JAMA Ophthalmology

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.601pmid: 15883277

ObjectiveTo report sites of second primary cancer and the time to first diagnosis during routine follow-up after treatment for choroidal melanoma.DesignProspective longitudinal follow-up of patients enrolled in 2 randomized trials conducted by the Collaborative Ocular Melanoma Study (COMS) Group.MethodsBaseline and annual or semiannual systemic and laboratory evaluations were performed according to a standard protocol for 2320 patients enrolled in the COMS without evidence of melanoma metastasis or other primary cancer at baseline. Deaths were coded by a mortality coding committee.ResultsSubsequent to treatment for choroidal melanoma, a total of 222 patients were diagnosed with a second primary cancer other than basal or squamous cell skin cancer (5-year rate of 7.7% [95% confidence interval, 6.6%-9.0%]). The most common sites were prostate (23% of reported cases) and breast (17%); 12 of these 222 patients were diagnosed simultaneously with second primary cancers in 2 or more sites. Of these 222 patients, 113 died; 37 (33%) were coded as dead with melanoma metastasis, 33 (29%) as dead with a malignant tumor other than metastatic melanoma, and 13 (11%) as dead with a malignancy of uncertain origin. Radiotherapy did not significantly increase the development of second primary cancers. The rate of diagnosis of second primary cancer did not differ significantly by smoking status, although the rate in former smokers was increased vs that observed in either current smokers or those who never smoked.ConclusionRoutine medical surveillance for development of second primary cancers among patients treated for choroidal melanoma is important, especially for those with a history of smoking, regardless of the size of choroidal melanoma at the time of treatment.There has been growing interest in the occurrence of second malignancies (second primary cancers) after treatment for primary cancer. Of particular concern is the development of treatment-induced, particularly radiation-induced, second primary cancers and their relationship with dose as well as mode of delivery.Increased risk of developing a second primary cancer has been reported with a number of cancers, including retinoblastoma,Hodgkin disease, and breast and lung cancer.In a recent study, Inskipinvestigated the relationship between cancer of the brain and central nervous system with other types of cancers using data from the Surveillance Epidemiology and End Results Program for cancers diagnosed in the United States from 1973 through 1998. Excess risk of solid cancers was discovered in patients receiving initial radiotherapy and those diagnosed before 17 years of age. Shared genetic susceptibility as well as close medical screening of such patients were hypothesized to explain some of the association.The risk of second primary tumors also has been investigated in breast cancer and patients with non-small-cell lung cancer.Analyses from the National Surgical Adjuvant Breast and Bowel Project suggest increased incidence of second primary lung tumors in patients with breast carcinoma receiving extensive postmastectomy chest-wall radiotherapy as part of their treatment. Such an association was not observed with postlumpectomy irradiation with lower radiation doses.Similarly, an analysis of the Surveillance Epidemiology and End Results Program data revealed an increased risk of ipsilateral lung cancer following postmastectomy radiotherapy but not after postlumpectomy radiotherapy.Increased risk postmastectomy was not observed until 10 years after treatment. The incidence of second primary tumors also has been studied in both stage I and stages II and IIA non-small-cell lung cancer. Findings have been comparable, with approximately 5% to 6% of patients developing nonskin second tumors.Recently, breast cancer risk was observed to increase with increasing radiation dose in female survivors of Hodgkin disease.Previous reports have suggested an association between development of second primary cancers and history of tobacco use.The effect modification of smoking and radiotherapy on mortality has been described.Wong et aldescribed the occurrence of second primary tumors in patients treated for retinoblastoma. Little has been published regarding the development of new primary tumors in patients treated for choroidal melanoma. The Collaborative Ocular Melanoma Study (COMS) was designed as 2 randomized trials to evaluate forms of radiotherapy for choroidal melanoma with respect to overall survival and metastasis-free survival.The COMS provides the largest series to date of patients with choroidal melanoma without detectable other cancers present at the time of treatment who were evaluated prospectively, enrolled, treated, and followed up in a standardized fashion. Our aim was to describe the sites and time to diagnosis of second primary tumors during follow-up among patients participating in these 2 randomized trials.METHODSThe COMS design and methods have been published.The COMS Manual of Proceduresand the COMS Study Forms Bookare available. Prior to patient enrollment, the institutional review boards of all participating institutions reviewed and approved the COMS protocol and patient consent forms. All patients gave written consent before enrollment and random assignment to treatment. Descriptions of patients who enrolled in the randomized trialsand initial mortality findings by treatment armalso have been published.A COMS medical evaluation of each patient, regardless of tumor size, was performed prior to enrollment in the COMS to determine eligibility and rule out metastatic disease or another malignancy. The systemic evaluation was performed by an appropriate specialist, preferably a medical oncologist or radiation oncologist. The evaluation included a complete cancer-oriented general physical examination, chest x-ray, and liver function tests. In each trial, patients were assigned randomly to enucleation or to radiotherapy.Each patient enrolled in one of the COMS trials was required to have an annual medical evaluation. Additional medical visits were scheduled to evaluate symptoms as required for good patient care. The follow-up evaluation was similar to that performed at the baseline visit and included a physical examination and liver function tests. A chest x-ray was performed annually. Whenever a new primary cancer or metastatic melanoma was diagnosed on the basis of any diagnostic study, a report was submitted by the clinical center coordinator to the COMS Coordinating Center (Baltimore, Md) along with copies of reports of all procedures that were performed to support the diagnosis. Biopsy or cytology slides or blocks of embedded tissue were sent to the COMS Pathology Center (Madison, Wis) for histopathologic review. Diagnosis of the new second primary cancer as reported by the clinical centers was confirmed by the COMS Mortality Coding Committee when the results of the histopathologic review were available for deceased patients. A new second primary cancer also may have been identified for the first time during the review by the Mortality Coding Committee.Kaplan-Meier estimates of time to diagnosis of new second primary cancer were calculated along with 95% confidence intervals.SAS statistical software (SAS Institute Inc, Cary, NC) was used for all statistical analysis. Scheduled clinical follow-up ended on July 31, 2000, and July 31, 2003, for patients in the large- and medium-tumor trials, respectively. This report is based on follow-up data reported and received at the COMS Coordinating Center as of February 9, 2004.RESULTSOwing to the COMS eligibility criteria, eligible patients were required to have no previous diagnosis of another primary cancer or metastasis. History of 1 or more primary cancers was the sole reason for exclusion in 28% and 20% of patients who were otherwise eligible for the large and medium trials, respectively.Patients with nonocular tumors represented approximately 10% of all patients with choroidal melanoma of all sizes who were evaluated for the COMS.For the 2320 patients enrolled in the COMS randomized trials, potential follow-up ranged from 5 to 16 years; the median follow-up was approximately 10 years. A total of 222 (9.6%) patients were reported by the clinical centers as having a diagnosis of 1 or more new second primary cancers, other than basal cell or squamous cell skin cancer, at some time during follow-up. Seventy-eight additional patients had a diagnosis of basal cell or squamous cell skin carcinoma only. The Tableprovides the distribution of sites of these second primary cancers associated with the time of first diagnosis. The most common sites were prostate (23%), breast (17%), and genitourinary, gastrointestinal, and leukemia/lymphoma (each, 9%-10%). Of sites coded as “other,” no single category exceeded 2 cases. The frequency distribution of number of reported sites at time of first diagnosis was 210 (95%), 9 (4%), and 3 (1%) for 1, 2, and 3 sites, respectively.Table. Sites at First Diagnosis of Second Primary Tumor (Excluding Basal or Squamous Cell Skin Carcinoma)*SiteNo. (%) of PatientsProstate50 (23)Breast37 (17)Lung or other respiratory26 (12)Genitourinary23 (10)Gastrointestinal21 (9)Leukemia/lymphoma19 (9)Skin, melanoma12 (5)Liver8 (4)Nodule/mass5 (2)Adenoma4 (2)Bone3 (1)Central nervous system3 (1)Lipoma/fatty tumor3 (1)Thyroid2 (1)Eye or orbit1 (<1)Other17 (8)Total patients222 (100)*Multiple sites possible per patient. Two patients with multiple sites also had basal cell or squamous cell skin cancer at the time of initial diagnosis of second primary tumor.Pathologic confirmation (biopsy, cytology, autopsy) was available for 55 cases. Clinical confirmation occurred frequently by scan, x-ray, and physical examination. A total of 113 patients with a second primary cancer reported by the clinical centers had died; the records of all of these patients were reviewed subsequently by the COMS Mortality Coding Committee. Of these reviews, 37 (33%) cases were coded as death with melanoma metastasis, 33 (29%) as death with a malignant tumor (not metastatic melanoma), 13 (11%) as death with a malignant tumor of unknown origin, and 30 (27%) with insufficient or no available clinical information.Overall, the 5-year cumulative second primary cancer rate (excluding basal cell skin carcinoma), based on clinical diagnosis and/or mortality reviews, was 7.7% (95% confidence interval, 6.6%-9.0%) and the 10-year rate was 14.9% (95% confidence interval, 12.9%-17.1%) (Figure 1). There was no statistically significant difference in these rates by treatment (radiotherapy or enucleation) nor tumor size (data not shown). Time to development of second primary cancer did not differ significantly by smoking history at baseline (Figure 2). However, the overall proportion developing a second primary cancer was slightly higher among former smokers.Figure 1.Cumulative proportion of patients developing a second primary cancer (excluding basal or squamous cell carcinoma of the skin).Figure 2.Cumulative proportion of patients developing a second primary cancer, by smoking history at baseline (current smoker [n = 504], former smoker [n = 876], never smoked [n = 940]).COMMENTThe COMS provided a unique opportunity to assess a large series of patients with choroidal melanoma, but no other known cancers, who were followed up prospectively and evaluated systematically using a standard protocol that included an annual medical evaluation for detection of new cancers and metastatic spread. In addition, the randomized design permitted assessment of the effects of local radiation on development of second primary tumors within the next 5 to 10 years.Our estimated 5- and 10-year second primary cancer rates are similar to the calculated 8% and 9% probabilities of developing invasive cancer during the 10-year interval between ages 40 to 59 years for men and women, respectively, in the United States based on data from 1998 to 2000.Also, our findings suggest that the occurrence of second primary cancers following treatment for choroidal melanoma is similar to that observed with other primary cancers, with prostate and breast cancers as the most commonly diagnosed cancers. Our data do not suggest increased incidence of second primary cancer in patients treated for choroidal melanoma. However, our findings support routine posttreatment surveillance since some second primary cancers may be treated effectively if detected early. There was no statistically significant increase in second primary cancers in patients receiving radiotherapy as compared with those not receiving radiotherapy. We agree with Rice et althat it may be especially important to monitor patients with a history of smoking for new primary cancers. Even if mortality is not decreased with improved detection of second primary cancers, it is possible that routine surveillance for second primary cancers will result in less patient morbidity and improved quality of life.Correspondence:Marie Diener-West, PhD, COMS Coordinating Center, Wilmer Clinical Trials and Biometry, 550 N Broadway, Ninth Floor, Baltimore, MD 21205 ([email protected]).Submitted for Publication:June 17, 2004; final revision received November 18, 2004; accepted December 28, 2004.Funding/Support:The COMS Group has received support from the National Eye Institute and the National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Md, through cooperative agreements EY06253, EY06257, EY06258, EY06259, EY06020, EY06264, EY06265, EY06266, EY06268, EY06269, EY06270, EY06274, EY06275, EY06276, EY06279, EY06280, EY06282, EY06283, EY06284, EY06287, EY06288, EY06289, EY06291, EY06839, EY06843, EY06844, EY06848, EY06858, and EY06899.REFERENCESEJHallC-SWuuRadiation-induced second cancers: the impact of 3D-CRT and IMRT.Int J Radiat Oncol Biol Phys200356838812694826CEngFPLiDHAbramsonMortality from second tumors among long-term survivors of retinoblastoma.J Natl Cancer Inst199385112111288320741PDInskipMultiple primary tumors involving cancer of the brain and central nervous system as the first or subsequent cancer.Cancer20039856257012879474EObedianDBFischerBGHafftySecond malignancies after treatment of early-stage breast cancer: lumpectomy and radiation therapy versus mastectomy.J Clin Oncol2000182406241210856100MDeutschSRLandMBegovicThe incidence of lung carcinoma after surgery for breast carcinoma with and without postoperative radiotherapy.Cancer2003981362136814508821LBZablotskaAINeugutLung carcinoma after radiation therapy in women treated with lumpectomy or mastectomy for primary breast carcinoma.Cancer2003971404141112627503SMKellerMGVangelHWagnerSecond primary tumors following adjuvant therapy of resected stages II and IIIa non-small cell lung cancer.Lung Cancer200342798614512191FEvan LeeuwenWJKlokmanMStovallRoles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin’s disease.J Natl Cancer Inst20039597198012837833AINeugutTMurrayJSantosIncreased risk of lung cancer after breast cancer radiation therapy in cigarette smokers.Cancer199473161516208156488DRiceH-WKimASabichiThe risk of second primary tumors after resection of stage I nonsmall cell lung cancerAnn Thorac Surg2003761001100814529975FLWongJDBoiceJrDHAbramsonCancer incidence after retinoblastoma: radiation dose and sarcoma risk.JAMA1997278126212679333268Collaborative Ocular Melanoma Study GroupDesign and methods of a clinical trial for a rare condition: the Collaborative Ocular Melanoma Study: COMS Report No. 3.Control Clin Trials1993143623738222668Collaborative Ocular Melanoma Study GroupCOMS Manual of Procedures.Springfield, Va: National Technical Information Service; 1995. Accession PB95-179693Collaborative Ocular Melanoma Study GroupCOMS Study Forms Book.Springfield, Va: National Technical Information Service; 1998. Accession PB98-139629Collaborative Ocular Melanoma Study GroupThe Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation for large choroidal melanoma, I: characteristics of patients enrolled and not enrolled: COMS Report No. 9.Am J Ophthalmol19981257677789645715Collaborative Ocular Melanoma Study GroupThe COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled: COMS Report No. 17.Arch Ophthalmol200111995196511448318Collaborative Ocular Melanoma Study GroupThe Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation for large choroidal melanoma, II: initial mortality findings: COMS Report No. 10.Am J Ophthalmol19981257797969645716Collaborative Ocular Melanoma Study GroupThe Collaborative Ocular Melanoma Study (COMS) randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: initial mortality findings: COMS Report No. 18.Arch Ophthalmol200111996998211448319Collaborative Ocular Melanoma Study GroupCause-specific mortality coding: methods in the Collaborative Ocular Melanoma Study: COMS Report No. 14.Control Clin Trials20012224826211384789Collaborative Ocular Melanoma Study GroupAssessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study (COMS): COMS Report No. 15.Arch Ophthalmol200111967067611346394ELKaplanPMeierNonparametric estimation from incomplete observations.J Am Stat Assoc195853457481APSchachatJAMarkowitzBSHawkinsSLFineNonocular cancers in patients with choroidal melanoma [letter to the editor].Ophthalmology1990978378382199887Cancer Facts and Figures 2004.Atlanta, Ga: American Cancer Society, Inc;2004:14

Taban, Mehran; Behrens, Ashley; Newcomb, Robert L.; Nobe, Matthew Y.; McDonnell, Peter J.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.605pmid: 15883278

ObjectiveTo determine the incidence of acute endophthalmitis following penetrating keratoplasty (PK) over time.MethodsA systematic review of English-language articles was conducted by performing a broad search of the PubMed database from 1963 through March 2003 using such keywords as penetrating keratoplasty, endophthalmitis, and postoperative complication. Additional studies were identified from bibliographies of relevant articles and published proceedings. The proportion of eyes with acute endophthalmitis as a postoperative complication was recorded, and pooled incidence rates were assessed over time.ResultsFrom 1870 unique, potentially relevant citations, 66 original studies that addressed endophthalmitis and met the selection criteria were analyzed. A total of 90 549 PKs were pooled, resulting in an overall estimate of 0.382% post-PK endophthalmitis, but a change over time was noted. The rate of endophthalmitis was 0.200% in the 2000-2003 period, 0.453% in the 1990s, 0.376% in the 1980s, and 0.142% during the 1970s. Furthermore, a downward trend in the incidence of endophthalmitis after 1992 was observed compared with 1991 and earlier.ConclusionsThis systematic review indicates that the incidence of endophthalmitis associated with PK has declined during the last decade.Endophthalmitis is an infrequent but devastating intraocular infection with high potential for ocular morbidity, including permanent severe vision loss.It has been classified by clinical setting and time of onset of clinically apparent inflammation into 4 categories: (1) postoperative (acute onset, delayed onset, bleb associated), (2) posttraumatic, (3) endogenous, and (4) miscellaneous (eg, secondary to microbial keratitis).Postoperative endophthalmitis is one of the most dreaded complications of intraocular surgery. The reported incidence of postoperative endophthalmitis varies by the specific surgical procedure and across studies, but the overall incidence has been declining since the late 19th century. Trends in the incidence of endophthalmitis following penetrating keratoplasty (PK), relative to cataract surgery, have been more difficult to follow owing to the smaller number of reported studies, but rates as high as 0.50% were reported until the late 1980s by a retrospective study based on nationwide patient registers.The relative rarity of endophthalmitis following intraocular surgery limits the ability of smaller studies to reveal clinical and statistical trends and demonstrates the difficulty in obtaining accurate incidence rates. Most reports regarding the rates of endophthalmitis are based on the experience of individual institutions or groups and are therefore limited by small sample sizes. Only more appropriate methods, such as comprehensive reviews or multicenter prospective studies, can help make comparisons and data statistically valid.To obtain the best available perspective, as reflected by the medical literature, and a better understanding of the recent trends in postoperative endophthalmitis following PK, we conducted a systematic review of the literature. The purposes of this study were to detect changes in the trends of acute endophthalmitis following PK over time and to compare these with changes after cataract extraction.Changes in the incidence of this complication over time, if detected, might provide clues regarding the value of newer perioperative chemical disinfectants or more broad-spectrum antibiotics.METHODSSTUDY DESIGNWe performed a systematic review of the literature to identify all published reports that pertained to the outcome of PK. The detailed methods used to identify, select, and analyze studies are described elsewhere.Briefly, studies were identified through (1) a computerized search of the Cochrane and PubMed (National Library of Medicine) databases from 1963 through March 2003, using a specific search strategy (Table 1); (2) a manual search of reference lists of original reports and review articles retrieved through the electronic search that met the selected criteria; (3) a review of major ophthalmic textbooks; and (4) a review of key published proceedings and scientific session abstracts (ie, Association for Research in Vision and Ophthalmology and American Academy of Ophthalmology). Keywords were selected based on expert opinion and evaluation of selected review articles on endophthalmitis and PK.Table 1. PubMed Search StrategyDescriptionNo. of ArticlesPubMed keyword searches Search 1, corneal transplantation*7583 Search 2, keratoplasty, penetrating1882 Search 3, penetrating keratoplasty2910 Search 3, endophthalmitis3684 Search 4, eye infection*17192 Search 5, surgical wound infection*17208 Search 6, panophthalmitis282 Search 7, postoperative complication*249356Combined searches (1 or 2) and (3 or 4 or 5 or 6 or 7)2296Exclusion criteria Limit by language type (English)1723*Searches also include the plural.SELECTION CRITERIAReports were considered eligible for our review if they satisfied our selection criteria. Each article had to meet all of the following inclusion criteria: (1) the article was written in English, (2) the study examined human cases, (3) the study examined PK, and (4) the article addressed post–corneal transplantation endophthalmitis occurrence (ie, reported the number of procedures and the number of postsurgical endophthalmitis cases even if zero or the numbers could be derived according to reported percentages). Articles were excluded from this review if they met any of the following exclusion criteria: (1) the study examined fewer than 10 eyes, (2) endophthalmitis cases were associated with an outbreak (eg, contaminated instruments or media), or (3) the study had less than 1 week of postoperative follow-up (unless a relatively large number of endophthalmitis cases were identified, in which case the study was included).DATA ABSTRACTIONArticles that satisfied the eligibility criteria underwent an intensive, structured review to abstract data on the postsurgical outcome of corneal transplant operations. Data extraction was performed using a standardized review form to record the following: (1) year of publication, (2) journal published, (3) location (ie, country) of trial, (4) the minimum (mean or maximum if minimum was not indicated) duration of follow-up on postsurgical patients, (5) number of eyes undergoing PK, and (6) number of patients who experienced acute endophthalmitis postoperatively (acute was defined as onset within 6 weeks).STATISTICAL ANALYSISDetails of the statistical methods used are described elsewhere.A weighted regression analysis was used to portray how the postoperative infection rates changed during the 40-year period from 1964 to 2003. The 40-year study period was also divided into 2 subperiods (ie, 1964-1991 and 1992-2003) to compare and contrast the trends with those of postcataract endophthalmitis occurrence.Infection rates were then fit by a weighted “piecewise” or “segmented” linear model, composed of 2 separate linear approximations of the infection rates reported in the articles published within each subperiod. The weighted regression analyses were based on units of analysis as defined in 1 of the following ways: either the units of analysis were the 66 qualifying PK articles or they were the 40 years in which those publications appeared. In either case, the statistics were then weighted proportional to the number of surgical procedures reported within each unit of analysis, which gave more power to studies per year with a higher number of surgical procedures and less to those with fewer operations. All coefficients for this weighted regression model were computed using the SAS NLIN procedure (SAS Institute Inc, Cary, NC).RESULTSYIELD OF PK LITERATURE SEARCHFigure 1illustrates the flow of literature reviewed. Our computerized search identified 1723 unique citations, whereas a manual search of references resulted in 101 additional articles. From these, 66 studies fulfilled our eligibility criteria. The 66 studies were published in 1 textbook and 17 journals (Figure 2) and were categorized by the year of publication (Figure 3). The studies were published fairly evenly across years; the largest number of published studies in any single year was 6 in 1993. The highest number of PKs was also reported in 1993 (n = 44 143), largely owing to a national database study of Medicare patients.There were no studies published in several years within the 1972-2002 period.Figure 1.Flow of reviewed literature.Figure 2.Number of articles from each journal.Figure 3.Distribution of the 66 studies according to each year.STUDY CHARACTERISTICSThe United States had by far the highest number of studies conducted (40), followed by Germany (3), India (3), the United Kingdom (3), African countries (2), Australia (2), Denmark (2), Israel (2), and Saudi Arabia (2). Canada, Finland, France, Singapore, Sweden, and Turkey each contributed 1 study to this analysis.Figure 4shows the distribution of sample sizes. The median number of corneal transplantations included in the 66 studies of our analysis was 159.5 (range, 10-40 351). The minimum (or mean if minimum was not indicated) duration of follow-up on postsurgical patients in the studies ranged from 1 month to 3 years.Figure 4.Frequency distribution of the total sample sizes (number of eyes studied) in the 66 studies.OVERALL RESULTSThe overall pooled estimate (1972-2002) of the incidence of acute endophthalmitis after PK was 0.382% based on 90 549 PKs. The rate for each decade was: 0.142% in the 1970s, 0.376% in the 1980s, 0.453% in the 1990s, and 0.200% during 2000 and beyond (Figure 5). The rate of endophthalmitis from 1972 to 1999 was 0.392%, whereas the rate from 2000 to 2003 was 0.200%, representing an almost 2-fold decrease in the incidence (relative risk, 1.96; 95% confidence interval, 1.01-3.80).Figure 5.Pooled estimates of endophthalmitis frequency following penetrating keratoplasty according to each decade.ENDOPHTHALMITIS FREQUENCY: TRENDS OVER TIMETo assess and compare potential changes in the incidence of acute endophthalmitis following PK relative to cataract surgery during the last decade,we chose to compare the rates of post-PK endophthalmitis from before 1992 with those from 1992 forward. A weighted analysis of the mean endophthalmitis rate for each year or article was used, both producing the same results (Figure 6A and B). The slope obtained for the years 1972-1991 was +0.0174 (suggesting a gradual uptrend), whereas the slope from 1992-2003 (–0.0208) was consistent with a gradual decrease. The difference between these 2 slopes was statistically significant (Figure 7).Figure 6.Trends of endophthalmitis rate. Slope is best-fit line from weighted regression analysis (see the “Methods” section). A, Trends based on each study or publication (weighted per surgery): 1972-1991 slope, +0.0174; 1992-2003 slope, –0.0208. B, Trends based on each year (weighted per surgery): 1963-1991 slope, +0.0174; 1992-2003 slope, –0.0208.Figure 7.The 95% confidence intervals of trends analysis. Slopes within each period, with error bars indicating 95% confidence intervals, are based on each study or publication (A) or on each year (B).CATARACT SURGERY vs PKOverall, the rate of acute endophthalmitis following PK (0.382%) was higher than that following cataract surgery (0.128%),representing an almost 3-fold increased risk associated with PK (Table 2). However, the trend for this risk has changed during the last decade, with PK demonstrating a gradual downtrend, in contrast to cataract surgery (Figure 7).The higher overall rate of endophthalmitis for keratoplasty compared with cataract extraction was statistically significant (P<.001), but the reverse was true after 2000, although the Pvalue was not statistically significant (P = .40).Table 2. Relative Risk Comparisons of Postcataract vs Penetrating Keratoplasty EndophthalmitisPeriodEndophthalmitis, %RR for Cataract vs PK (95% CI)Cataract*PK1964-20030.1280.3820.34 (0.30-0.37)1964-19990.1090.3920.28 (0.25-0.31)2000-20030.2650.2001.33 (0.69-2.56)Abbreviations: CI, confidence interval; PK, penetrating keratoplasty; RR, relative risk.*Data available elsewhere.COMMENTThe findings of this literature synthesis demonstrate an apparent decrease in the incidence of postoperative endophthalmitis following PK during the last decade. Our analysis for trends of endophthalmitis over time (Figure 6) revealed that postsurgical endophthalmitis after PK was on the rise from the early 1970s until 1992, when a statistically significant reversal of this trend was demonstrable. The opposite trends over time were observed for cataract surgery.The year 1992 was chosen as the breakpoint, since this represented the year when sutureless clear corneal cataract incision was introduced.THEORIES AND MECHANISMSWhile the incidence of acute endophthalmitis was increasing after cataract extraction,according to our data, the incidence after PK decreased. Several possible explanations exist for an apparent decreased incidence of this complication. The increasingly widespread use of povidone-iodine to disinfect the ocular surface at the time of postmortem harvesting of the donor tissueand intraoperatively could account for less bacterial contamination of donor tissue,as well as less risk of infection from organisms present on the recipient’s ocular surface.The evolution of eye-banking techniques may be another important factor to consider in the down-trend of endophthalmitis cases after PK. The addition of antibiotics for gentamicin-resistant species in the corneal storage media (eg, streptomycin for Optisol-GS [Bausch & Lomb, Irvine, Calif]) may also contribute to the achievement of a more appropriate environment for corneal transplantation. In addition, the greater gram-positive coverage offered by topical fluoroquinolones, introduced in the early 1990s and widely used (but in an off-label indication) for surgical prophylaxis, might theoretically contribute to a reduced incidence of endophthalmitis, which is typically related to gram-positive organisms. The data that support the value of perioperative antibiotics for ophthalmic surgical prophylaxis are, however, inconclusive at this time.STUDY LIMITATIONSThere are potential limitations to the present literature synthesis, some inherent to systematic reviews in general and some particular to our review. These limitations have been described elsewhere.Often, the reports do not provide detail regarding exactly what perioperative measures were used for infectious prophylaxis (eg, povidone-iodine or antibiotics), how surgical technique and adjunctive therapy might have varied among patients and surgeons, and other potentially relevant surgical details. Given these limitations, using the statistical methods described herein (eg, regression analysis and the weighting method), we have minimized the potential drawbacks for our trends analysis. Nonetheless, even with limitations in mind, we believe that the present review has allowed us to address the rate of a relatively rare complication (ie, post-PK acute endophthalmitis) using existing data with increased statistical power.CONCLUSIONSFirst conducted in 1905, corneal transplantation is now the most common transplant procedure performed in the United States. The high potential of expansion for its use highlights the importance of minimizing its complication rates. With more than 33 000 PKs performed each year in the United States aloneand an estimated 100 000 PKs performed worldwide,any increase in the incidence of post-PK complications can result in large absolute numbers of postoperative endophthalmitis cases. The current rate of endophthalmitis after PK (0.200% from 2000 and later vs 0.382% in 1963-1999) equals, respectively, 130 and 380 cases secondary to a seemingly preventable but unforgiving complication.The results of the present synthesis of the literature will need to be confirmed in further studies. Bias inevitably results from the selection of cases included in studies submitted or accepted for publication and hence can potentially affect a systematic review.One approach to the elimination of such bias is to attempt the gathering of nonpublished data from the institutions at which the participating studies were conducted. This is, however, logistically difficult. An alternative solution is to test the hypothesis generated by the review in a large-scale prospective controlled trial with defined inclusion and exclusion criteria, such as surgical technique and prophylactic measures.Correspondence:Peter J. McDonnell, MD, Wilmer Ophthalmological Institute, 727 Maumenee Bldg, 600 N Wolfe St, Baltimore, MD 21287-9278 ([email protected]).Submitted for Publication:March 31, 2004; final revision received August 25, 2004; accepted September 30, 2004.Funding/Support:This project was supported in part by grants EY10335 and CA-91717 from the National Institutes of Health (Bethesda, Md), an award from the Alcon Research Institute (Fort Worth, Tex), an unrestricted gift from Research to Prevent Blindness Inc (New York, NY), and Public Health Service research grant M01 RR00827 from The National Center for Research Resources (Bethesda).REFERENCESMSKresloffAACastellarinMAZarbinEndophthalmitis.Surv Ophthalmol1998431932249862309LPAielloJCJavittJKCannerNational outcomes of penetrating keratoplasty.Arch Ophthalmol19931115095138470985MTabanABehrensRL,NewcombAcute endophthalmitis following cataract surgery: a systematic review of the literature.Arch Ophthalmol2005123613620TACiullaMBStarrSMasketBacterial endophthalmitis prophylaxis for cataract surgery: an evidence-based update.Ophthalmology2002109132411772573JPAdenisPYRobertLocal antimicrobial prophylaxis in cataract surgery: recent controversies and clinical guidelines.Ophthalmologica1997211(suppl 1)77809065942AWFergusonJAScottJMcGaviganComparison of 5% povidone-iodine solution against 1% povidone-iodine solution in preoperative cataract surgery antisepsis.Br J Ophthalmol20038716316712543744Eye Bank Association of AmericaEye Banking Annual Statistical Report.Washington, DC: Eye Bank Association of America; 2000PAiken-O'NeillMJMannisSummary of corneal transplant activity Eye Bank Association of America.Cornea2002211311805497OSerdarevicWorldwide demand for corneal transplantation far outstrips donor tissue availability international agencies find.Euro Times200056

Taban, Mehran; Behrens, Ashley; Newcomb, Robert L.; Nobe, Matthew Y.; Saedi, Golnaz; Sweet, Paula M.; McDonnell, Peter J.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.613pmid: 15883279

ObjectivesTo determine the reported incidence of acute endophthalmitis following cataract extraction over time and to explore possible contributing factors, such as type of cataract incision.MethodsA systematic review of English-language articles was conducted by performing a broad search of PubMed from 1963 through March 2003 using such terms as cataract extraction, endophthalmitis, and postoperative complication. Additional studies were identified from bibliographies of relevant articles and published proceedings. Surgical approach was recorded, when available. Pooled incidence rates and relative risks of developing endophthalmitis using different incision techniques were assessed.ResultsFrom 4916 unique, potentially relevant citations, 215 studies that addressed endophthalmitis and met the selection criteria were analyzed. A total of 3 140 650 cataract extractions were pooled resulting in an overall rate of 0.128% of postcataract endophthalmitis. However, the incidence of acute endophthalmitis changed over time, with a significant increase since 2000 compared with previous decades (relative risk, 2.44 [95% confidence interval, 2.27-2.61]). The rate of endophthalmitis was 0.265% in the 2000-2003 period, 0.087% in the 1990s, 0.158% in the 1980s, and 0.327% during the 1970s. Furthermore, an upward trend in rates after 1992 was noted, compared with 1991 and prior. Incision type appeared to significantly influence risk, as endophthalmitis following clear corneal cataract extraction during the 1992-2003 period was 0.189% compared with 0.074% (relative risk, 2.55 [95% confidence interval, 1.75-3.71]) for scleral incision and 0.062% (relative risk, 3.06 [95% confidence interval, 2.48-3.76]) for limbal incision.ConclusionsThis systematic review indicates that the incidence of endophthalmitis associated with cataract extraction has increased over the last decade. This upward trend in endophthalmitis frequency coincides temporally with the development of sutureless clear corneal incisions.In the past 4 decades, cataract surgery has undergone remarkable technical refinement, with simplified postoperative care and faster visual recovery as consequences.With improved instrumentation, small-incision phacoemulsification became possible in the late 1980s, leading to the current state of the art of sutureless phacoemulsification surgery with foldable intraocular lens implantation.Removal of the lens through a corneal incision was reported as early as 1668; however, the current self-sealing clear corneal incision was first introduced in 1992 by I. Howard Fine, MD.Since then, increasing popularity of clear corneal incisions over limbal and scleral tunnel incisions among cataract surgeons across the United States and Europe has resulted in greater intraoperative control, decreased surgical time, simplified postoperative care, less induction of astigmatism, and faster visual recovery.In the most recent survey of American Society of Cataract and Refractive Surgery members (2003), Leamingreported that clear corneal incision was preferred by 72% of US surgeons and the no-suture closure was preferred by 92%. This acceptance is part of a gradual uptrend from 1.5%, 12.4%, 30%, 40%, and 47% in 1992, 1995, 1997, 1999, and 2000, respectively.Among European surgeons, a similar 51.4% prefer clear corneal incisions,while a 1999 French survey reported a more than 86% preference for clear corneal incisions.Furthermore, sutureless cataract incisions are reportedly preferred among 92%, 94%, and 58% of cataract surgeons in the United States, New Zealand, and Japan, respectively.Endophthalmitis is an uncommon but serious intraocular infection that occurs most commonly as a complication of intraocular surgery and often causes severe visual impairment or even the loss of an eye.The reported incidence of postoperative endophthalmitis varies by the specific surgical procedure and across studies, but the overall incidence has been declining since the late 19th to late 20th century. The incidence of endophthalmitis after cataract surgery was approximately 5% to 10% in the late 1800s and early 1900s,1.5% to 2% during the 1930s,0.5% to 0.7% in the mid 1900s,and 0.06% to 0.09% according to nationwide patient registries in the early 1990s.Improvements in microsurgical and aseptic techniques, advancements in surgical materials, and use of prophylactic broad-spectrum antibiotics, in combination with a better understanding of causes of the infection, may explain this favorable trend.In a meta-analysis of studies published from 1979 to 1991, a period that predates the use of self-sealing clear corneal incisions, Powe et alreported a 0.13% incidence of acute postoperative endophthalmitis following cataract extraction. However, recent reports suggest that the postcataract endophthalmitis rate may be substantially higher, suggesting a greater risk of endophthalmitis coincident with the increase in self-sealing clear corneal incisions.Colleaux and Hamiltonreported a 0.129% and 0.05% incidence of endophthalmitis following cataract extraction with sutureless clear corneal and scleral tunnel incisions, respectively. Similarly, 3 retrospective, comparative, case-controlled studies found a significantly higher endophthalmitis rate associated with clear corneal incisions compared with scleral tunnel incisions.In a study from the Massachusetts Eye and Ear Infirmary (Boston), the incidence of endophthalmitis was 0.68% for clear corneal incisions vs 0.18% for scleral tunnel incisions.More recently, Nakagi et alreported a statistically increased risk with clear corneal incisions (0.29%) compared with sclerocorneal incisions (0.05%). Various other anecdotal reports by cataract surgeons and retinal specialists have also claimed a higher incidence of endophthalmitis with clear corneal incisions.These studies indicate an apparently increased occurrence of endophthalmitis in the last decade and a several-fold increase in endophthalmitis risk associated with self-sealing clear corneal incisions compared with scleral tunnel and sclerocorneal wounds. However, the relative rarity of endophthalmitis following intraocular surgery poses significant difficulty in ascertaining accurate incidence rates or in analyzing effects of multiple risk factors. Most reports regarding the rates of endophthalmitis are based on the experience of individual institutions or groups of surgeons and are limited by the small sample sizes, thereby making comparisons and statistical validity of data difficult. Only more appropriate methods such as extensive reviews or multicenter, prospective studies can help reveal clinical and statistical trends for this adverse outcome. Depending on the projected incidence, a study would need to include as many as 100 000 patients to have sufficient study power to detect even a 50% difference in the risk of endophthalmitis between 2 groups of patients.To obtain the best available perspective, as reflected by the medical literature, and a better understanding of the recent trends in postoperative endophthalmitis following cataract surgery, we conducted a systematic review of the literature. The purpose of our study was to detect changes in the trends of endophthalmitis after cataract extraction and to determine, if present, possible associations of these changes with specific surgical approaches in cataract surgery. In light of the recent reports suggesting an increased incidence of endophthalmitis with clear corneal incisions, we analyzed possible differences in rates according to the date of the publication and the surgical techniques used (eg, clear corneal incision).METHODSSTUDY DESIGNWe performed a systematic review of the literature to identify all published reports pertaining to the outcome of cataract surgery or penetrating keratoplasty. Studies were identified through a search consisting of: (1) a computerized search of Cochrane and PubMed (National Library of Medicine) databases from 1963 through March 2003, using a specific search strategy (Table 1); (2) manual search of reference lists of original reports and review articles, retrieved through the electronic search, that met the selected criteria; (3) review of major ophthalmic textbooks; and (4) review of key published proceedings and scientific session electronic abstracts (ie, Association for Research in Vision and Ophthalmology [ARVO] [Rockville, Md] and American Academy of Ophthalmology [AAO] [San Francisco, Calif]) in 2001 through 2003. Because of the low occurrence of endophthalmitis, the importance of obtaining each published report addressing this potential complication was clearly apparent. Therefore, an intentionally broad search strategy was developed to identify all possible studies that met the eligibility criteria. Keywords were selected based on expert opinion and evaluation of selected review articles on endophthalmitis and cataract surgery.Table 1. PubMed Search StrategyDescriptionNo. of ArticlesPubMed keyword searches Search 1, cataract extraction*16243 Search 2, cataract surgery*16314 Search 3, lens, intraocular*8431 Search 4, lens implantation*5326 Search 5, endophthalmitis3684 Search 6, eye infection*17192 Search 7, surgical wound infection*17208 Search 8, panophthalmitis282 Search 9, postoperative complication*249356Combined searches (1 or 2 or 3 or 4) and (5 or 6 or 7 or 8 or 9)6235Exclusion criteria Limit by language type (English only)4564*Searches also include the plural.SELECTION CRITERIAReports were considered eligible for our review if they satisfied our selection criteria. Each article had to meet all of the following inclusion criteria: (1) the article was written in English; (2) the study examined human cases; (3) the study examined primary or secondary cataract surgery with or without intraocular lens implantation (“secondary cataract surgeries” were those cases involving secondary lens implantation or intraocular lens exchange); and (4) the article addressed postcataract endophthalmitis occurrence (reported the number of procedures and the number of postsurgical endophthalmitis cases even if zero or the numbers could be derived according to reported percentages). We chose to include clinically diagnosed (both culture-positive and culture-negative) cases because it allowed for the inclusion of more studies in order to generate more power for analyzing this relatively rare complication.Articles were excluded from this review if they met any of the following exclusion criteria: (1) the study examined fewer than 10 eyes; (2) the article primarily examined cataract surgery in conjunction with vitrectomy or in patients who underwent vitrectomy; (3) the article examined cataract surgery performed with any glaucoma procedure; (4) endophthalmitis cases were associated with an outbreak (eg, contaminated instruments or phacoemulsification tubing causing a series of these infections); or (5) if mentioned, the study had less than 1 week of postoperative follow-up (except if noticeable number of endophthalmitis cases were identified, in which case the study was included).IDENTIFICATION OF STUDIESThe process of identifying all possible studies satisfying our eligibility criteria involved several steps. Following the computerized search, we read the titles and abstracts of all retrieved citations. Articles were rejected after review of abstracts only if it could be determined that they did not meet the inclusion criteria or if any of the exclusion criteria applied. A full copy of the article was then obtained and reviewed in detail to determine whether the study satisfied the selection criteria.DATA ABSTRACTIONArticles that satisfied the eligibility criteria underwent an intensive, structured review to abstract data on the postsurgical outcome of cataract operations and any potentially significant variables. Data extraction was performed using a standardized review form to record the following: (1) year of publication; (2) journal published; (3) location (ie, country) of trial; (4) the minimum (mean or maximum if minimum was not indicated) duration of follow-up on postsurgical patients; (5) number of eyes undergoing cataract surgery; (6) number of patients who experienced acute endophthalmitis postoperatively (acutewas defined as onset within 6 weeks); if the timeline was not explicitly reported, then, based on review of the study, a determination was made whether it referred to cases with acute endophthalmitis; and (7) type of cataract wound (limbal, sclerocorneal, and corneoscleral incisions were treated as the same type of incision).With publications that reported on more than 1 group of patients or surgical procedures, only analysis of the pertinent groups was performed. If it could be determined that 2 or more studies presented the same data from a single participant population, these data were included only once in this review. Furthermore, if the data were published in more than 1 journal, only 1 was chosen for analysis.STATISTICAL ANALYSISThroughout this report, comparisons of postoperative infection rates were presented using the relative risk statistics. In most cases, the reported relative risk was accompanied by its 95% confidence intervals to provide a consistent criterion by which a difference in infection rates could be construed to be substantial.Weighted regression analysis was used to portray how the postoperative infection rates were changing during the 40-year period from 1964 to 2003. The period was also divided into 2 subperiods (ie, 1964-1991 and 1992-2003) to reflect the date that clear corneal incision was introduced. Infection rates were then fit by a weighted “piecewise” or “segmented” linear model, which was composed of 2 separate linear approximations of the infection rates reported in the articles published within each subperiod. This method produced 2 slope coefficients, which summarized the change in infection rates over time within the indicated subperiod. In addition to the slope coefficients, the weighted regression analysis also produced a pair of 95% confidence intervals for estimating the true value of each of these slopes.The weighted regression analyses described earlier were based on units of analysis as defined in 1 of the following ways: either the units of analysis were the 215 qualifying articles or they were the 40 years in which those publications appeared. When publication year was the unit of analysis, the postoperative infection rate for each year was determined by aggregating the data derived from all qualifying articles that were published in that year. In either case, the statistics were then weighted proportional to the number of surgeries reported within each unit of analysis. With this weighting strategy, statistical results can be directly linked to the overall postoperative infection rates, which would not have been the case under an equal case-weighting plan. In other words, the weighting was performed relative to the volume of surgeries both within each study or year, which gave more power to studies with higher numbers of surgeries and less to those with fewer operations. All coefficients for this regression model were computed using the SAS NLIN procedure.RESULTSYIELD OF LITERATURE SEARCHFigure 1illustrates the flow of literature reviewed. Our computerized search identified 4564 unique citations, while manual search of references resulted in 257 additional articles. From these, 215 studies fulfilled our eligibility criteria. The 215 studies were published in 2 textbooks, 3 published proceedings (2 ARVO, 1 AAO, 2 Eye World), and 40 journals (Figure 2) and were categorized by the year of publication (Figure 3). In general, we observed increasing numbers of published reports over time. The highest number of published studies in any single year was 18 in 2002, likely reflecting the fact that there are more investigators and journals in more recent times. The highest number of cataract surgeries was reported in 1997 (n = 777 367). There were no studies published in the years 1965, 1966, 1968, and 1970.Figure 1.Flow of reviewed literature.Figure 2.Studies from each journal.Figure 3.Distribution of the 215 studies according to each year.STUDY CHARACTERISTICSThe United States had the highest number of studies conducted (95), followed by the United Kingdom (29), India (9), Canada (7), Germany (7), African countries (6), Australia (6), Denmark (6), Spain (6), Sweden (6), Turkey (5), Belgium (4), Austria (3), Nepal (3), Pakistan (3), Finland (2), France (2), Japan (2), Netherlands (2), and New Zealand (2). Greece, Ireland, Israel, Malaysia, Norway, Russia, Saudi Arabia, Singapore, Switzerland, and Vietnam each contributed 1 study to this analysis.Figure 4shows the distribution of sample sizes. The median number of cataract surgeries included in the 215 studies of our analysis was 567 (range, 18-735 096). The minimum (or mean if minimum was not indicated) duration of follow-up on postsurgical patients in the studies ranged from 4 days to 5 years.Figure 4.Frequency distribution of the total sample sizes (number of eyes studied) in the 215 studies.OVERALL RESULTSThe overall pooled estimate (1964-2003) of the incidence of acute endophthalmitis after cataract surgery was 0.128% based on 3 140 650 cataract extractions. The rate for each decade was as follows: 0.138% in the 1960s, 0.327% in the 1970s, 0.158% in the 1980s, 0.087% in the 1990s, and 0.265% in 2000 and beyond (Figure 5). The rate of endophthalmitis from 1963 to 1999 was 0.109%, while the rate from 2000 to 2003 was 0.265%, representing an almost 2.5-fold increase in its incidence (relative risk, 2.44 [95% confidence interval, 2.27-2.61]).Figure 5.Pooled estimates of endophthalmitis frequency following cataract surgery according to year. The line indicates number of cataract surgeries; the bars indicate endophthalmitis frequency.ENDOPHTHALMITIS FREQUENCY—TRENDS OVER TIMETo assess potential changes in the incidence of acute endophthalmitis, we chose to compare the rates from before 1992 with those from 1992 forward, the year in which the self-sealing clear corneal incision was introduced.A weighted analysis of the mean endophthalmitis rate for each year or article was used, both producing the same results (Figure 6A and B). The slope obtained from the regression analysis for the years 1964 to 1991 was –0.0103, suggesting a gradual reduction in the incidence of postoperative endophthalmitis over time. The slope from 1992 to 2003 was 0.0257, indicating a gradual increase in the rate of endophthalmitis over this period. The difference between these slopes was significant (Figure 7).Figure 6.Trends of endophthalmitis rate. Slope is best-fit line from weighted regression analysis (see “Methods” section). A, Based on each study/publication (weighted per surgery), 1963-1991 slope, –0.0103; 1992-2003 slope, 0.0257. B, Based on each year (weighted per surgery), 1963-1991 slope, –0.0103; 1992-2003 slope, 0.0257.Figure 7.Ninety-five percent confidence intervals of trends analysis. Slopes within each period with error bars indicating 95% confidence intervals. A, Based on each study/publication. B, Based on each year.ENDOPHTHALMITIS FREQUENCY—EFFECT OF INCISION TYPEThe rates for this analysis were obtained from analyzing only those studies that specifically indicated the type of cataract incision performed from 1992 to 2003. This information was specified in 57 of the 117 (approximately 49%) published studies or 421 940 of the 2 232 026 (approximately 19%) cataract procedures reported during this period. The rate of acute endophthalmitis was significantly higher following clear corneal cataract extraction compared with both scleral and limbal incisions (Table 2). There was no significant difference between the rates for scleral and limbal incisions.Table 2. Relative Risks of Endophthalmitis Rate Among Cataract Incision Type*Incision TypeRelative Risk (95% Confidence Interval)Method 1 (Endo Rate, %)Method 2 (Endo Rate, %)Clear corneal (0.19)Scleral (0.07)2.55 (1.75-3.71)Clear corneal (0.19)Limbal (0.06)3.06 (2.48-3.76)Scleral (0.07)Limbal (0.06)1.20 (0.82-1.75)Abbreviations: endo, endophthalmitis; limbal, limbal or sclerocorneal or corneoscleral.*Based on the published studies reporting their cataract surgical technique (ie, incision type). This information was specified in approximately 49% of published studies or approximately 19% of the cataract surgeries reported from 1992 to 2003.COMMENTThe findings of this literature synthesis demonstrate an apparent increase in the incidence of postoperative endophthalmitis following cataract surgery during the last decade. The increased occurrence of endophthalmitis after cataract extraction has been temporally associated with the use of self-sealing clear corneal incisions, and we detected a statistically significant increase in risk associated with clear corneal incisions when compared with other incision types from 1992 to 2003. Our analysis for trends of endophthalmitis (Figure 6) over time revealed that the postsurgical endophthalmitis after cataract surgery was on the decline from the early 1960s until 1992 when sutureless clear corneal incision was introduced, at which time a statistically significant reversal of this trend was demonstrable. Comparing the overall rates of endophthalmitis following cataract extraction from before and after 2000 also revealed a significant increase with the more recent reports. We chose 2000 for this comparison for 2 reasons: (1) According to an American Society of Cataract and Refractive Surgery survey,this was the year when clear corneal incision was used by about half of US cataract surgeons. (2) There is a natural delay between the introduction of a new technique and the inherent gap between when a study is conducted until the publication of its results; therefore, an article published in 2000 would generally encompass a study conducted several years prior (eg, 1995-1998).THEORIES/MECHANISMSTheories to account for more frequent postcataract endophthalmitis with sutureless clear corneal incisions are centered on the stability of the surgical wound because its integrity is believed to be a critical factor. In a study by Maxwell et al,up to 80% of postsurgical cases of endophthalmitis were associated with wound defects, such as wound gape and/or malapposition and leakage. Montan et alfound wound abnormality to be a statistically significant risk factor in their review of more than 22 000 cataract surgeries. However, problems with clear corneal cataract wounds may not be readily apparent intraoperatively. Furthermore, wound integrity may vary as a function of intraocular pressure (IOP). Intraocular pressure has been known to vary in the postoperative period. In a report by Shingleton et al,21% of eyes had IOPs of 5 mm Hg or less following clear corneal phacoemulsification. Squeezing of the lids or even normal unconscious blinking have been shown to cause wide variations of IOP in both human and animal subjects.Doanedemonstrated that dramatic posterior movement of the globe occurs in relation to lid motion. He attributed this to the pressure of the lid on the globe, which resulted in a posterior movement of the globe, ranging between 0.7 to 1.6 mm.These pressure recordings thus confirm the clinically apparent fact that large fluctuations in IOP can occur during the postoperative period and blinking or squeezing of the lids can exert tremendous forces on the globe, which may be important following intraocular surgery.Recent imaging studies of clear corneal incisions using optical coherence tomography may explain the underlying cause of the increased risk of endophthalmitis associated with self-sealing clear corneal incisions.Optical coherence tomography reveals that transient fluctuations in IOP of a magnitude not uncommon in the postoperative period result in gaping of the unhealed wound margins. Furthermore, histologic examination of the clear corneal incisions showed that india ink particles could migrate from the ocular surface into the stroma through the wound.In addition, the lack of conjunctiva covering the clear corneal incisions and a possible increased technical difficulty in constructing a stable, self-sealing incision in the cornea compared with the sclera may contribute to an elevated risk of endophthalmitis with clear corneal incisions relative to scleral tunnel incisions.In the light of these findings, although not proven in any controlled study, the use of a suture to seal the wound might be justified if there is any question about the self-sealing properties of a clear corneal cataract incision.STUDY LIMITATIONSThere are potential limitations to the present literature synthesis, some inherent to systematic reviews in general and some particular to our review. First, the studies included in this analysis may be subject to some methodological variation. Definitions of endophthalmitis may have varied; in addition, inherent difficulties in the diagnosis of this complication are apparent secondary to the uncommon manifestation of the “classic” form of postsurgical endophthalmitis. Miscoding of endophthalmitis itself could be a serious concern for data quality of any epidemiological analysis, as demonstrated in 1 recent study where Li et alreported that up to 24% of postsurgical endophthalmitis cases were not coded as endophthalmitis. Second, the majority of studies were retrospective and the accumulation of study populations frequently took several years so the quality of data obtained within a single study may be uneven. Third, sample sizes varied across studies and years. However, using the statistical methods described earlier (eg, regression analysis and the weighting method), we minimized the potential drawbacks for our trends analysis.The overwhelming number of publications showing retrospective data, and the limited number of prospective, case-controlled studies with appropriate randomization methods, negatively affected the proportion of high-quality articles reviewed. To evaluate a trend in endophthalmitis rates over time, we decided to be more flexible in the article-inclusion criteria in spite of sacrificing the strength of the evidence. This was especially true with older citations, which frequently lacked more rigorous methods. These studies were included so that information from these years would not be missing.Systematic reviews have an intrinsic limitation: the quality of the outcome depends on the quality of the inputs. Therefore, their findings must be interpreted with caution. The issue of publication bias is important both from the scientific perspective (complete dissemination of knowledge) and from the perspective of those who combine results from a number of similar studies (literature synthesis). Positive-outcome bias, also termed publication bias, is a widely recognized phenomenon and refers to the higher likelihood of positive results to be published than studies with negative results.One reason for this bias is that authors and investigators are less likely to submit manuscripts reporting negative outcomes to journals.For example, studies with particularly high frequencies of occurrence of complications may not be reported.Although less clear, there have also been reports that journal reviewers and editors are more likely to publish positive results relative to negative ones (the file drawer problem).Evidence also exists that studies with positive results are published on average several years sooner than studies with negative results.Therefore, potentially additional unpublished evidence regarding rates of endophthalmitis following cataract surgery and clear corneal incisions during the past decade may be unavailable for analysis.Nonetheless, even with these limitations in mind, we believe that our analysis provides clear evidence to support the notion that postsurgical acute endophthalmitis following cataract extraction has been increasing during the past decade. Furthermore, there is evidence that this trend is associated with the increased prevalence of the self-sealing clear corneal incision technique. By synthesizing the results of multiple studies, the present review has allowed us to address the rate of a relatively rare complication using existing data with increased statistical power.CONCLUSIONS AND FUTURE DIRECTIONSAge-related cataract is one of the leading causes of visual impairment worldwide and cataract extraction is one of the most frequently performed surgical procedures in the world.Increasing age is associated with an increasing prevalence of cataract.With the projected doubling of the number of people older than 65 years by 2020,the volume of cataract surgery will increase dramatically both in developed and developing countries. Etzioni et alrecently reported a projected 47% increase in the demand for ophthalmologists by 2020, owing primarily to cataract surgeries. With such a high volume of cataract surgery worldwide, any increase in the incidence of endophthalmitis can lead to large absolute numbers of surgical failures. Considering a current (2002) volume of more than 2.5 and 10 million cataract surgeries performed annually in the United Statesand worldwide,the recent increase in endophthalmitis occurrence (0.265% from 2000 and later vs 0.109% in 1963-1999) can equate to approximately 4000 and 16 000 additional cases of endophthalmitis annually in the United States and worldwide, respectively. Since postoperative endophthalmitis continues to be a devastating, sight-threatening complication of cataract surgery, the global implications for the need for an effective prevention strategy are obvious. This encompasses the adoption of a surgical technique with the least risk for developing endophthalmitis.Some other factors inherent to the cataract surgery may also play a role in the increase of endophthalmitis rates in the past few years. These might include changes in outpatient vs inpatient surgery, a move from hospital operating rooms to a freestanding ambulatory setting, changes in anesthesia from injected to topical, changes in intraocular lens design or materials (eg, foldable vs nonfoldable, 1 piece vs 3 piece, rigid acrylic vs silicone vs foldable acrylic), and changes in antibiotic prophylaxis and sensitivity of organisms. In an attempt to control for these variables and minimize bias, we contrasted results of cataract surgery to those obtained after penetrating keratoplasty, because both surgeries have evolved in parallel over time.However, some of the former particular variables, other than incision type, may still be linked to the higher incidence of endophthalmitis and should be more thoroughly studied in large prospective trials in the future.The results of the present synthesis of the literature indicating an increased risk of endophthalmitis associated with self-sealing clear corneal cataract incisions will need to be confirmed in further studies. Bias inevitably results from the selection of cases included in studies submitted or accepted for publication and hence can potentially affect a review. One approach to elimination of such bias is to attempt the gathering of nonpublished data from the institutions at which the participating studies were conducted. This is, however, logistically impractical and leaves uncorrected errors owing to methodological anomalies. Dickersin and Rennie,among others before them, have proposed the comprehensive registration of all initiated clinical trials. Yet an alternative solution is to test the hypothesis generated by the review in a large-scale prospective trial with defined inclusion criteria, such as surgical technique. Large multicenter, prospective, controlled trials, such as the recent European Society of Cataract and Refractive Surgery–instigated, 16-center European study,are necessary to address the current observation of increased rate of endophthalmitis after cataract surgery and other key issues in postsurgical endophthalmitis. The Internet can provide a fast and easy avenue for the acquisition of scientific data from such a large multicenter trial.The Magdeburg University Eye Hospital (Magdeburg, Germany) recently initiated a national prospective study on “Intraoperative Anti-infective Prophylaxis for Cataract Surgery” using such a resource.This new way of paperless data recording can help realize such a multicenter clinical trial in the United States and worldwide.Correspondence:Peter J. 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Rezai, Kourous A.; Eliott, Dean; Ferrone, Philip J.; Kim, Rubin W.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.621pmid: 15883280

ObjectiveTo evaluate the effect of a near confluent pattern of indirect laser photocoagulation in reducing the rate of progression and re-treatment of threshold retinopathy of prematurity.MethodsThis study examined a noncomparative interventional case series. We performed a retrospective review of the medical records of patients who underwent peripheral laser ablation by 1 surgeon for threshold retinopathy of prematurity from 1997 to 2002. A total of 58 eyes from 31 patients were treated, and 44 eyes of 23 patients were included in the study. Ten eyes of 5 infants had zone 1 disease, and 34 eyes of 18 infants had zone 2 disease. Laser spots were placed in a near confluent pattern in the peripheral avascular retina between the ridge of extraretinal proliferation and the ora serrata. The mean ± SD number of laser spots was 2534 ± 455 for zone 1 (range, 2100-3378) and 1850 ± 487 for zone 2 (range, 1030-2689).ResultsIn 7 eyes of 4 infants with zone 1 disease, the retinopathy regressed and did not require any further treatment. Three eyes of 2 infants, however, progressed after laser treatment and required vitrectomy surgery. Progression was defined as the development of stage 4 or 5 disease. None of the patients with zone 2 disease had progression of retinopathy, and none of them needed more than 1 treatment. Patients tolerated the procedure well, and there were no complications at the time of the procedure or at follow-up visits.ConclusionsA near confluent pattern of laser photocoagulation may reduce the rate of progression of threshold retinopathy of prematurity in zone 2 (0%). The near confluent pattern of treatment may also reduce the re-treatment rate of the disease (0%). Larger studies are needed to confirm our findings.Retinopathy of prematurity (ROP) is a proliferative disease of the developing retinal vasculature in premature infants, which may lead to severe visual loss.The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity showed that cryoablation of the avascular peripheral retina significantly reduces the progression of threshold ROP.Threshold ROP is defined as stage 3 disease in zones 1 or 2 with at least 5 contiguous or 8 cumulative clock hours of extraretinal fibrovascular proliferation in the presence of plus disease.It was subsequently demonstrated that indirect laser photocoagulation is at least as effective as cryotherapy in preventing unfavorable outcomes of ROP.Indirect laser photocoagulation permits a precise and relatively atraumatic treatment to the retina, is more convenient and technically easier to administer, and results in less ocular and systemic adverse effects.The wavelength and pattern of laser application in ROP may affect the outcome. Comparisons have been made between argon and diode lasers, a dense vs less dense laser pattern, and treatment to the avascular peripheral retina with and without treatment of the ridge.Since 1997, one of us (D.E.) has been using the diode laser indirect ophthalmoscope to deliver a near confluent laser pattern to the peripheral avascular retina between the ridge and the ora serrata. To further evaluate the effect of the density of laser photocoagulation on the progression of threshold ROP, we compared a near confluent pattern of indirect infrared diode laser photocoagulation (wavelength, 810 nm) in threshold ROP with the previously reported patterns of laser treatment.Treatment was applied to the peripheral avascular retina with a near confluent pattern of laser spots, spaced approximately 0.25 burn width apart. By the end of the treatment session, the laser burns had expanded to a confluent pattern.METHODSA retrospective medical record review was performed on premature infants who underwent treatment for threshold ROP from 1997 to 2002 at Kresge Eye Institute (Detroit, Mich), Hutzel Hospital (Detroit), Children’s Hospital of Michigan (Detroit), Huron Valley Hospital (Commerce Township, Mich), and Detroit Riverview Hospital. All of the patients underwent preoperative examination and treatment by 1 surgeon (D.E.). A total of 58 eyes from 31 consecutive patients were diagnosed as having threshold ROP and were treated within 48 hours of diagnosis. Fourteen eyes of 8 patients with zone 2 disease were excluded from the study: 8 eyes of 4 patients had only 1 month of follow-up after laser treatment, 1 patient died 1 month after laser treatment, 2 eyes of 1 patient were treated with cryopexy owing to small pupils and extensive tunica vasculosa lentis, and 2 eyes of the remaining 2 patients had received previous laser treatment at another institution and received supplemental laser treatment by us. (In all 14 eyes, the retinopathy had regressed at the last examination.) Ten eyes of 5 patients with zone 1 disease and 34 eyes of 18 patients with zone 2 disease were included in the study. All of the eyes were treated with indirect diode laser photocoagulation and had at least 3 months of follow-up.The mean gestational age of the infants was 24.7 weeks (range, 23-27 weeks), and the mean birth weight was 674 g (range, 520-936 g). All eyes had reached a minimum of 5 contiguous or 8 total clock hours of extraretinal fibrovascular proliferation with vascular dilation and tortuosity in the posterior pole (plus disease).A complete examination was performed, including indirect ophthalmoscopy with 360° of scleral depression. Pupillary dilation was achieved with 2.5% phenylephrine hydrochloride and 1% tropicamide (1 drop of each, repeated once after 5 minutes). Examination findings were recorded on standardized data sheets. The zones and stages were documented as described by the Committee for the Classification of Retinopathy of Prematurity.Written informed consent from a legal guardian was obtained before treatment. If both eyes required treatment, they were treated at the same session.A portable indirect infrared diode laser (IRIS Medical Inc, Mountainview, Calif), a lid speculum, a scleral depressor, and a 28-diopter aspheric lens (Volk, Mentor, Ohio) were used for all of the treatments. One drop of proparacaine was placed in each eye before treatment. Balanced salt solution drops provided a clear view for the duration of the procedure. In all cases, the laser treatment was applied to the avascular retina between the anterior edge of the fibrovascular ridge and the ora serrata for 360°. Areas of retina that were covered with preretinal hemorrhage were not treated. A moderate white burn was the target intensity that was achieved at a power range of 300 to 500 mW. Duration of a single spot was 100 milliseconds. The laser burns were spaced approximately 0.25 burn width apart. By the end of the treatment session, the laser burns had expanded to a confluent pattern.Follow-up examinations were performed at weekly intervals until complete regression of extraretinal fibrovascular tissue had taken place. Once complete regression was achieved, follow-up was extended to biweekly and then monthly intervals until 6 months of age. Progression was defined as the development of any retinal detachment (stages 4A, 4B, and 5).RESULTSZONE 1 RETINOPATHYTen eyes of 5 patients with zone 1 disease were included in the study (Table 1). Three of the treated infants were male, and 3 were black. The mean gestational age of the infants was 24.6 weeks (range, 24-26 weeks), and the mean birth weight was 679 g (range, 620-770 g). The mean number of clock hours of stage 3 ROP was 10.6 (range, 8-12). Treatment intensity ranged from 300 to 500 mW, with a mean ± SD number of spots of 2534 ± 455 (range, 2100-3378). These infants were followed for up to 40 months. Both eyes of 1 infant progressed to stage 5, which required vitrectomy surgery. One eye of 1 infant developed anterior-posterior traction on the macula and underwent lens-sparing vitrectomy with a good final anatomic outcome. Neovascularization in the remaining 7 eyes with zone 1 disease regressed after laser treatment, and none of these eyes required additional treatment. Seven (70%) of 10 eyes with zone 1 disease had a favorable outcome (95% confidence interval [CI], 42%-98%).Table 1. Clinical Data for Patients Treated With Near Confluent Laser Pattern for Zone 1 Threshold Retinopathy of PrematurityPatient No./Sex/Gestational Age, wk/Race/Weight, gZoneClock Hours of NeovascularizationNo. of SpotsFollow-up, moOutcome1/F/24/AA/640 Right eye11221664Regressed Left eye1122100Regressed2/M/24/AA/650 Right eye111222628Stage 5, vitrectomy Left eye1112634Stage 5, vitrectomy3/M/25/W/620 Right eye11227193Regressed Left eye1122562Regressed4/M/24/W/770 Right eye19215040Regressed Left eye1112210Stage 4B, vitrectomy5/F/26/AA/755 Right eye18319310Regressed Left eye183378RegressedAbbreviations: AA, African American; W, white.ZONE 2 RETINOPATHYThirty-four eyes of 18 infants with zone 2 threshold ROP were included in the study (Table 2). Eight of the treated infants were male, and 8 were black. The mean gestational age was 24.7 weeks (range, 23-27 weeks), and the mean birth weight was 673 g (range, 520-936 g). The mean number of clock hours of stage 3 ROP was 8.4 (range, 5-12). Treatment intensity ranged from 300 to 500 mW, with a mean ± SD number of spots of 1850 ± 487 (range, 1030-2689). None of the eyes required supplemental laser treatment. Mean follow-up was 14.9 months. All eyes with zone 2 disease (100%) had a favorable outcome (95% CI, 90%-100%).Table 2. Clinical Data for Patients Treated With Near Confluent Laser Pattern for Zone 2 Threshold Retinopathy of PrematurityPatient No./Sex/Gestational Age, wk/Race/Weight, gZoneClock Hours of NeovascularizationNo. of SpotsFollow-up, moOutcome1/M/25/AA/680 Right eye2811627Regressed Left eye2101382Regressed2/M/24/AA/640 Right eye211&ap;250031Regressed Left eye211&ap;2500Regressed3/F/24/AA/630 Right eye210&ap;180016Regressed Left eye210&ap;1800Regressed4/F/24/A/640 Right eye26114814Regressed Left eye261181Regressed5/F/25/AA/520 Right eye26103022Regressed Left eye2121430Regressed6/F/26/AA/820 Right eye210268912Regressed Left eye2101789Regressed7/M/24/MR/645 Right eye21119486Regressed8/F/24/AA/620 Right eye21024903Regressed Left eye2102593Regressed9/M/24/W/630 Right eye29112060Regressed Left eye2101120Regressed10/F/25/AA/520 Right eye25&ap;250012Regressed Left eye25&ap;2500Regressed11/F/25/W/720 Right eye21020104Regressed Left eye2101956Regressed12/M/24/W/550 Right eye29176222Regressed13/M/25/W/800 Right eye25181041Regressed Left eye251790Regressed14/M/24/MR/540 Right eye2820893Regressed Left eye282398Regressed15/F/26/W/910 Right eye2921054Regressed Left eye252076Regressed16/F/25/W/764 Right eye21017013Regressed Left eye2102189Regressed17/M/27/W/936 Right eye2716177Regressed Left eye251892Regressed18/F/23/AA/540 Right eye26&ap;15003Regressed Left eye29&ap;1500RegressedAbbreviations: A, Asian; AA, African American; MR, mixed race; W, white.No cases of iris burn, cataract formation, or anterior segment ischemia in any of the treated eyes (both zone 1 and 2) were noted during the follow-up visits. In some infants, bradycardia and/or oxygen desaturation occurred during the laser treatment, which resolved after temporary discontinuation of the treatment.COMMENTRetinopathy of prematurity is a major cause of blindness in newborns.Ideally, premature infants are examined according to screening guidelines established by the American Academies of Ophthalmology and Pediatrics and by the Association for Pediatric Ophthalmology and Strabismus, and treatment is initiated shortly after threshold disease is reached. Recently, the Early Treatment of Retinopathy of Prematurity Cooperative Group recommended peripheral retinal ablation treatment to be considered for zone 1, any stage ROP with plus disease; zone 1, stage 3 ROP with or without plus disease; and zone 2, stage 2 or 3 ROP with plus disease.The main goal of treatment is to prevent the progression to retinal detachment, because the treatment of advanced stages of ROP (stages 4 and 5) is associated with a poor functional outcome.Although the exact cause of ROP is not known, it develops in premature infants with low birth weight.The disease is characterized by proliferation of abnormal fibrovascular tissue at the border of vascularized and nonvascularized retina.The liberation of various angiogenic molecules by cells in the hypoxic retina may contribute to the progression of the disease.It is likely that vascular endothelial growth factor is one of the molecules that contributes to vascular proliferation and vasodilation.The production of vascular endothelial growth factor is regulated by hypoxia, and both retinal pigment epithelial cells and glial cells contribute to the expression of vascular endothelial growth factor in the presence of hypoxia.As has been extensively reported, the ablation of the hypoxic peripheral retina with cryotherapy or photocoagulation increases the likelihood of regression of the disease.It was shown that a dense pattern of laser photocoagulation (649 spots for zone 2 disease and 1253 spots for zone 1) was more successful than a less dense pattern (457 spots for zone 2 disease and 592 spots for zone 1) in reducing disease progression.One may have expected this outcome, since more thorough ablation of hypoxic tissue would result in less angiogenic factors. These findings suggest that a near confluent laser pattern may be even more successful than the reported dense treatment pattern. Because the small sample size of our patients with zone 1 disease (10 eyes of 5 infants) would not enable us to directly compare our results with the recently reported data for dense and less dense laser photocoagulation patterns, we compared our results for zone 2 retinopathy.Our mean ± SD number of laser spots, 1850 ± 487, was much higher than that in the reported study for dense treatment of zone 2 eyes (649 spots) and less dense treatment of zone 2 eyes (457 spots). None of our patients progressed to stage 4A, 4B, or 5. The rate of progression in our group (0%) was lower than the reported study with dense laser treatment of zone 2 eyes (3.8%) and the less dense laser pattern (21.2%). The rate of re-treatment in our group (0%) was also lower than the re-treatment rates for the reported dense laser treatment (37.5%) and the less dense laser pattern (35.3%); however, the reported re-treatment rates involved patients with both zone 1 and zone 2 disease (our data include only zone 2; however, none of our zone 1 patients required re-treatment).In a recent retrospective study,however, it was shown that although confluent laser photoablation lowered the rate of supplemental treatment, the overall progression to stage 4 or 5 was similar to other treatment patterns. The number of laser spots in the eyes receiving confluent laser treatment (zone 1 or zone 2) ranged from 693 to 4535 spots, with a mean ± SD of 1943 ± 912 spots.A direct comparison of our results with this report is not possible, since the authors divided zone 2 into anterior and posterior and grouped their data for zone 1 and posterior zone 2 together. This division may be useful because posterior zone 2 disease may respond differently from anterior zone 2 disease; however, the retrospective nature of our study did not enable this division.In our study, 10 eyes of 5 patients with zone 1 disease and 34 eyes of 18 patients with zone 2 threshold ROP were treated with near confluent laser therapy within 48 hours of diagnosis. Although the number of laser spots is a useful measure of the extent of treatment, it is less important than the surface area of the treated retina, since spot size may vary when using the indirect ophthalmoscope to deliver laser photocoagulation. Spot size depends on several variables, including distance of the handheld aspheric lens from the eye, dioptric power of the aspheric lens, burn duration, and burn intensity. In addition, the visible burn expands shortly after treatment. Our goal was to create burns that were initially approximately 0.25 burn width apart, which expanded to a near confluent pattern by the end of the treatment session (typically 30 to 40 minutes per eye). In this manner, we attempted to treat almost the full extent of the hypoxic retinal surface area.We acknowledge that others may already have treated the avascular area with a large number of laser spots.The number of reported laser spots ranges from approximately 300 to 4535 per eye. There is great variability in the number of spots within each study, leading to a mean number of laser spots that is generally lower than ours. Furthermore, we emphasize that the treatment of the entire area of the avascular retina is more important than the actual number of spots.The most important outcome in assessing the treatment of threshold ROP is the progression of the disease to advanced stages. After a mean follow-up of 14.9 months (for zone 2 only), none of the eyes in our zone 2 series progressed to stage 4 or 5. One may hypothesize that the lower rate of progression for our near confluent treatment pattern for zone 2 disease (0%) compared with the reported dense treatment pattern for zone 2 disease (3.8%) and less dense pattern for zone 2 disease (21.2%) is based on more thorough ablation of the hypoxic tissue (in the near confluent treatment) that is responsible for angiogenesis.None of the eyes in our series for zone 2 disease required re-treatment. If progression of neovascularization occurred despite a near confluent laser pattern, there would be essentially no untreated peripheral avascular retina left for re-treatment (except for patients who experienced preretinal hemorrhage in the avascular peripheral retina before initial treatment). Our re-treatment rate for zone 2 disease (0%) compares favorably with the reported re-treatment rate in the dense treatment pattern (37.5%) and less dense pattern (35.3%).A statistical comparison is not possible, since the reported re-treatment rates involved patients with both zone 1 and zone 2 disease and our sample size for zone 1 disease was too small for direct comparison (although none of our zone 1 patients required re-treatment).It has been suggested that potential adverse effects of intense laser photocoagulation of the avascular retina include anterior segment ischemia and necrosis.It is not known whether this is the result of intense ablation of the retina or of the inadvertent treatment of anterior segment structures. In none of our infants did we observe signs of anterior segment ischemia. The development of cataract is another reported adverse effect of transpupillary laser treatment.The incidence of cataract formation is less with infrared diode lasers compared with argon lasers. In our series, we did not observe the development of cataract in any of our patients during the follow-up period. Although the exact mechanism is not known, it has been hypothesized that the laser energy may be absorbed by the dense tunica vasculosa lentis (when present), or it may lead to the destruction of long posterior ciliary arteries along the 3- and 9-o’clock meridians, leading to anterior segment ischemia and/or cataracts.Race may play a role in the progression of ROP in low-birth-weight infants.Severe, vision-threatening ROP occurs with greater frequency in white infants than in black infants. In our study, 8 of 18 patients with zone 2 disease were black. 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of vascular endothelial growth factor (VEGF) receptors flt-1 and flk-1 in the oxygen-injured rat retina.Growth Factors199816199777366JStoneTChan-LingJPe'erAItinHGnessinEKeshetRoles of vascular endothelial growth factor and astrocyte degeneration in the genesis of retinopathy of prematurity.Invest Ophthalmol Vis Sci1996372902998603833TLYoungDCAnthonyEPierceEFoleyLESmithHistopathology and vascular endothelial growth factor in untreated and diode laser-treated retinopathy of prematurity.J AAPOS1997110511010875087ISteinAItinPEinatRSkaliterZGrossmanEKeshetTranslation of vascular endothelial growth factor mRNA by internal ribosome entry: implications for translation under hypoxia.Mol Cell Biol199818311231199584152LPAielloJMNorthrupBAKeytHTakagiMAIwamotoHypoxic regulation of vascular endothelial growth factor in retinal cells.Arch Ophthalmol1995113153815447487623MABehzadianXLWangMShabraweyRBCaldwellEffects of hypoxia on glial cell expression of angiogenesis-regulating factors VEGF and TGF-beta.Glia1998242162259728767SRLambertACaponeJrKACingleAVDrackCataract and phthisis bulbi after laser photoablation for threshold retinopathy of prematurity.Am J Ophthalmol200012958559110844048MGogginMO’KeefeDiode laser for retinopathy of prematurity—early outcome.Br J Ophthalmol1993775595628218051TNFlemingPERungeSTCharlesDiode laser photocoagulation for prethreshold, posterior retinopathy of prematurity.Am J Ophthalmol19921145895921443021VSeiberthOLinderkampIVardarliMCKnorzHLiesenhoffDiode laser photocoagulation for threshold retinopathy of prematurity in eyes with tunica vasculosa lentis.Am J Ophthalmol19951197487517785689VSeiberthOLinderkampIVardarliTransscleral vs transpupillary diode laser photocoagulation for the treatment of threshold retinopathy of prematurity.Arch Ophthalmol1997115127012759338672RSKaiserMTTreseIris atrophy, cataracts, and hypotony following peripheral ablation for threshold retinopathy of prematurity.Arch Ophthalmol200111961561711296033AVDrackJPBurkeJSPulidoRVKeechTransient punctate lenticular opacities as a complication of argon laser photoablation in an infant with retinopathy of prematurity.Am J Ophthalmol19921135835841575234AEPogrebniakJPBollingMWStewartArgon laser-induced cataract in an infant with retinopathy of prematurity.Am J Ophthalmol19941172612628116758ACaponeJrAVDrackTransient lens changes after diode laser retinal photoablation for retinopathy of prematurity.Am J Ophthalmol19941185335357943140BNCampolattaroGTLuederCataract in infants treated with argon laser photocoagulation for threshold retinopathy of prematurity.Am J Ophthalmol19951202642667639320SPChristiansenJDBradfordCataract in infants treated with argon laser photocoagulation for threshold retinopathy of prematurity.Am J Ophthalmol19951191751807832223RSGoldCataracts associated with treatment for retinopathy of prematurity.J Pediatr Ophthalmol Strabismus1997341231249083960BDSimonsMCWilsonRWHertleDBSchaeferBilateral hyphemas and cataracts after diode laser retinal photoablation for retinopathy of prematurity.J Pediatr Ophthalmol Strabismus1998351851879627885JWO'NeilAKHutchinsonRASaundersMEWilsonAcquired cataracts after argon laser photocoagulation for retinopathy of prematurity.J AAPOS19982485110532367RASaundersMLDonahueLMChristmannRacial variation in retinopathy of prematurity: the Cryotherapy for Retinopathy of Prematurity Cooperative Group.Arch Ophthalmol19971156046089152127

Robertson, Dennis M.; McLaren, Jay W.; Salomao, Diva R.; Link, Thomas P.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.629pmid: 15883281

ObjectiveTo report retinopathy following exposure to light from a commercially available class 3A green laser pointer.MethodsA 55-year-old woman with a ring melanoma was scheduled for enucleation. The eye (visual acuity 20/20) had a healthy-appearing macular retina. The retina was exposed to light from a commercially available class 3A green laser: 60 seconds to the fovea, 5 minutes to a site 5° below the fovea, and 15 minutes to a site 5° superior to the fovea. Color photographs were obtained before and after exposure. The eye was enucleated 20 days after exposure.ResultsLaser power measurements averaged less than 5 mW. Retinopathy was observed 24 hours after laser exposure. This was characterized by a yellowish discoloration at the level of the retinal pigment epithelium (RPE) in the subfoveal region and at the site superior to the macula where the retina received 15 minutes of laser exposure. Each site developed granular changes at the level of the RPE within 5 days of exposure. Histologic study showed RPE damage in the exposed subfoveal and parafoveal regions.ConclusionA class 3A green laser pointer caused visible retinopathy in the human eye with exposures as short as 60 seconds.We report the development of clinically recognizable retinopathy following exposure of the human eye to light from a commercially available class 3A green laser pointer. A 55-year-old woman with a ring melanoma that involved the ciliary body was scheduled for enucleation. The eye had a healthy-appearing macular retina and good visual function (visual acuity 20/20). The patient agreed to have her retina exposed to laser light from the green laser pointer before enucleation. Continuous exposure was directed to the fovea for 1 minute, to the retina 5° below fixation for 5 minutes, and to the retina 5° above fixation for 15 minutes. The retina was evaluated ophthalmoscopically and the fundus was documented by color photography before, 24 hours after, and 6 and 20 days after laser exposure. Transient pink afterimages were observed by the patient for approximately 4 minutes after the laser exposure. The patient’s visual acuity was recorded as 20/20 the day after exposure and 20/20 at 6 and 20 days after exposure. The patient was unable to discern any visual abnormality and could not discern a scotoma on tangent screen or Amsler grid testing 6 and 20 days after exposure. Twenty-four hours after exposure, fundus examination revealed a distinct yellowish discoloration in the subfoveal region at the level of the retinal pigment epithelium (RPE). An area of yellowish discoloration was also recognized at the retinal site exposed to the laser for 15 minutes. A delicate granular irregularity developed in each site at the level of the pigment epithelium and was recognizable at the 6- and 20-day follow-ups. Histologic study of the enucleated eye showed a choroidal melanoma in the ciliary body, and thick sections revealed apical displacement of the nuclei of some RPE cells in the subfoveal region. The pigment granules were also displaced into the outer receptor layer, and many intracytoplasmic granules displayed irregular shapes and density characteristics of melanofuscin. Displacement of some of the pigment epithelial cells into the subretinal space was also observed at the exposed site. Although in this experiment a class 3A green laser pointer caused retinopathy with exposures as short as 60 seconds, the recognized ophthalmoscopic and histologic abnormalities were unaccompanied by visually perceptible abnormalities.In a previous study,we reported the absence of retinal injury following retinal exposures of laser light from commercially available class 3A red laser pointers with powers of 1, 2, and 5 mW. Three human eyes were exposed to light from these laser pointers for 1, 5, and 15 minutes. We documented no functional, ophthalmoscopic, histologic, or ultrastructural abnormalities that could be attributed to the laser exposures. We concluded that the risk to the adult human eye from transient exposure to light from these red laser sources was negligible, although 2 credible reportshave been published of visible retinal abnormalities after exposure to red laser pointers in 2 young patients, one 11 years old and the other 19 years old. Green laser pointers have been used interchangeably with red laser pointers by some lecturers, and green laser pointers are increasingly being used by amateur astronomers as pointers to deep sky objects. Unlike the beam of the red laser, which cannot be seen well in ordinary night atmosphere, the beam from the green laser can be easily seen in the deep night sky, where it can point to a single star. Additionally, since the green laser is visible in the daytime, when directed to outdoor objects of interest, the green laser pointer has proved useful to some instructors of outdoor painting, landscape design, architecture, and construction. Since the retina is increasingly more sensitive to shorter wavelengths, we were interested in learning if the green laser pointer could cause retinopathy in the human eye.REPORT OF A CASEA 55-year-old woman with a ring melanoma of the ciliary body was scheduled for enucleation. The eye was normotensive and had an uncorrected visual acuity of 20/20. The patient consented to participate in an experiment during which a green laser pointer would expose her retina to light for intervals of up to 15 minutes. The study was approved by our institutional review board before the experiment, and our patient was fully informed of the nature of the experiment and gave verbal and written informed consent to participate.METHODSAn apparatus was designed to direct the laser beam from a class 3A green laser pointer through a hole (5 mm in diameter created with a simple paper punch) in the center of a black Amsler grid and then into the patient's pupil to target the retina. This device was similar to that used by Robertson et al(as shown in their Figure 1). The apparatus was arranged on a slitlamp so the patient’s head could be positioned comfortably during the exposure. A paper clip and a rubber band held the switch of the laser on continuously. The front aperture of the laser pointer was fixed 15 cm from the estimated location of the posterior pole of the eye (macular retina). Two 1-mm white fixation targets were placed on the Amsler grid, one 2½ squares above and one 2½ squares below the center of the Amsler grid, thereby subtending angles approximately 5° above and 5° below the center of the Amsler grid. The pupil of the eye that contained the tumor was dilated to 8 mm with 2% cyclopentolate hydrochloride and 10% phenylephrine hydrochloride. The other eye was doubly patched. The eye that contained the melanoma was subjected to 3 durations of exposure from the laser pointer.The retina was exposed to light from a handheld green laser marketed as a laser pointer (LightVision Technologies Corp, Kaoyuan, Taiwan). Light output was continuous (not pulsed) and specified by the manufacturer as less than 5 mW at 532 nm. The beam power was measured with a radiometer (IL 700, SEE-100 probe; International Light Inc, Newburyport, Mass). From information relating to the retinal hazards of intrabeam viewing of lasers specified by the American National Standard for the Safe Use of Lasers,we calculated maximum permissible exposure at various exposure times.Exposures were administered as follows. The patient fixated her gaze for 60 seconds directly at the laser beam as it passed through the center of the aperture in the Amsler grid. Then the patient fixated her gaze for 5 minutes on the fixation target 2½ squares below the aperture and the laser beam. The last exposure was a 15-minute fixated gaze on the fixation target 2½ squares above the aperture and the laser beam. Normal blinking was allowed during the exposures. During each exposure, the patient's fixation was confirmed by one of us (D.M.R.), and the laser beam was maintained in the central 2 mm of the patient's widely dilated pupil. After each exposure the patient was asked to report any recognized afterimages or photopsias. Immediately after responding to this request, the patient was instructed to gaze at the center of a standard Amsler grid and report any defects in the grid. The patient wore corrective eyewear for this last assessment.The patient returned the following day, 6 days after exposure, and again 20 days after exposure for measurement of the Snellen visual acuity, ophthalmoscopic examination with slitlamp biomicroscopy aided by a Hruby lens and the 90-diopter (D) and 60-D fundus viewing lenses, and color photographic documentation of the fundus. The retina was examined by ocular coherence tomography (OCT) 24 hours after laser exposure. The central visual field was studied 24 hours and 20 days after laser exposure with the Amsler grid and tangent screen evaluations with a 1-mm white target. Sites in the fundus that were exposed to the laser light were carefully inspected for abnormalities. These sites included the fovea and the RPE complex 5° superior and 5° inferior to the fovea.RESULTSThe beam power of our green laser was variable and between 3 and 7 mW, although the manufacturer stated that the light output was less than 5 mW. The maximum permissible exposure is 0.39 mW for exposures between 1 and 15 minutes, assuming a 7-mm limiting aperture (pupil diameter).Retinal exposure from our laser exceeded this limit by 8 to 18 times.Pretreatment evaluation of the fundus of our patient revealed the presence of a small choroidal nevus beneath the inferior retinal vascular arcade. The central macula appeared normal (Figure 1A). The visual acuity was 20/20 uncorrected. After exposures to the laser pointer, the patient observed pink discoloration within her central visual field, which faded within 4 minutes of each laser exposure. The visual acuity was 20/25 within 3 minutes of exposure. No functional disturbance in visual acuity or the central visual field could be discerned at subsequent visits 24 hours, 6 days, and 20 days after laser exposure. The uncorrected visual acuity was 20/20 at each of these follow-up visits.Figure 1.Composite showing the fundus photographs and optical coherence tomographic images before and after exposure to the green laser pointer. A, Normal-appearing macula. An incidental choroidal nevus is visible inferior to the disc. B, Twenty-four hours after exposure to the green laser pointer, subtle yellowish discoloration at the level of the retinal pigment epithelium (site of 60-second exposure to the laser pointer) is apparent; abnormal yellowish discoloration superior to the fovea where the site was continuously exposed for 15 minutes to the laser beam is also apparent. C, Ocular coherence tomogram that shows tissue thickening at the level of the retinal pigment epithelium in the subfoveal region (top) and the area of the fundus superior to the fovea where the retina was exposed to the laser for 15 minutes (bottom, arrow). D, Six days after exposure to the green laser pointer, the 2 sites identified in panel B now exhibit a delicate granular irregularity at the level of the retinal pigment epithelium. E, Twenty days following exposure. The 2 sites identified in panels B and D are less evident. The abnormality in the foveal region shows a light creamy discoloration. F, Foveal region shows irregular discoloration (original magnification ×2).Twenty-four hours after laser exposure, an ophthalmoscopically distinct yellowish discoloration appeared in the subfoveal region at the level of the RPE (site of 60-second exposure) (Figure 1B). No abnormality was visible in the fundus at the site of the 5-minute exposure, but a distinct abnormal yellowish discoloration was apparent superior to the fovea where the retina had been exposed to the laser beam for 15 minutes (Figure 1B). An OCT examination 24 hours after exposure suggested tissue thickening at the level of the RPE in both the subfoveal location and the area of the fundus superior to the fovea where the retina was exposed to the laser for 15 minutes (Figure 1C). Each of these 2 sites developed a delicate granular irregularity at the level of the pigment epithelium that was visible at the 6-day follow-up (Figure 1D). Some of this granularity persisted at this follow-up, but by 20 days the abnormality at the fovea was characterized primarily by a more delicate creamy discoloration (Figure 1E and F). The eye was enucleated 20 days after laser exposure.The eye was received fresh from the operating room. It was sectioned at the equator. The anterior segment was placed in 10% buffered formalin and fixed for 48 hours before gross examination. The posterior segment was examined and dissected immediately. A small choroidal nevus (2 mm) was noted inferior to the fovea. No other gross abnormalities were noted. Small portions of the fovea, the macular region approximately 5 mm superior and inferior to the fovea, and the nasal retina opposite the fovea were placed in glutaraldehyde and examined by transmission electron microscopy.Gross examination of the anterior segment showed clear cornea that measured 12 × 12 mm. The iris contained a mass from 9- to 12-o’clock (5 × 3 × 2 mm) that adhered to the posterior corneal surface and extended posteriorly to the ciliary body. The anterior segment was sectioned clockwise, and all sections were embedded for histologic examination. Microscopically, a malignant melanoma, mixed cell type (spindle and epithelioid), was forming a predominant mass in the iris root that invaded anteriorly the trabecular meshwork and extended posteriorly to invade the ciliary body muscle. However, isolated tumor cells were observed in the trabecular meshwork and angle structures at approximately 360°. This morphologic impression was confirmed by melan-A immunostain, a melanoma marker.Examination by transmission electron microscopy of well-fixed tissue from the region of the fovea showed apical displacement of the nuclei in some of the RPE cells in addition to focal clumping of pigment granules within the RPE cell cytoplasm. Many of the pigment granules had irregular shapes and demonstrated densities characteristic of melanofuscin granules. Distinct displacement of RPE cells also occurred into the subretinal space in some sections (Figure 2A-C). We were unable to identify any abnormalities in the choriocapillaries. The outer segments of the photoreceptors appeared to be normal except for some minimal disruption of the lamellae attributed to prefixation autolysis (present both in the posterior pole and a control site nasal to the disc). We could not identify abnormalities in the other sites exposed to the laser.Figure 2.Composite showing both light microscopic and electron microscopic findings in the retina 20 days after laser exposure. A, Epoxy resin (Epon)–embedded thick section shows focal displacement of the retinal pigment epithelial cells into the subretinal space. No abnormalities are seen in the photoreceptor cells (epoxy resin–embedded toluidine blue stain, original magnification ×100). B, Transmission electron microscopic study shows clumping of pigment granules within the retinal pigment epithelial cells and dispersed in the subretinal space. The cross-sectional area of the outer segments appears normal (lead citrate, original magnification ×2500). C, Transmission electron microscopic study shows apical displacement of the nuclei of some pigment epithelial cells. Some pigment granules are irregular in shape and show densities characteristic of melanofuscin (epoxy resin–embedded toluidine blue stain, original magnification ×100).COMMENTIn this experiment, we documented the development of retinopathy in a human eye after purposeful exposure to light from a green laser pointer. In previous studies with red laser pointers, we failed to produce any evidence of retinopathy despite exposures of the retina to continuous light for up to 15 minutes.The fact that we were able to demonstrate green laser pointer–induced retinopathy with exposure times as short as 60 seconds may not be surprising, since the human retina is much more sensitive to shorter than longer wavelengths. Also, melanin in the pigment epithelium absorbs more energy at shorter wavelengths than longer wavelengths.The appearance of the lesion after 60 seconds of green laser exposure was similar to the clinical appearance of solar retinopathy in patients who have stared at a solar eclipse. The yellowish discoloration that was visible ophthalmoscopically probably represented a change at the level of the RPE where the pigment epithelium had received a mild thermal injury. Clinically, the discoloration did not appear at the inner retina in the region of greatest concentration of xanthophyll; an OCT study demonstrated thickening at the level of the pigment epithelium, which suggests that the ophthalmoscopically visible abnormality was at the level of the pigment epithelium. Why retinopathy was not visible 5° below fixation where the retina was exposed for 5 minutes cannot be readily explained, but the presence of a relatively broad area of retinopathy superior to the fovea where the retina had been exposed for 15 minutes suggests that the patient may have had difficulty maintaining precise fixation on the larger white target in the mounted apparatus as opposed to the more precise foveal fixation when the eye was gazing directly at the center of the laser beam. Microsaccades, micronystagmus, and slow drifts in eye position during fixation of a small target for more than a few seconds can spread the area of retina exposed to a laser.Perhaps the greater excursions of the eye during fixation on the white target distributed the laser exposure across a greater area on the retina and allowed heat dissipation so that the retina was not injured at 5 minutes but was injured over a relatively broad region of 500 to 700 &mgr;m after an exposure of 15 minutes.Our patient was unable to recognize any defect in central vision despite attempted efforts to identify a scotoma with the tangent screen using 1-mm targets and the Amsler grid study. The inability of the patient to recognize functional changes in vision may reflect either a true absence of functional damage or simply our inability to detect subtle changes in the central visual field function with the testing methods used. The histologic study indicated some damage to the RPE represented by displacement of the nuclei away from the basement membrane, dispersion of pigment granules, the development of melanofuscin changes near the site of maximum exposure at the fovea, and displacement of RPE cells into the subretinal space. These findings are consistent with thermal injury that affects primarily the RPE. Although it remains comforting that the patient did not experience any visual abnormalities up to 20 days following laser exposure, nevertheless the inducement of ophthalmoscopically visible photic damage along with the induced histologic abnormalities suggests the need for caution with the use of laser pointers and, more particularly, the green laser pointer. Fortunately, the risks to the human eye from transient exposure to light from laser pointers are minimized by the normal blink and aversion reflexes that occur within fractions of a second of exposure. Nevertheless, exposure of the retina to light from a commercially available green laser pointer carries a risk that is real; this risk appears to exceed the risk from commercially available red laser pointers.Correspondence:Dennis M. Robertson, MD, Mayo Clinic, 200 First St SW, Rochester, MN 55905.Submitted for Publication:February 2, 2004; final revision received August 18, 2004; accepted September 28, 2004.Funding/Support:This study was supported in part by a grant from Research to Prevent Blindness, Inc, New York, NY.Acknowledgment:We acknowledge Cheryl Hann, MS, for her assistance with the transmission electron microscopy and Bonnie Ronken for her secretarial assistance.REFERENCESDMRobertsonTHLimDRSalomaoTPLinkRLRoweJWMcLarenLaser pointers and the human eye: a clinicopathologic study.Arch Ophthalmol20001181686169111115266CHSellJSBryanMaculopathy from handheld diode laser pointer.Arch Ophthalmol19991171557155810565530EZamirIKaisermanIChowersLaser pointer maculopathy.Am J Ophthalmol199912772872910372889American National Standard for Safe Use of LasersANSI A136.1-2000.Orlando, Fla: Laser Institute of America; 2000MAMainsterWavelength selection in macular photocoagulation: tissue optics, thermal effects, and laser systems.Ophthalmology1986939529583763141JWNessHZwickBEStuckRetinal image motion during deliberate fixation: implications to laser safety for long duration viewing.Health Phys20007813114210647979

Murphy, Conor C.; Greiner, Kathrin; Plskova, Jarka; Duncan, Linda; Frost, N. Andrew; Forrester, John V.; Dick, Andrew D.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.634pmid: 15883282

ObjectivesTo compare the efficacy and tolerability of tacrolimus and cyclosporine therapy for noninfectious posterior segment intraocular inflammation and to evaluate their effect on peripheral blood CD4+T-cell phenotype and activation status.MethodsThirty-seven patients who required second-line immunosuppression for posterior segment intraocular inflammation were enrolled in this prospective randomized trial of tacrolimus vs cyclosporine therapy. The main outcome measures were visual acuity, binocular indirect ophthalmoscopy score, adverse effects, and quality of life. In addition, peripheral blood CD4+T-cell phenotype and activation status were evaluated by flow cytometry before treatment and at 2, 4, and 12 weeks using CD69, chemokine receptor (CCR4, CCR5, and CXCR3), and intracellular cytokine (tumor necrosis factor α, interferon-γ, and interleukin 10) expression.ResultsThirteen patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine responded to treatment. Cyclosporine therapy was associated with a higher incidence of reported adverse effects. Mean arterial pressure and serum cholesterol level were significantly higher at 3 months in the cyclosporine group than the tacrolimus group. No significant difference was detected with regard to effect on quality of life or CD4+T-cell phenotype.ConclusionsTacrolimus and cyclosporine were similar with regard to efficacy for posterior segment intraocular inflammation, but the results suggested a more favorable safety profile for tacrolimus therapy.Cyclosporine is an effective treatment for noninfectious posterior and intermediate uveitis and is now in widespread use in cases where prednisolone therapy has failed.However, enthusiasm is tempered by its toxic effect profile, which includes renal impairment, systemic hypertension, and metabolic abnormalities. Furthermore, it is estimated that approximately 20% of patients with uveitis are refractory to cyclosporine, indicating the need to evaluate more potent and safer treatment strategies.Tacrolimus, a natural metabolite of the bacterium Streptomyces tsukubaensis, is 10 to 100 times more potent as an immunosuppressive agent than cyclosporine on a weight-for-weight basis.It shares many features with cyclosporine, in particular its modulation of CD4+T-cell activity through the inhibition of interleukin 2 (IL-2) production, a mechanism that is pertinent to the treatment of noninfectious posterior uveitis. Several uncontrolled cohort studieshave demonstrated the efficacy of tacrolimus in the treatment of posterior uveitis.The safety and efficacy of tacrolimus- and cyclosporine-based immunosuppression have been extensively studied in solid organ transplantation. Tacrolimus has demonstrated a significant advantage over cyclosporine in relation to the incidence of transplant rejection episodes following kidney, liver, and pulmonary transplantation.In addition, it has a more favorable effect on systemic hypertension and lipid abnormalities after solid organ transplantation, giving it a safer cardiovascular risk profile.In contrast, substantive randomized trials that compared immunosuppressive agents for the treatment of noninfectious posterior segment intraocular inflammation (PSII), a term that encompasses intermediate, posterior, and panuveitis of presumed autoimmune etiology, are notably lacking. The aim of this study was to compare the efficacy and tolerability of tacrolimus and cyclosporine therapy for noninfectious PSII in a prospective randomized trial. In addition, we undertook a longitudinal study of the effect of tacrolimus and cyclosporine therapy on peripheral blood CD4+T-cell activation status and cytokine and chemokine receptor expression to assess if changes in CD4+T-cell phenotype correlated with effective immunosuppression.METHODSPATIENTSA total of 37 patients were recruited to this prospective randomized study of tacrolimus vs cyclosporine therapy for noninfectious PSII from 2 regional referral centers for uveitis in the United Kingdom (Bristol Eye Hospital [Bristol, England] and Aberdeen Royal Infirmary [Aberdeen, Scotland]) between May 2001 and April 2003. All patients who were invited to enroll in the study during this period agreed to participate. The study was approved by the ethics committee of each center, and informed consent was obtained from all patients. Inclusion criteria were chronic, noninfectious, sight-threatening PSII, which was defined as (1) unacceptably high doses of prednisolone (>10 mg/d), (2) recurrent high-dose steroid rescue for recurrent relapsing disease (>2 relapses per year despite maintenance prednisolone of >10 mg/d), or (3) severe sight-threatening disease that warranted immediate institution of high-dose prednisolone and a second-line agent. Reasons for exclusion from the study were pregnancy, diabetes mellitus, renal disease, concurrent infection, and recent live vaccinations.IMMUNOSUPPRESSION PROTOCOLPatients were randomized using a computer-generated nonstratified random-allocation sequence to receive either tacrolimus or cyclosporine at doses of 0.03 to 0.08 mg/kg daily and 2.5 to 5.0 mg/kg daily, respectively, with doses adjusted based on the clinical response and drug levels in the blood. Target whole blood trough levels were 8 to 12 ng/L for tacrolimus and 100 to 225 ng/L for cyclosporine, although trough levels below these ranges were acceptable, provided remission was achieved. All patients were analyzed in the group to which they were randomized. Neither the patients nor the investigators were masked to the treatment.CLINICAL ASSESSMENTSystemic and ophthalmic evaluation was undertaken before commencing tacrolimus or cyclosporine therapy, at 2 and 4 weeks, and then every 4 to 6 weeks thereafter according to clinical activity and response to treatment. Baseline assessment included history, general physical and ophthalmic examination, blood pressure, urinalysis, chest x-ray examination, and blood tests, including complete blood cell count, liver function tests, and creatinine, glucose, urate, C-reactive protein, and random serum cholesterol measurement. Patients were evaluated at each follow-up visit for adverse effects and clinical response to therapy. The International Uveitis Scoring System was used to assess clinical disease activity.OUTCOME MEASURESThe main outcome measures were best-corrected logMAR visual acuity measured at 4 m with the Early Treatment Diabetic Retinopathy Studychart scored for individual letters and the binocular indirect ophthalmoscopy (BIO) score. Secondary outcome measures were adverse effects, vision-related quality of life, and health-related quality of life. Treatment response was defined as an improvement in visual acuity of at least 2 lines (a decrease in logMAR score of at least 0.2) in either eye or a decrease in BIO score to 0 in either eye within 3 months of commencing treatment with cyclosporine or tacrolimus. Patients who did not achieve these clinical criteria were defined as having had failed treatment. Relapses of intraocular inflammation were defined by a decrease in visual acuity of at least 2 lines or an increase in BIO score of at least 1 grade after achieving a clinical response. The duration of response to treatment was defined as the interval between commencing treatment and when relapse occurred or final follow-up if the response was maintained for the duration of the study. Treatment outcome was evaluated in this way for all 37 patients who entered the trial, with no exclusions.QUALITY-OF-LIFE ASSESSMENTThree self-administered questionnaires were used to assess health-related quality of life, vision-related quality of life, and adverse effects experienced before treatment with cyclosporine or tacrolimus and after 1, 3, 6, and 12 months. The health-related quality of life was evaluated using the UK standard version of the 36-item Short-Form Health Survey (SF-36),which consists of 36 items grouped into 8 scales to measure health, including physical functioning, social functioning, role limitations because of physical problems, role limitations because of emotional problems, mental health, energy or vitality, bodily pain, and general health perception. The vision-related quality of life was measured using the Vision Core Module-1 (VCM-1), a 10-item questionnaire that provides a subjective measure of concern regarding vision, with scores ranging from 0.0 (best score) to 5.0 (worst score) with 50 intervals.Finally, patients completed an adverse-effect questionnaire that contained a comprehensive list of well-recognized adverse effects to immunosuppressive agents. This questionnaire, which addressed the overall effect of the adverse effects on quality of life by asking the question “How much have these problems interfered with your quality of life?,” was scored from 0 to 5, which corresponded to the answers “not at all,” “hardly at all,” “a little,” “a fair amount,” “a lot,” and “an extreme amount,” respectively.PERIPHERAL BLOOD CD4+T-CELL ANALYSISPatients underwent peripheral blood CD4+T-cell analysis before receiving tacrolimus or cyclosporine and after 2, 4, and 12 weeks, as described elsewhere.In brief, the expression of the activation marker CD69, the chemokine receptors CXCR3, CCR4, and CCR5, and the intracellular cytokines tumor necrosis factor α (TNF-α), interferon-γ (IFN-γ), and interleukin 10 (IL-10) by peripheral blood CD4+T cells was determined using flow cytometry after a 4-hour incubation in either basal medium (unstimulated culture) for CD69 and chemokine receptors or phorbol-12-myrisate 13-acetate with ionomycin and Golgi inhibitor (activated culture) for intracellular cytokines.Statistical analysis was performed using the Wilcoxon signed rank test for paired data and the Mann-Whitney Utest for unpaired data. Prism statistical software version 3.02 (GraphPad Software Inc, San Diego, Calif) was used for all statistical calculations, and significance was attributed at P<.05. To detect a difference in efficacy between cyclosporine and tacrolimus, we estimated that 72 patients would need to be recruited to each treatment group. This estimate was performed using a &khgr;2test with a 2-sided significance level of .05 and 80% power.RESULTSDEMOGRAPHIC AND CLINICAL CHARACTERISTICSEighteen patients were randomized to cyclosporine, and 19 patients were randomized to tacrolimus. No major differences occurred between the groups with regard to clinical and demographic characteristics (Table 1). The dosage of oral prednisolone, the only other immunosuppressant allowed for the duration of the study, was similar in both groups (Table 2). All patients were followed up for a minimum of 3 months.Table 1. Clinical and Demographic CharacteristicsCharacteristicTacrolimus Group (n = 19)Cyclosporine Group (n = 18)Age, median (IQR), y48 (40-59)38 (32-56)Female, No. (%)11 (58)10 (56)Duration of uveitis, median (IQR), y2 (0.8-6)1 (0.5-4)Follow-up, median (IQR), mo7 (4-18)4 (3-13)Laterality, No. (%) Bilateral14 (74)14 (78) Unilateral5 (26)4 (22)Uveitis diagnosis, No. Panuveitis  Idiopathic56  Behçet disease22  Sarcoidosis10  Sympathetic ophthalmia10 Intermediate uveitis  Idiopathic75  Sarcoidosis11 Posterior uveitis  Idiopathic21  PIC02  POH01Maintenance drug dose, median (IQR), mg4 (3-5)250 (200-344)Maintenance blood trough levels, median (IQR), μg/L7.3 (5.6-8.3)110 (100-179)Abbreviations: IQR, interquartile range; PIC, punctate inner choroidopathy; POH, presumed ocular histoplasmosis.Table 2. Oral Prednisolone DosesVisitTacrolimus GroupCyclosporine GroupPValueNo. of PatientsMedian (IQR) Prednisolone Dose, mg/dNo. of PatientsMedian (IQR) Prednisolone Dose, mg/dBaseline1920 (15-30)1825 (14-51).39Month 11915 (14-18)1815 (12-20)>.99Month 31910 (8-13)1810 (10-14).34Month 6115 (3-9)97 (7-8).27Abbreviation: IQR, interquartile range.CLINICAL EFFICACYA response to treatment, defined by an improvement in visual acuity of at least 2 lines in either eye or a decrease in BIO score to 0 in either eye within 3 months of commencing treatment, occurred in 13 patients (68%) taking tacrolimus and 12 patients (67%) taking cyclosporine. Nine patients (50%) taking cyclosporine and 8 patients (42%) taking tacrolimus achieved the visual acuity outcome measure within 3 months of commencing treatment. Nine (64%) of 14 patients taking cyclosporine and 8 (62%) of 13 patients taking tacrolimus who had a BIO score of greater than 0 at baseline achieved a decrease in BIO score to 0 in either eye within 3 months of commencing treatment. The significant improvements in visual acuity and BIO score were equivalent for cyclosporine and tacrolimus (P = .56 and P = .65, respectively, when comparing the groups) (Figure 1). Of the responders, 4 patients (33%) taking cyclosporine had a relapse during the follow-up period compared with 6 patients (46%) receiving tacrolimus. The median duration of response to cyclosporine and tacrolimus was 7 months (interquartile range, 4-13 months) and 6 months (interquartile range, 3-9 months), respectively. No difference was found between the 2 groups with regard to ability to taper oral prednisolone (Table 2).Figure 1.LogMAR visual acuity (A) and binocular indirect ophthalmoscopy (BIO) score (B) for tacrolimus and cyclosporine at baseline and 3 months after commencing treatment. The horizontal lines represent the median value for each data set.TOLERABILITYThe occurrence of adverse effects to tacrolimus and cyclosporine is presented in Table 3. Cyclosporine therapy was associated with a higher incidence of adverse effects, including headache, gingival hyperplasia, fatigue, and palpitations. Seven patients (37%) taking tacrolimus experienced no adverse effects compared with only 1 patient (6%) taking cyclosporine. Urinary frequency, which was not due to urinary tract infection, occurred exclusively in 2 female patients taking tacrolimus and improved with dose reduction.Table 3. Adverse EffectsAdverse EffectNo. (%) of PatientsTacrolimus Group (n = 19)Cyclosporine Group (n = 18)Headache3 (16)7 (39)Nausea1 (5)2 (11)Diarrhea1 (5)0 (0)Abdominal pain1 (5)0 (0)Warm sensation4 (21)8 (44)Paraesthesia7 (37)8 (44)Tremors6 (32)5 (28)Chest pain1 (5)1 (6)Insomnia0 (0)1 (6)Alopecia1 (5)1 (6)Hirsutism1 (5)1 (6)Anxiety1 (5)0 (0)Depression1 (5)0 (0)Gum hypertrophy0 (0)5 (28)Fatigue1 (5)10 (56)Rash1 (5)1 (6)Muscle cramps3 (16)2 (11)Frequency2 (10)0 (0)Palpitations0 (0)3 (17)Arthralgia0 (0)1 (6)Oral thrush0 (0)1 (6)The biochemical and cardiovascular adverse effects of tacrolimus and cyclosporine are given in Table 4. Hypertension (blood pressure >140/90 mm Hg on 2 or more consecutive visits) developed in 4 patients (22%) taking cyclosporine and 1 patient (5%) taking tacrolimus. Despite comparable mean arterial pressure (MAP) at baseline, this was significantly higher in the cyclosporine group at 3 months (P = .02). Although no increase in median MAP occurred with tacrolimus therapy, a significant increase in MAP was detected at 1 and 3 months after commencing cyclosporine therapy compared with baseline (P = .002 and P = .003, respectively). Total serum cholesterol level was significantly higher in the cyclosporine group at 1 month (P = .02) and 3 months (P = .04). No patient started taking cholesterol-lowering agents during the study, and only 1 patient (in the cyclosporine group) commenced antihypertensive treatment. No significant difference in serum creatinine level was detected between the treatment groups. Two patients taking cyclosporine and 1 patient taking tacrolimus experienced a greater than 30% increase in serum creatinine level during the study, requiring discontinuation of treatment for 1 patient in each treatment group. Hypomagnesemia (magnesium level below normal range on 2 or more consecutive visits) developed in 3 patients (17%) taking tacrolimus and 1 patient (6%) taking cyclosporine. Only 1 of these patients (in the tacrolimus group) received magnesium supplements. One patient (6%) taking cyclosporine, who was also taking prednisolone, developed hyperglycemia (serum glucose level >144.14 mg/dL [>8.0 mmol/L]). No patients taking tacrolimus developed hyperglycemia.Table 4. Cardiovascular and Biochemical Adverse EffectsAdverse EffectTacrolimus Group (n = 19)Cyclosporine Group (n = 18)PValueNo. of PatientsMedian (IQR)No. of PatientsMedian (IQR)Mean arterial pressure, mm Hg Baseline1899 (87-107)1793 (89-99).29 Month 11994 (87-104)1698 (95-107).18 Month 31991 (85-103)17105 (92-113).02Serum total cholesterol, mg/dL Baseline17216.22 (200.77-231.66)11216.22 (204.63-239.38).69 Month 17200.77 (166.02-220.08)6285.71 (247.10-324.32).02 Month 316204.63 (154.44-239.38)15243.24 (200.77-281.85).04Serum creatinine, mg/dL Baseline191.04 (1.00-1.12)181.00 (0.94-1.10).51 Month 1191.04 (0.97-1.10)181.03 (0.98-1.14).54 Month 3191.04 (0.94-1.19)171.04 (1.01-1.09).60Abbreviation: IQR, interquartile range.SI conversion factors: To convert serum total cholesterol to millimoles per liter, multiply by 0.0529; serum creatinine to micromoles per liter, 88.4.TREATMENT FAILURESSix patients in each treatment group were switched to alternative immunosuppression because of treatment failure, which was defined as failure to achieve an improvement of visual acuity of 2 or more lines in either eye or a decrease in BIO score to 0 in either eye within 3 months of commencing treatment. One of the patients in whom tacrolimus therapy failed was diagnosed as having intraocular lymphoma secondary to a systemic B-cell lymphoma 6 months after enrollment in the trial. This was characterized by chronic low-grade intermediate uveitis with cystoid macular edema, which rapidly resolved with systemic chemotherapy, having failed to respond to immunosuppressive therapy.Two patients discontinued cyclosporine therapy because of toxic effects, one because of severe treatment-related hypertension and adverse effects, including nausea, vomiting, fatigue, and headache, and another because of nephrotoxicity. One patient discontinued tacrolimus therapy as a consequence of nephrotoxicity. Overall, in 7 patients (37%) taking tacrolimus and 8 patients (44%) taking cyclosporine, treatment failed because of either refractory disease or drug toxicity.EFFECT OF CYCLOSPORINE AND TACROLIMUS ON QUALITY OF LIFEBoth tacrolimus and cyclosporine therapy led to significant improvements in vision-related quality of life (Figure 2). When comparing changes in VCM-1, the adverse effect questionnaire, and the SF-36 subscales after commencing treatment, we found no significant difference between the tacrolimus and cyclosporine groups. A significant improvement in the SF-36 mental health subscale was detected at 6 months for the tacrolimus group (P = .01). No significant changes in the other SF-36 subscales or the adverse effect questionnaire score were detected.Figure 2.Vision Core Module-1 (VCM-1) scores for patients taking cyclosporine (A) (P<.05 for baseline vs 6 and 12 months) and tacrolimus (B) (P<.05 for baseline vs 1, 3, 6, and 12 months). The horizontal lines represent the median value for each data set.EFFECT OF CYCLOSPORINE AND TACROLIMUS ON CD4+T-CELL PHENOTYPEResults pertaining to peripheral blood CD4+T-cell activation status and phenotype are given in Table 5. No significant difference was found on comparing the 2 treatment groups. A significant decrease in the percentage of CD4+T cells expressing the proinflammatory cytokine TNF-α occurred in the cyclosporine-treated group within 2 weeks of commencing treatment in parallel with the improvement in clinical activity (P = .03). No other significant changes in chemokine receptor, cytokine, or CD69 expression by CD4+T cells were detected in either group after commencing tacrolimus or cyclosporine therapy. When comparing treatment responders and nonresponders for the entire group, CD4+T-cell expression of TNF-α was significantly lower 2 and 4 weeks after commencing cyclosporine or tacrolimus therapy in the responder group, despite being comparable at baseline (Figure 3). No significant differences were found for the other cytokines, chemokine receptors, or CD69 when comparing responders and nonresponders.Figure 3.CD4+T-cell expression of tumor necrosis factor α (TNF-α) before and after treatment with cyclosporine or tacrolimus therapy, showing a significantly lower TNF-α expression 2 and 4 weeks after commencing treatment in responders (n = 13) compared with nonresponders (n = 8). The horizontal lines represent the median value for each data set.Table 5. CD4+ T-Cell Phenotype and Activation StatusStatusMedian (IQR)PValueCyclosporine Group (n = 14)Tacrolimus Group (n = 7)CD69 unstimulated, % Week 027.5 (23.8-46.8)26.4 (17.5-52.4).90 Week 224.7 (22.3-40.8)28.5 (17.5-37.2).81 Week 426.2 (21.9-36.0)39.0 (36.7-46.6).06 Week 1235.0 (27.8-37.0)20.5 (14.1-44.1).53IL-10 activated, % Week 02.8 (0.9-3.8)1.3 (1.1-2.1).62 Week 21.4 (1.0-2.9)0.6 (0.4-1.4).17 Week 44.0 (1.2-4.9)0.7 (0.2-2.2).08 Week 121.1 (0.7-1.3)0.6 (0.3-1.5).53TNF-α activated, % Week 070.8 (55.3-74.3)74.9 (60.2-89.0).38 Week 248.7 (41.9-80.0)*61.5 (50.3-73.3).63 Week 452.3 (35.1-68.6)67.8 (65.7-78.3).17 Week 1252.2 (43.2-67.4)51.8 (43.7-84.1).61IFN-γ activated, % Week 015.8 (9.3-21.9)19.0 (7.2-25.7)>.99 Week 219.4 (12.4-29.6)14.1 (5.3-27.0).40 Week 420.8 (10.2-27.9)28.1 (10.4-33.7).81 Week 1214.6 (10.1-27.4)24.3 (5.2-26.2).69Abbreviations: IFN-γ, interferon-γ; IL-10, interleukin 10; IQR, interquartile range; and TNF-α, tumor necrosis factor α.  *P = .03 compared with baseline for the cyclosporine group.COMMENTRetrospective case series and uncontrolled observational studieshave demonstrated a benefit for the use of cyclosporine and tacrolimus for sight-threatening PSII disease in combination with corticosteroids. In this prospective, randomized open-label trial, we observed that tacrolimus and cyclosporine had comparable efficacy (response rates of 67%% and 68% with cyclosporine and tacrolimus, respectively) in the treatment of noninfectious PSII but that tacrolimus had a superior adverse-event profile. These findings are similar to those reported in the transplantation literature, in which tacrolimus has been shown to cause significantly fewer toxic effects, particularly with regard to systemic hypertension and hyperlipidemia.Gingival hyperplasia was notably absent in the tacrolimus group, whereas it occurred in 5 patients (28%) taking cyclosporine. Fatigue and headache were also markedly more common with cyclosporine therapy, whereas urinary frequency, which was probably secondary to neurotoxicity, occurred exclusively in 2 patients taking tacrolimus. A key outcome measure with respect to adverse effects was the adverse-effect questionnaire. In contrast to the frequency of reported adverse effects in each group, which was greater for cyclosporine, no difference was found for the adverse effect questionnaire score. This may reflect the relatively low impact of these adverse effects on quality of life in the present study (the median scores for tacrolimus and cyclosporine at 1 month were 1 and 2, respectively, indicating that the adverse effects affected quality of life “hardly at all” and “a little”). Thus, although adverse effects were more common with cyclosporine therapy, their overall effect on patient well-being was not significantly greater than for tacrolimus therapy.A potential benefit of tacrolimus over cyclosporine therapy observed in this study was its more favorable effect on systemic blood pressure and serum cholesterol level. Since hypertension and hyperlipidemia are known to have a major impact on cardiovascular health, it is possible that a sustained increase in blood pressure and cholesterol level above pretreatment levels increases the risk of cardiovascular morbidity in patients with uveitis, especially if added to other risk factors, such as smoking, obesity, physical inactivity, and family history. The cardiovascular risks of tacrolimus and cyclosporine therapy have been extensively compared in solid organ transplantation, in which similar findings to the present study have been observed.In a prospective studyof 41 patients with uveitis treated with cyclosporine for 1 year at a mean daily dose of 4.1 mg/kg, a 78% incidence of systemic hypertension was noted, and after 5 years of treatment, hypertension persisted in 81% of the cohort despite cyclosporine dose reduction. Significant increases in serum cholesterol level in patients treated with cyclosporine for amyotrophic lateral sclerosis have also been reported.These problems are therefore not unique to the renal and hepatic transplantation population, in which metabolic and cardiovascular problems might be expected to occur. However, the significance of the increased cardiovascular risk, if any, presented by increases in serum cholesterol level and blood pressure in patients with uveitis and the decreased propensity to develop these adverse effects with tacrolimus compared with cyclosporine therapy is unknown at present and warrants further evaluation in long-term studies. Although hypertension and hypercholesterolemia may be controlled pharmacologically, complicating immunosuppressive regimens by the addition of these agents may lead to further adverse effects and poorer compliance. The more favorable toxic-effect profile of tacrolimus observed in this study may in part be explained by the relatively lower tacrolimus doses administered, as reflected by the drug trough levels. Equally, however, the results suggest that a similar efficacy to cyclosporine can be achieved with lower doses of tacrolimus. Therefore, in the treatment of uveitis, it may be more appropriate to aim for tacrolimus trough levels in the range of 5 to 10 μg/L rather than 8 to 12 μg/L as in the present study.Since both uveitis and its treatment can affect patient well-being, we investigated the effect of tacrolimus and cyclosporine therapy on health-related quality of life using the SF-36 questionnaire. Apart from the improvement in mental health that occurred in the tacrolimus group, which may have been a spurious finding given that 8 subscales were evaluated, significant changes in the quality-of-life subscale measures did not occur with treatment. We have previously shown that vision-related quality of life improved in parallel with improvements in uveitis activity.The improvements in VCM-1 scores that occurred in that and the present study support the use of vision-related quality of life as an outcome measure in clinical trials of immunosuppressive agents in the management of uveitis.The inclusion of the patient with presumed ocular histoplasmosis in this study reflects our approach to the treatment of patients with inflammatory choroidal neovascular membranes in the clinic. The improvement of visual acuity from 0.88 to 0.44 logMAR within 3 months of commencing cyclosporine and prednisolone therapy supports the use of immunosuppression for inflammatory choroidal neovascular membranes, as we have reported previously.Because this was an intent-to-treat study, we did not exclude the patient with intraocular lymphoma from the analysis because this origin was not recognized until after recruitment to the study. Excluding this patient from the analysis would alter the number of treatment failures in the tacrolimus therapy group from 6 (32%) to 5 (26%).The results of this study should be interpreted with several limitations in mind. First, since an insufficient number of patients were recruited based on the power calculation, the lack of difference between the 2 treatment groups with regard to efficacy may represent a type 2 error (false negative). However, an interim analysis of the data indicated that although the response rates for cyclosporine and tacrolimus were similar, significant differences in adverse-effect profile were apparent. Second, this was not a study of a single uveitis entity but a heterogeneous collection of PSII disorders that may differ with regard to clinical manifestations, severity, prognosis, and treatment response. Compensating for this heterogeneity would require the recruitment of large patient numbers, which is an impractical task given the rarity of these diseases. Finally, visual acuity is not an ideal outcome measure of treatment for uveitis, as recently highlighted by Rosenbaum et al.Thus, in patients with macular disruption, cataract, or glaucoma, the visual acuity may not improve despite the resolution of ocular inflammation. Using multiple outcome measures such as visual acuity, BIO score, and resolution of cystoid macular edema or fluorescein angiographic evidence of retinal vasculitis, for example, would allow the detection of all treatment responders but would also introduce significant bias because in some cases 1 or more of these outcome measures might be achieved spontaneously. As a compromise, we chose visual acuity and the BIO score as the 2 outcome measures for efficacy.The principal cell driving the efferent arm of the immune response in noninfectious PSII is the CD4+T cell. We studied the effect of tacrolimus and cyclosporine therapy on CD4+T-cell activation status by measuring CD69. We also investigated whether immunosuppression modulates CD4+T-cell phenotype by measuring its effect on chemokine receptor and intracellular cytokine expression (TH1-associated CXCR3, TNF-α, and IFN-γ and TH2-associated CCR4, CCR5, and IL-10). We found that CD69 expression was not useful as a surrogate marker of ocular inflammation because it did not decrease in parallel with the improvement in uveitis activity with tacrolimus or cyclosporine therapy, in contrast to a previous study.However, the greater reduction in CD4+T-cell expression of TNF-α in patients who responded to tacrolimus or cyclosporine therapy compared with patients who were refractory to treatment suggests that CD4+T-cell TNF-α may be a surrogate marker of treatment response. This finding and the significant decrease in TNF-α–positive CD4+T-cell expression in the cyclosporine group provide a rationale for the use of anti–TNF-α therapy in PSII when other immunosuppressants have failed.Correspondence:Andrew D. Dick, FRCP, FRCOphth, MD, Division of Ophthalmology, University of Bristol, Bristol Eye Hospital, Lower Maudlin Street, Bristol BS1 2LX, England ([email protected]).Submitted for Publication:March 19, 2004; final revision received August 18, 2004; accepted September 28, 2004.Author Contributions:Drs Murphy and Greiner made equal contributions to this study and stand as joint first authors.Funding/Support:Dr Murphy was funded by Fujisawa UK (London, England) and The National Eye Research Centre (Bristol, England), and Dr Greiner was funded by The Grampian University Hospital Trust for Research and Development (Aberdeen, Scotland).REFERENCESRBNussenblattAGPalestineCCChanCyclosporin A therapy in the treatment of intraocular inflammatory disease resistant to systemic corticosteroids and cytotoxic agents.Am J Ophthalmol1983962752826614105HMTowlerAMCliffePHWhitingJVForresterLow dose cyclosporin A therapy in chronic posterior uveitis.Eye198932822872612672ATVitaleARodriguezCSFosterLow-dose cyclosporin A therapy in treating chronic, noninfectious uveitis.Ophthalmology19961033653748600411ADDickMAzimJVForresterImmunosuppressive therapy for chronic uveitis: optimising therapy with steroids and cyclosporin A.Br J Ophthalmol199781110711129497474DHPetersAFittonGLPloskerDFauldsTacrolimus: a review of its pharmacology, and therapeutic potential in hepatic and renal transplantation.Drugs1993467467947506654MMochizukiKMasudaTSakaneA clinical trial of FK506 in refractory uveitis.Am J Ophthalmol19931157637697685147CMSloperRJPowellHSDuaTacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine.Ophthalmology199910672372810201592DJKilmartinJVForresterADDickTacrolimus (FK506) in failed cyclosporin A therapy in endogenous posterior uveitis.Ocul Immunol Inflamm199861011099689640SCJensikFK 506 Kidney Transplant Study GroupTacrolimus (FK 506) in kidney transplantation: three-year survival results of the US multicenter, randomized, comparative trial.Transplant Proc199830121612189636494JGO'GradyABurroughsPHardyDElbourneATruesdaleTacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial.Lancet20023601119112512387959BPGriffithKBandoRLHardestyA prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation.Transplantation1994578488517512292GLigtenbergRJHenePJBlankestijnHAKoomansCardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus.J Am Soc Nephrol20011236837311158228SCTextorRWiesnerDJWilsonSystemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients.Transplantation199355133213397685934SFriemannEFeuringWPadbergWErnstImprovement of nephrotoxicity, hypertension, and lipid metabolism after conversion of kidney transplant recipients from cyclosporine to tacrolimus.Transplant Proc199830124012429636504KClaessonADMayerJPSquiffletLipoprotein patterns in renal transplant patients: a comparison between FK 506 and cyclosporine A patients.Transplant Proc199830129212949636524DBenezraJVForresterRBNussenblattKTabbaraPTimonenUveitis Scoring System.Berlin, Germany: Springer-Verlag; 1991Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1: Early Treatment Diabetic Retinopathy Study research group.Arch Ophthalmol1985103179618062866759CJenkinsonRLayteLWrightACoulterThe UK-SF-36: An Analysis and Interpretation Manual.Oxford, England: Joshua Horgan Print Partnership; 1996NAFrostJMSparrowJSDurantJLDonovanTJPetersSTBrookesDevelopment of a questionnaire for measurement of vision-related quality of life.Ophthalmic Epidemiol199851852109894804KGreinerCCMurphyFWillermainAnti-TNFalpha therapy modulates the phenotype of peripheral blood CD4+ T cells in patients with posterior segment intraocular inflammation.Invest Ophthalmol Vis Sci20044517017614691170DOTaylorMLBarrBRadovancevicA randomized, multicenter comparison of tacrolimus and cyclosporine immunosuppressive regimens in cardiac transplantation: decreased hyperlipidemia and hypertension with tacrolimus.J Heart Lung Transplant19991833634510226898TRMcCuneLRThackerIITGPetersEffects of tacrolimus on hyperlipidemia after successful renal transplantation: a Southeastern Organ Procurement Foundation multicenter clinical study.Transplantation19986587929448150CIsnard BagnisSTezenas du MontcelHBeaufilsLong-term renal effects of low-dose cyclosporine in uveitis-treated patients: follow-up study.J Am Soc Nephrol2002132962296812444215CMBallantyneEJPodetWPPatschEffects of cyclosporine therapy on plasma lipoprotein levels.JAMA198926253562733125CCMurphyKGreinerJPlskovaNeutralizing tumor necrosis factor activity leads to remission in patients with refractory non-infectious posterior uveitis.Arch Ophthalmol200412284585115197059CDeesJJArnoldJVForresterADDickImmunosuppressive treatment of choroidal neovascularization associated with endogenous posterior uveitis.Arch Ophthalmol1998116145614619823346JTRosenbaumADeodharEBSuhlerJRSmithHow do you know?Br J Ophthalmol20048898098115258008DJKilmartinZJFletcherJAAlmeidaJLiversidgeJVForresterADDickCD69 expression on peripheral CD4+ T cells parallels disease activity and is reduced by mycophenolate mofetil therapy in uveitis.Invest Ophthalmol Vis Sci2001421285129211328741MSantos LacombaCMarcos MartinJMGallardo GaleraAqueous humor and serum tumor necrosis factor-alpha in clinical uveitis.Ophthalmic Res20013325125511586057PPSfikakisPGTheodossiadisCGKatsiariPKaklamanisNNMarkomichelakisEffect of infliximab on sight-threatening panuveitis in Behcet's disease.Lancet200135829529611498218

2005 Archives of Ophthalmology

doi: 10.1001/archopht.123.5.641

Congratulations to the winner of our January quiz, Salim Ben Yahia, MD, Fattouma Bourguiba University Hospital, Monastir, Tunisia. The correct answer to our January challenge was Coats disease. For a complete discussion of this case, see the Clinicopathologic Reports, Case Reports, and Small Case Series section in the February ARCHIVES (Lim WK, Nussenblatt RB, Chan CC. Immunopathologic features of inflammatory Coats disease. Arch Ophthalmol. 2005;123:279-281). Be sure to visit the Archives of Ophthalmology Web site (http://www.archophthalmol.com) and try your hand at our Clinical Challenge Interactive Quiz. We invite visitors to make a diagnosis based on selected information from a case report or other feature scheduled to be published in the following month’s print edition of the ARCHIVES. The first visitor to e-mail our Web editors with the correct answer will be recognized in the print journal and on our Web site and will also be able to choose one of the following books published by AMA Press: Clinical Eye Atlas, Clinical Retina, or Users’ Guides to the Medical Literature. View LargeDownload

Taban, Mehran; Sarayba, Melvin A.; Ignacio, Teresa S.; Behrens, Ashley; McDonnell, Peter J.

2005 JAMA Ophthalmology

doi: 10.1001/archopht.123.5.643pmid: 15883283

BackgroundSutureless clear corneal cataract incisions may be associated with an increased risk of endophthalmitis.ObjectiveTo assess the degree of ocular surface fluid ingress into the anterior chamber of cadaveric human globes with clear corneal wounds.MethodsSelf-sealing clear corneal incisions were created in 4 eyes, and intraocular pressure was controlled with an infusion cannula. To evaluate possible flow of surface fluid through the corneal wound, india ink was applied to the corneal surface while the intraocular pressure was varied, so as to simulate the intraocular pressure fluctuations secondary to blinking or eye squeezing. The optical density from aqueous samples of globes were measured both before and after india ink application using a spectrophotometer.ResultsAqueous aspirates from the 3 globes with sutureless clear corneal wounds revealed a significant increase in spectrophotometric readings (P<.01), in contrast to the sutured wound, which did not show an increase in absorbance level relative to the baseline. Ink particles were both grossly and microscopically visible inside the sutureless corneal wounds.ConclusionsFluctuations of intraocular pressure following sutureless clear corneal cataract surgery may allow entry of surface fluid into the anterior chamber during the initial postoperative period when the wound is not healed.Since the introduction of sutureless clear corneal cataract incisions in 1992, the procedure has gained increasing popularity worldwide because it offers several advantages over the traditional sutured scleral tunnels, such as faster visual recovery and minimizing induction of astigmatism.In recent reports, clear corneal incisions were preferred by 56% of cataract surgeons in the United States and 64% of cataract surgeons in New Zealand.However, numerous studies within the past several years have suggested that there is an increased risk of endophthalmitis with the use of sutureless clear corneal incisions.In a study by John and Noblitt,patient records from 1992 and 1996 revealed a rate of 0.29% and 0.02%, respectively, while Colleaux and Hamiltonreported a 0.13% and 0.05% incidence of endophthalmitis following cataract extraction with sutureless clear corneal and scleral tunnel incisions, respectively. More recently, Nagaki et alalso reported a statistically increased risk with clear corneal incisions (0.29%) compared with sclerocorneal incisions (0.05%). These studies indicate a several-fold increase in endophthalmitis risk associated with clear corneal incisions compared with scleral and sclerocorneal wounds.Although rare, acute endophthalmitis is still a devastating complication with high potential for ocular morbidity including permanent severe vision loss. With more than 2.5 million cases of cataract surgery performed each year in the United States alone,an increase in the incidence of this complication can result in large absolute numbers of surgical failures.Integrity of the surgical wound is an important factor in the prevention of postoperative infection. Maxwell et alreported that 80% of postsurgical cases of endophthalmitis were associated with wound defects including wound gape and malapposition. However, problems with clear corneal wounds may not be readily apparent intraoperatively. Wound integrity may vary as a function of intraocular pressure (IOP). Intraocular pressure is known to vary in the postoperative period following clear corneal phacoemulsification with 21% of eyes having an IOP of 5 mm Hg or less.Variations of IOP in both human and animal subjects following squeezing of the lids or even normal unconscious blinking further supports the notion that large fluctuations in IOP can occur during the postoperative period.Optical coherence tomographs of clear corneal incisions created in cadaveric human and rabbit eyes demonstrate that transient fluctuations in IOP of a magnitude not uncommon in the postoperative period resulted in gaping of the wound margins.This effect was more noticeable at lower IOP and less pronounced when the eye was well pressurized for standard self-sealing incisions. Furthermore, histologic examination of the incisions showed that india ink particles could migrate from the ocular surface into the stroma even though there were no particles seen adhering to the Descemet membrane to prove a full-thickness penetration.The present study was designed to further investigate the potential of extraocular microorganisms gaining access to the anterior chamber and hence creating a risk for endophthalmitis following clear corneal incisions. Using india ink and measuring optical density of the aqueous humor, we attempted to qualitatively and quantitatively assess the possibility and degree of surface fluid ingress into the anterior chamber. India ink was chosen because of its broadly similar size to bacteria and simple spectrophotometric analysis.METHODSTISSUE PREPARATION AND SURGICAL PROCEDURESFive human cadaveric eyes ranging from 1 to 4 days post mortem were obtained from the Central Florida Lions Eye & Tissue Bank (Tampa). All globes were kept at 4°C in a moist chamber prior to use. Globes were placed in a globe holder and oriented so that the temporal cornea was placed at the 6-o’clock position under the operating microscope. A 23-gauge butterfly needle was inserted through the limbus at approximately the 12-o’clock position, 180° from the incision site, connected by intravenous tubing to a 250-mL bottle of normal saline (Figure 1). Intraocular pressure was varied by adjusting the height of the bottle.Figure 1.Experimental setup. Human globe is placed in a globe holder and oriented so that the temporal cornea is at the 6-o’clock position under the operating microscope. The globe is cannulated through the limbus at approximately the 12-o’clock position, 180° away from the incision site (arrow), connected by intravenous tubing to a 250-mL bottle of normal saline.Standard self-sealing, 2-planed clear corneal cataract incisions were created under microscopic visualization using a 2.5-mm disposable keratome (Alcon, Forth Worth, Tex) with extension of the wound to 3.0 mm. Incisions were made approximately 1 to 2 mm anterior to the limbus and tunnel lengths varied from 2.0 to 2.5 mm. In 1 globe, the corneal wound was closed using a single 10-0 nylon, 15.24-cm monofilament suture (Alcon). The corneal surfaces peripheral to the incisions were depressed with a cellulose acetate sponge to test for leakage. All surgical incisions were performed by an experienced ophthalmic surgeon.SPECTROPHOTOMETRYTo examine for evidence of fluid ingress into the corneal wound, black india ink (Sanford Corp, Bellwood, Ill) was applied to the corneal surface over the region of the incision. The ink solution was a commercially available waterproof drawing ink with a specific gravity of 1.03 to 1.04. We used a UV-visible recording spectrophotometer (UV160U; Shimadzu Corp, Kyoto, Japan) to quantitatively assess the india ink concentration in a given sample by measuring its absorbance level.To analyze the level of india ink in a sample, a standard curve was created using the spectrophotometer. Serial dilutions with normal saline were performed starting from the original india ink solution (1:1 or 100%) down to 1:100 000 dilution.The india ink was applied over the incision using a supersaturated cellulose sponge placed above the wound site. Using a dropper, the sponge was kept moist continuously with the india ink. The IOP was then varied by raising and lowering the infusion bottle. The infusion bottle height was modified abruptly (so as to simulate blinking) once every 15 seconds for a period of 2 minutes, followed by once every minute for another 10 to 13 minutes. The pressure was varied over a period of a few seconds. The IOP was varied from approximately 0 to 75 mm Hg. The corneal surface was then gently irrigated with normal saline to wash away the excess india ink present on the corneal surface.One globe without any incision was used as a negative control. Clear corneal wounds were created in 4 globes. Three remained sutureless, while 1 was closed with a suture. Following cannulation, anterior chamber aspirations of 0.2 mL were obtained from all eyes using a 27-gauge needle. Samples were obtained prior to creation of the corneal incision, after creation of the incision but prior to india ink application, and following india ink application and IOP variation. Absorbance levels of the samples were then measured after addition of 0.8 mL of normal saline to the cuvette.LIGHT MICROSCOPYTo find morphologic evidence of ingress of surface fluid into the sutureless corneal wound, histologic testing of the corneal tissue was performed to determine if india ink particles were present along the incision edges. After all procedures described earlier, the cornea was excised from the limbus and fixed in 10% buffered formaldehyde for 72 hours. Histologic corneal sections were then prepared, with sections oriented radially from 3 to 9 o’clock so as to demonstrate the course of the clear corneal incisions from the corneal surface to the Descemet membrane.STATISTICAL ANALYSISUnpaired ttests were performed to compare differences between the measured absorbance levels and dilution factors.RESULTSSPECTROPHOTOMETRYThe spectrophotometric absorbance levels of different india ink concentrations are represented in both tabular (Table 1) and graphical (Figure 2) forms. We were able to accurately measure india ink concentrations down to 1:100 000 dilution. As an example, the 1:1000 sample corresponded to 1 μL of the india ink in 999 μL of normal saline.Figure 2.Spectrophotometry of india ink. Serial dilutions of india ink solution were performed with normal saline and the optical density (absorbance) measured at λ = 800 nm. Represents absorbance level of sample “sutureless incision 1.”Table 1. Spectrophotometric Measurements of India Ink*India Ink Concentration or Dilution FactorLog of Dilution FactorAbsorbance (λ = 800 nm)1:1 = 100%0.0002.2871:501.6992.2801:1002.0002.2881:5002.6992.2071:10003.0001.5231:20003.3010.8461:40003.6020.3971:80003.9030.1851:100004.0000.1621:200004.3010.0671:400004.6020.0311:800004.9030.0081:1000005.0000.006*The spectrophotometer was calibrated relative to normal saline. Normal saline was used for the serial dilutions from the original india ink solution.CONTROL AQUEOUS SAMPLESTable 2represents the spectrophotometric analysis of anterior chamber taps. The absorbance levels of the aqueous samples prior to india ink application was very close to those of normal saline. The absorbance levels of the aqueous samples after creation of the corneal incision but before applying ink were also the same as prior to creation of the incision. Thus, simply making clear corneal incisions with the keratome did not alter absorbance levels. In addition, application of india ink to the surface of unincised control corneas did not result in changed absorbance levels of the aqueous samples, indicating that the india ink particles were unable to traverse intact stroma.Table 2. Spectrophotometric Readings and Corresponding India Ink Concentrations From Anterior Chamber AspirationsSampleAbsorbance (λ = 800 nm)*Corresponding Log of Dilution FactorFinal Concentration or Dilution Factor†Control (no incision)0.00000Incision with suture0.00000Sutureless incision 10.0334.501:32000 (1:6400)Sutureless incision 20.0264.641:43450 (1:8690)Sutureless incision 30.0154.781:60260 (1:12050)*For each globe, the absorbance level from the initial anterior chamber tap prior to india ink application was subtracted from that after india ink application to obtain this value.†Multiplied by 5 since each anterior chamber sample was diluted 5 times prior to spectrophotometric measurement.SUTURELESS CLEAR CORNEAL INCISIONSAqueous samples from the 3 globes with sutureless corneal incisions revealed a significant increase in spectrophotometric readings (Table 2) relative to control (P<.01). Thus, absorbance level measurements were consistent with a small volume of india ink traversing the corneal incision and being diluted in aqueous samples.SUTURED CORNEAL INCISIONThe aqueous aspirate from a corneal incision that was sutured prior to application of india ink did not show an increase in absorbance level above the baseline (Table 2).INDIA INK PENETRATIONWhen india ink was applied to the corneal surface, the dye quickly became visible through the operating microscope within the sutureless clear corneal incisions. However, following the application of the dye and rinse, black particles were visible even with the naked eye. Histologic examination of the wound confirmed full penetration of india ink particles along the edges of the corneal incision (Figure 3). Ink particles were present within the incision in a confluent distribution involving the deeper one third of the wound length.Figure 3.India ink penetration into clear corneal incision. A, Low-power micrograph demonstrates a heavy, confluent accumulation of india ink particles (arrowhead) toward the Descemet side of the corneal incision (hematoxylin-eosin, original magnification × 20). B, Higher-power micrograph demonstrates accumulation of india ink particles (arrowhead) along the margins of the wound extending the full length of the incision (hematoxylin-eosin, original magnification × 40).COMMENTThe findings of the present study suggest that there is a potential for microorganisms such as bacteria to gain access to the intraocular compartment through apparently self-sealing clear corneal wounds as demonstrated by the entry of india ink into the anterior chamber. In the sutureless clear corneal wounds, a spectrophotometer detected a significant level of absorbance in aqueous samples following india ink application and IOP variation within a physiologic range (<5-75 mm Hg) performed to mimic fluctuations of IOP that have been demonstrated to occur after cataract surgeryor during normal activities (eye blinking, eye rubbing, eye squeezing).When the clear corneal incision was sutured, however, the absorbance level of the aqueous samples did not increase relative to the baseline.The light micrographs of the sutureless clear corneal incision show penetration of india ink along the entire length of the incision, which indicates the potential for self-sealing incisions to draw surface tear fluid into and along the incisions before the occurrence of any wound healing or closure of the surface epithelial defect. The technique used in this study may have possibly washed away some india ink particles that entered the corneal incision. Thus, we believe that the results underestimate the degree to which surface fluid penetrates into the sutureless clear corneal incisions when IOP is low (≤5 mm Hg).The level of pressure applied to the globe by squeezing of the lids or normal unconscious blinking is substantial. The presence of this force has been recognized for decades. In the 1940s, Burtondemonstrated that the upper eyelid or orbicularis oculi muscle exerts a squeeze force of up to 50 to 70 g on the globe. Coleman and Trokelmeasured IOP variations from blinking and squeezing in a human subject by inserting a 23-gauge needle directly into the anterior chamber. They showed that blinking resulted in pressure increases of up to 10 mm Hg, while squeezing of the lids produced prompt elevation to levels up to 110 mm Hg (or a 90 mm Hg increase), followed by 8 mm Hg undershoot after lid opening relative to baseline IOP.Using a different technique, Milleralso measured lid tension on 10 human subjects and determined that the average pressure developed during a blink was 10.3 mm Hg, while a mean of 51 mm Hg was produced during a hard lid squeeze. In his article, Miller also cited an experiment performed by Comberg during the 1920s where the reported effect of lid pressure on a human globe caused the IOP to go from 18 mm Hg to 70 mm Hg during a hard lid squeeze. These pressure recordings confirm the clinically apparent fact that blinking or squeezing of the lids can exert tremendous forces on the globe that may be important following intraocular surgery.We examined the ex vivo dynamic changes in unhealed clear corneal cataract incisions that might adversely affect the risk of intraocular infection.Optical coherence tomography demonstrated variation of corneal wound morphology in response to IOP fluctuations. High IOP was associated with close apposition of the wound edges in standard self-sealing incisions. At low IOP (≤5 mm Hg), however, wound edges were seen to gape, starting at the internal wound aspect. The variation in wound apposition and ability of surface fluid to traverse the wounds suggest a mechanism by which microorganisms from the ocular surface can gain access to the anterior chamber during the early postoperative period, at a time when little, if any, wound healing has taken place.We propose that a physiological mechanism analogous to the lacrimal sac and tear drainage system may allow inflow of organisms present in the tear film. Mauriceobserved that a negative pressure is present within the lacrimal sac, rising to positive values during a blink. The negative pressure in the sac during the time between blinks is due to elastic expansion of the sac after compression during the blink. This elastic force causes a partial vacuum or negative pressure to form within the canaliculi and sac, leading to the suction of fluid. Using high-speed close-up cinematography, the findings of Doanefurther supported these observations and those of Rosengrenin the early 1970s.McGowannoted that a suction mechanism might be responsible for the development of endophthalmitis following clear corneal cataract surgery, making an analogy to a squash ball with a puncture, that when squeezed and placed in a fluid medium, results in aspiration of fluid. Doanedemonstrated the dramatic posterior movement of the globe associated with lid motion. He attributed this to the pressure of the lid on the globe; indeed, the tendency for the globe to come forward in conjunction with the relaxation of the lids supports this view. Doane described that during each blink cycle, the upper lid sweeps down over the eye with its intimate and forceful contact with the cornea acting much like a windshield wiper blade. This pressure is often great enough to push the anterior surface of the globe in a posterior direction. The amount of posterior movement of the globe varies considerably, ranging between 0.7 to 1.6 mm, perhaps reflecting differences in eyelid tightness and orbital resistance to retropulsion.The elastic expansion of the globe during the opening phase of the blink potentially creates a scenario during which suction might draw tear fluid and microorganisms into the anterior chamber through a sutureless clear corneal wound.The use of spectrophotometric measurement of india ink in the present study proved to be a valuable tool in assessing the degree of ocular surface fluid inflow. India ink has proved to be a valuable research tool as evident in numerous studies, including some in ophthalmology. It is often used in the dental industry as an indicator of root canal sealing ability and for the detection of root canal orifices.In ophthalmology, india ink has been used for the visualization of uveoscleral drainage routes,the investigation of neovascularization,the morphologic examination of conjunctival mucus,the examination of the structure of corneal stroma and its fibroblasts,and for the creation of an experimental glaucoma model.India ink is broadly similar in size to most bacteria.Although the biomass of bacteria varies more than 10 orders of magnitude, from 0.2 to 750 μm in diameter, most are less than 10 μm.Using a particle size apparatus, Ahlberg et alreported that the average particle size of india ink is 10 μm. In another report, Youngson et aldetermined that the india ink particle sizes ranged from less than 1 to 600 μm in diameter with a mean particle size of 236 μm, which is considerably greater than the average value of 10 μm noted by Ahlberg et al.However, by excluding larger particles, Youngson derived a mean diameter of 9.6 μm, agreeing closely with the findings of Ahlberg. In yet another study of corneal fibroblasts, Fujita et aldetermined that ink particles were 0.5 to 10 μm in diameter. Yoshikawa et almeasured india ink particles using a microtrack particle size distribution indicator and reported a mean size of 3.8 to 5.9 μm. Therefore, it should be recognized that a range of particle sizes exists within an ink suspension. In a recent in vitro study investigating different tracers and assessment methods in the sealing ability of retrograde root fillings, it was noted that bacterial ingress and india ink penetration provided a similar rank order for the sealing ability of the material tested.Hence, we believe that the body of literature supports our use of measured increases in aqueous sample absorbance levels due to india ink penetration as a reasonable surrogate for bacterial penetration.The concentration of india ink detected by spectrophotometry in our samples was quite small, indicating that the volume of surface fluid that traverses the clear corneal incisions is small. While some ingress of fluid may be common, the low volume may explain the relative rarity of clinical infection. According to the mechanism we propose, endophthalmitis may only develop when the quantity of bacteria traversing the wound overwhelms the natural clearing mechanism of the aqueous humor, or when a particularly virulent organism gains access.In a previous study, we were able to demonstrate macroscopically the inflow of extraocular india ink through clear corneal incisions using a Miyake microscopy approach.Although this method was useful to qualitatively detect ingress of surface fluid in some of the eyes where the IOP was experimentally lowered at certain levels, not all eyes showed the same response. Additionally, external mechanical forces were required to demonstrate the penetration of india ink into the eye. The more sensitive method used in this study allows us to detect ink inflow at a level not observable with the Miyake approach. Using spectroscopy measurements, we were able to quantitatively show the intraocular penetration of minimal amounts of ink into the eye in all globes after inducing IOP changes, without need for manual globe compression. In addition, we were able to demonstrate in this study that suturing the wound prevents the passage of india ink through these incisions, similar to the behavior of an intact globe. We believe this model of intraocular pressure variation more closely mimics the clinical situation.If confirmed, our findings have several implications in the postsurgical management of patients. First, the physician should carefully evaluate the wound for signs of leakage and gaping and should consider having a low threshold for placing a suture if there is any question about wound integrity. Second, the demonstrated possibility of imbibition of surface fluid into the aqueous humor within the setting of constantly fluctuating IOP underscores the need for prophylactic antibiotic therapy in the early postoperative period. A broad-spectrum antibiotic frequently applied to the ocular surface may be useful in reducing the risk of introducing pathogenic organisms into the eye by eliminating them from the tear film. Even if surface tear fluid did gain access to the interior of the eye, the fluid would contain concentrations of antibiotic sufficiently high to suppress bacterial replication in the aqueous humor.The present study represents an effort to evaluate in vitro the stability of clear corneal wounds and the potential of ocular surface fluid ingress in the first several hours after surgery before wound healing. Further in vivo studies are warranted to confirm our concerns about these wounds because of possible limitations of ex vivo experiments such as lack of a functional endothelial pump and eyelid dynamics, and to address possible solutions.Considering the relevance of the current hypothesis on the etiology of such a potentially devastating condition, we believe it is most appropriate to create different experimental approaches to mimic the in vivo situation. Ethical limitations in the study of these events in real patients may justify further research using ex vivo models of wound construction and incisionbiomechanics.Correspondence:Peter J. 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