- Email: [email protected]
Acute depigmentation of the iris: a retrospective analysis of 22 cases
Acute depigmentation of the iris: a retrospective analysis of 22 cases Ankush Kawali, DNB,* Padmamalini Mahendradas, DNB,* Rohit Shetty, PhD† ABSTRACT ● Objective: To present clinical manifestations of bilateral acute depigmentation of Iris (BADI) and bilateral acute iris transillumination (BAIT) and discuss its pathogenesis. Design: Retrospective descriptive case study. Participants: Twenty-two patients diagnosed with BADI or BAIT. Methods: Case records of the above patients presented between May 2014 and November 2017 were retrospectively studied for history of present illness, clinical findings, and course of the disease. Results: Forty-one eyes of 22 patients were studied (17 cases of BADI and 5 cases of BAIT). Only 7 patients consumed oral fluoroquinolone (FQL), whereas 17 patients used topical FQL. Three patients did not use any FQL but did take ayurvedic medications. Seven patients had systemic viral prodrome, 12 had presumed viral conjunctivitis, and 3 had abundant sunlight exposure after FQL use (due to a road trip, sunbathing on a beach, and working as a traffic police officer). Three cases of BADI had unilateral depigmentation; 1 case of BAIT had iris transillumination only in one eye and a patch of depigmentation without transillumination in the other eye, akin to presentation of BADI. A PCR test for viral genome (HSV, VZV, CMV, and Rubella) revealed negative results in 2 cases of BADI and 3 cases of BAIT. Only 1 case of BADI had recurrence after 10 months. Conclusions: Presentation of BADI and BAIT could be grossly asymmetric or unilateral. Clinical signs of BAIT and BADI can occur simultaneously in different eyes. The role of FQL in the pathogenesis of BADI and BAIT remains uncertain.
Bilateral acute depigmentation of the iris (BADI) is a newly described uveitic masquerade characterized by acute onset of pigment dispersion in the anterior chamber (AC), depigmentation of the iris stroma, and pigment deposition in the AC angle and on the back of the cornea.1–3 BADI presents with redness, pain, and moderate to severe photophobia. On examination, bulbar conjunctival congestion is evident, but no inflammatory keratic precipitate or white blood cells in the AC are seen. Bilateral acute iris transillumination (BAIT) is characterized by clinically evident iris transillumination defects (TIDs) due to loss of iris pigment epithelium and pupillary distortion, with or without formation of posterior synechiae in addition to the findings of BADI (vide supra). Although the exact etiopathogeneses of BADI and BAIT are unknown, few authors presume an emerging virus which also causes upper respiratory tract disease as a causative agent for BADI,2 whereas BAIT has been linked with use of systemic fluoroquinolone (FQL) by some authors and opposed by others.2,4–9 In this retrospective study we examine the history of present illness, clinical manifestation, course of the disease, and treatment outcomes of acute iris depigmentation (BADI and BAIT), and discuss probable factors responsible for this rare and novel entity.
SUBJECTS
AND
METHODS
This is a retrospective, descriptive case study of patients diagnosed with BADI and BAIT treated at a single eye
institution in south India between May 2014 and November 2017. The case records of consecutive patients diagnosed with BADI and BAIT were analyzed. Histories of present illness, clinical findings, anterior segment optic coherence tomography (OCT) findings, intraocular pressure (IOP), course of the disease, treatment, and recurrences were noted. The study was approved by the Internal review board of Narayana Nethralaya Eye Hospital and adhered to the Declaration of Helsinki. The diagnosis of BADI, as reported previously,1,2 is based on clinical presentation: sudden onset of pain, redness, pigments only in the AC (no white or red blood cells) and (or) pigments on the endothelium (no inflammatory KP), iris depigmentation (without iris transillumination defects, without inflammatory iris nodules, without posterior synechiae), and normal posterior segment. The patients presenting with pain, redness, and iris depigmentation with pigment dispersion, as seen in BADI, but with TIDs and pupillary involvement characterized by pupillary distortion with or without posterior synechiae, poor response to light but no posterior segment or optic nerve disease, were diagnosed as BAIT.6 Exclusion of similar conditions such as iris depigmentation following trauma or surgery, pseudoexfoliation, pigment dispersion syndrome, or angle closure glaucoma and viral uveitis (herpes, poxviruses) was done by taking relevant histories, clinical examination, and appropriate lab investigations where needed; and with the treatment response. Routine clinical examination
& 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2018.03.020 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al. included visual acuity examination with Snellen visual acuity charts, non-contact or Goldmann applanation tonometry, undilated slit-lamp biomiroscopy, gonioscopy, dilated fundus examination, and anterior segment OCT scanning. AC tap for polymerase chain reaction (PCR) analysis was performed to rule out viral infections in early cases.
RESULTS Thirty-one eyes of 17 patients were diagnosed as BADI and 10 eyes of 5 patients were diagnosed as BAIT, over 3.5 years. The mean age of presentation in the BADI series was 40.47 years (range, 10–76) and in BAIT was 44.6 (range, 37–56). There were 9 males and 8 females in the BADI series, and 3 males and 7 females in the BAIT series. Presenting complaints were redness, pain, burning sensation, and photophobia. Seven patients had a history of oral FQLs use, whereas 17 patients received topical FQLs before presentation (Tables 1, 2). Systemic FQLs were given for the common cold (n ¼ 2), fever with presumed asthma and gastritis (n ¼ 1), fever with vomiting and skin rash (n ¼ 1), diarrhoea with fever (n ¼ 1), surgery for anal fistula (n ¼ 1), and genital lesion (n ¼ 1); topical FQLs were given for conjunctivitis (n ¼ 12). The mean duration of topical FQL use was 10.6 days (range, 3–30 days). Of the 17 cases of BADI, 3 were unilateral and they had used topical FQL in the affected eye only. Three BADI patients had geographic atrophy of the peripheral iris (Fig. 1A) while others had subtle diffuse depigmentation of the iris in the periphery (Fig. 1B). Gonioscopy revealed densely pigmented trabecular meshwork in all patients who underwent the procedure (n ¼ 22 eyes) (Fig. 1C). Anterior segment OCT revealed loss of anterior surface reflectivity of the iris with mild thinning,
and ruled out concave iris configuration in all patients who underwent the procedure (n ¼ 25) (Fig. 1D). One case of BADI showed mild pupillary involvement (akin to BAIT) in one eye and typical BADI depigmentation in other eye (Fig. 2), whereas a case of BAIT showed a small patch of superior iris depigmentation without TIDs (as in BADI) in one eye and typical BAIT features in the other eye (Fig. 3). Lens, vitreous, and fundus examinations were normal in all cases. Intraocular pressure (IOP) was high in only one BADI patient and was suspected to be a response to steroid treatment, whereas 5 eyes in the BAIT group showed high IOP. Iris infra-red autofluorescence was helpful in demarcating the atrophic area in cases with subtle depigmentation (Fig. 4). Two eyes in the BADI group and 3 eyes in the BAIT group underwent AC tap for viruses (HSV, VZV, CMV, and Rubella) using nested PCR, which revealed negative results (Tables 1, 2). Serological investigations for viruses were not available in our series except in case 5 in the BAIT series, which showed high IgG titres for the Rubella virus (53.3 IU/mL). All patients were treated with topical steroids and cycloplegic agents; oral steroids were required in 3 cases of BADI and 1 case of BAIT. The mean follow-up periods of the BADI and BAIT patients were 6.6 weeks (range, 1–19 weeks) and 60 weeks (range, 4–96 weeks), respectively. Three cases of BAIT had 2 years of follow-up; iris TIDs and pupillary distortion persisted in all 3 cases after 2 years. One case of BADI had 2.5 years of follow-up; depigmentation of the iris persisted in both the eyes. Ten BADI patients and all BAIT patients were monitored regularly until complete resolution. Acute symptoms and signs of BADI and BAIT lasted for 8.3 weeks (range, 3–16 weeks) and 8.8 weeks (range, 4–16 weeks) on average, respectively. Three BADI patients had mild relapses of acute depigmentation after
Table 1—Brief case summary of BADI cases Case
Age/Sex
Month of presentation
Laterality
Use of oral FQL
Use of topical FQL
Reason for FQL use
AC tap for viruses
1 2 3 4 5 6 7 8
47/M 38/F 33/F 76/M 40/F 34/F 27/M 55/M
Jan 2015 May 2015 May 2015 Jun 2015 Jun 2015 Aug 2015 Nov 2015 Jan 2016
Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Unilateral
Y (moxi) Y (moxi) N N N N N Y (norflox,3 months before)
Y (gati) Y (cipro) Y (moxi þ dexa) Y (moxi) Y (cipro) Y (moxi) Y (moxi) Y (cipro, moxi, gati)
N N HSV, VZV: negative N N CMV: negative N N
9 10 11 12 13 14 15 16 17
25/F 30/F 51/M 53/M 41/M 58/M 10/M 54/F 16/F
May 2016 Jul 2016 Oct 2016, Jul 2017 Dec 2016 Apr 2017 Mar 2016 Aug 2017 Sep 2017 Nov 2017
Bilateral Unilateral Bilateral Unilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Y (moxi) Y (oflox, cipro)
Y (moxi) N Y (gati þ moxi) Y (moxi þ tobra) Y (tobra þ gati þ dexa) N Y (gati þ dexa) N Y (Gati)
Fistulectomy, red eye URTI (?), mild fever Conjunctivitis Conjunctivitis Red eye Viral fever (?), red eye URTI, red eye Systemic use: unknown Topical use: conjunctivitis Common cold, red eye Fever with diarrhoea Kerato-conjunctivitis Conjunctivitis Cold, conjunctivitis NA Conjunctivitis NA Fever, Conjunctivitis
†
N †
N* N N* Y (Moxi)
N N N N N N N N N
FQL, fluoroquinolone; moxi, moxifloxacin; gati, gatiofloxacin; cipro, ciprofloxacin; URTI, upper respiratory tract infection; dexa, dexamethasone; HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalo virus; norflox, norfloxacin; oflox, ofloxacin; tobra, tobramycin. Y, yes; N, no; NA, not applicable. *used ayurvedic medications (for asthma; after spinal surgery). †unknown.
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Acute depigmentation of the iris—Kawali et al. Table 2—Brief case summary of BAIT cases Case Age/Sex Month of presentation Laterality Use of oral FQL Use of topical FQL 1 2 3 4 5
37/M 55/M 56/F 38/M 37/F
Feb 2015 May 2015 Apr 2016 May 2017 Jul 2014
Bilateral Bilateral Bilateral Bilateral Bilateral
Y (oflox) N N * *
Y (moxi) Y (moxi) N Y (moxi þ dexa) N
Reason for FQL use
AC tap for viruses
Genital lesions, conjunctivitis Presumed viral conjunctivitis NA Conjunctivitis
HSV, VZV: Neg HSV, VZV: Neg N N HSV, VZV, CMV, Rubella: Neg
*
FQL, fluoroquinolone; oflox, ofloxacin; moxi, moxifloxacin; HSV, herpes simplex virus; VZV, varicella zoster virus; dexa, dexamethasone; CMV, cytomegalo virus. Y, yes; N, no; NA, not applicable. *unknown.
a month during tapered topical steroid and were managed with increasing topical and adding low-dose oral steroids. Another BADI patient (case 11) had a recurrence after 10 months, suffering a mild fever and cough for which antibiotics were prescribed (details unknown). This patient also experienced superficial punctate keratopathy in the left eye, and underwent cataract surgery on the right eye, for which moxifloxacin and prednisolone eye drops were prescribed. No fresh iris depigmentation was noted after 1 month following the surgery. Another BADI patient (case 17) had a history of being treated with norfloxacin and ofloxacin for fever (more than a year previously) and had no ocular complaints that time, but
developed BADI after being treated with moxifloxacin for a fever with skin rash and vomiting. No recurrences were noted in BAIT patients after complete resolution of the condition. All patients maintained normal best corrected visual acuity throughout their follow-up periods.
DISCUSSION Although BADI and BAIT resemble each other, they are distinguished by the involvement of iris stroma and iris pigment epithelium, respectively. The involvement of the pupil and iris TIDs are seen in BAIT but not in BADI; reversibility of iris depigmentation was reported in BADI
Fig. 1 — (A) Case 3 (BADI): shows bulbar conjunctival congestion and geographic iris depigmentation (arrows). (B) Case 2 (BADI): Subtle diffuse iris depigmentation with a faint demarcation line (arrows), while on treatment with topical and oral steroids. (C) Gonioscopy shows dense pigmentation of trabecular meshwork (arrow). (D) Anterior segment OCT shows iris thinning and loss of outer iris surface reflectivity (arrow). CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al.
Fig. 2 — Case 12 (BADI) shows iris depigmentation with pupillary distortion (arrows) but without iris TIDs in the right eye (A) and peripheral subtle iris depigmentation without pupillary distortion and without iris TIDs in the left eye (B).
during long term follow up but not in BAIT.1,2,6 Both conditions have been reported separately in the literature. A combination of features of BADI and BAIT in a single patient, as seen in BADI case 12 and BAIT case 1 in our series, has not been previously described (Figs. 2, 3). Moreover, unilaterality, as noted in 3 cases of BADI, has not been previously reported. Although it is possible that unilaterality could be due to gross asymmetric involvement at presentation, during follow-up over 3 months involvement of the other eye was not evident clinically when only the affected eye was treated. Depigmentation in BADI and BAIT must be differentiated from other pigment conditions such as pigment dispersion syndrome (PDS), which is a chronic condition. Pain, redness, photophobia, absence of concave iris configuration, and limited course of the disease will favour a diagnosis of BADI or BADI rather than PDS. Dermal phototoxicity, cardiotoxicity, arthropathy, and tendinitis are known adverse reactions to systemic FQLs.10 Although various case reports have suggested systemic FQL as a cause of iris depigmentation,4,5 two large studies deduced an “emerging viral etiology” for both BADI and
BAIT.2,6 This conclusion was mainly based on the absence of systemic FQLs in few patients, recent respiratory infections, and the clustering of cases during the summer months in each series. In the present study we noted exposure not only to systemic but also to topical FQLs and considered not only systemic viral prodrome but ocular as well, which presented in the form of conjunctivitis or keratoconjunctivitis and months of presentation of each case (Tables 1, 2). Surprisingly, there are no reports of FQL induced dermal phototoxicity with concomitant BAIT or BADI. FQL-induced dermal phototoxicity generally occurs in areas exposed to ultraviolet A rays (UVA). Three of our BADI patients had history of abundant sunlight exposure after using topical moxifloxacin and oral ciprofloxacin, but no patient developed a skin rash or eyelid involvement. We also noted that the iris depigmentation began in the area of the iris covered by the superior lid in some cases (Fig. 3A) and in the peripheral iris in all cases, contradicting the role of FQL-phototoxicity in iris depigmentation. This paradox of FQL-dermal phototoxicity without iris phototoxicity may also suggest that iris melanocytes
Fig. 3 — Case 1 (BAIT) shows peripheral patch of depigmentation (arrows) without pupillary involvement and iris TIDs in the right eye (A) and classical BAIT pattern in the left eye with iris TIDs (encircled) (B).
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Acute depigmentation of the iris—Kawali et al.
Fig. 4 — Infra-red iris autofluorescence of case 16 (BADI) highlights atrophic areas with hypofluorescence.
could be different in some respects from retinal pigment epithelium and dermal melanocytes. Perhaps for similar reasons, in contrast to sunset glow fundus in VogtKoyanagi-Harada (VKH) syndrome, iris depigmentation has rarely been reported in the literature.11 The effect of FQLs on melanocytes has been evaluated in experimental studies in great detail. FQLs are known to cause loss of melanocyte viability and to inhibit tyrosinase activity in human skin melanocytes.12,13 Several compounds in the FQL family, such as norfloxacin, moxifloxacin, sparfloxacin, and ciprofloxacin, showed significant dermal melanocyte toxicity in vitro.13,14 The effects of moxifloxacin on human iris pigment epithelium in vitro has also been studied, and showed significant toxicity at doses greater than 100µg/mL15; it is known that moxifloxacin achieves a concentration of 1.71 ± 0.82 μg/mL after topical application.16 Although a large “clinical study” with intracameral use of moxifloxacin during cataract surgery as a prophylaxis for postoperative endophthalmitis reported no clinically evident iris toxicity, a recently conducted “experimental study” on a cataract patient after topical application of FQLs as a preoperative medication showed subclinical toxicity due to FQLs (moxifloxacin, ciprofloxacin) as well as aminoglycosides such as tobramycin.17,18 None of these patients developed iris depigmentation or TIDs before or after the cataract surgery. This study also showed that moxifloxacin significantly decreased tyrosinase (a rate-limiting enzyme for melanin production) activity in the aqueous compared to tobramycin and ciprofloxacin. Tobramycin, a member of aminoglycoside family, has also been shown to bind strongly with melanin and it has been speculated that it is involved in ototoxicity.19,20 Five of the BADI cases in our series received topical tobramycin along with FQL, and 2 of the BAIT cases had a history of treatment with aminoglycosides. It is noteworthy that case 17 in the BADI series developed the phenotype after the use of systemic moxifloxacin but not with norfloxacin or ofloxacin. Consistently, case 8 in the BADI series had a history
of angioedema characterized by swelling of the upper lip after consumption of norfloxacin and indomethacin and was treated with intravenous steroids due to suspected idiosyncratic drug reactions. Three months after this episode, the patient developed conjunctivitis in the right eye, as did the patient’s immediate family members. All received topical FQL; all of the family members were cured except the patient, who went on to develop unilateral BADI. Levofloxacin-induced retinopathy has also been reported recently.21 In addition, studies reported that ABCG2 as a candidate gene for FQL-induced retinopathy in cats.22 Hence, there is some experimental evidence that FQL can be held responsible for melanocyte toxicity under certain conditions such as exposure to UVA rays, excessive drug dosage, and genetic susceptibility. Although most of our patients had a history of FQL use, they scored less than 4 on the Narenjo Adverse Drug Reaction Probability Scale (livertox.nih.gov/Naranjoassess ment.pdf) and were categorised as experiencing a “possible relation” based on the World Health Organization’s causality assessment of suspected adverse drug reactions.23 Although drug re-challenge is a possible method to prove FQL toxicity, it may not be an ethical practice. Case 11 of the BADI series, the only patient who had a recurrence after 10 months, could not provide details of the medications taken to treat a fever and cough, but this patient did not show fresh iris depigmentation when exposed to topical moxifloxacin-prednisolone after cataract surgery. Although there was no clustering of cases in our series (which may suggest a viral etiology, as reported previously),2 many of our patients had an episode of presumed viral conjunctivitis. Again, however, almost all these patients were primarily seen by general ophthalmologists elsewhere, and thus the possibility of a misdiagnosis of BADI or BAIT as conjunctivitis cannot be completely excluded. Herpetic viral (HSV, VZV, CMV) etiology for BADI or BAIT is unlikely, as aqueous tap PCR was negative in all tested cases in our series, as well as in previous reports.1,2 Contrarily, occurrence of high IOP in CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al. Table 3—FQL versus viral etiology Points in favour of FQL toxicity and against viral etiology
Almost all patients exposed to FQLs (topical and [or] systemic) Experimental evidence of FQL toxicity on iris melanocytes15,18 History of UV exposure in few patients Absence of clustering of cases in our series unlike reported previously2 Negative PCR studies for common herpetic viruses Absence of true uveitis (with inflammatory KPs and WBCs in AC)
BAIT series as compared to BADI series may suggest a viral etiology. An “emerging virus” causing iris depigmentation and TIDs without inflammatory KPs and white blood cells in the AC is also possible, and next-generation gene-sequencing analysis of aqueous or tears from BADI or BAIT patients may help to discover the unknown organism, if any. Despite the reported experimental evidence of FQL toxicity on melanocytes, no firm causal relation with either topical or systemic FQL use was found in our clinical study (Table 3). Our study does contribute the new information that the signs of BADI and BAIT can be seen in different eyes of same patient, and that BADI can be unilateral or grossly asymmetric and can recur months after complete resolution. In conclusion, acute iris depigmentation and transillumination (BADI and BAIT) are uveitic masquerades and self-limiting conditions, and the exact mechanism of pathogenesis is still unknown. FQL toxicity on iris melanocytes in vivo under certain circumstances in certain individuals and the possibility of a novel virus as an etiological agent remains to be determined.
REFERENCES 1. Tugal-Tutkun I, Urgancioglu M. Bilateral acute depigmentation of the iris. Graefes Arch Clin Exp Ophthalmol. 2006;244:742-6. 2. Tugal-Tutkun I, Araz B, Taskapili M, et al. Bilateral acute depigmentation of the iris: report of 26 new cases and four-year follow-up of two patients. Ophthalmol. 2009;116:1552-7. 3. Goktas A, Goktas S. Bilateral acute depigmentation of the iris first misdiagnosed as acute iridocyclitis. Int Ophthalmol. 2011;31:337-9. 4. Hinkle DM, Dacey MS, Mandelcorn E, et al. Bilateral uveitis associated with fluoroquinolone therapy. Cutan Ocul Toxicol. 2012;31:111-6. 5. Knape RM, Sayyad FE, Davis JL. Moxifloxacin and bilateral acute iris transillumination. J Ophthalmic Inflamm Infect. 2013;3:10. 6. Tugal-Tutkun I, Onal S, Garip A, et al. Bilateral acute iris transillumination. Arch Ophthalmol. 2011;129(10):1312-9. 7. Bringas Calvo R, Iglesias Cortiñas D. Acute and bilateral uveitis secondary to moxifloxacin [in Spanish]. Arch Soc Esp Oftalmol. 2004;79:357-9. 8. Wefers Bettink-Remeijer M, Brouwers K, van Langenhove L, et al. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye. 2009;23:2260-2.
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Points against FQL toxicity and in favour of novel viral etiology
Narenjo adverse drug reaction score less than 4 History of presumed viral conjunctivitis/kerato-conjunctivitis Superior lid covered iris involvement in few patients Systemic viral prodrome in 6 patients Absence of concomitant dermal phototoxicity Three patients did not use any FQLs (but ayurvedic medications). A known case of BADI underwent cataract surgery, did not develop fresh iris depigmentation despite use of topical moxifloxacin (but together with steroids)
9. Willermain F, Deflorenne C, Bouffioux C, Janssens X, Koch P, Caspers L. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye. 2010;24:1419-20. 10. De Sarro A, De Sarro G. Adverse reactions to fluoroquinolones: an overview on mechanistic aspects. Curr Med Chem. 2001;8:371-84. 11. Cuevas M, de-la-Torre A, Córdoba A. Bilateral iris depigmentation and ocular hypotony as end-stage manifestations of untreated Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm. 2017;26: 1-6. 12. Beberok A, Buszman E, Wrzesniok D, Otreba M, Trzcionka J. Interaction between ciprofloxacin and melanin: the effect on proliferation and melanization in melanocytes. Eur J Pharmacol. 2011;669:32-7. 13. Beberok A, Wrzesniok D, Otreba M, Buszman E. Impact of sparfloxacin on melanogenesis and antioxidant defense system in normal human melanocytes HEMa-LP—an in vitro study. Pharmacol Rep. 2015;67:38-43. 14. Beberok A, Wrzesniok D, Otreba M, Milinski M, Rok J, Buszman E. Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes. Mol Cell Biochem. 2015;401:107-14. 15. Perin A, Lyzogubov V, Bora N, Morshedi G. In vitro assessment of moxifloxacin toxicity to human iris pigment epithelium. Invest Ophthalmol Vis Sci. 2015;56:5729. 16. Halder S, Mondal KK, Biswas S, Mandal TK, Dutta BK, Haldar M. Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery. Indian J Pharmacol. 2013;45:223-6. 17. Haripriya A, Chang DF, Ravindran RD. Endophthalmitis reduction with intracameral moxifloxacin prophylaxis: analysis of 600,000 surgeries. Ophthalmol. 2017;124:768-75. 18. Mahanty S, Kawali AA, Dakappa SS, et al. Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity. Exp Eye Res. 2017;162:79-85. 19. Buszman E, Wrzesniok D, Trzcionka J. Interaction of neomycin, tobramycin and amikacin with melanin in vitro in relation to aminoglycosides-induced ototoxicity. Pharmazie. 2007;62:210-5. 20. Wrzesniok D, Otreba M, Beberok A, Buszman E. Viability of human melanocytes HEMa-LP exposed to amikacin and kanamycin. Indian J Pharm Sci. 2013;75:102-6. 21. Butler NJ, Suhler EB. Levofloxacin-associated panuveitis with chorioretinal lesions. Arch Ophthalmol. 2012;130:1342-4. 22. Ramirez CJ, Minch JD, Gay JM, et al. Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats. Pharmacogenetics Genomics. 2011;21:66-75. 23. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10:93-102.
Footnotes and Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
Acute depigmentation of the iris—Kawali et al. No one anyone other than the authors listed on page 1 help write or revise this manuscript. No monetary support was received for this study.
From the *Uveitis and Ocular Immunology Department, Narayana Nethralaya, Bangalore; †Department of corneal and refractive surgery, Narayana Nethralaya, Bangalore.
Dr. Ankush Kawali: literature search, figure creation, study design, clinical study, concept, definition of intellectual content, data collection, data interpretation, and writing manuscript. Dr. Padmamalini Manhendradas: Clinical studies, Manuscript editing, definition of intellectual content, data collection, data interpretation. Dr. Rohit Shetty: Manuscript editing, definition of intellectual content, data interpretation.
Originally received Jan. 27, 2018. Final revision Mar. 16, 2018. Accepted Mar. 27, 2018. Correspondence to: Dr. Ankush Kawali, Narayana Nethralaya, Chord Road, Rajajinagar, Bangalore; [email protected]
CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Bilateral acute depigmentation of the iris (BADI) is a newly described uveitic masquerade characterized by acute onset of pigment dispersion in the anterior chamber (AC), depigmentation of the iris stroma, and pigment deposition in the AC angle and on the back of the cornea.1–3 BADI presents with redness, pain, and moderate to severe photophobia. On examination, bulbar conjunctival congestion is evident, but no inflammatory keratic precipitate or white blood cells in the AC are seen. Bilateral acute iris transillumination (BAIT) is characterized by clinically evident iris transillumination defects (TIDs) due to loss of iris pigment epithelium and pupillary distortion, with or without formation of posterior synechiae in addition to the findings of BADI (vide supra). Although the exact etiopathogeneses of BADI and BAIT are unknown, few authors presume an emerging virus which also causes upper respiratory tract disease as a causative agent for BADI,2 whereas BAIT has been linked with use of systemic fluoroquinolone (FQL) by some authors and opposed by others.2,4–9 In this retrospective study we examine the history of present illness, clinical manifestation, course of the disease, and treatment outcomes of acute iris depigmentation (BADI and BAIT), and discuss probable factors responsible for this rare and novel entity.
SUBJECTS
AND
METHODS
This is a retrospective, descriptive case study of patients diagnosed with BADI and BAIT treated at a single eye
institution in south India between May 2014 and November 2017. The case records of consecutive patients diagnosed with BADI and BAIT were analyzed. Histories of present illness, clinical findings, anterior segment optic coherence tomography (OCT) findings, intraocular pressure (IOP), course of the disease, treatment, and recurrences were noted. The study was approved by the Internal review board of Narayana Nethralaya Eye Hospital and adhered to the Declaration of Helsinki. The diagnosis of BADI, as reported previously,1,2 is based on clinical presentation: sudden onset of pain, redness, pigments only in the AC (no white or red blood cells) and (or) pigments on the endothelium (no inflammatory KP), iris depigmentation (without iris transillumination defects, without inflammatory iris nodules, without posterior synechiae), and normal posterior segment. The patients presenting with pain, redness, and iris depigmentation with pigment dispersion, as seen in BADI, but with TIDs and pupillary involvement characterized by pupillary distortion with or without posterior synechiae, poor response to light but no posterior segment or optic nerve disease, were diagnosed as BAIT.6 Exclusion of similar conditions such as iris depigmentation following trauma or surgery, pseudoexfoliation, pigment dispersion syndrome, or angle closure glaucoma and viral uveitis (herpes, poxviruses) was done by taking relevant histories, clinical examination, and appropriate lab investigations where needed; and with the treatment response. Routine clinical examination
& 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jcjo.2018.03.020 ISSN 0008-4182/17 CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al. included visual acuity examination with Snellen visual acuity charts, non-contact or Goldmann applanation tonometry, undilated slit-lamp biomiroscopy, gonioscopy, dilated fundus examination, and anterior segment OCT scanning. AC tap for polymerase chain reaction (PCR) analysis was performed to rule out viral infections in early cases.
RESULTS Thirty-one eyes of 17 patients were diagnosed as BADI and 10 eyes of 5 patients were diagnosed as BAIT, over 3.5 years. The mean age of presentation in the BADI series was 40.47 years (range, 10–76) and in BAIT was 44.6 (range, 37–56). There were 9 males and 8 females in the BADI series, and 3 males and 7 females in the BAIT series. Presenting complaints were redness, pain, burning sensation, and photophobia. Seven patients had a history of oral FQLs use, whereas 17 patients received topical FQLs before presentation (Tables 1, 2). Systemic FQLs were given for the common cold (n ¼ 2), fever with presumed asthma and gastritis (n ¼ 1), fever with vomiting and skin rash (n ¼ 1), diarrhoea with fever (n ¼ 1), surgery for anal fistula (n ¼ 1), and genital lesion (n ¼ 1); topical FQLs were given for conjunctivitis (n ¼ 12). The mean duration of topical FQL use was 10.6 days (range, 3–30 days). Of the 17 cases of BADI, 3 were unilateral and they had used topical FQL in the affected eye only. Three BADI patients had geographic atrophy of the peripheral iris (Fig. 1A) while others had subtle diffuse depigmentation of the iris in the periphery (Fig. 1B). Gonioscopy revealed densely pigmented trabecular meshwork in all patients who underwent the procedure (n ¼ 22 eyes) (Fig. 1C). Anterior segment OCT revealed loss of anterior surface reflectivity of the iris with mild thinning,
and ruled out concave iris configuration in all patients who underwent the procedure (n ¼ 25) (Fig. 1D). One case of BADI showed mild pupillary involvement (akin to BAIT) in one eye and typical BADI depigmentation in other eye (Fig. 2), whereas a case of BAIT showed a small patch of superior iris depigmentation without TIDs (as in BADI) in one eye and typical BAIT features in the other eye (Fig. 3). Lens, vitreous, and fundus examinations were normal in all cases. Intraocular pressure (IOP) was high in only one BADI patient and was suspected to be a response to steroid treatment, whereas 5 eyes in the BAIT group showed high IOP. Iris infra-red autofluorescence was helpful in demarcating the atrophic area in cases with subtle depigmentation (Fig. 4). Two eyes in the BADI group and 3 eyes in the BAIT group underwent AC tap for viruses (HSV, VZV, CMV, and Rubella) using nested PCR, which revealed negative results (Tables 1, 2). Serological investigations for viruses were not available in our series except in case 5 in the BAIT series, which showed high IgG titres for the Rubella virus (53.3 IU/mL). All patients were treated with topical steroids and cycloplegic agents; oral steroids were required in 3 cases of BADI and 1 case of BAIT. The mean follow-up periods of the BADI and BAIT patients were 6.6 weeks (range, 1–19 weeks) and 60 weeks (range, 4–96 weeks), respectively. Three cases of BAIT had 2 years of follow-up; iris TIDs and pupillary distortion persisted in all 3 cases after 2 years. One case of BADI had 2.5 years of follow-up; depigmentation of the iris persisted in both the eyes. Ten BADI patients and all BAIT patients were monitored regularly until complete resolution. Acute symptoms and signs of BADI and BAIT lasted for 8.3 weeks (range, 3–16 weeks) and 8.8 weeks (range, 4–16 weeks) on average, respectively. Three BADI patients had mild relapses of acute depigmentation after
Table 1—Brief case summary of BADI cases Case
Age/Sex
Month of presentation
Laterality
Use of oral FQL
Use of topical FQL
Reason for FQL use
AC tap for viruses
1 2 3 4 5 6 7 8
47/M 38/F 33/F 76/M 40/F 34/F 27/M 55/M
Jan 2015 May 2015 May 2015 Jun 2015 Jun 2015 Aug 2015 Nov 2015 Jan 2016
Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Bilateral Unilateral
Y (moxi) Y (moxi) N N N N N Y (norflox,3 months before)
Y (gati) Y (cipro) Y (moxi þ dexa) Y (moxi) Y (cipro) Y (moxi) Y (moxi) Y (cipro, moxi, gati)
N N HSV, VZV: negative N N CMV: negative N N
9 10 11 12 13 14 15 16 17
25/F 30/F 51/M 53/M 41/M 58/M 10/M 54/F 16/F
May 2016 Jul 2016 Oct 2016, Jul 2017 Dec 2016 Apr 2017 Mar 2016 Aug 2017 Sep 2017 Nov 2017
Bilateral Unilateral Bilateral Unilateral Bilateral Bilateral Bilateral Bilateral Bilateral
Y (moxi) Y (oflox, cipro)
Y (moxi) N Y (gati þ moxi) Y (moxi þ tobra) Y (tobra þ gati þ dexa) N Y (gati þ dexa) N Y (Gati)
Fistulectomy, red eye URTI (?), mild fever Conjunctivitis Conjunctivitis Red eye Viral fever (?), red eye URTI, red eye Systemic use: unknown Topical use: conjunctivitis Common cold, red eye Fever with diarrhoea Kerato-conjunctivitis Conjunctivitis Cold, conjunctivitis NA Conjunctivitis NA Fever, Conjunctivitis
†
N †
N* N N* Y (Moxi)
N N N N N N N N N
FQL, fluoroquinolone; moxi, moxifloxacin; gati, gatiofloxacin; cipro, ciprofloxacin; URTI, upper respiratory tract infection; dexa, dexamethasone; HSV, herpes simplex virus; VZV, varicella zoster virus; CMV, cytomegalo virus; norflox, norfloxacin; oflox, ofloxacin; tobra, tobramycin. Y, yes; N, no; NA, not applicable. *used ayurvedic medications (for asthma; after spinal surgery). †unknown.
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Acute depigmentation of the iris—Kawali et al. Table 2—Brief case summary of BAIT cases Case Age/Sex Month of presentation Laterality Use of oral FQL Use of topical FQL 1 2 3 4 5
37/M 55/M 56/F 38/M 37/F
Feb 2015 May 2015 Apr 2016 May 2017 Jul 2014
Bilateral Bilateral Bilateral Bilateral Bilateral
Y (oflox) N N * *
Y (moxi) Y (moxi) N Y (moxi þ dexa) N
Reason for FQL use
AC tap for viruses
Genital lesions, conjunctivitis Presumed viral conjunctivitis NA Conjunctivitis
HSV, VZV: Neg HSV, VZV: Neg N N HSV, VZV, CMV, Rubella: Neg
*
FQL, fluoroquinolone; oflox, ofloxacin; moxi, moxifloxacin; HSV, herpes simplex virus; VZV, varicella zoster virus; dexa, dexamethasone; CMV, cytomegalo virus. Y, yes; N, no; NA, not applicable. *unknown.
a month during tapered topical steroid and were managed with increasing topical and adding low-dose oral steroids. Another BADI patient (case 11) had a recurrence after 10 months, suffering a mild fever and cough for which antibiotics were prescribed (details unknown). This patient also experienced superficial punctate keratopathy in the left eye, and underwent cataract surgery on the right eye, for which moxifloxacin and prednisolone eye drops were prescribed. No fresh iris depigmentation was noted after 1 month following the surgery. Another BADI patient (case 17) had a history of being treated with norfloxacin and ofloxacin for fever (more than a year previously) and had no ocular complaints that time, but
developed BADI after being treated with moxifloxacin for a fever with skin rash and vomiting. No recurrences were noted in BAIT patients after complete resolution of the condition. All patients maintained normal best corrected visual acuity throughout their follow-up periods.
DISCUSSION Although BADI and BAIT resemble each other, they are distinguished by the involvement of iris stroma and iris pigment epithelium, respectively. The involvement of the pupil and iris TIDs are seen in BAIT but not in BADI; reversibility of iris depigmentation was reported in BADI
Fig. 1 — (A) Case 3 (BADI): shows bulbar conjunctival congestion and geographic iris depigmentation (arrows). (B) Case 2 (BADI): Subtle diffuse iris depigmentation with a faint demarcation line (arrows), while on treatment with topical and oral steroids. (C) Gonioscopy shows dense pigmentation of trabecular meshwork (arrow). (D) Anterior segment OCT shows iris thinning and loss of outer iris surface reflectivity (arrow). CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al.
Fig. 2 — Case 12 (BADI) shows iris depigmentation with pupillary distortion (arrows) but without iris TIDs in the right eye (A) and peripheral subtle iris depigmentation without pupillary distortion and without iris TIDs in the left eye (B).
during long term follow up but not in BAIT.1,2,6 Both conditions have been reported separately in the literature. A combination of features of BADI and BAIT in a single patient, as seen in BADI case 12 and BAIT case 1 in our series, has not been previously described (Figs. 2, 3). Moreover, unilaterality, as noted in 3 cases of BADI, has not been previously reported. Although it is possible that unilaterality could be due to gross asymmetric involvement at presentation, during follow-up over 3 months involvement of the other eye was not evident clinically when only the affected eye was treated. Depigmentation in BADI and BAIT must be differentiated from other pigment conditions such as pigment dispersion syndrome (PDS), which is a chronic condition. Pain, redness, photophobia, absence of concave iris configuration, and limited course of the disease will favour a diagnosis of BADI or BADI rather than PDS. Dermal phototoxicity, cardiotoxicity, arthropathy, and tendinitis are known adverse reactions to systemic FQLs.10 Although various case reports have suggested systemic FQL as a cause of iris depigmentation,4,5 two large studies deduced an “emerging viral etiology” for both BADI and
BAIT.2,6 This conclusion was mainly based on the absence of systemic FQLs in few patients, recent respiratory infections, and the clustering of cases during the summer months in each series. In the present study we noted exposure not only to systemic but also to topical FQLs and considered not only systemic viral prodrome but ocular as well, which presented in the form of conjunctivitis or keratoconjunctivitis and months of presentation of each case (Tables 1, 2). Surprisingly, there are no reports of FQL induced dermal phototoxicity with concomitant BAIT or BADI. FQL-induced dermal phototoxicity generally occurs in areas exposed to ultraviolet A rays (UVA). Three of our BADI patients had history of abundant sunlight exposure after using topical moxifloxacin and oral ciprofloxacin, but no patient developed a skin rash or eyelid involvement. We also noted that the iris depigmentation began in the area of the iris covered by the superior lid in some cases (Fig. 3A) and in the peripheral iris in all cases, contradicting the role of FQL-phototoxicity in iris depigmentation. This paradox of FQL-dermal phototoxicity without iris phototoxicity may also suggest that iris melanocytes
Fig. 3 — Case 1 (BAIT) shows peripheral patch of depigmentation (arrows) without pupillary involvement and iris TIDs in the right eye (A) and classical BAIT pattern in the left eye with iris TIDs (encircled) (B).
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Acute depigmentation of the iris—Kawali et al.
Fig. 4 — Infra-red iris autofluorescence of case 16 (BADI) highlights atrophic areas with hypofluorescence.
could be different in some respects from retinal pigment epithelium and dermal melanocytes. Perhaps for similar reasons, in contrast to sunset glow fundus in VogtKoyanagi-Harada (VKH) syndrome, iris depigmentation has rarely been reported in the literature.11 The effect of FQLs on melanocytes has been evaluated in experimental studies in great detail. FQLs are known to cause loss of melanocyte viability and to inhibit tyrosinase activity in human skin melanocytes.12,13 Several compounds in the FQL family, such as norfloxacin, moxifloxacin, sparfloxacin, and ciprofloxacin, showed significant dermal melanocyte toxicity in vitro.13,14 The effects of moxifloxacin on human iris pigment epithelium in vitro has also been studied, and showed significant toxicity at doses greater than 100µg/mL15; it is known that moxifloxacin achieves a concentration of 1.71 ± 0.82 μg/mL after topical application.16 Although a large “clinical study” with intracameral use of moxifloxacin during cataract surgery as a prophylaxis for postoperative endophthalmitis reported no clinically evident iris toxicity, a recently conducted “experimental study” on a cataract patient after topical application of FQLs as a preoperative medication showed subclinical toxicity due to FQLs (moxifloxacin, ciprofloxacin) as well as aminoglycosides such as tobramycin.17,18 None of these patients developed iris depigmentation or TIDs before or after the cataract surgery. This study also showed that moxifloxacin significantly decreased tyrosinase (a rate-limiting enzyme for melanin production) activity in the aqueous compared to tobramycin and ciprofloxacin. Tobramycin, a member of aminoglycoside family, has also been shown to bind strongly with melanin and it has been speculated that it is involved in ototoxicity.19,20 Five of the BADI cases in our series received topical tobramycin along with FQL, and 2 of the BAIT cases had a history of treatment with aminoglycosides. It is noteworthy that case 17 in the BADI series developed the phenotype after the use of systemic moxifloxacin but not with norfloxacin or ofloxacin. Consistently, case 8 in the BADI series had a history
of angioedema characterized by swelling of the upper lip after consumption of norfloxacin and indomethacin and was treated with intravenous steroids due to suspected idiosyncratic drug reactions. Three months after this episode, the patient developed conjunctivitis in the right eye, as did the patient’s immediate family members. All received topical FQL; all of the family members were cured except the patient, who went on to develop unilateral BADI. Levofloxacin-induced retinopathy has also been reported recently.21 In addition, studies reported that ABCG2 as a candidate gene for FQL-induced retinopathy in cats.22 Hence, there is some experimental evidence that FQL can be held responsible for melanocyte toxicity under certain conditions such as exposure to UVA rays, excessive drug dosage, and genetic susceptibility. Although most of our patients had a history of FQL use, they scored less than 4 on the Narenjo Adverse Drug Reaction Probability Scale (livertox.nih.gov/Naranjoassess ment.pdf) and were categorised as experiencing a “possible relation” based on the World Health Organization’s causality assessment of suspected adverse drug reactions.23 Although drug re-challenge is a possible method to prove FQL toxicity, it may not be an ethical practice. Case 11 of the BADI series, the only patient who had a recurrence after 10 months, could not provide details of the medications taken to treat a fever and cough, but this patient did not show fresh iris depigmentation when exposed to topical moxifloxacin-prednisolone after cataract surgery. Although there was no clustering of cases in our series (which may suggest a viral etiology, as reported previously),2 many of our patients had an episode of presumed viral conjunctivitis. Again, however, almost all these patients were primarily seen by general ophthalmologists elsewhere, and thus the possibility of a misdiagnosis of BADI or BAIT as conjunctivitis cannot be completely excluded. Herpetic viral (HSV, VZV, CMV) etiology for BADI or BAIT is unlikely, as aqueous tap PCR was negative in all tested cases in our series, as well as in previous reports.1,2 Contrarily, occurrence of high IOP in CAN J OPHTHALMOL — VOL. ], NO. ], ] 2018
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Acute depigmentation of the iris—Kawali et al. Table 3—FQL versus viral etiology Points in favour of FQL toxicity and against viral etiology
Almost all patients exposed to FQLs (topical and [or] systemic) Experimental evidence of FQL toxicity on iris melanocytes15,18 History of UV exposure in few patients Absence of clustering of cases in our series unlike reported previously2 Negative PCR studies for common herpetic viruses Absence of true uveitis (with inflammatory KPs and WBCs in AC)
BAIT series as compared to BADI series may suggest a viral etiology. An “emerging virus” causing iris depigmentation and TIDs without inflammatory KPs and white blood cells in the AC is also possible, and next-generation gene-sequencing analysis of aqueous or tears from BADI or BAIT patients may help to discover the unknown organism, if any. Despite the reported experimental evidence of FQL toxicity on melanocytes, no firm causal relation with either topical or systemic FQL use was found in our clinical study (Table 3). Our study does contribute the new information that the signs of BADI and BAIT can be seen in different eyes of same patient, and that BADI can be unilateral or grossly asymmetric and can recur months after complete resolution. In conclusion, acute iris depigmentation and transillumination (BADI and BAIT) are uveitic masquerades and self-limiting conditions, and the exact mechanism of pathogenesis is still unknown. FQL toxicity on iris melanocytes in vivo under certain circumstances in certain individuals and the possibility of a novel virus as an etiological agent remains to be determined.
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Points against FQL toxicity and in favour of novel viral etiology
Narenjo adverse drug reaction score less than 4 History of presumed viral conjunctivitis/kerato-conjunctivitis Superior lid covered iris involvement in few patients Systemic viral prodrome in 6 patients Absence of concomitant dermal phototoxicity Three patients did not use any FQLs (but ayurvedic medications). A known case of BADI underwent cataract surgery, did not develop fresh iris depigmentation despite use of topical moxifloxacin (but together with steroids)
9. Willermain F, Deflorenne C, Bouffioux C, Janssens X, Koch P, Caspers L. Uveitis-like syndrome and iris transillumination after the use of oral moxifloxacin. Eye. 2010;24:1419-20. 10. De Sarro A, De Sarro G. Adverse reactions to fluoroquinolones: an overview on mechanistic aspects. Curr Med Chem. 2001;8:371-84. 11. Cuevas M, de-la-Torre A, Córdoba A. Bilateral iris depigmentation and ocular hypotony as end-stage manifestations of untreated Vogt-Koyanagi-Harada disease. Ocul Immunol Inflamm. 2017;26: 1-6. 12. Beberok A, Buszman E, Wrzesniok D, Otreba M, Trzcionka J. Interaction between ciprofloxacin and melanin: the effect on proliferation and melanization in melanocytes. Eur J Pharmacol. 2011;669:32-7. 13. Beberok A, Wrzesniok D, Otreba M, Buszman E. Impact of sparfloxacin on melanogenesis and antioxidant defense system in normal human melanocytes HEMa-LP—an in vitro study. Pharmacol Rep. 2015;67:38-43. 14. Beberok A, Wrzesniok D, Otreba M, Milinski M, Rok J, Buszman E. Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes. Mol Cell Biochem. 2015;401:107-14. 15. Perin A, Lyzogubov V, Bora N, Morshedi G. In vitro assessment of moxifloxacin toxicity to human iris pigment epithelium. Invest Ophthalmol Vis Sci. 2015;56:5729. 16. Halder S, Mondal KK, Biswas S, Mandal TK, Dutta BK, Haldar M. Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery. Indian J Pharmacol. 2013;45:223-6. 17. Haripriya A, Chang DF, Ravindran RD. Endophthalmitis reduction with intracameral moxifloxacin prophylaxis: analysis of 600,000 surgeries. Ophthalmol. 2017;124:768-75. 18. Mahanty S, Kawali AA, Dakappa SS, et al. Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity. Exp Eye Res. 2017;162:79-85. 19. Buszman E, Wrzesniok D, Trzcionka J. Interaction of neomycin, tobramycin and amikacin with melanin in vitro in relation to aminoglycosides-induced ototoxicity. Pharmazie. 2007;62:210-5. 20. Wrzesniok D, Otreba M, Beberok A, Buszman E. Viability of human melanocytes HEMa-LP exposed to amikacin and kanamycin. Indian J Pharm Sci. 2013;75:102-6. 21. Butler NJ, Suhler EB. Levofloxacin-associated panuveitis with chorioretinal lesions. Arch Ophthalmol. 2012;130:1342-4. 22. Ramirez CJ, Minch JD, Gay JM, et al. Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats. Pharmacogenetics Genomics. 2011;21:66-75. 23. Edwards IR, Biriell C. Harmonisation in pharmacovigilance. Drug Saf. 1994;10:93-102.
Footnotes and Disclosure: The authors have no proprietary or commercial interest in any materials discussed in this article.
Acute depigmentation of the iris—Kawali et al. No one anyone other than the authors listed on page 1 help write or revise this manuscript. No monetary support was received for this study.
From the *Uveitis and Ocular Immunology Department, Narayana Nethralaya, Bangalore; †Department of corneal and refractive surgery, Narayana Nethralaya, Bangalore.
Dr. Ankush Kawali: literature search, figure creation, study design, clinical study, concept, definition of intellectual content, data collection, data interpretation, and writing manuscript. Dr. Padmamalini Manhendradas: Clinical studies, Manuscript editing, definition of intellectual content, data collection, data interpretation. Dr. Rohit Shetty: Manuscript editing, definition of intellectual content, data interpretation.
Originally received Jan. 27, 2018. Final revision Mar. 16, 2018. Accepted Mar. 27, 2018. Correspondence to: Dr. Ankush Kawali, Narayana Nethralaya, Chord Road, Rajajinagar, Bangalore; [email protected]
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