JAMA Ophthalmology

Jampel, Henry D.; Moon, Jung Il; Quigley, Harry A.; Barron, Yolanda; Lam, Kwok-Wai

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.281pmid: 9514479

ObjectiveTo determine if there is an association between the surgical outcome of trabeculectomy and uric acid and ascorbic acid concentrations in the aqueous humor at the time of the procedure.Patients, Materials, and MethodsAqueous humor samples were collected from the eyes of 169 of 249 adult patients who underwent trabeculectomy alone for any type of glaucoma between April 1989 and July 1995. Postoperatively, all medical records were reviewed and outcomes were classified as successful, unsuccessful, or indeterminate. The ascorbic acid and uric acid concentrations were determined in masked fashion by high-pressure liquid chromatography. Factors associated with surgical outcome were determined.ResultsUric acid concentration was higher in unsuccessful eyes (mean±SD, 0.21±0.08 mmol/L, n=26) than in successful eyes (0.15±0.09 mmol/L, n=91, 95% confidence interval for difference, 0.02-0.10 mmol/L). Ascorbic acid levels were not significantly different in the eyes with unsuccessful (1129.9±601.9 µmol/L) and successful (1334.3±511.0 µmol/L) surgery (95% confidence interval for difference, −475.2 to 66.4 µmol/L, P=.13) surgery. Other factors associated with failure were previous surgery and surgery performed at the inferior limbus. A multiple polytomous logistic regression analysis was performed, after excluding the small number of operations performed at the inferior limbus. The odds ratio for failure increased by a factor of 1.68 for every 1-mmol/L increase in uric acid (95% confidence interval, 1.16-2.43, P=.006).ConclusionsUric acid levels were higher at the time of surgery in eyes that had unsuccessful outcomes than in those with successful outcomes. No significant difference in ascorbic acid levels was detectable. A higher uric acid level in the aqueous humor is a risk factor for trabeculectomy failure and might be tested as a prognostic indicator. Understanding the host characteristics that determine whether a trabeculectomy will be successful in a given eye is important. Data from the Fluorouracil Filtering Surgery Study Group suggest that in eyes with previous surgery the following are risk factors for surgical failure: time elapsed since the last procedure involving a conjunctival incision, the number of previous procedures involving conjunctival incisions, high preoperative intraocular pressure, and Hispanic ethnicity. In addition, previous intraocular surgery itself, age, race, and the diagnosis of uveitic or neovascular glaucoma are generally considered risk factors for trabeculectomy failure.CERTAIN factors have been associated with poorer prognosis in trabeculectomy, namely, time elapsed since the last procedure involving a conjunctival incision, the number of previous procedures involving conjunctival incisions, high preoperative intraocular pressure (IOP), and Hispanic ethnicity.In addition, previous intraocular surgery itself,age,race,and the diagnosis of uveitic or neovascular glaucomaare also generally considered risk factors for trabeculectomy failure. Why these factors are associated with a poorer surgical prognosis is unknown. Eyes with unsuccessful surgical outcomes exhibit a more vigorous wound healing response than their successful counterparts.There are 2 possible explanations for this more vigorous wound healing response. First, the conjunctiva may be more prone to scarring, a hypothesis supported by the observation that increased cellularity of the conjunctiva is associated with a decreased success rate.Second, the composition of the aqueous humor that bathes the surgical site in these unsuccessful trabulectomies may stimulate wound healing.We have previously shown that ascorbic acid, at concentrations present in human aqueous humor, is cytotoxic to human Tenon capsule fibroblasts.This observation led us to hypothesize that the ascorbic acid concentration in the aqueous humor might affect the outcome of surgery. Because there might be an important interaction between ascorbic acid and uric acid, we assayed uric acid as well.PATIENTS, MATERIALS, AND METHODSAll procedures were approved by the Joint Committee on Clinical Research of The Johns Hopkins University School of Medicine and The Johns Hopkins Hospital, Baltimore, Md.PATIENTSFrom April 1989 to July 1995, all patients older than 18 years who underwent trabeculectomy by one surgeon (H.D.J.) at the Wilmer Institute, Baltimore, were asked if an aqueous humor specimen could be collected during their surgery and frozen for further analysis. Three hundred six trabeculectomies were performed during this period (Figure 1), and aqueous humor specimens were obtained in 169 of the procedures.Flowchart explaining subsets of eyes analyzed.AQUEOUS HUMOR SPECIMENSAqueous humor specimens were obtained by a technique similar to that in previous studies.In preparation for surgery all patients received intravenous sedation, and local anesthesia was given in retrobulbar or peribulbar locations that included a 50:50 mixture of 2% lidocaine hydrochloride and 0.75% bupivacaine hydrochloride. In all eyes, aqueous humor was removed before the eye had been entered with any instrument. Approximately 100 µL of aqueous humor was removed using a 27-gauge needle on a tuberculin syringe over the course of 2 to 3 seconds. Care was taken not to contact the iris or the lens. The aqueous humor specimens were immediately placed in 600-µL microcentrifuge tubes (United Scientific, San Leandro, Calif) and kept on dry ice until storage at −85°C.REVIEW OF PATIENT MEDICAL RECORDSThe clinical records of 249 patients were studied (Figure 1). Criteria for success and failure of surgery were established before clinical records were reviewed. The surgical outcomes were characterized as (1) successful: IOP equal to or less than 17 mm Hg and more than 25% lowering of IOP without IOP-lowering medications, and follow-up of 5 months or more; (2) indeterminate: IOP 17 mm Hg or lower with medications or 18 mm Hg or higher without medications, and follow-up of 5 months or more; (3) unsuccessful, IOP 21 mm Hg or lower, or more than or equal to preoperative levels, with at least 1 medication, and a follow-up of 5 months or more; or (4) incomplete: not enough information available from the medical record.DETERMINATION OF ASCORBIC ACID AND URIC ACID CONCENTRATIONSAqueous humor from all 169 eyes with specimens was sent on dry ice to a laboratory for analysis of ascorbic and uric acid. Four batches of specimens were analyzed at different times. The first 3 batches (from 1992, 1993, and 1995) included only specimens from eyes in the successful or unsuccessful categories; the last batch (from 1996) included specimens from eyes with all 4 outcomes.High-pressure liquid chromatography was performed using an o-Bondapax–NH2(Waters Associates, Medford, Mass) column and a 5-mmol NH4H2PO4/0.05-mol EDTA buffer as previously described.The eluate from the column was monitored at 254 nm for ascorbic acid and 280 nm for uric acid. The operator of the high-pressure liquid chromatography was masked to the clinical outcome.DATA ANALYSISDifferences in mean values for continuous variables, such as uric acid concentration, were analyzed using an unpaired ttest, and the 95% confidence interval (CI) for the difference between 2 means was calculated. Comparisons of more than 2 means were made by analysis of variance (ANOVA). Proportions were analyzed using a χ2test, and the odds ratio and 95% CI for the odds ratio were calculated.Univariate polytomous logistic regression analyses were performed to determine which variables were statistically significantly associated with risk of failure. The statistically significant variables were entered into a multiple polytomous logistic regression model.RESULTSThe patients from whose eyes specimens were obtained and those from whose eyes specimens were not obtained were similar for age, sex, race, preoperative diagnosis, preoperative medications, use of an antifibrosis agent, and the location of their surgery (Table 1). The eyes from those patients from whom specimens were not obtained had a higher likelihood of having had previous surgery, and a slightly higher preoperative IOP than those from whom specimens were obtained.Table 1. Clinical Feature of Eyes That Underwent Trabeculectomy*See table graphicIn those eyes with specimens, the concentrations of ascorbic acid and uric acid were analyzed by outcome and by year of analysis (Table 2). For the analysis of uric acid, there was no difference in the mean uric acid concentrations among the assay years (P=.12, ANOVA). Therefore, further analysis of uric acid concentration was done on pooled data from all 4 batches. However, for the ascorbic acid assay, the mean ascorbic acid concentration was much lower in the 1996 batch (P<.001, ANOVA) than in the preceding analyses, which did not differ from one another (P=.11, ANOVA). The lower values in the 1996 batch were not correlated with an increased duration of freezing (data not shown). Because of the discrepancy between the 1996 results and the earlier batches, only the ascorbic acid data from the 1992, 1993, and 1995 batches were used in the analysis.Table 2. Uric Acid and Ascorbic Acid Concentrations by Year of Analysis and OutcomeSee table graphicThe eyes in the unsuccessful group were more likely to have had a trabeculectomy performed at the inferior limbus and to have undergone previous conjunctival surgery than the eyes in the other groups (Table 3). There were no differences among the successful, unsuccessful, and indeterminate groups in age, preoperative IOP, sex, race, preoperative diagnosis, use of preoperative medications, or use of antifibrosis agents.Table 3. Factors Associated With Surgical Success in Eyes With Specimens*See table graphicThe uric acid concentration in the eyes in the unsuccessful group was higher than in the other 2 groups (P=.006, ANOVA), which did not differ from one another (P=.38, unpaired ttest). The 95% CIs for the difference between the means were 0.35 to 1.6 for the unsuccessful vs successful eyes (P=.005), and 0.42 to 2.33 for the unsuccessful vs indeterminate eyes (P=.004). The uric acid concentration was lower in the indeterminate group than in the successful group, but the difference was not statistically significant (95% CI for the difference, −1.13 to 0.33, P=.38). All the above analyses were repeated with the incomplete eyes included, with similar results (data not shown). The ascorbic acid concentration in the unsuccessful group was lower than in the successful group, but the difference was not statistically significant (95% CI for the difference, −1.48 to 8.68, P=.77). The power of our study to detect a difference of this size, however, was only 0.30.We performed univariate polytomous logistic regression analysis to determine if uric acid concentration was independently associated with outcome, and whether there were other variables that were significantly associated with outcome. Previous surgery (P=.02), location of surgery (P<.001), and uric acid concentration (P=.01) were significantly associated with outcome in this model. We next performed multiple polymotous logistic regression analysis, after including variables of age, race, sex, previous surgery, location of surgery, and uric acid level. In this model, there was only a trend for surgical failure with increasing uric acid concentration (the odds of failure increased by a factor of 1.33 for every 1-mmol/L increase in uric acid concentration [95% CI, 0.94-1.88, P=.1]).We studied the data in an attempt to explain the discrepancy between the univariate analysis, in which uric acid concentration was strongly associated with surgical outcome, and the multivariate analysis, in which the association was weaker. This discrepancy seemed related to the inclusion of the 14 eyes that underwent trabeculectomy at the inferior limbus. This small group of eyes had a large variance in uric acid concentrations, and had an absolute association with previous surgery (all eyes that underwent surgery at the inferior limbus had undergone previous surgery). When those eyes that had undergone surgery at the inferior limbus were excluded from the multiple polytomous logistic regression analysis, so that only eyes undergoing trabeculectomy at the superior limbus were analyzed, uric acid concentration was more strongly associated with outcome (P=.01). The odds of being in the unsuccessful group compared with the successful group increased by a factor of 1.68 for every 1-mmol/L increase in uric acid concentration (95% CI, 1.16-2.43, P=.006). The odds of being in the indeterminate group compared to the successful group decreased by a factor of 0.73 for every 1-mmol/L increase in uric acid, although the difference was not statistically significant (95% CI, 0.4-1.33, P=.3).COMMENTWe have previously postulatedthat the high concentration of ascorbic acid in the aqueous humor might explain the incomplete wound healing response that characterizes successful trabeculectomy surgery. To lend support to this hypothesis, we sought to discover whether aqueous humor ascorbic acid levels were associated with trabeculectomy success. Although the mean ascorbic acid concentration was higher in the successful group than in the unsuccessful group, the difference was not statistically significant. Unfortunately, the data from the 1996 batch of aqueous humor could not be used because of the markedly lower ascorbic acid values in that batch. The lower ascorbic acid values may have been due to oxidation of the ascorbic acid during transport for analysis. Perhaps if that assay had yielded credible data it might have confirmed an association.We did find, however, that eyes that have had unsuccessful trabeculectomy surgery have higher aqueous humor uric acid concentrations than eyes that have had successful surgery. This association was seen in all 4 batches analyzed and was statistically significant in the pooled data. Thus we have shown for the first time, to our knowledge, that a feature of the aqueous humor is associated with the outcome of glaucoma surgery.The observation that the indeterminate group had the lowest mean uric acid concentration complicates the interpretation of our finding concerning the association of uric acid with outcome. If there were an important relationship between uric acid and surgical outcome, one would expect the uric acid concentration in the indeterminate group to be intermediate between the successful and unsuccessful groups. The number of eyes in the indeterminate group was small, however, and the difference in uric acid concentration between it and the successful group was not statistically significant. Furthermore, the eyes in the indeterminate group may not have differed greatly in outcome from those in the successful group.In addition to uric acid, a history of previous conjunctival surgery and the location of the operation at the inferior limbus were also associated with a poor surgical outcome, confirming data from other studies.The inclusion of operations performed at the inferior limbus complicated the statistical modeling, both because of the small number of eyes and the fact that these operations were only performed on eyes that had had previous surgery. In fact, the association between previous surgery and outcome disappeared when only surgery performed at the superior limbus was considered. This lack of association could be explained by the greater use of antifibrosis agents in eyes with conjunctival scarring. Similar to the findings of the Fluorouracil Filtering Surgery Study Group,we were also unable to find an association between African American race and surgical outcome.Why was the uric acid level higher in eyes that had unsuccessful surgery? It is unlikely that the excess uric acid was derived from the serum. Experiments in rabbits in which hyperuricemia was induced failed to raise the levels of uric acid in the aqueous humor.Furthermore, the levels of uric acid reported in serumare comparable to those present in the aqueous humor, so breakdown of the blood-aqueous barrier is unlikely to be an explanation. We know of no studies correlating aqueous humor and plasma uric acid levels, and unfortunately, we did not obtain serum specimens at the time of surgery. A more likely explanation for the higher uric acid concentration is local production. Uric acid is a product of the catabolism of nucleotides; and xanthine oxidase, which catalyzes the conversion of xanthine to uric acid, is present within the eye.Uric acid concentration can be expected to increase in situations in which there is tissue breakdown and death. We speculate that the eyes that had failed trabeculectomies were those with high rates of tissue breakdown and cell death, indicated by higher aqueous humor uric acid levels, although there are no data to support this hypothesis.We would like to perform aqueous humor studies during the postoperative period, since it is the postoperative aqueous humor that bathes the surgical wound. Unfortunately this is incompatible with safe patient care, is impractical in monkeys, and may not be relevant in other laboratory animals such as the rabbit. The measurement of uric acid from aqueous humor obtained at the time of surgery could nevertheless be used as a prognostic marker, although it would be unlikely to affect clinical care. However, if uric acid levels in the aqueous humor could be measured preoperatively and noninvasively, the results could be used to determine whether or not, and how aggressively, to use an antifibrosis agent.Aqueous humor composition is clearly not the sole determinant of the outcome of trabeculectomy surgery. Nevertheless, we hope this work will stimulate others to consider the composition of the aqueous humor as one determinant of the outcome of trabeculectomy.The Fluorouracil Filtering Surgery Study GroupFive-year follow-up of the Fluorouracil Filtering Surgery Study.Am J Ophthalmol.1996;121:349-366.ARBellowsMAJohnstoneSurgical management of chronic glaucoma in aphakia.Ophthalmology.1983;90:807-813.DKHeuerMGGresselRKParrishTrabeculectomy in aphakic eyes.Ophthalmology.1984;91:1045-1051.ALSchwartzDRAndersonTrabecular surgery.Arch Ophthalmol.1974;92:134-138.MGGresselDKHeuerRKParrishTrabeculectomy in young patients.Ophthalmology.1984;91:1242-1246.JCMerrittFiltering procedures in American blacks.Ophthalmic Surg.1980;11:91-94.RDMillerJCBarberTrabeculectomy in black patients.Ophthalmic Surg.1981;12:46-50.RCAllenARBellowsBTHutchinsonSDMurphyFiltration surgery in the treatment of neovascular glaucoma.Ophthalmology.1982;89:1181-1187.GLSkutaRKParrishWound healing in glaucoma filtering surgery.Surv Ophthalmol.1987;32:149-170.DCBroadwayIGriersonCO'BrienRAHitchingsAdverse effects of topical antiglaucoma medication, II: the outcome of filtration surgery.Arch Ophthalmol.1994;112:1446-1454.RLRadiusJHerschlerAClaflinGFiorentinoAqueous humor changes after experimental filtering surgery.Am J Ophthalmol.1980;89:250-254.HDJampelAscorbic acid is cytotoxic to dividing human Tenon's capsule fibroblasts: a possible contributing factor in glaucoma filtration surgery success.Arch Ophthalmol.1990;108:1323-1325.HDJampelNRocheWJStarkABRobertsTransforming growth factor-β in human aqueous humor.Curr Eye Res.1990;9:963-969.KWLamKMLiuRWYeePLeeDetection of uric acid in aqueous humor by high-pressure liquid chromatography.Curr Eye Res.1982;2:645-649.CHBonneyKWLamDFongOcular hyperuricosis in the rabbit following hyperuricemia and topical epinephrine.J Ocul Pharmacol.1986;2:55-58.MHerschfieldGout and uric acid metabolism.In: Bennett J, Plum F, eds. Cecil Textbook of Medicine.Philadelphia, Pa: WB Saunders Co; 1996:1508-1515.HZhangCDAgardhEAgardhIncreased catalase levels and hypoxanthine-enhanced nitro-blue tetrazolium staining in rat retina after ischemia followed by recirculation.Curr Eye Res.1995;14:47-54.Accepted for publication December 1, 1997.This research was supported in part by grant EY 01765 (Core Facility Grant, Wilmer Institute) from the National Eye Institute, National Institutes of Health, Bethesda, Md.Corresponding author: Henry D. Jampel, MD, Maumenee B-110, 600 N Wolfe St, Baltimore, MD 21287-9205.

Scott, Ingrid U.; Greenfield, David S.; Schiffman, Joyce; Nicolela, Marcelo T.; Rueda, Juan C.; Tsai, James C.; Palmberg, Paul F.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.286pmid: 9514480

ObjectiveTo investigate the efficacy and safety of adjunctive mitomycin when used during a primary trabeculectomy within a series of 89 consecutive patients at 1 and 2 years postoperatively.DesignA cohort study of all patients who underwent primary trabeculectomy, performed by one of us (P.F.P.), between April 1, 1991, and December 31, 1994. Patients received topical mitomycin in conjunction with a corneal safety valve incision. A trabeculectomy was considered "successful" if it resulted in an intraocular pressure (IOP) of 21 mm Hg or lower and a 30% or greater reduction in the IOP at and after 1 year of follow-up, with or without medications and without a reoperation for an elevated IOP. Survival analysis was used to calculate success rates.ResultsThe 1- and 2-year success rates were 85.4% and 77.9%, respectively. The mean IOP was reduced from 26.3 to 11.3 mm Hg at 1 year (n=68) and to 11.9 mm Hg at 2 years (n=56), with 60 (88.2%) of 68 patients off medication at 1 year and 47 (83.9%) of 56 patients off medication at 2 years. Trabeculectomy success rates were significantly lower in black compared with nonblack patients (76.2% vs 87.5% at 1 year, P=.03). Trabeculectomy failure occurred throughout the follow-up period. Endophthalmitis occurred in 2 (2.2%) of the patients, and hypotonia requiring revision occurred in 4 (4.5%) of the patients.ConclusionsPrimary trabeculectomy with the use of intraoperative mitomycin lowered the IOP by 30% or more in 78% (at 2 years) to 86% (at 1 year) of the cases and is associated with a marked reduction in the percentage of patients who require glaucoma medication. Success rates must be evaluated in light of such risks as endophthalmitis and hypotony.MITOMYCIN, like 5-fluorouracil, has been shown to improve the success of trabeculectomy in eyes with a high risk of surgical failure.These antifibrotic agents result in blebs that exhibit greater filtrationand somewhat greater vulnerability to leakage and infection.In high-risk cases, the visual risk-benefit ratio for using antifibrotic agents is favorable.The risk-benefit ratio of using antifibrotic agents is less well established in primary filtering surgery. For this study, primary trabeculectomy was defined as a trabeculectomy performed in an eye not previously operated on and not deemed to be at high risk for trabeculectomy failure (excluded from the overall study analysis were eyes with glaucoma associated with anterior segment neovascularization, uveitis, and the iridocorneal endothelial syndrome, as well as eyes with juvenile glaucoma). In favor of the use of antifibrotic agents in primary filtering surgery is the observation that surgery performed without them generally yields suboptimal results, with half of the patients requiring supplemental medical therapy within 2 years.Further, the mean intraocular pressure (IOP) 5 years after surgery is usually 16 to 21 mm Hg, and 35% to 58% of patients with glaucoma with pressures in this range have been noted to suffer progressive visual field loss within those 5 years.In contrast, in the few studies in which mean pressures of 15 mm Hg or lower were achieved, the risk of progressive visual field loss is reported to be only 6% to 18%.Previous reports of the use of low-dose 5-fluorouracil and of mitomycin in primary filtering surgery have shown that they yield lower mean pressures.For instance, in a prospective, randomized, multicenter study, eyes treated with postoperative 5-fluorouracil achieved significantly lower pressures and required fewer postoperative antiglaucoma medications than control eyes.The few published studies that report the efficacy of mitomycin when used during a primary trabeculectomy are limited by a small sample size, a short length of follow-up, or both.Our study investigates the efficacy and safety of intraoperative mitomycin when used during a primary trabeculectomy within a larger series of consecutive patients at 1 and 2 years postopratively.PATIENTS AND METHODSApproval for the study was obtained from the Medical Sciences' Subcommittee for the Protection of Human Subjects at the University of Miami School of Medicine, Miami, Fla. A standardized surgical technique was used in all consecutive patients who underwent primary filtering surgery, performed by one of us (P.F.P.), at the Bascom Palmer Eye Institute, Miami, between April 1, 1991, and December 31, 1994. Guarded filtration procedures were performed following the administration of regional anesthesia and preparation with povidone-iodine. Incisions of the conjunctiva and Tenon capsule were made in the superior quadrant, 10 mm posterior to the surgical limbus, to create a limbus-based flap. Meticulous hemostasis was achieved with bipolar cautery. A half-thickness, rectangular, 2.5×1.0-mm scleral miniflap was outlined at the surgical limbus. In all cases, mitomycin, 0.5 mg/mL, was applied for 5 minutes with a saturated surgical spear (Weck Cel, Weck Ophthalmics, Jacksonville, Fla) that was placed on the sclera while the conjunctiva and Tenon flap were pulled firmly over the sponge with nontoothed forceps. Copious irrigation was then performed with saline solution. A clear corneal paracentesis was placed temporally. A corneal safety valve incision was created as prophylaxis against postoperative hypotony by making a 1.0-mm clear corneal tunnel anterior to the base of the scleral flap.A 0.75-mm Kelly-Descemet punch (Storz Ophthalmics, St Louis, Mo) was used to remove an internal block of clear corneal tissue from the posterior lip of the anterior chamber entry site. Wound resistance was adjusted by taking additional partial bites with the punch until an estimated IOP of 4 to 6 mm Hg was achieved. The scleral flap was then reapposed with 2 to 3 interrupted 10-0 monofilament nylon sutures, and the scleral flap resistance was adjusted to achieve an estimated IOP at equilibrium flow of 8 to 12 mm Hg. The limbus-based conjunctival incision was closed with a running 10-0 nylon suture on a needle (CU-5, Alcon, Ft Worth, Tex). Additional balanced salt solution was placed into the anterior chamber to re-form the filtering bleb and to monitor for leaks. No subconjunctival injections were administered, and the eye was patched after the administration of topical neomycin sulfate, polymyxin B sulfate, and 0.1% dexamethasone ointment. Postoperatively, 1% prednisolone acetate was prescribed every 2 hours for the first week, with gradual tapering over several months, and 1% atropine sulfate was prescribed twice daily for 1 to 2 weeks. Ointment (0.1% dexamethasone) was administered nightly for 2 weeks.Demographic and clinical data were abstracted from the medical records of those patients who underwent primary trabeculectomy. Excluded from the overall study analysis were 15 eyes deemed to be at high risk for trabeculectomy failure (eyes with glaucoma associated with anterior segment neovascularization, uveitis, and the iridocorneal endothelial syndrome, as well as eyes with juvenile glaucoma).For those patients who underwent a trabeculectomy in both eyes during the study period, data relating to only the first eye were included in this study. Clinic visits from 9 through 18 months postoperatively were analyzed as 1-year postoperative visits, and clinic visits from 18 through 30 months postoperatively were analyzed as 2-year postoperative visits.The best-corrected visual acuity status was summarized in logMAR units, which equals −log(MAR), where MAR indicates the numerator of visual acuity divided by the denominator of visual acuity. Visual acuities classified as counting fingers, hand motions, light perception, and no light perception were assigned values of 1.000/200, 0.500/200, 0.250/200, and 0.125/200, respectively.In this study, a "successful" trabeculectomy was defined as a trabeculectomy that resulted in an IOP of 21 mm Hg or lower and a 30% or greater reduction in IOP at 1 or 2 years of follow-up, with or without medications, and without a reoperation for an elevated IOP. Trabeculectomy survival rates between patient subgroups were compared using Kaplan-Meier survival analysis (log-rank test).RESULTSData concerning 89 patients were included in this study. One-year follow-up data were available for 68 patients, and 2-year follow-up data were available for 56 patients. The characteristics of the study patients are shown in Table 1.Table 1. Patient Characteristics (N=89)*See table graphicTo seek evidence of bias in our study due to the lack of follow-up for all patients, the 68 patients with at least 1 year of follow-up were compared with the 21 patients with less than 1 year of follow-up; no statistically significant differences in age, sex, race, preoperative IOP, number of preoperative glaucoma medications, or number of previous laser treatments for glaucoma were found between the 2 groups. However, the median preoperative visual acuity was somewhat worse among patients with less than 1 year of follow-up than among patients with at least 1 year of follow-up (20/80 vs 20/30, P<.001, Mann-Whitney Utest).The types of glaucoma treated were as follows: primary open-angle glaucoma, 69 (77.5%) of the patients; secondary open-angle glaucoma, 1 (1.1%) of the patients; chronic angle-closure glaucoma, 7 (7.9%) of the patients; mixed-mechanism glaucoma, 2 (2.2%) of the patients; angle-recession glaucoma, 3 (3.4%) of the patients; pseudoexfoliation, 5 (5.6%) of the patients; and pigmentary glaucoma, 2 (2.2%) of the patients.Table 2shows the IOP results at 1 and 2 years postoperatively after primary trabeculectomy with the use of adjunctive intraoperative mitomycin. At 1 and 2 years postoperatively, the proportion of patients with an IOP of 15 mm Hg or lower was 62 (91.2%) of 68 patients and 47 (83.9%) of 56 patients, respectively.Table 2. Intraocular Pressure (IOP) After Primary Trabeculectomy With the Use of Adjunctive Intraoperative Mitomycin*See table graphicVisual acuity changes among the patients during the study period are displayed in Table 3. The number of patients with a visual acuity on a standard Snellen visual acuity chart within 0.3 logMAR units (less than a doubling of the visual angle) of their preoperative visual acuity at 1 and 2 years postoperatively was 61 (89.7%) of 68 patients and 46 (83.6%) of 55 patients, respectively.Table 3. Visual Acuity After Primary Trabeculectomy With the Use of Adjunctive Intraoperative MitomycinSee table graphicTable 4demonstrates the results of a Kaplan-Meier survival analysis, which adjusts for different lengths of follow-up. Success rates using various definitions of success are demonstrated in Table 4.Table 4. Success Rates of Primary Trabeculectomy With the Use of Adjunctive Intraoperative Mitomycin, Using Survival Analysis (N=89)*See table graphicTrabeculectomy failed in 14 of the 89 patients during the study period. Seven trabeculectomies were considered failures because the postoperative IOP reduction was less than 30%; in 3 patients, the postoperative IOP was higher than 21 mm Hg; and 4 failures were due to reoperations for inadequate IOP control. Reoperations were performed between 3 and 17 months after the first trabeculectomies.Nine patients underwent needle elevation of the scleral flap between 2 days and 6 months after filtration surgery for pressures between 20 and 54 mm Hg, using a technique previously described.In 2 patients, a further glaucoma procedure was performed. As in the Fluorouracil Filtering Surgery Study,scleral flap needling was not considered a reoperation, as this is an office procedure that does not require the patient to return to the operating room.The results of univariate survival analyses investigating the associations between trabeculectomy failure and age, race, type of glaucoma, preoperative IOP, preoperative visual acuity, number of preoperative glaucoma medications, and previous laser treatments are shown in Table 5. The only baseline variable examined that was statistically significant was race (P=.03, log-rank test). No statistically significant differences were found between younger (<50 years) and older (≥50 years) patients, between patients with high (≥25 mm Hg) and low (<25 mm Hg) preoperative pressures, between those with a poor (<20/40) and a good (≥20/40) visual acuity, between those with and without prior laser treatment, or between those using more (>2) and those using fewer (≤2) glaucoma medications.Table 5. Baseline Clinical Variables and Success Rates of Primary Trabeculectomy With the Use of Adjunctive Intraoperative Mitomycin, Using Survival Analysis (Categorical Variables)*See table graphicThe complications of primary trabeculectomy with the use of adjunctive intraoperative mitomycin were as follows: endophthalmitis, 2 (2.2%) of the patients; hyphema, 1 (1.1%) of the patients; hypotonia requiring bleb revision, 4 (4.5%) of the patients; scleral flap needling, 9 (10.1%) of the patients; suprachoroidal hemorrhage, 1 (1.1%) of the patients; wound leak, 1 (1.1%) of the patients; and pars plana vitrectomy for malignant glaucoma, 1 (1.1%) of the patients. Endophthalmitis due to Haemophilus influenzaedeveloped 1 month postoperatively in 1 patient with a preinfection visual acuity of 20/50; this patient achieved a final visual acuity of 20/200. A bleb leak and subsequent endophthalmitis secondary to Streptococcus viridansdeveloped 24 months postoperatively in another patient with a preinfection visual acuity of 20/60; this patient achieved a final visual acuity of 20/50.Four patients underwent scleral flap revision (using a 2 sets of stitches technique) for reduced vision due to hypotonia between 1 and 7 months postoperatively. In all of these cases, the pressures remained well controlled after the filter revisions throughout the follow-up period. The final visual acuity of 2 of these patients was 20/20, and the 2 other patients achieved a final visual acuity of 20/25.A small suprachoroidal hemorrhage developed in 1 patient; this hemorrhage resolved spontaneously by 10 weeks after filtration surgery. Because of irritation secondary to a distended bleb over the cornea, 1 patient underwent a bleb revision 11 months after filtration surgery. A slow bleb leak subsequently developed in this patient; the leak resolved with the application of trichloroacetic acid to the bleb.COMMENTAlthough intraoperative mitomycin has been shown to improve the success of trabeculectomy in eyes with a high risk of surgical failure,the few published studies that report the efficacy of mitomycin when used during a primary trabeculectomy are limited by a small sample size, a short length of follow-up, or both.In this study of consecutive primary trabeculectomies performed by one of us (P.F.P.), intraoperative mitomycin was associated with a 78% (at 2 years) to 86% (at 1 year) success rate, even with a rather stringent definition of success. In addition to reducing the mean IOP 13 mm Hg or more at 1 and 2 years postoperatively, primary trabeculectomy with the use of adjunctive intraoperative mitomycin greatly reduced the need for glaucoma medication. Although quality of life was not assessed in this study, decreasing the need for glaucoma medication may be associated with improved quality of life by decreasing toxic and unpleasant side effects of such medication. Further, a decreased need for medication has cost implications and is particularly important for patients with poor compliance with medical therapy.The goal of glaucoma filtration surgery is to slow or eliminate pressure-dependent retinal ganglion cell loss during the lifetime of the patient. Unfortunately, the usual trabeculectomy without an antifibrotic agent yields pressure control in the upper normal pressure range, at which one third to one half of patients will suffer additional visual field loss within 5 years.Furthermore, in half of the cases, filtration must be supplemented by the reinstitution of medical therapy to achieve even that level of control, meaning that patients unable or unwilling to use medical therapy have an even worse prognosis.Evidence has been accumulating that a dose-response relationship exists between the mean IOP obtained after filtration surgery and the risk of further visual field loss (Table 6). Similar dose-response relationships between IOP and progressive visual field loss have been reported for mixed medical-surgical therapy in patients with advanced glaucoma by Odbergand in patients with early glaucoma by Mao et al.Table 6. Dose-Response Relationship Between Mean Intraocular Pressure (IOP) After Filtration Surgery and Risk of Further Visual Field (VF) LossSee table graphicIn an effort to achieve low to normal pressures, we employed antifibrotic agents in primary filtering surgery. Between 1984 and 1991, we performed primary filtering surgery with 5 injections of 5-fluorouracil in numerous eyes and observed a significantly lower mean IOP than in comparable or lower-risk eyes operated on without 5-fluorouracil.The mean IOP at 1 year was 10.9 mm Hg with 5-fluorouracil and 15.0 mm Hg without it. In addition, at 18 months, the rate of failure by the usual criteria (IOP >20 mm Hg and taking medication) was 17% without 5-fluorouracil vs 5% with it, the percentage of patients requiring medical therapy was 33% vs 11%, and the percentage of patients reaching our goal of an IOP lower than 16 mm Hg without medication was 35% vs 81%. These results are consistent with those found through a prospective, randomized, multicenter study of 5-fluorouracil in patients undergoing primary trabeculectomy.In the present study, the mean IOP after 2 years was 11.9 mm Hg (Table 2), the number of patients not taking supplemental medication was 60 (88.2%) of 68 patients at 1 year and 47 (83.9%) of 56 patients at 2 years (Table 2), the rate of failure (an IOP >21 mm Hg, a <30% reduction in IOP, or a reoperation for an elevated IOP) was 14.6% at 1 year and 22.1% at 2 years (Table 4), and the percentage of patients reaching the conservative goal of an IOP of 15 mm Hg or lower without medication or a reoperation was 82.4% at 1 year and 69.3% at 2 years (Table 4).Thus, it seems that the improvement in success rates by various criteria (mean IOP and percentage of patients with an IOP of 15 mm Hg or lower without medication) in our patient population was comparably improved at 18 to 24 months of follow-up by the use of either 5 injections of 5-fluorouracil or intraoperative mitomycin. Similarly, Smith et alreported comparable outcomes in eyes following initial trabeculectomy supplemented intraoperatively with 5-fluorouracil or mitomycin. In 1 study of high-risk filtering procedures, the pressure-lowering effect was more persistent with mitomycin than with 5-fluorouracil, with a mean follow-up of 32 months.Further follow-up is needed to determine if this is also true in primary filtering surgeries.The overall benefit to visual function by a greater IOP reduction at 5 years was demonstrated for the use of 5-fluorouracil in complex filtering surgeryand may be even more favorable for the use of mitomycin than for 5-fluorouracil in complex filtering surgeryand combined procedures.It has yet to be proved that the benefit-risk ratio for the use of antifibrotic agents in primary filtering surgery will also be favorable. While precise estimates of incidence rates are difficult to determine without a larger series, there is increasing concern about a seemingly higher rate of endophthalmitisand hypotonyafter filtering surgery with the use of adjunctive mitomycin. In our study, endophthalmitis occurred in 2 (2.2%) of the patients. Furthermore, although in this series the final visual outcomes of patients with hypotonia were quite good, it is important to note that 4 (4.5%) of the patients underwent revision for hypotonia.The success and complication rates reported in this study were obtained for the use of adjunctive mitomycin, 0.5 mg/mL, for 5 minutes; inferences about the results using a lower dose of mitomycin cannot be made based on the data provided in this study. Few glaucoma surgeons use 0.5-mg/mL applications of mitomycin for 5 minutes in primary trabeculectomies. In fact, results comparable with those in our study have been reported for the use of adjunctive mitomycin, 0.2 mg/mL, for 3 to 5 minutes.The surgeon (P.F.P.) whose patient series is reported in this study is using mitomycin, 0.4 mg/mL, for 2 minutes in primary trabeculectomies.In our study, primary trabeculectomy with the use of adjunctive intraoperative mitomycin lowered the IOP by at least 30% in approximately 78% (at 2 years) to 86% (at 1 year) of the cases and was associated with a marked reduction in the percentage of patients who required glaucoma medication. There was a significantly (P=.03) lower success rate in black patients. Because trabeculectomy may fail at any time postoperatively, continued careful follow-up is necessary. Successful lowering of the IOP with the use of adjunctive intraoperative mitomycin must be considered in light of such risks as endophthalmitis and hypotony.GJKatzEJHigginbothamPRLichterMitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery.Ophthalmology.1995;102:1263-1269.KALampingJKBelkin5-Fluorouracil and mitomycin C in pseudophakic patients.Ophthalmology.1995;102:70-75.JAPrataDSMincklerGBaerveldtTrabeculectomy in pseudophakic patients: postoperative 5-fluorouracil versus intraoperative mitomycin C antiproliferative therapy.Ophthalmic Surg.1995;26:73-77.HMietzGKKrieglsteinMitomycin C for trabeculectomy in complicated glaucoma: preliminary results after 6 months.Ger J Ophthalmol.1994;3:164-167.AMermoudJFSalmonADMurrayTrabeculectomy with mitomycin C for refractory glaucoma in blacks.Am J Ophthalmol.1993;116:72-78.GLSkutaCCBeesonEJHigginbothamIntraoperative mitomycin versus postoperative 5-fluorouracil in high-risk glaucoma filtering surgery.Ophthalmology.1992;99:438-444.SSPalmerMitomycin as adjunct chemotherapy with trabeculectomy.Ophthalmology.1991;98:317-321.YKitazawaKKawaseHMatsushitaTrabeculectomy with mitomycin: a comparative study with fluorouracil.Arch Ophthalmol.1991;109:1693-1698.CWChenHTHuangJSBairTrabeculectomy with simultaneous topical application of mitomycin C in refractory glaucoma.J Ocul Pharmacol.1990;6:175-182.CWChenEnhanced intraocular pressure controlling effectiveness of trabeculectomy by local application of mitomycin C.Trans Asia Pacific Acad Ophthalmol.1983;9:172-177.The Fluorouracil Filtering Surgery Study GroupFive-year follow-up of the Fluorouracil Filtering Surgery Study.Am J Ophthalmol.1996;121:349-366.EJHigginbothamRKStevensDCMuschBleb-related endophthalmitis after trabeculectomy with mitomycin C.Ophthalmology.1996;103:650-656.RMCaroniaJMLiebmannRFriedmanTrabeculectomy at the inferior limbus.Arch Ophthalmol.1996;114:387-391.DSGreenfieldIJSunerMPMillerEndophthalmitis after filtering surgery with mitomycin.Arch Ophthalmol.1996;114:943-949.JMLiebmannRRitchMMarmorInitial 5-fluorouracil trabeculectomy in uncomplicated glaucoma.Ophthalmology.1991;98:1036-1041.PFPalmbergThe role of IOP in the success or failure of medical and/or surgical therapy.In: Preferred Practice Pattern for Primary Open-Angle Glaucoma, Appendix I.San Francisco, Calif: American Academy of Ophthalmology; 1992.THKupinMSJuzychDHShinAdjunctive mitomycin C in primary trabeculectomy in phakic eyes.Am J Ophthalmol.1995;119:30-39.YKitazawaHSuemori-MatsushitaTYamamotoLow-dose and high-dose mitomycin trabeculectomy as an initial surgery in primary open-angle glaucoma.Ophthalmology.1993;100:1624-1628.RRamakrishnanJMichonALRobinSafety and efficacy of mitomycin C trabeculectomy in southern India: a short-term pilot study.Ophthalmology.1993;100:1619-1623.MGoldenfeldTKrupinJMRuderman5-Fluorouracil in initial trabeculectomy: a prospective, randomized, multicenter study.Ophthalmology.1994;101:1024-1029.DJAnnenJSturmerFollow-up of a pilot study of trabeculectomy with low dosage mitomycin C: independent evaluation of a retrospective nonrandomized study.Klin Monatsbl Augenheilkd.1995;206:300-302.GEMirzaSKarakucukHDoganFiltering surgery with mitomycin-C in uncomplicated (primary open angle) glaucoma.Acta Ophthalmol (Copenh).1994;72:155-161.CHongSMHyungKYSongEffects of topical mitomycin C on glaucoma filtration surgery.Korean J Ophthalmol.1993;7:1-10.KSinghPREgbertSByrdTrabeculectomy with intraoperative 5-fluorouracil vs mitomycin C.Am J Ophthalmol.1997;123:48-53.VPCostaLJKatzGLSpaethPrimary trabeculectomy in young adults.Ophthalmology.1993;100:1071-1076.MFSmithJWDoyleQHNguyenMBSherwoodResults of intraoperative 5-fluorouracil or lower dose mitomycin C administration on initial trabeculectomy surgery.J Glaucoma.1997;6:104-110.PFPalmbergPrevention and management of complicated hypotony in trabeculectomy with mitomycin.Highlights Ophthalmol.1993;9:66-77.IJSunerDSGreenfieldMPMillerHypotony maculopathy following filtering surgery with mitomycin C: incidence and treatment.Ophthalmology.1997;104:207-215.IUScottODScheinSWestFunctional status and quality of life measurement among ophthalmic patients.Arch Ophthalmol.1994;112:329-335.EKHarrisAAlbertSurvivorship Analysis for Clinical Studies.New York, NY: Marcel Dekker Inc; 1991.DSGreenfieldMPMillerIJSunerNeedle elevation of the scleral flap for failing filtration blebs after trabeculectomy with mitomycin C.Am J Ophthalmol.1996;122:195-204.SMRothGLSpaethRJStaritaEMBirbillisWCSteinmannThe effects of postoperative corticosteroids on trabeculectomy and the clinical course of glaucoma: five-year follow-up study.Ophthalmic Surg.1991;22:724-729.MNKiddMO'ConnorProgression of field loss after trabeculectomy: a five year follow-up.Br J Ophthalmol.1985;69:827-831.AEKolkerVisual prognosis in advanced glaucoma: a comparison of medical and surgical therapy for retention of vision in 101 eyes with advanced glaucoma.Trans Am Ophthalmol Soc.1977;75:539-555.ELGreveCLDakeFour-year follow-up of a glaucoma operation: prospective study of the double flap Scheie.Int Ophthalmol.1979;1:139-145.DFRollinsSMDranceFive-year follow-up of trabeculectomy in the management of chronic open-angle glaucoma.In: Transactions of the New Orleans Academy of Ophthalmology: Symposium on Glaucoma, March 22-26, 1980.1981:295-300.TOdbergVisual field prognosis in advanced glaucoma. A long-term clinical follow-up.Acta Ophthalmol (Copenh).1993;71:721-726.LKMaoWCStewartMBShieldsCorrelation between intraocular pressure control and progressive glaucomatous damage in primary open-angle glaucoma.Am J Ophthalmol.1991;111:51-55.PFPalmbergScar wars.In: Bass SF, Franklin RM, eds. Transactions of the New Orleans Academy of Ophthalmology.Amstelveen, the Netherlands: Kugler Publications; 1993:131-137.KMJoosMJBuechePFPalmbergOne year follow-up results of combined mitomycin C trabeculectomy and extracapsular cataract extraction.Ophthalmology.1995;102:76-83.PFPalmbergCombined cataract and glaucoma surgery with mitomycin.Ophthalmol Clin North Am.1995;8:365-381.RKParrishDMinckler‘Late' endophthalmitis: the filtering surgery time bomb.Ophthalmology.1996;103:1167-1168.Accepted for publication November 19, 1997.This study was supported in part by a fellowship from the Heed Ophthalmic Foundation, Cleveland, Ohio (Dr Scott); the Ronald G. Michels Fellowship Foundation, Baltimore, Md (Dr Scott); Public Health Service grant EY10900 from the Department of Health and Human Services, Bethesda, Md; the Kaster family trust; Mary Mikesell Mapp; the Anthony Abraham Foundation, Miami, Fla; the Perlberg family; and a grant from Research to Prevent Blindness Inc, New York, NY.Corresponding author: Paul F. Palmberg, MD, PhD, Bascom Palmer Eye Institute, PO Box 016880, Miami, FL 33101-6880.

Lewallen, Susan; Taylor, Terrie E.; Molyneux, Malcolm E.; Semba, Richard D.; Wills, Bridget A.; Courtright, Paul

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.293pmid: 9514481

ObjectiveTo investigate the relationship between serum vitamin A levels and conjunctival impression cytology and retinal whitening present in Malawian children with cerebral malaria.MethodsStandard retinal examination and conjunctival impression cytology were performed at hospital admission on 101 consecutively admitted children with cerebral malaria. Blood samples were drawn from 56 children at 24 hours, frozen at −20°C, and transported for assessment of vitamin A levels by high-performance liquid chromatography. Associations among fundus findings and vitamin A measurements were sought.ResultsThe whitening of the retina that we have previously described in children with cerebral malaria was found to be associated with a mean±SD serum vitamin A level of 0.29±0.1 µmol/L, compared with a mean vitamin A level of 0.41±0.2 µmol/L in children without retinal whitening. Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times more likely to have abnormal conjunctival impression cytology results than those without whitening. No child had any clinical or ophthalmologic evidence of chronic vitamin A deficiency.ConclusionsThe retinal whitening described in children with cerebral malaria is associated with low serum vitamin A levels and with abnormal conjunctival impression cytology results and may be due to acute vitamin A deficiency at the tissue level.MORE THAN 500 million people live in areas where malaria is endemic.Cerebral malaria is one of the most severe syndromes of infection by Plasmodium falciparum. In sub-Saharan Africa, malaria is responsible for death in 1 in 20 children younger than 5 years.We have described changes in the appearance of the ocular fundus in children with cerebral malaria,these changes being predictive of outcome.One of the most distinctive of the features was a mosaic pattern of whitening of the retina; this occurs either in the macula or outside the arcades, in the midperipheral retina. Children with extramacular whitening had a relative risk of poor outcome (death or neurologic sequelae) 2.2 times (95% CI, 1.2-3.8) higher than those without this finding.Occasionally the whitening is severe and coalesces into large areas (Figure 1). In these cases, the ophthalmologic appearance bears a striking resemblance to commotio retinae. The appearance of commotio retinae is due to trauma-induced abnormalities in the outer segment of the rods and cones.In animal models, the outer segments of the rods are known to show degeneration in vitamin A deficiency.Figure 1.A severe case showing midperipheral whitening that is confluent in some areas, resembling commotio retinae.In the past few decades, the important role of vitamin A in host defense against infection has become increasingly well recognized. Vitamin A deficiency, even subclinical deficiency, has been shown to cause reduced childhood survival and to increase the incidence and severity of several infectious diseases; specifically, measles, diarrheal disease, urinary tract infections, otitis media, and possibly respiratory disease.One of the difficulties in studying vitamin A is that there is no one best measure of vitamin A status. The various techniques available for assessing vitamin A, along with their limitations, are well described.Serum vitamin A levels do not necessarily reflect total body stores of vitamin A and they may drop precipitously in the face of febrile illness; specifically, they have been shown to fall to very low levels during malaria attacks, even in subjects who are not likely to be vitamin A deficient.Compared with serum vitamin A measurements, the conjunctival impression cytology technique may be a better measure of target tissue sufficiency of vitamin A. However, while it has been shown to be useful in measuring the vitamin A status of populations,its usefulness in individual patients has been questioned.We studied both serum vitamin A levels and conjunctival impression cytology results in the context of detailed clinical and ophthalmologic assessments in children with cerebral malaria enrolled in the Malaria Research Project in Blantyre, Malawi, in 1993 and 1994, and present an analysis of the findings.PATIENTS AND METHODSThe patients in this study were a consecutive subset consisting of two thirds of the patients enrolled in the Malaria Research Project at the Queen Elizabeth Central Hospital in Blantyre during 1992 and 1993, as part of a multicenter trial comparing artemeter with quinine in the treatment of cerebral malaria. Inclusion criteria and clinical assessments have been described elsewhere.Permission for this study was granted by the Health Science Research Committee of Malawi and children were enrolled only after informed consent was given by the child's guardian. Briefly, children were admitted if they had P falciparummalaria on blood smear, had a coma score of at least 2 on the Blantyre Coma Scale, and had no other cause of illness identified on clinical or laboratory assessment, which included culture of blood and cerebrospinal fluid. The examination on hospital admission included examination of the external eye by penlight and funduscopic inspection (after pupillary dilation) by indirect ophthalmoscopy by one ophthalmologist (S.L.); results were recorded on a standard form. Conjunctival impression cytology was performed on hospital admission according to previously described methods.Briefly, vacuum pump–held precut filter paper circles were applied to the temporal conjunctiva of each eye, placed immediately in fixative and stained with periodic acid–Schiff reagent and Harris hematoxylin, then read in a masked fashion by 2 trained observers (S.L. and P.C.) and graded (based on the presence of goblet cells) as normal, abnormal, or unreadable. Problems with purity of reagents necessitated restaining of a number of conjunctival impression cytology samples. Plasma samples were collected at 24 hours after hospital admission and frozen at −20°C. Samples were transported after several months via liquid nitrogen dry shipper to Baltimore, Md, where one investigator (R.S.) measured vitamin A in a masked fashion using high-performance liquid chromatography.Vitamin A reference standards from the National Institute of Standards and Technology, Gaithersburg, Md, and pooled vitamin A reference standards were run with the study samples to monitor accuracy.RESULTSWe performed retinal examinations and conjunctival impression cytology on 101 children. Fifty-six of these were consecutive admissions and had serum samples available for vitamin A measurement.Thirty-five (35%) of the children had retinal whitening. In 15 the whitening was confined to the macula, in 3 it was extramacular only, and in 17 there was both macular and extramacular whitening.Serum vitamin A concentrations ranged from 0.06 to 0.84 µmol/L, with a mean±SD of 0.37±0.15 µmol/L and a median of 0.36 µmol/L. Conjunctival impression cytology results were normal in 65 children, abnormal in 33, and unreadable in 3.Patients with retinal whitening had a mean±SD serum vitamin A concentration of 0.29±0.11 µmol/L, while children without retinal whitening had a mean±SD serum vitamin A level of 0.41±0.16 µmol/L (P=.002) (Table 1). Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times as likely to have an abnormal conjunctival impression cytology result as children without retinal whitening. There was no association between serum vitamin A levels or conjunctival impression cytology results and papilloedema or retinal hemorrhages.Association Between Presence of Retinal Whitening and Vitamin A StatusSee table graphicThe mean±SD serum vitamin A level in children with abnormal conjunctival impression cytology results was 0.34±0.14 µmol/L compared with 0.40±0.16 µmol/L in children with a normal conjunctival impression cytology result (nonsignificant).There was no association between outcome (death) and serum vitamin A concentration. Nine (27%) children with abnormal conjunctival impression cytology results and 13 children (20%) with normal conjunctival impression cytology results died (nonsignificant).COMMENTWe have demonstrated an association between 2 different measures of vitamin A status and the retinal whitening that occurs in children with cerebral malaria. A possible explanation for this association is that the retinal whitening is a consequence of low serum vitamin A levels or reduced vitamin A availability at the tissue level. The retinopathy of vitamin A deficiency in humans has been described as consisting of white or yellow lesions, deep in the retina, patchy or punctate, in the midperiphery, and most pronounced along vessels. The typical whitening we see in cerebral malaria is indeed a patchy mosaic (though not punctate), it is frequently most prominent along vessels, and it is deep in the retina (Figure 2). It is often present in the midperiphery but may also or exclusively involve the macula. This last characteristic differs from reports of vitamin A deficiency retinopathy, which is described as always occurring outside the temporal vascular arcade.We have noted that when the macula is affected in cerebral malaria, the foveola is always completely spared (Figure 3). This could be due to the fact that the foveola is predominantly cones, which do not have the same dependence on vitamin A as do the rods. These considerations, along with our epidemiologic evidence, lend further support to the possibility that the whitening may be a manifestation of vitamin A deficiency at the tissue level. It is not clear, however, whether these children actually have systemic vitamin A deficiency, because the acute-phase reaction itself causes an acute lowering of serum vitamin A concentration.Figure 2.Typical mosaic pattern of whitening in the midperiphery.Figure 3.Whitening in the macula. Note the sparing of the foveola in both a florid case (left) and a more mild case (right).Reported descriptions of retinopathy in vitamin A deficiency are from patients who have decreased vitamin A stores, either due to limited dietary intake of vitamin A or to disease that leads to limited absorption of ingested vitamin A. These patients presumably are in a true state of chronic vitamin A deficiency. None of the children in our study exhibited the macroscopic conjunctival or corneal manifestations of chronic vitamin A deficiency. Some (those with abnormal conjunctival impression cytology results) may well have had mild or moderate vitamin A deficiency, but others (those with normal conjunctival impression cytology results) are likely to have had sufficient vitamin A stores. Acute lowering of serum vitamin A concentration is a feature of the acute-phase responseoccurring in the children in our study, all of whom had low serum vitamin A levels. Children with both normal and abnormal conjunctival impression cytology results showed retinal whitening, although the retinal lesions were more frequent among those with abnormal conjunctival impression cytology results. A possible interpretation of these findings is that an acute drop in serum vitamin A levels, such as occurs in the acute-phase response in malaria, is enough to cause the retina to show the signs resembling those of vitamin A deficiency, especially in children with already impaired tissue vitamin A status (those with abnormal conjunctival impression cytology results).We have followed up several children who manifested retinal whitening during the episode of cerebral malaria and have found that the whitening disappears during a period of weeks to months, leaving no sequelae detectable on funduscopy. The children's diets are not supplemented with vitamin A during or after the malaria episode. If acute vitamin A deprivation causes the retinal lesions, then the rise in serum vitamin A levels associated with the cessation of the acute-phase response is enough to allow the retina to recover.Other recent reports and photographs of fundus findings similar to ours come from Kenyan children with severe malaria. Researchers there found the same pattern of whitening and demonstrated by fluorescein angiography that this is not associated with leakage of vessels.We have examined many children in the same setting with coma and fever from other causes, such as encephalitis, meningitis, and poisoning, who are also undergoing an acute-phase reaction, and have never seen this pattern of whitening except in cases of malaria. We have seen it predominantly in cerebral malaria as opposed to less severe malariaand the retinal whitening is only one component of the spectrum of retinal changes in children with cerebral malaria.It therefore seems likely that additional mechanisms contribute to retinal abnormalities in severe malaria.Our findings raise many questions about the possible role of altered vitamin A metabolism or availability in the pathophysiology and prognosis of cerebral malaria. Nevertheless, we hope that the identification of inverse correlations between retinal whitening and the levels of tissue and serum vitamin A will encourage further investigations into a phenomenon with potentially important therapeutic implications.Not AvailableWorld malaria situation 1990.World Health Stat Q.1992;445:257-266.Not AvailableMalaria Research: An Audit of International Activity.London, England: Wellcome Trust; 1996.SLewallenTETaylorMEMolyneuxBAWillPCourtrightOcular fundus findings in Malawian children with cerebral malaria.Ophthalmology.1993;100:857-861.SLewallenHBakkerTETaylorBAWillsPCourtrightMEMolyneuxRetinal findings predictive of outcome in cerebral malaria.Trans R Soc Trop Med Hyg.1996;90:144-146.JOSipperlyHAQuigleyJDMGassTraumatic retinopathy in primates: the explanation of commotio retinae.Arch Ophthalmol.1978;96:2267-2273.KCHayesRetinal degeneration in monkeys induced by deficiencies of vitamin E or A.Invest Ophthalmol.1974;13:499-510.ASommerKPWest JrVitamin A Deficiency: Health, Survival, and Vision.New York, NY: Oxford University Press; 1996.DIThurnhamRSingkamaniThe acute phase response and vitamin A status in malaria.Trans R Soc Trop Med Hyg.1991;85:194-199.GNatadisastraJRWittpennKPWestNot availableMuhilalLMeleASommerImpression cytology: a practical index of vitamin A status.Am J Clin Nutr.1988;48:695-701.JFuchsSAusayakhunSRuckphaopuntATansuhajRMSuskindRelationship between vitamin A deficiency, malnutrition, and conjunctival impression cytology.Am J Clin Nutr.1994;60:293-298.Not AvailableAssessment of Vitamin A Status and Impression Cytology: Training Manual.Baltimore, Md: International Center Epidemiologic and Preventive Ophthalmology; 1988.GArroyaveCOChichesterHFloresBiochemical Methodology for the Assessment of Vitamin A Status: Report of the International Vitamin A Consultative Group (IVACG).Washington, DC: Nutrition Foundation; 1982.TKHingFurther contributions to the fundus xerophthalmicus.Ophthalmologica.1965;150:219-238.MHeroSHardingCERivaPAWinstanleyNPeshuKMarshPhotographic and angiographic characteristics of retinal appearances in severe malaria in Kenyan children.Arch Ophthalmol.1997;115:997-1003.SLewallenBAWillRetinal haemorrhage in children with malaria.Lancet.1993;341:442.Accepted for publication November 26, 1997.Funding for the vitamin A and conjunctival impression cytology measurements was provided by the International Eye Foundation, Bethesda, Md, the Hoffmann-LaRoche Sight and Life Programme, Basel, Switzerland, and the US Agency for International Development, Washington, DC (Cooperative Agreement DAN-0045-A-5094-00). Financial support for the care of children with severe and complicated malaria was provided by a grant from the Product Development Unit of the World Health Organization, Geneva, Switzerland.We thank the patients, their parents, and the staff of the Malaria Research Project, the Department of Paediatrics of the College of Medicine, University of Malawi, and the Senior Medical Superintendent of the Queen Elizabeth Central Hospital, Blantyre (Ministry of Health and Population, Government of Malawi), for encouragement and permission to conduct the study.Reprints: Susan Lewallen, MD, British Columbia Centre for Epidemiologic and International Ophthalmology, University of British Columbia, St Paul's Hospital, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6.

1998 Archives of Ophthalmology

doi: 10.1001/archopht.116.3.296

In the article titled "MSL-109 Adjuvant Therapy for Cytomegalovirus Retinitis in Patients With Acquired Immunodeficiency Syndrome" published in the December 1997 issue of the ARCHIVES (Arch Ophthalmol. 1997;115:1528-1536), the reported values for the "Increase in retinal area involved by CMV" given in the "Other Visual Outcomes" subsection on page 1532 and in Table 3 on page 1534 are incorrect. The correct values for the MSL-109 group, placebo group, and P are 1.49, 1.55, and .93, respectively.

Kohner, Eva M.; Aldington, Stephen J.; Stratton, Irene M.; Manley, Susan E.; Holman, Rury R.; Matthews, David R.; Turner, Robert C.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.297pmid: 9514482

ObjectivesTo report on the prevalence of retinopathy in patients with newly diagnosed non–insulin-dependent diabetes mellitus (NIDDM) and to evaluate the relationship of retinopathy to clinical and biochemical variables.DesignA multicenter, randomized, controlled clinical study of therapy in patients with NIDDM.Setting and PatientsPatients were part of the United Kingdom Prospective Diabetes Study, a 23-center study of 2964 white patients who had both eyes photographed and assessed.Outcome MeasuresThe presence and severity of diabetic retinopathy were evaluated by sex, and the relationship of retinopathy to medical and biochemical parameters was assessed.ResultsRetinopathy, defined as microaneurysms or worse lesions in at least 1 eye, was present in 39% of men and 35% of women. Marked retinopathy with cotton wool spots or intraretinal microvascular abnormalities was present in 8% of men and 4% of women. The severity of retinopathy was related in both sexes to higher fasting plasma glucose levels, higher systolic and diastolic blood pressure, lower serum insulin levels, and reduced β-cell function. In addition, in men, increased alcohol consumption was related to increased severity of retinopathy, while leaner women had more severe eye lesions. Visual acuity was normal in most patients, but in men there was a trend for those with more severe retinal lesions to have worse visual acuity.ConclusionsDiabetic retinopathy is common in patients with newly diagnosed NIDDM. Careful ophthalmic assessment at diagnosis is important.THE UNITED Kingdom Prospective Diabetes Study (UKPDS) is a multicenter, randomized, controlled clinical trial of therapy in patients with newly diagnosed non–insulin-dependent diabetes mellitus (NIDDM) that aims to determine whether improved blood glucose control will prevent microvascular and macrovascular morbidity and mortality and whether any specific therapy is advantageous or disadvantageous. Details of the study design and randomization have been described previously.In brief, patients with newly diagnosed NIDDM were treated for 3 months with diet only, and if the fasting plasma glucose level was not adequately controlled at the end of this time, were randomized into treatment by diet only, oral agents, sulfonylureas (chlorpropamide, glyburide, or glipizide), or insulin. In addition, obese patients (≥120% of ideal body weight) were also randomized to be treated with the biguanide agent metformin. The study started in 1977, and retinal photography was included during 1983.This report describes the retinal status of the patients at entry into the UKPDS and relates this to various clinical and biochemical variables. This gives insight into possible risk factors for the development of retinopathy and highlights the importance of full medical and eye examination at diagnosis of NIDDM.PATIENTS AND METHODSPatients with newly diagnosed NIDDM (fasting plasma glucose level >6 mmol/L [>108 mg/dL] on 2 occasions) between the ages of 25 and 65 years were recruited into the study between 1977 and 1991. Exclusion criteria were severe vascular disease, accelerated hypertension, preproliferative or proliferative or previously photocoagulated retinopathy, renal failure (serum creatinine level >175 µmol/L [>2.0 mg/dL]), life-threatening disease, disease requiring steroid treatment, or occupation precluding treatment with insulin (eg, bus driver). The patients gave informed consent, and the study was approved by the ethics committee of each participating center.A total of 5102 patients were recruited into the study. Of these, 4177 were white, while the others were mostly Asian from the Indian subcontinent or Afro-Caribbean. The present analysis deals only with the 2964 whites who entered after 1983 (when retinal photography started) and who had both eyes photographed and assessed.EYE EXAMINATIONBest corrected visual acuity was measured using the Snellen chart and, since 1986, the Early Treatment Diabetic Retinopathy Study logMAR charts.Earlier Snellen chart data were corrected to their equivalent logMAR values. After pupillary dilation, eye examination was carried out using direct ophthalmoscopy. Four standard 30° fields of each eye were photographed in stereo pairs (lateral to macula, macula, disc, and nasal) and analyzed centrally, as described by Aldington et al.All identifying information was masked, and each photograph was allocated a unique identification number. Assessments were carried out in duplicate, with independent adjudication of differences between graders.Photographs were initially assessed for quality and adherence to protocol, then were graded in comparison to Early Treatment Diabetic Retinopathy Study standard photographsfor severity of retinopathy features. Subsequently, a computer algorithm assigned a numerical level to each eye (the modified Wisconsin level),summarizing the severity of the lesions found. A simplified description of the levels allocated is shown in Table 1. As a modified Wisconsin level was assigned to each eye individually, for the purpose of this report, results are categorized based on the worse eye/better eye system.Thus, 10/10 indicates absence of any retinopathy in both eyes; 20/10, microaneurysms in 1 eye only; and 20/20, both eyes with microvascular abnormalities only. Similarly, 31/<31 indicates that the worse eye has some retinal hemorrhages and/or hard exudates in addition to microvascular abnormalities, with the better eye having less retinopathy, while 31/31 also indicates those features, but in both eyes. This yields a possible 21-point scale (10/10 to 75/75) for each patient.Table 1. Retinopathy Grades*See table graphicMEDICAL EXAMINATIONAt entry, a full medical history was obtained, including details of physical activity. Patients were categorized as sedentary (rarely participates in physical activity), moderately active (on their feet less than half the day, weekend exercise only), active (on their feet more than half day, bicycle to work, regular exercise), or fit (manual worker, or regular and vigorous exercise at least 3 times each week). The history also included smoking (never, ex-smoker, current smoker) and alcohol consumption (none, occasional or social, regular, heavy). A full medical examination was carried out, including measurement of height and weight. Body mass index was calculated by dividing the weight in kilograms by the square of height in meters.BIOCHEMICAL MEASUREMENTSEach participating center measured fasting plasma glucose levels. These measurements were monitored by the UKPDS glucose quality assurance scheme, with an interlaboratory coefficient of variation of approximately 4%.All other samples were transported to the coordinating laboratory overnight at 4°C. Assays were monitored by trilevel quality-control serum samples with Westgard rulesfor acceptance and by external quality-control schemes where possible.Analytical methods were upgraded during the study, and data were realigned according to new methods after relevant laboratory comparisons.Data in this report are presented using laboratory methods previously described.Glycosylated hemoglobin levels were measured by high-pressure liquid chromatography (Biorad Diamat automated glycosylated hemoglobin analyzer, Biorad Laboratories Ltd, Hemel Hempstead, England) (normal range, 0.045-0.062 [n=145], 2.5-97.5 percentiles). Urine albumin concentrations were expressed relative to the mean creatinine concentration of 8 mmol/L (90 mg/dL) in women and 11 mmol/L (125 mg/dL) in men to allow for urine dilution.Fasting insulin levels were measured by double antibody radioimmunoassay (PhRIA 100, Pharmacia Ltd, Milton Keynes, England) with 100% cross-reactivity to proinsulin (normal range, 21-111 pmol/L [2.9-15.5 µU/mL]). β-cell function and insulin sensitivity were assessed using fasting plasma glucose and insulin levels by homeostasis model assessment.This assesses, in a structural model of glucose-insulin relationships, the degree of impairment of β-cell function and insulin sensitivity required to produce each patient's fasting plasma glucose and insulin levels. The model was calibrated to give β-cell function and insulin sensitivity of 100% in a group of normal subjects aged 18 to 25 years. Plasma lipid and lipoprotein, urine albumin, and urine creatinine levels were measured by standard laboratory techniques.STATISTICAL ANALYSESAll data were analyzed using software from SAS Institute Incand BMDP Statistical Software Inc.Continuous variables are described in the form mean (SD) if approximately normally distributed or in the form geometric mean (1-SD range) if approximately log-normal. We used a polychotomous logistic regression model to identify important variables and to estimate odds ratios. In detail, this entailed examining the association between retinopathy level and covariates 1 by 1 in a univariate model (procedure PR in the BMDP software) to investigate, for example, whether those with more severe retinopathy at diagnosis had higher levels of plasma glucose. Since the variables measured at diagnosis were not independent, this model was then used, with stepwise selection of variables, to arrive at a subset of variables that together best explained the retinopathy level. The continuous variables chosen by this method were split into quartiles, and the PR procedure was used to calculate the odds ratios. P<.02 was considered statistically significant.RESULTSOf the 4177 white patients, 3315 had baseline photographs, and 3185 (96.1%) of these were taken within the allowed window of 6 months before to 18 months after randomization. In 2972 patients (93.3%), photographs of both eyes could be graded. Photographs of only 1 eye could be graded in 112 patients (3.5%), and in 101 patients (3.2%) neither eye was gradable. Eight patients had photocoagulation before randomization; these patients were excluded from the analyses. The data presented, therefore, are for the 2964 patients in whom both eyes were graded. The quality of the photographs was high; only 1.7% of photographs temporal to the macula, 3.5% of the macula photographs, 2.5% of the disc photographs, and 5.5% of the nasal photographs could not be graded. In these patients, retinopathy level was assigned on the basis of the remaining fields.Lesions other than diabetic retinopathy were present in some eyes. The most common of these were extensive drusen, present in 270 eyes; a nevus in 52 eyes, pigment epithelial defects in 55 eyes, and retinal branch vein occlusion in 5 eyes. None of these conditions or other nondiabetic conditions excluded grading for diabetic retinopathy.RETINOPATHY PREVALENCERetinopathy was present in 39% of the men and 35% of the women. However, 19% of the men and 20% of the women had microaneurysms in 1 eye only, with no other features of diabetic retinopathy. In most of these patients (97%) there were only 3 or fewer microaneurysms. More severe forms of retinopathy were significantly more common in men (χ2for trend, P<.001), with a retinopathy grade of 41/<41 or more severe in 7.9% of men and 4.5% of women (Table 2).Table 2. Retinopathy Distribution by Sex*See table graphicDemographic and Clinical VariablesDemographic and clinical results are shown in Table 3. Women were older and more obese at diagnosis and had higher blood pressure than men. They had higher fasting plasma glucose levels (P<.001) and slightly higher glycosylated hemoglobin levels (P<.02). Plasma cholesterol levels and both high-density lipoprotein and low-density lipoprotein cholesterol levels were higher in women (P<.001 for all). Women also had higher insulin levels and were more insulin resistant (P<.001 for both). Women were less active but smoked and drank less than men; more women were treated with diuretic agents, and more were receiving antihypertensive therapy (P<.001 for all).Table 3. Biometric and Biochemical Variables in Subjects With Retinal Photographs at Diagnosis of Type 2 DiabetesSee table graphicUNIVARIATE ASSOCIATION OF RETINOPATHY WITH CLINICAL AND BIOCHEMICAL VARIABLESIn both sexes the presence and severity of retinopathy and demographic variables were associated univariately (Table 4), with higher fasting plasma glucose levels (P=.02 for men, P=.002 for women) and higher systolic (P=.006 for men, P<.001 for women) and diastolic (P=.009 for men, P=.004 for women) blood pressures. More severe retinopathy was also associated with lower plasma insulin levels (P=.005 for men, P=.002 for women) and reduced β-cell function (P<.001 for men and women). In addition, in men, higher high-density lipoprotein cholesterol levels (P=.009) and increased alcohol consumption (P=.005) were also associated with more severe retinopathy, while in women there was a significant trend for those who were leaner (P=.005) and who had higher glycosylated hemoglobin levels (P=.005) to have more severe lesions. Triglyceride levels, low-density lipoprotein cholesterol levels, smoking, physical exercise, treatment with antihypertensive or diuretic therapy, and, in women, hormone replacement therapy did not appear to be related to severity of retinopathy.Table 4. Severity of Retinopathy Related to Medical and Biochemical ParametersSee table graphicWhen patients (both men and women) with microaneurysms in only 1 eye (level 20/10) were compared with those who had no retinopathy (level 10/10), they were not significantly different in any of the clinical variables. When they were compared with patients who had more severe retinopathy (levels ≥20/20), there were some differences (Table 4), suggesting that patients with a retinopathy level of 20/10 resembled those without retinopathy.MULTIVARIATE ANALYSIS OF ASSOCIATIONS OF RETINOPATHY WITH CLINICAL AND BIOCHEMICAL VARIABLESTable 5presents the results of a polychotomous logistic regression analysis that associates increasing severity of retinopathy with variables commonly measured in routine clinical practice, blood pressure and fasting plasma glucose level. After adjusting for systolic blood pressure and fasting plasma glucose level, female subjects presented with less severe retinopathy at diagnosis. The risk of increasing severity of retinopathy increased with higher fasting plasma glucose level and was about 30% higher for those in the top half of the distribution. The odds ratio for systolic blood pressure rose steadily with each quartile of systolic blood pressure: 11% higher in the second quartile, 23% higher in the third quartile, and 31% higher for the top quartile.Table 5. Polychotomous Stepwise Logistic Regression Model to Examine the Relationship of Sex, Fasting Plasma Glucose Level, and Systolic Blood Pressure to Increasing Severity of Diabetic Retinopathy*See table graphicA stepwise procedure was used to determine which variables found to be significant in the univariate model were significant in the multivariate model. After adjusting for sex, 3 variables remained in the model: β-cell function, fasting plasma insulin level, and systolic blood pressure (Table 6). Systolic blood pressure was strongly associated with steadily increasing risk of retinopathy. Fasting plasma insulin level below the top quartile was associated with higher levels of retinopathy. β-Cell function in the lower half of the distribution was associated with increased risk of retinopathy.Table 6. Polychotomous Stepwise Logistic Regression Model to Examine the Relationship of Fasting Plasma Insulin Level, β-Cell Function, and Systolic Blood Pressure to Increasing Severity of Diabetic Retinopathy*See table graphicVISUAL ACUITYThe great majority of patients had normal visual acuity of 0.0, 0.1, or less than 0.2 on the logMAR chart (6/5 or better and 6/6 on the Snellen chart) in their worse eye at diagnosis (Table 7). Among the men, there was a significant trend for worsening visual acuity with increasing retinopathy severity (P=.005). There was no similar relationship among the women. Visual acuity was worse in the women than in the men (P<.001).Table 7. Visual Acuity at Diagnosis Assessed by LogMAR Score and Retinopathy GradeSee table graphicCOMMENTAmong white patients with newly diagnosed NIDDM referred from primary care physicians, diabetic retinopathy was present at diagnosis in 39% of the men and 35% of the women. This figure is consistently higher than in other studies, which have recorded prevalences of retinopathy at diagnosis of 18% to 22%.Most previous studies used ophthalmoscopy for the diagnosis of diabetic retinopathy. Even when it is performed by skilled observers, 1 to 3 microaneurysms may well be missed on ophthalmoscopy. It could be argued that a few microaneurysms without any other lesions do not indicate diabetic retinopathy. Klein et alreported finding microaneurysms among subjects without diabetes. The fact that the clinical characteristics of patients with microaneurysms in only 1 eye resembled those of patients without retinopathy suggests the possibility that the microaneurysms were an incidental finding. However, follow-up of these patientsindicates that microaneurysms alone are important predictors of progression to more severe retinopathy. Furthermore, the 4- and 10-year follow-up data of Wisconsin patients with microaneurysms onlyalso emphasizes the importance of microaneurysms as a risk factor for both proliferative retinopathy and macular edema. It is unlikely that these patients had undiagnosed diabetes for a longer period than patients in other studies,as the National Health Service enables patients to present early without financial disincentives. Furthermore, primary care physicians were encouraged to send all their newly diagnosed patients to the hospital in the districts of the participating centers.Increased systolic and diastolic blood pressures were associated with the severity of retinopathy. This might signify that patients with microvascular disease in the retina may also have renal involvement and secondary higher systolic blood pressure. However, increased urine albumin concentrations showed only a weak association with retinopathy in women and no association in men, and albuminuria was not included in the multivariate model. The data therefore suggest that higher systolic blood pressure per se is probably an important determinant of retinopathy. This is in accordance with the theory that hypertension, by increasing retinal blood flow, is important in the evolution of diabetic retinopathy.Retinopathy was also associated with increased fasting plasma glucose levels in women and showed a similar trend in men. This would have been anticipated from the Diabetes Control and Complications Trialand the Kumamoto study.Measurement of β-cell function from fasting glucose and insulin levels by homeostasis model assessmentshowed an even stronger relationship of retinopathy with impaired β-cell function. Since the increasing hyperglycemia of NIDDM is associated with progressive deterioration of β-cell function,it is possible that the assessment of β-cell function provides a better guide to the severity of diabetes and the hyperglycemic exposure over the previous years than the measurement of fasting plasma glucose and glycosylated hemoglobin levels at a single clinic visit. The lesser association of retinopathy with these indices of glycemia might in part be because some patients had already restricted their diet between the time when the diagnosis was suspected by their primary care physician and their first clinic visit.Retinopathy was more prevalent in men than women, but this could not be explained by the major risk factors, since women had higher blood pressure and glucose levels than men. Men were less obese than women, but body mass index was not related to the presence or severity of retinopathy in men, while in women the leaner subjects had more severe retinopathy. Retinopathy was not associated with greater impairment of insulin sensitivity, although this has been suggested in a small study of NIDDM patients using clamp studies.Other factors thought to be of importance in some previous studies, such as smokingand exercise, were not found to be important. These results emphasize the importance of large studies for obtaining definitive data.In conclusion, diabetic retinopathy was common in patients with newly discovered NIDDM, although much of this was restricted to just a few microaneurysms in 1 eye only. This high prevalence underlines the importance of detailed ophthalmic investigation of newly diagnosed patients. The major associated variables were higher systolic blood pressure and hyperglycemia. Ongoing large-scale trials—the Hypertension in Diabetes Study,in which patients have been allocated to improved blood pressure control, and the UKPDS, in which patients are allocated randomly to improved glucose and blood pressure control—will determine whether careful attention to these risk factors will reduce the incidence of related clinical end points, such as reduced visual acuity and need for photocoagulation.United Kingdom Prospective Diabetes Study GroupUK Prospective Study of Therapies of Maturity-Onset Diabetes, I: effect of diet, sulphonylurea, insulin or biguanide therapy on fasting plasma glucose and body weight over 1 year.Diabetologia.1983;24:404-411.United Kingdom Prospective Diabetes Study GroupUK Prospective Study, VIII: study design progress and performance.Diabetologia.1991;34:877-890.FLFerris IIIAKassoffGHBresnickIBaileyNew visual acuity charts for clinical research.Am J Ophthalmol.1982;94:91-96.SJAldingtonIMStrattonRRHolmanHJLipinskiEMKohnerAssessment of Diabetic Retinopathy in the United Kingdom Prospective Diabetes Study (UKPDS).Springfield, Va: National Technical Information Service.In press.Not AvailableClassification of diabetic retinopathy: detailed grading of stereo-color photographs.In: Early Treatment of Diabetic Retinopathy Study Manual of Operations.Baltimore, Md: Early Treatment of Diabetic Retinopathy Study Coordinating Center, Dept of Epidemiology and Preventive Medicine, University of Maryland; 1985:chap 18.BEKKleinMDDavisPSegalAssessment of severity and progression of diabetic retinopathy.Ophthalmology.1984;91:10-17.RKleinBEKKleinSEMossMDDavisDLDeMetsThe Wisconsin Epidemiologic Study of Diabetic Retinopathy, II: prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.Arch Ophthalmol.1984;102:520-526.JOWestgardPLBarryMRHuntA multi-rule Shewart chart for quality control in clinical chemistry.Clin Chem.1981;27:493-501.UK Prospective Diabetes Study GroupUK Prospective Study, 11: biochemical risk factors in type II diabetic patients at diagnosis compared with age matched normal subjects.Diabet Med.1994;11:534-544.DRMatthewsJPHoskerASRudenskiBANaylorDFTreacherRCTurnerHomeostasis model assessment: insulin resistance and beta cell function from fasting plasma glucose and insulin concentration in man.Diabetologia.1985;28:412-419.SAS Institute IncSAS/STAT Users Guide.Cary, NC: SAS Institute Inc; 1989:851-859, 1071-1126.BDMP Statistical Software IncBMDP Statistical Software[computer program].Berkeley: University of California Press; 1990.ADorfEJBallintinePHBennettMMillerRetinopathy in Pima Indians: relationship to glucose level, duration of diabetes, age at diagnosis of diabetes and age at examination in a population with high prevalence of diabetes mellitus.Diabetes.1976;25:554-560.DROwensAVolundDJonesRetinopathy in newly presenting non insulin dependent diabetic patients.Diabetes Res.1988;9:59-62.RKleinBEKKleinSEMossQWangHypertension and retinopathy, arterial narrowing, and arteriovenous nicking in a population.Arch Ophthalmol.1994;112:92-98.DRMatthewsEMKohnerSJAldingtonIStrattonRelationship of microaneurysm count to progression of retinopathy over 6 years in non-insulin dependent diabetes.Diabetes.1995;9(suppl 1):117A.RKleinSMMeuerSEMossBEKKleinThe relationship of retinal microaneurysm counts to the 4-year progression of diabetic retinopathy.Arch Ophthalmol.1989;107:1780-1785.RKleinSMMeuerSEMossBEKKleinRetinal microaneurysm counts and 10-year progression of diabetic retinopathy.Arch Ophthalmol.1995;113:1386-1392.MIHarrisRKleinTAWelbornMWKnuimanOnset of NIDDM occurs at least 4-7 years before clinical diagnosis.Diabetes Care.1992;15:815-819.VPatelSRassamRNewsomJWiekEMKohnerRetinal blood flow in diabetic retinopathy.BMJ.1992;305:678-683.SMBRassamVPatelEMKohnerThe effect of experimental hypertension on retinal autoregulation in humans: a mechanism for the progression of diabetic retinopathy.Exp Physiol.1995;80:53-68.The Diabetes Control and Complications Trial Research GroupThe effect of intensive treatment of diabetes on development and progression of long term complications in insulin dependent diabetes mellitus.N Engl J Med.1993;329:977-986.YOhkuboHKishikawaAArakiIntensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomised prospective 6 year study.Diabetes Res Clin Pract.1995;28:103-117.United Kingdom Prospective Diabetes Study GroupUK Prospective Study, 16: overview of 6 year therapy of type 2 diabetes: a progressive disease.Diabetes.1995;44:1249-1258.FManeschiKMashiterEMKohnerInsulin resistance and insulin deficiency in diabetic retinopathy of non-insulin dependent diabetes.Diabetes.1983;32:82-87.JMWalkerDHCoveDGBeeversCigarette smoking, blood pressure and the control of blood glucose in the development of diabetic retinopathy.Diabetes Res.1985;2:183-186.IMuhlhauserPSawickiMBergerCigarette smoking as a risk factor macroproteinuria and proliferative retinopathy in type 2 insulin dependent diabetes.Diabetologia.1986;29:500-502.The Hypertension in Diabetes Study GroupHypertension in diabetes, I: prevalence of hypertension in newly presenting type 2 diabetic patients and the association of risk factors for cardiovascular and diabetic complications.J Hypertens.1993;11:309-317.Accepted for publication December 1, 1997.This work was supported by grant 2 UO1 EY07049-09 from the National Eye Institute, Bethesda, Md; by grants from the British Diabetic Association, London, England; Medical Research Council, London; National Institutes of Digestive Disorders and Kidney Disease, National Institutes of Health, Bethesda, Md; United Kingdom Department of Health, London; British Heart Foundation, London; by grants from pharmaceutical companies, including Bayer AG, Leverkeusen, Germany; Bristol-Myers Squibb Co, Princeton, NJ; Hoechst-Roussel Pharmaceuticals Inc, Somerville, NJ; Eli Lilly & Co, Indianapolis, Ind; Novo-Nordisk Pharmaceuticals Inc, Princeton, NJ; Lipha, Lyons, France; and Farmitalia Carlo Erba, Milan, Italy; and by grants from additional companies, including Securicor Plc, Sutton, England; Eastman Kodak Co, Rochester, NY; and Cortecs Diagnostics, Clwyd, Wales.Participating centers included the Royal Infirmary, Aberdeen, Scotland; City Hospital, Belfast, Northern Ireland; Royal Victoria Hospital, Belfast; General Hospital, Birmingham, England; St Helier Hospital, Carshalton, England; Derbyshire Royal Hospital, Derby, England; Ninewells Hospital, Dundee, Scotland; Royal Devon and Exeter Hospital, Exeter, England; Ipswich Hospital, Ipswich, England; Leicester General Hospital, Leicester, England; St George's Hospital, London; Hammersmith Hospital, London; Whittington Hospital, London; Royal Infirmary, Manchester, England; Northampton General Hospital, Northampton, England; Norfolk and Norwich Hospital, Norwich, England; Radcliffe Infirmary, Oxford, England; Peterborough Hospital, Peterborough, England; Hope Hospital, Salford, England; Lister Hospital, Stevenage, England; North Staffordshire Royal Infirmary, Stoke-on-Trent, England; Torbay Hospital, Torbay, England.Reprints: Eva M. Kohner, MD, Department of Endocrinology, Diabetes & Metabolic Medicine, Division of Medicine, UMDS Guy's and St Thomas's Medical and Dental School, Fourth Floor, North Wing, St Thomas's Hospital, Lambeth Palace Road, London SE1 7EH, England.

Finger, Paul T.; Romero, Juan M.; Rosen, Richard B.; Iezzi, Raymond; Emery, Richard; Berson, Anthony

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.305pmid: 9514483

ObjectiveTo evaluate the use of 3-dimensional (3D) ultrasonography for the localization of episcleral eye plaques during the treatment of choroidal melanomas.MethodsA series of 13 patients with choroidal melanoma were treated with radioactive palladium 103 seeds affixed into gold eye plaques. During surgery, 3D ultrasonography was performed with a commercially available system to evaluate the relative position of radioactive plaques secured beneath their intraocular tumors. This system consists of an automated, rotating, handheld, B-scan ultrasonographic probe operating at 10 MHz, a personal computer, and 3D imaging software.ResultsWe measured the margins of the plaque extending beyond the tumor and the distance between the radioactive seeds and the tumor apex. We also evaluated the relationship between the plaque edge, the episclera, and the tumor's edges. While the plaques were well centered over the tumor in all cases, the plaque margins around the tumor were found to be variably sized. When comparing measurements taken at the time of plaque insertion with those taken at the time of plaque removal, we noted changes in the apical tumor height and in plaque centration. In the 1 patient with a juxtapapillary tumor, the posterior margin of the plaque was found to be displaced away from the sclera, or "tilted."ConclusionsThree-dimensional ultrasonography offers a new method for ophthalmic plaque localization. Unique perspectives can be visualized through the use of computer-aided 3D reconstructions that permit the assessment of the relative position of the plaque to the optic nerve and the measurement of the distance between the in vivo radioactive seed and the tumor apex. Our experience suggests that when compared with 2-dimensional ultrasonography, 3D ultrasonography offers new capabilities that can be used to improve plaque placement and radiation dose calculations.EPISCLERAL plaque brachytherapy is the most frequently used "eye-sparing" treatment for choroidal melanoma.In North America, eye plaques primarily consist of iodine 125 seeds affixed in a bowl-shaped gold shell. The gold of the eye plaque blocks most irradiation traveling in any direction other than toward the episcleral surface. Thus, gold eye plaques are safer, with less irradiation of normal ocular structures and less exposure to operating room personnel.Directional, low-energy (125I and palladium 103) irradiation also requires the precise localization of the ophthalmic plaque onto the sclera, over the tumor's base.To date, the accurate surgical placement of episcleral plaques (to cover their intraocular tumor) has relied on marking the transillumination shadow of the intraocular tumor, indirect ophthalmoscopy with scleral depression around the plaque, and 2-dimensional (2D) intraoperative ultrasonography.In most cases, transillumination with visualization of an anterior tumor shadow can be performed with ease and offers an excellent method to ensure proper plaque localization. Small choroidal melanomas located in the posterior uvea are the most difficult to localize and are associated with the highest rate of irradiation failure.To ensure proper plaque localization of small posterior tumors, ophthalmic oncologists commonly use ophthalmoscopy with scleral depression, 2D ultrasonography (2D-US), or both. Magnetic resonance imaging has also been used to investigate plaque placement for radiotherapy.Because plaque placement is critical to successful radiotherapy of a choroidal melanoma, and because reports suggest that failure of local control may reduce a patient's chance of survival, there is a need for improved methods to confirm proper plaque placement at the time of plaque insertion.This study investigates the usefulness of 3-dimensional ultrasonography (3D-US) for imaging radioactive plaques during radiotherapy. We describe how we measured the relative position of the eye plaques over their intraocular tumors and how computer-aided reconstructions can create new perspectives not previously available with 2D-US.PATIENTS AND METHODS3D ULTRASONOGRAPHYThree-dimensional ultrasonographic studies were performed using a commercially available system (3D i-scan, Ophthalmic Technologies Inc, Toronto, Ontario). Three-dimensional ultrasonography uses a conventional brightness mode transducer combined with a motorized, rotating holder and computerized image processing (Figure 1). During data acquisition, the transducer is rotated while 1802D images are collected and processed by the computer to form a 3D image. After acquisition, it is possible to view and manipulate the 3D image interactively. Because the 3D image can be rotated and sliced, it reveals unique 2D images derived from new perspectives (Table 1).Figure 1.Diagrammatic representation of 3-dimensional image formation (from Downey et al).Table 1. Two-Dimensional vs 3-Dimensional UltrasonographySee table graphicThe B-scan ultrasonographic probe operates at a frequency of 10 MHz, with an axial resolution of 0.1 mm. The focal point is 25 mm, with a total image depth of 50 mm. For image processing, the proprietary software (3D i-scan) was run on a personal computer (Power MacIntosh 7500/100, Apple Computers, Cupertino, Calif). The acquisition and reconstruction times were 7.5 and 6.0 seconds, respectively. All 3D-US measurements were made at an almost equivalent sound velocity of 1532 m/s compared with 1550 m/s used for standardized A-scan ultrasonographic images.This difference was not thought to have an effect on this study in our measurements of heights, widths, lengths, or volumes (Table 1).ACCURACY AND REPRODUCIBILITYFisher et alhave studied the accuracy and reproducibility in vitro of measurements with this 3D-US system. The largest error (±SD) for repeated measurements was as follows: 0.02% (±0.06%) for linear measurements, 14.00 (±6.81) mm2for area measurements, and 19.0 (±18.4) mm3for volume measurements.For this study, one of us (J.M.R.) studied the intraobserver variability in vivo of measurements of intraocular tumors during radioactive plaque therapy. The SD for repeated measurements was found to be 0.2 mm for tumor diameter, 0.1 mm for tumor height, 7.8 mm3for tumor volume, 0.4 mm for plaque margins around the tumor, and 0.1 mm for the distance between the radioactive seeds and the tumor apex.PATIENTSBecause 2D-US is commonly used to aid in plaque placement, and because the methods of accession of 3D-US were essentially equivalent, no international review board approval or informed consent was considered necessary.In this series, 13 patients not included in the Collaborative Ocular Melanoma Study underwent ultrasonography. Patients were selected for 3D-US in addition to 2D-US based on the availability of the ultrasonograph. All tumors were treated at the Ocular Tumor Service, the New York Eye and Ear Infirmary, New York City, between October 1996 and August 1997; all patients underwent ophthalmic plaque brachytherapy, which was performed by one of us (P.T.F.). The following data were obtained from the patient medical records: affected eye, tumor location, shortest distance between the tumor and the fovea and between the tumor and the optic nerve, plaque size, and prescription point (tumor height measured as the distance between the tumor apex and the inner sclera, as measured by a preoperative A-scan ultrasonographic image) (Table 2). As possible, 3D-US was performed immediately after plaque insertion or just prior to plaque removal.Table 2. Case Characteristics*See table graphicPLAQUE DESIGN AND CONSTRUCTIONStandard eye plaques (Trachsel Dental Studio Inc, Rochester, Minn) were chosen (in part) to provide standard dimensions that could be compared with those obtained during our study and repeated in other centers. The radioactive plaque diameters in this series were as follows: 12 mm (2), 14 mm (6), 16 mm (1), 18 mm (3), and 20 mm (1). Plaques were made radioactive by affixing 103Pd seeds (model 200, Theragenics Corp, Norcross, Ga) onto the inner wall of the plaques with a thin layer of dental acrylic fixative (Figure 2).Figure 2.A cutaway illustration of the relative positions of a standard Collaborative Ocular Melanoma Study–type ophthalmic plaque and seeds secured to the episclera beneath an intraocular tumor.The calculated seed-to-tumor apex distance (STAD) is defined as the distance between the central axis of the seed located in the middle of the gold plaque and the apex of the tumor. The actual dose of radiation is calculated based on the relative location of all the seeds affixed within the plaque. The calculated STAD for this study was determined as follows: the tumor height (determined by A-scan ultrasonography)+1.00 mm of sclera (the Collaborative Ocular Melanoma Study default value)+1.4 mm of acrylic fixative in front of the seed (measured value)+0.4 mm (half the thickness of the seed).PLAQUE INSERTION AND REMOVALAll patients underwent ophthalmic plaque insertion while under general anesthesia. After the patient was draped and the affected eye was isolated, indirect ophthalmoscopy was performed to confirm the presence, location, and condition of the eye and tumor. Then, a 360° conjunctival peritomy was performed at the corneal-scleral limbus, the Tenon fascia was opened with curved Steven scissors, and the rectus muscles were isolated as needed. In some cases, muscle disinsertion was necessary. In most cases, transillumination could be used to delineate the anterior tumor margins. Direct, transpupillary, and transocular transillumination techniques were employed. A surgical marking pen was used to mark the edges of the transillumination shadow on the episclera. Then, a 2- to 3-mm shadow-free margin was marked on the episclera around the tumor's base. A minimum of 4 interrupted episcleral sutures were used to anchor the plaque to the sclera, with its edges covering the tumor and its shadow-free margin (Figure 2). At this time, epibulbar contact 3D-US was performed. In this series, the information obtained by the 3D-US examination was not used to center the plaque. At the end of the procedure, the muscles were affixed to the sclera in positions and at tensions thought not to affect the plaque position. Last, the conjunctiva was closed. After radiotherapy, the plaques were removed while the patients were under local anesthesia.SCANNING TECHNIQUEAt the time of scanning, the patients were on the operating table and in a supine position. Intraoperative localization involved placing the probe into a sterile plastic bag containing coupling gel. Saline solution was irrigated onto the surface of the globe. Postoperative confirmation of plaque position usually involved direct placement of the ultrasonographic probe on the eyelid and coupling gel. Because eyelid tissue is not a refractive surface for ultrasonography, we did not expect this difference to notably affect our measurements. A minimum of 2 sets of data were acquired for each eye plaque. One was oriented in a transverse direction, and a second was oriented in a longitudinal direction; both were centered in the meridian of the location of the intraocular tumor and plaque.RESULTSIN VITRO IMAGE ASSESSMENTIn vitro imaging of an eye plaque with dummy (nonradioactive) seeds was performed in 7% glycerin at room temperature (Figure 3). This phantom material was used because it was acoustically equivalent to vitreous (the speed of sound in vitreous=1532 m/s). During this study, we were able to define 3 echogenic interfaces corresponding to the surface of the acrylic fixative, the seeds, and the posterior wall of the plaque. The plaque's edges could also be identified and measured to be equivalent to the known diameter of the plaque. This in vitro experience confirmed our opinion about which linear echodensities represented the radioactive seeds in vivo (Figure 3).Figure 3.In vitro images of a 14-mm Collaborative Ocular Melanoma Study–type gold eye plaque in 7% glycerin in water (room temperature). Left, A transverse section of the plaque contains small arrows that indicate the location of the seeds within the plaque. The 2 large arrows indicate the edges of the plaque. The small black arrowheads illustrate the location of the surface of the acrylic fixative and the plaque's posterior surface. Right, A coronal reconstruction of the plaque demonstrates the suture eyelets (white arrows) and the edge of the plaque (black arrow).IN VIVO IMAGE ASSESSMENTOne hundred eighty sequential, stored, 2D images were used to reconstruct the 3D image (Figure 4). Like a 2D image, the 3D image demonstrates the high reflectivity of the gold plaque. Like a 2D image, the highest reflectivity is noted at the plaque's edges and posterior face. These surfaces generate edge distortions as well as shadowing of the structures posterior to the plaque (Figure 4). Unlike a 2D image, the 3D reconstructions demonstrate the volume of plaque-induced shadowing. Edge reflections were found to be important in determining the relative position of the plaque in relation to the tumor and the adjacent structures (such as the optic nerve).Figure 4.A 3-dimensional ultrasonographic reconstruction of an episcleral radioactive plaque in vivo. Characteristics that can be appreciated include the highly reflective back and edge of the plaque and shadowing behind the plaque (arrow).Because the plaque diameter is known prior to insertion, its size was found to be a useful reference to determine the position of the plaque in relation to the tumor's margins. The plaque diameter in the horizontal and vertical planes perpendicular to the plaque circumference was displayed. Measurements of the margin between the plaque's edge and the tumor's borders were determined in each quadrant. A replay of 3D reconstructions allows for the visualization of all the plaque edges and an assessment of the plaque's contact with the sclera. Unlike 2D-US images, 3D-US reconstructions can be visualized from unique perspectives. To demonstrate this property, we have rotated the reconstructed eye to view it from behind and show a unique coronal perspective of the relative positions of a juxtapapillary eye plaque and the optic nerve (Figure 5). This view is not possible with standard 2D-US because ultrasonographic waves cannot pass through orbital bones.Figure 5.Left, A 3-dimensional reconstruction of a radioactive plaque beneath a juxtapapillary choroidal melanoma. This computer-generated reconstruction demonstrates the relationship between the optic nerve (arrow) and the radioactive plaque. The posterior (nasal) edge of the plaque tilts as it rests against the optic nerve. Right, A coronal section demonstrating the plaque (P) next to the optic nerve (ON).TUMOR DIMENSIONSThree-dimensional ultrasonography was performed immediately after plaque insertion in 6 cases and immediately prior to plaque removal in all 13 cases. Measurements of tumor length, width, height, and volume were obtained. Tumors were located in various anterior-posterior and clock positions (Table 2). Case 9 was a juxtapapillary tumor. Tumor shapes were noted to be either dome or collar button. The prescription points ranged between 2.0 and 10.6 mm. Three-dimensional ultrasonographic apical height measurements were measured in a masked manner immediately after plaque insertion and were found to be essentially equivalent (P=.85) (Table 3).Table 3. Comparative Height MeasurementsSee table graphicAlthough most tumor dimensions were noted to increase after radiotherapy, we found that only the changes in height and volume were statistically significant (P=.001 and P=.01, respectively) (Table 4). Without histopathologic correlation, we can only hypothesize that these changes may have been due to acute radiation angiitis or postsurgical inflammation with secondary tumor and scleral thickening.Table 4. Change in Tumor Dimensions During RadiotherapySee table graphicPLAQUE PLACEMENTIn all cases, we found that the tumors were covered by the plaques at the time of imaging (Table 5). While the edges of the plaques were found to be in good contact with the sclera in 12 cases, the plaque covering the juxtapapillary tumor was found to be displaced away from the sclera at the optic nerve margin, or "tilted" (Figure 5). We also found evidence suggesting displacement or "movement" of the eye plaques during treatment (Table 5). In the 6 plaques measured at the time of insertion and the time of removal, the largest measured change at any margin was 2.1 mm (along the temporal margin of case 3). However, because the original margin was 3.1 mm, the plaque continued to cover the tumor. Table 5also demonstrates that the mean changes were in a range from −0.9 to 0.4 mm, and the average of those changes was −0.4 mm. This negative number corresponds (in part) to our observation that the tumor width and length may have increased during the course of radiotherapy (Table 4).Table 5. Plaque Margins at the Time of Insertion and Before Removal*See table graphicSEED-TO-TUMOR APEX DISTANCEOnce sewed to the eye wall, we assessed the position of the plaque in relation to the tumor apex by viewing 2D planes sliced perpendicular to the tumor base. Then, a computer-generated perpendicular line was created to measure the distance from the tumor apex to the layer of seeds within the plaque.In Table 6, we provide the "calculated" STAD prior to surgery (based on presumptions commonly used for plaque dosimetry), the STAD immediately after plaque insertion, and the STAD immediately prior to plaque removal. Unlike standard 2D or A-scan ultrasonographic studies, 3D reconstructions allowed for a measurement of the distance between the radioactive seeds at the middle of the plaque and the tumor's apex (Table 6). Because all the radioactive seeds are affixed to the inner aspect of the plaque's posterior wall, we could (for the first time) calculate the actual distance between the radioactive seeds and points within the tumor at the time of plaque insertion and removal.Table 6. Comparison of the Calculated With the Measured Seed–to–Tumor Apex Distance (STAD)See table graphicOur measured STAD was found to be shorter than our calculated STAD. The calculated STAD was an average of 1.2 mm longer than our measured STAD at the time of plaque insertion and 0.8 mm longer at the time of plaque removal (Table 6). This means that even though the tumors, surrounding tissues, or both were found to enlarge during the course of radiotherapy, the actual dose to the tumor's apex was higher compared with what it might have been determined using the measured STAD at the time of either insertion or removal (Table 6). The increase in the STAD during the course of treatment could be attributed to acute vasocongestion and edema as a result of surgery, irradiation, or both. However, changes in the STADs of as little as 0.8 mm (as found on average at the time of plaque removal) can have a notable effect on the calculation of the tumor dose.COMMENTStandard 2D-US techniques have been used intraoperatively and postoperatively to assess episcleral radioactive plaque position.Yet, the role of ultrasonographic imaging has largely been defined as an adjunct to transillumination or scleral indentation in cases of small posterior tumors. Although ophthalmic oncologists have used ultrasonographic information, most are uncomfortable in relying on 2D image "slices" to confirm plaque placement.3D-US VS 2D-USWhile 2D-US and 3D-US studies are dynamic, they differ in that the collected images from conventional 2D-US studies are usually stored in a 2D format (Table 1). Typically, the surgeon takes 5 to 15 minutes imaging the plaque and the tumor while performing a mental 3D reconstruction.In contrast, with 3D-US, 180 images are acquired and stored with each transducer rotation. Software uses this information to reconstruct a 3D image (Table 1). Then, without further contact with the patient, the entire examination can be played back over and over again (with the same perspective) or the eye (its tumor and plaque) can be rotated and viewed from any orientation. For example, the tumor and plaque can be viewed from oblique, mediolateral, or coronal views that cannot be acquired by 2D-US because of the presence of orbital bones (Figure 5).Previous 2D-US imaging studies have been performed for the localization of episcleral radioactive plaques. Harbour et alimaged 29 cases using intraoperative evaluations; in 4 (14%) of the cases, the plaque did not cover at least 1 tumor margin, and in 2 (7%) of the juxtapapillary tumors, the plaques were found to be tilted away from the optic nerve. Williams et alperformed postoperative ultrasonography on 16 cases and found accurate positioning in all of them. Pavlin et alscanned 9 cases postoperatively and found that 1 (11%) of the cases was malpositioned, 3 (33%) were eccentric, and 2 (22%) were displaced or tilted outwards.Our study (using 3D-US) found that changes in tumor height during radiotherapy were statistically significant (P<.001), while changes in the tumor width (P=.08) and length (P=.09) were not significant. This finding underscores the difficulty in assessing changes in plaque centration and movement. Further refinements or additional techniques may be required to study plaque movements and changes in tumor basal dimensions.3D-US VS OTHER FORMS OF TUMOR LOCALIZATIONAlthough relatively expensive and unavailable, magnetic resonance imaging has also been used to assess plaque position and offers computer-assisted multiplanar imaging capabilities (transverse, sagital, and coronal planes). Magnetic resonance imaging also provides 3D information; however, magnetic resonance imaging has some disadvantages. It is time consuming (40 minutes) and has a relatively low resolution (slice thickness, 3 mm; resolution, 0.5 mm). In contrast with magnetic resonance imaging, 3D-US allows for rapid acquisition (7.5 seconds) of multiple 2D images around a given axis. This data can be used to reconstruct a 3D image of the area of interest (6 seconds) that can be sectioned and viewed in any direction or orientation.Transillumination and scleral depression will continue to be indispensable methods for episcleral plaque placement. The drawbacks of ultrasonographic and transillumination techniques reside in their relative inability to define tumor margins that extend anteriorly into the zone of the ora serrata, the ciliary body, and the iris. Transillumination shadows typically merge with the highly pigmented and thickened ciliary body, and orbital bones impede low-frequency contact ultrasonographic imaging of the anterior segment. The only way to image anterior segment tumors with standard ultrasonography is with water bath techniques that allow the transducer sufficient distance from the study object. Unfortunately, construction of a water bath during surgery is impractical, and the plaque's ultrasonographic shadow can obscure the tumor.MEASURING THE STADThe methods of radiation dose calculation are based on ultrasonographic measurements of tumor thickness because the prescription point is the tumor's apex. Certain assumptions are made regarding the thickness of the sclera, the positioning of the plaque as "flush" with the episclera, and the location of the seeds within the plaque. In vivo tumor measurements of the STAD suggested that the tumor and the sclera may have thickened during the course of radiotherapy (Table 4, Table5 and Table 6). Although knowledge of the actual STAD would allow for less variability in irradiation dose and a better analysis of the effects of radiotherapy (local control and complications), it may require flexible scheduling of the operating room and multiple physics calculations. It is reasonable to assume that improved plaque localization and dosimetry would make radiotherapy more effective and would improve local control.SUMMARYThis study demonstrates that 3D-US offers unique views of episcleral plaques beneath their intraocular tumors. Three-dimensional ultrasonography suffers from some of the same limitations that affect 2D-US, but its ability to store and replay the examination from any orientation offers the potential to improve plaque placement and irradiation dosimetry.SPackerSStollerMLLessorLong-term results of 125I irradiation of uveal melanoma.Ophthalmology.1992;99:767-774.BRGarretsonDMRobertsonJDEarleChoroidal melanoma treatment with 125I brachytherapy.Arch Ophthalmol.1987;105:1394-1397.PKLommatzschResults after beta-irradiation (106Ru/106Rh) of choroidal melanomas: 20 years' experience.Br J Ophthalmol.1986;70:844-885.PTFingerDFLuABuffaPalladium-103 versus 125I for ophthalmic plaque radiotherapy.Int J Radiat Oncol Biol Phys.1993;27:849-854.PTFingerABuffaSMishraPalladium-103 plaque radiation therapy for uveal melanoma: clinical experience.Ophthalmology.1994;101:256-263.PTFingerRadiation therapy for choroidal melanoma.Surv Ophthalmol.1997;42:215-232.JEarleRWKlineDMRobertsonRMinnSelection of iodine 125 for the Collaborative Ocular Melanoma Study.Arch Ophthalmol.1987;105:763-764.JWHarbourTGMurraySFByrneIntraoperative echographic localization of iodine-125 episcleral radioactive plaques for posterior uveal melanoma.Retina.1996;16:129-134.CJPavlinBJappERSimpsonUltrasound determination of the relationship of radioactive plaques to the base of choroidal melanomas.Ophthalmology.1989;96:538-542.DFWilliamsWFMielerMLewandowskiMGreenbergEchographic verification of radioactive plaque position in the treatment of melanomas.Arch Ophthalmol.1988;106:1623-1624.DMRobertsonDGFullerREAndersonA technique for accurate placement of episcleral iodine-125 plaques.Am J Ophthalmol.1987;103:63-65.WBSnyderDGFullerGEFishAn inexpensive fiberoptic light pipe to aid in placement of episcleral radioactive plaques.Ophthalmic Surg.1988;19:62-63.DHCharJMQuiveyJRCastroHelium ions versus 125I brachytherapy in the management of uveal melanoma: a prospective, randomized, dynamically balanced trial.Ophthalmology.1993;100:1547-1554.PKLommatzschRLommatzschTreatment of juxtapapillary melanomas.Br J Ophthalmol.1991;75:715-717.DFWilliamsWFMielerGJJaffeMagnetic resonance imaging of juxtapapillary plaques in cadaver eyes.Br J Ophthalmol.1990;74:43-46.SLHannaMALemmiJWLangstonTreatment of choroidal melanoma: MR imaging in the assessment of radioactive plaque position.Radiology.1990;176:851-853.PVHoudekJGSchwadeAJMedinaMR technique for localization and verification procedures in episcleral brachytherapy.Int J Radiat Oncol Biol Phys.1989;17:1111-1114.BRStraatsmaSLFineJDEarleEnucleation versus plaque irradiation for choroidal melanoma.Ophthalmology.1988;95:1000-1004.HDSuitSJWestgateImpact of improved local control on survival.Int J Radiat Oncol Biol Phys.1986;12:453-458.DBDowneyDANicolleMFLevinAFensterThree-dimensional ultrasound imaging of the eye.Eye.1996;10:75-81.SFByrneRLGreenUltrasound of the Eye and Orbit.St Louis, Mo: Mosby–Year Book Inc; 1992:164-167.YFisherPHanustsahaSTongThree-dimensional ophthalmic contact B-scan ultrasonography of the posterior segment.Retina.In press.Accepted for publication November 26, 1997.Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Ft Lauderdale, Fla, May 14, 1997.Reprints: Paul T. Finger, MD, the Ocular Tumor Service, the New York Eye and Ear Infirmary, 310 E 14th St, New York, NY 10003 (e-mail: [email protected]).

Meldrum, Melissa L.; Tse, David T.; Benedetto, Pasquale

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.315pmid: 9514484

ObjectiveTo investigate a new chemotherapeutic regimen as an adjunct to the conventional surgical management of patients with advanced adenocystic carcinoma of the lacrimal gland.Patients and MethodsTwo patients with extensive adenocystic carcinoma of the lacrimal gland were treated with intracarotid cisplatin and intravenous doxorubicin hydrochloride prior to orbital exenteration. Postoperatively, the patients received 55 to 60 Gy of orbital irradiation, augmented by additional intravenous cisplatin and doxorubicin. Serial clinical and computed tomographic scan examinations were performed to monitor for evidence of recurrent disease.ResultsTumor shrinkage was documented radiographically following this preoperative chemotherapy regimen, downstaging the disease in one case from intracranial involvement to a more surgically amenable intraorbital process. Tumor necrosis was confirmed in the exenteration specimen. Limited morbidity was experienced and both patients have achieved long-term survival to date of 912years (114 months) and 712years (94 months).ConclusionsTo our knowledge, this is the first report of the efficacy of neoadjuvant intracarotid chemotherapy in the treatment of an advanced adenocystic carcinoma of the lacrimal gland. The combination of cisplatin and doxorubicin and the methods of drug delivery may be factors contributory to the favorable response. The results of this new treatment regimen are encouraging and justify further investigation.AN ADENOCYSTIC carcinoma of the lacrimal gland is the most common nonlymphoid malignant tumor of the lacrimal gland, accounting for 25% to 30% of epithelial lacrimal gland tumors.Despite extensive surgery and radiation therapy, the prognosis for these patients remains grim, with survival of less than 50% at 5 years and a dismal 20% at 10 years.In an effort to improve survival, we incorporated neoadjuvant intracarotid chemotherapy combined with intravenous chemotherapy into the conventional treatment for this disease.Chemotherapy has been used in the treatment of malignant epithelial tumors of the parotid and salivary glands, neoplasms that are of similar embryogenesis and biological behavior to an adenocystic carcinoma of the lacrimal gland. These tumors have demonstrated salutary response to cisplatin and doxorubicin therapy.Intra-arterial delivery of chemotherapy is an accepted treatment for extremity osteosarcoma,central nervous system tumors,primary and metastatic livertumors, and breast cancer in selected patients.The major advantage of intra-arterial drug infusion is the ability to administer a dose of therapeutic agent to the area of involvement through an undisturbed vascular system, resulting in a better therapeutic index (Table 1). Depending on the target organ, the extraction rate may result in drug delivery that is many times higher than that achieved with standard intravenous therapy, and simultaneously associated with limited systemic toxic effects.In addition, neoadjuvant chemotherapy, chemotherapy given prior to the "primary" or definitive treatment, induces tumor cell necrosis and potentially minimizes dissemination of viable tumor cells during the subsequent surgical manipulation. Finally, induction chemotherapy may induce a reduction in tumor size, rendering the mass more amenable to surgery.Table 1. Glossary of Oncologic TerminologySee table graphicExtrapolating from the use of regional infusion in other disease sites and the potential advantages described above, we treated 2 patients with locally advanced adenocystic carcinomas of the lacrimal gland using a new multidisciplinary treatment regimen of preoperative cytoreductive intracarotid chemotherapy and postoperative intravenous chemotherapy as an adjunct to conventional orbital exenteration and radiation therapy.PATIENTS AND METHODSTwo patients with biopsy-proven adenocystic carcinomas of the lacrimal gland were treated with the new chemotherapeutic protocol (Table 2).Table 2. Treatment Regimen for Adenocystic Carcinoma of the Lacrimal GlandSee table graphicREPORT OF CASESCASE 1A 29-year-old man complained of a bulging right eye of 3 weeks' duration. He denied any pain or double vision. Ocular examination findings were normal with the exception of limitation on upgaze of the right eye, mild ptosis with a decrease in levator function, 2-mm proptosis recorded by the Hertel measurement, and 2 mm of inferior globe displacement. Computed tomography scan examination disclosed an infiltrative lesion in the superior right orbit with intracranial extension through the superior orbital fissure (Figure 1). A transcutaneous biopsy of the lesion revealed an adenocystic carcinoma of the lacrimal gland exhibiting combined basaloid and Swiss-cheese patterns. Given the extent of local disease involvement, tumor-free margins could not be assured even with a combined ophthalmic and radical neurosurgical resection. The rationales for selecting intra-arterial neoadjuvant chemotherapy for this patient were (1) to induce tumor shrinkage in an attempt to bring the tumor margins to within the orbit, such that the entire lesion could be removed by orbital exenteration, and (2) to induce tumor cell necrosis to minimize dissemination of viable tumor cells during surgical manipulation.Figure 1.A, Axial orbital computed tomographic scan view, with contrast, of case 1 at presentation. The lacrimal gland mass extends to the orbital apex and into the cranial cavity through the superior orbital fissure (arrow). B, Coronal view of the orbital apex. Note intracranial tumor extension (arrow).Following a negative systemic evaluation, which included bone scan and computed tomographic scan of the chest and abdomen and appropriate baseline assessment of renal and cardiac function, the patient underwent 3 cycles of intracarotid cisplatin perfusion, combined with intravenous doxorubicin hydrochloride (Adriamycin) given at 3-week intervals. The cisplatin (100 mg/m2) was delivered via a catheter inserted through the ipsilateral femoral artery to the external carotid artery under angiographic control, selecting placement to achieve maximal distribution to the orbital structures using dominant tumor vessels as a guide. The dose of cisplatin was diluted in 500 mL of normal saline solution and delivered over 1 hour. Immediately following the intracarotid cisplatin infusion, the intracarotid catheter was removed and doxorubicin hydrochloride (25 mg/m2per day) was given intravenously. Additional doxorubicin hydrochloride doses (25 mg/m2per day) were given on each of the 2 subsequent days. Prior to chemotherapy, the patient was rehydrated overnight with 250 mL D5 0.45% NS to achieve a urine output greater than 150 mL/h. Hydration continued throughout the hospital stay. Antiemetic premedication included ondansetron hydrochloride (Zofran), dexamethasone sodium phosphate, and lorazepam (Ativan). The patient remained hospitalized for the 3 days of treatment. Complications included initial segmental scalp hair loss in the region of perfusion, neutropenia, and fever. An episode of sepsis was encountered during intravenous chemotherapy treatment attributable to a dental abscess.Computed tomography scans of the orbit (Figure 2) obtained 1 month after completion of the 3 cycles of intra-arterial drug perfusion demonstrated shrinkage of the tumor, downstaging the disease from intracranial involvement to a more surgically amenable intraorbital process. Following hematologic recovery from chemotherapy, exenteration without bone removal was performed. A gross tumor was identifiable only within the orbit. Biopsy specimens of tissues in the region of the superior orbital fissure were free of tumor cells. The socket was lined with a split-thickness skin graft. Histopathologic examination of the main specimen contained areas of calcification and necrosis consistent with tumor lysis (Figure 3).Figure 2.A, Axial computed tomographic scan projection, with contrast, showing reduction in orbital tumor mass 3 months following completion of intracarotid cisplatin perfusion. Intracranial tumor infiltration in a region of superior orbital fissure is no longer present (arrow). B, Coronal view of the orbital apex. In comparison with Figure 1, B, note disappearance of the intracranial component of the tumor following neoadjuvant chemotherapy (arrow).Figure 3.A, Tumor appearance of case 1 before chemotherapy. Note this section of tumor is predominantly basaloid (black arrow) pattern with a cribriform (white arrow) component. B, Exenteration specimen following intracarotid chemotherapy. Note the prominent calcification (black arrow) and cellular necrosis (arrowhead). C, Exenteration specimen showing framework for tumor clusters with loss of cells. Black arrow highlights loss of all but a small rim of tumor cells (hematoxylin-eosin, original magnification ×50).Approximately 6 weeks after exenteration and following complete healing of the socket, the patient began to receive fractionated radiation therapy to the orbit. A total of 55 Gy was delivered. Radiation therapy was given in concert with intravenous radiosensitizing cisplatin (20 mg/m2) once weekly on an outpatient basis. Four weeks following completion of radiation therapy, he was retreated with intravenous cisplatin (100 mg/m2) and doxorubicin (20 mg/m2daily for 3 days). A total of 6 cycles of chemotherapy were planned to eradicate any residual occult tumor cells, but patient fatigue precluded further treatment. He therefore received a total of 4 cycles of chemotherapy, 3 before and 1 after orbital exenteration. Subsequent serial clinical examinations and radiographic surveys have failed to demonstrate any evidence of recurrent local or distant disease 912years (114 months) following primary surgery. The patient is completely functional and is comfortable wearing an exenteration prosthesis.CASE 2A 31-year-old man was seen with a several-year history of gradually decreasing vision in the right eye and a 6-month history of inferior globe displacement. He also noticed a firm mass in the supertemporal quadrant of the orbit. The patient denied any orbital discomfort but complained of diplopia on upgaze. Ocular examination results were remarkable for best-corrected visual acuity of 20/200 OD attributed to chorioretinal folds noted in the fundus. No afferent pupillary defect was present. There was limitation on upgaze on the right side. A firm, nonmobile mass was palpable in the supertemporal orbit associated with 3 mm of proptosis by Hertel measurement. An orbital computed tomographic scan (Figure 4) revealed a 2.5×3.0-cm extraconal mass and bony fossa remodeling. An excisional biopsy with en bloc removal of the mass via the lateral orbitotomy approach was performed. Pitting of the bone was noted at the time of tumor excision. Histopathologic examination disclosed a sclerosing cribriform pattern adenocystic carcinoma of the lacrimal gland with perineural infiltration and positive margins of the en bloc resection. Despite the fact that an excisional biopsy had been performed, it was believed that possible tumor residual, prominent perineural infiltration, and bony involvement justified the use of neoadjuvant intra-arterial chemotherapy prior to exenteration.Figure 4.Axial orbital computed tomographic scan view of case 2. Note the large supertemporal mass indenting the globe and the bony fossa remodeling (arrows).Following a negative systemic evaluation, the patient underwent neoadjuvant therapy with intracarotid cisplatin (100 mg/m2) and intravenous doxorubicin hydrochloride (25 mg/m2daily for 3 days) for 2 cycles delivered in an identical fashion as in case 1. A standard exenteration, combined with removal of the lateral orbital rim bone flap created during the initial lateral orbitotomy procedure, was done. A meshed split-thickness skin graft was placed in the orbit. Postoperatively, the patient received a total of 60 Gy of radiation therapy combined with radiosensitizing intravenous cisplatin (20 mg/m2per day). This regimen is administered once per week, prior to receiving radiation treatment for that day. Postradiation intravenous cisplatin (100 mg/m2) and doxorubicin hydrochloride (20 mg/m2daily for 3 days) were given every 3 to 4 weeks for 4 cycles. The patient received a total of 6 cycles of chemotherapy, 2 before and 4 after surgery. Adverse treatment effects experienced by this patient included hair loss, neutropenia, and fever. The patient has no evidence of recurrence 712years (94 months) following completion of treatment.COMMENTAdenocystic carcinoma of the lacrimal gland is a rare but devastating disease. The dismal prognosis is well documented. A study by Lee et alreported that 23 of 26 patients died of their disease. Forrestdescribed a series of 20 patients, 11 of whom died of the disease within 8 years and 3 additional patients who died within 15 years. Of the remaining 6 patients, 2 died of causes unrelated to the lacrimal gland tumor and 2 had recurrent adenocystic carcinomas. The 2 patients who were disease-free had a follow-up period of only 2 and 4 years, respectively. In a more recent study, Wright et alreported a lower mortality rate with 12 of 38 patients succumbing to the disease, 11 within 4 years and 1 at 13 years. In the group of survivors, 6 patients were alive with recurrent tumor. Of the 18 patients dead or alive with recurrent disease, 16 (89%) had recurrences within 1 year, 1 within 2 years, and 1 at 9 years. Of the 17 patients described as disease free, 11 (65%) had less than 4 years of follow-up. Font and Gamelreported a series of 60 patients for whom follow-up information was available. Of these, 35 were dead of tumor, 3 were dead of other or unknown causes, 12 were alive with tumor, and 10 were without evidence of disease.THESE STUDIES THUS document a recurrence rate of 55% to 88% generally within 5 to 6 years of diagnosis and significant mortality rate with standard local therapies. The series of Font and Gamelreported an actuarial survival rate of approximately 20% at 10 years regardless of treatment regimen that included local excision alone, exenteration, radiation alone, exenteration combined with radiation, and an unspecified chemotherapeutic protocol.Henderson,in an effort to further document and clarify long-term survival, surveyed experts in the field of orbital oncology. Of 26 respondents across the country, only 2 "possible cures" were identified, achieving 20 and 11.7 years disease-free survival from the initial treatment. The patient surviving 20 years was treated with exenteration and radiation therapy while the other patient underwent exenteration with removal of the roof and lateral wall of the orbit. No postoperative radiation was given in the latter case.The poor survival rate has been attributed to the aggressive biological behavior of this tumor. The neoplasm tends to invade nerves and lymphatic channels, resulting in microscopic spread. Local recurrence is common, occurring in nearly half of patients within 2 years,with soft tissues or orbital bone as the most frequent sites. Bone and lung are common foci of distant metastases. An adenocystic lacrimal gland carcinoma also has a propensity for intracranial extension via the lacrimal nerve through the superior orbital fissure. Frequently, intracranial involvement is the principal cause of death.Because an adenocystic carcinoma has a proclivity for microscopic, soft tissue, and bone infiltration, surgery alone does not routinely effect a cure in high proportion. Radiation therapy may "mop up" residual cancer cells but tissue penetration by radiation can be a limiting factor. Not surprisingly, exenteration, exenteration combined with radiation,and radical cranio-orbital resectionhave not resulted in improved survival.Of cancer treatment options, chemotherapy has the greatest potential to eradicate occult metastatic disease. The experience of using chemotherapy in treating adenocystic carcinomas of the lacrimal gland is limited. A review of published data revealed that only 6 patients have received this form of therapy. In the retrospective study of Lee et al,1 patient was treated with fluorouracil. Five patients received an unspecified chemotherapeutic regimen in a series reported by Font and Gamel.In the latter series, 4 patients died within 1 year and the fifth patient survived 3 years before succumbing to the disease. It is unclear whether chemotherapy was given alone or in conjunction with exenteration. Furthermore, our review of the literature failed to show that the combination of cisplatin and doxorubicin was ever used as a chemotherapy regimen. This drug combination was chosen because of the activity of these agents in tumors of similar embryogenesis, namely, salivary gland cancers.Intra-arterial delivery of chemotherapy has been used for adenocystic carcinomas of the salivary glandand is a well-recognized and accepted method in treating a variety of tumors, including osteosarcoma,brain tumors,breast carcinoma,skin neoplasms,gastric cancer,invasive bladder cancers,head and neck carcinomas,and primary and metastatic liver cancers.The advantages of this method of delivery are 2-fold. First, a very high dose of drug is delivered to the target area.This potentially enhances tumor cell kills by increasing area-under-curve concentration and shifting the dose-response curve to the right. Second, systemic toxic effects may be limited if a high percentage of the drug is removed as it passes through the target capillary bed and the remainder is diluted in the systemic circulation. To optimize drug delivery, the intra-arterial treatment should be performed prior to surgery or radiation therapy before disruption of the tumor blood supply.To be effective, intra-arterial perfusion must fulfill the following criteria: (1) the tumor area should be supplied by a single (or less optimally, predominant) feeding arterial vessel capable of cannulation, (2) the tumor must be chemosensitive, (3) the chemotherapeutic agent must be active in its injected state, and (4) there should be an enhanced therapeutic index and response compared with conventional systemic therapy.The lacrimal gland receives its blood supply from both the internal and external carotid systems. The internal carotid artery gives off the ophthalmic artery, which then branches into the lacrimal artery. The lacrimal artery anastomoses with branches of the external carotid system in the orbit and within the eyelids. The carotid system is easily accessed via the ipsilateral femoral artery. Because delivery of chemotherapy via the internal carotid would lead to direct perfusion of the brain and potential untoward consequences, chemotherapy is given via the external carotid system and reaches the lacrimal artery via anastomotic branches in the orbit. Smaller catheters are now available that permit direct cannulation of the ophthalmic artery.The choice of chemotherapeutic agents is derived from the experience in treating epithelial tumors of the parotid and salivary glands. Like adenocystic carcinomas of the lacrimal gland, epithelial tumors of the salivary glands are rare, rendering large chemotherapeutic trials difficult. However, intravenous cisplatin and doxorubicin have been used with success for these tumors.In vivo, cisplatin functions as an "alkylating agent," producing interstrand and intrastrand cross-links in DNA. Since the drug is not cell-cycle specific, it is effective against carcinomas with slower growth cycles, such as an adenocystic carcinoma. Suen and Johnstreated 53 patients with adenoid cystic carcinoma of the head and neck with cisplatin alone (45 patients) or in combination with other agents (8 patients). The overall response rate, defined as a reduction in tumor size, was 64%. Schramm and colleaguesused cisplatin as a single agent in a pilot study and reported an overall response rate of 70%. Two other studies of recurrent salivary gland epithelial tumors revealed response rates of 36%(cisplatin combined with cyclophosphamide and pirarubicin) and 35%(cisplatin combined with doxorubicin and fluorouracil). These response rates were achieved despite the fact that the patients had a poor prognosis due to advanced tumor involvement. Kaplan et alreported a 59% response rate, defined as 50% reduction in tumor size, when cisplatin was used as a single agent; a 100% response rate was achieved when combined with doxorubicin in the treatment of salivary gland carcinomas.The rationale for the 6 cycles of chemotherapy is based on the theoretical principle that at diagnosis a tumor has a population of approximately 1012cells. A highly effective (99%) chemotherapy regimen will kill 102or 2 log-unit cells with each application. Thus, 6 applications (102×102×102× 102×102× 102=1012) would theoretically be required to effect a "cure." This still leaves 100or 1 cell. It is presumed the host immune defenses will play a role in eradicating small numbers of cancer cells, such that a cure is possible. This principle is borne out in the demonstrated efficacy of 6 cycles of methotrexate, vincristine sulfate (Oncovin), prednisone, and procarbazine (MOPP) therapy as curative in Hodgkin disease, 6 cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF) in adjuvant breast cancer, or 6 cycles of leucovorin and fluorouracil in adjuvant colon cancer. All these therapies were compared with longer courses of treatment without added benefit. The rationale for continued chemotherapy after surgery is to provide adequate therapy to decrease distant disease relapse using a drug protocol known to work in vivo in the same patient.Common complications of this chemotherapy program include myelosuppression, nausea, vomiting, fever, sepsis, hair loss, and potential for cardiac damage, renal dysfunction, ototoxicity, and thrombotic or vascular compromise related to the intra-arterial approach. Reported ocular complications due to the regional administration include retinal vascular occlusion, exudative retinal detachment, ophthalmoplegia,optic neuropathy,and maculopathy.In the case of adenocystic carcinoma of the lacrimal gland, in which exenteration is planned, ocular complications to the ipsilateral eye are not a major consideration. Our patients tolerated the administration of chemotherapy well and experienced manageable side effects including hair loss, nausea, and fever. There were no ophthalmic complications to the fellow eye. It must be emphasized that the treatment regimen described is quite toxic, predicted to produce significant, but manageable cytopenia. The risks of neutropenic fever and sepsis and potential complications from intracarotid catheter placement and chemotherapy infusion including a neurologic catastrophe do exist. This treatment protocol should not be used without adequate support services available.We believe this is the first report describing the use of neoadjuvant intracarotid chemotherapy in conjunction with the conventional orbital exenteration and radiation for the treatment of locally advanced adenocystic carcinoma of the lacrimal gland. This series also demonstrates for the first time that this combination of drugs and mode of delivery may be effective for this lethal orbital neoplasm. Tumor response is well documented radiographically and histologically in case 1. This patient's 912-year survival is unprecedented in someone with a nonresectable lesion and a histologic type of adenocystic carcinoma known to confer a poor prognosis.Of the 60 cases reported by Gamel and Font,54 patients with a basaloid pattern as a component of the tumor had a 5-year survival rate of 21% and a median survival of 3 years. Patient 2 had a large, long-standing tumor with prominent perineural invasion and bony involvement, features most responsible for early tumor recurrence and ultimate death.Yet despite these poor prognostic indicators, this patient has achieved a survival of 712years following this treatment regimen. When compared with the known recurrence rate of nearly 50% by 2 yearsand a mortality rate of 80% by 10 years,our patients have shown a favorable response. Even though these 2 patients have had prolonged disease-free survival, the possibility of late recurrence does exist.Actuarial analysis performed by Wright et alsuggested that the risk of recurrent adenoid cystic carcinoma continues for many years after various modes of therapy. In their series of 38 patients, 1 patient developed recurrence at 7 years and another at 9 years following initial treatment. There were only 2 disease-free survivors after 16 years of follow-up. Clearly, an additional 10 years of follow-up is mandatory for the present cohort to substantiate this form of therapy. We believe the neoadjuvant chemotherapy strategy used in this treatment protocol, coupled with the selection of an appropriate drug combination, offered the theoretical advantage of "mopping up" occult tumor cells beyond the surgical margins. This approach may prove to be an important difference in minimizing distant disease relapse as compared with conventional therapies. Although the number of patients treated in this series is small, we are encouraged by the early results that intracarotid chemotherapy may be an effective adjunct to the conventional surgical treatment of a devastating disease in which successful therapy has been elusive. As with any new treatment modality of a rare tumor, additional clinical studies, longer follow-ups, and sharing of data are needed to validate efficacy.LEZimmermanTESandersLVAckermanEpithelial tumors of the lacrimal gland: prognostic and therapeutic significance of histologic types.Int Ophthalmol Clin.1962;2:337-367.RLFontJWGamelAdenoid cystic carcinoma of the lacrimal gland: a clinicopathologic study of 79 cases.In: Nicholson DH, ed. 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Cancer Treatment: An Update.New York, NY: Springer-Verlag; 1994:291-294.FOStephensInduction (neo-adjuvant) chemotherapy: systemic and arterial delivery techniques and their clinical applications.Aust N Z J Surg.1995;65:699-707.JYSuenMEJohnsChemotherapy for salivary gland cancer.Laryngoscope.1982;92:235-239.VLSchramm JrCSrodesENMyersCisplatin therapy for adenoid cystic carcinoma.Arch Otolaryngol.1981;107:739-741.MTsukudaTKokatsuKItoIMochimatsuAKubotaSSawakiChemotherapy for recurrent adeno- and adenocystic carcinomas in the head and neck.J Cancer Res Clin Oncol.1993;119:756-758.APVenookATseng JrFJMeyersCisplatin, doxorubicin, and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group.J Clin Oncol.1987;5:951-955.CEMargoFRMurtaghOcular and orbital toxicity after intracarotid cisplatin therapy.Am J Ophthalmol.1993;116:508-509.KMaiseRWWalkerRGarganJDVictorIntra-arterial cisplatin-associated optic and otic toxicity.Arch Neurol.1992;49:83-86.YShimamuraMChikamaTTanimotoYKawakamiATsutsumiOptic nerve degeneration caused by supraophthalmic carotid artery infusion with cisplatin and ACNU: case report.J Neurosurg.1990;72:285-288.MJKupersmithWHSeipleKHolopigianKNobleEHiesigerFWarrenMaculopathy caused by intra-arterially administered cisplatin and intravenously administered carmustine.Am J Ophthalmol.1992;113:435-438.JWGamelRLFontAdenoid cystic carcinoma of the lacrimal gland: the clinical significance of a basaloid histologic pattern.Hum Pathol.1982;13:219-225.Accepted for publication October 27, 1997.Supported in part by Research to Prevent Blindness, Inc, New York, NY.Presented in part at the American Society of Ophthalmic Plastic and Reconstructive Surgery Preacademy Meeting, Atlanta, Ga, October 28, 1995.Reprints: David T. Tse, MD, Bascom Palmer Eye Institute, PO Box 016880, Miami, FL 33101 (e-mail: [email protected]).

Kushner, Burton J.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.324pmid: 9514485

BackgroundClassic teaching suggests that surgery for intermittent exotropia should be based on distance/near differences. Divergence excess, according to tradition, should be treated with symmetric lateral rectus recessions; simulated divergence excess and basic deviations should be treated with a recess/resect procedure. This teaching, to our knowledge, has not been systematically tested.ObjectivesTo evaluate the appropriateness of selective surgery based on distance/near differences and to determine if bilateral lateral rectus recessions affect the distance deviation more than the near deviation.Patients and MethodsPatients with basic type intermittent exotropia were randomized to 2 groups, those receiving either unilateral recess/resect procedures or symmetric lateral rectus recessions. Patients with simulated divergence excess intermittent exotropia received symmetric lateral rectus recessions. Outcome was observed 1 year after surgery.ResultsOf 19 patients with basic exotropia receiving lateral rectus recessions, 10 patients (52%) had a satisfactory outcome compared with 14 (82%) of the 17 patients who had recess/resect procedures (P>.05). Of the 68 patients with simulated divergence excess, 55 patients (80%) had a satisfactory outcome after bilateral lateral rectus recessions. This result was significantly better than the outcome for patients with basic exotropia who underwent lateral rectus recessions (P>.05). The decrease in the distance/near difference after surgery was essentially identical for patients with basic exotropia who underwent lateral rectus recessions as for those who received recess/resect procedures (means, 2.4 prism diopters vs 2.1 prism diopters, respectively).ConclusionsAlthough this study did not evaluate increasing the amount of symmetric lateral rectus recessions for patients with basic exotropia, these data suggest that patients with basic type intermittent exotropia should be treated with recess/resect procedures. Data also suggest that patients with simulated divergence excess do well with lateral rectus recessions. Recess/resect procedures and symmetric surgery affect distance/near differences equally in patients with basic exotropia.IN A SERIES of classic articles, Burian and colleaguesclassified intermittent exotropia based on distance/near differences and recommended different surgical procedures based on this classification. They defined the condition of patients in whom the distance deviation equaled the near deviation as a basic type of exotropia and recommended it be treated with unilateral recess/resect surgery. Patients in whom the distance deviation exceeded the near deviation were considered to have a divergence excess type of exotropia; for such patients Burian and colleagues recommended symmetric lateral rectus recessions. They based these recommendations on the unproven hypothesis that bilateral lateral rectus recessions would affect the distance deviation more than the near deviation, and that a recess/resect procedure would affect the distance and near deviation equally. Scobeeobserved that many patients with an apparent divergence excess type of exotropia would manifest an increase in their near deviation after 24 hours of monocular occlusion. Subsequently it was determined that approximately 1 hour of occlusion was sufficient to elicit this increase.Burian and colleaguesdefined the condition of these patients as a simulated divergence excess type of exotropia. Because they believed these patients really had a near deviation that equaled the distance deviation but that it was masked by fusional vergences at near, they recommended that they be treated as if the patients had a basic type of exotropia and undergo recess/resect surgery. Subsequently, other authors have described good results in treating patients with all 3 of these patterns of intermittent exotropia with symmetric lateral rectus recessions.In the 18th Annual Scobee Lecture, November 10, 1987, Dallas, Tex, I reported that patients with a simulated divergence excess exotropia (according to Burian'sclassification) did as well as patients with a true divergence excess pattern if they were treated with bilateral lateral rectus recessions. However, patients with a basic type of exotropia did not do as well if treated with bilateral lateral rectus recessions as patients with either true divergence excess or simulated divergence excess exotropia.I explained my findings based on a concept of distance/near differences in intermittent exotropia that differed from that of Burian. Rather than considering a patient in whom the distance exotropia exceeded the near exotropia to have an excess of divergence, I conceptualized the patient as having a strong convergence or fusional mechanism holding the eyes straighter at near. I described the patient in whom the near deviation increased after prolonged monocular occlusion as having a "tenacious proximal fusional" (TPF) mechanism. This phenomenon appears to be similar to what had been described previously as a slow vergence, or vergence aftereffect.I speculated that the presence of the TPF mechanism would work in the patient's favor for maintaining alignment after surgery.Accordingly, I proposed that the patient with simulated divergence excess type of exotropia could be treated equally satisfactorily by receiving lateral rectus recessions or a recess/resect procedure, depending on the surgeon's choice. Patients who lacked the TPF mechanism had a poorer fusional process and might benefit from a recess/resect procedure, which tends to tether the eye against abduction. Also, the incomitance produced by a recess/resect procedure may have sensory advantages over symmetric surgery in these patients.Recess/resect surgery typically results in an esotropia in the field of action of the recessed lateral rectus for a prolonged period after surgery, and this tends to eliminate suppression. I therefore suggested that the difference in success between the outcome obtained with bilateral lateral rectus recessions and that obtained with a recess/resect procedure was unrelated to a differential effect on the distance vs near measurement. Instead, it was due to the relative tethering effect of the recess/resect procedure. In the Scobee lecture I proposed a prospective study to investigate the hypothesis that people with divergence excess exotropia and those with simulated divergence excess exotropia can be treated equally well with bilateral lateral rectus recessions, but patients with the basic type of exotropia would respond better with a recess/resect procedure. The primary purpose of this article is to report the results of that study. A secondary purpose is to investigate the validity of the hypothesis underlying the recommendation of Burian and colleaguesthat surgery be based on distance/near differences. Specifically, that hypothesis is based on the unproven concepts that bilateral lateral rectus recessions affect the distance deviation more than the near deviation, and that a recess/resect procedure affects them equally.SUBJECTS AND METHODSBetween 1985 and 1996 all patients seen consecutively in my private practice who were undergoing surgery for intermittent exotropia, and in whom the near deviation was within 10 prism diopters (Δ) of the distance deviation (prior to monocular occlusion or the use of +3 lenses at near) were included in this study subject to the following exclusion criteria: untreated or unsuccessfully treated amblyopia, the presence of an A or V pattern requiring treatment, simultaneous oblique muscle surgery, lateral incomitance of more than 10Δ,history of previous strabismus surgery, the use of adjustable sutures, follow-up of less than 1 year, insufficient cooperation for the above-mentioned measurements, or unwillingness to be randomized. Because I wanted to limit this study to patients in whom accurate measurements could be obtained with the prism and alternate cover test, the lower age for inclusion was 3 years. Also, because I frequently use adjustable sutures on postadolescent patients and because I wished to eliminate the confounding variable that would be introduced by the use of adjustable sutures, I set the upper age limit for inclusion at 18 years. In addition, patients were excluded if I knew at the time of surgery that their follow-up would be carried out by the referring physician. I considered patients to have intermittent exotropia if their deviation was intermittently manifest at either distance or near. Consequently, I included patients who had a constant exotropia at distance but an intermittent exotropia at near. Randomization to 1 of 2 groups occurred when each patient was scheduled for surgery and after I obtained informed consent. One group, referred to as the "recess/resect group," underwent a recession of the lateral rectus and a resection of the medial rectus of the nondominant eye. The second group, referred to as the "lateral rectus recession group," underwent symmetric lateral rectus recessions. For both groups, surgery was based on the measurement obtained at 6 m with appropriate optical correction in place and prior to monocular occlusion. If patients had been treated with minus lens therapy or base-in prism prior to surgery, they were put in their appropriate cycloplegic spectacle correction without prism; it was with those spectacles that the measurements for this study were obtained. For myopic patients, the full cycloplegic refraction was dispensed. For hyperopic patients, spectacles were prescribed if there was any substantial astigmatic refractive error, anisometropia greater than one half diopter (D), or hyperopia greater than 2 D. In most cases, patients with hyperopic intermittent exotropia were given spectacles that incorporated approximately 1 to 112D less than the full cycloplegic hyperopic refraction. Outcome determination was made at the earliest examination date performed at least 1 year after surgery (range, 12-15 months). An outcome was considered satisfactory if there was between 10Δ of exophoria and 5Δ of esophoria. An intermittent or manifest tropia of any amount, either exotropic or esotropic, was considered an unsatisfactory outcome. Patients who underwent a reoperation, who needed prisms after surgery, or who needed manipulation of their accommodation with plus or minus lenses to meet the aforementioned criteria were considered to have an unsatisfactory outcome. Table 1gives the popular surgical formula that was used for both groups.In addition, any patients in whom the angle of exotropia at 6 m increased after 1 hour of monocular occlusion or while looking out a window at a far distant target were excluded from this study because they were the subject of a simultaneously conducted, different randomized clinical trial (see "Comment" section for significance of this exclusion).The outcome measurements were not masked.Table 1. Surgical FormulaSee table graphicThe decision to perform surgery on a given patient was not made according to a rigid predetermined protocol; however, certain factors consistently influenced the decision. In general, surgery was recommended if there was a deterioration of the frequency or magnitude of the exotropia, despite nonsurgical therapy (eg, alternate occlusion, prisms, or minus lens therapy, or a combination of these). These nonsurgical modalities were attempted in most patients who were younger than 7 years; typically I have found such treatment approaches to be most effective in this age range. In addition, surgery was advised if there was a manifest tropia present more than 50% of the time as determined either by examination or by obtaining an opthalmic history.For each patient I calculated the preoperative distance/near difference by subtracting the near angle of exotropia (prior to monocular occlusion or the use of +3 lenses) from the deviation obtained at 6 m, and compared this with the distance/near difference (calculated the same way) obtained 1 year after surgery. By subtracting the distance/near difference 1 year after surgery from the preoperative distance/near difference, I obtained the drop in the distance/near difference that occurred for each patient as a result of surgery.During the same period, all patients I operated on for simulated divergence excess exotropia (Burian'sclassification) were treated with symmetric lateral rectus recessions according to the same surgical formula and analyzed according to the aforementioned criteria. Concurrent with this study, another clinical trial was being conducted at our facility on patients with intermittent exotropia. It focused on patients with intermittent exotropia who manifested an increase in their deviation when looking out a window, or at 6 m after 1 hour of monocular occlusion. They were randomized to surgery either for the initial deviation at 6 m or for the larger deviation.Patients in that study who had simulated divergence excess and who were randomized to surgery for the initial deviation at 6 m (standard treatment) were included in the analysis for this study of symmetric lateral rectus recessions for simulated divergence excess.RESULTSDuring the enrollment period, I operated on 99 patients with a basic type of exotropia. Sixty-three patients were eliminated for the aforementioned exclusion criteria, leaving 36 patients who make up this study. Two patients (1 in each group) were excluded because they were lost to follow-up; 42 patients were excluded because they were enrolled in my other randomized clinical trial of patients with intermittent exotropia whose deviation increased after occlusion or while fixating outdoors.Another 19 patients were eliminated for meeting various exclusion criteria listed earlier.Nineteen patients with basic exotropia were randomized to symmetric lateral rectus recessions, of whom 10 (52%) had a satisfactory outcome, 2 (11%) were overcorrected, and 7 (37%) were undercorrected. Seventeen patients underwent unilateral recess/resect surgery, of whom 14 (82%) had satisfactory outcomes, 1 (6%) was overcorrected, and 2 (12%) were undercorrected. This difference was significant (P>.02, χ2test). There were 68 patients with simulated divergence excess exotropia who underwent symmetric lateral rectus recessions who made up the control group and were subject to the same exclusion criteria as the study group. Fifty-five (81%) had a satisfactory outcome; 3 (4%) were overcorrected and 10 (15%) were undercorrected. These results differ significantly from the results of patients with basic exotropia who underwent lateral rectus recessions (P>.05, χ2test) but were essentially identical to the results of patients with basic exotropia who underwent recess/resect surgery. See Table 2for descriptive characteristics of the 3 groups.Table 2. Characteristics of Control and Study GroupsSee table graphicTable 3compares the effects of recess/resect surgery and lateral rectus recessions on the distance/near difference in patients with basic exotropia. Data show that the 2 surgical procedures have essentially identical effects on the distance/near difference in patients with basic exotropia.Table 3. Change in Distance/Near Difference After Surgery*See table graphicCOMMENTThis study suggests that Burian and colleagueswere correct in recommending that patients with a basic type of intermittent exotropia be treated with a recess/resect procedure. It does not support, however, their recommendation that patients with a simulated divergence excess type of exotropia must be treated similarly. This study also suggests that the hypothesis that lateral rectus recessions selectively affect the distance deviation more than the near deviation, and that the recess/resect procedure affects both deviations equally, is untrue. If distance/near differences in a patient with intermittent exotropia are primarily a function of the TPF mechanism, the relative effect of surgery on the distance and near deviation, respectively, is self-adjusting in patients with basic exotropia. The amount of correction obtained at each distance is a function of how much deviation is present.Burian and colleagueshad recommended that patients with simulated divergence excess exotropia be treated with a recess/resect procedure. Others have suggested they can be as effectively treated with symmetric lateral rectus recessions.This study does not directly compare the effectiveness of those 2 procedures for simulated divergence excess exotropia. Indirectly, however, these data suggest that patients with simulated divergence excess exotropia can be treated effectively with either procedure. My results using lateral rectus recessions in this group of patients were essentially as good as those obtained for patients with basic exotropia who were treated with a recess/resect procedure. This is in contradiction to von Noorden'sconclusion that results would be better if the recommendations of Burian were followed. In von Noorden's study, there was one group in which he treated both divergence excess and simulated divergence excess with symmetric lateral rectus recessions, and another in which he treated these 2 subtypes differently according to Burian and colleagues' recommendations. The latter group had better results. In his report, he did not separate the results for the subsets of patients with simulated divergence excess from those of the patients with true divergence excess in each group. He only compared the results for each group, both of which contained a mixture of patients with divergence excess and simulated divergence excess. This makes it difficult to determine how the 2 different treatment approaches affected the results for simulated divergence excess exotropia. Also, his study did not address the treatment of basic exotropia.Hardesty et alreported equally satisfactory results using symmetric lateral rectus recessions for all subsets of intermittent exotropia, regardless of the distance/near difference. This is different from my findings. Hardesty et al relied on only a 5Δ difference between the distance and near measurement for the purpose of classification; Burian and Spiveyhad recommended a 10Δ difference; others have relied on a 15Δ value.This would result in Hardesty et al labeling some patients as having a divergence excess pattern who would be considered to have a basic pattern according to the recommendations of Burian and colleagues.These criteria would tend to homogenize the outcomes between the 2 groups of patients described by Hardesty et al, and might explain some of the differences between his results and mine.I wish to stress that this study does not prove that a recess/resect procedure is better, per se, than symmetric lateral rectus recessions for basic intermittent exotropia. It only suggests as much within the context of the specific surgical formulae I was comparing. Possibly symmetric lateral rectus recessions could work as well as recess/resect surgery if a larger amount of recession is performed. Mims and Woodhave reported that they increase the amount of lateral rectus recession in patients with intermittent exotropia as the size of the near deviation approaches that of the distance deviation. This study does not evaluate the effectiveness of increasing the amount of symmetric lateral rectus recession for patients with basic exotropia. I do not believe, however, that the poorer results I obtained in my lateral rectus recession group were simply a matter of an inadequate amount of recession. The mean deviation in my 2 groups immediately after surgery (&ap;1 week) was essentially identical. Instead, it appeared as if the recess/resect procedure guarded against later exotropic drift. In the other aforementioned clinical trial, however, I found that 23 patients with basic exotropia who underwent symmetric lateral rectus recessions for the largest deviation measured (eg, after prolonged occlusion or while looking out a window) had a 74% success rate.Although this is a poorer outcome than that obtained in my study with recess/resect surgery for basic exotropia, and better than that obtained for symmetric lateral rectus recessions, the numbers are too small to be significant. Further studies will be needed to determine if increasing the surgical dose will produce better results with symmetric lateral rectus recessions in basic exotropia.In general this study confirms the hypothesis that I proposed in 1988.Specifically, I had found that patients who did not have the TPF mechanism (patients with a basic exotropia) faired more poorly with lateral rectus recessions than patients who had the TPF mechanism (simulated divergence excess exotropia). I postulated that a recess/resect procedure might work better in patients who do not have this beneficial mechanism because of the tethering effect caused by the recess/resect procedure. On the other hand, I suggested that patients who had the benefit of the TPF mechanism could be treated with whichever surgical procedure was the surgeon's preference, either a recess/resect procedure or lateral rectus recessions. The relative benefit of one procedure over the other has little to do with its having a selective effect on the distance vs near deviation. In fact, there is substantial reason to doubt that patients whom Buriandescribed as having a divergence excess type of exotropia actually have an excess of divergence. Studies have shown that such patients will be approximately 30Δ more exotropic under deep anesthesia than in the awake state.This observation has been consistent with my own unpublished observations during the last 2 decades. It is difficult to explain the presence of a large exotropia at 6 m on the basis of an excess of active divergence, if the deviation increases further with the suspension of neuromuscular tonus as occurs under deep anesthesia. Other authors have questioned the role of an active divergence mechanism in these patients.This study needs to be viewed in the light of several limitations. My outcome criteria for a satisfactory result were arbitrary and can be subject to question. Some authors have used more liberal outcome criteria in studying intermittent exotropia, and some have used more stringent criteria.This study addressed only the outcome 1 year after surgery. It is recognized that intermittent exotropia tends to recur with time, and long-term follow-up is needed to determine a cure.In this study I specifically avoided referring to my satisfactory outcome patients as being "cured" because I do not know their long-term results. I was merely comparing 2 different treatment modalities and using the same outcome criteria for each group. Also, these were the same criteria used in my previously published report to which I wanted to compare these results.However, if I am correct in proposing that the beneficial effect of a recess/resect procedure is related to its tethering action against abduction, then possibly the apparent benefit will dissipate over time. If that were true, then using a recess/resect procedure might only delay failure. In theory, however, a longer period of good fusion might help maintain a long-term good outcome. Longer follow-up is needed to answer this question.In addition, the lack of masking could possibly introduce some bias. Many patients were excluded from this study because their deviation increased in the distance after 1 hour of monocular occlusion or while looking out a window; they were recruited for another study. Consequently this study compared recess/resect surgery with lateral rectus recessions only for those patients with basic type intermittent exotropia who did not show an increase in their distance angle of exotropia with either of those 2 specific testing modalities. Whether those excluded patients would have responded differently and altered the outcome of this study cannot be determined. Finally, I emphasize that this study included only patients with intermittent exotropia without A or V patterns, oblique dysfunction, lateral incomitance, or a history of surgery. Also, it excluded patients who had a constant deviation at both distance and near. One cannot extrapolate results from this study with confidence to patients who have those criteria that were excluded. Although there is no reason to suspect that patients with those characteristics would behave differently, no data substantiates that assumption.HMBurianSelected problems in the diagnosis and treatment of the neuromuscular anomalies of the eyes.In: Curso Internacional de Oftalmologia.Vol 2. Barcelona, Spain: Publicaciones del Instituto Barraquer; 1958:456-467.HMBurianBESpiveyThe surgical management of exodeviations.Trans Am Ophthalmol Soc.1964;62:276-305.HMBurianExodeviations: their classification, diagnosis, and treatment.Am J Ophthalmol.1966;62:1161-1166.HMBurianATFranceschettiEvaluation of diagnostic methods for the classification of exodeviations.Trans Am Ophthalmol Soc.1970;68:56-71.HMBurianDRSmithComparative measurements of exodeviations at twenty and one hundred feet.Trans Am Ophthalmol Soc.1971;69:188-199.RGScobeeExophoria.In: The Oculorotary Muscles.St Louis, Mo: CV Mosby Co; 1952:171.BJKushnerExotropic deviations: a functional classification and approach to treatment.Am Orthoptic J.1988;38:81-93.ONiederkerWScottThe value of diagnostic occlusion for intermittent exoptropia.Am Orthoptic J.1975;38:107-110.HHHardestyJRBoyntonJPKeenanTreatment of intermittent exotropia.Arch Ophthalmol.1978;96:268-274.MMParksConcomitant exodeviations.In: Ocular Motility and Strabismus.Hagerstown, Md: Harper & Row; 1975:113-122.JCooperKCuiffredaPKrugerStimulus and response AC/A ratios in intermittent exotropia of the divergence excess type.Br J Ophthalmol.1982;66:398-404.JCooperNMedowIntermittent exotropia basic and divergene excess type.Binocular Vis Eye Muscle Surg Q.1993;8:185-216.BSethiVergence adaptation: a review.Doc Ophthalmol.1986;63:247-263.HHardestyManagement of intermittent exotropia.Binocular Vis Q.1990;5:145-152.SMooreThe prognostic value of lateral gaze measurements in intermittent exotropia.Am Orthopt J.1969;19:69-71.MXRepkaKAArnoldiLateral incomitance in exotropia: fact or artifact?J Pediatr Ophthalmol Strabismus.1991;28:125-130.BKushnerThe distance angle to target in surgery for intermittent exotropia.Arch Ophthalmol.1998;116:189-194.MMParksConcomitant exodeviations.In: Tasman W, Jaeger EA, eds.Duane's Clinical Ophthalmology.Vol 1. Philadelphia, Pa: JB Lippincott; 1989:chap 13.GKvon NoordenDivergence excess and simulated divergence excess: diagnosis and surgical management.Doc Ophthalmol.1969;26:719-728.JMimsRWoodThe effect of preoperative alternate day patching on surgical results in intermittent exotropia: a retrospective study of 66 cases.Binocular Vis Q.1990;5:189-195.PRomanoLGabrielWBennettBSnyderStage I intraoperative adustment of eye muscle surgery under general anesthesia: consideration of graduated adjustment.Graefes Arch Clin Exp Ophthalmol.1988;226:235-240.LAptSIsenbergEye position of strabismic patients under general anesthesia.Am J Ophthalmol.1977;84:574-579.FBlodiMvan AllenElectromyography in intermittent exotropia: recordings before, during, and after corrective operation.Doc Ophthamol.1962;16:21-34.AJampolskyOcular divergence mechanisms.Trans Am Ophthalmol Soc.1970;68:730-822.PKnappTreatment of divergent deviations.In: Allen H, ed. Strabismus Ophthalmic Symposium II.St Louis, Mo: CV Mosby; 1958:364-376.ETamlerAJampolskyEMargElectromyography in strabismus.California Med.1959;90:437-439.JPratt-JohnsonJBarlowGTilsonEarly surgery for intermittent exotropia.Am J Ophthalmol.1977;84:689-694.JRichardMParksIntermittent exotropia.Ophthalmology.1983;90:1172-1177.WEScottRKeechAJMashThe postoperative results and stability of exodeviations.Arch Ophthalmol.1981;99:1814-1818.SStollerJSimonLLiningerBilateral lateral rectus recession for exotropia: a survival analysis.J Pediatr Ophthalmol Strabismus.1994;31:89-94.This article is the second of a 3-part series. The third part will appear next month.Accepted for publication October 21, 1997.Supported by an unrestricted grant from Research to Prevent Blindness Inc, New York, NY, and the Wisconsin Lions Foundation, Stevens Point, to the Department of Ophthalmology & Visual Sciences, University of Wisconsin, Madison.Presented in part at the Fourth Annual N. Edgar Miles Lecture, Charleston, SC, April 2, 1997.Corresponding author: Burton J. Kushner, MD, 2870 University Avenue, Suite 206, Madison, WI 3705-3611 (e-mail: [email protected]).

Bremer, Don L.; Palmer, Earl A.; Fellows, Rae R.; Baker, John D.; Hardy, Robert J.; Tung, Betty; Rogers, Gary L.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.329pmid: 9514486

ObjectivesTo present the 3- and 12-month strabismus data from 3030 premature infants with birth weights less than 1251 g enrolled in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.DesignData from the 3- and 12-month examinations conducted at 23 regional study centers were tabulated for all infants. The main outcome measure, ocular motility, was compared with baseline demographic variables and retinopathy of prematurity severity for the worse eye. Findings at 3 months were compared with the incidence of strabismus at 12 months.ResultsAt 3 months, 200 (6.6%) of the 3030 infants were strabismic. In the 2449 infants examined at both time points, 289 (11.8%) were found to have strabismus at 12 months. Retinopathy of prematurity was significant for strabismus at both 3 and 12 months (P<.001). The presence of strabismus at 3 months was found to be a highly significant predictor of strabismus at 12 months. Anisometropia, abnormal fixation, and unfavorable retinal structure also were significant predictors of strabismus at 1 year. The total prevalence of strabismus in the first year of life was 14.7%.ConclusionThe presence of acute-phase retinopathy of prematurity places the premature infant at increased risk for strabismus.THE GREATEST fear for parents and physicians who deal with retinopathy of prematurity (ROP) is retinal detachment and blindness. Fortunately, only a small minority of premature infants each year suffer the severe cicatricial complications that lead to visual impairment.However, many premature infants experience less severe ROP that resolves spontaneously, and strabismus is a significant concern in these infants.Strabismus causes abnormal binocular vision development and can lead to amblyopia. The cosmetic effect of misaligned eyes can have an adverse effect on the psychosocial development of the child.Strabismus also creates a potential need for expensive surgical remedies.The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) collected motility data prospectively on thousands of premature infants with birth weights less than 1251 g. The purposes of this article are (1) to determine the overall prevalence of strabismus in the first year of life among premature infants enrolled in this study; (2) to analyze demographic factors and characteristics of ROP that predict strabismus at 3 or 12 months of age; and (3) to examine factors present at 3 months (including fixation behavior, retinal structure, anisometropia, neurological development, and strabismus) that predict strabismus at 12 months.PATIENTS AND METHODSThe study population consisted of 4099 infants with birth weights less than 1251 g. The CRYO-ROP study obtained informed consent from parents or guardians and enrolled these infants at 23 participating centers between January 1, 1986, and November 30, 1987. For details concerning the study cohort, the examination and randomization of patients, the International Classification of ROP, and the cryotherapy trial, see previous publications.Subsequent to serial examinations for acute-phase ROP, the infants were seen at 3 and 12 months of corrected age. These follow-up examinations included assessment of fixation behavior, ocular motility, anterior segment, refractive error, and fundus findings. The examinations were carried out according to a protocol detailed in the CRYO-ROP Manual of Procedures.Fixation behavior was tested binocularly, then with each eye occluded separately. If the infant made eye contact or looked toward a moving face or toy, his or her fixation was judged to be normal. Smooth pursuit movements were not required. If the infant consistently objected to the covering of the eye, the uncovered eye was marked "abnormal." A sleeping or extremely uncooperative infant was judged "unable to assess."At the 3- and 12-month examinations, strabismus evaluation was summarized only as "normal alignment and motility," "strabismus present," or "unable to assess." Because ocular motility status was not a primary outcome of the study, those infants whose alignment could not be assessed at the regularly scheduled examination were not brought back solely for that purpose. Refractive error was measured at both outcome visits following cycloplegia. Anisometropia was defined as a difference of greater than 2 diopters (spherical equivalent).After a careful examination of the fundus, the ophthalmologist provided a summary grade of the structural outcome of the retina for each eye. These grades were used to determine favorable or unfavorable outcome. Unfavorable outcomewas defined as (1) retinal fold involving the macula; (2) retrolental opacity encroaching on the pupil and/or partial retinal detachment; or (3) total retinal detachment or total pupillary occlusion by fibrovascular membrane.An abbreviated developmental screening examination was also done. At 3 months, an attempt was made to elicit a response smile, either with direct frontal eye contact or, in the case of a blind infant, by voice alone. The infant's caretaker was also asked whether a smile could usually be elicited at home. If the infant failed both items (a smile could not be elicited at home or during the examination), the infant was considered to have delayed development for the purposes of this study. These developmental screening items were obtained from the Revised Denver Developmental Screening questionnaire.For the purposes of this report, each infant's ROP severity was based on the worse eye for that infant. It was determined by the highest stage of ROP and the lowest zone in which ROP occurred. Because there were few infants with ROP in zone I, all stages of ROP in zone I are combined for statistical analysis. Since most ROP in zone III was stage 1, all ROP in zone III was analyzed together.RESULTSOf the 4099 infants enrolled in the study, 187 died before age 3 months. Of the remainng infants, 3155 (80.6% of the survivors) were examined at 3 months of corrected age. Motility status could be observed in 3030 infants, of whom 200 (6.6%) were reported to be strabismic. The remaining 125 infants' motility status could not be determined at the 3-month examination.Table 1indicates the incidence of strabismus at 3 months by demographic variables (birth weight, gestational age, race, sex, inborn or outborn [born in the hospital or transferred to a study nursery], and single or multiple births) and ROP severity. The highest incidence of strabismus was noted in infants with any ROP in zone I. With higher stages of ROP in zone II, the incidence of strabismus increased accordingly. The incidence of strabismus increased as birth weight or gestational age decreased when analyzed by these variables alone.Table 1. Incidence of Strabismus at 3 Months by Demographic Variables and ROP Severity*See table graphicMultiple logistic regression analysis was used to determine the significance of these variables for strabismus at 3 months of corrected age (Table 2). When the confounding effects of each of the independent factors on the development of strabismus were adjusted by this analysis, demographic variables (including birth weight and gestational age) were not found to have made a significant contribution to the risk for strabismus at 3 months. Retinopathy of prematurity was found to be a significant predictor of strabismus at 3 months (P<.001) when the group of infants who had any ROP was compared with those who had no ROP. Subgroup analyses showed an increased risk for strabismus with more severe ROP. Although black race has been shown to be a relative protective factor against the development of ROP,there was no racial influence on the incidence of strabismus.Table 2. Multiple Logistic Regression Showing the Relative Effects of Various Risk Factors on Incidence of Strabismus at 3 MonthsSee table graphicOf the 4099 infants enrolled in the study, 2449 (59.7%) had their ocular motility evaluated at both 3 and 12 months after their full-term due dates. Of this group, 11.8% were found to have strabismus at their 12-month examination. Data collected on this cohort were used to compare the incidence of strabismus at 12 months with demographic variables and severity of ROP (Table 3). The incidence of strabismus increased as the zone was more posterior and the stage of ROP worsened.Table 3. Prevalence of Strabismus at 12 Months for Infants Assessed at Both 3 and 12 MonthsSee table graphicThis cohort of infants evaluated at both 3 and 12 months was used to compare the incidence of strabismus at 12 months with fixation behavior, anisometropia, retinal structure, neurological development, and strabismus status at 3 months. While the incidence of strabismus at 12 months was 9% for infants who had normal fixation in each eye at 3 months, it was 63.9% for infants with abnormal fixation in 1 eye at 3 months (Table 4). The incidence of strabismus at 12 months was 43.1% in patients who had anisometropia at 3 months, but only 9.5% in patients without anisometropia at that age. If the retinal structure at 3 months was favorable in both eyes, the incidence of strabismus at 12 months was 10.3%, while it was 68.2% in infants with unfavorable retinal structure in both eyes at 3 months.Table 4. Strabismus at 12 Months by 3-Month Fixation Behavior for Infants Assessed at Both 3 and 12 MonthsSee table graphicMultiple logistic regression analysis was used to determine the significance of these variables for strabismus at 12 months of corrected age (Table 5). The presence of acute-phase ROP was found to be a significant predictor of strabismus at 12 months (P<.001) when all ROP was compared with no ROP. Subgroup analysis showed all zones and stages of ROP were significantly correlated except for zone I disease.Table 5. Multiple Logistic Regression Showing the Relative Effects of Various Risk Factors on 12-Month Strabismus and on Incidence of Strabismus Between 3 and 12 MonthsSee table graphicThe presence of strabismus at 3 months was found to be a highly significant predictor of strabismus at 12 months (P<.001). When strabismus was present at 3 months, it was almost 11 times more likely that the infant would be strabismic at 1 year.Overall, both abnormal fixation behavior at 3 months and unfavorable retinal structure at 3 months were significant predictors of strabismus at 12 months. Subgroup analysis showed that although abnormal fixation in both eyes was a significant predictor of strabismus (P<.005) compared with bilaterally normal-fixating eyes, abnormal fixation in 1 eye and normal fixation in the other eye was not. By contrast, abnormal retinal structure in only 1 eye was significant for strabismus (P<.01) compared with a bilaterally favorable structure, whereas abnormal retinal structure in both eyes was not.The presence of anisometropia and delayed development at 3 months were also significant for predicting strabismus at 12 months. Anisometropia was a significant contributing factor at the P<.001 level; delayed development was significant at the P<.01 level.Of the 2449 infants who had their motility evaluated at 3 and 12 months of age, 155 (6.3%) were reported to be strabismic at 3 months. At 12 months of age, 82 of those 155 infants were still reported to be strabismic and had not undergone any therapy for their strabismus, 57 were no longer strabismic without receiving any treatment, and 16 had been treated in the interim. Between 3 and 12 months of age, another 206 infants (8.4%) became strabismic for the first time. Therefore, the total prevalence for strabismus in the first year of life for these 2449 infants was 361 (14.7%).COMMENTThis report presents prospectively collected ocular alignment data on thousands of low-birth-weight infants from the CRYO-ROP study. When compared with full-term infants,premature infants in this study have a higher rate of strabismus. These results confirm what other authors have reported (Table 6).This study also shows that the presence of acute-phase ROP is a strong predictor for strabismus in the first year of life (Table 2and Table 5). As the severity of ROP increases, the incidence of strabismus increases. Birth weight and gestational age were not found to be significant risk factors within this restricted group of premature infants weighing less than 1251 g. Any appearance to the contrary is due to the previously reported association of ROP with these factors.Strabismus outcome is dictated by events affecting the retina during the acute phase of ROP, and not by birth weight or gestational age.Table 6. Previous Reported Incidence of Strabismus in Preterm Infants*See table graphicMost of the children in this study who reached threshold ROP were treated with cryotherapy to 1 eye per study protocol. The CRYO-ROP study was designed to evaluate the efficacy of cryotherapy in treating threshold ROP, and not the effect of cryotherapy on the development of strabismus. Therefore the role, if any, of cryotherapy in the development of strabismus in this group of children could not be determined.The CRYO-ROP protocol required examinations at 3 and 12 months of age. Characteristics of the 3-month evaluation that predicted strabismus at 12 months include anisometropia, unfavorable retinal structure, abnormal fixation, poor neurological development, and strabismus. These results support the value of an examination at 3 months of corrected age for infants who had ROP.The fact that developmental delay or strabismus at 3 months of age predicts strabismus at 12 months could be expected, as it is known that children with neurological handicaps have an increased incidence of strabismus. While the developmental evaluation of study infants at 3 months was rudimentary (presence or absence of response smile), future analysis of the results of later CRYO-ROP evaluations (which included annual eye examinations and developmental screenings at ages 12-66 months) may provide further insight into the relationship between developmental delay and strabismus.The large cohort, prospective data collection, and good follow-up rate should make the statistics in this report more definitive than previous smaller studies. In this population of very low-birth-weight infants who had their ocular motility evaluated at 3 months of corrected age, 6.6% were reported to be strabismic. The incidence of strabismus for all infants examined at 12 months was 12.8%, as previously reported.For infants examined at both 3 and 12 months of age, 6.3% (155/2449) were strabismic at 3 months of age and 8.4% (206/2449) became strabismic for the first time between age 3 and 12 months. The total prevalence of strabismus in the first year was 14.7%.Results of the 3-month examination may be compared with data from the 12-month examination to consider the natural history of strabismus in these infants. One hundred fifty-five infants who were strabismic at 3 months were also seen for follow-up at 12 months. Of these, 57 (36.8%) had no strabismus at 12 months without receiving any intervention. Given the likelihood for spontaneous improvement in many of these children, a conservative approach to surgery at an early age in the preterm infant appears warranted.EAPalmerJTFlynnRJHardyIncidence and early course of retinopathy of prematurity.Ophthalmology.1991;98:1628-1640.DBSchafferGEQuinnLJohnsonSequelae of arrested mild retinopathy of prematurity.Arch Ophthalmol.1984;102:373-376.BJKushnerStrabismus and amblyopia associated with regressed retinopathy of prematurity.Arch Ophthalmol.1982;100:256-261.MSnirINissenkornISherfSCohenIBen SiraVisual acuity, strabismus, and amblyopia in premature babies with and without retinopathy of prematurity.Ann Ophthalmol.1988;20:256-258.BPCatsEWPTan KarelPrematures with and without regressed retinopathy of prematurity: comparison of long-term (6-10 years) ophthalmological morbidity.J Pediatr Ophthalmol Strabismus.1989;26:271-275.DLawsDEShawJRobinsonHSJonesYKNgARFielderRetinopathy of prematurity: a prospective review at six months.Eye.1992;6:477-483.RRobinsonMO'KeefeFollow-up study on premature infants with and without retinopathy of prematurity.Br J Ophthalmol.1993;77: 91-94.GSummersDLPhelpsBTungEAPalmerfor the Cryotherapy for Retinopathy of Prematurity GroupOcular cosmesis in retinopathy of prematurity.Arch Ophthalmol.1992;110:1092-1097.Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter trial of cryotherapy for retinopathy of prematurity: preliminary results.Arch Ophthalmol.1988;106:471-479.Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter trial of cryotherapy for retinopathy of prematurity: three-month outcome.Arch Ophthalmol.1990;108:195-204.The Committee for the Classification of Retinopathy of PrematurityAn international classification of retinopathy of prematurity.Arch Ophthalmol.1984;102:1130-34.Cryotherapy for Retinopathy of Prematurity Cooperative GroupMulticenter trial of cryotherapy for retinopathy of prematurity, one-year outcome: structure and function.Arch Ophthalmol.1990;108:1408-1416.Multicenter Trial of Cryotherapy for Retinopathy of Prematurity Cooperative GroupManual of Procedures.Springfield, Va: National Technical Information Service; 1985.WKFrankenburgRevised Denver Developmental Screening Test.Denver, Colo: Denver Developmental Materials Inc; 1978.LFriedmanBBiednerRDavidScreening for refractive errors, strabismus, and other ocular anomalies from ages 6 months to 3 years.J Pediatr Ophthalmol Strabismus.1980;17:315-317.Accepted for publication November 6, 1997.Corresponding author: Don L. Bremer, MD, Children's Hospital Outpatient Care Center, Suite 4C, 555 S 18th St, Columbus, OH 43205.

Del Priore, Lucian V.; Tezel, Tongalp H.

1998 JAMA Ophthalmology

doi: 10.1001/archopht.116.3.335pmid: 9514487

ObjectivesTo determine the reattachment rate of human retinal pigment epithelium (RPE) to different layers of human Bruch's membrane (BM).MethodsExplants of BM were prepared from 10 human cadaver eyes by removing native RPE. The RPE basal lamina, inner collagenous layer, elastin layer, and outer collagenous layer were exposed by sequentially removing each apical layer by mechanical or enzymatic means. First-passage human RPE was plated onto the surface and the RPE reattachment rate to each layer of BM was determined.ResultsRetinal pigment epithelial cell reattachment was highest to the inner aspects of BM and decreased as deeper layers of BM were exposed (ie, reattachment rate to basal lamina was higher than to the inner collagenous layer, which was higher than to the elastin layer, which was higher than to the outer collagenous layer). The reattachment rate to the inner collagenous layer, elastin layer, and outer collagenous layer harvested from elderly donors (age >60 years) was less than the reattachment rate to corresponding layers harvested from younger (age <50 years) donors.ConclusionsRetinal pigment epithelial cell reattachment depends on the anatomical layer of BM present in the host tissue. Age-related changes in BM may interfere with RPE reattachment. Our observations may have implications for understanding the pathogenesis of age-related macular degeneration and its potential treatment with RPE transplantation techniques.DURING the last 2 decades, numerous researchers have transplanted retinal pigment epithelium (RPE) into the subretinal space in normal eyes and in eyes with retinal or tapetoretinal degenerations.Typically, these studies have involved delivering suspensions, sheets, or patches of RPE into the subretinal space without removing the native RPE or altering the underlying Bruch's membrane (BM).The status of the underlying BM has not been considered in many of these investigations, but BM is a complex, multilaminated structure that will affect the reattachment, morphology, differentiation, and subsequent proliferation of transplanted RPE.We have previously shown that dissociated RPE must reattach to a substrate to avoid apoptosis.These results suggest that the host BM must be able to support the reattachment of donor RPE for the graft to survive.However, BM may be abnormal in patients who are candidates for RPE transplantation, including patients with age-related macular degeneration (ARMD). Thickening of BM and the formation of basal laminar deposits, basal linear deposits, and drusen occur early in the pathogenesis of ARMD.In addition, surgical removal of subfoveal choroidal neovascularization in ARMD may disrupt the inner aspects of BM, so that the lamellae of BM available for RPE reattachment may not be uniform throughout the transplantation bed.In this article, we address the question of which layers of BM are able to support the reattachment of transplanted RPE, and determine whether the age of the host BM affects RPE reattachment.MATERIALS AND METHODSPREPARATION OF RPE CULTURESRetinal pigment epithelial cell cultures were prepared from human cadaver eyes obtained from the Mid-America Tissue Bank (St Louis, Mo) as previously described.Primary RPE cell cultures became confluent in about 10 days, and cultures were passaged by trypsinization of the cells. First-passage RPE was used in all experiments. Cells were stained using a pancytokeratin antibody to verify that all cells were of epithelial origin as previously described.HARVESTING OF HUMAN BM EXPLANTSExplants of human BM were prepared from the periphery of 5 younger (average age, 40.6±11.3 years; range, 23-50 years) and 5 older donors (average age, 72.2±10.1 years; range, 63-89 years) (P=.001). There were no significant differences between the younger and older donor eyes in terms of death-to-enucleation time (5.8±1.9 hours vs 4.1±1.6 hours, respectively; P=.16) and death-to-explant preparation time (59.6±30.7 hours vs 57.0±40.9 hours, respectively; P=.91). A full-thickness circumferential incision was made posterior to the ora serrata and the anterior segment and vitreous were carefully removed. The posterior pole of each eyecup was inspected visually with direct and retroillumination under a dissecting microscope, and globes were discarded if there was any evidence of subretinal blood, extensive drusen, or irregular pigmentation of the macular RPE. The eyecups were put in carbon dioxide–free media (Gibco, Grand Island, NY) and a scleral incision was made 3 mm from the limbus and extended circumferentially. Four radial incisions were then made and the sclera was peeled away. A circumferential incision was made into the subretinal space 1 mm posterior to the ora serrata. The choroid-BM-RPE complex was then carefully peeled toward the optic disc and removed after trimming its attachment to the optic nerve. Native RPE was removed by bathing the explant with 0.02 N ammonium hydroxide in a 50-mm polystyrene petri dish (Falcon, Becton Dickinson, Lincoln Park, NJ) for 20 minutes at room temperature, followed by washing 3 times in phosphate-buffered saline (PBS).The explant was then floated in carbon dioxide–free media over an unlaminated, hydrophobic 125- to 175-µm-thick polytetrafluoroethylene membrane (Millipore, Bedford, Mass) with 0.5-µm pores, with the basal lamina of the RPE facing the membrane. The curled edges were flattened from the choroidal side with fine forceps, and care was taken to avoid touching BM. We then poured 4% agarose (Sigma Chemical Co, St Louis) on the BM-choroid complex from the choroidal side and the tissue was kept at 4°C for 2 to 3 minutes to solidify the agarose. The polytetraethylfluoroethylene membrane was peeled off, and 6-mm circular buttons were then trephined from peripheral BM on a Teflon sheet and placed on 4% agarose at 37°C in nontreated polystyrene wells of a 96-well plate (Corning Costar Corp, Cambridge, Mass). The agarose solidified within 2 to 3 minutes at room temperature, thus stabilizing the BM explant. Typically, 6 to 8 explants could be harvested from each eye. A photograph of a typical explant is shown in Figure 1.Figure 1.Photograph of apical surface of the explant surrounded by a ring of agarose (AGR) prior to plating retinal pigment epithelium. Large choroidal vessels are seen deep to the apical surface of Bruch's membrane (BM).PREPARATION OF DIFFERENT LAYERS OF BMExplants containing different layers of BM on the apical surface were prepared as summarized in the legend for Figure 2. To prepare heparinase- or chondroitinase-treated explants, triplicate buttons from each donor were treated at 37°C with 2.4-U/mL heparinase (Sigma) in PBS at pH 7.5 for 2 hours to remove the heparitin sulfate proteoglycans from the basal lamina of BM, or with 0.1-U/mL chondroitinase ABC (Sigma) in Tris buffer at pH 7.5 for 2 hours to digest chondroitin A, B, C, and dermatan sulfate proteoglycan groups of the basal lamina (Figure 2). Some buttons were treated with heparinase followed by chondroitinase to determine the effects of removing both proteoglycan groups on RPE reattachment. After the enzymatic treatment, the exposed surface was washed 3 times with PBS for 5 minutes. Control explants were washed 3 times with PBS.Figure 2.Schematic describing preparation of different anatomical layers of Bruch's membrane. Explants containing native retinal pigment epithelium (RPE) on Bruch's membrane are harvested from human cadaver eyes. Treatment with ammonium hydroxide removes the RPE, but leaves the RPE basal lamina (RPE BL) intact. The basal lamina can be treated with heparinase and/or chondroitinase. The basal lamina can be removed with gentle suction, exposing the fibers of the inner collagenous layer (ICL). Treatment with collagenase removes the inner collagenous layer and exposes the native elastin layer (EL). Treatment with elastase removes the elastin layer and exposes the native outer collagenous layer (OCL). Choriocapillaris basal lamina (CC BL) is present in all preparations.The BM explant from the fellow eye was prepared by removing the RPE with 0.02 N ammonium hydroxide as described earlier. The BM explant was then put on a 12- to 18-µm-thick hydrophilic polycarbonate-polyvinylpyrrolidone membrane with 0.4-µm pores (Millipore) with the basal lamina facing toward the membrane. The agarose was allowed to solidify at 4°C, and the hydrophilic membrane was peeled off along with the basal lamina of the RPE, thus exposing the bare inner collagenous layer (Figure 2). Triplicate buttons from each donor were further treated at 37°C with 1-mg/mL collagenase (Sigma) in PBS at pH 7.5 for 1 hour to remove the inner collagenous layer and expose the elastic layer, and with collagenase followed with 20-U/mL elastase (Sigma) in PBS at pH 8.5 for 1 hour to digest the inner collagenous and elastin layers and expose the outer collagenous layer (Figure 2). Some BM explants containing native basal lamina were digested with trypsin to determine the effects of nonspecific proteolysis on RPE reattachment. After the enzymatic treatment, 6-mm-diameter peripheral buttons were trephined and placed on 4% agarose in untreated polystyrene 96-well plates. The wells were gently rinsed with PBS 3 times for 5 minutes, and then stored at 4°C.ASSAY FOR RETINAL PIGMENT EPITHELIAL ADHESIONThe number of attached live RPE in each well was determined using a colorimetric assay, which indirectly estimates the number of live cells by measuring intracellular dehydrogenase activity (CellTiter 96 aqueous nonradioactive cell proliferation assay, Promega, Madison, Wis). Dehydrogenase enzymes found in live cells reduce MTS (3-[4,5-dimethylthiazol-2-yl]-5-(3-carboxymethoxyphenyl)-2-[4-sulfophenyl]-2H-tetrazolium) into the aqueous-soluble formozan in the presence of an electron coupling agent (phenazine methosulfate [PMS]). The quantity of formozan product can be determined from the absorbance at 490 nm, and is directly proportional to the number of living cells in culture.The assay was performed in dark conditions owing to the light sensitivity of MTS and PMS. One hundred microliters of Eagle minimum essential medium without phenol red was added to each well; the added solution contained 1.0-g/mL glucose in a bicarbonate-based buffer that maintains the pH at 7.3 to 7.4 in 5% carbon dioxide and 95% air, thus minimizing the effects of changes in glucose and pH on the colorimetric assay.Freshly prepared MTS/PMS solution (20 µL, 20:1) was added to each well, resulting in a final concentration of 333 µg/mL of MTS and 25 µmol of PMS. Plates were incubated for 4 hours at 37°C; 100 µL of medium from each well was transferred to the corresponding wells of another 96-well plate and read at 490 nm using an enzyme-linked immunosorbent assay plate reader. The corrected absorbance was obtained by subtracting the average optical density reading from triplicate sets of control sets containing the BM explant on 4% agarose without plated cells. The number of viable cells was estimated from a standardized curve obtained by plating 100 to 20000 viable, synchronized RPE cells from the same donor in triplicates on BM explants that had been stabilized on 4% agarose. A linear relationship (r=0.93) was observed between the number of viable cells and the absorbance at 490 nm (Figure 3). We also performed the assay for unattached cells (100-20000) on agarose to demonstrate that cell binding to a surface did not affect the MTS/PMS assay (r=0.97, data not shown).Figure 3.There was excellent correlation (r=0.93) between the optical density read on an enzyme-linked immunosorbent assay plate reader using a colorimetric assay and the number of viable retinal pigment epithelium (RPE) cells.STATISTICAL ANALYSISAll experiments were done using BM explants harvested from 5 younger donors (age <50 years) and 5 older donors (age >60 years). The reattachment rate for each well was defined as the ratio of the number of attached viable cells to the number of plated viable cells. Triplicate wells were used to calculate the average reattachment ratio to each layer of BM. Data from all experiments were pooled and expressed as mean±SEM. The attachment rates to different substrates between young and old donors were compared by the Mann-Whitney Utest, and the differences between the mean rates of various groups were analyzed in pairs by the Dunn multiple comparison test.A confidence level of P<.05 was considered to be statistically significant.RESULTSFigure 4shows the ultrastructure of the explants after sequential removal of each layer of BM. Retinal pigment epithelial basal lamina is visible after ammonium hydroxide treatment (Figure 4, A), and the inner collagenous layer is exposed after mechanical removal of the basal lamina (Figure 4, B). Subsequent treatment with collagenase exposes the elastin layer (Figure 4, C), and treatment with elastase exposes the outer collagenous layer (Figure 4, D).Figure 4.Transmission electron microscopy of human Bruch's membrane explants. A, Retinal pigment epithelial basal lamina is visible after ammonium hydroxide treatment. B, Mechanical removal of the basal lamina exposes the inner collagenous layer. C, Treatment of (B) with collagenase exposes the elastin layer. D, Treatment of (C) with elastase exposes the outer collagenous layer. RPE-BL indicates retinal pigment epithelial basal lamina; ICL, inner collagenous layer; EL, elastin layer; OCL, outer collagenous layer; and CC-BM, basal lamina of the choriocapillaris.Figure 5shows the ability of human RPE to attach to different layers of BM 6 hours after plating. The overall RPE reattachment rate to its own basal lamina (53.9±4.3%) was not altered by treating the basal lamina with heparinase (49.6±5.11%, P>.05), but was decreased by treating with chondroitinase alone (42.2±5.6%, P<.01) or chondroitinase with heparinase (34.0±10.7%, P<.01). The RPE reattachment rate to the inner collagenous layer (37.1±4.9%, P<.02), elastin layer (21.1±3.1%, P<.01), and outer collagenous layer (11.0±8.4%, P<.01) were reduced compared with untreated basal lamina. Extensive digestion of the ammonium hydroxide–treated basal lamina with trypsin markedly decreased the RPE reattachment rate to the surface (9.6±2.1%, P<.01). Washing the basal lamina 3 times with PBS did not alter cell reattachment significantly (54.4±12.1%, P>.05). Cell reattachment to tissue culture plastic (41.8±3.0%) and agarose (0.001±0%) served as positive and negative controls, respectively.Figure 5.Reattachment rate of human retinal pigment epithelium (RPE) to different layers of Bruch's membrane 6 hours after plating. Results are expressed in 3 groups: treated or untreated basal lamina