JAMA Ophthalmology

Bosworth, Charles F.; Sample, Pamela A.; Gupta, Neeru; Bathija, Renuka; Weinreb, Robert N.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1153pmid: 9747672

ObjectiveTo determine if motion automated perimetry can identify early glaucomatous visual field defects in patients with suspected glaucoma (by disc), those with ocular hypertension, and those with primary open-angle glaucoma.MethodsMotion automated perimetry, a foveally centered motion test, and standard visual field tests were conducted on one randomly selected eye of normal patients (n=38), patients with suspected glaucoma (by disc) (n=28), patients with ocular hypertension (n=18), and patients with primary open-angle glaucoma (n=21). Subjects' performance on both motion tests were compared with their performance on standard perimetry.ResultsPerimetric motion thresholds significantly distinguished the groups (P≤.001), while the foveally centered motion test was unable to separate them (P≤.32). Of the total patients, 90.5% of those with glaucoma, 39.3% of those with suspected glaucoma, 27.8% of those with ocular hypertension, and 5.3% of the normal subjects had abnormal results on motion automated perimetry testing. Perimetric motion thresholds were significantly correlated with standard visual field thresholds (P≤.001).ConclusionMotion automated perimetry identifies visual field defects in patients who already show standard visual field loss as well as in a moderate percentage of those with suspected glaucoma and ocular hypertension, indicating that the testing of discrete locations might be necessary for increased diagnostic utility.DETECTABLE OPTIC nerve head change or visual field loss may not be observed until there is considerable neural damage; hence, the development of new testing paradigms that can identify patients likely to have or develop glaucoma is of interest.Psychophysical tests of both the parvocellular and the magnocellular visual systems have indicated abnormalities in patients with glaucoma and suspected glaucoma relative to normal controls.Magnocellular retinal ganglion cell function has been evaluated with various types of stimuli in patients with glaucoma,suspected glaucoma, and ocular hypertension (OHT).The studies evaluating motion perception have indicated that both patients with glaucoma and those with suspected glaucoma with normal standard visual fields often have defects in motion sensitivity. While there is still debate over which type of motion stimulus is the best, testing motion perception with random-dot kinematograms (RDKs) reduces the presence of cues (position and form) that nonmagnocellular ganglion cells can process.The purpose of this study was to determine if a perimetric motion test using RDKs in a direction discrimination paradigm, motion automated perimetry (MAP), can differentiate among normal subjects, those with suspected glaucoma (by disc), those with pure OHT, and those with primary open-angle glaucoma, and to compare it with both a separate full-field foveally centered RDK and standard automated perimetry.SUBJECTS AND METHODSSUBJECTSSubjects for this study were patients with primary open-angle glaucoma (n=21), patients with suspected glaucoma (by disc) (n=28), patients with OHT (n=18), and normal controls (n=38). One eye was randomly chosen from each subject. The different subject groups were not significantly different in age (P≤.09). Mean (±SD) ages were 66.3±11.8 years for the glaucoma group, 62.2±11.2 years for the suspected glaucoma group, 57.1±12.7 years for the OHT group, and 62.0±10.3 years for the normal control group.Patients with primary open-angle glaucoma were defined by the following criteria: (1) open angles with abnormal optic discs based on 1 or more of the following: cup-disc ratio asymmetry between the 2 eyes of 0.2 mm or more, localized or diffuse rim defects, excavation, retinal nerve fiber layer defects, or disc hemorrhages as determined by masked review of simultaneous stereophotographs by a glaucoma expert; (2) previously documented standard visual field loss determined by visual field analysis (program 24-2, Humphrey Visual Field Analyzer 640, Humphrey Instruments, San Leandro, Calif), with corrected pattern SDs outside the 95% confidence limits or glaucoma hemifield test results outside the 99% confidence limits.Patients with suspected glaucoma were identified by the above criteria for abnormal optic discs. However, they had normal standard visual fields, with corrected pattern SDs within the 95% confidence limits and glaucoma hemifield test results within normal limits.Normal controls met the following inclusion criteria: (1) normal optic discs based on above criteria; (2) intraocular pressures less than 21 mm Hg on all prior examinations; and (3) normal standard visual fields based on above criteria.Patients with OHT met all of the above criteria for normal controls except they had intraocular pressures greater than 23 mm Hg on 2 separate examinations.For this study, visual field reliability indices were set at 25% or less for fixation losses, false-positive errors, and false-negative errors. Mean (±SD) defects on standard perimetry were −7.6±5.61 for eyes with glaucoma, −0.69±1.9 for eyes with suspected glaucoma, 0.26±1.12 for eyes with OHT, and 0.42±1.4 for normal control eyes.This study was approved by the Human Subjects Committee of the University of California, San Diego, and was undertaken with the informed consent of each subject.RANDOM-DOT MOTION DISPLAYThe stimulus parameters and design of MAP have been previously reported.The current stimulus was within known ranges for testing the motion system while still allowing glaucoma patients with impaired vision to perceive the display.The motion stimulus was produced on a computer-controlled imaging display monitor (Barco, Kennesow, Ga) with 1024×768 lines of resolution and a refresh rate of 75 Hz. Each pixel subtended 0.31 mm (7.35 minutes of arc at the viewing distance of 16.5 cm). The monitor was driven by a Power PC 8100 Macintosh computer (Apple, Cupertino, Calif) using a 24×li video card (RasterOps, Santa Clara, Calif).Seven frames were shown in rapid succession to create the apparent motion stimulus, which lasted for 420 milliseconds. Within each of these frames, 20 dots were randomly placed within a circular test region of 7.3° of visual angle. These dots moved at a constant velocity of 8.2° per second in random directions. A new direction of motion was chosen after each spatial displacement. Randomly chosen signal dots were displaced together in 1 of 4 cardinal directions (right, left, up, down) to create the coherent motion signal that the patients were to detect. The signal ranged in strength from 0% to 100% coherence. Signal dots remained the same for all 7 frames of the display and had the same spatial displacement as the noise. This aspect of the stimulus makes it differ slightly from a traditional RDK, which randomly selects the signal dots after each displacement. The implications of this signal rule have been discussed in a previous article,where it was shown that a signal of this nature embedded in a surround of vectored motion is not significantly influenced by nonmotion cues.Thresholds were determined by means of a staircase procedure. Staircases began with a coherence value of 80% and a step size of 20% coherence. Each staircase reversal resulted in a halving of the step size down to the minimum of 5% coherence. The staircase was terminated by 3 reversals at the minimum step size. Threshold was taken as the mean of the last 3 reversal points.We designed the perimetric motion stimulus to test 14 retinal locations because early glaucoma is often characterized by localized peripheral visual field loss. The test locations were arranged in a pattern that mapped the subject's motion thresholds across the central 24° of visual field in approximately 15 minutes (Figure 1). The locations of test were chosen to identify peripheral arcuate and nasal step defects and to overlap with visual field testing locations.Figure 1.An example of standard visual field (program 24-2, Humphrey Instruments, San Leandro, Calif) showing the actual threshold values in numeric decibels (left) and the gray scale (right). Motion automated perimetry thresholds are superimposed over the standard gray scale to show the 14 test locations. The number at the origin is threshold for the foveally centered motion test; it was actually much larger than is depicted (diameter, 25.1°). The remaining 14 are in the correct scale (diameter, 7.3°) and show threshold values from the perimetric motion test for this patient.The stimulus for the foveally centered motion test was centered on the fovea and subtended a circular region 25.1° in diameter with a dot density identical to that used in the smaller perimetric displays. All other parameters remained the same.TEST PROCEDURESThe patient sat in a darkened room with a patch placed over the nontest eye. He or she rested in a chin rest while viewing the screen through proper refraction for the test distance of 16.5 cm.The patient focused on a black fixation "X" in the center of the display and adapted for 2 minutes to the background illumination. Fixation was monitored by the test administrator on a separate video display system. Trials where fixation was lost were aborted and retested later in the program. The testing procedure was then explained to the subject.The session began with a foveal practice test, which was identical to the foveally centered single-stimulus test. The patient's performance on these trials was observed by the test administrator to make sure that the task was properly understood. After completing the foveal practice, the patient either received the larger foveally centered test or the 14-location perimetric motion test. The order of presentation for the 2 types of motion stimuli was randomized.For all testing, the patient verbally reported the perceived direction (left, right, up, or down) in which the dots were moving in a 4-alternative forced-choice paradigm. The test administrator pressed an arrow key corresponding to the direction indicated by the subject. The patient could respond at any time during or after the stimulus presentation. The program gave a 2-second delay before presenting the next stimulus. Subjects were informed that they could pause and rest at any time during the test. The whole procedure lasted approximately 30 minutes.STATISTICAL ANALYSESThe perimetric threshold values averaged across the 14 test points (whole field), the perimetric threshold values averaged across the 7 superior field test points (superior field), the perimetric threshold values averaged across the 7 inferior field test points (inferior field), and motion coherence thresholds for the foveally centered motion test were the main dependent measures of this study. Analysis of variance was performed on all dependent measures to indicate if a significant difference existed in motion thresholds among the normal, suspected glaucoma, OHT, and glaucoma subjects. If a significant difference was indicated, a Tukey-Kramer honestly significant difference test was performed to localize the effect.The Pearson rwas computed for the correlation of the mean defects on MAP and standard perimetry. Mean defect on standard perimetry was computed by averaging the patient's threshold values for standard visual field test points that overlapped with each of the MAP test locations to create 14 values. These values were subtracted from the normal averages for each test point separately. The obtained difference scores for all 14 points were averaged to give an overall mean defect on standard perimetry for each patient. Mean defect on MAP was the average of 14 difference scores from normal.An abnormal MAP field was defined as having 3 or more motion threshold values at least 2 SDs above normal with at least 2 of the abnormal points adjacent to each other. This is a conservative definition because 3 motion locations would cover at least 8 standard visual field locations.Receiver operator characteristic (ROC) analysis was performed on the percent coherence variables for the glaucoma patients. Receiver operator characteristic curves were plotted for sensitivity vs 1 − specificity for possible cutoff points from 0% to 100% coherence. Sensitivity is the ability to correctly identify glaucoma. Specificity is the ability to correctly confirm a normal field. To quantify the ability of each measure to separate the normal subjects and those with glaucoma, we calculated the percentage of area under the ROC curve. This was accomplished by fitting a function to the ROC from the point (x=100, y=100) in the upper left corner to the first point where x=0 (Figure 2). A fit to the data points was accepted if more than 95% of the variance between the points could be accounted for by the function. The area under the curve was determined by integrating the function from x=0 to x=100 with the x-axis defining the lower bound of the integration area. Because the total area possible is known, the percent area is the area under the curve divided by 100. Using this measure, an area under the ROC curve of 50% represents chance while an area under the ROC curve of 100% represents perfect discrimination.Figure 2.Receiver operator characteristic analysis results for the glaucoma patients' mean motion coherence thresholds for the foveally centered motion test, motion automated perimetry averaged across the 14 test points (whole field), motion automated perimetry averaged across the 7 superior field test points (superior field), and motion automated perimetry averaged across the 7 inferior field test points (inferior field). The line from (0, 0) to (100, 100) represents chance performance. The curves are the best-fit functions for each average accounting for more than 95% of the variance. Each function was integrated from x=0 to x=100 to give an estimate of the area under the curve for the 3 measures separately.Optimal general error rates were computed for the different measures. The general error rate is the percentage of subjects misclassified when a specific cutoff value in percent coherence is selected. Therefore, choosing a cutoff that minimized the general error rate represents a balance between sensitivity and specificity such that the lowest percentage of misses and false alarms possible occurs. The sensitivity, specificity, and optimal cutoff for the different measures are reported at the lowest general error rate.RESULTSAnalysis of variance indicated that the foveally centered motion test was unable to differentiate the patients with glaucoma, suspected glaucoma, or OHT from normal controls (P≤.32) while MAP was able to do so (Table 1). Additional pairwise comparisons on the perimetric results indicated that the patients with glaucoma and those with suspected glaucoma were significantly different from normal controls throughout the visual field (Table 1). Considering the means for the foveally centered motion test, however, a nonsignificant trend is apparent with increasing coherence thresholds for the OHT and suspected glaucoma groups compared with normal controls. Using an α level of .05, the power of the foveally centered test was relatively low (0.32), with 233 observations required to obtain a significant result. This is in contrast to the 14 subjects required for a significant result when the superior field average from the perimetric motion test was used in the power calculations. Because the mean defect for patients with glaucoma on standard perimetry ranged from −0.57 to −20.26, the analysis was redone excluding all mean defects greater than −6.0 dB to give an evaluation of MAP for detection of early glaucoma (n=9). The patients with early glaucoma remained significantly different from normal controls (Table 1).Table 1. Mean (±SD) Motion Coherence Thresholds for All Patients and Patients With a Mean Defect Less Than −6.0 dBSee table graphicAlthough MAP did not differentiate the patients with OHT from normal controls, it did identify 5 (27.8%) of the 18 patients with OHT, 19 (90.5%) of the 21 patients with glaucoma, 11 (39.3%) of the 28 patients with suspected glaucoma, and 2 (5.3%) of the 38 normal subjects as abnormal on the examination.Receiver operator characteristic analysis indicated that the superior field average from MAP gave the largest area under the ROC curve (98.2%). The general error rate for the superior field average was 5.7%, yielding a specificity of 97.4% and a sensitivity of 91.3%. The larger foveally centered stimulus scored the poorest, with 62.4% of the total area under the ROC curve. See Table 2for a full listing of the ROC results.Table 2. Receiver Operator Characteristic Analysis Results for the Foveal Motion Test and Motion Automated Perimetry Comparing Eyes With Glaucoma With Normal EyesSee table graphicA significant correlation between all patients' standard visual field and MAP mean defects was found (r2=0.35, P<.001) (Figure 3).Figure 3.This graph shows the correlation between the mean defect on standard automated perimetry and the mean defect on motion automated perimetry across the patients with glaucoma, ocular hypertension, and suspected glaucoma (r2=0.35, P<.001).Individual patient data are shown as illustrations. Glaucoma patients 1 (Figure 4, top) and 3 (Figure 4, bottom) show a good correspondence between standard visual fields and MAP. Patient 3 was one of the 2 glaucoma patients who were not identified by MAP because 3 test points were not 2 SDs above normal. Patient 2 (Figure 4, center) shows a more extensive defect on MAP than is present on standard automated perimetry.Figure 4.Pattern deviation plots for standard automated perimetry (left side) showing the match with their results on motion automated perimetry (right side) in 3 patients with glaucoma. For motion automated perimetry, the number at the origin is threshold for the foveally centered motion test, while the remaining 14 numbers are threshold values from motion automated perimetry.Figure 5shows the results for 3 patients at risk for developing primary open-angle glaucoma. Patients 5 and 7 had suspected glaucoma. Patient 6 had OHT. All 3 patients' standard visual fields were normal while their MAP results showed clear defects.Figure 5.Pattern deviation plots for standard automated perimetry (left side) showing the match with their results on motion automated perimetry (right side) in 2 patients with suspected glaucomaand 1 patient with ocular hypertension.For motion automated perimetry, the number at the origin is threshold for the foveally centered motion test, while the remaining 14 numbers are threshold values from motion automated perimetry.It should be noted that in Figure 4and Figure 5the pattern deviation plot (STATPAC II analysis, Humphrey Instruments) was used for comparison to motion threshold values. We chose to use pattern deviation because it reduces the effects on the visual field due to general reduction in sensitivity from optical factors, such as blurring, cataract, and pupil size. Because MAP is resilient to the confounding influences of blurring, cataract, and pupil size,using the pattern deviation makes it more likely that the results are due to glaucomatous damage and thereby more comparable to MAP.COMMENTEarly attempts to measure motion discrimination thresholds with RDKs used large centrally presented fields of dots and produced mixed results. Silverman et alfound that motion thresholds were elevated in patients with glaucoma and OHT. This finding was later replicated by Trick et al,but could not be replicated by Bullimore et aland Graham et al.The lack of sensitivity to glaucoma reported in these studies could have resulted from either their long presentation durations (>1 second) or their large stimulus aperture sizes (>19°). Long display durations could provide even a damaged motion system with enough time to integrate a noisier or weaker motion signal. Large aperture sizes could allow both spared and nonspared regions of the visual field to contribute to a motion percept.Consistent with the theory that larger aperture sizes might have lower diagnostic power, perimetric motion tests using small localized targets have had considerable success in detecting glaucomatous visual field loss. Using RDKs with variable aperture sizes in a detection paradigm, Wall and colleagues have reported significant elevations in perimetric size thresholds for patients with glaucomaand OHT.Similar results using RDKs in perimetric direction discrimination tasks rather than detection tasks have been reported in patients with glaucomaand those with suspected glaucoma.A pure OHT group has not previously been assessed using RDKs in a perimetric direction discrimination paradigm. This could have clinical significance as the sensitivity of direction discrimination tasks to glaucomatous visual field loss might exceed that of motion detection tasks.In a previous study to determine if glaucoma-related loss of motion sensitivity is localized in retinal locus, we presented a discrete motion target at a location of standard visual field loss and a location of standard visual field sparing in the same eye of a glaucoma patient.The 2 test locations mirrored each other across the horizontal midline. The results indicated a significant difference between spared and nonspared retinal locations, suggesting that glaucoma causes localized loss of motion sensitivity.The ROC results of the present study further confirm that a foveally presented RDK is less sensitive to glaucomatous visual field loss than MAP, which tests discrete retinal locations. This becomes apparent when comparing the percentage of area under the ROC curves. The greatest area under the ROC curve and therefore the greatest sensitivity was found for the superior half of the MAP field.Motion automated perimetry can also identify field loss in a percentage of the patients with suspected glaucoma and those with OHT, suggesting that loss of motion sensitivity may precede standard visual field loss. The percentage of patients with OHT identified as abnormal is consistent with previous work using RDKs in a detection paradigmand indicates that MAP visual field abnormality might exist prior to detectable abnormality of the optic nerve.While the stimulus design used in this study was successful in separating glaucomatous from normal eyes, more work is necessary to evaluate possible limitations of the current test design. A stimulus duration of 420 milliseconds necessitates careful fixation monitoring in the administration of MAP. A second possible limitation is normal variability. The normal variability creates a relatively high SD (between 8.0% and 11.6% coherence) (Table 1). Future work using direction discrimination tasks should assess test-retest variability and ways to reduce it.Longitudinal follow-up with MAP and conventional automated perimetry is required to determine if the eyes with OHT and suspected glaucoma with MAP defects will eventually develop standard visual field loss.PASampleMEMadridRNWeinrebEvidence for a variety of functional defects in glaucoma-suspect eyes.J Glaucoma.1994;3(suppl):S5-S18.EJCassonCAJohnsonLRShapiroLongitudinal comparison of temporal-modulation perimetry with white-on-white and blue-on-yellow perimetry in ocular hypertension and early glaucoma.J Opt Soc Am.1993;10:1792-1806.PASampleCFBosworthRNWeinrebShort-wavelength automated perimetry and motion automated perimetry in glaucoma.Arch Ophthalmol.1997;115:1129-1133.CFBosworthPASampleRNWeinrebMotion perception thresholds in areas of glaucomatous visual field loss.Vision Res.1997;37:355-364.CFBosworthPASampleRNWeinrebPerimetric motion thresholds are elevated in glaucoma suspects and glaucoma patients.Vision Res.1997;37:1989-1997.KMJoffeJERaymondACrichtonMotion coherence perimetry in glaucoma and suspected glaucoma.Vision Res.1997;37:955-964.MABullimoreJMWoodKSwensonMotion perception in glaucoma.Invest Ophthalmol Vis Sci.1993;34:3526-3533.ASahraieJLBurberDFEdgarLWeiskrantzMotion discrimination of single targets: comparison of preliminary findings in normal subjects and patients with glaucoma.Graefs Arch Clin Exp Ophthalmol.1996;234:553-560.MWallKMKetoffRandom dot motion perimetry in patients with glaucoma and in normal subjects.Am J Ophthalmol.1995;120:587-596.SLGrahamSMDranceBCChauhanComparison of psychophysical and electrophysiological testing in early glaucoma.Invest Ophthalmol Vis Sci.1996;37:2651-2662.FFitzkeDPoinoosawmySNagasubramanianRAHitchingsPeripheral displacement thresholds in glaucoma and ocular hypertension.In: Heijl A, ed. Perimetry Update. Amsterdam, the Netherlands: Kugler & Ghedini Publications; 1989:399-405.SESilvermanGLTrickWMHart JrMotion perception is abnormal in primary open-angle glaucoma and ocular hypertension.Invest Ophthalmol Vis Sci.1990;31:722-729.RWatkinsTBuckinghamMotion perception hyperacuity is abnormal in primary open-angle glaucoma and ocular hypertension [abstract].Invest Ophthalmol Vis Sci.1991;32(suppl):1103.GLTrickSBSteinmanMAmyotMotion perception deficits in glaucomatous optic neuropathy.Vision Res.1995;35:2225-2233.CAJohnsonDMarshallKMEngDisplacement threshold perimetry in glaucoma using a Macintosh computer system and a 21-inch monitor.In: Mills RP, Wall M, eds. Perimetry Update.Amsterdam, the Netherlands: Kugler Publications; 1995:103-110.HPNSchollEZrennerMotion thresholds of colored stimuli of different luminance contrasts are increased in ocular hypertension and early primary-open-angle-glaucoma (POAG).Color Vision Deficiencies.1995;13:73-85.MWallCSJennischPMMundenMotion perimetry identifies nerve fiber bundlelike defects in ocular hypertension.Arch Ophthalmol.1997;115:26-33.KNakayamaCWTylerPsychophysical isolation of movement sensitivity by removal of familiar position cues.Vision Res.1981;21:427-433.KTuranoXWangMotion thresholds in retinitis pigmentosa.Invest Ophthalmol Vis Sci.1992;33:2411-2422.Accepted for publication June 3, 1998.This study was supported by grant EY-08208 from the National Eye Institute, Bethesda, Md (Dr Sample), and by the Samuel E. McLaughlin Foundation of Canada, Toronto, Ontario (Dr Gupta).Corresponding author: Pamela A. Sample, PhD, Department of Ophthalmology-0946, University of California, San Diego, La Jolla, CA 92093-0946 (e-mail: [email protected]).

Weiner, Asher; Schmidt, Matthew E.; Patel, Sangita; Gussler, Carter H.; Remler, Bernd F.; Kaufman, Stephen R.; Kohn, Howard D.; Weidenthal, Daniel T.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1161pmid: 9747673

ObjectiveTo determine whether foveal outer retinal dysfunction is common in eyes with unexplained visual symptoms or acuity loss.DesignProspective study.ParticipantsSeventy-three eyes of 44 consecutive patients with unexplained visual symptoms or acuity loss, 39 eyes of 39 control subjects, and 12 eyes of 7 patients with known maculopathy.InterventionFoveal cone electroretinography (ERG) and letter recognition perimetry.Main Outcome MeasuresFoveal cone ERG data.ResultsAbnormal foveal cone ERG data were recorded in 35 (48%) of 73 eyes (23 [52] of 44 patients). Among these 35 eyes, amplitude was lower than in normal controls (P<.001) and was correlated with visual acuity and the number of letter recognition perimetry errors (P<.05 for both). The latter was higher in eyes with abnormal retinal responses than in symptomatic eyes with normal responses (P<.01). However, initial symptoms, visual acuity, and macular appearance did not differentiate between these 2 groups. Foveal cone ERG test vs retest data showed consistent results.ConclusionFoveal outer retinal dysfunction is a common underlying mechanism of previously unexplained visual symptoms or acuity loss. Foveal cone ERG testing should be considered early in the evaluation of eyes with this presentation.PATIENTS WITH foveal outer retinal dysfunction may present with diminished acuities or with visual symptoms such as blurred vision, glare, photophobia, a preference for dim lighting conditions, central or paracentral scotomata, or color vision defects. However, retinal appearance may be deceivingly healthy.In such patients, foveal cone electroretinography (ERG) is the diagnostic test of choice,without which these patients may be left with the diagnosis of unexplained visual symptoms or acuity loss despite comprehensive and costly ophthalmic, neurologic, and radiological evaluations.Results of previous studies demonstrate that foveal cone ERG testing provides an objective measurement of the electrical activity of the foveal outer retina,that amplitude is correlated with visual acuity in some forms of maculopathy,and that it can help differentiate visual loss related to maculopathy from that in amblyopia or optic neuropathy.Foveal cone ERG also has been shown to be a reliable tool in identifying macular dysfunction not only in eyes with overt maculopathy on ophthalmoscopybut also in those with mild and nondiagnostic macular changes or with an entirely healthy macular appearance.Thus, foveal cone ERG facilitates the diagnosis of such conditions as idiopathic macular dysfunction or macular degeneration with normal fundusand familial occult macular dystrophy.However, no information is available regarding whether foveal outer retinal dysfunction is common in eyes with unexplained visual symptoms or acuity loss. Such information could help the practicing ophthalmologist formulate a cost-effective evaluation for these eyes. If foveal cone ERG testing can help disclose foveal dysfunction in a significant number of these eyes, this test should be performed early in their evaluation. Conversely, if foveal outer retinal dysfunction is rare, then the current frequent and early use of the low-yielding,costly, and potentially invasive neuro-imaging studies should perhaps persist. In the present study, we recorded foveal cone ERG data from 73 eyes with unexplained visual symptoms or acuity loss to obtain this information.PATIENTS AND METHODSPATIENT ENROLLMENTWe tested 73 symptomatic eyes of 44 consecutive patients, aged 10 to 80 years, evaluated from January 1996 to July 1997. Referrals to our service were made from local practices and several major medical centers after extensive but unrevealing evaluations for unexplained visual symptoms or acuity loss. Inclusion criteria included visual symptoms or acuity loss determined to be of unexplained nature by at least 2 ophthalmologists. Exclusion criteria were any of the following: best-corrected Snellen visual acuity of less than 20/300, inability to maintain fixation sufficient for reliable foveal cone ERG testing regardless of visual acuity, significant media opacities or small pupils preventing continuous observation of the foveal ERG test target on the fovea throughout testing, any intraocular surgery, intraocular pressure of 22 mm Hg or greater, overt retinopathy or maculopathy on ophthalmoscopy, or general medical conditions that may affect foveal responses, such as diabetes mellitus.Because in our experience isolated foveal outer retinal dysfunction may be a unilateral or a bilateral finding, and because the origin of this dysfunction in many patients may not be clear, we treated each eye as an independent event rather than assuming bilaterality in each patient. Both eyes of 29 patients and 1 eye of 15 patients were symptomatic eyes that met all inclusion and exclusion criteria and were included in our study.PATIENT EVALUATION AND CLINICAL FINDINGSMean±SD patient age was 50.9±18.1 years. Twenty-one (48%) participants were male and 23 (52%) were female patients. We documented detailed medical and ocular histories before performing any test to prevent questioning bias by test results. The most common presenting symptoms were gradually increasing blur in 50 (68%) of 73 eyes and "glare" in 29 eyes (40%) (Table 1and Table 2). The symptom of glare could include significant discomfort or slow recovery from any bright light or specifically from oncoming headlights during dusk and nighttime driving or an expressed preference for dim lighting conditions. Additional symptoms were paracentral scotomata, described as nonmobile dark, white, or missing spots, in 9 eyes (12%); similar scotomata centrally in 5 eyes (7%); incidental finding of abnormal acuity in 4 eyes (6%); difficulty reading in 4 eyes (6%); central visual distortion in 3 eyes (4%); and incidental finding of suspected abnormal color vision in 2 eyes (3%). Although most patients related these symptoms voluntarily, some symptoms were extracted after specific questioning. The most common previously known associated conditions were systemic hypertension in 8 (18%) of 44 patients and history of smoking in 6 patients (14%). Family history of visual loss was present in 5 patients (11%). In 4 of these cases, relatives from 1 or more generations experienced significant visual loss of unclear cause. In the fifth case, a relative had age-related macular degeneration.Table 1. Eyes With Unexplained Visual Symptoms or Acuity Loss and Abnormal Foveal Cone ERG Recordings*See table graphicTable 2. Eyes With Unexplained Visual Symptoms or Acuity Loss and Normal Foveal Cone ERG Recordings*See table graphicThe most common unrevealing tests previously performed by the referring ophthalmologists were Humphrey 30-2 full-threshold visual fields in 40 (55%) of 73 eyes, fluorescein angiography in 37 eyes (53%), and magnetic resonance imaging or computed tomography of the brain and orbit done with fine cuts (3.5 mm for magnetic resonance imaging and 3.0 mm for computed tomography) in 31 eyes (42%) (Table 1and Table 2). Additional tests were full-field ERG in 16 eyes (22%), pattern visual evoked responses in 12 eyes (16%), and electro-oculography in 9 eyes (12%). These tests were performed by different laboratories following such protocols as those of the International Standardization Committee.On examination, best-corrected Snellen visual acuity ranged from 20/20 to 20/300 (mean ± SD, 0.57±0.30; &ap;20/36; Table 1and Table 2). We found approximately 20/40 or better acuity in 43 eyes (59%). Refractive spherical equivalent ranged from -7.50 to +5.00 diopters (D) (mean ± SD, −0.35±2.30 D). Ishihara pseudoisochromatic plates and Farnsworth D-15 panel testing did not reveal any color confusion pattern consistent with an inherited color vision defect in any of the eyes tested. Visual field deficits in the central 10°×10° area of each eye were mapped by letter recognition perimetry (LRP) (Table 3).This test consists of monocular identification of letters flashed consecutively and separately on a computer screen situated 30 cm from the patient's eye. The letters are flashed in random order for 20 milliseconds each to 1 of 100 locations arranged in a grid with 1° intervals and to the location of a fixation cross that disappears when a letter is flashed, for a total of 101 locations. The letters are scaled in size according to their distance from fixation to compensate for the normal decline in visual acuity with eccentricity from the foveola. Full near refractive correction is used. Black spots represent missed letters (Figure 1). The upper limit of normal is 4 errors.Table 3. Test FeaturesSee table graphicFigure 1.Letter recognition perimetry (LRP) and foveal cone electroretinography (ERG) results from 1 control and 4 representative eyes with unexplained visual symptoms or acuity loss. For LRP, the bar at the bottom of the column indicates the central 10° of visual field. The central 4° area of the control LRP is shaded to indicate the retinal area tested with foveal cone ERG. For foveal cone ERG, the vertical dashed line indicates stimulus onset; arrows, averaged response implicit times; and bars at the bottom of the column, amplitude (vertical bar) and implicit time (horizontal bar). Each response represents a summation of 2500 sweeps, and at least 3 response averages are superimposed for each eye.All eyes had normal intraocular pressures and minimal or no media opacities. After pupillary dilation, we found an entirely normal retinal appearance in 55(75%) of 73 eyes and minimal and nondiagnostic macular changes—including mild retinal pigment epithelial mottling, granularity, or focal depigmentation or few small drusen—in 18 eyes (25%) (Table 1and Table 2). These changes were previously determined by 2 or more ophthalmologists, including retinal specialists, to be insufficient to explain the extent of visual symptoms or acuity loss in the studied eyes. Unrecognized vitreomacular traction was ruled out by careful slitlamp biomicroscopy using appropriate optical means.FOVEAL CONE ERG TESTINGAll foveal cone ERG testing (Table 3) was done by one of us (A.W.). Recordings were obtained in a dimly lit room with a hand-held, dual-beam stimulator-ophthalmoscope (Maculoscope Spectrum, Doran Instruments, Littleton, Mass), similar to instrumentation described previously.Photocell light-response calibration, in addition to the stimulator-ophthalmoscope internal calibration, was routinely performed before testing each patient. Before testing, the patients were subjected to ambient room illumination with dilated pupils. Responses were elicited with a 4° white stimulus of 4.8–log troland retinal illuminance flickering at 42 Hz with a 50% duty-cycle, resulting in a mean retinal illuminance of 4.5 log trolands. The stimulus was positioned on the fovea and was centered within a 12° white, steady surround of 5.5 log trolands that eliminated stray-light stimulation. Responses were monitored with a bipolar contact lens electrode (GoldLens, Doran Instruments) on the topically anesthetized cornea. Using the stimulator-ophthalmoscope factory default software, signals were differentially amplified, smoothed by a narrow bandpass filter tuned to 42 Hz, and summed by a signal-averaging computer containing an artifact reject buffer that eliminated voltage deflections of greater than 5 µV because of eye or eyelid movements. Testing involved consecutive recording periods lasting between 60 and 120 seconds each and separated from each other by 5 to 10 seconds of darkness. In all patients, 3 or more recordings were performed until responses had stabilized to ensure response reproducibility and reliability (Figure 1). We considered stabilization to have occurred if the last recording showed a change in amplitude opposite in direction to the previous trend and amplitude and implicit time (ie, the time from stimulus onset to the corresponding cornea-positive response peak) that were not different from those of the previous response by more than 10% and 1 millisecond, respectively. This response stabilization allows for the foveal cone ERG light adaptation process to take full effect.The foveal ERG measures studied were stabilized amplitude and implicit time; published lower limit of normal for amplitude is 0.18 µV, and upper limit of normal for implicit time is 38 milliseconds.CONTROL METHODSWe documented medical, ocular, and family histories and performed psychophysical testing and complete eye examinations before foveal cone ERG testing to avoid potential bias imposed by knowledge of the latter testing results.We compared foveal cone ERG testing results with those obtained from 39 eyes of 39 control subjects who were not related to the study patients but were matched for age, sex, refractive error, and ethnic (white) origin. We determined the false-positive rate among these healthy eyes. Inclusion criteria for controls included volunteers with no visual complaints and no ocular history except for refractive error. Exclusion criteria included those described above for the study patients as well as best-corrected visual acuity of less than 20/25 or family history of visual loss other than that related to trauma. Among these 39 controls, mean ±SD age was 49.3±17.5 years and mean ±SD refractive spherical equivalent was −0.22±1.65 D.To determine the degree of recording variability and the false-negative rate, we tested 24 eyes of 16 patients twice within 1 to 3 months and compared the amplitude and implicit time data between the 2 testing sessions for each eye. Twelve of 24 eyes (7 patients) had known maculopathy and were not part of the study population, and the remaining 12 eyes (9 patients) had unexplained visual symptoms or acuity loss.STATISTICAL ANALYSISWe studied differences in age, best-corrected Snellen visual acuity, refractive error, and the number of errors on LRP between eyes with abnormal retinal responses and symptomatic eyes with normal responses with Student nonpaired ttest analysis. Differences in amplitude and implicit time between eyes with abnormal responses and eyes of controls were analyzed similarly. In eyes with abnormal responses, we studied relations between foveal cone ERG data and visual acuity and the number of errors on LRP with correlation analyses. We studied intertest differences and relations in foveal cone ERG data with Student paired ttest analysis and with a correlation analysis. Differences in initial symptoms, sex, and associated conditions between eyes with abnormal responses and symptomatic eyes with normal responses were studied with χ2analysis. We performed statistical analyses on a personal computer (Macintosh, Apple Computer, Cupertino, Calif) with a statistical analysis software package (StatView SE+Graphics v.1.03, Abacus Concepts Inc, Berkeley, Calif).This study followed the tenets of the Declaration of Helsinki. Before testing, all participants gave informed consent after our explanations regarding the nature, the possible consequences, and the possible complications of the tests used.Data are given as mean ± SD.RESULTSAmong eyes of controls, we measured amplitudes of 0.18 µV or greater in all 39 eyes (100%) and implicit times of 38.0 milliseconds or less in 38 (97%) of 39 eyes. Thus, we found amplitudes of less than 0.18 µV sufficient to define abnormal responses, a figure in agreement with previously published data.Among the 73 eyes with unexplained visual symptoms or acuity loss, we measured averaged amplitudes of less than 0.18 µV in 35 eyes (48%) and implicit times of greater than 38.0 milliseconds in 7 eyes (10%). All latter 7 eyes demonstrated amplitudes of less than 0.18 µV as well. Accordingly, we recorded abnormal foveal cone ERG data in 35 (48%) of 73 eyes (23 [52]of 44 patients, Figure 1and Figure 2).Figure 2.Foveal cone electroretinography (ERG) data scattergram for 35 eyes with unexplained visual symptoms or acuity loss and foveal outer retinal dysfunction and 39 eyes of 39 control subjects. Vertical dashed line indicates lower normal limit for amplitude (0.18 µV); horizontal dashed line, upper normal limit for implicit time (38 milliseconds).Compared with eyes of controls, the 35 eyes with abnormal retinal responses had significantly lower mean amplitudes (0.33±0.10 vs 0.12±0.04 µV, respectively; P<.001; t72=12.24). Mean implicit time was not significantly different between these 2 groups, although the eyes with abnormal responses showed a trend toward slower responses (34.56±1.76 vs 36.28±5.25 milliseconds, respectively; P=.06). Mean age (55.0±15.3 years) and mean refractive spherical equivalent (−0.44±1.76 D) of the 35 abnormal eyes did not differ significantly from those of the 39 eyes of controls (see data in the "Control Methods" subsection).Among the 35 eyes with abnormal retinal responses, we found amplitude to be significantly correlated with best-corrected Snellen visual acuity (P=.02, r=0.40), and the lower the amplitude the lower the visual acuity. However, amplitude data accounted for only 16% of the variability in visual acuity. Amplitude was also significantly correlated with the number of missed letters on LRP (P=.02, r=0.40), and the lower the amplitude the higher the number of errors. Again, amplitude data accounted for only 16% of the variability in LRP results.We found all initial symptoms, all associated conditions, and the male-female ratio not to be significantly different among the 35 eyes with abnormal retinal responses and the 38 symptomatic eyes with normal responses. Mean age (46.9±20.1 years) and mean refractive spherical equivalent (−0.30±2.77 D) of the 38 symptomatic eyes with normal responses did not differ significantly from those of the 35 abnormal eyes (P=.07 and P=.29, respectively) or from those of the 39 eyes of controls (P=.30 and P=.21, respectively).We found a significantly larger number of errors made within the central 10°×10° area on LRP among the 35 eyes with abnormal retinal responses than among the 38 symptomatic eyes with normal responses (mean, 49.7±32.3 vs 32.0±34.9, respectively; P<.05; t71=−2.24; Table 1and Table 2). Moreover, when we compared the number of errors made within the central 4°×4° area only, an area more closely corresponding to the 4° size of the foveal cone ERG test target, the difference reached even higher significance (mean, 10.7±6.1 vs 6.1±6.3, respectively; P<.01; t71=−3.20).Visual acuity of 20/40-2 or better was retained by 21 (60%) of 35 eyes with abnormal retinal responses and by 22 (58%) of 38 symptomatic eyes with normal retinal function. Although mean acuity was slightly lower in the former group (0.52±0.3 vs 0.60±0.3, respectively), the difference was not significant (P=.30). Similarly, the number of eyes demonstrating any macular changes on ophthalmoscopy was not significantly different between these 2 groups (7 vs 11 eyes, respectively; Table 1and Table 2).Among the 24 eyes tested twice within 1 to 3 months, we found no statistically significant differences in mean amplitude and mean implicit time between the 2 recording sessions. Although amplitude data from all 24 eyes were used for these comparisons, amplitudes in 3 of these eyes were too low to allow for reliable measurement of implicit time, excluding these 3 eyes from implicit time comparisons. Mean amplitudes and mean implicit times in the first and second test sessions were 0.130±0.080 vs 0.127±0.073 µV and 36.22±4.82 vs 36.01±4.95 milliseconds, respectively. We found significant correlations between the 2 sessions in amplitude (P<.001, r=0.89, Figure 3) and implicit time (P<.001, r=0.99). However, amplitudes were subnormal in the first testing session and normal in the second in 2 of 12 eyes with known maculopathy, and vice versa in 2 other eyes with maculopathy, suggesting a 17% rate of false-negative results for each session (Figure 3). In contrast, 9 eyes with unexplained visual symptoms or acuity loss and no previously known maculopathy had consistently abnormal retinal responses in both sessions, and the remaining 3 symptomatic eyes had consistently normal responses in both sessions. Thus, we could not demonstrate significant recording variability among eyes with unexplained visual symptoms or acuity loss.Figure 3.Scattergram for test vs retest foveal cone electroretinography (ERG) amplitude in 24 eyes. Diagonal dashed line indicates line of zero variance between test and retest for each eye; vertical and horizontal dashed lines, lower normal limit for amplitude (0.18 µV) for tests 1 and 2 (retest), respectively; and circled points, eyes with known maculopathy and normal amplitudes in 1 recording session and subnormal amplitudes in the other.COMMENTThe results of our study suggest that foveal outer retinal dysfunction, as measured by foveal cone ERG testing, can be found in as many as 48% of eyes (52% of patients) with unexplained visual symptoms or acuity loss. We also found that amplitudes were correlated with 2 subjective measures of visual function in eyes with abnormal foveal responses, namely, best-corrected Snellen visual acuity and LRP. These correlations suggest that the mechanism of visual symptoms and acuity loss in these eyes could be related at least in part to foveal outer retinal dysfunction.The true prevalence of foveal outer retinal dysfunction among eyes with unexplained visual symptoms or acuity loss cannot be clearly established for several reasons. One is that our study population could have been affected by a biased referral to our service. A second reason is foveal cone ERG recording variability, sensitivity, and specificity. We evaluated variability by testing 24 eyes—12 with known maculopathy and 12 with unexplained visual symptoms or acuity loss—twice within 1 to 3 months. We found no statistically significant differences in mean amplitude or mean implicit time between the 2 testing sessions, suggesting low recording variability. However, we found a sensitivity rate of 83.3% among eyes with known maculopathy in each recording session. This rate is in agreement with published data. A previous study found a sensitivity rate of 66% in eyes with maculopathy and 20/40 or better acuity and a higher sensitivity rate of 86% to 91% in eyes with maculopathy and less than 20/40 acuity.This acuity-dependent difference in sensitivity is supported by a studythat showed normal foveal cone ERGs in some eyes with known maculopathy and visual acuity of 20/40 or better. In our study, 22 (58%) of 38 symptomatic eyes with normal retinal responses had approximately 20/40 or better acuity. Based on the acuity-dependent sensitivity rates, the corrected prevalence of foveal outer retinal dysfunction among eyes with unexplained visual symptoms or acuity loss in our study population may increase from 48% to 65%.However, false-positive rates that would lower the true prevalence should also be considered. In our study, we found a specificity rate of 97.4% among eyes of controls. Published specificity rates are 92% to 95%.Based on these rates, the corrected prevalence in our study population may decrease from 65% to 62%.In conclusion, although the true prevalence of foveal outer retinal dysfunction among eyes with unexplained visual symptoms or acuity loss may not be clearly determined, our results suggest that foveal outer retinal dysfunction is certainly not rare among these eyes.WE BELIEVE that malingering was not a significant factor affecting the results of our study. One of our exclusion criteria was inability to maintain fixation sufficient for reliable foveal cone ERG testing regardless of visual acuity. Our method of foveal cone ERG testing requires direct observation of the patient's fovea by the tester through a dual-beam stimulator-ophthalmoscope throughout testing. Consequently, the patient's fixation is controlled at all times. In addition, the instrument records foveal outer retinal electrical response data that are entirely objective and that cannot be falsified by the patient being tested. This is in contradistinction to tests that record subjective data, such as visual acuity, color vision, or visual fields (Table 3).The relations between visual function measurements and foveal cone ERG data may not be straightforward. Some previous studiesfound good correlations between visual acuity and amplitude data. However, amplitude may not fully predict acuity in some forms of maculopathy, such as juvenile macular degenerationand macular holes.In our study, amplitude data in eyes with abnormal retinal responses were significantly correlated with visual acuity and with the number of errors on LRP but accounted for only 16.1% to 16.2% of the variance in both measures, suggesting that additional variables may be affecting results. Moreover, 3 of 35 eyes with foveal dysfunction (patient 3, OD and OS, and patient 23, OS; Table 1) demonstrated an apparent discrepancy between relatively preserved visual acuity, borderline or normal results on LRP, and normal macular appearance on one hand and complaints of increasing visual blur or glare and abnormal foveal cone ERG responses consistently during 2 separate testing sessions on the other hand.One possible explanation for these apparent inconsistencies is that although foveal cone ERG test target size is 4° (12.6° area), the retinal central 1° to 2° (0.8°-3.1° area) are sufficient to maintain visual acuity within normal limits.Thus, if enough cones are functioning normally within the central 4°, although cones are damaged in the central 1° to 2°, foveal cone ERG may still be within normal range, whereas acuity is reduced. Conversely, if cones in the central 1° to 2° are still normal while many of the surrounding cones are affected, acuity may be normal in the presence of abnormal retinal responses and otherwise unexplainable visual symptoms. Similarly, LRP assesses the central 10°×10° (100°) area, an area 8 times larger than that tested with the currently used foveal cone ERG stimulator-ophthalmoscope (Figure 1). Indeed, the difference in the number of missed letters on LRP between eyes with abnormal and normal responses was more significant when only results from the central 4°×4° (16°) area rather than from the full 10°×10° area were compared between the 2 groups. An alternative explanation is that dysfunctional cones respond differently to the 42-Hz flickering light of the foveal cone ERG stimulator-ophthalmoscope than to the high-contrast, nonflickering Snellen chart letters or the letters flashed on LRP. In view of all these possible explanations, the notion that foveal cone ERG amplitude data, obtained with the currently used stimulator-ophthalmoscope, should account alone for all variability in central visual function may not be justified.Our results also showed that visual acuity did not differ significantly between eyes with abnormal foveal responses and symptomatic eyes with normal responses. This may not be surprising because the eyes with abnormal responses were compared not with asymptomatic eyes with normal visual function but rather with symptomatic eyes with subjectively abnormal vision. These latter eyes remained undiagnosed after our evaluation and could represent foveal cone ERG false-negative results, or nonretinal causes of visual loss or symptoms such as unrecognized refractive errors or media abnormalities, optic neuropathy, or functional visual loss. Regardless of the cause of visual loss, the mean initial acuity was abnormal and was not necessarily different from that of eyes with foveal outer retinal dysfunction.In summary, while previous studies demonstrated foveal outer retinal dysfunction in some eyes with unexplained visual loss, our results suggest that this type of previously unsuspected retinal dysfunction is in fact a common underlying mechanism of unexplained visual symptoms or acuity loss. Our study also shows that neither initial symptoms or level of visual acuity nor macular appearance can differentiate between eyes with and without foveal outer retinal dysfunction. Because several forms of occult maculopathy have been described already,ophthalmologists cannot exclude foveal outer retinal dysfunction and occult maculopathy without foveal cone ERG testing.At which stage of the evaluation of these patients foveal cone ERG should be recorded is also an important issue. Some patients with foveal dysfunction in our study were previously diagnosed as having functional visual loss, including malingering, and received recommendations to seek psychiatric help. Early foveal cone ERG testing could have helped avoid these recommendations and the resulting frustration. Furthermore, before our recordings, many of our patients with foveal dysfunction had undergone extensive neurologic and radiological evaluations. Although the authors were not in control of these prestudy evaluations, fine-cut neuro-imaging studies were included. However, neuro-imaging studies previously have been shown to be low yielding,are potentially invasive, are significantly more costly than foveal cone ERG recording (Table 4), and were unrevealing in our patients. Thus, when no neurologic signs or symptoms that may give priority to neuro-imaging studies are present, we propose that foveal cone ERG recording be used routinely early in the evaluation of eyes with unexplained visual symptoms or acuity loss.Table 4. Medicare Facility Reimbursement for Some Tests Ordered for Patients With Unexplained Visual Symptoms or Acuity LossSee table graphicSEBrodieEMNaiduJGoncalvesCombined amplitude and phase criteria for evaluation of macular electroretinograms.Ophthalmology.1992;99:522-530.GPMatthewsMASandbergELBersonFoveal cone electroretinograms in patients with central visual loss of unexplained etiology.Arch Ophthalmol.1992; 110:1568-1570.YMiyakeKIchikawaYShioseKKawaseHereditary macular dystrophy without visible fundus abnormality.Am J Ophthalmol.1989;108:292-299.YMiyakeMHoriguchiNTomitaOccult macular dystrophy.Am J Ophthalmol.1996;122:644-653.PJDeLintJEEKeunenATALiemDVan NorrenScanning laser densitometry in visual loss of unknown origin.Br J Ophthalmol.1996;80:1051-1054.MASandbergSGJacobsonELBersonFoveal cone electroretinograms in retinitis pigmentosa and juvenile macular degeneration.Am J Ophthalmol.1979;88:702-707.MASandbergObjective assessment of retinal function.In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical Practice.Vol 2. Philadelphia, Pa: WB Saunders Co; 1994:1196-1206.MASandbergAHHansonELBersonFoveal and parafoveal cone electroretinograms in juvenile macular degeneration.Ophthalmol Paed Gen.1983;3:83-87.AWeinerMMKiniARGaudioMASandbergELBersonHydroxychloroquine retinopathy.Am J Ophthalmol.1991;112:528-534.WHSeipleIMSiegelRECarrCMayronEvaluating macular function using the focal ERG.Invest Ophthalmol Vis Sci.1986;27:1123-1130.GEFishDGBirchThe focal electroretinogram in the clinical assessment of macular disease.Ophthalmology.1989;96:109-114.DGBirchGEFishFocal cone electroretinograms: aging and macular disease.Doc Ophthalmol.1988;69:211-220.GBArdenJLKBankesFoveal electroretinogram as a clinical test.Br J Ophthalmol.1966;50:740.WRBiersdorfDADillerLocal electroretinogram in macular degeneration.Am J Ophthalmol.1969;68:296-303.GEFishDGBirchDGFullerRStraachA comparison of visual function tests in eyes with maculopathy.Ophthalmology.1986;93:1177-1182.WHSeipleIMSiegelRECarrCMayronEvaluating macular function using the focal electroretinogram.Invest Ophthalmol Vis Sci.1986;27:1123-1129.JFCRemullaARGaudioSMillerMASandbergFoveal electroretinograms and choroidal perfusion characteristics in fellow eyes of patients with unilateral neovascular age-related macular degeneration.Br J Ophthalmol.1995;79:558-561.SGJacobsonMASandbergMHEffronELBersonFoveal cone electroretinograms in strabismic amblyopia: comparison with juvenile macular degeneration, macular scars, and optic atrophy.Trans Ophthalmol Soc U K.1979;99:353-356.Not AvailableVaeganFABillsonMacular electroretinograms and contrast sensitivity as sensitive detectors of early maculopathy.Doc Ophthalmol.1986;63:399-406.PCAcostaJDTrobeJJShusterJPKrischerDiagnostic strategies in the management of unexplained visual loss: a cost-benefit analysis.Med Decis Making.1981;1:125-144.AWeinerVAChristopoulosCHGusslerFoveal cone function in non-proliferative diabetic retinopathy and macular edema.Invest Ophthalmol Vis Sci.1997;38:1443-1449.MASandbergARGaudioSMillerAWeinerIris pigmentation and extent of disease in patients with neovascular age-related macular degeneration.Invest Ophthalmol Vis Sci.1994;35:2734-2740.MJTolentinoSMillerARGaudioMASandbergVisual field deficits in early age-related macular degeneration.Vision Res.1994;34:409-413.AWeinerMASandbergNormal change in the foveal cone ERG with increasing duration of light exposure.Invest Ophthalmol Vis Sci.1991;32:2842-2845.GWestheimerVisual acuity.In: Moses RA, Hart WM, eds. Adler's Physiology of the Eye: Clinical Applications. St Louis, Mo: Mosby–Year Book Inc; 1987:423.Accepted for publication June 5, 1998.Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla, May 14, 1997, and at the annual meeting of American Academy of Ophthalmology, San Francisco, Calif, October 26, 1997.We thank Michael A. Sandberg, PhD, of Harvard Medical School for his advice in statistical analysis, and A. Douglas Mathews, Yolonda E. Howard, Jill E. Mounger, and Nancy K. Burton for their technical assistance.Corresponding author: Asher Weiner, MD, Division of Ophthalmology, Saint Luke's Medical Center, 11311 Shaker Blvd, Cleveland, OH 44104 (e-mail: [email protected]).

Weiner, Asher; Ripkin, Douglas J.; Patel, Sangita; Kaufman, Stephen R.; Kohn, Howard D.; Weidenthal, Daniel T.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1169pmid: 9747674

ObjectiveTo determine whether foveal function distal to the ganglion cell layer is an independent predictor of central visual field function in glaucoma.SettingUniversity affiliated hospital and private practice.ParticipantsTwenty-seven eyes (27 patients) with normal-pressure glaucoma, 10 eyes (10 patients) with primary open-angle glaucoma, and 47 eyes of 47 matched normal volunteers.Intervention and Main Outcome MeasuresFoveal cone electroretinogram (ERG) amplitude, relative optic cup to disc area and their relations to Humphrey full-threshold 30-2 visual field central 4-point mean total deviation (C4MTD) and pattern deviation (C4MPD).ResultsFoveal cone ERG amplitude was subnormal in 14 (37.8%) of the 37 glaucomatous eyes and lower in the glaucoma group compared with normal eyes (P<.01). The C4MTD and C4MPD were lower in glaucomatous eyes with subnormal amplitudes compared with those with normal amplitudes (P<.01 and P<.05, respectively). Amplitude was directly correlated with C4MTD (P<.01) and C4MPD (P<.01). Relative optic cup to disc area was inversely correlated with C4MTD (P<.001) and C4MPD (P<.001). Partial correlation analysis revealed that amplitude and relative optic cup to disc area were independent predictors of C4MTD and C4MPD.ConclusionFoveal function distal to the ganglion cell layer and optic disc cupping independently predict central visual field function in glaucoma.OPTIC NEUROPATHY and nerve fiber layer loss have historically been considered the main if not the sole mechanism of visual field loss in glaucoma. Retinal dysfunction distal to the ganglion cell layer (GCL) has also been documented in glaucoma,but no information is available to help determine whether this dysfunction is also an underlying mechanism of visual field loss in glaucoma. That mechanisms other than optic neuropathy alone may lead to visual field loss in this disease was supported by the demonstration that total visual field loss may not be directly correlated with optic disc changes in normal pressure glaucoma (NPG).Central visual field loss is not rare among patients with NPG or primary open-angle glaucoma (POAG).In the present study, we investigated whether foveal dysfunction distal to the GCL could be an underlying mechanism of central visual field loss in glaucoma in addition to optic neuropathy. To that end we used stimulator-ophthalmoscope foveal cone electroretinography (ERG) that allows for accurate control of the retinal area tested.This technique has also been determined to be the most reliable tool for evaluating macular function not only in eyes with overt maculopathybut also in those with an entirely normal macular appearance on ophthalmoscopic examination,as is the case in many eyes with glaucoma. Furthermore, while the recorded foveal ERG amplitudes are reduced in many types of maculopathy,they are normal in optic neuropathy and amblyopia.We present foveal cone ERG recording data and their relation to central visual field function in eyes with NPG and POAG.PATIENTS AND METHODSTwenty-seven eyes of 27 patients with NPG and 10 eyes of 10 patients with POAG (age range, 39-80 [mean±SD, 66.8±8.5] years) were tested. Eyes with NPG were from patients extracted from our database and who were available for testing. Eyes with POAG were preselected based on past Humphrey visual fields demonstrating reduced total or pattern deviation in one or more of the central 4 points. Inclusion criteria included the diagnosis of NPG or POAG based on the characteristic combination of optic disc cupping, progressive visual field loss, and intraocular pressure (IOP). Exclusion criteria were any of the following: media opacities or insufficient pupillary dilation precluding reliable observation of the ERG test target on the fovea by the tester throughout recording; best-corrected visual acuity less than 20/50 impeding fixation; any maculopathy or other retinopathy on ophthalmoscopic examination; previous ocular surgery; any general medical condition such as diabetes mellitus that may affect retinal functionand family history positive for retinal or macular dystrophies.PATIENT EVALUATION AND CLINICAL FINDINGSAssociated conditions included systemic hypertension, ischemic heart disease, and hypothyroidism in 4 patients each (10.8%), and treated pulmonary tuberculosis in 1 patient (2.7%). Ocular medications included 0.5% timolol maleate in 12 eyes (32.4%), 0.5% betaxolol hydrochloride in 11 eyes (29.7%), 0.005% latanoprost in 6 eyes (16.2%), 2% pilocarpine hydrochloride in 4 eyes (10.8%), methazolamide tablets orally and 2% dorzolamide hydrochloride drops in 3 eyes each (8.1%), 0.2% brimonidine tartrate and 1% carteolol hydrochloride in 2 eyes each(5.4%), and 0.1% dipivefrin hydrochloride in 1 eye (2.7%). Family history was positive for glaucoma in 5 patients (13.5%).Best-corrected Snellen visual acuity was 20/20-20/50 (mean±SD, 0.79±0.20, approximately 20/25). Refractive error spherical equivalent ranged from −4.50 to +5.00 diopters (D) (mean±SD, +0.08±2.34 D). Intraocular pressure measured 10 to 27 mm Hg (mean±SD, 14.9±4.2 mm Hg). Results of detailed ophthalmoscopic examination in all 37 eyes tested revealed no notable media opacities and normal fundus appearance except for nerve fiber layer loss and abnormal optic disc cupping.RELATIVE CUP TO DISC AREA (RCDA)Optic disc area can be calculated reliably by slitlamp biomicroscopy.We defined RCDA as the product of horizontal cup-disc ratio × vertical cup-disc ratio, also determined on slitlamp biomicroscopy. The RCDA is thus a relative number, not expressed in area units, and was found in our pilot studies to be better correlated with central visual field indices than either horizontal or vertical cup-disc ratio alone. In our study RCDA ranged from 0.12 to 0.81 (mean±SD, 0.46±0.20).CENTRAL VISUAL FIELD INDICESWe performed Humphrey full-threshold 30-2 visual fields following pupillary dilation if pupillary diameter was 3 mm or less. Appropriate near correction was used in all cases. Data were collected only from visual fields that demonstrated no significant fixation losses, false negatives, or false positives. Since foveal ERG tests only the retinal central 4°, we used only the central 4 points of the visual field that are aligned on the central 3° isopter. Averaging these 4 points, we calculated central 4-point mean total deviation (C4MTD) and central 4-point mean pattern deviation (C4MPD). Based on the Humphrey field analyzer database, C4MTD represents the age-corrected total deviation from normal of data collected from the central 4 points of the visual field, and C4MPD represents the age-corrected focal (interpoint) deviation from normal of data collected from these 4 points.FOVEAL CONE ERG RECORDINGAll ERG testing was done by one of us (A.W.) following visual field testing. Recordings were obtained with a handheld, dual-beam stimulator-ophthalmoscope (Maculoscope Spectrum, Doran Instruments, Littleton, Mass), similar to instrumentation and techniques described previously.Briefly, foveal responses were elicited through dilated pupils in a dark room with a 4° white stimulus of 4.8–log trolands (td) retinal illuminance, flickering at 42 Hz with a 50% duty-cycle resulting in 4.5–log td mean retinal illuminance. The stimulus was positioned on the fovea and centered within a 12° white, steady surround of 5.5 log td. Responses were monitored with a bipolar contact lens electrode (GoldLens, Doran Instruments). Using the stimulator-ophthalmoscope, factory default software signals were differentially amplified, smoothed by a narrow bandpass filter tuned to 42 Hz, and summed by a signal-averaging computer containing an artifact reject buffer that eliminated voltage deflections of more than 5 µV due to eye or eyelid movements. Testing involved consecutive recording periods lasting 60 to 120 seconds each depending on response phase reliability and separated from each other by 5 to 10 seconds in the dark. Responses were quantified with respect to stabilized amplitude and implicit time. In all cases, 3 or more recordings were performed until responses had stabilized to ensure response reproducibility and reliability.The published lower limit of normal for amplitude is 0.18 µV and the upper limit of normal for implicit time is 38 milliseconds.CONTROL METHODSThe RCDA was determined for each eye by two of us (A.W. and D.J.R.) separately. Their results did not differ significantly but when 2 determinations for an eye differed the average was used.The ERG tester and the visual field technicians were masked to each other's data. However, the ERG tester could not be masked to optic disc cupping data since we record foveal cone ERGs under direct observation of the fovea and the tester cannot avoid observing the optic disc. Nevertheless, we believe that the objective nature of foveal cone ERG recording is a safeguard against biased recording data.Immediately prior to each ERG testing we routinely performed a photocell light-response calibration of the stimulator-ophthalmoscope, in addition to the instrument internal calibration, to verify system integrity and stability.Foveal cone ERG testing results were compared with those obtained from 47 eyes of 47 normal volunteers and we determined the false-positive rate among these normal eyes. The volunteers were not related to the patients with glaucoma and were matched for age, sex, refractive error, and ethnic origin. Inclusion criteria included volunteers with no ocular history except for refractive error. Exclusion criteria included those described above for patients with glaucoma as well as visual complaints, a best-corrected visual acuity less than 20/25, an IOP greater than 21 mm Hg, any abnormal finding on dilated ocular examination, and vertical or horizontal cup-disc ratio of 0.4 or greater on slitlamp biomicroscopy. Among these 47 normal volunteers, mean (±SD) age was 63.1±12.3 years, and mean refractive spherical equivalent was −0.32±1.65 D.To determine whether IOP-lowering medications overtly depress foveal function, we selected 6 eyes of 6 patients with NPG that were judged not to be at a significant risk for visual loss from short-term medication washout. Of these eyes, 4 were treated with 0.5% betaxolol , 2 each with 0.5% timolol and 0.005% latanoprost, and 1 each with methazolamide tablets and 2% dorzolamide drops. Visual field and foveal cone ERG testing were repeated in these eyes following 2.5 to 5.0 weeks (mean [±SD]3.5±0.6 weeks) of medication washout and we compared the results between the 2 testing sessions.To determine the degree of foveal cone ERG recording variability and false-negative rate, we tested a separate group of 12 eyes (7 patients) with known maculopathy twice within 1 to 3 months and compared the recording data between the 2 testing sessions.STATISTICAL ANALYSISWe studied relations between ERG amplitude, RCDA, and central visual field indices with least squares (simple) regression analysis. The independent effects of amplitude and of RCDA on central visual field indices were studied with multiple regression and partial correlation analyses, after effects of possible confounding factors were excluded. Differences in central visual field indices among different groups of glaucomatous eyes, and between eyes of normal volunteers and eyes with glaucoma, were studied with Student nonpaired ttest analysis. We studied ERG test vs retest relations with Student paired ttest analysis and with least squares (simple) regression analysis. We compared ERG and central visual field data before and after IOP-lowering medication washout with Student paired ttest analysis as well.This study followed the tenets of the Declaration of Helsinki and was approved by our Institutional Review Board. Prior to testing, all subjects gave informed consent after the nature, possible consequences, and the possible complications of the tests used were explained.RESULTSWe found foveal function to differ significantly between eyes of matched normal volunteers and eyes with glaucoma. Among the 47 normal eyes, the foveal ERG mean (±SD)amplitude was 0.310±0.098 µV. This is consistent with the previously published value of 0.18 µV as the lower normal limit for amplitude.Based on this value we found subnormal amplitudes in 14 (37.8%) of the 37 eyes with glaucoma (Figure 1). Of these 14 eyes, 9 had NPG and 5 had POAG. Among all glaucomatous eyes amplitude range was 0.08 to 0.47 µV and mean (±SD) amplitude (0.236±0.103 µV) was significantly lower than in the normal eyes (P=.0013, t82=-3.339). Mean (±SD) implicit time did not differ significantly between these 2 groups (34.81±1.78 milliseconds and 34.28±1.39 milliseconds, respectively).Figure 1.Foveal cone electroretinographic (ERG) data scatterplot for 37 eyes of 37 patients with glaucoma and 47 eyes of 47 matched normal volunteers. Foveal cone ERGs were elicited with a stimulator-ophthalmoscope. Vertical dashed line designates the lower normal limit for amplitude (0.18 µV).We found foveal function distal to the GCL to correlate significantly with central visual field indices in eyes with glaucoma. Foveal cone ERG amplitude was directly correlated with C4MTD (P=.004, r36=0.464, Figure 2) and C4MPD (P=.006, r36=0.445, Figure 3). Furthermore, when we compared central visual field indices in glaucomatous eyes with subnormal amplitudes with those with normal amplitudes, C4MTD (mean±SD, −11.2±10.4 vs −3.6±6.0, respectively, P=.008, t35= −2.808), and C4MPD (mean±SD,−8.8±7.9 vs −3.7±4.3, respectively, P=.013, t35=−2.608) were significantly lower in the former group.Figure 2.Scatterplot and fitted least squares (simple) regression line for foveal cone electroretinogram (ERG) amplitude vs Humphrey 30-2 visual field central 4-point mean total deviation in 37 eyes with glaucoma and normal macular appearance. Vertical dashed line designates the lower normal limit for amplitude (0.18 µV); solid line, y=38.95x−15.671, r2=0.216.Figure 3.Scatterplot and fitted least squares (simple) regression line for foveal cone electroretinogram (ERG) amplitude vs Humphrey 30-2 visual field central 4-point mean pattern deviation in 37 eyes with glaucoma and normal macular appearance. Vertical dashed line designates the lower normal limit for amplitude (0.18 µV); solid line, y=27. 347x−12.088, r2=0.198.We found RCDA to be correlated with central visual field indices among the glaucomatous eyes as well. It was inversely correlated with C4MTD (P=.0001, r36=0.616) and C4MPD (P=.0001, r36=0.613). However, multiple regression analysis indicated that both foveal ERG amplitude and RCDA were independently correlated with C4MTD (P=.0004 and P=.0001, respectively) and C4MPD (P<.001 and P=.0001, respectively). Partial correlation analysis showed that amplitude and RCDA were independent predictors of C4MTD and C4MPD. Amplitude explained 31.4% and 28.1% of C4MTD and C4MPD variance, respectively, and RCDA explained 44.9% of C4MTD and of C4MPD variance, when one independent predictor was controlled for the other.We found that a 2.5- to 5.0-week (mean±SD, 3.5±0.6 weeks) IOP-lowering medication washout period did not help demonstrate an overt medication-induced depression of foveal function. When we retested 6 eyes with NPG following this washout period, foveal ERG amplitude, C4MTD, and C4MPD did not rise in any of these eyes. This also helped to verify a low intertest variability for C4MTD and C4MPD.Foveal ERG amplitude false-positive rate was determined based on data collected from the 47 normal eyes. Among these eyes, amplitude was less than 0.18 µV in 2 eyes (4.3%), constituting a specificity rate of 95.7%, similar to previously published rates of 92% to 95%.The amplitude false-negative rate was determined based on test vs retest data collected from 12 eyes with known maculopathy. Among these eyes we found no significant difference in amplitude between the 2 recording sessions, suggesting low intertest recording variability. However, amplitudes were subnormal in the first testing session and normal in the second in 2 of these 12 eyes, and vice versa in 2 other eyes, suggesting a 16.7% false-negative rate (sensitivity rate, 83.3%) for each of the recording sessions. This rate is in agreement with published rates of 66% to 91% depending on visual acuity levels.Our specificity and sensitivity rates may suggest that the number of eyes with foveal dysfunction distal to the GCL among the glaucomatous eyes we studied is in the range of 13.4 to 17.8 (36.2%-48.1%).COMMENTThe results of our study suggest that foveal dysfunction distal to the GCL can be found in a significant number of eyes with NPG and POAG, and that glaucomatous eyes have significantly lower foveal cone ERG amplitudes compared with eyes of matched normal volunteers. Thus, our findings are in agreement with results of other studies that demonstrated retinal dysfunction distal to the GCL in glaucomatous eyes based on abnormal flash full-field and focal ERG data.Furthermore, among the glaucomatous eyes in our study, foveal function was directly correlated with central visual field indices, and glaucomatous eyes with subnormal ERG amplitudes had significantly lower central visual field indices compared with glaucomatous eyes with normal amplitudes. While RCDA, a measure of optic disc cupping, was also correlated with central visual field indices, we found that ERG amplitude and RCDA were independent predictors of these indices; amplitude explained 28.1% to 31.4% and RCDA explained 44.9% of their variance. Since foveal cone ERG amplitudes are well correlated with visual function in various retinal conditions,our findings suggest that at least some degree of central visual field loss in glaucoma can be explained by foveal dysfunction distal to the GCL in addition to loss explained by optic nerve axonal damage. To the best of our knowledge, this is also the first report of a significant direct correlation between foveal cone ERG amplitude and central visual field indices in any patient group.We found foveal dysfunction in 14 (37.8%) of the 37 eyes tested. Our foveal cone ERG sensitivity rate (83.3%) and specificity rate (95.7%) are comparable to those previously published from other laboratories.Taking these rates into account, the number of glaucomatous eyes with foveal dysfunction in our study was in the range of 13.4 to 17.8 (36.2%-48.1%). However, the true prevalence of foveal dysfunction among glaucomatous eyes cannot be clearly defined from these results since not all of our patients with NPG were available for testing and since eyes with POAG were preselected based on their past visual fields. Nevertheless, our results suggest that foveal dysfunction distal to the GCL is not rare among eyes with glaucoma and could be a significant mechanism of visual loss in this disease.The origin of this foveal dysfunction is not clear. Glaucomatous optic neuropathy itself cannot be regarded as the underlying cause since studies demonstrated normal retinal function distal to the GCL, as measured by flash ERG recording, in eyes with optic atrophyand even months after optic nerve resection.Retinal dystrophy or macular degeneration associated with glaucoma are not likely causative factors as well. We have excluded from our study all eyes with any retinal or macular changes on ophthalmoscopic examination. Furthermore, results from previous histopathological studies of eyes with POAGand NPGhave shown that photoreceptors and other outer retinal elements are of normal appearance even at an advanced stage of glaucoma. In addition, our results cannot substantiate foveal dysfunction as an adverse effect or an artifact of IOP-lowering medications, at least not a dysfunction that can be reversed within weeks of medication washout.One possible cause of foveal dysfunction distal to the GCL in glaucoma is vascular insufficiency. On one hand, several studies demonstrated abnormal flash full-field and foveal ERGs in various retinal vasculopathiesand choroidal perfusion abnormalities.On the other hand, a previous finding of reduced oscillatory potentials in eyes with glaucoma,similar to reductions found in diabetic vasculopathyand central retinal vein occlusioncan be consistent with underlying vascular insufficiency in some eyes with glaucoma.Indeed, evidence supporting abnormal ocular blood flow in some eyes with NPG and POAG is mounting.That these abnormalities may be related to visual loss was demonstrated by a study that correlated Humphrey visual field mean deviation to the ophthalmic artery Pourcelot resistivity index in eyes with NPG.These ocular blood flow abnormalities should not be interpreted as a potential cause of optic neuropathy alone. Rather, other ocular structures including the choroid and the retina may be affected by vascular insufficiency. This is particularly suggested by the blood flow abnormalities found in the short posterior ciliary arteriessupplying the choroid underlying the macular area, and by abnormal ocular blood flow measurements reflecting abnormal choroidal blood flow in eyes with NPG.Since the outer 130 µm of the retina, including the photoreceptors and other retinal elements to the level of the outer part of the inner nuclear layer are dependent on the choroidal vascular bed,abnormal choroidal blood flow could result in outer retinal dysfunction in glaucomatous eyes. Furthermore, abnormalities in the vascular supply of the optic nerve head and the fovea may be interrelated since both the prelaminar optic disc and the foveal outer retina are nourished by the choroidal circulation.Other hypothetical causes of foveal dysfunction distal to the GCL in glaucoma could be neurotoxic effects of compounds, such as glutamate that was found in excessive concentrations in glaucomatous eyes,or the negative feedback of dying ganglion cells on more distal retinal elements.Our results may also have some future therapeutic implications. Studies have shown that central visual loss in eyes with NPG may be potentially reversible with vasodilators.Since our study suggests that foveal dysfunction contributes significantly to central visual loss in some glaucomatous eyes, at least some of the therapeutic effect of vasodilators on central visual functionmay have occurred through improved choroidal perfusion pressure in the macular area rather than improved optic disc vascular supply. Therefore, foveal cone ERG, being a sensitive and an objective measure of foveal function distal to the GCL,could be considered as a monitoring tool to determine the therapeutic effect of various agents on foveal function in glaucoma.Not AvailableVaeganSLGrahamIGoldbergLBucklandFCHollowsFlash and pattern electroretinogram changes with optic atrophy and glaucoma.Exp Eye Res.1995;60:697-706.DTFazioJRHeckenlivelyDAMartinREChristensenThe electroretinogram in advanced open-angle glaucoma.Doc Ophthalmol.1986;63:45-54.JVOdomJGFeghaliJCJinGWWeinsteinVisual function deficits in glaucoma. Electroretinogram pattern and luminance nonlinearities.Arch Ophthalmol.1990;108:222-227.KHolopigianWSeipleCMayronRKotyMLorenzoElectrophysiological and psychophysical flicker sensitivity in patients with primary open angle glaucoma and ocular hypertension.Invest Ophthalmol Vis Sci.1990;31:1863-1868.PFazioTKrupinMEFeitlEBWernerDACarreOptic disc topography in patients with low-tension and primary open angle glaucoma.Arch Ophthalmol.1990;108:705-708.BJLachenmayrSMDranceCentral function and visual field damage in glaucoma.Int Ophthalmol.1992;16:203-209.MSMarxIBodis-WollnerJSLustgartenSMPodosElectrophysiological evidence that early glaucoma affects foveal vision.Doc Ophthalmol.1987;67:281-301.AEisnerJRSamplesHMCampbellGACioffiFoveal adaptation abnormalities in early glaucoma.J Opt Soc Am A.1995;12:2318-2328.MASandbergSGJacobsonELBersonFoveal cone electroretinograms in retinitis pigmentosa and juvenile macular degeneration.Am J Ophthalmol.1979;88:702-707.GEFishDGBirchDGFullerRStraachA comparison of visual function tests in eyes with maculopathy.Ophthalmology.1986;93:1177-1182.SGJacobsonMASandbergMHEffronELBersonFoveal cone electroretinograms in strabismic amblyopia: comparison with juvenile macular degeneration, macular scars, and optic atrophy.Trans Ophthalmol Soc U K.1979;99:353-356.Not AvailableVaeganFABillsonMacular electroretinograms and contrast sensitivity as sensitive detectors of early maculopathy.Doc Ophthalmol.1986;63:399-406.MASandbergObjective assessment of retinal function.In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology: Clinical Practice. Vol 2. Philadelphia, Pa: WB Saunders Co; 1994:1196-1206.GPMatthewsMASandbergELBersonFoveal cone electroretinograms in patients with central visual loss of unexplained etiology.Arch Ophthalmol.1992;110:1568-1570.YMiyakeMHoriguchiNTomitaOccult macular dystrophy.Am J Ophthalmol.1996;122:644-653.DGBirchGEFishFocal cone electroretinograms: aging and macular disease.Doc Ophthalmol.1988;69:211-220.GEFishDGBirchThe focal electroretinogram in the clinical assessment of macular disease.Ophthalmology.1989;96:109-114.AWeinerMMKiniARGaudioMASandbergELBersonHydroxychloroquine retinopathy.Am J Ophthalmol.1991;112:528-534.JFCRemullaARGaudioSMillerMASandbergFoveal electroretinograms and choroidal perfusion characteristics in fellow eyes of patients with unilateral neovascular age-related macular degeneration.Br J Ophthalmol.1995;79:558-561.WRBiersdorfThe foveal electroretinogram is normal in optic atrophy.Doc Ophthalmol Proc Ser.1984;40:127-135.AWeinerVAChristopoulosCHGusslerFoveal cone function in non-proliferative diabetic retinopathy and macular edema.Invest Ophthalmol Vis Sci.1997;38:1443-1449.JBJonasKPapastathopoulosOphthalmoscopic measurement of the optic disc.Ophthalmology.1995;102:1102-1106.AWeinerMASandbergNormal change in the foveal cone ERG with increasing duration of light exposure.Invest Ophthalmol Vis Sci.1991;32:2842-2845.YTakatsunaEAdachi-UsamiNKurodaLong-standing follow-up electroretinographic studies after surgical resection of optic nerve glioma.Ophthalmologica.1993;206:94-101.KRKendellHAQuigleyLAKerriganMEPeaseENQuigleyPrimary open-angle glaucoma is not associated with photoreceptor loss.Invest Ophthalmol Vis Sci.1995;36:200-205.SRBennettWLAlwardRFolbergAn autosomal dominant form of low-tension glaucoma.Am J Ophthalmol.1989;108:238-244.SEBrodieEMNaiduJGoncalvesCombined amplitude and phase criteria for evaluation of macular electroretinograms.Ophthalmology.1992;99:522-530.SJuenGFKieselbachElectrophysiological changes in juvenile diabetics without retinopathy.Arch Ophthalmol.1990;108:372-375.JFCRemullaARGaudioSMillerMASandbergFoveal electroretinograms and choroidal perfusion characteristics in fellow eyes of patients with unilateral neovascular age-related macular degeneration.Br J Ophthalmol.1995;79:558-561.JRBrunetteGLafondElectroretinographic evaluation of diabetic retinopathy: sensitivity of amplitude and time of response.Can J Ophthalmol.1983;18:285-289.MASandbergHLeeGPMatthewsARGaudioRelationship of oscillatory potential amplitude to a-wave slope over a range of flash luminances in normal subjects.Invest Ophthalmol Vis Sci.1991;32:1508-1516.AHarrisRCSergottGLSpaethJLKatzJAShoemakerBJMartinColor Doppler analysis of ocular vessel blood velocity in normal-tension glaucoma.Am J Ophthalmol.1994;118:642-649.AHarrisGLSpaethRCSergottLJKatzLBCantorBJMartinRetrobulbar arterial hemodynamic effects of betaxolol and timolol in normal-tension glaucoma.Am J Ophthalmol.1995;120:168-175.SJRankinBEWalmanARBuckleySMDranceColor Doppler imaging and spectral analysis of the optic nerve vasculature in glaucoma.Am J Ophthalmol.1995;119:685-693.YYamazakiFHayamizuComparison of flow velocity of ophthalmic artery between primary open angle glaucoma and normal tension glaucoma.Br J Ophthalmol.1995;79:732-734.SSHayrehProgress in the understanding of the vascular etiology of glaucoma.Curr Opin Ophthalmol.1994;5:26-35.SSHayrehIn vivo choroidal circulation and its watershed zones.Eye.1990;4:273-289.EBDreyerDZurakowskiRASchumerSMPodosSALiptonElevated glutamate levels in the vitreous body of humans and monkeys with glaucoma.Arch Ophthalmol.1996;114:299-305.LEPillunatGKLangAHarrisThe visual response to increased ocular blood flow in normal pressure glaucoma.Surv Ophthalmol.1994;38(suppl):S139-S147.PANetlandNChaturvediEBDreyerCalcium channel blockers in the management of low-tension and open-angle glaucoma.Am J Ophthalmol.1993;115:608-613.AZGasparJFlammerPHendricksonInfluence of nifedipine on the visual fields of patients with optic-nerve-head diseases.Eur J Ophthalmol.1994;4:24-28.AZGasparPGasserJFlammerThe influence of magnesium on visual field and peripheral vasospasm in glaucoma.Ophthalmologica.1995;209:11-13.Accepted for publication June 9, 1998.Presented as a poster at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Fla, May 13, 1997, as a lecture at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, May 14, 1998, and at the annual meeting of the American Academy of Ophthalmology, San Francisco, Calif, October 28, 1997.We thank Michael A. Sandberg, PhD, Massachusetts Eye and Ear Infirmary, Boston, for his advice in statistical analysis and the staff of Northeast Ohio Eye Surgeons, Kent, for their technical assistance.Corresponding author: Asher Weiner, MD, Division of Ophthalmology, St Luke's Medical Center, 11311 Shaker Blvd, Cleveland, OH 44104 (e-mail: [email protected]).

Folk, James C.; Boldt, H. Culver; Keenum, Deborah G.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1177pmid: 9747675

ObjectiveTo define the clinical findings, cause, and outcome of patients with foveal cysts due to vitreous traction.MethodsFollow-up of 18 patients with foveal cysts and no posterior vitreous detachment (PVD). Changes were documented in visual acuity, the appearance of the fovea, or the development of a macular hole or PVD. We studied 8 eyes using the retinal thickness analyzer.ResultsOn follow-up, 9 of 23 eyes did not develop a PVD and still had a foveal cyst; 8 of 23 developed a full-thickness macular hole; 4 of 23 developed a PVD with resolution of the cyst; and 2 eyes underwent vitrectomy for the cyst before a full-thickness hole developed. Analysis with the retinal thickness analyzer showed splitting within the middle retinal layers and in some cases unroofing or absent inner retinal layers in the center of the cyst.ConclusionsFoveal cysts are caused by vitreous traction. These eyes may remain stable, develop full-thickness holes, or develop a PVD with resolution of the cystic changes. A foveal cyst seems to be a common finding in patients with foveal traction from a variety of mechanisms.GASSHAS provided an elegant biomicroscopic classification of the development of a macular hole. He believes that vitreous traction causes a localized detachment of the fovea that is seen as a yellow spot. A dehiscence of the fovea then occurs that is usually located in the center of the umbo. The dehiscence causes centrifugal displacement of the foveolar retina that includes the xanthophyll which is seen as an enlarging yellow ring. The dehiscence in the fovea may be hidden initially, however, because of contraction and opacity of the prefoveolar vitreous cortex. Eventually the condensed cortical vitreous separates slightly from the retina or thin areas develop in the cortical vitreous allowing for visualization of the underlying macular hole. Usually within months of the initial symptoms and appearance of the yellow ring, the vitreous either detaches from the fovea and the yellow ring resolves with good vision or a readily visible full-thickness macular hole with surrounding subretinal fluid develops.A growing number of reports indicate that not all patients with foveal changes caused by vitreous traction follow the Gass classification. Most of the authors have described such foveas as appearing "cystic." Bronstein et aldescribed a group of patients with a macular hole in one eye and a macular cyst in the fellow eye. McDonnell et aldocumented 30 eyes with macular cysts within a larger report on macular holes. Both of these reports, however, were published prior to the Gass classification on the stages of a macular hole. Therefore, some of the eyes these authors described as having cysts may actually have had stage 1 or 2 macular holes according to Gass. Guyer et al"observed premacular hole lesions without yellow dots or halos" that were purely cystic and did not seem to fit into the Gass classification and thus were termed stage 1c lesions. Guyer et alalso described the histopathologic features of 7 eyes with macular cysts. Acosta et alused the scanning laser ophthalmoscope to test fixation and central fields in patients with macular holes and also in patients who they believed had macular cysts. They found dense scotomas in eyes with macular holes but not in most eyes with macular cysts. Hee et aldemonstrated cysts in the fovea using optical coherence tomography. Kishi et al,after imaging patients with various stages of macular holes using the helium-neon laser, concluded that "tractional elevation of Henle's fiber layer with intraretinal foveolar cyst formation is the initial feature of macular hole development."Following is our study of 18 patients who had cysts in the fovea that appeared to be due to vitreous traction and often represented a premacular hole condition. We use the term cysts because it has been prevalent in the literature and is descriptive of the outer thinning seen in the fovea on biomicroscopic examination of these patients. We realize that the areas of thinning are probably not lined by epithelium and the term "cyst" may therefore be a misnomer.PATIENTS AND METHODSPATIENTSPatients were included if they were symptomatic; on biomicroscopic examination were found to have striae that were usually radial and appeared to be located in the vitreous cortex overlying the fovea or perhaps in the inner retina along with outer retinal thinning or schisis; had no posterior vitreous detachment (PVD); and were followed up by one of the senior authors (J.C.F. or H.C.B.). The absence of a vitreous detachment was confirmed by echography or by peeling of the posterior vitreous during vitrectomy. Foveal cysts can result from a variety of mechanisms of traction on the retina that include epiretinal membranes and vitreomacular traction syndrome. In an attempt to report on a homogeneous group of patients, we excluded those patients with any areas of vitreous detachment on examination or echography, or visible epiretinal membranes or traction lines located outside the fovea that could be due to transparent epiretinal membranes.Our criteria for inclusion into the study were developed as we were seeing these patients. About half of the data were analyzed retrospectively and half collected and analyzed prospectively. Eighteen patients (23 eyes) met our criteria. Evaluation of these patients included a complete eye examination including slitlamp biomicroscopy, the Watzke-Allen test and 50-µm aiming beam test for a central scotoma, fundus photography and fluorescein angiography, and echography. Eight eyes were also evaluated using the retinal thickness analyzer (Talia Technology Ltd, Zion, Israel).Patients were observed at frequent intervals because of the traction on the fovea. At the beginning of this study, the eye examinations and ancillary tests were performed as part of the routine management of the patient. When we decided to analyze and then publish the accumulated data, we obtained informed consent to do so from the patients.DESCRIPTION OF FOVEAL CYSTUnfortunately we do not have clinical pathologic correlation for any of these patients. Patients with foveal cysts had combinations of two findings although one could be more prominent than the other. First there were striae present either in the vitreous cortex overlying the fovea or within the inner retina. Usually the striae radiated outward from the fovea in a spokelike pattern. The overall thickness of the fovea is normal, although in some cases the inner layer of the fovea appears to be pulled forward slightly. However, it is seldom pulled forward to the level of the retina surrounding the fovea or as forward as the inner retina in eyes with holes that follow the Gass classification.The second main finding of eyes with cysts is a reddish appearance to the outer retina beneath the inner striae. This reddish appearance appears as tissue loss within the layers of the fovea, perhaps like a very localized area of schisis. The area of redness (or perhaps schisis) is usually circular or oval although it can have scalloped edges. It usually involves an area about equal to the foveal avascular zone. Ocassionally, however, the reddish change is confined to just a few small round or oval facets in the fovea. In patients who developed full-thickness holes, the hole started as a small round defect in the center of the outer wall of thinning or schisis within the fovea. Patients could have decreased vision but no detectable central scotoma until a full-thickness hole formed.REPORT OF CASESCASE 1A 65-year-old woman (patient 13 in Table 1) was first seen with a 2-month history of decreased visual acuity and metamorphopsia in the left eye. The visual acuity was 20/40 OS and radial striae were seen that were thought to be either in the cortical vitreous or inner layers of the foveal retina (Figure 1, A). The patient denied a central scotoma. One month later the visual acuity was still 20/40 and the clinical findings were unchanged. Seven months later the visual acuity was 20/200 and a full-hickness hole with surrounding fluid had developed (Figure 1, C).Patients With Foveal Cysts*See table graphicFigure 1.A, The left eye of case 1 (patient 13 described in Table 1) when she first was seen. The main findings at this time were radial folds in the overlying vitreous cortex and possibly in the inner retina of the fovea. B, Drawing of Figure 1, A, left showing radial folds. C, This patient was followed up and developed a full-thickness retinal hole with a cuff of fluid 7 months later. No pictures were taken at that time, but a follow-up photograph 15 months after our initial examination shows a well-developed macular hole with surrounding fluid. D, Initially the right eye was normal on multiple follow-up visits. Forty-five months after the patient had first been seen, she developed symptoms and now had developed radial striae and outer retinal thinning in the fovea as shown in the fundus photograph. E, Drawing showing radial striae that are most prominent in the superotemporal aspect of the fovea as well as an oval area of outer retinal thinning. F, The vision and cystic change in the fovea stayed relatively stable for an additional 40 months at which time the patient returned with complaints of further decreased acuity. A small full-thickness macular hole was noted in the center of the floor of the outer retinal thinning as shown in the photograph.When the patient was initially examined, the right eye was asymptomatic. The visual acuity was 20/15, the macula looked normal, and there was no PVD. Forty-five months later the patient noticed decreased acuity in the right eye. The acuity was now 20/25 and radial striae with outer retinal redness were seen in the fovea of the right eye (Figure 1, D). The appearance of the fovea and visual acuity remained fairly stable on multiple visits until 40 months after the striae had first appeared. The patient then returned with complaints of further decrease in vision. The acuity was now 20/40 and a small full-thickness macular hole was noted in the center of the floor of the outer retinal thinning (Figure 1, F). A vitrectomy was performed and the vitreous was peeled from the posterior pole using suction followed by a fluid-gas exchange. The hole sealed and the patient regained 20/20 acuity. Twenty-six months after surgery the acuity is 20/40, probably due to nuclear sclerosis of the lens.CASE 2A 66-year-old woman (patient 9 in Table 1) was referred for "macular holes in both eyes." The acuity was 20/200 OS and a full-thickness macular hole with a cuff of fluid was present.The acuity was 20/20 OD and a small round area of outer retinal thinning was seen in the fovea. Over multiple visits during the next 3 years, the visual acuity decreased to 20/40 and the outer thinning became more prominent, but the patient denied a central scotoma. Forty-four months after the initial visit the patient returned complaining of further loss of visual acuity. The acuity was now 20/70 and a small full-thickness macular hole was noted in the center of the base of the outer retinal thinning. A vitrectomy was performed and the vitreous was peeled from the posterior retina using suction followed by a fluid-gas exchange. The hole sealed and the acuity was 20/40 7 months after the vitrectomy at which time the patient returned to her referring physician.CASE 3A 66-year-old woman (patient 8 in Table 1) was first seen with decreased acuity in both eyes that was worse in the right. The acuity was 20/200 OD and a full-thickness macular hole with a cuff of fluid was seen.The acuity was 20/30 OS. There was a cloverleaf pattern of radial striae along with outer retinal thinning seen in the fovea. No PVD was seen clinically or on echography. The patient was followed at 4- to 6-month intervals and there was no change in acuity or the appearance of the fovea. Eighteen months after our initial examination, the patient returned and the acuity was 20/20. The striae and thinning were now barely evident. Findings from repeated echography now revealed a total PVD. Eleven months after this last visit the acuity remains 20/20 and the fovea appears normal.CASE 4A 64-year-old man (patient 3 in Table 1) was seen with decreased acuity in the left eye and metamorphopsia in the right. The acuity was 20/200 OS and a stage 2 full-thickness macular hole was seen. A vitrectomy was performed and the hyaloid peeled from the retinal surface. The hole sealed, but the patient developed extensive pigmentary changes in the posterior pole that were thought to be due to phototoxicity. The acuity is 20/300 6 years after the vitrectomy.The acuity was 20/20 OD. Radial striae and minimal outer retinal thinning were seen in the fovea. Seventy-one months later, the visual acuity was 20/25 and minimal radial striae with outer thinning was still seen in the fovea. The patient denies a central scotoma. Findings on echography show an attached vitreous. The retinal thickness analyzer showed an optically empty region in the middle retinal layers of the fovea. This optically empty region extended throughout most of the 2-mm section, or for perhaps 1.5 mm. In the center of the optically empty region, the inner retina appeared to be absent.CASE 5A 48-year-old woman (patient 7 in Table 1) was seen with decreased acuity in the left eye. The acuity was 20/200 and a stage 2 full-thickness macular hole was present. A vitrectomy was performed with peeling of vitreous from the retina followed by fluid-gas exchange. The hole sealed and the acuity was 20/30 34 months after surgery.On examination, the acuity was 20/25 OD and there were prominent striae and mild outer retinal thinning present in the fovea (Figure 2). The acuity and foveal appearance remained stable over multiple follow-up visits. Thirty-four months after the initial presentation the acuity remained 20/30 and minimal stria and thinning were still present although minimal. Findings from echography show no vitreous detachment. The retinal thickness analyzer shows an optically empty region within the middle retinal layers but no unroofing of the cyst or defect in the inner wall.Figure 2.A, The right eye of case 5 (patient 7 described in Table 1). Striae and mild cloverleaf outer retinal thinning were seen in the fovea of the right eye on examination. This eye has remained stable over 34 months of follow-up. B, Drawing showing a small cloverleaf area of outer retinal thinning.RESULTSEighteen patients had foveal cysts and no vitreous detachment. Fourteen of the patients were women. Fifteen patients were between the ages of 59 and 70 at the time of our examination. The remaining 3 were seen at ages 48, 75, and 78. Five patients had cysts in both eyes making 23 total eyes in the study. Eighteen eyes in 13 patients underwent fundus fluorescein angiography. The capillaries surrounding the foveal avascular zone did not appear to be distorted on fluorescein angiography even in eyes with prominent striae. There was also no evidence of late leakage or cystoid macular edema in these eyes. There was either normal background or slight hyperfluorescence in the center of eyes with prominent thinning. The hyperfluorescence was minimal, however, and not as prominent as seen with a full-thickness macular hole. Stereoscopic fluorescein angiography was the best method to detect when a hole did develop in the outer retinal layer because it resulted in a small round transmission defect in the center of the fovea.On final follow-up, 9 of the 23 eyes did not develop a PVD and still had a cystic appearance in the fovea. The times of follow-up after the cystic fovea was first seen and the acuities in these 9 patients are as follows: 3 months (20/15); 26 months (20/50); 34 months (20/30); 40 months (20/30); 56 months (20/25); 70 months (20/40); 71 months (20/25); 114 months (20/30); and 168 months (20/20).Eight of the 23 eyes developed full-thickness macular holes on follow-up. The time between when the foveal cyst was first seen and the macular hole detected on examination, the acuity at the time the hole was first diagnosed, and the follow-up acuities are as follows: 4 months (20/50; now 20/25 after vitrectomy); 5 months (20/50; now 20/200 with no treatment); 7 months (20/200; no treatment); 7 months (20/200; no treatment); 11 months (20/80; now 20/25 after vitrectomy); 11 months (20/200; now 20/60 after vitrectomy); 40 months (20/40; was 20/20 after vitrectomy, now 20/40 due to cataract); 44 months (20/70; now 20/40 after vitrectomy).Four of the 23 eyes developed PVDs on follow-up. The time the PVD was noted after the cysts were first seen and the final acuity of these eyes are as follows: 3 weeks (20/25); 4 months (20/20); 18 months (20/20); and 31 months (20/20) (Figure 3).Figure 3.A, Slitlamp photograph of the fovea of patient 5 in Table 1. On examination, this patient had a cloverleaf area of outer retinal thinning with mild inner striae in the right eye. B, Drawing of the area illuminated by slitlamp showing highlight over the superior fovea that probably represents thickened cortical vitreous as well as a cloverleaf area of outer retinal thinning. C, Fundus photograph of the right eye taken at the same time as seen in Figure 3, A. D, The patient developed a posterior vitreous detachment 4 months after the initial examination and the area of thinning and striae became much less prominent as shown in the follow-up fundus photograph. Visual acuity has remained 20/20 23 months after the posterior vitreous detachment.Two of the 23 eyes had undergone vitrectomies for the cysts before either a macular hole or PVD had developed (Figure 4). One of these eyes had a vitrectomy only 1 week after the cyst was first noted and acuity improved from 20/40 to 20/20. The other eye had a vitrectomy 19 months after first being seen with a cyst. The acuity decreased slightly to 20/60 after vitrectomy from the 20/50 preoperative value. There was also pigmentation in the macula thought to be due to phototoxicity.Figure 4.Fundus photograph of the right eye of patient 6 described in Table 1 showing prominent outer retinal thinning at the time of initial examination. The visual acuity was 20/30 and the patient denied a central scotoma. No full-thickness macular hole was seen in the base of the cyst.Eight patients and eyes were investigated using the retinal thickness analyzer. Two patients (Nos. 3 and 4 in Table 1) showed optically empty regions within the middle layers of the retina that extended well beyond the area of the cyst visible on clinical examination and also unroofing of the cyst or loss of the inner layer centrally (Figure 5). Both of these patients denied a central scotoma and had 20/25 and 20/30 acuity. Two patients (Nos. 7 and 18 in Table 1) had optically empty regions in the middle layers of the retina but no unroofing of the cyst or tissue loss in the inner layer. Both patients denied a central scotoma and had 20/30 visual acuity. One patient (No. 14 in Table 1) had only 3 months of follow-up after minimal cystic changes were seen in the fovea. The retinal thickness analyzer showed no splitting, but the fovea was not shaped perfectly because one side was steep rather than gently sloping posteriorly as seen in normal patients. The visual acuity was 20/15 in this eye. One patient (No. 5 in Table 1) was examined 23 months after a PVD and had an essentially normal fovea. Another patient (No. 6 in Table 1) had what appeared to be a lamellar hole with inner retinal tissue loss in the fovea. The patient had an acuity of 20/20, denied symptoms, and was examined with the retinal thickness analyzer 47 months after a PVD in this eye. The final patient (No. 2 in Table 1) had an irregular foveal depression 41 months after a vitrectomy to seal a stage 2 macular hole.Figure 5.Slitlamp images taken with the retinal thickness analyzer centered on the fovea of the right eye of case 4 (patient 3 in Table 1). Images at the far left and right show an optically empty region in the middle retinal layers. The central 2 images show an absent or extremely attenuated inner retinal layer in the center of the fovea.COMMENTOn biomicroscopic examination, radial striae were seen in the vitreous cortex immediately overlying the fovea in most patients. In some cases it appeared that the striae also involved the superficial retina; although on fluorescein angiography, we did not detect distortion of the foveal capillaries that were surrounding the perimeter of the striae. Kishi et albelieve that the radial striae are due to traction and distortion of Henle's layers.These patients also have round or oval red cysts often with sharp margins deep to the striae. The round cysts usually comprise an area about equal to the foveal avascular zone or slightly smaller. Sometimes the round areas appear to composed of smaller lobules or facets although this segmented appearance may be due to blocking by the overlying striae. We believe these lesions are the ones described in the previous reports as macular cysts.Within this report we have described this outer retinal thinning as "redness," "thinning," "tissue loss," a "cyst," or "schisis." It seems clinically that the redness represents tissue loss or splitting within the fovea. However, histopathologic examinations of patients with well documented foveal cysts are needed to provide the conclusive answer.We excluded patients with the vitreomacular traction syndrome or visible epiretinal membranes. Both of these conditions, however, can cause cystic changes in the fovea indistinguishable clinically from the patients described. The foveal changes in all of these conditions are probably the same or very similar because the common cause appears to be traction from the vitreous or preretinal membranes. An advantage of this study is that these patients were followed up sequentially by 1 of 2 of us (J.C.F. or H.C.B.) and the status of a PVD was documented by multiple echographic examinations or by peeling of the posterior hyaloid during a vitrectomy. When the traction was relieved by a spontaneous PVD or a vitrectomy, the cystic changes became much less prominent or disappeared and the acuity stablilized or improved.Nine of the patients so far still have no PVD despite a prolonged follow-up in some cases and these patients still have foveal cysts. Eight patients developed full-thickness holes on follow-up. These patients noticed an abrupt decrease in visual acuity and there was a sharp decrease in acuity on examination. The holes first appeared on bimomicroscopic examination as small round defects in the center of the outer layer of the cyst often with a thin surrounding border of yellowish subretinal fluid or perhaps luteal pigment. A defect in the outer layer centrally exposing the underlying retinal pigment epithelium was also readily visible on fluorescein angiography.Examination with the retinal thickness analyzer revealed splitting or schisis in the middle layers of the retina in 4 patients and unroofing of the central area of splitting in 2 of these 4. These findings are not conclusive, however, because the retinal thickness analyzer shows mainly reflections from the inner retina and the retinal pigment epithelium. Therefore, the "splitting" of the middle layers could be due to fluid at the margins of a full-thickness macular hole. The area of splitting was often large which would mean that there would have to be an extensive, albeit shallow, detachment of the perifoveal retina that was not observed clinically. In addition, the visual function in these patients was good which does not support the presence of an extensive detachment of the perifoveal retina. Therefore, we believe the splitting is within the retinal layers. In addition, there may still have been an extremely attenuated layer of inner retina present that was not detected by the "gain" of the machine in the cases that showed unroofing of the cyst or absent inner retinal layers. If the inner retinal layers were indeed absent, these patients could be said to now have lamellar holes in addition to splitting within the retina. The vitreous remained attached in these patients, however, so they are probably still at risk for the future development of a full-thickness macular hole.The findings of schisis and unroofing of the inner layer found by the retinal thickness analyzer do correlate nicely with the clinical findings and course. We believe that foveal cysts are caused by traction on or at the edges of the fovea for whatever reason. The traction is evident by radial folds in the vitreous cortex immediately overlying the foveal retina and perhaps folds in Henle's layer within the retina. The traction causes damage to the fovea that is seen as reddish cystlike areas clinically and as splitting in the middle retinal layers on examination with the retinal thickness analyzer. The vision remains good even with unroofing of the inner retinal layers. The outer fovea appears to be markedly resistant to traction. The vision and cyst can remain stable for years; but once a small defect develops in the center of the outer retinal thinning, there is an abrupt loss of acuity and a larger stage 3 full-thickness macular hole with surrounding fluid follows quickly.The correct management appears to be to follow up on these patients and warn them to return promptly if their visual acuity decreases. A defect in the outer wall of the cyst is an early full-thickness macular hole. Three of such eyes were followed up without treatment and progressed to large macular holes with surrounding fluid and poor vision. Five had vitrectomies with peeling of the posterior hyaloid and intraocular gas. Four regained 20/20 to 20/25 acuities and the fifth has an acuity of 20/60 with signs of phototoxicity. Therefore, a prompt vitrectomy with gas should be considered once a full-thickness macular hole occurs.JDMGassReappraisal of biomicroscopic classification of stages of development of a macular hole.Am J Ophthalmol.1995;119:752-759.MABronsteinCLTrempeHMFreemanFellow eyes of eyes with macular holes.Am J Ophthalmol.1981;92:757-761.PJMcDonnellSLFineAIHillisClinical features of idiopathic macular cysts and holes.Am J Ophthalmol.1982;93:777-786.DRGuyerSdeBustrosMDiener-WestSLFineObservations on patients with idiopathic macular holes and cysts.Arch Ophthalmol.1992;110:1264-1268.DRGuyerWRGreenSdeBustrosSLFineHistopathologic features of idiopathic macular holes and cysts.Ophthalmology.1990;97:1045-1051.FAcostaKLashkariXReynaudAEJalkhFVanDeVeldeNChedidCharacterization of functional changes in macular holes and cysts.Ophthalmology.1991;98:1820-1823.MRHeeCAPuliafitoCWongOptical coherence tomography of macular holes.Ophthalmology.1995;102:748-756.JKishiYKameiKShimizuTractional elevation of Henle's fiber layer in idiopathic macular holes.Am J Ophthalmol.1995;120:486-496.Accepted for publication May 18, 1998.This research was supported in part by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY.Emanuel Binnun of Talia Technology Ltd, Mevaseret, Zion, Israel, performed the studies using the Retinal Thickness Analyzer.Reprints: James C. Folk, MD, Department of Ophthalmology, The University of Iowa Hospitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242-1091 (e-mail: [email protected]).

Sears, Jonathan; Gilman, James; Sternberg, Jr, Paul

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1185pmid: 9747676

BackgroundFamilial arteriolar tortuosity is an autosomal dominant disorder affecting the retinal arterioles.Objectives:To report a pedigree with this disorder and describe a systemic workup to determine whether this vascular abnormality is limited to the eye.ResultsA 58-year-old woman referred for retinal hemorrhages was found to have retinal arteriolar tortuosity of both eyes, especially in the macular area. Her 63-year-old brother had a history of retinal hemmorhages beginning at age 18 years and had similar fundoscopic examination findings. The proband had an extensive systemic workup, including magnetic resonance imaging, and cardiac and renal angiography, that failed to demonstrate any other sequelae of this inherited ocular syndrome. However, each member of the family expressing this phenotype did have hypertension.ConclusionInherited retinal arteriolar tortuosity is an autosomal dominant disorder limited to the eye, at least in this pedigree, within the sensitivity of the systemic workup we used.A 58-YEAR-OLD woman referred for retinal hemorrhages was found to have retinal arteriolar tortuosity of both eyes, especially in the macular area. Her 63-year-old brother had a history of retinal hemorrhages beginning at age 18 and similar findings on funduscopic examination. The proband had an extensive systemic workup, which included magnetic resonance imaging (MRI) and cardiac and renal angiography, that failed to demonstrate any other sequelae of this inherited ocular syndrome. However, each member of this family expressing the abnormal phenotype did have hypertension (Figure 1).Figure 1.Pedigree of family with retinal arteriolar tortuosity. Although patient I-a had a history of retinal hemorrhages suggesting that she expressed the phenotype of arteriolar tortuosity, she may have suffered from other causes of retinal hemorrhage.Retinal arteriolar tortuosity is reported to be an autosomal dominant disorder characterized by tortuous small retinal arterioles, frequent occurrence of superficial intraretinal hemorrhages, and the progressive expression of this abnormal vascular phenotype beginning in adolescence. This report describes an additional pedigree and details an extensive systemic workup that the proband underwent because of complaints of headache and fatigue.PATIENTS AND METHODSThe proband complained of intermittent blurred vision and dark spots in both eyes. She noted that her brother had had 2 similar episodes. Informed consent was obtained from all family members after which complete ophthalmic examinations of family members were performed and findings from systemic examinations reviewed. Fluorescein fundus photographs were taken with a Zeiss fundus camera (Carl Zeiss, Oberkochen, Germany) of the proband. Fundus photographs were obtained on all of the family members.REPORT OF CASESPATIENT II-bA 58-year-old woman was referred for evaluation and management of retinal tortuosity and retinal hemorrhage. Her ocular history is remarkable for a retinal hemorrhage 7 years earlier that cleared spontaneously and an exotropia since age 2 years for which she underwent strabismus surgery. The patient's medical history is noteworthy for migraine headaches, mitral valve prolapse secondary to rheumatic fever at age 6 years, aortic regurgitation, and hypertension. Her migraine headaches occur 2 or 3 times a year as an arc of flashing light that lasts for 20 minutes and are accompanied by arm or leg paresthesia. These migraines have resolved by taking nadolol (Corgard). Results of MRI and computed tomographic (CT) scans 5 years prior to our first seeing her at the retina clinic, obtained by her neurologist because of a complaint of headache and throbbing in her ears, showed multiple small areas of ischemia in the midbrain consistent with vascular changes from migraines. Four years before we saw her at the retina clinic, she underwent cardiac catheterization and ultrasonography to investigate complaints of weakness and vertigo. Blood pressure at the time of catheterization was 175/78 mm Hg with a mean of 110 mm Hg. Catheterization demonstrated elevated diastolic dysfunction with mild left ventricular hypertrophy, aortic regurgitation (1+), mitral valve regurgitation (1+), and an ejection fraction of 55%. The coronary arteries were normal as were the results of a pharmacologically induced coronary artery spasm test. The study also revealed normal renal arteries. Ultrasound confirmed the angiographic findings and did not demonstrate a source of emboli from valve leaflet calcification to explain the prior MRI and CT scan findings. Findings from Ml laboratory studies, which included antiphospholipid antibody, lupus anticoagulant, clotting parameters, and complete blood cell count were normal in the past. Medications currently being taken include naldolol, and clonazepam, and use of a beclomethasone dipropionate (Beconase) inhaler. Family history is noteworthy for a mother who died of hypertension and "vascular problems," a brother with a history of retinal hemorrhages, and 2 daughters in good health. Review of systems did reveal that the patient had multiple areas of cutaneous nevi that were larger than 5 cm in diameter.Visual acuity was 20/30 OD and 20/30 OS. The entire arteriolar tree of both eyes was tortuous, especially in the macular area (Figure 2). There was no venous tortuosity, arteriovenous communications, or angiomas. There was no hemorrhage or exudate. Findings from fluorescein angiography showed no other abnormality (Figure 3). The patient returned 1 month later with a complaint of paracentral scotomas in both eyes. Results from retinal examination at that time demonstrated superficial ovoid macular hemorrhages in both eyes (Figure 4).Figure 2.Red free photograph of the proband's right (left) and left (right) eyes demonstrates arteriolar tortuosity, especially in the macular region. The arrow marks the disc hemorrhage in the left eye.Figure 3.Fluorescein angiogram with transit of the macula in the left eye in early laminar flow defines the strictly arteriolar, not venular, tortuosity. There is asymmetry in the superior and inferior retinal artery filling. Late frames of the angiogram showed no leakage.Figure 4.Kodachrome of the proband 6 weeks after first being examined demonstrates retinal hemorrhages that caused scotomas in the patient's central visual field.PATIENT II-cA 63-year-old man had a history of retinal hemorrhages at ages 18 and 56 years. His medical history is noteworthy for hypertension and arthritis. His ocular history is notable for bilateral pseudophakia. His hypertension was controlled with verapamil.Visual acuity was 20/20 OD and 20/20 OS. Findings from slitlamp examination revealed centered posterior chamber lens implants within an intact capsular bag in both eyes. Dilated funduscopic examination findings demonstrated tortuous retinal arteriolar vessels, especially in the macular area (Figure 5). The left optic disc was surrounded by a myelinated nerve fiber layer that extended for 1 disc diameter nearly 360° around the disc. There were no retinal hemorrhages or exudate.Figure 5.Kodachrome of patient II-c shows identical arteriolar tortuosity as was seen in patient II-a. There is a myelinated nerve fiber layer in the left eye.PATIENTS III-a AND III-bTwo women aged 29 and 26 years have no history of retinal hemorrhages. Both patients have a medical history noteworthy for Marfan syndrome. Visual acuity and ocular findings were normal in each, including the absence of ectopia lentis.PATIENT I-aA 90-year-old man has had no history of retinal hemorrhages. His medical history is notable for rheumatoid arthritis. His visual acuity was 20/40 OD and 20/60 OS. He is bilaterally pseudophakic. The retinal vessels were attenuated but not tortuous and exhibited mild atherosclerotic changes. The macula had areas of retinal pigment epithelial rarefaction.COMMENTFamilial retinal arteriolar tortuosity with superficial macular hemorrhages was first reported by Beyer in 1958.Since that original report, other families have been identified in Europe, North America, and Japan.These cases, like ours, are characterized by arteriolar tortuosity, competency of the retinal vessels on fluorescein angiography, intermittent superficial retinal hemorrhages, and autosomal dominant transmission. Venules are normal. The single other syndrome that produces arteriolar tortuosity alone without venous involvement is coarctation of the aorta.Other congenital diseases, such as familial dysautonomia, or congenital storage diseases, such as Fabry or Marteaux-Lamy syndrome, can cause combined venular and arteriolar tortuosity. Congenital syndromes associated with classic phacomatosis are associated with vascular tortuosity secondary to arteriovenous shunts, as in Wyburn-Mason syndrome, or hemagiomas, as in von Hippel-Lindau syndrome. Although we were curious as to whether our patient's nevi and history of MRI documented central nervous system vascular abnormalities might demonstrate that this autosomal dominant defect was a forme fruste of a phacomatois, her affected brother had no similar skin pigmentations and the findings from his MRI did not demonstrate intracranial arteriolar tortuosity. Other syndromes that are associated with venous and arterial tortuosity include macroglobulinemia, cryoglobulinemia, leukemia, and polycythemia vera. The natural history of patients with familial retinal arteriolar tortuosity is favorable,demonstrating that once the diagnosis is established by physical examination findings of the propositus' relatives, a benign prognosis can be offered to the patient. We cannot demonstrate that the intracranial lesions found by MRI were caused by abnormal vessels and therefore associated with retinal arteriolar tortuosity. It may prove worthwhile to determine whether there is a history of migraine or central nervous system abnormalities in existing pedigrees.EMBeyerFamiliare tortuositas der kleinen netzhautarterien mit makulablutung.Klin Monatsbl Augenheilkd.1958;132:532-539.HWernerFGafnerBeitrag zur familiaren tortuositas der kleinen netzhautarterien.Ophthalmologica.1961;141:350-356.BCagianutHWernerZum krankheitsbild der familiaren tortuositas der kleinen netzhautarterien mit maculablutung nethautgefasse.KIin Monatsbl Augenheilkd.1968;153:533-542.BCagianutZum krankheitsbild der familiaren tortuositas der nethautgefasse.Ophthalmologica.1968;156:322-324.MFGoldbergIPPollackWRGreenFamilial retinal arteriolar tortuosity with retinal hemorrhage.Am J Ophthalmol.1972;73:183-191.PTesinskyALorenzTortuosity of small retinal arteries connected with bleeding in a family.Cesk Slov Oftalmol.1975;31:172-175.FHStefaniJHGreiteWSchrammRezidivierende Netzhautblutungen bei tortuositas der netzhautarteriolen.Klin Monatsbl Augenheilkd.1975;167:608-612.EGOlsenRetinal arteriolar tortuosity with retinal hemorrhage; a case report.Acta Ophthalmol.1978;56:322-325.WJBartlettJPriceFamilial retinal arteriolar tortuosity with retinal hemorrhage.Am J Ophthalmol.1983;95:556-558.FKayazawaTMachidaRetinal arteriolar tortuosity with macular hemorrhage.Ann Ophthalmol.1983;15:42-43.CGWellsREKalinaProgressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages.Ophthalmology.1985;92:1015-1021.BWConnellyGGGibsonThe retinal arterioles in coarctation of the aorta; 14 year observation of a case.Am J Ophthalmol.1949;32:1513-1516.MFGoldbergIn discussion of: Wells CG, Kalina RE. Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages.Ophthalmology.1985;92:1015-1023.Accepted for publication June 17, 1998.Dr Sears was a vitreoretinal fellow at the Department of Ophthalmology, and Dr Sternberg is the Thomas M. Aaberg Professor of Ophthalmology, Emory University School of Medicine, Atlanta, Ga.Dr Sears was a Heed Ophthalmic Fellow, Heed Ophthalmic Foundation, Cleveland, Ohio. Dr Sears is supported in part by an unrestricted departmental grant from the Research to Prevent Blindness, Inc, New York, NY.Reprints: Paul Sternberg, Jr, MD, Department of Oph-thalmology, Emory Eye Center, Emory University School of Medicine, 1365 B Clifton Rd NE, Atlanta, GA 30322.

Mittra, Robert A.; Huynh, Linh T.; Ruttum, Mark S.; Mieler, William F.; Connor, Thomas B.; Han, Dennis P.; Pulido, Jose S.; Dev, Sundeep

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1190pmid: 9747677

ObjectiveTo determine the visual outcome after surgery for persistent hyperplastic primary vitreous using modern vitreoretinal techniques.DesignRetrospective medical record review during a 5-year period (June 1992 to June 1997). Information recorded for each patient included age, medical history, sex, results of preoperative ocular examination, age at diagnosis, procedure performed, intraoperative and postoperative complications, location and number of sclerotomy sites, type of aphakic rehabilitation, amblyopic therapy given, final visual acuity, and length of follow-up.ResultsFourteen patients who underwent surgical management of combined anterior and posterior persistent hyperplastic primary vitreous were identified. Eleven patients underwent aphakic rehabilitation and aggressive amblyopic therapy consisting of occlusive therapy for several waking hours each day. One additional older patient received aphakic rehabilitation only. Ten eyes (71%) achieved a visual acuity of 20/300 or better, and 8 (57%) obtained a final visual acuity of 20/100 or better. Average length of follow-up was 22 months (range, 4-57 months). Nine patients were fitted with an aphakic soft contact lens, 2 older patients had a posterior chamber intraocular lens placed at the time of vitrectomy, and 1 patient wore aphakic spectacles.ConclusionsWith modern vitreoretinal techniques, aphakic rehabilitation, and aggressive amblyopic therapy, useful vision can be obtained in the majority of patients with combined anterior and posterior persistent hyperplastic primary vitreous.PERSISTENT hyperplastic primary vitreous (PHPV), also known as persistent fetal vasculature, is a congenital anomaly in which the normal regression of the primary vitreous and hyaloid vasculature does not occur.Classically, PHPV appears unilaterally in an otherwise healthy, full-term newborn.A retrolental fibrovascular mass is seen on ocular examination. Contraction of this mass can draw the ciliary processes into the visual axis or cause recurrent intraocular hemorrhage. Most eyes are microphthalmic, and while the lens is clear initially, a progressive cataract develops with time in most cases. With this lens opacity present, diagnosis is often difficult without the use of ultrasonography, computed tomography, or magnetic resonance imaging.If left untreated, many eyes with severe PHPV will develop severe glaucoma, retinal detachment, or phthisis early in life.Some authors have separated PHPV into anterior and posterior forms.Ocular findings in purely anterior PHPV can include microphthalmia, cataract, elongated ciliary processes, retrolental fibrovascular membrane, and glaucoma. Posterior PHPV can consist of microphthalmia, usually without cataract, vitreous membrane and stalk, retinal fold, traction retinal detachment, and hypoplastic optic nerve and macula. The separation of PHPV into these distinct anterior and posterior varieties is arbitrary, as many cases will exhibit some features of both.In an effort to counteract the dismal natural history of PHPV, numerous operative techniques for removal of the cataract and retrolental membrane have been used during the last several decades. Initially, an open-sky cataract wound was fashioned and the cataract and membrane were evacuated in a 1- or 2-stage procedure.With the advent of mechanical suction-cutting devices, the visual axis could be cleared using a closed-system intraocular approach that provided superior control of any bleeding encountered while dissecting the retrolental tissue.In these studies surgery was used solely to save the eye from enucleation, and visual results were poor. Outcomes have improved as surgical techniques and instrumentation have advanced, aphakic soft contact lenses in pediatric sizes developed, and greater importance placed on early amblyopic occlusive therapy.In an effort to determine the current visual results following surgery for PHPV, we undertook a retrospective review to evaluate visual outcomes after modern vitrectomy surgery for combined anterior and posterior PHPV with the use of prompt aphakic rehabilitation and aggressive amblyopic therapy.SUBJECTS AND METHODSWe undertook a retrospective record review of all patients with the diagnosis of PHPV who underwent vitreoretinal surgical rehabilitation after appropriate informed consent at the Eye Institute, Medical College of Wisconsin, Milwaukee, from June 1992 to June 1997. We recorded the following information from each record when available: patient name, date of birth, medical history including any history of prematurity, sex, age at diagnosis, type of PHPV, initial visual acuity, surgical procedure performed, age at time of surgical procedure, intraoperative and postoperative complications, location and number of sclerotomy sites, postoperative appearance, type of aphakic rehabilitation, amount of amblyopic patching therapy, final visual acuity, and length of follow-up. Visual acuity was assessed with age-appropriate tests such as the Teller and Snellen-equivalent methods. Those too young for this method of acuity testing had fixation patterns assessed and recorded by an experienced pediatric ophthalmologist (M.S.R.). These fixation patterns were then extrapolated to visual acuity measurements using a previously described technique modified from Zipfby Karr and Scottas follows:See table graphicwhere C indicates central; S, steady; M, maintained; UC, uncentral; US, unsteady; and UM, unmaintained.Amblyopia therapy consisted of patching the better eye for several (2 hours to full-time) waking hours each day. An attempt was made to limit patching to no more than 80% to 90% of waking hours for patients younger than 6 years. Contact lens power was checked every 4 months and replaced if more than 6 diopters (D) over-plus for infants and more than 3 D over-plus for older children.RESULTSFourteen patients were identified from the surgical records of the retina service at the Eye Institute (Table 1). Six patients were male and 8 were female. The age at diagnosis varied from 1 week to 7 years, although 13 patients were diagnosed prior to 9 months of age. Five patients were born prematurely, but only 2 patients were more than 1 month premature. No patient had a significant systemic illness. All patients had features of combined anterior and posterior PHPV with cataract formation and a fibrovascular stalk extending from the optic nerve to posterior lens in one eye only. In addition, 2 patients had a tractional retinal detachment on initial examination, and 1 patient exhibited neovascularization of the iris, vitreous hemorrhage, and advanced glaucoma. The initial visual acuity in the affected eye was light perception in 12 younger patients and 5/200 and 20/200 in the 2 older patients, aged 7 and 17 years, respectively. Average follow-up after operation was 22 months (range, 4-57 months).Patient Data*See table graphicNine patients had a primary lensectomy and vitrectomy procedure performed (7 performed through the pars plana and 2 through the limbus), and the 2 older patients had a combined phacoemulsification/posterior chamber intraocular lens placement surgery with pars plana vitrectomy. The 3 remaining patients had an initial cataract extraction performed with subsequent posterior vitrectomy. In 2 of these patients the diagnosis of PHPV was made at the time of surgery for unilateral congenital cataract, and the operation was terminated after lens removal only. In the remaining patient, who preoperatively was thought to have a mild form of PHPV, a posterior capsulotomy and pupillary membrane removal with an anterior vitrectomy unit was performed at the time of cataract surgery. Postoperatively, this patient developed a dense vitreous hemorrhage, an organized secondary membrane surrounding the residual posterior stalk, and hemolytic glaucoma necessitating a complete posterior vitrectomy. The age at surgery varied from 2 weeks to 17 years.Surgical complications of posterior vitrectomy included a retinal tear in 1 patient. This patient had a massive tractional retinal detachment preoperatively, and after the lens was removed it was noted that the retina inserted directly into the pars plicata with no visible pars plana. The instrument placed through the superotemporal sclerotomy (2.5 mm posterior to limbus) caused enough traction on the nearby retina to cause a retinal tear. This necessitated placement of a scleral buckle with endolaser treatment and an air-fluid exchange. The retina has remained attached postoperatively. Another patient developed a secondary pupillary membrane with increased intraocular pressure and a vitreous hemorrhage. On further follow-up, an organized retinal detachment, judged to be inoperable, was noted. Both of these patients were thought to have insufficient visual potential to warrant aphakic rehabilitation and amblyopic therapy; however, neither patient has gone into phthisis or has had to have an enucleation as of the last follow-up visit. Vitrectomy port location varied according to the age of the patient and surgeon preference from the limbus to 2.75 mm posterior to the limbus. Posterior placement of the vitrectomy ports seemed to cause a complication in only 1 case.Aphakic rehabilitation was carried out in 12 patients. Nine received an aphakic soft contact lens after surgery (1-12 weeks postoperatively), while 2 patients had a posterior chamber intraocular lens placed at the time of surgery. One patient was bilaterally aphakic and wore aphakic spectacles. Amblyopic therapy was instituted in 11 of the 12 patients and consisted of occlusion of the better eye from 2 hours to full-time patching for the waking hours each day. Compliance with the contact lens and patching regimen was good for patients 1, 3, 7 through 10, 12, and 13 and poor for patients 2, 5, and 14 (Table 1). Only 1 of the patients with poor compliance had a final visual acuity worse than 20/300.Final visual acuity in the 12 patients who had visual potential and underwent amblyopic therapy varied from less than 20/300 to 20/30. No patients had a visual acuity less than 5/200. Ten (83%) of these 12 patients achieved a visual acuity of 20/300 or better and 8 (66%) obtained a final vision of 20/100 or better (Table 1). Including all the patients in the study, 71% achieved a visual acuity of 20/300 or better, and 57% of patients obtained 20/100 or better. Elevated intraocular pressure (>20 mm Hg) was present at the initial visit in 1 patient and developed later in 2 patients (Table 1).COMMENTHiles and Reynoldsin 1983 and Pollard in 1991and 1997reported on their respective series of PHPV patients managed with a variety of surgical techniques. Their conclusions were that patients who had a purely anterior form of PHPV (ie, no stalk or retinal abnormalities) had visual potential, while those with combined or posterior forms of the disease did not. Our study clearly illustrates that patients with combined anterior and posterior disease can achieve functional visual acuities when managed with modern vitreoretinal techniques and aggressive amblyopic therapy. In another large series of patients in which PHPV was not classified into anterior, combined, or posterior forms, 8 (44%) of 18 patients with visual potential achieved a final visual acuity of 20/200 or better.This study included 4 patients managed with an older technique of lens needling and aspiration with a scissors membranectomy. We attribute the improved outcomes seen in our study to advances in instrumentation for vitrectomy and cataract surgery that were applied uniformly to all the patients and to prompt aphakic rehabilitation and amblyopic therapy instituted in all patients with visual potential.The diagnosis of PHPV can be difficult when a dense cataract is present. This scenario was demonstrated by 2 of our patients in whom the correct diagnosis was not made until the time of cataract extraction. Ultrasonography in these small infants is challenging, and the stalk can be thin and thus overlooked, as it was in these 2 patients. In another patient, a very thin, partial stalk was noted on ultrasonography and it was felt that cataract extraction alone would be sufficient to clear the visual axis; however, at surgery a substantial, thick fibrovascular stalk was uncovered. Even though an anterior vitrectomy with partial membranectomy was performed on this patient at the time of cataract surgery, eventually a posterior vitrectomy was required for a dense postoperative vitreous hemorrhage with vitreous organization around the residual stalk and a secondary pupillary membrane. After this case, no further cases of combined anterior and posterior PHPV were primarily handled with anterior segment surgical techniques alone for fear of postoperative hemorrhagic complications. If any posterior fibrovascular stalk is visible on ultrasonography, regardless of its perceived thickness, posterior vitrectomy and lensectomy should probably be performed. Computed tomography and/or magnetic resonance imaging may have helped in the diagnosis of PHPV in these 3 patients and might have enabled us to eliminate the additional surgical procedure that each required. Unfortunately, computed tomography or magnetic resonance imaging in these patients usually requires heavy sedation or general anesthesia.Although historical comparison among different studies is problematic, the visual results obtained in our study seem to approximate those acquired after surgery for unilateral congenital cataracts without PHPV.This similarity implies that the presence of PHPV alone does not necessarily confer a poor prognosis. Two eyes in our study were operated on at 5 and 10 months of age, respectively. Despite the enhanced susceptibility to irreversible amblyopia, visual acuities of 20/100 and 20/70 were obtained. Similar results have been achieved by others for late surgery for unilateral congenital cataract, both with and without PHPV.These findings suggest that whenever the diagnosis of PHPV is made, evaluation for possible surgical rehabilitation should be undertaken if light perception acuity exists.The one major surgical complication noted during our study was a retinal tear that resulted partially from the posterior placement of a sclerotomy incision in a patient with a preoperative tractional retinal detachment. Anterior placement of incisions to avoid this type of complication has previously been suggested for these small eyes that frequently have a poorly developed pars plana region.Our incision site placement varied according to surgeon preference and the age of the patient. Transillumination is occasionally helpful in locating the ora serrata, but is often unsuccessful.In our opinion, placement of incisions as anteriorly as possible is beneficial, especially if a retinal detachment is noted on preoperative ultrasonography.Two of our patients were considered to have insufficient visual potential postoperatively to warrant amblyopic therapy. One had a secondary membrane develop before a late inoperable retinal detachment, and the other had extensive macular changes after repair of a complex tractional/rhegmatogenous retinal detachment. We believe that almost every child deserves a trial of occlusion therapy after removal of media opacity. In cases with advanced retinal or optic nerve pathology, however, amblyopic therapy should be promptly terminated after a short trial (&ap;2 months) if no improvement is noted, to avoid undue psychosocial impairment.Eyes with PHPV have a lifetime risk of glaucoma and retinal detachment. While our study exhibited the attainment of useful vision in the majority of patients, the follow-up was brief. One study has shown that glaucoma develops in 32% of patients with PHPV at a mean of 64.6 months postoperatively.With our current intermediate follow-up, we have demonstrated that a visual acuity of 20/300 is obtainable in the majority of patients with a combined form of anterior and posterior PHPV using modern vitreoretinal surgical techniques and aggressive amblyopic therapy. Continued surveillance of these young patients will be necessary to ensure that their present vision is maintained for the future.MFGoldbergPersistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV).Am J Ophthalmol.1997;124:587.ZFPollardPersistent hyperplastic primary vitreous: diagnosis, treatment and results.Trans Am Ophthamol Soc.1997;95:487-549.RHaddadRLFontFReeserPersistent hyperplastic primary vitreous: a clinicopathologic study of 62 cases and review of literature.Surv Ophthalmol.1978;23:123-134.MFMafeeMFGoldbergGEValvassoriVCapekComputed tomography in the evaluation of patients with persistent hyperplastic primary vitreous.Radiology.1982;145:713-717.MFGoldbergMMafeeComputed tomography for diagnosis of persistent hyperplastic primary vitreous.Ophthalmology.1983;90:442-451.MFMafeeMFGoldbergPersistent hyperplastic primary vitreous: role of computed tomography and magnetic resonance.Radiol Clin North Am.1987;25:683-692.MFMafeeMFGoldbergSBCohenMagnetic resonance imaging versus computed tomography of leukocoric eyes and use of in vitro proton magnetic resonance spectroscopy of retinoblastoma.Ophthalmology.1989;96:965-976.SCKaseJJJenkinsDMeyerJFontanesiCBPrattPersistent hyperplastic primary vitreous of the eye: imaging findings with pathologic correlation.Am J Radiology.1994;162:437-440.PDe PotterCLShieldsJAShieldsAEFlandersThe role of magnetic resonance imaging in children with intraocular tumors and simulating lesions.Ophthalmology.1996;103:1774-1783.ABReesePersistent hyperplastic primary vitreous: Jackson Memorial Lecture.Trans Am Acad Ophthalmol Otolaryngol.1955;59:271-286.JLFedermanJAShieldsBAltmanHKollerThe surgical and nonsurgical management of persistent hyperplastic primary vitreous.Ophthalmology.1982;89:20-24.AGSpauldingGNaumannPersistent hyperplastic primary vitreous in an adult: a brief review of the literature and a histopathologic study.Arch Ophthalmol.1967;77:666-671.GIMasonFUHuamontePHPV in an adult managed by vitrectomy.Ophthalmic Surg.1979;10:93-98.RHRaskindPersistent hyperplastic primary vitreous: necessity of early recognition and treatment.Am J Ophthalmol.1966;62:1072-1076.PAMaurerDAHilesUnoperated persistent hyperplastic primary vitreous.Trans Pa Acad Ophthalmol Otolaryngol.1986;38:518-522.WLAlwardMAKrasnowRVKeechJSPulidoGLSuttonPersistent hyperplastic primary vitreous with glaucoma presenting in infancy.Arch Ophthalmol.1991;109:1063-1064.ZFPollardTreatment of persistent hyperplastic primary vitreous.J Pediatr Ophthalmol Strabismus.1985;22:180-183.TEAcersTOCostonPersistent hyperplastic primary vitreous: early surgical management.Am J Ophthalmol.1967;64:734-735.JDMGassSurgical excision of persistent hyperplastic primary vitreous.Arch Ophthalmol.1970;83:163-168.HEVolckerGKLangGOHNaumannSurgery of persistent hyperplastic primary vitreous.Dev Ophthalmol.1985;11:188-193.GAPeymanDRSandersKCNagpalManagement of persistent hyperplastic primary vitreous by pars plana vitrectomy.Br J Ophthalmol.1976;60:756-758.SJNankinWEScottPersistent hyperplastic primary vitreous: roto-extraction and other surgical experience.Arch Ophthalmol.1977;95:240-243.WJStarkHRTaylorRGMichelsAEMaumeneeManagement of congenital cataracts.Ophthalmology.1979;86:1571-1578.GTreisterRMachemerPars plana surgical approach for various anterior segment problems.Arch Ophthalmol.1979;97:909-911.WJStarkSurgical management of persistent hyperplastic primary vitreous.Dev Ophthalmol.1981;5:115-121.SLaatikainenATarkkanenMicrosurgery of persistent hyperplastic primary vitreous.Ophthalmologica.1982;185:193-198.WJStarkPSLindseyWRFagadauRGMichelsPersistent hyperplastic primary vitreous: surgical treatment.Ophthalmology.1983;90:452-457.WJStarkWFagadauPSLindseyHRTaylorRGMichelsManagement of persistent hyperplastic primary vitreous.Aust J Ophthalmol.1983;11:195-200.RFrezzottiAMBardelliAMorocuttiSPanniniThe pars plana approach in two cases of persistent hyperplastic primary vitreous (PHPV).Ophthalmic Paediatr Genet.1984;4:107-110.DJKarrWEScottVisual acuity results following treatment of persistent hyperplastic primary vitreous.Arch Ophthalmol.1986;104:662-667.RFZipfBinoncular fixation pattern.Arch Ophthalmol.1976;94:401-405.DAHilesJDReynoldsPersistent hyperplastic primary vitreous.Trans Pa Acad Ophthalmol Otolaryngol.1983;36:31-36.ZFPollardResults of treatment of persistent hyperplastic primary vitreous.Ophthalmic Surg.1991;22:48-52.WEScottTreatment of congenital cataracts and persistent hyperplastic primary vitreous.Trans New Orleans Acad Ophthalmol.1986;34:461-477.RMRobbDLMayerBDMooreResults of early treatment of unilateral congenital cataracts.J Pediatr Ophthalmol Strabismus.1987;24:178-181.WEScottGTDrummondDJKarrManagement and visual acuity results of monocular congenital cataracts and persistent hyperplastic primary vitreous.Aust N Z J Ophthalmol.1989;17:143-152.KWWrightLEChristensenBANoguchiResults of late surgery for presumed congenital cataracts.Am J Ophthalmol.1992;114:409-415.LLHYangSRLambertReappraisal of occlusion therapy for severe structural abnormalities of the optic disc and macula.J Pediatr Ophthalmol Strabismus.1995;32:37-41.CPJohnsonRVKeechPrevalence of glaucoma after surgery for PHPV and infantile cataracts.J Pediatr Ophthalmol Strabismus.1996;33:14-17.Accepted for publication June 9, 1998.This study was supported in part by an unrestricted core grant from Research to Prevent Blindness Inc, New York, NY, core grant P30 EY01931 from the National Institutes of Health, Bethesda, Md, and the Heed Ophthalmic Foundation, Cleveland, Ohio.Presented in part at the annual meeting of the Academy of Ophthalmology, San Francisco, Calif, October 28, 1997.Reprints: William F. Mieler, MD, Eye Institute, Medical College of Wisconsin, 925 N 87th St, Milwaukee, WI 53226.

Woodman, Troy J.; Coats, David K.; Paysse, Evelyn A.; Demmler, Gail J.; Rossmann, Susan N.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1195pmid: 9747678

ObjectiveTo evaluate the effectiveness of 70% isopropyl alcohol swabs in disinfecting eyelid speculums after examination for retinopathy of prematurity .MethodsTwo phases. Phase 1: 46 autoclave-sterilized eyelid speculums randomized into either a cleaned or control group following examination for retinopathy of prematurity. Speculums in the cleaned group were disinfected with a 70% isopropyl alcohol swab while control speculums were not cleaned. Bacterial and fungal cultures were then obtained. Phase 2: 20 autoclave-sterilized eyelid speculums inoculated with a clinically relevant dilution of adenovirus serotype 5 or herpes simplex virus type 2. Inoculated speculums were randomized into either a cleaned or control group.ResultsPhase 1: 17 (70.8%) of 24 cultures from the cleaned group yielded bacteria compared with 21 (95.5%) of 22 controls. Fungi were isolated from only 1 control and from no cleaned speculums. Phase 2: all speculums inoculated with adenovirus supported growth of the organism irrespective of cleaning with 70% isopropyl alcohol swabs. None of 5 cleaned speculums inoculated with herpes simplex virus type 2 supported viral growth, compared with 3 (60%) of 5 cultures positive for growth in the control group.ConclusionCleaning eyelid speculums with 70% isopropyl alcohol swabs provided inadequate disinfection against bacteria following examination for retinopathy of prematurity and against adenovirus in a laboratory simulation.AT MOST centers, examinations for retinopathy of prematurity (ROP) are performed sequentially on multiple patients in a neonatal intensive care unit setting. A reusable metallic eyelid speculum is often used to facilitate examination and enhance diagnostic accuracy,followed by thorough cleaning between patients. Cleaning methods available include wiping with 70% isopropyl alcohol or Betadine swabs, soaking in hydrogen peroxide or 70% isopropyl alcohol, and autoclave sterilization. Because premature infants are immunocompromised and at high risk for life-threatening infection,it is important to assure that cleaning methods used are satisfactory. This study was designed to evaluate the effectiveness of cleaning speculums with 70% isopropyl alcohol swabs against bacteria, fungi, and 2 viruses. This particular cleaning method was chosen because it is commonly used, readily available, and has been demonstrated to be effective in cleaning other ophthalmic instruments.RESULTSPHASE 1Seventeen (70.8%) of 24 cultures in the cleaned group demonstrated microbial growth whereas 21 (95.5%) of 22 cultures in the control group showed growth (P<.O5) (Figure 1). Of the cultures positive for organisms in the cleaned group, 16 yielded coagulase-negative Staphylococcus(CONS); and 1, Bacillus cereus(Figure 2). No fungus grew in any of the cultures from the cleaned group. The organisms grown in the control group were considerably more varied and contained not only CONS and Bacillusspecies, but also methicillin-resistant Staphylococcus aureus, Enterococcus, and multiple gram-negative rods (Figure 2). One control speculum yielded fungus (Candida albicans). All cultures obtained from speculums cleaned immediately after removal from the sterile packaging were negative for organisms.Figure 1.Growth rates for phase 1 (bacterial and fungal). Despite cleaning, bacteria were cultured from 17 cleaned speculums (70.8%).Figure 2.Comparison of organisms cultured from phase 1 (bacterial and fungal) cleaned group (left), and control group (right). MRSA indicates methicillin-resistant Staphylococcus aureus; CONS, coagulase-negative Staphylococcus.PHASE 2Five (100%) cleaned and 5 (100%) control speculums inoculated with adenovirus serotype 5 were positive for the virus (Figure 3). No cultures positive for organisms were found in the HSV-2 group after cleaning, while 3 (60%) of 5 controls were positive for organisms (P=1.7).Figure 3.Growth rates for phase 2 (viral). Ten (100%) speculums grew adenovirus irrespective of cleaning. Herpes simplex virus type 2 was effectively eliminated.METHODSPHASE 1Forty-six autoclave-sterilized Alfonso pediatric eyelid speculums (Storz Inc, Ophthalmic Instrumentation Division, Cleveland, Ohio) were randomized into a cleaned or control group following examinations for ROP in the neonatal intensive care unit. Using sterile gloves, the examiner (D.K.C. or E.A.P.) placed a sterile speculum within the eyelids of a neonate and performed indirect ophthalmoscopy with scleral depression in the usual manner of examination for ROP.To minimize possible contamination by the examiner, a separate pair of sterile gloves was used to remove the speculum. Speculums in the cleaned group were cleaned thoroughly with a 70% isopropyl alcohol preparation pad (Webcol, Kendall Co, Mansfield, Mass) for 10 seconds and allowed to air dry. An attempt was made to clean all surfaces of the speculums. Each speculum was then transferred in a sterile manner to a 100-mL sterile container that held 10 mL of trypticase soy broth with 5% Fildes Enrichment (Becton Dickinson Microbiology Systems, Cockeysville, Md), which completely covered the instrument. Speculums in the control group were allowed to air dry and then placed in identical containers without cleaning. Last, 5 sterile, unused speculums were cleaned in the above fashion immediately after removal from the sterile packaging, allowed to air dry, and placed into the culture media to test for possible contamination inherent to the cleansing technique itself.The speculums were then incubated at 35°C in 5% to 10% carbon dioxide and observed for 7 days. If the broth became turbid during the 7-day incubation period, a Gram stain was performed and the broth was inoculated to trypticase soy agar II with 5% SRBC, chocolate II agar, and MacConkey II agar (all from Becton Dickinson Microbiology Systems). Organisms were then isolated and identified using standard laboratory methods. After the incubation period, a Gram stain was done on each broth to detect any organisms not previously recovered. The Fisher exact test was used for statistical analysis. This protocol adhered to the Declaration of Helsinki.PHASE 2Stock strains of adenovirus serotype 5 and herpes simplex virus type 2 (HSV-2) were grown in cell culture and diluted in minimal essential media to 10−3log virus, which was thought to be a clinically relevant titer of virus and comparable to other studies of viral disinfection.Ten eyelid speculums were assigned to each of the 2 viruses. The sterile speculums were then immersed in their respective viral suspensions for 1 minute. Using sterile forceps and gloves, the speculums were removed, separated, and placed on a sterile platform. Five speculums from each group were randomly chosen as controls and allowed to air dry under a biologic safety cabinet and fluorescent lighting. The remaining speculums from each group were thoroughly swabbed with a 70% isopropyl alcohol pad for 10 seconds and allowed to air dry. Separate sterile forceps were used to transfer each speculum to individual containers of viral transport media sufficient for its immersion. Meticulous sterile technique was maintained to prevent contamination. The solution was then agitated and a 0.2-mL aliquot of media was removed from each container and inoculated onto cell culture monolayers of human foreskin fibroblasts, rhesus monkey kidney, and A549 cells. The inoculum was allowed to adsorb for 4 hours, washed, and refed with media. The cell cultures were incubated on a roller drum in a warm airflow incubator at 37°C, observed daily for cytopathic effect, and the results recorded. Preliminary identification of each virus was by cytopathic effect with confirmation by immunoflourescence assay, using an adenovirus monoclonal antibody reagent (Bartels, Inc, Issaquah, Wash). The Fisher exact test was used for statistical analysis.COMMENTExaminations for ROP are often performed sequentially on multiple infants. Equipment that comes into contact with the infants during examination must be adequately disinfected between examinations to eliminate the risk of transmission of iatrogenic infectious disease. Several recent studies have demonstrated that Goldmann tonometer tips can be adequately disinfected with an alcohol swab against adenovirus,HSV, and human immunodeficiency virus.Corboy and Borchardtfound certain bacteria inoculated onto tonometer tips to be susceptible to simply wiping with a dry tissue. Many nonsurgical examination instruments, such as Goldmann tonometer tips, Schiötz tonometers, diagnostic contact lenses, etc, can be sufficiently cleaned using an alcohol swab technique.These findings and practices may encourage practitioners to use this cleaning technique for eyelid speculums following examination for ROP. However, important differences between the instruments to be cleaned and the patient populations make direct comparisons problematic. For instance, there is a fundamental difference in the shape and configuration of an eyelid speculum compared with a Goldmann tonometer tip. An eyelid speculum is bent in several places, making much of its surface difficult to clean with a swab, whereas a Goldmann tonometer tip has a flat applanation surface making the entire contact area readily amenable to swabbing (Figure 4).Figure 4.An Alfonso eyelid speculum (left) and a Goldmann tonometer tip (right). Design properties of each instrument probably explain differences in efficacy of 70% isopropyl alcohol disinfection.Additionally, a cleaning technique that is adequate for instruments used on healthy adults may not be adequate for instruments used on premature infants. Neonates at risk for ROP are typically immunocompromised and commonly exhibit extremely low birth weight, and such infants are at significantly increased risk for life-threatening infections.Organisms often disregarded as "normal flora" in healthy patients can be devastating to the premature infant. For instance, CONS, a common environmental organism,was responsible for as many as 49% of the cases of neonatal sepsis in 2 major centers.Coagulase-negative Staphylococcuscan also cause other life-threatening infections in this population, including meningitis, pneumonia, and endocarditis, as well as ocular infections such as conjunctivitis, keratitis, and endophthalmitis. Our data demonstrate that cleaning an Alfonso eyelid speculum with a 70% isopropyl alcohol swab is ineffective against this organism, as more than two thirds of the cleaned speculums yielded cultures positive for CONS. Not only does the design of the speculum render cleaning difficult, but CONS-related factors may also contribute to problems associated with this method of disinfection. Certain strains of Staphylococcus epidermidis, a commonly isolated member of the CONS family, produce a mucoid substance, or slime, that makes the bacteria highly adhesive.This material may allow organisms to more firmly adhere to regions on the speculum that are difficult to clean with an alcohol pad.Fungal (yeast) growth was confirmed in only 1 culture of the control group and in none of the cleaned speculums. Fildes Enrichment was used to fortify the culture broth in an effort to promote the growth of any fungal organisms adherent to the speculums, but the low fungal growth rate in both the control and cleaned groups does not allow for conclusions about fungal growth to be made.Cleaning with 70% isopropyl alcohol swabs proved completely ineffective against adenovirus serotype 5 in our laboratory simulation. The prolonged survival of adenovirus has been previously demonstrated on inorganic surfaces and some investigators have recovered this organism from plastic and metal surfaces as long as 1 to 7 weeks after inoculation.Nevertheless, the poor performance of this cleaning technique on eyelid speculums was surprising, as others have clearly demonstrated alcohol wipes to be quite effective against adenovirus on Goldmann tonometer tips.This difference is most likely because of the structural design differences of the 2 instruments. The clinical relevance of these findings is apparent when one considers that adenovirus not only causes keratoconjunctivitis, but it can produce severe pneumonia and enteritis with potential life-threatening complications in the neonatal population. Our data on HSV-2 corresponds well with Goldmann tonometer data.The higher kill rate for HSV-2 may be related to the fact that this virus is enveloped and therefore more susceptible to the disinfectant properties of isopropyl alcohol.In summary, cleaning Alfonso pediatric eyelid speculums with 70% isopropyl alcohol swabs was ineffective in disinfecting them against potentially dangerous bacteria in a clinical study and ineffective against adenovirus in a laboratory simulation. These organisms not only pose a serious threat to vision but have the potential to cause serious systemic disease in the population at risk for ROP. Although we have not attempted to demonstrate an increase in actual infection rates, the mere presence of these organisms on cleaned speculums warrants discontinuation of this particular cleaning method for eyelid speculums used during examinations for ROP. We recommend the use of a new or autoclave-sterilized speculum on each patient examined for ROP and discourage the use of other common cleaning methods until their efficacy against bacteria, fungi, and viruses has been demonstrated in a controlled study.BDhillonEWrightBWFleckScreening for retinopathy of prematurity: are a lid speculum and scleral indentation necessary?J Pediatr Ophthalmol Strabismus.1993;30:377-381.JOKleinSMMarcyBacterial sepsis and meningitis.In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant.Philadelphia, Pa: WB Saunders Co; 1995:836-890.EAPalmerJTFlynnRJHardyIncidence and early course of retinopathy of prematurity.Ophthalmology.1991;98:1628-1640.ABThrelkeldJWFroggatt IIIODScheinMSFormanEfficacy of a disinfectant wipe method for the removal of adenovirus 8 from tonometer tips.Ophthalmology.1993;100:1841-1845.ERCravenSLButlerJPMcCulleyJPLubyApplanation tonometer tip sterilization for adenovirus type 8.Ophthalmology.1987;94:1538-1540.JSPeposeGLinetteSFLeeSMacRaeDisinfection of Goldmann tonometers against human immunodeficiency virus type 1.Arch Ophthalmol.1989;107:983-985.JMCorboyKABorchardtMechanical sterilization of the applanation tonometer, 1: bacterial study.Am J Ophthalmol.1971;71:889-891.American Academy of Ophthalmology, National Society to Prevent Blindness, Contact Lens Association of OphthalmologistsClinical Alert 2/4: updated recommendations for ophthalmic practice in relation to the human immunodeficiency virus.Ophthalmology.1989;96:1ff.TVesikariMJanasPGronroosNeonatal septicaemia.Arch Dis Child.1985;60:542-546.DPMunsonTRThompsonDEJohnsonFSRhameNVanDrunenPFerrieriCoagulase-negative staphylococcal septicemia: experience in a newborn intensive care unit.J Pediatr.1982;101:602-605.OJHenseyCAHartRWICookeSerious infection in a neonatal intensive care unit: a two-year survey.J Hyg (Cambridge).1985;95:289-297.SBaumgartSEHallJMCamposRAPolinSepsis with coagulase-negative staphylococci in critically ill newborns.AJDC.1983;137:461-463.MTojoNYamashitaDAGoldmannGBPierIsolation and characterization of a capsular polysaccharide adhesin from Staphylococcus epidermidis.J Infect Dis.1988;157:713-722.GDChristensenWASimpsonALBisnoEHBeacheyAdherence of slime-producing strains of Staphylococcus epidermidisto smooth surfaces.Infect Immun.1982;37:318-326.YJGordonRYGordonERomanowskiTPAraullo-CruzProlonged recovery of desiccated adenoviral serotypes 5,8, and 19 from plastic and metal surfaces in vitro.Ophthalmology.1993;100:1835-1840.JHaraSOkamatoYMinekawaKYamazakiTKaseSurvival and disinfection of adenovirus type 19 and enterovirus 70 in ophthalmic practice.Jpn J Ophthalmol.1990;34:421-427.MKleinADeforestVirucidal activity of disinfection.In: Russell AD, Hgo WB, Ayliffe, GAJ. Principles and Practice of Disinfection, Preservation and Sterilization. 2nd ed. Oxford, Enlgand: Blackwell Scientifc ublications; 1992:150-170.Accepted for publication June 5, 1998.This study was supported in part by a grant from Research to Prevent Blindness Inc, New York, NY (Drs Coats and Paysse), and an Everett L. Goar resident award from the Cullen Eye Institute, Baylor College of Medicine, Houston, Tex (Dr Woodman).Presented as a poster at the American Association of Pediatric Ophthalmology and Strabismus Annual Meeting, Palm Springs, Calif, April 7, 1998.Reprints: David K. Coats, MD, Texas Children's Hospital, 1102 Bates, Suite 300, MC 3-2700, Houston, TX 77030 (e-mail: [email protected]).

Christmas, Nancy J.; Gordon, Craig D.; Murray, Timothy G.; Tse, David; Johnson, Thomas; Garonzik, Scott; O'Brien, Joan M.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1199pmid: 9747679

BackgroundMany different types of orbital implants have been used after enucleation. Associated complications such as infection, exposure, extrusion, and ptosis have been reported.ObjectiveTo describe 342 consecutive patients who underwent enucleation with intraorbital implant placement at the Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla, during the past 10.5 years and their complications.MethodsMedical records of orbital implantation after enucleation performed by 3 surgeons (T.G.M., D.T., and T.J.) were reviewed retrospectively. Demographic data, ocular diagnosis, previous ophthalmic surgery, implant characteristics, and postoperative complications were described in all patients, with a minimum of 2 months' follow-up, using a standardized format.ResultsEleven complications were observed in 7 patients. Four patients had exposure of the implant, and 1 of these patients developed associated infection. Three patients developed pyogenic granulomas, 1 patient developed ptosis requiring surgical intervention, 1 patient had long-term orbital discomfort, and 1 patient developed an inclusion cyst.ConclusionComplications after enucleation with orbital implant placement are minimal and are observed with both porous and acrylic orbital implants.REMOVAL OF an eye for treatment of ocular disease was first described by Bartisch in 1583.The modern form of this operation was introduced in 1841 by Farrell and Bonnet, and in 1885, Mules placed the first orbital implant after evisceration.A year later, Frost described the utility of orbital implant placement after enucleation surgery. In 1941, Ruedemann proposed the use of partially exposed, integrated implants with the attachment of extraocular muscles to allow for better prosthesis movement; he acknowledged the potential risks of extrusion and infection. Use of completely buried integrated implants began in the 1950s, bringing improved cosmesis but relatively poor motility.An ideal orbital implant should offer excellent motility, cosmesis, and few complications. Various orbital implant configurations are available.Different materials may be used to create orbital implants, including cartilage, bone, fat, cork, rubber, gold, silver, silk, wool, aluminum, ivory, petroleum jelly, acrylics, silicone, quartz, glass, titanium, and porous materials such as polyethylene and hydroxyapatite (HA).Other buried, quasi-integrated, irregularly shaped implants derived from acrylics have been used.In these, muscles are passed through tunnels, as in the Allen implant, or through grooves, as in the Iowa and Universal implants.Currently, porous spherical implants are most widely used. Porous polyethylene is made from synthetic, high-density polyethylene powder that is easily molded into shapes.Hydroxyapatite, a porous material derived from reef-building coral of genus Porites, was introduced as a buried orbital implant by Perry in 1985.These porous spherical implants are nontoxic, nonallergenic, and biocompatible, and they become integrated into the host by fibrovascular ingrowth.Fibrovascular ingrowth offers the theoretical advantages of less implant extrusion or migration and less secondary infection, and permits drilling of a tunnel into the implant and insertion of a peg. Coupling of the peg to the prosthesis enhances motility, a feature other implants lack.Although the literature includes many successful reports of intraorbital implant use,several reports can be found regarding associated complications, such as exposure, infection, and peg extrusion.We describe 342 patients who underwent intraorbital implant placement at Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla, during the past 10.5 years and their complications.PATIENTS AND METHODSPATIENTSInstitutional Review Board approval from the University of Miami was obtained before chart review. A retrospective chart review was performed for 405 patients who underwent primary enucleation with orbital implant placement (performed by T.G.M., D.T., and T.J.) at Bascom Palmer Eye Institute from January 1, 1987, to June 30, 1997. All these cases were analyzed, but data are reported only on 342 patients who had at least 2 months' follow-up. Mean patient age at surgery was 49 years (range, 0.17-91 years). Mean follow-up was 97.2 weeks (median, 78 weeks; range, 8-460 weeks). One hundred eighty-seven patients (54.7%) were male and 155 (45.3%) were female. The demographics of this cohort included 228 whites (66.7%), 47 African Americans (13.7%), 48 Hispanics (14.0%), 12 others (3.5%), and 7 unknowns (2.0%).Reasons for primary surgery included diagnoses of uveal melanoma in 104 patients (30.4%), retinoblastoma in 39 (11.4%), ruptured globe in 14 (4.1%), blind painful eye in 162 (47.4%), metastatic cancer in 2 (0.6%), and other various diagnoses in 21 (6.1%) (Table 1). In total, 208 patients had undergone treatment before enucleation, with 6 patients undergoing plaque radiotherapy, 5 undergoing external beam radiation therapy, 9 undergoing ruptured globe repair, and 188 undergoing a spectrum of other ophthalmic surgeries. Final histopathologic diagnoses included atrophi bulbi, phthisis bulbi, rupture secondary to trauma or corneal ulceration, neovascular glaucoma secondary to central retinal vein occlusion or Coats disease, proliferative vitreoretinopathy, retinal detachment, malignant melanoma, medulloepithelioma, endophthalmitis, persistent hyperplastic primary vitreous, microphthalmos, and squamous cell carcinoma with intraocular extension.Table 1. Indications for EnucleationSee table graphicAcrylic implants used in this series included the sphere (8 patients), Iowa (29 patients), and Universal (1 patient) types (Table 2). Microporous implants were limited to HA (275 patients) and porous polyethylene (Medpor) (22 patients). Implants made of silicone (6 patients) and glass (1 patient) were also used. In 288 patients (84.2%), the implant was wrapped in a donor scleral shell. The mean implant size was 20 mm (median, 20 mm; range, 14-22 mm). Drilling for peg placement was performed on 5 HA implants.Table 2. Types of ImplantsSee table graphicSURGICAL TECHNIQUEThis technique has been reported previously.Briefly, enucleation was performed by opening the conjunctiva and the Tenon capsule for 360° around the corneal limbus with Wescott scissors. Hemostasis was achieved with wet field cautery. The 4 quadrants were opened using Stevens scissors. Each of the 4 rectus muscles was isolated on a muscle hook and cleaned of surrounding Tenon attachments; secured on a double-armed 5-0 polyglactin suture, with locking bites at each end; and then disinserted from the globe. The superior and inferior oblique muscles were dissected from the globe. The optic nerve was cut deep within the orbit with the Foster enucleation snare or with long Metzenbaum scissors. The globe was removed from the socket and was sent to the pathology laboratory for evaluation in all cases. If the implant was covered in donor sclera, windows were made. The implant was placed into the orbit. The 4 rectus muscles were sutured securely into the scleral windows. The Tenon capsule was closed in a double-layered fashion using interrupted 5-0 polyglactin sutures. The conjunctiva was closed with running 7-0 polyglactin suture. An antibiotic ophthalmic ointment was applied to the wound, and a conformer was inserted. A pressure patch was then applied.The socket was evaluated at each postoperative visit. Socket motility was determined subjectively by assessing the patient's ocular motility in cardinal positions of gaze. The cosmetic appearance was determined subjectively by evaluation of eyelid contour and symmetry with the fellow eye. Complications throughout the postoperative period were recorded.RESULTSPostoperative follow-up was recorded for an average of 97.2 weeks (median, 78 weeks; range, 8-460 weeks). During this period, no instance of orbital hemorrhage or implant migration was noted. Complications occurred in 7 patients (Table 3). These complications were noted 7 days to 25 months after placement of the intraorbital implant. These patients ranged in age from 4 to 89 years (mean, 56.3 years) and included 3 males and 4 females. Six patients had received treatment or surgery before enucleation. Final histopathologic diagnoses included retinoblastoma, traumatic rupture, perforated corneal ulcer, endophthalmitis, and phthisis bulbi.Table 3. Clinical Data of 7 Patients With Complications of Orbital ImplantsSee table graphicFour cases of exposure of the implant were noted, 1 related to a recurrent infection and 2 related to conjunctival dehiscence or to paucity of conjunctiva covering the implant. Two of these patients had a small area of exposure, with 1 healing spontaneously and 1 undergoing drilling with peg placement in the area of exposure. The other 2 patients had larger areas of exposure resulting in partial extrusion of the implant; both patients underwent implant removal, with 1 undergoing implant exchange.Excessive orbital pain was noted in 1 patient who had long-term discomfort for more than 3 years. In this patient, the Iowa implant was replaced with a sphere.One patient had significant ptosis after enucleation and placement of the orbital implant. The ptosis was greater than 2 mm, and surgical repair was recommended.Three patients developed pyogenic granulomas within the socket. In all 3 patients these granulomas were excised, but in 1 patient multiple recurrences of inflammation were observed. One inclusion cyst of the socket was observed without treatment.None of the patients with complications had undergone drilling or peg placement before the complication.Patients were typically fitted with a prosthesis approximately 6 to 8 weeks after surgery. All patients had good socket motility and good cosmesis.COMMENTAn ideal orbital implant should yield excellent motility and cosmesis with few complications. Many authorshave suggested that an implant that is completely buried will minimize migration and extrusion. Attachment of the extraocular rectus muscles to the implant results in improved motility and cosmesis. The microporous HA implant fulfills these criteria and, therefore, has come into popular use, as demonstrated by this series. Other implants, such as the porous polyethylene sphere (Medpor) and acrylics, including the sphere and the older quasi-integrated Iowa and Universal implants, were also used after primary enucleation in this series. Simple spheres composed of silicone and glass were used less frequently.Complications in our series were minimal, with a rate of 3%. Five implants underwent drilling for prosthetic integration. This small number did not allow for significant evaluation of complications related to this procedure. The final cosmetic appearance and socket or prosthesis motility were judged by the surgeon to be good in all 342 patients, and this was true even without placement of a peg in most cases of HA implantation. This observation was, however, based on a subjective grading and is, therefore, less reliable than if gauged by a standardized objective rating based on photographs and measurements. In our series, different types of implants were used, but it is difficult to determine the best type of implant based on statistical analysis with the small number of complications. Also, our review of the indications for enucleation shows no correlation of complications based on histopathologic diagnosis.Several studies explore the use of porous implants and their complications (Table 4). Karesh and Dresnerreported no extrusions, infections, or exposures of porous polyethylene implants in 21 patients after a mean follow-up of 19 months. Reported exposure rates of HA implants range from 0% to 22%.Nunery and colleaguesshowed that the exposure rate of HA implants (11.1%) was higher than that of silicone spheres (0%). They also noted increased incidence of postoperative inflammation with HA implants.Buettner and Bartleyproposed that exposure of HA implants is related to the inflammatory reaction incited by the implant or by delayed fibrous ingrowth. Remulla and coworkersemphasized the advantage of wrapping the implant for better protection from extrusion; these authors were unable to correlate preoperative diagnosis or treatment with exposure rates. Kim and colleaguesdemonstrated that, with HA implants, small areas of exposure (<3 mm) may close spontaneously but that larger defects require surgical treatment. Goldberg and coworkerssuggested that use of HA implants, even with exposure, was less likely to lead to extrusion or infection compared with exposure with silicone or acrylic implants. Ashworth and colleaguesreported 60 cases of HA implantation: 3 patients (11%) in the primary implant group had exposure and 1 patient (4%) developed orbital cellulitis. In their secondary implant group, there was 1 patient with exposure, 1 patient with conjunctival cyst, 1 patient with socket infection, and 3 patients with eccentric implants. Shields and colleaguesdescribed 100 cases of HA implants, among which they reported 6 patients with excessive postoperative orbital pain, 2 patients with wound edema, and 1 patient with erosion. As in the present series, Shields et al had excellent cosmesis in 98% and excellent motility in 99% of nondrilled patients. In their subsequent report of 250 patients with HA implants, Shields et aldescribed 8 patients with conjunctival thinning, 4 patients with erosions, and 1 patient with orbital infection. Jordan and coworkersdescribed 2 patients with abscesses found within HA implants.Table 4. Studies of Complications Associated With Intraorbital ImplantsSee table graphicThe most common complication observed with the Iowa implant is late exposure of the mounds and possible extrusion of the implant. Spivey and colleaguesalso described ptosis and pain occurring with these implants. The Universal implant was designed to shorten the protracted implantation procedure and to reduce the rate of extrusion associated with the Iowa implant while still offering good motility, as demonstrated by Anderson and coworkers.Contraindications for the use of these quasi-integrated implants include congenital nystagmus and severe scarring. The Allen implant has been shown by Fan and Robertsonto have a low long-term incidence of superficial tissue breakdown (2.2%) and exposure (1.1%), with satisfactory motility.Several techniques may be used to minimize complications after enucleation with placement of orbital implants. These techniques include choosing an appropriately sized implant, positioning the implant deeply in the orbit, wrapping the implant with donor sclera, meticulously closing the anterior Tenon capsule over the implant, securing the conjunctiva over the implant without tension, and using a posterior vault on the prosthesis to minimize wear.Orbital implants have been used for more than a century. Serious complications can occur, but they do so infrequently, as demonstrated by this series. Long-term benefits and risks of different implant types require ongoing evaluation.CMLuceA short history of enucleation.Int Ophthalmol Clin.1970;10:681-687.HPGougelmanThe evolution of the ocular motility implant.Int Ophthalmol Clin.1970;10:689-711.RLAndersonSMThieseJANeradDRJordanDTseLAllenThe Universal orbital implant: indications and methods.Adv Ophthal Plast Reconstr Surg.1990;8:88-99.CBeardRemarks on historical and newer approaches to orbital implants.Adv Ophthal Plast Reconstr Surg.1995;11:89-90.JJDuttonCoralline hydroxyapatite as an ocular implant.Ophthalmology.1991;98:370-377.JTFanDMRobertsonLong-term follow-up of the Allen implant (1967 to 1991).Ophthalmology.1995;102:510-516.AHornblassBSBiesmanJAEviatarCurrent techniques of enucleation: a survey of 5,439 intraorbital implants and a review of the literature.Ophthal Plast Reconstr Surg.1995;11:77-88.BLeatherbarrowJKwartzSSunderlandRBrammerENicholThe "baseball" orbital implant: a prospective study.Eye.1994;8:569-576.BESpiveyLAllenCABurnsThe Iowa enucleation implant: a 10-year evaluation of technique and results.Am J Ophthalmol.1969;67:171-188.WStone JrSymposium: orbital implants after enucleation: causes of complications and their solution.Trans Am Acad Ophthalmol Otolaryngol.1952;56:35-42.RCTroutmanFive-year survey on use of a magnetic implant for improving cosmetic result of enucleation.Arch Ophthalmol.1954;52:58-62.AGTyersJRCollinBaseball orbital implants: a review of 39 patients.Br J Ophthalmol.1985;69:438-442.HAHelmsHEZeiger JrACallahanComplications following enucleation and implantation of multiple glass spheres in the orbit.Ophthal Plast Reconstr Surg.1987;3:87-89.AHornblassBJHerschornDouble sphere orbital implantation in enucleation and evisceration.Ophthal Plast Reconstr Surg.1985;1:65-68.JTJacob-LaBarreDADiLoretoTotal integration of an ocular implant/prosthesis: preliminary in vivo study of a new design.Ophthal Plast Reconstr Surg.1995;11:200-208.JWKareshSCDresnerHigh density porous polyethylene (Medpor) as a successful anophthalmic socket implant.Ophthalmology.1994;101:1688-1696.SMoraxUse of GORE-TEX (polytetrafluoroethylene) in the anophthalmic socket.Adv Ophthalmic Plast Reconstr Surg.1990;8:82-87.ACPerryIntegrated orbital implants.Adv Ophthal Plast Reconstr Surg.1990;8:75-81.HDRemullaPARubinJWShoreComplications of porous spherical orbital implants.Ophthalmology.1995;102:586-593.ACPerryAdvances in enucleation.Ophthalmol Clin North Am.1991;4:173-182.CLShieldsJAShieldsRCEaglePDe PotterHistopathologic evidence of fibrovascular ingrowth four weeks after implantation of the hydroxyapatite orbital implant.Am J Ophthalmol.1991;111:363-366.BSSiresJBHoldsCRArcherMCKincaidGSHagemanHistological and radiological analyses of hydroxyapatite orbital implants in rabbits.Ophthal Plast Reconstr Surg.1995;11:273-277.JLAshworthMRhatiganRSampathRBrammarSSunderlandBLeatherbarrowThe hydroxyapatite orbital implant: a prospective study.Eye.1996;10:29-37.PDe PotterCLShieldsJAShieldsADSinghUse of the hydroxyapatite ocular implant in the pediatric population.Arch Ophthalmol.1994;112:208-212.AMcNabHydroxyapatite orbital implants: experience with 100 cases.Aust N Z J Ophthalmol.1995;23:117-123.CLShieldsJAShieldsPDe PotterHydroxyapatite orbital implant after enucleation: experience with initial 100 consecutive cases.Arch Ophthalmol.1992;110:333-338.CLShieldsJAShieldsPDe PotterHydroxyapatite orbital implant after enucleation for intraocular tumors.Int Ophthalmol Clin.1993;33:83-93.CLShieldsJAShieldsPDe PotterADSinghLack of complications of the hydroxyapatite orbital implant in 250 consecutive cases.Trans Am Ophthalmol Soc.1993;91:177-195.HBuettnerGBBartleyTissue breakdown and exposure associated with orbital hydroxyapatite implants.Am J Ophthalmol.1992;113:669-673.FSel-ShahedMMSherifATAliManagement of tissue breakdown and exposure associated with orbital hydroxyapatite implants.Ophthal Plast Reconstr Surg.1995;11:91-94.RAGoldbergJBHoldsJEbrahimpourExposed hydroxyapatite orbital implants: report of six cases.Ophthalmology.1992;99:831-836.DEHolckCMDe BackerJJDuttonDeviated hydroxyapatite orbital implant syndrome.Am J Ophthalmol.1997;124:123-125.DRJordanSBrownsteinSSJollyAbscessed hydroxyapatite orbital implants: a report of two cases.Ophthalmology.1996;103:1784-1787.SAKaltreiderSANewmanPrevention and management of complications associated with the hydroxyapatite implants.Ophthal Plast Reconstr Surg.1996;12:18-31.YDKimRAGoldbergNShorrKDSteinsapirManagement of exposed hydroxyapatite orbital implants.Ophthalmology.1994;101:1709-1715.WRNuneryGWHeinzJMBonninRTMartinMACapelaExposure rate of hydroxyapatite spheres in the anophthalmic socket: histopathologic correlation and comparison with silicone sphere implants.Ophthal Plast Reconstr Surg.1993;9:96-104.JHOestreicherELiuMBerkowitzComplications of hydroxyapatite orbital implants: a review of 100 consecutive cases and a comparison of Dexon mesh (polyglycolic acid) with scleral wrapping.Ophthalmology.1997;104:324-329.CLShieldsJAShieldsPDe PotterADSinghProblems with the hydroxyapatite orbital implant: experience with 250 consecutive cases.Br J Ophthalmol.1994;78:702-706.DRBuusJWKronishDTTseEnucleation and techniques of orbital implant placement.In: Wright KW, ed. Color Atlas of Ophthalmic Surgery: Oculoplastic Surgery. Philadelphia, Pa: JB Lippincott; 1992:348-364.Accepted for publication June 9, 1998.We appreciate the editorial efforts of Sharon Wheeler, MA.Reprints: Timothy G. Murray, MD, Bascom Palmer Eye Institute, University of Miami School of Medicine, 900 NW 17th St, Miami, FL 33136 (e-mail: [email protected]).

Azar, Dimitri T.; Pluznik, Daniel; Jain, Sandeep; Khoury, Johnny M.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1206pmid: 9747680

ObjectiveTo compare the expression of gelatinases in the corneal epithelium and stroma after laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK).MethodsRabbit eyes were treated with LASIK (n=11), PRK (n=12), or corneal flap construction (n=12); 4 eyes served as unwounded controls. Zymography was performed on the central epithelium and the stroma 1, 3, and 7 days after surgery to determine the expression of gelatinases.ResultsEpithelial expression of gelatinase B in the LASIK group (0%-25%) was lower than that in the PRK group at all time points (50%-100%) and was identical to the corneal flap group. Stromal expression of gelatinases A and B was similar after LASIK and PRK, but was minimal after corneal flap construction at all time points. Epithelial expression of gelatinase A was similar for the first 3 days after LASIK and PRK but not thereafter.ConclusionsGelatinase B epithelial expression was upregulated after PRK but not after LASIK. Gelatinase B stromal expression was up-regulated after both procedures.Clinical RelevanceDifferences in wound healing and subepithelial scarring after these 2 procedures may be related to gelatinase B.EXCIMER LASER photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK) are used to modify corneal shape to correct refractive errors. Compared with LASIK, PRK more often results in corneal subepithelial haze leading to reduced best-corrected visual acuity.Gelatinases A and B are important members of the matrix metalloproteinase family, consisting of protein-cleaving enzymes that degrade extracellular matrix and basement membrane components.Matrix metalloproteinases may play a role in corneal wound healing and scarring after PRK.In the rabbit cornea, gelatinase B expression peaks 1 to 3 days after surgery in the epithelium and returns to baseline 7 to 10 days after surgery. Gelatinase A is expressed in the keratocytes of unwounded corneas and peaks 1 to 3 days after PRK.Construction of a corneal flap before PRK during LASIK preserves the structural integrity of the epithelial basement membrane zone and seems to reduce postoperative corneal haze.We have reported increased corneal light scattering as seen by scatterometry in rabbit eyes treated with −10 diopters (D) PRK compared with −10 D LASIK.This study tests the hypothesis that the higher incidence of corneal haze after PRK than after LASIK may be associated with greater expression of matrix metalloproteinases.MATERIALS AND METHODSThirty-nine eyes from pigmented rabbits were divided into 4 groups: Group 1 (n=11) received LASIK treatment. Group 2 (n=12) received PRK treatment. Group 3 (n=12) received corneal flaps and no laser treatment. Group 4 (n=4) was the control group and was not treated.Rabbits were anesthetized with an intramuscular injection of a 1:1 mixture of ketamine hydrochloride (40 mg/kg body weight) and xylazine hydrochloride (7 mg/kg body weight). Proparacaine hydrochloride and atropine sulfate eye drops were used for topical anesthesia and cycloplegia. The surgical procedures were performed as described earlier.In the LASIK group (group 1), with a rotating microkeratome we constructed a nasally based corneal flap approximately 100 µm thick and 8 mm in diameter. We then performed a 5-mm, −10 D PRK ablation (89-µm stromal ablation) using an excimer laser (VISX, Santa Clara, Calif), and repositioned the flap.In the PRK group (group 2), we scraped the epithelium with a No. 15 blade, and performed a 5-mm, −10 D PRK stromal ablation. In group 3, we constructed corneal flaps similar to those of group 1 and then repositioned and secured them without excimer laser treatment.All eyes received the same postprocedural medications and treatments—atropine eye drops, topical erythromycin ointment, and 24 hours of tarsorrhaphy. Rabbits were examined every 24 to 48 hours after surgery.Rabbits in groups 1, 2, and 3 were killed 1, 3, or 7 days, respectively, after surgery with an intravenous overdose injection of pentobarbital (n=4/time point). Control rabbits (group 4) were killed on day 7. The epithelium within a 6.5-mm area demarcated by a trephine was scraped and immediately frozen at −70°C. Stromal buttons were frozen at −70°C after scraping the endothelium. Zymography was performed to determine matrix metalloproteinase expression as previously described.Briefly, 0.1% gelatin (Sigma, St Louis, Mo) was mixed with 10% acrylamide before standard sodium dodecyl sulfate–polyacrylamide gel electrophoresis. Corneal tissue was homogenized in 100 µL of sample buffer and incubated at room temperature for 5 minutes. The supernatant (20 µL) was placed in the electrophoresis wells and later incubated with 2.5% Triton X-100 (Sigma) for 1 hour. Proteinase reactions were carried out for 18 hours at room temperature. Gels were stained with Coomassie blue, destained with a solution of 7% methanol and 7% acetic acid, dried, and photographed.HT-1080 human fibrosarcoma cell–conditioned media (American Tissue Culture Collection, Rockville, Md) was run concomitantly (positive control). The percentage of corneas showing enzyme activity (visible bands) was calculated.RESULTSAfter PRK, central corneal epithelial defects were closed by days 3 to 7. A faint reticular haze was observed 7 days after PRK. In eyes that were treated with LASIK or in which corneal flaps were constructed, an arcuate epithelial defect was seen at the edge of the flap on day 1 that healed by day 3. There was no evidence of corneal epithelial ingrowth, infection, ulceration, or haze after LASIK or flap surgery.Gelatinases B and A migrated on the gels as 92- and 72-kd bands of gelatin digestion, respectively. The epithelial expression of gelatinase B in the LASIK group (0%-25%) was similar to that in the corneal flap group (Figure 1), but was significantly lower than in the PRK group (P<.01). The stromal expression of gelatinase B was similar after LASIK and PRK and significantly lower after corneal flap construction (Figure 1, P<.01). The percentage of LASIK eyes with epithelial gelatinase A expression was similar to that of the PRK eyes 1 and 3 days after surgery (Figure 2, left). However, the percentage of LASIK eyes with epithelial gelatinase A expression (0%) was significantly lower than that of the PRK eyes (75%) 7 days after surgery, and was similar to the corneal flap group (0%); P<.01.Figure 1.Gelatinase B expression after photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), or corneal flap. Left, Expression of gelatinase B in the corneal epithelium is shown as the percentage of corneas with identifiable matrix metalloproteinase–9 bands on zymography on days 1, 3, and 7 after wounding. Right, Expression of gelatinase B in the corneal stroma after wounding.Figure 2.Gelatinase A expression after photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), or corneal flap. Left, Expression of gelatinase A in the corneal epithelium is shown as the percentage of corneas with identifiable matrix metalloproteinase–2 bands on zymography at days 1, 3, and 7 after wounding. Right, Expression of gelatinase A in the corneal stroma.COMMENTCorneal wound healing after PRK differs from healing after LASIK and may account for the differences in the procedure outcomes.After LASIK, there is minimal corneal subepithelial scarring and haze, and the visual recovery is more rapid compared with that found after PRK. In addition, the presence of a corneal flap with LASIK reduces interactions between the epithelial and stromal layers.We observed that there is less synthesis of gelatinases in the corneal epithelium during the first week after treatment with LASIK compared with PRK. The regenerating corneal epithelium after PRK is metabolically active, producing several proteolytic enzymes, such as gelatinases A and B.Evidence from several studies suggests that destruction of the epithelial adhesion structures in the basement membrane zone may be the primary role of gelatinase B after deep keratectomy and ulcerating corneal wounds, and this may occasionally interfere with normal reepithelialization.In this study, we observed up-regulation of gelatinase B expression in the corneal epithelium in the first week after PRK, but not after LASIK or after the construction of corneal flaps. In contrast, expression of gelatinase B in the stroma was higher after both PRK and LASIK, but was negligible after corneal flaps. The epithelial pattern for gelatinase A after LASIK was not parallel to that after the construction of corneal flaps. We did not compare these results with those after epithelial scrape wounds.In previous studies we showed that gelatinase B synthesis is consistently induced after deep keratectomy and PRK wounds, but not after superficial epithelial scraping.We further used in situ hybridization and confocal microscopy to localize gelatinase B, and observed that it is synthesized by the basal cell layers of migrating epithelial cells, particularly at the leading edges over the PRK ablation bed.This would place the enzyme in the appropriate location to induce remodeling of the anterior stroma. In these wounds, epithelial migration occurs over the stroma in the first 3 to 4 days, prior to re-formation of the basement membrane. It is thus unlikely that gelatinase B is primarily involved in basement membrane degradation. In addition to their role in the remodeling of the anterior stroma, gelatinases A and B may play a role in inhibiting the angiogenesis that is known to occur in other systems of wound healing. Gelatinase B is involved in angiostatin production.We are investigating whether the absence of neovascularization after excimer laser keratectomy wounds is directly related to matrix metalloproteinase expression.The mechanism of corneal scar formation after PRK is not fully understood.The expression of gelatinases A and B in the stroma in our study was essentially identical after LASIK and PRK, but gelatinase B expression was minimal after flap surgery. This is consistent with the notion that gelatinase production may be an essential component of stromal remodeling after keratectomy wounds.There may have been quantitative differences in the production of gelatinase A that we were unable to measure, particularly because the expression of gelatinase A is constitutively present in the stroma of normal unwounded corneas (Figure 2, right). Alternatively, corneal scarring and subepithelial haze may be primarily related to epithelial rather than stromal factors, including gelatinase B production. Additional studies are needed to understand the exact mechanisms of scar formation after PRK, which may lead to a new target for therapeutic strategies.FEFantesKDHannaGOWaring IIIYPouliquenKPThompsonMSavoldelliWound healing after excimer laser keratomileusis (photorefractive keratectomy) in monkeys.Arch Ophthalmol.1990;108:665-675.REBraunsteinSJainRLMcCallyWJStarkPJConnollyDTAzarObjective measurement of corneal light scattering after excimer laser keratectomy.Ophthalmology.1996;103:439-443.IGPallikarisMEPaptzanakiDSSiganosMKTsilimbarisA corneal flap technique for laser in situ keratomileusis: human studies.Arch Ophthalmol.1991;109:1699-1702.PRamaWChamonCGenisiDTAzarExcimer laser in situ keratomileusis (LASIK).In: Azar DT, ed. Refractive Surgery. Stamford, Conn: Appleton & Lange; 1997:455-469.SJainJMKhouryWChamonDTAzarCorneal light scattering after laser in situ keratomileusis and photorefractive keratectomy.Am J Ophthalmol.1995;120:532-534.LALiottaWStettler-StevensonMetalloproteinases and malignant conversion: does correlation imply causality?J Natl Cancer Inst.1989;81:556-557.MEFiniMTGirardExpression of collagenolytic/gelatinolytic metalloproteinases by normal cornea.Invest Ophthalmol Vis Sci.1990;31:1779-1788.DTAzarTWHahnSJainYCYehWGStetler-StevensonMatrix metalloproteinases are expressed during wound healing after excimer laser keratectomy.Cornea.1996;15:18-24.SJainWChamonWJStarkWRGreenRAPrendergastDTAzarIntrastromal epithelial accretion follows deep excimer annular keratectomy.Cornea.1996;15:248-257.MMatsubaraJDZieskeMEFiniMechanisms of basement membrane dissolution preceding corneal ulceration.Invest Ophthalmol Vis Sci.1988;29:727-736.DJSchanzlinJVJesterKEunDuckCryolathe corneal injury.Cornea.1983;2:57-68.WVLVillarJMShipleyRMohanJDZieskeRMSeniorMEFiniThe role of gelatinase B in normal repair and failure to re-epithelialize after corneal injury.Invest Ophthalmol Vis Sci.1997;38(suppl):5405.MASteppSSpurr-MichaudATisdaleJElwellIKGipsonα6β4integrin heterodimer is a component of hemidesmosomes.Proc Natl Acad Sci U S A.1990;87:8970-8974.DTAzarSJSpurr-MichaudASTisdaleMBMooreIKGipsonReassembly of the corneal epithelial adhesion structures following human epikeratoplasty.Arch Ophthalmol.1991;109:1279-1284.IKGipsonSSpurr-MichaudATisdaleMKeoughReassembly of the anchoring structures of the corneal epithelium during wound repair in the rabbit.Invest Ophthalmol Vis Sci.1989;30:425-434.HYeDTAzarExpression of gelatinases A and B, and TIMPs 1 and 2 during corneal wound healing.Invest Ophthalmol Vis Sci.1998;39:1-9MSO'ReillyLHolmgrenYShingAngiostatin: a novel angiogenesis inhibitor that mediates the suppression of metastases by a Lewis lung carcinoma.Cell.1994;79:315-328.MSO'ReillyLHolmgrenCChenJFolkmanAngiostatin induces and sustains dormancy of human primary tumors in mice.Nat Med.1996;2:689-692.Accepted for publication May 14, 1998.This study was supported by grant EY10101 from the National Eye Institute, Bethesda, Md.Reprints: Dimitri Azar, MD, Corneal and Refractive Surgery Services, Massachusetts Eye & Ear Infirmary, 243 Charles St, Boston, MA 02114 (e-mail: [email protected]).

Mendelsohn, Mary E.; Abramson, David H.; Madden, Timothy; Tong, William; Tran, Hai T.; Dunkel, Ira J.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.9.1209pmid: 9747681

ObjectivesTo investigate the concentrations of carboplatin and etoposide achieved in the aqueous and vitreous humors after intravenous infusion in nonhuman primates, and to investigate whether local administration of carboplatin might result in higher concentrations in the vitreous humor.MethodsMacaca fascicularisprimates were treated with 1 of 3 regimens: (1) intravenous carboplatin (18.7 mg/kg), etoposide (5 mg/kg), and vincristine sulfate (0.05 mg/kg), (2) peribulbar carboplatin (10 mg/mL), or (3) episcleral balloon carboplatin (10 mg/mL). Concentrations of chemotherapeutic agents were measured in the plasma and in the aqueous and vitreous humors.ResultsNo measurable amount of etoposide was detected in the aqueous or vitreous humor after intravenous administration. Mean measured peak vitreous concentration of carboplatin after intravenous administration was 0.31 µg/mL, which was 1% of the peak plasma value. Mean measured peak vitreous concentrations of carboplatin after peribulbar or episcleral balloon administration were 2.38 µg/mL and 2.95 µg/mL, respectively, which represent 7.68- and 9.52-fold increases over the concentration achieved after intravenous administration. No serious toxic effect was observed in any animal.ConclusionsPeribulbar and episcleral balloon administration of carboplatin seemed to be safe and resulted in higher vitreous concentrations than intravenous administration in this model. These results suggest that these alternate routes of delivery should be explored in children with vitreous seeding of retinoblastoma.SYSTEMIC CHEMOTHERAPY is being used with increasing frequency to treat children with intraocular retinoblastoma in an attempt to avoid external beam radiation therapy and enucleation. External beam radiation therapy, although effective against retinoblastoma, is associated with increased mortality from radiation-induced tumors in patients carrying the RB-1germ-line mutation.Chemotherapy has been hypothesized to be less likely than radiation therapy to induce second malignant neoplasms in these patients. Chemotherapeutic regimens vary, though most centers use combinations of vincristine, carboplatin, and an epipodophyllotoxin, either etoposide or teniposide.These regimens have been developed empirically, and it is not known which agents reach therapeutic concentrations in the eye, nor which are most effective against intraocular retinoblastoma. This knowledge would be particularly useful for designing a regimen to treat intravitreous retinoblastoma, which is often resistant to all other treatments, including radiation therapy.We used a non–tumor-bearing primate model to determine the timing and degree to which 2 agents commonly used for intraocular retinoblastoma treatment (carboplatin and etoposide) penetrate into the humors of the eye. After intravenous delivery of chemotherapy, drug concentrations in aqueous and vitreous humors were measured over time. To determine whether local delivery could achieve concentrations comparable with those achieved by intravenous delivery of chemotherapy, intraocular concentrations of chemotherapeutic drugs achieved after intravenous administration were compared with concentrations obtained after peribulbar injection and episcleral balloon placement.MATERIALS AND METHODSCHEMOTHERAPY PROTOCOLSNormal adult Macaca fascicularismonkeys were used. The animals were anesthetized with ketamine hydrochloride during the procedures. The research protocols were approved by the Memorial Sloan-Kettering Cancer Center Institutional Animal Care and Use Committee, New York, NY.In the first group, 3 animals received intravenous vincristine sulfate, carboplatin, and etoposide in doses similar to those used in patients with retinoblastoma. Carboplatin (18.7 mg/kg) and etoposide (5 mg/kg) were administered simultaneously and infused over 1 hour, followed by an intravenous push of vincristine sulfate (0.05 mg/kg) at the end of the hour. Samples of aqueous and vitreous humors were drawn before any chemotherapy administration, then at half-hour intervals from completion of the chemotherapy infusion to 2 hours after the end of the infusion. Aqueous humor samples were drawn via clear corneal paracentesis from the superotemporal or superonasal area of the cornea. Vitreous humor samples were drawn transconjunctivally through the pars plana 3.5 to 4 mm posterior to the limbus in the superotemporal or superonasal quadrant. Venous blood and approximately 50 to 100 µL of aqueous and vitreous humors were sampled at each time point, alternating eyes.In the second group, 3 animals received 1 mL of 10-mg/mL carboplatin injected transconjunctivally into the inferior peribulbar space of one eye. This concentration was chosen as the highest stable concentration recommended by the manufacturer. The injection was given far enough posteriorly to avoid any ballooning of the anterior conjunctiva and possible contamination of the pars plana vitreous sampling area, which was about 180° away. Samples of aqueous and vitreous humors were drawn every half hour from the ipsilateral eye, with samples for the zero time point taken before injection. At the final time point, blood was sampled as well.In the third group, 2 animals had a recently described therapeutic episcleral balloonplaced in the inferotemporal posterior peribulbar space of 1 eye, and 1 mL of a 10-mg/mL carboplatin solution was instilled into the catheter, delivering the carboplatin into the posterior peribulbar space. Aqueous and vitreous humor samples were taken from the ipsilateral eye every half hour for 2 hours, with time zero samples taken before instillation of the chemotherapy. At 2 hours, blood was sampled.All animals had twice-weekly complete blood cell counts done for 3 weeks to observe for signs of bone marrow suppression. All animals had 1 postoperative ophthalmoscopic examination performed within the first several days after the procedure, with dilation and scleral depression to ensure that no peripheral retina trauma had occurred.DRUG ASSAYSSamples were assayed for etoposide by one of us (W.T.) with the use of high-performance liquid chromatography. The lower limit of detection of etoposide with this assay, remaining in linear range, is 0.2 µg/mL.Plasma samples were injected onto a 3-µm 6×40-mm column (Reliance ODS; Mac-Mod Analytical, Chadds Ford, Pa) at a flow rate of 1 mL/min. The mobile phase was 400 mL of methanol and 600 mL of 100-mmol/L sodium dihydrogen phosphate with 0.02-mmol/L dioctyl sodium sulfosuccinate and 0.5% triethylanine adjusted to pH 6 with phosphoric acid. The eluent was monitored at 235 nm at 0.002 absorbance units full scale.Samples were analyzed for platinum by 2 of us (H.T.T. and T.M.) by flameless atomic absorption spectroscopy (SPECTRAA-300; Varian, Sugar Land, Tex) by use of a graphite tube atomizer as described by Madden et aland Mulder et alwith minor modifications. Briefly, standards, controls, and samples were injected at a volume of 20 µL onto the graphite tube at a temperature of 25°C. The furnace temperature was increased from 25°C to 1300°C in 5 steps over 1.5 minutes, held at 1300°C (ashing) for 2 minutes, and raised to 2700°C over 60 seconds (atomization) and held for 5 seconds. Argon gas flow was 3 L/min. The hollow cathode lamp current was 10 mA; the spectral bandwidth was 0.7 nm at a monochromator wavelength of 265.9 nm, with a signal integration time of 5 seconds and background correction by hydrogen-2 lamp. A linear standard curve covering the range of 50 to 400 ng of platinum per milliliter was run at the start of each assay day and after each change to a new graphite tube. Aqueous and vitreous humor samples were diluted with 0.1N hydrochloric acid–0.25% Triton-X. Plasma ultrafiltrate samples were diluted in 0.1N hydrochloric acid. All samples were diluted to achieve concentrations that were within the linear portion of the standard curve. Sample concentrations were determined by comparison of sample peak areas vs that of external standards by use of linear least-squares regression.We were unable to assay vincristine because of technical difficulty of the assay method and the small sample volumes available.RESULTSINTRAVENOUS DELIVERYMeasured peak plasma concentrations of etoposide after intravenous delivery occurred at either 30 or 60 minutes after delivery and gradually declined to approximately 50% of peak concentrations at 2 hours. Mean measured peak plasma etoposide concentration was 18.8 µg/mL. No etoposide was detected in the aqueous or vitreous humor in any animal.Measured peak plasma concentrations of carboplatin after intravenous administration occurred 30 minutes after completion of the infusion and gradually declined to approximately 50% of peak levels at 2 hours. Mean peak carboplatin concentration in plasma was 30.2 µg/mL. Carboplatin was detected in both aqueous and vitreous humors after intravenous delivery. Aqueous humor concentrations of carboplatin after intravenous delivery continued to rise over 2 hours in 2 animals and peaked at 60 minutes in the third animal. The mean measured peak aqueous humor concentration was 6.2 µg/mL, 20% of the peak serum value. Vitreous humor concentrations of carboplatin after intravenous delivery continued to rise over 2 hours in 2 animals and peaked at 90 minutes in the third animal (Table 1). The mean measured peak vitreous humor concentration was 0.31 µg/mL, 1% and 5%, respectively, of the peak plasma and aqueous humor concentrations.Carboplatin Concentrations in the Vitreous HumorSee table graphicPERIBULBAR INJECTIONAqueous humor concentrations of carboplatin after peribulbar injection peaked at 90 or 120 minutes. The mean measured peak aqueous humor carboplatin concentration was 2.0 µg/mL, 32% of the peak aqueous humor value after intravenous carboplatin. At 2 hours, the mean concentration of carboplatin in the plasma was 0.89 µg/mL, 2.9% of the peak plasma concentration after intravenous administration.Vitreous humor concentrations of carboplatin after peribulbar injection peaked at 30 minutes, dropped, then rose slowly until 120 minutes. The mean measured peak vitreous humor concentration was 2.38 µg/mL. This is more than 7 times (768%) the peak vitreous humor value after intravenous administration (Figure 1).Mean peak measured carboplatin concentrations in the aqueous and vitreous humors after each route of administration.EPISCLERAL BALLOONAqueous humor concentrations of carboplatin after episcleral balloon delivery peaked at 60 minutes in both animals. Mean measured peak aqueous humor carboplatin concentration was 1.74 µg/mL, 28% of the peak aqueous humor value after intravenous delivery. At 2 hours the mean carboplatin concentration in the plasma was 0.056 µg/mL, 0.2% of the concentration after intravenous administration.Vitreous humor concentrations of carboplatin after delivery through the episcleral balloon catheter peaked at 30 or 60 minutes, and the mean measured peak vitreous humor concentration was 2.95 µg/mL. This is more than 9 times (952%) the measured peak vitreous humor concentration after intravenous administration.TOXIC EFFECTSNo animal showed ill effects in behavior or on dilated examination. One of the animals in the intravenous group had a mild transient neutropenia, which resolved without intervention.COMMENTThere is little information regarding the concentrations of chemotherapeutic agents achieved in the aqueous and vitreous humors of the eye after intravenous administration to humans or animals. While intraocular retinoblastoma has been clearly demonstrated to be responsive to intravenous combination chemotherapy, the regimens used have been developed completely empirically. It is important to establish which effective agents reach therapeutic concentrations in the vitreous humor and to avoid those that do not and, therefore, may be contributing toxic effects without compensatory efficacy. Samples of aqueous and vitreous humors cannot be taken from eyes afflicted with retinoblastoma in vivo because of this cancer's ability to metastasize outside the eye through needle biopsy sites.A primate model may be relevant to the clinical situation, but it must be noted that these results in a normal eye may not mirror those in an eye with retinoblastoma. The presence of tumors in the retina may disrupt the vascular anatomy sufficiently to increase concentrations of chemotherapeutic agents in the vitreous humor after intravenous administration.This study demonstrated that, after intravenous administration, 1% of the plasma carboplatin level was achieved in the vitreous humor. It should be noted, however, that the vitreous humor was not sampled beyond 2 hours, and it is possible that the true peak occurred later. This is somewhat less than the 20% to 30% of the plasma concentration that has been reported to be achieved in the cerebrospinal fluid,but the measured peak concentration in the vitreous humor of 0.31 µg/mL is comparable with the concentration of 0.19 µg/mL previously reported in a rabbit model.Clinical trials with single-agent intravenous carboplatin have demonstrated efficacy against both intraretinal and intravitreous retinoblastoma,and intravitreous and subconjunctival carboplatin have also been shown to inhibit growth of intraocular retinoblastoma in transgenic mice.Carboplatin is clearly an active agent against intraocular retinoblastoma, and there is a good rationale for its inclusion in multidrug regimens.In contrast, no etoposide was detected in the normal primate eye after intravenous delivery. This is similar to data indicating that less than 5% of the plasma etoposide concentration is achieved in the cerebrospinal fluid.This may indicate that etoposide is a poor choice for inclusion in multidrug regimens for the treatment of intravitreous retinoblastoma in children. Alternatively, as noted above, retinoblastoma-containing eyes may have alterations of barriers to drug delivery present in the non–tumor-bearing primate model. No phase II study of the effectiveness of etoposide in patients with intraocular retinoblastoma has been published.Intravenous chemotherapy carries with it the attendant risks of systemic side effects. When only intraocular disease is being treated, a local administration system would be preferable. We compared carboplatin concentrations obtained after intravenous administration with concentrations achieved after peribulbar injection and episcleral balloon placement. The concentrations in the vitreous humor after local administration were 7 to 9 times higher than those obtained after intravenous administration. Local administration may be advantageous for treatment of vitreous seeds; however, intraretinal tumors may still require intravenous administration.The concentrations in the aqueous humor after local administration were approximately 30% of those after intravenous administration, and the concentrations in plasma after local administration were substantially lower than after intravenous administration (<3% with peribulbar injection, <0.2% with balloon). Local administration should, therefore, decrease the risk of systemic toxic effects and may potentially decrease anterior segment toxic effects. No animal showed evidence of toxic effects, irritation, or pain to the eye or peribulbar tissues after local administration of carboplatin by external or dilated examination, but ocular toxic effects of locally administered carboplatin require further study. In a rabbit model, 10 µg of carboplatin injected into rabbit vitreous humor was the lowest dose that caused retinal toxic effects.This work stimulated the development of a phase I/II clinical protocol. 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Philadelphia, Pa: Lippincott-Raven; 1997:228.TWWilsonHSLChanGMMoselhyDDHeydtCMFreyBLGalliePenetration of chemotherapy into vitreous is increased by cryotherapy and cyclosporin in rabbits.Arch Ophthalmol.1996;114:1390-1395.IJDunkelMEMendelsohnLBayerA pilot phase II trial of carboplatin in children with intraocular retinoblastoma [abstract].Proc Am Soc Clin Oncol.1996;15:A1439.JWHarbourTGMurrayDHamasakiLocal carboplatin therapy in transgenic murine retinoblastoma.Invest Ophthalmol Vis Sci.1996;37:1892-1898.TGMurrayNCicciarelliJMO'BrienSubconjunctival carboplatin therapy and cryotherapy in the treatment of transgenic murine retinoblastoma.Arch Ophthalmol.1997;115:1286-1290.Accepted for publication April 20, 1998.This work was supported by the David Warfield fellowship program in ophthalmology of the New York Community Trust and the New York Academy of Medicine, and by the Louis and Rachel Rudin Foundation, all in New York, NY.Reprints: Ira J. Dunkel, MD, Memorial Sloan-Kettering Cancer Center, Box 185, 1275 York Ave, New York, NY 10021 (e-mail: [email protected]).