthis dosage for several years.6 In the present4-year study, patients on 15 000 IU/d of vitamin A for 2 or more yearsprior to entry showed a significantly smaller loss of remaining 30-Hz ERGamplitude per year (7.9%) compared with those not on vitamin A prior to entry(13%) or on vitamin A for less than 2 years (11.6%) (Table 5). A similar trend was seen for visual field results. Thesedata suggest that, in the absence of docosahexaenoic acid supplementation,at least 2 years are required before the beneficial effect of vitamin A onthe course of retinitis pigmentosa is fully achieved.

Together the results show that docosahexaenoic acid supplementationshortens the interval for vitamin A to take its full effect and supports arecommendation that most adult patients with the typical forms of retinitispigmentosa who start vitamin A therapy at a dosage of 15 000 IU/d shouldalso take docosahexaenoic acid, 1200 mg/d for 2 years (600 mg twice a day).No evidence was found of a continued benefit of docosahexaenoic acid supplementationbeyond the first 2 years, leading to the recommendation that patients receivingvitamin A should stop docosahexaenoic acid supplementation after 2 years.A slight tendency toward adversity was noted in years 3 and 4 among patientson vitamin A, 15 000 IU/d, prior to entry in the DHA + A group (Figure 1B), further supporting discontinuationof docosahexaenoic acid therapy at a dosage of 1200 mg/d after 2 years.

It must be emphasized that these conclusions are based on group averages,and, therefore, no assurance can be given that a specific patient will benefitfrom this treatment. This study did not include patients younger than 18 yearsor those receving a dosage of less than 1200 mg/d of docosahexaenoic acid,and therefore no formal recommendation can be made for younger patients orfor a smaller dosage. The study also did not include patients with centralvisual field sensitivity in the HFA of less than 250 dB with a size V testlight or patients with best-corrected visual acuity of less than 20/100 inboth eyes, and therefore no formal recommendation can be made for such patients.Because patients were advised to stop docosahexaenoic acid and vitamin A therapyduring pregnancy and because of the increased risk of birth defects amongpatients receiving high-dose vitamin A supplementation,16 patientswho are pregnant or planning to become pregnant should not take this combinationof supplements.

In addition, these data suggest that adult patients with retinitis pigmentosawho have taken 15 000 IU/d of vitamin A for at least 2 years should eat1 to 2 servings of fish rich in ω-3 fatty acids weekly (equivalent toan average food intake of ω-3 fatty acids of at least 0.20 g/d) to maintainan RBC PE DHA level of at least 5% of total RBC PE fatty acids. A test todetermine RBC PE DHA level is not widely available. As an alternative, physiciansshould consider obtaining a fasting RBC DHA level about 3 months (ie, consideringRBC turnover) after patients start eating ω-3-rich fish and periodicallythereafter. We have observed a high correlation between RBC PE DHA and RBCDHA levels in patients with retinitis pigmentosa not on docosahexaenoic acidsupplementation (r = 0.96, n = 49); an RBC DHA levelof 4% of RBC total lipid fatty acids will ensure with 95% confidence thatthe RBC PE DHA level is at least 5% in a given patient (E.L.B., B.R., M.A.S.,C.W.-D., and A.M., unpublished data, 2004).

The present study also supports a previous recommendation6 thatmost adults with the typical forms of retinitis pigmentosa should continueto take 15 000 IU/d of vitamin A palmitate under medical supervisionto slow the course of their condition. It should be noted that the precursorof vitamin A, betacarotene, is not predictably converted into vitamin A; therefore,betacarotene is not a suitable substitute for vitamin A palmitate in the contextof this treatment regimen.

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Article Information

Correspondence: Eliot L. Berson, MD, Berman-Gund Laboratory for theStudy of Retinal Degenerations, 243 Charles St, Boston, MA 02114.

Submitted for publication July 14, 2003; final revision received January8, 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 acknowledgethe following individuals who contributed to the conduct of this trial: TinaSkop-Chaput, Michele Berry, Melissa Stillberger, Peggy Rodriguez, Kevin McDermott,Linda Berard, Heather Lee, Susana Chung, Shyana Harper, Anna Marie Baglieri,Ciara Rice, Cathy Lonergan, Suzanne Dalton, Marion McPhee, Martin Van Denburgh,Sherrie Kaplan, PhD, Anita Liu, and David Jones.

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