A Little Algae a Day Keeps the Retinal Degeneration Specialist Away

Retinitis pigmentosa (RP) is a genetically heterogeneous inherited retinal degeneration that leads to slow but relentless vision loss, usually starting in the midperipheral field. Although there is no known cure for RP, many dietary supplements have been advocated to slow the progression of retinal degeneration. Based on several studies, the most frequently recommended supplements are vitamin A palmitate,1 docosahexaenoic acid,2 and lutein.3 The exact dietary formulations vary fromcenter to center, anddisagreement exists over the efficacy of one compoundvs another.4Nonetheless,most centers do advise some combination of nutritional supplements for individuals with RP. β-Carotene, a plant carotenoid commonly found in fruits andvegetables, is aprecursor tovitaminA.5 It is absorbed in the small intestine,where it is cleavedbyβ,β-carotene15,15’-monooxygenase to form 2 molecules of retinol. Because this reaction is inhibited by high levels of vitamin A, it has an inherent feedback mechanism toprevent high levels of thisvitaminfromaccumulating.β-Carotenehasalsobeenshown to be a potent antioxidant and is one of the components of the formulation currently recommended by the Age-Related Eye Disease Study to prevent the progression of age-relatedmacular degeneration.However, β-carotene supplementation is not without some risk. The incidence of lung and gastrointestinal cancers has been shown to be increased in smokers and asbestos workers who take this supplement.6 In the article by Rotenstreich et al,7 the authors describe a subset of patientswithRPwhodemonstrated improvement in their scotopic full-field electroretinograms (ERGs) after receiving β-carotene supplements. Such findingswill undoubtedly be exciting to patientswith RP, but these resultsmust be met with cautious optimism. This study, which included 34 patients with autosomal recessive and dominant RP, was designed as a randomized, double-masked, placebo-controlled, crossover study. The authors are to be commended for carrying out awell-designed trial. Patientswere treatedwith either placeboor capsules containingapproximately 20mgofβ-carotene derived from the alga Dunaliella bardawil. The primary end point of the study was change in the maximum scotopic ERGb-waveamplitudeat thebeginningof the trialperiodcompared with 90 days later. The secondary end points included photopic ERG b-wave amplitude, dark-adapted chromatic visual field area, light-adapted visual field area, and bestcorrectedvisualacuity.Therewasnosignificantchange inbestcorrected visual acuity or visual field area. For the primary end point, maximum scotopic ERG b-wave amplitude, patients demonstrated on average an 8-μV increase in amplitude while taking β-carotene as compared with a 6-μV decrease while receiving placebo. There are several important things to realize about these results. First, only 10 of 29 patients showed an improvement (defined by the authors as an increase of 10 μV). Because RP is a genetically heterogeneous disease, it is possible that only patients with a subset of mutations benefited from this therapy. Alternatively, as is common in many patients with advanced RP, the ERG amplitudes may have been so diminished that any improvement in amplitude may have been below the threshold of detectability. Second, it is important to note that the magnitude of the change, while statistically significant, is still quite small. Peak amplitudes vary from system to system, but it is not uncommon to obtain maximal scotopic b-wave amplitudes measuring 500 to 700 μV in healthy patients. Therefore, a change of 10 to 15 μV is small and must be compared with the intervisit variation for recording this signal. For example, Fishman et al8 demonstrated that in their ERG system when such variation is taken into account, the maximal b-wave needs to increase by 80% to be considered significant in low-amplitude cohorts and 25% in higher-amplitude cohorts. When both groups were pooled together, the threshold for a significant increase was 32%. In this study, the treatment group demonstrated a 40% improvement from baseline of the scotopic maximal b-wave compared with a 16% loss in the placebo group, which is suggestive of a significant improvement, although we cannot stratify the groups into lowand high-amplitude cohorts because 30-Hz flicker data were not provided. Light-adapted single-flash ERGs did show a change that was statistically significant (an 18% improvement), but when intervisit variation is taken into account, this change is less impressive. Measurements of the intervisit variation of the ERG system being used in this study would be important for fully interpreting the data. Finally, although the increase in ERG amplitude is suggestive of an improvement in the functioning of remaining cells in the retina, it does not necessarily indicate a sustainedprotective effect. Theamplitudeof 30-Hz flickerERG responses has been correlated with long-term prognosis in patientswith RP, but the same correlation has not beenmade for themaximal scotopic b-wave amplitude.9 Because β-carotene ismetabolized to vitaminA, it is tempting to compare its efficacy with previous trials using vitamin A supplementation for RP.1 Such a direct comparison is difficult, though, because the current study was of much shorter duration, inRelated article on page 985 Opinion