Accepted foFrom the

A. Wynn InClinics, IowOphthalmolSinai, New YThe JohnsBaltimore, M

Benjaminof Ophthalm

Inquiries tof Iowa Hose-mail: Ellio

0002-9394/$http://dx.doi.

Peripheral Cryoablation for Treatment of ActivePars Planitis: Long-Term Outcomes

of a Retrospective Study

ELLIOTT H. SOHN, BENJAMIN C. CHAON, DOUGLAS A. JABS, AND JAMES C. FOLK

� PURPOSE: To compare the long-term outcomes of pe-ripheral retinal cryoablation to conventional treatmentfor active pars planitis.� DESIGN: Retrospective, interventional, comparativecase series.� METHODS: Review at a single institution was conduct-ed to compare the effect of cryotherapy to eyes with parsplanitis to those receiving conventional therapy (topical,regionally injected, or oral corticosteroid therapy). Best-corrected visual acuity (VA), complications, resolutionof cystoid macular edema (CME), and anterior chamberand vitreous inflammation were assessed.� RESULTS: One hundred thirty-six eyes were treatedconventionally, 50 eyes were treated with cryotherapy.Median follow-up was 60.8 months (range 8.1–223.1 months) in the cryotherapy group and 45.0 months(range 3.1–339.0 months) in the controls. There were nosignificant differences in baseline VA, anterior chamberand vitreous inflammation, presence of CME, and prioruse of regional corticosteroid injections. VA improvedover time in the cryotherapy group (slope of L0.0018logMAR units per month; P [ .023) but declined inthe controls (slope of D0.0011 logMAR units permonth; P [ .023). Kaplan-Meier survival estimatesdemonstrated faster times to resolution of anterior cham-ber cell, vitreous cell, and CME in the cryotherapy-treated eyes. Hazard ratios of remission (adjusted forconfounding factors) for vitreous cell and CME for thosetreated with cryotherapy compared to controls were 4.73(95% confidence interval 1.63, 13.63; P [ .004) and6.85 (95% confidence interval 1.06, 44.78; P [ .044),respectively. No ocular complications were identified inthe cryotherapy group.

r publication Nov 5, 2015.Department of Ophthalmology and Visual Sciences, Stephenstitute for Vision Research, University of Iowa Hospitals anda City, Iowa (E.H.S., B.C.C., J.C.F.); Departments ofogy and Medicine, Icahn School of Medicine at Mountork, New York (D.A.J.); and Department of Epidemiology,Hopkins University Bloomberg School of Public Health,aryland (D.A.J.).C. Chaon is now at the University of Minnesota Departmentology, Minneapolis, Minnesota.o Elliott H. Sohn, Department of Ophthalmology, Universitypitals and Clinics, 200 Hawkins Dr, Iowa City, IA 52242;tt.Sohn@gmail.com

36.00org/10.1016/j.ajo.2015.11.009

� 2016 BY ELSEVIER INC.

� CONCLUSIONS: These data suggest that peripheralretinal cryoablation therapy is an effective treatmentfor active pars planitis and may be better thanconventional regional corticosteroid injections and oralcorticosteroid therapy for induction of remission. (AmJ Ophthalmol 2016;162:35–42. � 2016 by Elsevier Inc.All rights reserved.)

PARS PLANITIS IS A SUBSET OF INTERMEDIATE UVEITIS

characterized by chronic vitreous inflammation andthe accumulation of fibroinflammatory debris over

the pars plana, occurring in the absence of any associatedinfection or systemic disease.1 Clinically, these collectionsof inflammatory material resemble yellow-gray or white ag-gregates visible in the mid- and posterior vitreous and col-lections of inflammatory debris on the pars plana(particularly inferiorly), known as ‘‘snowballs’’ and ‘‘snow-banks,’’ respectively. The most frequent structural compli-cation of pars planitis is macular edema, and mosttreatment regimens are directed at controlling macularedema.2,3 Other, less common structural complicationsinclude traction retinal detachments and vitreoushemorrhage from neovascularization of the snowbank.Although a subset of patients with pars planitis do not

have macular edema or visual impairment and may beobserved, the majority of patients need treatment. Con-ventional treatment regimens typically have used a step-ped approach starting with regional corticosteroidinjections (either periocular or intravitreal), followed byoral corticosteroids, supplemented with immunosuppres-sion as needed for more difficult or bilateral cases.2,3

Regional corticosteroid injections have the potential forelevated intraocular pressure and cataract formation/progression and typically have a duration of effect of3 months, thereby requiring repetitive injections.Although when used properly, oral corticosteroids andimmunosuppression can be administered with minimalto no increase in side effects in adults, in children long-term use of oral corticosteroids is avoided owing to therisk of growth retardation.4–6 Furthermore, the chronicnature of the disease often requires long-term therapy;there is a low sustained, drug-free remission rate; andsome patients’ uveitis will not be controlled by thisapproach.7 Although some clinicians have advocatedtherapeutic vitrectomy for pars planitis, a review

35ALL RIGHTS RESERVED.

concluded that methodological problems and study con-founders resulted in insufficient evidence to support orrefute its use.8 In 1973, Aaberg and associates reportedin 23 eyes in 14 patients affected by pars planitis that pe-ripheral retinal ablation directed at the inflammatory ex-udates overlying the pars plana with transconjunctivalcryopexy (cryotherapy) was effective at decreasing vitritisand improving visual acuity.9 These observations subse-quently were supported by data from other small case se-ries; however, these studies evaluated the effect ofcryotherapy on relatively few eyes and were limited by arelatively short duration of follow-up.10–13

There are limited data on the long-term effectiveness ofperipheral retinal cryoablation therapy in controllingintraocular inflammation, improving visual acuity out-comes, and reducing structural complications of pars plani-tis. Our retrospective study compared the long-termclinical outcomes of eyes receiving cryotherapy to thosereceiving conventional therapy for active pars planitis.We sought to determine if cryotherapy resulted in better vi-sual outcomes and faster time to resolution of cystoid mac-ular edema, vitreous, and anterior chamber cell comparedto conventional therapy.

METHODS

A RETROSPECTIVE, INTERVENTIONAL, COMPARATIVE

study of all known patients with active pars planitis treatedin the Department of Ophthalmology and Visual Sciencesat the University of Iowa from January 1, 1983 (near thetime cryotherapy for pars planitis was first used at the Uni-versity of Iowa) to January 1, 2013 was conducted. The re-cords of patients with ICD-9 diagnosis code 363.21corresponding to a diagnosis of pars planitis were reviewedfor inclusion in this study. Included patients met thefollowing criteria: (1) presence of intraocular inflammationin the vitreous in at least 1 eye; (2) presence of inflamma-tory vitreous debris with snowbanks on the pars plana of theinflamed eye; and (3) a follow-up ophthalmic evaluationperformed at least 3 months after the diagnosis of parsplanitis. Exclusion criteria included (1) serologic evidenceof an infectious etiology for the ocular inflammation or aknown associated systemic disease (eg, sarcoidosis or multi-ple sclerosis); (2) clinical history or physical examinationfinding(s) to suggest a diagnosis other than pars planitis(eg, oral lesions in patients with Behcet disease); (3) inter-mediate uveitis without evidence of snowbanks; (4)isolated anterior or posterior uveitis; and (5) significant dia-betic retinopathy, macula-off retinal detachment, uncon-trolled glaucoma, or a disease other than pars planitisthat could account for a loss of visual acuity. Only de-identified data were used in the analyses. Institutional Re-view Board approval at the University of Iowa was obtained

36 AMERICAN JOURNAL OF

for this project, which adhered to the principles of theDeclaration of Helsinki.Data were extracted from review of patient charts at the

time of pars planitis diagnosis (the ‘‘baseline’’ visit) and atconsecutive follow-up visits. Follow-up visits were groupedas sequential 3-month ‘‘contiguous visit windows’’ extend-ing until the last follow-up visit (eg, the 3-month follow-upwindow extended from 1.5 to 4.5 months post-baseline, the6-month follow-up visit window from 4.5 to 7.5 monthspost-baseline, etc). Data collected at presentation, base-line, and follow-up visits included (1) best-correctedSnellen visual acuity; (2) presence or absence of cystoidmacular edema identified by stereoscopic funduscopic ex-amination and/or fluorescein angiography, which wasconfirmed by optical coherence tomography imagingwhen this modality became available (2004); (3) gradingof anterior chamber cell; (4) grading of vitreous chambercell; (5) lenticular status (phakic, aphakic, pseudophakic);(6) use of topical corticosteroid medications; (7) use of oralcorticosteroid medications; (8) use of periocular corticoste-roid injections within the previous 120 days; (9) treatmentof glaucoma with topical medication; (10) interval glau-coma surgery; (11) interval cataract surgery; and (12) pres-ence of retinal detachment. Also noted in treated eyes wasthe date of the first cryotherapy and the total number ofcryotherapy treatments per eye.Visual acuity data were converted to logMAR (loga-

rithm of the minimal angle of resolution) values(logMAR ¼ log [1/Snellen visual acuity]) to allow for sta-tistical analysis. The following logMAR values wereassigned: for hand motion, 3.3 logMAR; light perception,4.3 logMAR; and no light perception, 5.3 logMAR. Eachdifference of þ0.3 logMAR between the baseline andfollow-up visual acuity corresponds to a loss of 3 lines onan Early Treatment Diabetic Retinopathy Study (ETDRS)eye chart and a doubling of the visual angle.10,11

Much of the grading of anterior chamber cell and vitre-ous chamber cell was performed prior to publication of theStandardization of Uveitis Nomenclature’s (SUN) publica-tion of their standardized grading schema.1 However, thegrading used appears to correspond reasonably well withthe SUN schema. The early grading used a 1 3 1 mmbeam on the brightest illumination on slit-lamp bio-microscopy and had the following grades: 0 for no cells,0.5þ for 1–2 cells, 1þ for 5–10 cells, 2þ for 10–20 cells,3þ for 20–30 cells, and 4þ for over 30 cells. Anteriorchamber and vitreous inflammatory activity outcomeswere dichotomized based on a threshold of anterior cham-ber cell or vitreous chamber cell ranking less than or equalto 0.5þ, corresponding to ‘‘trace’’ inflammatory activity orless. The proportion of patients with anterior chamber cellor vitreous cell ranking less than or equal to 0.5þ at base-line and the rate at which patients’ anterior chamber andvitreous inflammation fell below this threshold wascompared between eyes treated with cryotherapy andeyes treated with conventional therapy alone.

FEBRUARY 2016OPHTHALMOLOGY

FIGURE 1. Technique for an eye with active pars planitis undergoing external cryoablation. (Left) Cryotherapy application withprobe to snowbanks. (Right) En face view of the retina during treatment; note additional single-freeze thaw applications given 1 cryo-therapy spot posterior to the snowbanks.

� CRYOABLATION PROCEDURE AND CONVENTIONALTHERAPY: With visualization using the indirect ophthal-moscope and condensing lens, single freeze-thaw, confluent,but not overlapping applications of cryotherapy were appliedto all areas of snowbanking along involved areas of the parsplana (Figure 1, Left). Procedures were performed by 1 of 2surgeons (E.H.S. or J.C.F.). A single row of cryotherapywas also applied just posterior to the most posterior aspectof snowbanking (Figure 1, Right). Depending on the amountof snowbanking, the average eye may receive between 10and 20 spots of cryotherapy. If the snowbanking involvedmore than 6 clock hours of the periphery, treatment wasplanned in 2 sessions because of the concern that moreextensive cryopexy at a single session could cause exacerba-tion of the inflammation and/or peripheral retinal traction.A second session of cryotherapy was also performed if theinflammation remained active. All patients received prepro-cedure topical anesthesia with proparacaine eye drops and, ifthe cryotherapy was performed in the clinic, subconjunctival2% lidocaine without epinephrine; those intolerant of thisapproach were given a peribulbar block with 2% lidocainewithout epinephrine. Children under the age of 16 yearsor those with substantial anxiety or discomfort were broughtto the operating room for monitored anesthesia care orlaryngeal mask anesthesia for the procedure. No postopera-tive antibiotic drops were given to patients. To blunt any in-flammatory response and the potential for retinaldetachment from cryotherapy, some patients not alreadyon oral prednisone received either (1) a posterior superiorsub-Tenon injection of 20 mg triamcinolone acetonide orintravitreal 2 mg triamcinolone acetonide injection at thetime of cryotherapy (n ¼ 21) or (2) oral prednisone at adose of 20–60 mg daily for 3 days prior to treatment, thena rapid taper and discontinuation over 9 days after cryo-therapy (n ¼ 6).

VOL. 162 CRYOABLATION FOR

Patients receiving conventional therapy (ie, controls)received either topical prednisolone acetate 1% eye dropsor a posterior superior sub-Tenon or an intravitreal triam-cinolone acetonide injection for unilateral active parsplanitis. Oral prednisone was used for recalcitrant unilat-eral cases, eyes with a history of a corticosteroid-relatedintraocular pressure rise, or bilateral active disease; patientswho could not tolerate prednisone or had recalcitrant dis-ease despite prednisone 80 mg daily were started oncorticosteroid-sparing immunomodulatory therapy. Rela-tively few eyes were treated with pars plana vitrectomywith or without adjunctive cryotherapy; any eyes receivingcryotherapy were placed in the cryotherapy group. Someeyes with bilateral active disease received cryotherapy inonly 1 eye; in these instances the eye with more severe dis-ease was always selected for cryotherapy.

� STATISTICAL ANALYSIS: Kaplan-Meier curves andrandom-effects Cox proportional hazards models were fitfor time-to-event data, such as resolution of macularedema, vitreous cell, and anterior chamber cell. Visual acu-ity (logMAR after conversion from Snellen) trajectorieswere obtained using linear model with random effects (ie,mixed model). Resolution was defined as going from a vit-reous (or anterior) chamber cell rating greater than 0.5þ atbaseline (ie, time of cryotherapy or time or presentation inthe control group) to the first occurrence of vitreous (oranterior) cell rating less than 0.5þ at least 3 months afterbaseline, with additional qualifiers of having no periocularor intravitreal corticosteroid injections within the previous120 days and no oral corticosteroids or immunosuppressiveagents. The 120-day time lag was used to account for theduration of the effect of regional corticosteroid injectionsin both groups. Baseline for the controls was defined asthe time of presentation; for the cryotherapy group it was

37PARS PLANITIS

TABLE.Cryoablation for Treatment of Pars Planitis: BaselineCharacteristics of Cryotherapy-Treated Versus Control Eyes

Characteristic

Cryotherapy

Group

Control

Group

P

Value

Number of patientsa 40 86

Number of eyes 50 136

Median age (y) 17.4 23.0 <.001

Age range 12–70 12–74

Sex (%)

Men 55 46 .37

Women 45 54

Race/ethnicity (%)

White, non-Hispanic 95.0 98.8 .19

African-American 2.5 1.2 .59

Asian 2.5 0 .14

Bilateral uveitis (%) 92.5 76.7 .03

Treatment at baseline

% who received regional

corticosteroids within 3

months of baseline

0 1.5 .44

Current prednisone use (%) 28.2 2.9 .001

Immunosuppression (%) 0 0

Ocular characteristics

Presenting visual acuity

Median logMAR 0.4 0.3 .23

Range, logMAR �0.12 to 3.3 �0.12 to 3.3

Snellen equivalent 20/50 20/40

Anterior chamber median

grade cell

0.5 0.5 .68

Range 0–3 0–3

Vitreous cell median grade 2 2 .20

Range 0–3 0–3

Lens status (%)

Phakic 100.0 99.3 .54

Pseudophakic 0 0.07 .56

Macular edema (%) 47.9 45.2 .71

aTwenty bilateral patients were treated with cryotherapy in 1

eye and not in the second eye and are included in both groups.

FIGURE 2. Visual acuity (logMAR) trajectory over timeshowing a significant improvement after cryotherapy and wors-ening in the control group of eyes with active pars planitis.

the date the treatment was performed or most recent visitbefore cryotherapy. Time-varying covariate analysis wasperformed to account for confounding factors found be-tween the groups at baseline and during follow-up,including bilaterality, vitrectomy, and regional corticoste-roid injections given after baseline.

RESULTS

OF THE CHARTS REVIEWED FOR INCLUSION IN THIS STUDY,

58 patients were excluded because they did not meet thediagnostic criteria for pars planitis and 3 patients wereexcluded owing to follow-up of less than 3 months. Thestudy population consists of 186 eyes (136 control eyes;50 cryotherapy eyes) from 95 patients (69 control patients,

38 AMERICAN JOURNAL OF

6 cryotherapy patients with unilateral pars planitis, and 20patients with bilateral uveitis where 1 eye was treated withcryotherapy and the second eye was in the control group).Characteristics of the study population are shown in theTable. Cryotherapy-treated patients were followed for amedian of 60.8 months (range 8.1–223.1 months) andcontrols were followed for a median of 45.0 months (range3.1–339.0 months). Ten eyes in the cryotherapy group sus-tained more than 1 treatment. The 2 groups were relativelywell balanced at baseline with no significant differencesbetween the groups in baseline visual acuity, anteriorchamber and vitreous inflammation, presence of macularedema, and prior use of regional corticosteroid injections.There were significant differences in the ages of the 2groups, with the cryotherapy group being somewhatyounger (median 17.4 years vs 23.0 years) and in the higheruse of oral corticosteroids in the cryotherapy group at base-line (28.2% vs 2.9%, P ¼ .001).Regarding other potential confounders occurring during

follow-up, 13 eyes (9.6%) in the control group underwentpars plana vitrectomy, compared to 11 eyes (22%) in thecryotherapy group (P ¼ .038). Of the 11 cryotherapy-treated eyes that underwent vitrectomy, 4 underwent itat the time of cryotherapy and 7 underwent it subsequently.The mean number of regional (ie, sub-Tenon or intravi-treal) corticosteroid injections after baseline in thecryotherapy-treated group was 2.13/eye and in the controlgroup was 0.85/eye (P < .001). Potential confounders atbaseline and follow-up between the 2 groups wereaccounted for using time-varying covariate analyses.

� VISUALACUITYOUTCOMES: Over time, visual acuity onaverage improved in the cryotherapy-treated eyes andworsened slightly in the control eyes (Figure 2). Specif-ically, in the cryotherapy-treated eyes, visual acuity valuestended to improve (decreasing logMAR) during follow-up

FEBRUARY 2016OPHTHALMOLOGY

FIGURE 3. Kaplan-Meier survival estimate showing morerapid resolution of vitreous cell in the cryotherapy groupcompared to control eyes with active pars planitis.

FIGURE 4. Kaplan-Meier survival estimate showing morerapid resolution of cystoid macular edema in the cryotherapygroup compared to control eyes with active pars planitis.

by an average of 0.0018 logMAR units per month (P ¼.023). In the control eyes, the visual acuity values tendedto worsen (increasing logMAR) during follow-up by0.0011 logMAR units per month (P ¼ .023). A formaltest of interaction to see if the slopes were different was sig-nificant (P ¼ .024). After adjusting for bilateral status, vit-rectomy, and regional corticosteroid injections duringfollow-up, there was still a suggestion that the slopes weredifferent (P ¼ .069).

� VITREOUS CELL: Resolution of vitreous cell occurredwith greater frequency in cryotherapy-treated eyes. At 1year, 49.8% of eyes in the cryotherapy group had experi-enced resolution of vitreous cell and were not taking eitherprednisone or immunosuppressive agents, compared to22.5% in the control group (P ¼ .0071). At 1 year,43.7% of eyes in the cryotherapy group had resolution ofthe vitreous cell, were not receiving oral corticosteroidsor immunosuppressive agents, and had not received aregional corticosteroid injection within the previous120 days, compared to 18.5% in the control group (P ¼.0115). Kaplan-Meier survival estimates depicting resolu-tion of vitreous cell are presented in Figure 3. The hazardratio for ‘‘remission’’ (inactive disease without treatment)for the cryotherapy group compared to the control groupwas 3.79 (95% confidence interval [CI] 1.47, 9.76, P ¼.002). After adjusting for bilaterality, vitrectomy, andregional corticosteroid use, the hazard ratio for remissionwith cryoablation vs none was 4.73 (95% CI 1.65, 13.63,P ¼ .004).

� CYSTOID MACULAR EDEMA: Cryotherapy-treated eyesappeared more likely to obtain resolution of macular edemacompared to control eyes. The Kaplan-Meier survival esti-mates of the resolution of macular edema are shown inFigure 4; differences were significant by 6 months (P ¼.007). At 1 year resolution of macular edema without recur-rence and without use of systemic medications or use ofregional corticosteroid injections within the previous120 days occurred in 57.7% of eyes treated with cryo-therapy compared to 41.0% of control eyes. At 1 year, res-olution of macular edema without systemic medicationsbut allowing regional corticosteroid injections within theprevious 120 days occurred in 68.9% of cryotherapy-treated eyes compared to 42.8% of control-treated eyes.These percentages are Kaplan-Meier estimates based on18 cryotherapy-treated eyes and 58 control eyes. The crudehazard ratio for remission of the macular edema was 4.12(95% CI 0.87, 19.44; P ¼ .074) in favor of thecryotherapy-treated eyes, and after adjustment for bilater-ality, vitrectomy, and regional corticosteroid injectionsthe hazard ratio was 6.85 (95% CI 1.06, 44.78; P ¼ .044).

� ANTERIOR CHAMBER CELL: Cryotherapy appeared to beassociated with resolution of anterior chamber cell whencompared to control eyes (Figure 5). Kaplan-Meier survival

VOL. 162 CRYOABLATION FOR

estimates of resolution of anterior chamber cell were signif-icantly different between the 2 groups by 6 months(P ¼ .005). The crude hazard ratio for remission (inactivedisease off all therapy) was 12.62 (95%CI 0.96, 165.25; P¼.053), and after adjustment for bilaterality, vitrectomy, andregional corticosteroid use during follow-up it was 21.74(95% CI 1.11, 425.68; P ¼ .043).

� COMPLICATIONS AND OTHER TREATMENTS: Otherthan transient erythema of the conjunctiva over thetreated areas, there were no complications resulting fromcryotherapy. No eyes developed retinal detachment as aresult of cryotherapy. In fact, 1 eye had an inferior retinaldetachment before treatment that resolved 3 months aftercryotherapy. Six eyes in the cryotherapy group had poste-rior subcapsular cataract noted on examination (5 hadcataract surgery); 18 of the control eyes had posterior sub-capsular cataract (16 had cataract surgery)—the number

39PARS PLANITIS

FIGURE 5. Kaplan-Meier survival estimate showing morerapid resolution of anterior chamber cell in the cryotherapygroup compared to control eyes with active pars planitis.

that had cataracts was not significantly different betweenthe 2 groups (P ¼ .83).

Four eyes in the control group and 4 eyes in the cryo-therapy group needed glaucoma surgery, and all had multi-ple periocular corticosteroid injections preceding theglaucoma procedure. Five patients started corticosteroid-sparing immunosuppressive agents during follow-up, 2 inthe control group and 3 in the cryotherapy group. All 3of these cryotherapy group patients had bilateral diseasewith cryotherapy given to only 1 eye.

DISCUSSION

PARS PLANITIS IS THE THIRD MOST COMMON UVEITIC DIS-

ease affecting the pediatric population1,9,12 and has anoverall annual incidence of 2 per 100,000 persons.3,13–16

Standard approaches to treatment have advantages anddisadvantages, including cataracts and ocularhypertension/glaucoma from regional corticosteroidinjections.17,18 Nevertheless, because of the chronicnature of this disease, these treatments often requirelong-term use. Our data suggest that many eyes treatedwith peripheral retinal cryoablation can achieve ‘‘inac-tive’’ disease without attendant systemic medicationsand that this rate may be greater than that in eyes treatedconventionally. Furthermore, cryotherapy-treated eyesappeared to have faster resolution of macular edema andbetter visual outcomes. In addition, we did not identifyany greater rate of ocular complications in thecryotherapy-treated eyes, suggesting that this treatmentcan be administered safely.

Some clinicians have employed peripheral laser photoa-blation instead of cryoablation for pars planitis, with goodresults reported in uncontrolled case series. These authorshave expressed concern about the complications of cryo-therapy, particularly retinal detachment.13 However, in

40 AMERICAN JOURNAL OF

our series no retinal detachments were identified despiterelatively long follow-up. Nevertheless, it is possible, orperhaps even likely, that peripheral retinal ablation byeither means (cryotherapy or laser photoablation) may besimilarly effective for the treatment of pars planitis, asthe key issue is not the mode of ablation but that peripheralretinal ablation was performed.Histopathologic studies of human eyes with pars plani-

tis have demonstrated fibroglial proliferation and lympho-cytic infiltration of the snowbank as well as retinalvasculitis, cyclitis, and choroiditis.19,20 Though B cellshave been identified posterior to the junction of the irisand ciliary body, there was a predominance of T cells inthe pars plana of these donor eyes along with a highratio of helper T cells to suppressor cells.20 Elevatedlevels of specific T cell subtypes in the peripheral bloodof patients with pars planitis further implicate therole of T cell activation in this disorder.21,22 Thus amechanism of action for cryotherapy is unknown;hypotheses have included altering the blood-ocularbarrier (allowing better ingress of drugs and egress ofinflammatory mediators) and destruction or reduction ofan antigenic stimulus in the pars plana. The retinal S-antigen that has been used to cause experimental autoim-mune uveitis21,22 has been suggested as a potentialcandidate,23 but antibodies to the S-antigen were notfound in a donor eye with pars planitis, suggesting thatit may not be important in the pathogenesis.20 There isno doubt that further research is needed to elucidatethe pathogenetic mechanisms involved.There are several potential limitations to this study,

many inherent in its retrospective nature. Although wecould not identify any evident selection bias in the eyeschosen for cryotherapy (aside from choosing the ‘‘worse’’eye for unilateral treatment in a patient with bilateral dis-ease), unidentified selection bias could have influenced theresults. Observers were not masked as to treatment, allow-ing for potential observer bias to influence the results. Asthis was a retrospective study, it is difficult to know forcertain which type of patients would benefit most fromcryotherapy. These potential biases can only be addressedthrough a randomized clinical trial with masked assessmentof outcomes. Variable concomitant therapy is a potentialconfounder. There was a baseline imbalance in oral corti-costeroid use, with a higher percentage of patients in thecryotherapy group using oral corticosteroids at baseline.Given our stepwise treatment algorithm, this greater usecould reflect more severe disease or the greater frequencyof bilateral disease in the cryotherapy group. Given thesimilarity of vision, macular edema percentage, and inflam-mationmedian grades, it is likely that the difference reflectsthe difference in bilateral disease. As some of these patientswere treated before the advent of optical coherence tomog-raphy, it is possible that cystoid macular edema could havebeen present despite not being seen ophthalmoscopically;however, both groups would have been subjected to this

FEBRUARY 2016OPHTHALMOLOGY

and thus the effect on the results of this study should beminimal.

Any differential treatment during follow-up also couldhave influenced the outcomes, including resolution ofanterior chamber and vitreous cells, resolution of macularedema, and improvement in vision. For instance, onaverage there were fewer periocular injections given tothe control group during the follow-up period, and parsplana vitrectomy was used in a greater percentage of pa-tients (albeit still a minority) in the cryotherapy group.We sought to mitigate any potential confounding factorsin 2 ways. The first was analyzing outcomes that includedbeing off systemic and regional treatments as part of thedefinition of remission, and the second was adjusting for po-tential confounders statistically (including postbaselineperiocular injections and vitrectomy) using time-varyingcovariate analysis. In this regard, our data suggest greaterrates of resolution of anterior chamber cells, vitreous cells,and macular edema despite discontinuing concomitant oraltherapy in the cryotherapy group. Nevertheless, despite theapparent success of cryotherapy and the significant adjustedhazard ratios (favoring cryotherapy), the small sample sizeled to wide confidence intervals, so that the magnitude ofthe benefit is less certain. Finally, observers were notmasked as to treatment, potentially introducing observer

VOL. 162 CRYOABLATION FOR

bias. As such, our data should be viewed as highly sugges-tive rather than conclusive.There were no standard follow-up protocols, resulting in

variable follow-up intervals. We attempted to mitigate thisvariable follow-up by recording only visits that corre-sponded to 3-month intervals after baseline and usingcontiguous visit windows. Heterogeneous follow-up alsowas addressed by using statistical tools such as Kaplan-Meier product-limit estimation and random-effectsmodeling. The sample size of eyes treated with cryotherapywas small, so that estimates of side effects also are impre-cise. For example, the upper 95% CI on the detachmentrate is approximately 6% of eyes treated with peripheralretinal cryoablation.In conclusion, for eyes with active pars planitis, our data

suggest that peripheral retinal cryoablation appears to bean effective treatment that can potentially result in a‘‘remission,’’ a result that appears to be seen less commonlywith conventional corticosteroid treatments. This treat-ment appears to have a low risk of side effects and to be areasonable addition to the armamentarium of therapiesfor pars planitis. Because of the limitations inherent in aretrospective study of this type, its role vis-a-vis conven-tional treatment will need to be evaluated in a randomizedclinical trial.

FUNDING/SUPPORT: NO FUNDING OR GRANT SUPPORT. FINANCIAL DISCLOSURES: ELLIOTT H. SOHN: OXFORD BIOMEDICA,Oxford, United Kingdom (research support); GlaxoSmithKline, Middlesex, United Kingdom (research support); Douglas A. Jabs: Applied GeneticTechnologies, Inc, Alachua, Florida (Data and Safety Monitoring Committee); James C. Folk: IDx LLC, Iowa City, Iowa (Shareholder, Officer,and Board Member). The following author has no financial disclosures: Benjamin C. Chaon. All authors attest that they meet the current ICMJEcriteria for authorship.

The authors thank Jeffrey Dawson, ScD (University of Iowa) for his assistance with statistical analysis and Alton Szeto (altonszeto.com) for creation ofthe eye schematic figure.

REFERENCES

1. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization ofUveitis Nomenclature (SUN) Working Group. Standardiza-tion of uveitis nomenclature for reporting clinical data. Re-sults of the First International Workshop. Am J Ophthalmol

2005;140(3):509–516.2. Raja SC, Jabs DA, Dunn JP, et al. Pars planitis: clinical fea-

tures and class II HLA associations. Ophthalmology 1999;106(3):594–599.

3. Donaldson MJ, Pulido JS, Herman DC, Diehl N, Hodge D.Pars planitis: a 20-year study of incidence, clinical fea-tures, and outcomes. Am J Ophthalmol 2007;144(6):812–817.

4. Zhang L, Prietsch SOM, Ducharme FM. Inhaled corticoste-roids in children with persistent asthma: effects on growth.Cochrane Database Syst Rev 2014;7:CD009471.

5. MacGregor RR, Sheagren JN, Lipsett MB, Wolff SM. Alter-nate-day prednisone therapy. Evaluation of delayed hypersen-sitivity responses, control of disease and steroid side effects.NEngl J Med 1969;280(26):1427–1431.

6. Kelly HW, Van Natta ML, Covar RA, et al. Effect of long-term corticosteroid use on bone mineral density in children:

a prospective longitudinal assessment in the childhoodAsthma Management Program (CAMP) study. Pediatrics

2008;122(1):e53–61.7. Multicenter Uveitis Steroid Treatment (MUST) Trial

Research Group, Kempen JH, Altaweel MM, et al. Ran-domized comparison of systemic anti-inflammatory ther-apy versus fluocinolone acetonide implant forintermediate, posterior, and panuveitis: the multicenteruveitis steroid treatment trial. Ophthalmology 2011;118(10):1916–1926.

8. BeckerM, Davis J. Vitrectomy in the treatment of uveitis.AmJ Ophthalmol 2005;140(6):1096–1105.

9. Aaberg TM, Cesarz TJ, Flickinger RR. Treatment of periph-eral uveoretinitis by cryotherapy. Am J Ophthalmol 1973;75(4):685–688.

10. Lehpamer B, Moshier E, Goldberg N, Ackert J, Godbold J,Jabs DA. Subretinal fluid in uveitic macular edema: effecton vision and response to therapy. Am J Ophthalmol 2013;155(1):143–149.

11. Klein R, Klein BE, Lee KE, Cruickshanks KJ, Chappell RJ.Changes in visual acuity in a population over a 10-yearperiod: the Beaver Dam Eye Study. Ophthalmology 2001;108(10):1757–1766.

41PARS PLANITIS

12. Smith JA, Mackensen F, Sen HN, et al. Epidemiology andcourse of disease in childhood uveitis. Ophthalmology 2009;116(8):1544–1551. 1551.e1.

13. Okinami S, Sunakawa M, Arai I, Iwaki M, Nihira M,Ogino N. Treatment of pars planitis with cryotherapy.Ophthalmologica 1991;202(4):180–186.

14. Verma L, Kumar A, Garg S, Khosla PK, Tewari HK. Cryo-pexy in pars planitis. Can J Ophthalmol 1991;26(6):313–315.

15. Josephberg RG, Kanter ED, Jaffee RM. A fluorescein angio-graphic study of patients with pars planitis and peripheralexudation (snowbanking) before and after cryopexy.Ophthal-mology 1994;101(7):1262–1266.

16. Prieto JF, Dios E, Gutierrez JM, Mayo A, Calonge M,Herreras JM. Pars planitis: epidemiology, treatment, and asso-ciation with multiple sclerosis. Ocul Immunol Inflamm 2001;9(2):93–102.

17. Leder HA, Jabs DA, Galor A, Dunn JP, Thorne JE. Perioculartriamcinolone acetonide injections for cystoid macular

42 AMERICAN JOURNAL OF

edema complicating noninfectious uveitis. Am J Ophthalmol2011;152(3):441–448.e442.

18. Sallam A, Taylor SRJ, Habot-Wilner Z, et al. Repeat intravi-treal triamcinolone acetonide injections in uveitic macularoedema. Acta Ophthalmol 2012;90(4):e323–325.

19. Pederson JE, Kenyon KR, Green WR, Maumenee AE. Pathol-ogy of pars planitis. Am J Ophthalmol 1978;86(6):762–774.

20. Wetzig RP, Chan CC, Nussenblatt RB, Palestine AG,Mazur DO, Mittal KK. Clinical and immunopathologicalstudies of pars planitis in a family. Br J Ophthalmol 1988;72(1):5–10.

21. Boyd SR, Young S, Lightman S. Immunopathology of thenoninfectious posterior and intermediate uveitides. Surv

Ophthalmol 2001;46(3):209–233.22. Caspi RR, Silver PB, LugerD, et al.Mousemodels of experimental

autoimmune uveitis.Ophthalmic Res 2008;40(3-4):169–174.23. Nussenblatt RB, Gery I, Ballintine EJ, Wacker WB. Cellular

immune responsiveness of uveitis patients to retinal S-anti-gen. Am J Ophthalmol 1980;89(2):173–179.

FEBRUARY 2016OPHTHALMOLOGY

Biosketch

Dr Elliott H. Sohn is vitreoretinal surgeon-scientist at the Wynn Institute for Vision Research/University of Iowa with

special expertise in inherited retinal degenerations, AMD, and diabetic retinopathy and is surgeon/PI/co-investigator for

several gene therapy trials. His laboratory focuses on efficacy and immunologic effects of stem cell and gene therapy and

the pathophysiology and novel therapies for AMD. He serves on ARVO, AAO, and ABO committees and is editorial

board member for Scientific Reports (Nature Publishing).

VOL. 162 42.e1CRYOABLATION FOR PARS PLANITIS

Biosketch

Dr James C. Folk is the Judith (Gardner) and Donald Beisner, Professor of Vitreoretinal Disease and Surgery in the

Department of Ophthalmology and Visual Sciences and Wynn Institute of Vitreoretinal Research at the University of

Iowa. He is an officer of the Macula Society and member of the Retina Society and American Society of Retinal

Specialists. Although he treats a wide variety of vitreoretinal disease he has a particular interest in ocular inflammatory

diseases. He is active in both clinical and translational research.

42.e2 FEBRUARY 2016AMERICAN JOURNAL OF OPHTHALMOLOGY