International Journalof Retina and VitreousLally et al. Int J Retin Vitr (2016) 2:18DOI 10.1186/s40942-016-0042-yORIGINAL ARTICLEOpen AccessExpanded spectral domain‑OCT findingsin the early detection of hydroxychloroquineretinopathy and changes following drugcessationDavid R. Lally1,2, Jeffrey S. Heier2, Caroline Baumal1, Andre J. Witkin1, Steven Maler1, Chirag P. Shah2,Elias Reichel1, Nadia K. Waheed1, Igor Bussel1, Adam Rogers1 and Jay S. Duker1,2*AbstractPurpose: To report expanded SD-OCT findings of HCQ retinopathy that may assist the clinician in earlier diagnosis. Tocharacterize structural changes of HCQ retinopathy with SD-OCT after drug cessation.Methods: Setting: Private practice and academic institution. Patient Population: Patients at New England Eye Centerand Ophthalmic Consultants of Boston in Boston, MA diagnosed with HCQ retinopathy and followed after drug cessation. Retrospective clinical data review by the Boston Image Reading Center. Main Outcome Measures: SD-OCT findings suggestive of HCQ retinopathy before parafoveal ellipsoid disruption. Change in SD-OCT morphological appearance and retinal thickness of each of the nine subfields corresponding to the Early Treatment of Diabetic RetinopathyStudy areas.Results: Thirty eyes with HCQ retinopathy were followed with SD-OCT after drug cessation. Findings before disruption of the parafoveal EZ included parafoveal outer nuclear layer (ONL) thinning, disruption of the parafovealinterdigitation zone, and reduced reflectivity of the parafoveal EZ. In early toxicity, 75 % developed progression afterdrug cessation, including disruption of the parafoveal EZ and retinal pigment epithelium and thinning of the ONL.Eyes with obvious toxicity had greater inferior outer ring thinning 12 months after drug cessation compared to earlytoxicity (p 0.002, 95 % CI 2 to 8 μm). In obvious toxicity, the nasal inner subfield showed more thinning than thetemporal inner subfield at 12 months after drug cessation (p 0.018, 95 % CI 1 to 8 μm).Conclusions: Once HCQ retinopathy is diagnosed and the medication is discontinued, structural retinal changescommonly occur.BackgroundHydroxychloroquine (HCQ) has been used for therapyof rheumatologic disorders since the 1950s. Ocular toxicity associated with HCQ use was initially described inthe 1960s [1, 2]. The incidence of HCQ retinopathy isestimated at 1 % after consumption of HCQ for 5 years[3]. It is marked by paracentral and central scotoma and*Correspondence: [email protected] Service, Departments of Ophthalmology, New England EyeCenter, Tufts University School of Medicine, 260 Tremont Street, Boston,MA 02116, USAFull list of author information is available at the end of the articledecreased color vision. Risk factors predisposing to thedevelopment of HCQ retinopathy include a daily dose 6.5 mg/kg, cumulative dose 1000 g, duration of useover 5 years, elderly age, kidney or liver dysfunction, orpreexisting maculopathy [4]. HCQ retinopathy is rareconsidering the widespread utilization of this drug; however, the retinopathy has potential to produce irreversiblevisual loss [1].There is limited data regarding structural and functionalchanges of HCQ retinopathy after drug cessation [5–7].Studies from the 1960s and 1970s evaluated individualstaking the more toxic, related drug chloroquine, but were 2016 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International /), which permits unrestricted use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated.

Lally et al. Int J Retin Vitr (2016) 2:18limited to visual acuity, visual fields, and fundus examination to assess for progression of retinopathy. In addition,these studies typically evaluated patients with advanceddisease who had already developed a Bull’s eye fundusappearance. In the present day, the less toxic HCQ is usedinstead of chloroquine. The American Academy of Ophthalmology revised the screening guidelines in 2011 toinclude spectral domain-optical coherence tomography(SD-OCT), fundus autofluorescence (FAF), and multifocal ERG (mfERG) when available to assess the macula inpatients taking HCQ [4]. The new guidelines were designedfor earlier detection of HCQ retinopathy before funduscopic changes become apparent. Studies reviewing mfERGand FAF after drug cessation have demonstrated both progression and improvement in retinal function in moderateto severe toxicity [8–11]. It is unclear whether less severecases of retinopathy progress after HCQ cessation.SD-OCT is a highly sensitive and reproducible imagingmodality commonly used in clinical practice. SD-OCTis capable of detecting characteristic macular changesof HCQ toxicity. These typical macular abnormalitiesinclude loss of the parafoveal ellipsoid zone (EZ), parafoveal thinning of the outer nuclear layer (ONL) andinner plexiform layer (IPL), the “flying saucer” sign, andperipapillary nerve fiber layer thinning [12–14]. Fewreports have examined progression of changes in SDOCT appearance after drug cessation. Marmor et al. [11]reported that SD-OCT appearance in patients with earlyHCQ toxicity, defined as patchy parafoveal visual fielddefects, did not change after drug cessation. However,moderate cases, defined as a 50–100 % parafoveal ringof damage on visual field testing, did demonstrate progressive parafoveal thinning. Kellner et al. [15] showedlong-term follow-up of eyes with moderate to severechloroquine/HCQ toxicity resulting in cystoid macularedema and epiretinal membrane formation. However, nochanges were observed in early toxicity.This study examines longitudinal SD-OCT scans aftercessation of HCQ and stratifies eyes based on severityof retinopathy to evaluate whether this plays a role instructural changes. An independent reading center wasused to limit observational bias in interpreting the SDOCT scans. Furthermore, SD-OCT findings are identified before clear parafoveal ellipsoid zone (EZ) disruptionbecomes apparent, which may enable earlier diagnosis ofHCQ retinopathy.MethodsData collection was obtained following approval from theInternal Review Board (IRB) of Tufts Medical Center, andwas in compliance with the Health Insurance Portabilityand Accountability Act. Research tenets were followed inaccordance with the Declaration of Helsinki.Page 2 of 11A retrospective, consecutive case series of eyes withHCQ retinopathy that were followed after drug cessation was conducted at New England Eye Center, Boston,Massachusetts and Ophthalmic Consultants of Boston,Boston, Massachusetts. The study interval was from January 1, 2006 to July 12, 2013. Eyes were included if theywere diagnosed with HCQ retinopathy and had SD-OCTimaging at the time of drug cessation and on follow-upexam. In addition, eyes were included only if the followup SD-OCTs were performed on the same machine—either Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA)or Heidelberg Spectralis HRA OCT (Heidelberg Engineering, Germany).HCQ retinopathy was diagnosed by detecting abnormalities attributable to HCQ on clinical examination,Humphrey 10-2 or 24-2 visual fields, SD-OCT, and/orFAF when available. Of note, all eyes in this study hadvisual field defects consistent with HCQ toxicity. Multifocal ERG was performed in only 8 eyes, and in theseeyes, toxicity was confirmed with visual field defects andSD-OCT findings. Therefore, mfERG was not included inthe analysis. Eyes were excluded if there was no clinicalexamination on record coincident with the time of HCQcessation, if the follow up OCT was performed on a different OCT machine than at the time of drug cessation,or if time-domain OCT was performed. Ocular symptoms, best-available visual acuity, macular appearance,and imaging modalities (OCT, FAF) available at the timeof HCQ retinopathy diagnosis and after HCQ cessationwere recorded. The cumulative HCQ dose was calculated.The first primary outcome measure was the morphological change in 1-line horizontal OCT scans from thetime of discontinuing HCQ to the most recent examination. Vertical OCT scans were not routinely ordered bythe treating physician and therefore unable to be includedin analysis. If there were SD-OCT images available thatdemonstrated findings that preceded disruption of theparafoveal EZ, these findings were recorded and analyzedby the reading center. The second primary outcome measure was the change in retinal thickness in each of the 9Early Treatment of Diabetic Retinopathy Study (ETDRS)OCT sub-fields at 12 months after drug cessation.The SD-OCT scans were evaluated by two masked,trained readers from the Boston Image Reading Center(BIRC, Boston, MA). The readers were provided raw datafrom the cube scans, which were qualitatively assessedfor alterations in the normal morphological retinal features. Readers analyzed SD-OCT images from the timeof drug cessation and most recent follow up exam, andassessed whether any interval changes had occurred.After careful deliberation, common features which weremost consistently recorded were decreased reflectivity ofthe ellipsoid zone (EZ), disruption of the EZ, disruption

Lally et al. Int J Retin Vitr (2016) 2:18of the interdigitation zone (IZ), disruption of the retinalpigment epithelium (RPE), disruption of the external limiting membrane (ELM), and thinning of the outer nuclearlayer (ONL). These characteristics were evaluated tobe present or absent in both the foveal region (central1500 μm) and parafoveal region (0–2000 μm from theborder of the foveal region on either side). The findingswere considered true findings only if both readers agreedon the finding (i.e. hyporeflective, RPE atrophy, etc.) andthe location of the finding (i.e. fovea, nasal parafovea,temporal parafovea, or both nasal and temporal parafovea). In no instances was there an opposite finding oneither side of the fovea, such as hyperreflectivity on thenasal side and hyporeflectivity on the temporal side.For data analysis, the primary cohort was divided intothree groups based on BIRC’s grading of the 1-line horizontal OCT scan through the fovea at the time of drugcessation (Fig. 1). The purpose of the division was toseparate early, obvious, and severe cases of toxicity, asthe development of new screening modalities such as SDOCT has allowed for detection of earlier cases of HCQtoxicity. The Early group consisted of eyes presentingwithout clear disruption of both the foveal and parafovealellipsoid zone (EZ) as judged by BIRC’s interpretation ofthe SD-OCT at the time of drug cessation. Fundus examination of these eyes showed early macular findings, ornone at all, at the time of diagnosis. The Obvious groupconsisted of eyes presenting with an intact foveal EZ but aclearly disrupted parafoveal EZ on either one or both sidesof the fovea as judged by the BIRC graders. These eyesclinically manifested the classic parafoveal RPE changes.The Severe group consisted of eyes presenting with clearfoveal EZ disruption with associated parafoveal EZ disruption. These eyes had poor visual acuity at presentationdue to foveal and parafoveal outer retinal atrophy.Page 3 of 11Retinal thickness measurements of each of the ninesubfields corresponding to the Early Treatment of Diabetic Retinopathy Study (ETDRS) areas were examined.ETDRS SD-OCT thickness measurements consist of nineseparate regions, which are defined by three concentricrings centered on the fovea with diameters of 1, 3, and6 mm, respectively. The two outer rings are divided intoquadrants by two intersecting orthogonal lines. Onlyeyes that underwent SD-OCT imaging at baseline andfollow-up with either Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) or Heidelberg Spectralis HRA OCT(Heidelberg Engineering) were included in this analysis.Eyes that had baseline Stratus OCT (Carl Zeiss Meditec,Dublin, CA) were excluded.Statistical analysis was performed using GraphPad(GraphPad Software, Inc., La Jolla, CA USA). We used anunpaired t test to compare the changes in retinal thickness between the groups, while a paired t-test was usedto compare the changes within a group. 95 % confidenceintervals were calculated for any statistically significantchanges observed as defined as p 0.05.ResultsThirty-six patients were identified with HCQ retinopathy.Thirteen patients were excluded because an OCT wasnot performed at the time of diagnosis. Eight patientswere excluded for having a time domain-OCT at the timeof drug cessation. Thirty eyes of 15 female patients metinclusion criteria and were followed by repeated examinations after drug cessation. Clinical features of eachpatient are outlined in Table 1 and in each of the threegroups in Table 2. All patients were Caucasian. Half ofthe eyes were emmetropic, and half were ametropic(range 6.0 to 6.0 diopters). None of the patients hadkidney or liver dysfunction.Fig. 1 Fundus photograph and SD-OCT example of each group. Cohort divided into three groups based on BIRC’s grading of ellipsoid zone at thetime of drug cessation. Early—no disruption of parafoveal or foveal EZ; Obvious—disruption of parafoveal EZ with intact foveal EZ; Severe—disruption of both foveal and parafoveal EZ

Lally et al. Int J Retin Vitr (2016) 2:18Page 4 of 11Table 1 Clinical summary of patientsPatient/sex/ HCQ cumu‑agelative dose(g)Body massindexHCQ indica‑ Follow-uptionafter HCQcessation(months)HCQ cessa‑tion VAMost recentVASymptomsat HCQ ces‑sationSymptoms Progressionat follow-up after 20OS:20/20OD:20/20OS:20/20NoneNoneYes (OCT, 40Decreasednear visionDecreasednear visionYes /30NoneNoneYes /20OD:20/20OS:20/20FloatersNoneYes (OCT, /30NoneNoneYes 0/20FloatersFloatersYes 0/50Blurry visionBlurry S:20/25FloatersFlashesYes 0/25GlareGlare, 25OS:20/25NoneNoneYes 0/40NoneDecreasednear visionYes (OCT, 25NoneDecreasednear visionYes onYes :20/100Blurry visionBlurry visionNoE2 left eye was included in Severe group analysis. E3 right eye was included in Obvious group analysisaInformation unavailableSD-OCT data was available for all 30 eyes at the timeof drug cessation and follow up examinations. The Earlygroup comprised of eight eyes of 5 patients. The Obviousgroup comprised of 17 eyes of 9 patients. The Severe groupcomprised of 5 eyes of three patients. The right eye ofpatient E2 qualified for the Early group and the left eye forthe Severe group. The right eye of patient E3 qualified forthe Obvious group and the left eye for the Early group. Allqualitative observations had a strong inter-observer correlation between the two observers from the reading center.SD‑OCT at time of drug cessationMorphological appearance of 1-line horizontal SD-OCTscans in each of the groups at the time of drug cessationis shown in Fig. 2. In the fovea, 25 % of the Early eyesand 59 % of the Obvious eyes had clear disruption of theinterdigitation zone (IZ) in the absence of ellipsoid zoneTable 2 Baseline characteristics of each groupEarlyObviousSevereAge (years)63 (57–74)65 (48–75)74 (63–76)Cumulative dose(g)730 (438–949) 1933 (584–4380) 1030 (890–1679)Baseline vision20/20–20/40Follow-up (months) 13 (12–56)20/20–20/6020/100–20/40036 (12–56)14 (13–36)Median (range) reported for age, cumulative dose, and follow-updisruption, suggesting that IZ disruption may precedeEZ disruption. By our definition of the three groups, nopatients in the Early or Obvious group had foveal disruption of the EZ while all patients in the Severe groupdid. In the Severe group, foveal external limiting membrane (ELM) disruption was observed in 40 %, while this

Lally et al. Int J Retin Vitr (2016) 2:18Page 5 of 11Fig. 2 (Top row) reading center’s grading of SD-OCTs at time of HCQ discontinuation in fovea and parafovea. (Bottom row) reading center’s gradingof interval changes in SD-OCT appearance of most recent follow-up exam compared to time of HCQ cessation. If thinning, disruption, or thickening was present at the time of drug cessation and an interval change was noted, the change was progressive or worsening thinning, disruption, orthickeningfinding was not present in the other two groups. Fovealretinal pigment epithelium (RPE) disruption was notobserved at baseline in any group. Foveal thinning of theouter nuclear layer (ONL) was not present at baseline inany group.In the parafoveal region, early SD-OCT findings werefrequently detected in Early eyes in the absence of clearparafoveal EZ disruption (Fig. 3). Outer nuclear layer(ONL) thinning was present in 100 % and observed as afocal indentation in the parafoveal ONL when comparedto peripheral ONL thickness. Disruption of the parafoveal interdigitation zone (IZ) was recorded in 88 % andreduced reflectivity of the parafoveal EZ band in theabsence of definitive disruption was observed in 50 %.The reduced reflectivity of the parafoveal EZ enhancedthe appearance of the foveal EZ, creating the illusion ofincreased prominence or hyperreflectivity of the fovealEZ (Fig. 4). Parafoveal RPE disruption was not detectedin Early eyes, but was notable in 47 % of Obvious eyesand 40 % of Severe eyes.Progression of SD‑OCT changes after drug cessationMorphological SD-OCT changes in each group afterdrug cessation is shown in Fig. 2. An interval change inSD-OCT appearance suggesting structural progressionof toxicity was observed in 75 % Early, 71 % Obvious, and100 % of Severe eyes. In the Early group, 50 % developedclear parafoveal EZ disruption after drug cessation witha median follow-up of 13 months (range 12–77 months;Fig. 5). Increased parafoveal EZ disruption was observedin 60 % of the Obvious and Severe eyes. Increased parafoveal RPE disruption was detected in 13 % Early eyes, 47 %Obvious eyes, and 60 % Severe eyes. There was no significant difference in the frequency or severity of temporalparafovea changes compared to the nasal parafovea. Foveally, the most common change seen on SD-OCT afterdrug cessation was progressive ONL thinning in 25 %Early, 35 % Obvious, and 40 % Severe eyes. Progressivefoveal RPE disruption was not detected. The latest timepoint in which progression was observed was progressiveparafoveal RPE atrophy continuing for 4 years after drug

Lally et al. Int J Retin Vitr (2016) 2:18Page 6 of 11Fig. 3 SD-OCT findings of early toxicity preceding the development of parafoveal EZ disruptionFig. 4 Examples of two Early patients. a E1, fundus photograph shows mild parafoveal RPE changes in each eye with unremarkable FAF. HVF 10-2shows incomplete parafoveal ring scotoma in right eye and parafoveal ring scotoma in left eye. SD-OCT of each eye shows no clear disruption ofparafoveal EZ. However, reduced reflectivity of the parafoveal EZ (arrow) on both sides of the fovea is observed and enhances the appearance of thefoveal EZ. Abrupt discontinuation of the parafoveal interdigitation zone (IZ) (arrowhead) is also observed on both sides of the fovea. b E4, Fundusautoflourescence is unremarkable. HVF 10-2 shows incomplete parafoveal ring scotomas in each eye. No clear disruption of the parafoveal EZ isseen on SD-OCT. However, the reflectivity of the parafoveal EZ is diminished (arrow) and enhances the appearance of the foveal EZ. There is alsothinning of the parafoveal outer nuclear layer causing broadening of reflectivity of the parafoveal Henle’s fiber layer (arrowhead) on both sides of thefoveacessation (Fig. 6). Finally, a reduction in disruption orimprovement in SD-OCT appearance was not observed.Macular thickness changesFigure 7 illustrates the change between HCQ cessationand 12 months after cessation in each of the 9 ETDRSSD-OCT subfields. Decreases in central macular thicknesses were 3, 6, and 2 μm in the Early, Obvious, andSevere groups, respectively. The largest reduction inETDRS map region thickness was 7 μm in the superior,nasal, and inferior outer rings of the Obvious group.When comparing thickness changes in the Obvious

Lally et al. Int J Retin Vitr (2016) 2:18Page 7 of 11Fig. 5 Examples of changes in SD-OCT appearance from the time of diagnosis of HCQ retinopathy (left column) to after drug cessation (rightcolumn). E1, left eye, shows progressive interdigitation zone disruption (arrow). E4, right eye, shows development of parafoveal EZ disruption (arrow).O4, right eye, shows progressive RPE atrophy of the temporal parafovea (arrow) and progressive EZ disruption of the nasal parafovea (arrowhead).O4, left eye, shows progressive disruption of the ELM, EZ, and RPE in the temporal parafovea (arrow). S1, left eye, shows progressive loss of the fovealELM (arrow), foveal RPE migration into outer retina, and disruption with shortening of foveal RPE (ruler)group to the Early group, a significant difference wasfound in the inferior outer ring (p 0.002, 95 % CI 2 to 8 μm). No differences between the groups were foundin the other subfields. When comparing different subfieldthickness changes within an individual group, no differences were observed within the Early or Severe groups.However in the Obvious group, the nasal inner subfieldshowed more thinning than the temporal inner subfield(p 0.018, 95 % CI 1 to 8 μm; Table 3).A subanalysis of eyes with at least 3 years of follow-upafter drug cessation (N 11 eyes; patients E3, E5, O2,O3 OD, O4, O7; O3 OS excluded because of poor qualityimage at 42 month follow-up visit; S1 excluded becauseof widespread atrophy) was performed (Fig. 8). A progressive decline in retinal thickness beyond 1 year wasobserved in 62 % of eyes. Median subfoveal thicknessreduction was 14 μm. The largest decline in thickness wasobserved in the nasal inner ring (15 μm). A difference inthickness change was not detected between nasal andtemporal outer or inner rings (p 0.50; p 0.11, respectively) or superior and inferior outer and inner rings(p 0.60; p 0.65, respectively). In the Early patients,E3 developed thinning at 50 months compared to baseline, but had no follow-up visits in between. Therefore,it is uncertain at what time point the thinning occurred.Patient E5 showed thinning for the first 18 months afterdrug cessation but then the thickness increased betweenmonths 18 and 42.DiscussionBy using masked, trained SD-OCT graders from theBoston Image Reading Center (BIRC), we determinedthat structural retinal changes were common after HCQcessation, occurring in 73 % of all eyes included in this

Lally et al. Int J Retin Vitr (2016) 2:18Page 8 of 11Fig. 6 SD-OCT changes 4 years after HCQ cessation. O6, right eye, shows development of parafoveal RPE atrophy that becomes evident 2 yearsafter drug cessation and progresses at 4 year follow up. O7, left eye, shows progressive parafoveal RPE atrophy (arrow) with broadening of RPEmigration into outer retina in the nasal parafovea (ruler)Fig. 7 Median change in thickness in each ETDRS subfield at 12 months after HCQ cessationTable 3 P values for the comparison of ETDRS subfieldthickness changes for Obvious groupEarlyObviousSevereNasal versus temporal inner1.0000.660Superior versus inferior inner0.7560.018CI 8 to 10.2260.658Nasal versus temporal outer1.0000.2850.155Superior versus inferior outer0.6260.2910.264Italic value indicates significance of p value (p 0.05)CI 95 % confidence interval in micrometersstudy at a mean follow up of 26 months. All changes wereconsistent with progression of toxicity and may continuebeyond 1 year most commonly as thinning of the parafoveal RPE (Fig. 6). In the Early group, 75 % had evidenceof structural progression after drug cessation, includingdisruption of the parafoveal EZ and RPE and thinningof the ONL (Table 1). These eyes developed structuralprogression despite presenting with subtle changes onSD-OCT at the time of HCQ cessation. Three of the fiveEarly patients developed worsening visual field defects in

Lally et al. Int J Retin Vitr (2016) 2:18Page 9 of 11Fig. 8 Subanalysis for eyes with at least 3 years of follow-up after drug cessation (E3, E5, O2, O3 OD, O4, O7). (Top left) Subfoveal thickness changeafter drug cessation. (Bottom left) Example of nasal inner ring ETDRS subfield thickness change after drug cessation. (Bottom right) Mean change(Median change) in thickness in each ETDRS subfieldconjunction with structural changes. Importantly however, visual acuity and symptoms in these patients did notchange significantly.The disruption of the parafoveal ellipsoid zone is wellreported in HCQ toxicity, and clinicians commonly lookfor this finding in clinical practice [4, 11–13]. In thisreport, we describe three additional, clinically useful earlySD-OCT signs of HCQ retinal toxicity that may precededisruption of the parafoveal ellipsoid zone (Fig. 3). We recommend looking carefully for these early findings to assistin the earliest detection of retinopathy. If an abnormality is detected, the authors recommend carefully checking the visual field searching for paracentral defects, as allEarly eyes in this series had paracentral visual field defectsat the time of drug cessation. This fact has been reportedpreviously by Marmor and Melles [16] who describedeyes with HCQ retinopathy in which the SD-OCT imageswere interpreted as normal but had paracentral visual fielddefects consistent with HCQ toxicity. Our review of thesepublished images reveals that 8 of the 10 eyes displayedreduced reflectivity of the parafoveal EZ creating theappearance of a prominent foveal EZ band, suggesting thatthose eyes may have had reduced reflectivity of the parafoveal ellipsoid zone, as found in many of the Early eyes inour study. A criticism of this finding that we recognize isthat the finding may be too subtle to be assuredly detectable in clinical practice. Often a ‘normal’ SD-OCT canhave variance in scan brightness affecting EZ reflectivity.However, in these cases, the entire EZ band, including thefoveal and parafoveal EZ, should have homogenous or nearhomogenous reflectivity. In our study, the masked graderswere agreeable to the interpretation of EZ reflectivity, andtherefore, we believe the reduced reflectivity of the parafoveal EZ is a real detectable SD-OCT finding in early HCQ

Lally et al. Int J Retin Vitr (2016) 2:18toxicity. This sole finding should not be diagnostic of toxicity, but rather used to raise suspicion for toxicity and generate further investigation.Disruption of the parafoveal interdigitation zone (IZ)was another common finding (88 %) preceding parafoveal EZ disruption. The interdigitation zone, also knownas the cone outer segment tip (COST) line, is the brightreflective line located between the EZ and the retinalpigment epithelium and is visible as a continuous linein 95 % of normal subjects [17]. This finding has beenreported in HCQ retinopathy two times previously, andappears to be another important but early finding inEarly HCQ toxicity [18, 19].Macular thickness changes in the Early and Severegroups were minimal at 12 months after drug cessation.Changes in the Severe group were presumed secondary toglial and RPE remodeling as these eyes had severe parafoveal and foveal outer retinal atrophy at the time of drugcessation. Obvious eyes had foveal thinning at 12 monthssimilar to a previous report [11], and the macular thinningwas not equal between the subfields. Greater thinning wasdetected in the nasal inner ring when compared to thetemporal inner ring. This may be attributable to a thickerbaseline nasal inner retina with more opportunity forthinning compared to the temporal inner retina. In addition, Obvious eyes developed greater thinning in the inferior outer ring as compared to Early eyes. This suggests anacceleration of thinning in the inferior outer ring as toxicity progresses. Interestingly, two other studies have notedthe inferior macula may be the earliest affected quadrantin HCQ toxicity, but further studies are needed [18, 20].Finally, this study included myopic eyes up to 6D. Therelationship between axial length and macular thickness measurements needs to be further clarified becauseaxial length has both been negatively correlated to macular thickness but also not observed [21, 22]. Therefore, itremains unclear whether macular thickness changes inmyopic eyes are different from emmetropic eyes.Retained HCQ in the RPE cell may be the underlyingcause of progressive retinal thinning observed in Obviouseyes after 12 months drug cessation. After intravenousinjection of chloroquine into a rabbit, high concentrations of chloroquine are found in the pigmented oculartissues (RPE, choroid, iris) [23]. These levels remain highfor over 2 months following a single administration ofchloroquine. Albino rabbits, on the other hand, do notretain chloroquine in the uvea or RPE indicating thatmelanin pigment is responsible for the binding and trapping of chloroquine within the cell. Once inside the RPEcell, HCQ disrupts lysosomal function leading to lipofuscin accumulation and photoreceptor degeneration [24].We suspect HCQ is retained in

either Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) or Heidelberg Spectralis HRA OCT (Heidelberg Engi-neering, Germany). HCQ retinopathy was diagnosed by detecting abnor-malities attributable to HCQ on clinical examination, Humphrey 10-2 or 24-2 visual fields, SD-OCT, and/o