Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial.

OBJECTIVES: Peroxisome assembly disorders are genetic disorders characterized by biochemical abnormalities, including low docosahexaenoic acid (DHA). The objective was to assess whether treatment with DHA supplementation would improve biochemical abnormalities, visual function, and growth in affected individuals. METHODS: This was a randomized, double-blind, placebo-controlled trial conducted at a single center. Treatment groups received supplements of DHA (100 mg/kg per day). The primary outcome measures were the change from baseline in the visual function and physical growth during the 1 year follow-up period. RESULTS: Fifty individuals were enrolled and randomized. Two were subsequently excluded from study analysis when it was determined that they had a single enzyme disorder of peroxisomal beta oxidation. Thirty-four returned for follow-up. Nine patients died during the trial of their disorder, and 5 others were lost to follow-up. DHA supplementation was well tolerated. There was no difference in the outcomes between the treated and untreated groups in biochemical function, electroretinogram, or growth. Improvements were seen in both groups in certain individuals. CONCLUSIONS: DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders. CLASSIFICATION OF EVIDENCE: This interventional study provides Class II evidence that DHA supplementation did not improve the visual function or growth of treated individuals with peroxisome assembly disorders during an average of 1 year of follow-up in patients aged 1 to 144 months.

Redefining papillorenal syndrome: an underdiagnosed cause of ocular and renal morbidity.

PURPOSE: To report ocular and renal findings specific to the inheritable entity called papillorenal (also known as renal-coloboma) syndrome and relate these to a common cause. DESIGN: Observational case series and genetic study. PARTICIPANTS: Two unrelated probands presenting with absent central retinal vessels and 11 available family members. TESTING: Doppler ultrasonographic imaging of the optic nerves and kidneys, fluorescein angiography, and genetic testing for PAX2 mutations were performed. In selected cases, indocyanine green angiography, scanning laser ophthalmoscope perimetry, Retinal Thickness Analyzer measurements, visual evoked potentials, and magnetic resonance imaging were also performed. MAIN OUTCOME MEASURES: Better defined characteristics of the papillorenal syndrome. RESULTS: Numerous cilioretinal vessels were present with rudimentary or absent central retinal vessels. Superonasal visual field defects, typical for papillorenal syndrome, corresponded to inferotemporal areas of anomalous retinal and choroidal perfusion and hypoplastic retina. Renal hypoplasia was discovered in two affected members of one family (with previously unsuspected renal failure in one case), and recurrent pyelonephritis was discovered in four affected members of the other family. No PAX2 mutations were detected. CONCLUSIONS: In the papillorenal syndrome, the hereditary absence of central retinal vessels may be missed, leading to confusion with isolated coloboma, low-tension glaucoma, and morning glory anomaly. Greater awareness of this syndrome will avoid unneeded glaucoma therapy, allow earlier recognition of renal diseases, and allow genetic counseling. We propose that the papillorenal syndrome is a primary dysgenesis that causes vascular abnormalities predominantly affecting the eye, kidney, and urinary tract, leading to hypoplasia of these structures. The absence of defects in the PAX2 gene in these families suggests that mutations in other genes may also be responsible for this syndrome.

Improvement of visual acuity over time in patients with bilateral geographic atrophy from age-related macular degeneration.

PURPOSE: To study the improvement in visual acuity over time in patients with central scotomas. METHODS: In a prospective natural history study of geographic atrophy (GA) from age-related macular degeneration (ARMD) with annual follow-up, 36 patients with bilateral GA completed 3 years of follow-up. Protocol visual acuity (VA) measurements were performed. Scanning laser ophthalmoscopy (SLO) was performed, and the areas of GA were measured from fundus photographs. RESULTS: Six eyes of six patients with VA ranging from 20/80 to 20/500 had a VA improvement of two or more lines (mean, 3.2 lines). This was found only in the worse-seeing eyes of the patients and was contemporaneous with the deterioration in VA of the better-seeing eyes. Four of six eyes that improved in acuity had an improvement in the ability to find and hold the fixation target in an area of seeing retina, as assessed by SLO at follow-up, and a fifth eye changed from one fixation site that had little functional retina to another site. CONCLUSIONS: Spontaneous improvement in VA in eyes with bilateral GA and central scotomas may occur. It appears to be related to deterioration in VA of the better-seeing fellow eye and is associated with improvement of fixation in the worse-seeing eye. The worse-seeing eye of a patient with bilateral ARMD may have the potential for better vision than measured VA indicates. This finding may have implications for the choice of patients in treatment trials, for interpretation of long-term results, and for planning and assessment of low vision intervention.

Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy.

PURPOSE: To test the hypothesis that healthy fetal retinal pigment epithelium (RPE) can rescue the remaining viable RPE and choriocapillaries and thereby the photoreceptors in non-neovascular age-related macular degeneration (ARMD) (geographic atrophy [GA]). METHODS: A 65-year-old legally blind woman with non-neovascular ARMD underwent fetal RPE transplantation. Best-corrected visual acuity testing, detailed fundus examination, fundus photography, fluorescein angiography, scanning laser ophthalmoscope macular perimetry, and humoral and cellular immune response testing were performed. A suspension of RPE was infused into the subretinal space through a retinotomy along the superotemporal arcade at the edge of the area of GA. The patient did not take systemic immunosuppressants. RESULTS: The patient's vision remained unchanged for 5 months after the surgery. Fluorescein angiography after transplantation showed leakage and staining at the level of the outer retina. There was progressive subretinal fibrosis in the area of the transplant. Immune response studies showed a weakly positive mixed lymphocyte response against phosducin and rhodopsin. CONCLUSION: Although it is surgically feasible to transplant fetal RPE to the subretinal space of patients with GA, such an allogenic RPE transplant without immunosuppression leads to leakage on fluorescein angiography and eventual fibrosis. A very weak immune response against proteins associated with photoreceptors is also of concern.

A novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease.

PURPOSE: To identify additional mutations in the ABCR gene and describe the clinical features of four affected siblings with autosomal recessive Stargardt disease. METHODS: A cohort of eight siblings was identified for study. Four of these individuals were diagnosed with Stargardt disease based on clinical evaluation and fluorescein angiography. Blood samples were obtained from seven of eight siblings, including all those affected. All 50 exons of the ABCR gene were analyzed by single-stranded confirmation polymorphism analysis, followed by direct sequencing of observed variants, to identify mutations in the ABCR gene. RESULTS: We identified a previously unreported kindred of eight siblings, four of whom had mutations in both of their ABCR alleles. A previously described G-to-C transversion of nucleotide 2588, predicting a Gly863Ala amino acid substitution, and a novel G-to-A transition of nucleotide 161, resulting in a Cys54Tyr substitution, were identified. These mutations co-segregated with the affected members of this family. Three of the siblings demonstrated clinical features characteristic of classic Stargardt disease, with bilateral regions of macular atrophy associated with yellow-white "flavimaculatus" flecks in the posterior pole at the level of the retinal pigment epithelium. The fourth affected sibling showed features of early Stargardt disease, with a beaten-bronze appearance to both maculas, as well as perimacular flecks. In all four affected patients, fluorescein angiography showed a characteristic peripheral dark choroid. CONCLUSIONS: We have identified both a previously described and a novel mutation in the ABCR gene in four patients with autosomal recessive Stargardt disease. In-depth knowledge of the ABCR mutation spectrum in patients with Stargardt disease will provide for more efficient screening and may provide potential therapies for Stargardt disease and other retinal diseases.

The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration.

Geographic atrophy is the advanced form of atrophic age-related macular degeneration. It is present in 3.5% of people age 75 and over in the United States. It progresses gradually over time, often sparing the fovea until late in the course of the disease. Forty to fifty percent of eyes with geographic atrophy and good visual acuity at baseline lose three or more lines of acuity by two years and 27% become worse than 20/200 by four years. This article discusses the information known about age-related geographic atrophy at the present time.

Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration.

OBJECTIVE: To describe the progression of geographic atrophy (GA) from age-related macular degeneration (AMD) with respect to visual acuity (VA) loss and enlargement of atrophy. DESIGN: A prospectively observed case series. SETTING: Tertiary retinal referral center. PARTICIPANTS: One hundred twenty-three patients with GA due to AMD who completed at least 1 year of follow-up (median follow-up, 3 years) were examined annually. METHODS: At each examination, a protocol best-corrected VA of each eye was measured, a clinical examination was performed, and color fundus photographs were taken. The areas of atrophy were drawn and measured. MAIN OUTCOME MEASURES: Visual acuity loss and enlargement of total and central atrophy. RESULTS: At baseline, median VA was poorer with larger areas of atrophy, but there was wide variation related to sparing of the fovea. Thirty-one percent of all study eyes suffered a three-line VA loss from baseline by 2 years, and 53% had a three-line loss by 4 years. Those eyes with VA better than 20/50 had the highest rate of acuity loss; 27% of these eyes had acuities of 20/200 or worse at 4 years. Visual acuity loss in the GA study eye was similar in patients with bilateral GA and in those with choroidal neovascularization in the fellow eye. Total atrophy enlarged a median of 1.8 Macular Photocoagulation Study disc areas (DA) at 2 years; atrophy within a 4-DA circle centered on the fovea enlarged a median of 0.9 DA. Two (22%) of nine patients with GA in one eye and only drusen without advanced AMD in the fellow eye developed GA in the fellow eye at 2 years. CONCLUSIONS: Geographic atrophy is associated with a significant decline in VA over time in many eyes. Areas of atrophy continue to enlarge over time, even when already large at baseline. The combination of reduced VA with enlargement of atrophy, occurring bilaterally in most patients, can lead to significant impairment of visual function.

Measuring geographic atrophy in advanced age-related macular degeneration.

PURPOSE: To present a method developed for measuring areas of geographic atrophy (GA) in advanced age-related macular degeneration, METHODS: A microfilm reader projected the 30 degrees fundus photograph of the macula. Retinal landmarks, atrophic areas, and spared areas within the atrophy were traced, without access to drawings of other years. The total atrophic area was calculated, as was the atrophy within a four-disc-area circle entered on the estimated foveal center. The configuration of the atrophy was documented. RESULTS: Avoidable sources of discrepancy included variability in peripapillary atrophy seen on the photograph, and variability seen in the extent of the field. Reproducibility studies found a median absolute difference of 0.19 Macular Photocoagulation Study disc areas (DA) in total atrophy between repeat drawings, with 75% of repeat drawings having a difference of less than 0.33 DA. For central atrophy measures, there was a median difference of 0.08 DA, with 75% of pairs having a difference of less than 0.18 DA. Features making the definition of borders of GA difficult include the presence of drusen and pigmentary alteration, a fundus in which choroidal vessels are easily visible, and variation in the appearance of GA within a single area of atrophy. CONCLUSIONS: This method provides a reliable means of measuring the size of atrophic areas in GA and will be useful for measuring longitudinal change. It may be difficult to determine whether central spared areas are present, and correlation with visual acuity and macular perimetry may be helpful.

The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration.

OBJECTIVE: To determine the rate of developing choroidal neovascularization (CNV) in eyes with geographic atrophy (GA) from age-related macular degeneration (AMD) and the characteristics of the CNV in these eyes. DESIGN: Prospective natural history study with cohort analysis. PARTICIPANTS: One hundred fifty-two patients with GA and no CNV by fluorescein angiography in at least 1 eye, with annual follow-up. MAIN OUTCOME MEASURES: The development of CNV. RESULTS: Thirteen eyes with GA developed CNV. For patients with bilateral GA and no CNV at baseline, 2% developed CNV by 2 years and 11% by 4 years. For patients with CNV in the fellow eye, 18% developed CNV in the study eye with GA by 2 years and 34% by 4 years. The eyes that developed CNV experienced more acuity loss than did the eyes with only GA. Within the fellow eye CNV group, those study eyes with GA that had less central atrophy (and better acuity) at baseline were more likely to develop CNV. The CNV developed at a peripheral border of GA in nine eyes, in the spared foveal region in two eyes, and in both center and border in one eye. No eye developed CNV in the area of atrophy itself. The appearance of CNV was evanescent in some cases and had a final appearance of an enlarged area of GA. Twelve other eyes had hemorrhages without definite evidence of CNV; three were thought to be suspicious for CNV and the remainder were thought to be hemorrhages that may be seen in elderly patients. CONCLUSION: An eye with GA whose fellow eye has CNV is at significant risk for the development of CNV in the GA eye. A patient with bilateral GA and no evidence of CNV is at relatively low risk for developing CNV. The CNV may be evanescent and may not be detected. Intraretinal hemorrhages unrelated to CNV are relatively common in this older population.

Scanning laser ophthalmoscope fundus perimetry after surgery for choroidal neovascularization.

PURPOSE: Submacular surgery is under investigation for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration, ocular histoplasmosis syndrome, and other causes. The aims of this study were to determine whether the macular area from which choroidal neovascularization was removed surgically remained functional and whether there was any qualitative difference between eyes with different disease conditions or between eyes of younger and older patients. METHODS: Our study included 19 patients (19 eyes) with choroidal neovascularization, seven cases caused by age-related macular degeneration and 12 caused by ocular histoplasmosis syndrome, pathologic myopia, or idiopathic causes. All tests were performed at least 6 months after surgical removal of choroidal neovascularization. All patients underwent fundus perimetry with the scanning laser ophthalmoscope for evaluation of dense and relative scotomas and fixation site. RESULTS: After submacular surgery in 19 patients, 10 patients (one with age-related macular degeneration and nine with pathologic myopia, ocular histoplasmosis syndrome, or an idiopathic cause of choroidal neovascularization) fixated within an area that ophthalmoscopically and angiographically was an area of retinal pigment epithelial disturbance occupied by choroidal neovascularization preoperatively. Of 12 patients without age-related macular degeneration, seven of eight patients younger than 50 years of age compared with two of four patients 50 years or older fixated within the area of retinal pigment epithelial disturbance. CONCLUSIONS: Our data suggest that in patients without age-related macular degeneration who undergo submacular surgery, the surgically disturbed area previously occupied by choroidal neovascularization can remain functional postoperatively. Furthermore, occasionally a patient with age-related macular degeneration undergoing submacular surgery still can fixate in the area from which the choroidal neovascularization was removed.

Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity.

PURPOSE: Geographic atrophy (GA) may cause significant compromise of visual function, even when there still is good visual acuity (VA), because of parafoveal scotomas and foveal function abnormalities antedating visible atrophy. This study evaluates the visual function abnormalities at baseline and the 2-year worsening of VA and reading rate for eyes with GA compared with a group of eyes with drusen only. METHODS: Seventy-four eyes with GA and VA greater than or equal to 20/50 from a prospective natural history study of GA were included, as were 13 eyes with only drusen. Baseline visual function testing and 2-year VA and maximum reading rate are reported. RESULTS: The worsening of VA in decreased luminance and foveal dark-adapted sensitivity showed severe abnormalities for the GA group. Contrast sensitivity was significantly reduced for the eyes with GA. Half the eyes with GA, but none of the drusen eyes, had maximum reading rates below 100 words per minute. A scanning laser ophthalmoscope (SLO) measure of the scotoma near fixation combined with a measure of residual foveal function accounted for 54% of the variability in maximum reading rate in the eyes with GA. Of 40 eyes with GA observed for 2 years, half lost greater than or equal to 3 lines of VA and one quarter lost greater than or equal to 6 lines. The nine eyes with drusen with follow-up had no significant change in VA. Low foveal dark-adapted sensitivity, SLO measures of the scotoma within 1 degree of fixation, and low maximum reading rate were statistically significant risk factors for doubling of the visual angle. Significant reduction in maximum reading rates at 2 years was present for the eyes with GA. CONCLUSIONS: The eyes with GA with good VA have profound decreases in visual function, particularly in dim lighting and in reading. Half the eyes with GA had doubling in visual angle at 2 years after the baseline examination, whereas the drusen eyes remained essentially unchanged. Impaired visual function at baseline was predictive of an adverse outcome for the eyes with GA.

Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease.

PURPOSE: To study fixation patterns and reading rates in eyes with central scotomas from geographic atrophy (GA) of age-related macular degeneration and to compare fixation patterns with those of patients with Stargardt disease. METHODS: Scanning laser ophthalmoscope analysis of fixation patterns in eyes with 20/80 to 20/200 visual acuity. Included were 41 eyes of 35 patients with GA and 10 eyes of 5 patients with Stargardt disease. The patients with GA also were tested for maximum reading rate, and the size of the areas of atrophy were measured by fundus photograph analysis. RESULTS: Sixty-three percent of GA eyes fixating outside the atrophy placed the scotoma to the right of fixation in visual field space, 22% placed the scotoma above fixation, and 15% placed it to the left, regardless of the laterality of the GA eye. Fixation was stable in subsequent years of testing for scotoma placement to the right of or above fixation. All GA eyes fixated immediately adjacent to the atrophy. In contrast, seven of ten eyes with Stargardt disease fixated at a considerable distance from the scotoma border, with the dense scotoma far above the fixation site in visual field space. For the patients with GA, the maximum reading rate was highly correlated with size of the atrophic area, but not with age or visual acuity within the limited visual acuity range tested. There was a trend to more rapid reading with the scotoma above fixation and slower reading with the scotoma to the left. CONCLUSION: There is a preference for fixation with the scotoma to the right in eyes with GA. Patients with Stargardt disease use different strategies for fixation, perhaps due to subclinical pathology adjacent to the atrophic regions. The size of the atrophic area in GA plays the predominant role in reading rate for eyes that have already lost foveal vision.

Landmark-driven fundus perimetry using the scanning laser ophthalmoscope.

PURPOSE: To present a new method of performing scanning laser ophthalmoscope perimetry that compensates for eye movements so that the correct retinal location is tested even if fixation changes. This allows for accurate testing of patients with central scotomas and for repeating testing longitudinally at the same retinal locations even if central fixation is lost. METHODS: The operator views the retina and selects a retinal landmark, such as a vessel bifurcation, that can be identified easily. A testing strategy is preselected, and the computer saves the landmark and stimulus coordinates. To present each stimulus, the operator positions a cursor over the retinal landmark, and the computer adjusts the site of presentation of the stimulus for any change in landmark position caused by an eye movement. At the conclusion of the testing, the results are displayed in the proper retinal location on a fundus image. RESULTS: Sixty-seven eyes with macular disease were tested with the landmark-driven method, using the same preplanned strategy for each eye for both a bright and a dim stimulus. There was a low rate of inconsistent points (seen with dim but not bright stimuli), and virtually all of these bordered a dense scotoma. Those eyes with more inconsistent points had a significantly greater percentage of dense scotoma points and significantly lower visual acuity. The technique significantly corrected error in retinal localization resulting from large eye movement. There is no significant rotation or magnification change during the procedure, so specifying the change in location of one landmark is sufficient to describe movement of the retina. The technique is rapid and easy to administer to elderly patients and to children. CONCLUSIONS: This technique allows for accurate and repeatable measures of retinal sensitivity in specific locations. It is useful in following change over time. It can be developed further to allow for fully automated, retinally correct testing.

Scanning laser ophthalmoscopic analysis of the pattern of visual loss in age-related geographic atrophy of the macula.

PURPOSE: We explored the clinical impression that geographic atrophy of the retinal pigment epithelium, a form of advanced age-related macular degeneration, is perceived by the patient as progressing gradually, even when fixation switches from foveal to extrafoveal. METHODS: We analyzed the responses of 60 patients with geographic atrophy to a questionnaire administered as part of a five-year study of the natural course of geographic atrophy, funded by the National Eye Institute. We performed scanning laser opthalmoscope perimetry on all patients. We examined two additional patients with geographic atrophy who reported abrupt visual loss. RESULTS: No eye with geographic atrophy was reported by any patient to have had sudden visual loss. Although most patients with geographic atrophy show foveal fixation until the fovea is atrophic and then show extrafoveal fixation, scanning laser ophthalmoscope perimetry in three patients with geographic atrophy showed alternation between a foveal and an extrafoveal retinal locus for fixation. Two patients with geographic atrophy who complained of abrupt visual loss were found to have occult choroidal neovascularization, which evolved in one patient to classic choroidal neovascularization. The neovascularization was difficult to detect because of the presence of geographic atrophy and its associated ophthalmoscopic and fluorescein angiographic features. CONCLUSIONS: Visual loss in geographic atrophy is nearly always perceived by the patient as being gradual, even when considerable decreases in visual acuity occur and when foveal vision and fixation are lost. A possible explanation for this perception is that there is a transitional period during which a patient uses both a foveal and extrafoveal site for fixation. The complaint of abrupt visual loss in a patient with geographic atrophy should raise the suspicion of choroidal neovascularization, which may be occult and difficult to detect.

Central serous chorioretinopathy and pregnancy.

BACKGROUND AND OBJECTIVE: Fourteen cases of central serous chorioretinopathy in pregnancy had been reported before this study was conducted. These cases have suggested a nonwhite predominance. Subretinal fibrinous exudates have been seen in 90% of the patients, compared with fewer than 20% of patients in typical (nonpregnant) central serous chorioretinopathy. No case has recurred outside of pregnancy, to our knowledge, and there have been no reports of subsequent pregnancies uninvolved by this disorder. These findings led us to collect our cases of central serous retinopathy in pregnancy because our experience differed from that of previous reports and provides additional new information. DESIGN: Case series. SETTING: The Wilmer Institute Retinal Vascular Center, Baltimore, Md. PATIENTS: Questionnaires sent to retinal faculty and fellows and a review of files revealed four patients, all included herein, with central serous chorioretinopathy presenting during pregnancy. RESULTS: All four patients were white. Three patients had subretinal fibrinous exudates and/or precipitates. All experienced resolution of the serous detachment near the end of the pregnancy or within the first few months after delivery. Only one patient had a subsequent pregnancy, and this was not complicated by the presence of central serous chorioretinopathy. One other patient experienced a recurrence 2 1/2 years after her last pregnancy. CONCLUSIONS: There may be no racial predominance in the development of central serous chorioretinopathy in pregnancy. Subretinal fibrinous exudates are quite common, independent of race. The uninvolved subsequent pregnancy suggests that recurrence in the context of pregnancy is not inevitable. This disorder may recur outside of pregnancy.

Retinal pigment epithelial tears through the fovea with preservation of good visual acuity.

We describe two patients with spontaneous retinal pigment epithelial tears through the fovea who have maintained at least 20/40 visual acuity for 1 year and 3 years following the rip. Both patients had long-standing serous detachments of the retinal pigment epithelium associated with age-related macular degeneration prior to the development of the tear. Each tear was at least five disc areas in size and centered on the fovea. Foveal fixation was documented despite the presumed absence of pigment epithelium. This observation suggests either that there may be remaining or redundant pigment epithelium or that pigment epithelium directly beneath the central macula is not required for maintenance of 20/40 visual acuity.