Outcomes of Cataract Surgery in Graft-Versus-Host Disease

CLINICAL SCIENCE

Rafael de Melo Franco, MD,*† Michelle M. Kron-Gray, MD, PhD,* Paola De la Parra-Colin, MD, MSc,* Yan He, MD,*‡ David C. Musch, PhD,* Shahzad I. Mian, MD,* Leslie Niziol, MS,* and H. Kaz Soong, MD*

llogeneic hematopoietic stem cell transplantation (HSCT) Purpose: To study the outcomes of cataract surgery in patients with Ais an important treatment modality for hematological graft-versus-host disease (GVHD) after allogeneic hematopoietic malignancies, aplastic anemia, and a number of hereditary, stem cell transplantation (HSCT). immunologic, or metabolic hemoglobinopathies.1–6 It uses Methods: Retrospective review of 72 eyes of 41 patients (age, 17– multipotent hematopoietic stem cells from bone marrow, 69 years at the time of surgery) with chronic GVHD after HSCT, peripheral blood, or umbilical cord. Graft-versus-host disease who underwent cataract surgery between 2008 and 2012 at the (GVHD) is a major cause of morbidity and mortality in Department of Ophthalmology and Visual Sciences, W. K. Kellogg patients after HSCT. Details of the updated criteria and staging of GVHD have been published in a National Institutes of Eye Center, University of Michigan. Ophthalmic data collected 7 included best-corrected visual acuity (BCVA), responses to Ocular Health GVHD consensus workshop. The most common Surface Disease Index (OSDI) questionnaire, dry eye severity, and ocular consequence is dry eye disease (DED) due to the postoperative complications. deleterious effects of GVHD on aqueous tear production, sometimes leading to corneal epithelial defects, ulceration, Results: BCVA improved from 20/49 to 20/25 (P , 0.0001) and perforation.8 These ocular complications may occur in up after surgery. Eight patients (20%) had pretransplantation total to 90% of patients with GVHD.7 body irradiation and 39 patients (95%) received systemic Recent advances in pretransplantation conditioning corticosteroids for the treatment of GVHD. Postoperative com- regimens, GVHD prophylaxis and therapy, and treatment of plications included cystoid macular edema (4 eyes), corneal opportunistic infections after allogeneic HSCT have ulceration with perforation (2 eyes: 1 infected and 1 sterile), and improved patient survival and longevity.9–12 With increased band keratopathy (1 eye). After surgery, subjective OSDI longevity, patients are more apt to encounter late complica- responses and dry eye disease (DED) did not change signiﬁcantly tions of HSCT, among which is visually signiﬁcant cata- from before cataract surgery, although OSDI showed a trend ract.5,6 Together with punctate keratopathy from dry eyes, toward worsening. cataract is one of the principal causes of poor vision in HSCT recipients. It is multifactorial in origin, resulting from Conclusions: With careful monitoring and management of DED a combination of toxicity from antimitotic chemotherapeutic and concurrent ocular surface disease, cataract surgery generally has agents, total body irradiation (TBI) during the pre–bone good visual outcomes in patients with GVHD. However, aggravation marrow transplant (BMT) conditioning process, and pro- of the preexisting ocular surface disease is frequent, and despite longed use of high-dose systemic corticosteroids in the meticulous postoperative maintenance therapy, vision-threatening treatment of GVHD.13–19 In older patients with HSCT, complications may occur. additional involutional cataract formation is also to be Key Words: graft-versus-host disease, cataract surgery expected. Comparatively little has been published in the literature (Cornea 2015;34:506–511) concerning the results and complications of cataract extraction in patients with GVHD.10,13,15 This study expands upon our own previous preliminary small study in 2002.13

Received for publication November 12, 2014; revision received January 3, 2015; accepted January 11, 2015. Published online ahead of print March MATERIALS AND METHODS 2, 2015. From the *Department of Ophthalmology and Visual Sciences, W. K. Kellogg A retrospective cohort study was conducted through Eye Center, University of Michigan Medical School, Ann Arbor, MI; a review of the medical records of all patients who underwent † Department of Ophthalmology, Cornea and External Disease Division, allogeneic HSCT, between January 2006 and 2011, at the Santa Casa de Misericórdia, São Paulo, Brazil; and ‡Beijing Ophthalmic and Visual Science Key Laboratory, Beijing Tongren Eye Center, Capital University of Michigan Comprehensive Cancer Center (Ann Medical University, Beijing, China. Arbor, MI). All patients undergoing HSCT at the University The authors have no funding or conﬂicts of interest to disclose. of Michigan are referred before HSCT to the cornea clinic Presented at the Annual Association for Research in Vision and Ophthal- GVHD specialists (H.K.S., S.I.M.) for a baseline eye mology conference, May 6, 2014, Orlando, FL. Reprints: H. Kaz Soong, MD, W.K. Kellogg Eye Center, 1000 Wall St, Ann examination and are followed at 3-month intervals after Arbor, MI 48105 (e-mail: [email protected]). HSCT for the ﬁrst year and then every 6 to 8 months Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. thereafter, depending on the degree of severity. All 41

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patients in our series had underlying systemic GVHD (skin, cataract surgery, for example, frequency of artificial tear and mucosa, gastrointestinal tract, liver, and/or lungs) diagnosed lubricating ointment, use of moisture chamber goggles, by our specialists on the bone marrow transplant service of topical corticosteroids or 0.05% cyclosporine A eye drops, the oncology division. Ocular GVHD was diagnosed by serum eye drops, punctal occlusion with either plugs or severe dry eyes (low Schirmer, low tear meniscus, increased cautery, and Prosthetic Replacement of the Ocular Surface debris in the tear film, increased superficial punctate kerat- Ecosystem (PROSE) scleral contact lens (previously known opathy with Rose Bengal or lissamine green dye in a DED as the Boston Rosenthal Scleral Contact Lens; Boston distribution, and filamentary keratitis) occurring months after Foundation for Sight, Needham, MA).21 BCVA was con- HSCT. Two of our patients with ocular GVHD also had verted to logarithm of the minimum angle of resolution madarosis and conjunctival scarring (blunting of the cul-de- (logMAR) equivalent to facilitate statistical study. Subjective sac or symblepharon or trichiasis) after the onset of systemic Ocular Surface Disease Index (OSDI) questionnaire re- GVHD. Of the 261 patients who developed chronic ocular sponses were obtained by a technician and recorded from GVHD during this period, 72 eyes of 41 patients underwent the preoperative and final postoperative visit, with higher cataract extraction by phacoemulsification and implantation scores indicating worse dry eye symptoms. of an injectable acrylic intraocular lens through a temporal, clear corneal, sutureless incision between 2008 and 2012. Postoperatively, patients were started on combined cortico- Statistical Methods steroid/antibiotic eye drops (either tobramycin/dexametha- Descriptive statistics of the sample were provided using sone or neomycin/polymyxin B/dexamethasone) 4 times means and SDs for continuous variables and frequencies and a day with weekly taper. Beginning in 2011, patients received percentages for categorical variables. intracameral cefuroxime 1.0 mg in addition for endophthal- BCVA was converted to LogMAR equivalent for mitis prophylaxis. Four surgeons, including 2 of the authors statistical analysis. Preoperative to postoperative cataract (S.I.M. and H.K.S.) from the Cornea Service of the W.K. surgery change in BCVA, clinical DED severity grade, and Kellogg Eye Center, University of Michigan, performed the OSDI scores were tested using paired t tests for continuous operations. Patients were scheduled for surgery only if their measures and the Bowker test for categorical measures. cataracts caused significant visual loss and disabling glare, Linear mixed regression modeling was also used to test and were confirmed by slit-lamp biomicroscopy and graded preoperative to postoperative change while accounting for for clinical severity (on a scale of 1–4 of nuclear sclerosis, intereye dependency. Kaplan–Meier analysis was used to cortical change, and/or posterior subcapsular cataract). estimate the time-related probability of BCVA 20/25 or better A brightness acuity tester (BAT; Marco, Jacksonville, FL) following cataract surgery. SAS version 9.3 statistical soft- was used to assess the drop in visual acuity under glare ware (SAS, Cary, NC) was used. conditions. The presence and degree of superficial punctate Retrospective review of medical records and the clinical keratopathy were assessed in relation to the severity of study protocol were approved by the Institutional Review cataract, and retinas were carefully examined to rule out the Board of the University of Michigan Medical School presence of disease, particularly viral retinitis and macular (IRBMED). disease. Cataract surgery was performed only after ocular inflammation, DED, and other ocular surface disorders were well controlled. RESULTS Data collected included patient demographics, such as A total of 72 eyes of 41 patients were identified for this age and gender, type of cataract, best-corrected visual acuity study. Mean age of the patients at the time of cataract surgery (BCVA) before and after cataract surgery, time interval on the first eye was 56 years (range, 17–69 years) and the between HSCT and cataract surgery, details of ocular surface sample consisted of 21 men and 20 women. For patients who and anterior segment examination before and after surgery, contributed 2 eyes, age at first cataract surgery was used. and postoperative surgical complications. We also recorded Types of cataract consisted of posterior subcapsular cataract whether patients underwent TBI as a part of the pre-HSCT (PSC) in 9 of 72 eyes (12.5%), nuclear sclerosis (NS) in 16 of conditioning regimen and whether they had been on systemic 72 eyes (22.2%), and combined PSC and NS in 47 of 72 eyes corticosteroids for the treatment of GVHD. (65.3%). Involutional cataracts, typical of the NS variety, A clinical diagnosis of DED was made by a 5-minute were seen in only patients older than 45 years, as NS alone or Schirmer test (with topical anesthesia) of less than 5.0 mm, as NS combined with PSC. However, pure PSC was seen a low tear-film meniscus, increased debris in the tear film, only in patients younger than 45 years. Mean time interval filamentary keratitis, corneal epithelial defects, and corneal between HSCT and cataract surgery was 114 weeks (range, superficial punctate keratopathy by vital dye staining (Rose 34–299 weeks) and mean postoperative follow-up was 55 Bengal or lissamine green dye) in a distribution typical of weeks (range, 4–201 weeks). Patients with shorter time DED. After 2009, tear-film osmolality measurements were intervals between HSCT and cataract surgery (34–100 weeks) also performed. Severity of DED was scored, based on the already had incipient cataracts noted at the time of HSCT, due above clinical indices and according to the grading scheme of to age (nuclear sclerosis in patients older than 50 years) the 2007 Dry Eye WorkShop, by categorizing the operative and/or previous corticosteroid therapy as a part of the pre- eyes into no DED, mild, moderate, or severe DED.20 We HSCT cancer treatments (PSC). These patient characteristics recorded the treatment modalities of DED before and after are summarized in Table 1.

TABLE 1. complications are summarized in Table 2, with tabulation of Demographics of Cataract Patients With GVHD type, incidence, postoperative time period, and visual acuity. Parameters Eight patients (20%) received pre-HSCT TBI as Age, mean (range), yr 56 (17–69) a conditioning regimen and 39 patients (95%) received Gender (N = 41 patients) systemic corticosteroids for the treatment of GVHD. Con- Male, n (%) 21 (51) versely, only 3 of 41 patients (7%) who had cataract surgery Female, n (%) 20 (49) did not receive any of these treatments. Cataract type (n = 71 eyes) Seventeen subjects completed the OSDI both preoper- PSC, n (%) 9 (13) atively and postoperatively, at last follow-up visit. The mean NS, n (%) 15 (21) postoperative, subjective OSDI score of 37 (SD = 25) was not PSC + NS, n (%) 47 (66) significantly different from the preoperative value of 46 (SD = Time between HSCT and cataract surgery, mean (range), wk 114 (34–299) 27) (P = 0.1743; Table 3), although the scores demonstrated No. patients with dry eye disease (%) 41 (100) a trend toward worsening DED severity at the last post- Cataract postoperative follow-up time, mean (range), wk 55 (4–201) operative visit following cataract surgery; they did noticeably worsen in 21 eyes (31%) compared with preoperative severity. The degree of DED by clinical examination, based on the grading scheme of the 2007 Dry Eye Workshop, was All patients underwent cataract extraction with phacoe- also not statistically significant (P = 0.144; Table 3). In the mulsification using temporal clear corneal, sutureless inci- postoperative period, punctal occlusion (by plugs or thermal sions. Cystoid macular edema (CME) was the most common cautery) was necessitated in 31 eyes (43%) for worsening postoperative complication and was seen in 4 eyes (5.6%) dryness. In 9 patients (16 eyes), the PROSE scleral contact (Table 2). In 3 eyes, this was successfully reversed with lens was used, and in all these patients, its application in the aggressive topical corticosteroid and 0.5% ketorolac therapy; postoperative period effectively ameliorated the severe ocular however, in 1 eye, CME was irreversible despite prolonged discomfort and poor vision from severe superficial punctate treatment and led to no improvement in visual acuity from keratopathy.21 before surgery (20/200). BCVA improved in 62 eyes (87%) at the last post- One severely dry eye developed sterile central corneal operative follow-up visit, with mean LogMAR visual acuity ulceration with perforation 7 weeks postoperatively, but it improving from 0.39 (20/49) to 0.08 (20/25) (P , 0.0001). A was successfully treated with cyanoacrylate tissue adhesive. similar result was seen when accounting for intereye corre- At 7 months after surgery, this eye required vision-restoring lation with mixed linear regression modeling. Figure 1 penetrating keratoplasty. Another severely dry eye developed displays preoperative LogMAR compared with postoperative an infectious central corneal ulceration with a perforation 1 LogMAR at 1 month and $15 months after cataract surgery. year after cataract surgery and underwent 2 penetrating Nearly all eyes showed the same or better BCVA post- keratoplasties with tarsorrhaphies, but visual acuity remained operatively compared with preoperative values; however, at poor from dense corneal scarring. Visual acuities of these final follow-up, BCVA did not change in 6 eyes and eyes at their latest postoperative visits were light perception worsened in 3 eyes after surgery. One eye had no follow-up and hand motions, respectively. BCVA data. Figure 2 displays the cumulative probability of One eye developed severe calcific band keratopathy that VA of 20/25 or better over time following cataract surgery. spared the visual axis 14 weeks after surgery. Postoperative Twelve eyes (17%) had 20/25 or better vision before cataract

TABLE 2. Complications After Cataract Surgery in GVHD Patients After HSCT Time From BCVA (Snellen) HSCT to CE BCVA and From CE Pre- (Snellen) Age at to Complication, HSCT Type of Before Corrective Other CE, yr Gender wk Dx Preoperative Postoperative Complication Complication Treatment Treatment 62 M 78 4 AML 20/200 20/200 CME 20/200 Cort/NSAID Punctal occlusions 42 F 181 2 CML 20/30 20/20 CME — Cort/NSAID None 51 M 143 8 AML 20/60 20/30 CME 20/25 Cort/NSAID None 51 M 107 4 AML 20/50 20/40 CME 20/20 Cort/NSAID None 65 F 205 14 CML 20/40 20/15 Band keratopathy 20/20 None None 52 M 98 48 BCL 20/50 HM Corneal ulcer and 20/50 PKP (2·)/ None perforation (infected) tarsor. 55 F 65 7 AML 20/200 LP Corneal ulcer and 20/80 Glue (2·) Punctal perforation (sterile) occlusions

AML, acute myelocytic leukemia; BCL, B-cell lymphoma; CE, cataract extraction; CML, chronic myelocytic leukemia; Cort, corticosteroid; Dx, diagnosis; F, female; Glue, cyanoacrylate tissue glue; HM, hand motions; LP, light perception; M, male; NSAID, nonsteroidal anti-inﬂammatory drug; PKP, penetrating keratoplasty; tarsor., tarsorrhaphy.

TABLE 3. Parameters Statistically Analyzed Before and After Cataract Surgery Mean (SD) Range P Parameters Before After Before After Dry eye severity* 1.83 (0.91) 2.06 (0.92) ——0.144 OSDI 46.3 (26.6) 36.9 (25.1) 0 to 90.9 0 to 85.4 0.174 BCVA (Snellen)† 20/49 (0.39) 20/25 (0.08) 20/20 to 20/2000 20/15 to 20/2000 ,0.0001

*Converted to numeric scale (0 = no dry eye, 1 = mild, moderate = 2, severe = 3) to enable analysis. †SD in logMAR.

surgery. At 1 year following surgery, 81% of eyes had BCVA medications that could reduce tear production, use of of 20/25 or better. omega-3-dietary supplements, punctal occlusion, muco- Postoperative treatment for DED included artiﬁcial lytic eye drops (N-acetyl cysteine 10%–20%) for excessive tears, lubricating ointments, serum tears (20%–50% con- mucus or ﬁlamentary keratitis, moisture goggles, and centration), cessation (whenever possible) of systemic PROSE scleral lenses.

FIGURE 1. Comparison of preoperative logMAR BCVA with 1 month (31 eyes) (A) and less than 15 months (20 eyes) (B) postoperative for patients with GVHD who had cataract surgery. Points above or below the line indicate worsening or improvement in BCVA, respectively. Some data points represent more than 1 patient, thus the apparent discrepancy in the total number of patients and the number of data points.

FIGURE 2. Kaplan–Meier curve demonstrating probability of BCVA of 20/25 or better after cataract surgery.

DISCUSSION It is likely that the aggressive care of DED in the Forty-one of 261 patients (16%) with chronic GVHD patients reported here contributed to generally good visual studied required cataract surgery for improvement of vision. outcomes in most eyes. However, corneal ulceration and band Thirty-one patients (76%) had bilateral surgery. The most keratopathy are worrisome complications directly attributable common type of cataract was PSC, reflecting the high to the poor ocular surface associated with GVHD. These incidence of systemic corticosteroid use (93%) in patients with occurred despite close monitoring and aggressive mainte- GVHD, whereas NS cataracts were present only in patients nance therapy of ocular surface disease. older than 45 years, reflecting the additional cataract risk factor The reported rates of chronic GVHD range from 6% to from the natural ageing process. A combination of NS and PSC 80%, but its pathogenesis is not yet well understood.7 Dry eye was seen in 7 of 8 patients who had received previous TBI, disease in GVHD is believed to be mainly due to lymphocytic reflecting the concurrent effects of TBI and older age. invasion of the lacrimal gland, but toxicity from chemother- Our incidence of clinical CME (5.6%) for small- apy and previous exposure to therapeutic ionizing radiation incision phacoemulsification in the absence of intraoperative may also contribute.6 Yoshida et al8 observed lymphocytic complications is on the higher side compared with other infiltration in a histological study of a perforated corneal reports.15 This may represent an insignificant statistical spike button from a patient with extensive chronic GVHD. because of our low sample number or may be related to an Systemic corticosteroids are used in the treatment of increased overall inflammatory diathesis in the setting of both the underlying disease leading to HSCT and the resulting GVHD with severe ocular surface disease. In 1 eye, CME GVHD after HSCT.13 They represent a major causal factor for was irreversible despite aggressive treatment, resulting in no PSC in these patients.9 Coexisting age-related cataracts of the change in BCVA from the preoperative value (Table 2). NS type were also frequently seen in our older patients.22 The observed worsening, although not statistically T-cell depletion of the donor stem cells and bone marrow significant, of clinical DED after surgery may be a direct tissue by use of monoclonal antibodies may reduce the sequel of cataract surgery or because of the underlying natural frequency and severity of posttransplantation GVHD and course of ocular GVHD. Lack of change in the preoperative may additionally have an indirect ocular benefit of reducing and postoperative subjective OSDI responses, however, may cataract risk.6 However, this must be balanced with the risk be attributable to lack of sensitivity typical of a subjective of reduced protection offered by GVHD against relapse questionnaire, especially in the presence of such widely of malignant cells from the original cancer cells. A high variable subjective responses among the patients. Lack of incidence of PSC and cortical cataracts has been reported in a statistically significant difference may also be due to the HSCT recipients who received TBI therapy.9 relatively low patient sample and may become significant if Although DED is the most frequent ocular manifestation the sample were much larger. Two severely dry eyes that of chronic GHVD, frequent concurrence of cataracts may developed central corneal ulceration after surgery, despite contribute to severe visual disability.11 Although cataract aggressive medical and surgical treatment, ended up with surgery is effective in improving vision in patients with poor visual acuities. One patient developed severe peripheral, GVHD, special attention must be paid to control the underlying nonvisually significant band keratopathy 14 weeks after and associated ocular surface problems to achieve a favorable cataract surgery. surgical outcome. Nevertheless, severe complications may

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