Anterior Uveitis and Concurrent Allergic Conjunctivitis Associated with Long-Term Use of Topical 0.2% Figure 6

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11. Gehrig A, Schmidt SR, Muller CR, Srsen S, Srsnova K, Kress W. Molecular defects in alkaptonuria. Cytogenet Cell Genet. 1997;76:14- 16. 12. Beltran-Valero de Bernabe D, Granadino B, Chi- arelli I, et al. Mutation and polymorphism analy- sis of the human homogentisate 1,2- dioxygenase gene in alkaptonuria patients. Am J Hum Genet. 1998;62:776-784. 13. Higashino K, Liu W, Ohkawa T, et al. A novel point mutation associated with alkaptonuria. Clin Genet. 1998;53:228-229.

Anterior Uveitis and Concurrent Allergic Conjunctivitis Associated With Long-term Use of Topical 0.2% Figure 6. The large masses of ochronotic pigment (under the epithelium) and the marked actinic Brimonidine Tartrate elastosis of the stroma stain black with the stain for elastic fibers (Movat pentachrome, original magnification ϫ64). Brimonidine tartrate is a relatively ␣ selective 2-agonist that lowers characterized. Two missense muta- Arun Nayer, MD, provided the intraocular pressure by reducing tions cosegregating with alkapton- clinical photograph and additional pa- aqueous humor production and by uria in 2 Spanish pedigrees and a tient history. increasing uveoscleral aqueous third missense and a frameshift Correspondence: Dr Che´vez Bar- humor outflow. Ocular side effects mutation in Slovakian families rios, Department of Pathology, Bay- associated with brimonidine use established HGO as the defective lor College of Medicine, One Baylor include pruritus, as well as follicu- gene in alkaptonuria.8,11 Concur- Plaza, Houston, TX 77030 (pchevez lar conjunctivitis. Recently, 2 rently, 13 additional mutations @bcm.tmc.edu). reports have described the devel- were found in unrelated subjects opment of anterior uveitis in 5 pa- with alkaptonuria from 6 Euro- tients treated with brimonidine.1,2 pean countries, Algeria, Turkey, 1. Garrod E. The incidence of alkaptonuria: a study Herein we report 4 additional cases 12,13 in chemical individuality. Lancet. 1902;2:1616- of uveitis and concurrent allergic and Japan. The latest published 1620. 7 study in 1999 describes the identi- 2. Garrod E. The Croonian lectures on inborn er- conjunctivitis associated with the fication of 2 homozygous missense rors of metabolism: lecture II: alkaptonuria. Lan- use of 0.2% brimonidine tartrate. cet. 1908;2:73-79. mutations in 2 unrelated German 3. La Du BN, Zannoni VG, Laster L, Seegmiller The 4 cases are summarized in the patients who were first diagnosed JE. The nature of the defect in tyrosine me- Table. with this congenital disorder after tabolism in alcaptonuria. J Biol Chem. 1958; 230:251-260. their referral to ophthalmologists. 4. Soker Cakmak S, Cevik R, Aksunger A, Unlu Report of Cases. Case 1. An 82- The importance of recognizing this K, Ava S. Ocular ochronosis: a case report and year-old woman sought care from clinical findings. Acta Ophthalmol Scand. 2002; entity, which enters in the differen- 80:340-342. her general ophthalmologist be- tial diagnosis of pigmentations and 5. Kampik A, Sani JN, Green WR. Ocular ochro- cause of redness, blurred vision, deposits of the conjunctiva, is nosis: clinicopathological, histochemical, and and photophobia in her right eye. ultrastructural studies. Arch Ophthalmol. 1980; emphasized in our report, in which 98:1441-1447. The patient had a history of glau- the recognition of this systemic 6. O’Brien WM, La Du BN, Bunim JJ. Biochemi- coma and had been treated with disease was the initial ocular mani- cal, pathologic, and clinical aspects of alcap- 0.2% brimonidine tartrate in the tonuria, ochronosis and ochronotic arthropa- festation of the disease. thy: review of world literature. Am J Med. 1963; right eye during the previous 16 34:813-838. months. Anterior uveitis was diag- 7. Felbor U, Mutsch Y, Grehn F, Muller CR, Kress Patricia Che´vez Barrios, MD W. Ocular ochronosis in alkaptonuria pa- nosed in the right eye and resolved Ramon L. Font, MD tients carrying mutations in the homogenti- after a 5-week course of topical 1% sate 1,2-dioxygenase gene. Br J Ophthalmol. prednisolone acetate. The uveitis 1999;83:680-683. The authors have no relevant finan- 8. Fernandez-Canon JM, Granadino B, Beltran- recurred after the corticosteroids cial interest in this article. Valero de Bernabe D, et al. The molecular were discontinued, and it failed to This study was supported in basis of alkaptonuria. Nat Genet. 1996;14:19- improve after 3 weeks of treat- 24. part by grants from the Retina 9. Montagutelli X, Lalouette A, Coude M, Ka- ment with topical corticosteroids. Research Foundation, Houston, Tex, moun P, Forest M, Guenet JL. aku, A muta- The patient was referred to a tion of the mouse homologous to human al- and Research to Prevent Blindness, kaptonuria, maps to chromosome 16. Genomics. uveitis specialist, and examination Inc, New York, NY. Dr Font is recipi- 1994;19:9-11. disclosed conjunctival injection in ent of a Senior Investigator Award 10. Fernandez-Canon JM, Penalva MA. Fungal the right eye with mutton-fat ke- metabolic model for human type I hereditary from Research to Prevent Blindness, tyrosinaemia. Proc Natl Acad Sci U S A. 1995; ratic precipitates, +2 anterior cham- Inc. 92:9132-9136. ber cells and flare, posterior syn-

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Eye(s) Treated With Follow-up Patient No./ Eye(s) Brimonidine; Duration Concurrent Topical Laboratory and After Resolution Sex/Age, y Affected of Treatment, mo Medications Radiographic Studies† of Uveitis, mo 1/F/82 OD OD; 16 None CBC, HLA-B27, FTA-ABS, 36 ACE, CXR 2/F/83 OU OU; 12 Dorzolamide hydrochloride, FTA-ABS, ACE, CXR 22 0.5% timolol maleate 3/F/81 OU OU; 12 Carteolol hydrochloride CBC, FTA-ABS, ACE, 18 lysozyme, PPD, CXR 4/M/77 OU OU; 16 0.5% Loteprednol etabonate, CBC, FTA-ABS, ACE, CXR 36 0.1% fluorometholone

Abbreviations: ACE, angiotensin-converting enzyme level; CBC, complete blood cell count; CXR, chest x-ray film; FTA-ABS, fluorescent treponemal antibody absorption test; PPD, purified protein derivative. *Mean age, 81 years; mean duration of treatment, 14 months; mean follow-up, 28 months. †Studies showed no abnormalities associated with uveitis.

cells and +1 flare in each anterior chamber were present (Figure 2). Results of serologic testing for syphilis, serum angiotensin-converting enzyme level, and a chest x-ray film were normal. Brimonidine was discontinued and the patient started treatment with oral prednisone and famciclovir. Four days later, the uveitis was improved and the famciclovir was discontinued. A prednisone taper was begun, and examination 2 weeks later showed no anterior chamber cells and diminished keratic precipitates bilaterally. After this episode of bilateral anterior uveitis, the patient experienced several Figure 1. Bilateral periorbital inflammation and conjunctivitis in patient 2. flares of uveitis in the right eye pre- sumed to be associated with her history of herpes zoster ophthalmi- echiae, and Koeppe nodules. The left tinuation of the brimonidine. There- cus, but her left eye remained quiet eye was quiet. after, topical 2% dorzolamide hy- for 22 months. A complete blood cell count, drochloride was used in the right Case 3. An 81-year-old woman HLA-B27 typing, fluorescent trepo- eye, and no additional episodes of with chronic open-angle glaucoma nemal antibody absorption test, an- uveitis occurred in 3 years. was examined because of photopho- giotensin-converting enzyme level, Case 2. An 83-year-old woman bia and redness in both eyes of 1 and chest x-ray film showed no ab- sought care because of redness, tear- week’s duration. Her ocular medi- normalities. ing, and photophobia of both eyes. cations were carteolol hydrochlo- The uveitis resolved during 6 The patient had a history of pigmen- ride and brimonidine drops for 12 weeks of treatment with 1% pred- tary dispersion glaucoma, cataract months in both eyes. Examination nisolone acetate, and the corticoste- surgery in the right eye, and an epi- showed mild erythema of the lids roids were tapered and discontin- sode of right-sided herpes zoster with an intense palpebral papillary ued. One month later, the uveitis ophthalmicus 13 months before this reaction, conjunctival scarring, for- recurred in the right eye and re- episode. Her ocular medications in- nix shortening with symblepha- solved with corticosteroid drops as cluded brimonidine for 12 months, ron, bulbar follicles, and granulo- well as discontinuation of bri- dorzolamide for 11 months, and matous keratic precipitates in both monidine. After 3 months, the pa- 0.5% timolol maleate for 20 months eyes. No cells were visible in the an- tient’s ophthalmologist once again in both eyes. terior chambers. Complete blood cell prescribed brimonidine, and 2 weeks Examination disclosed ery- count, serum angiotensin-convert- later, the uveitis recurred in the right thema and scaling of the periocular ing enzyme level, serum lysozyme eye. Again the uveitis responded to skin (Figure 1). Bilateral mutton- level, and results of purified pro- topical corticosteroids and discon- fat keratic precipitates with +2 to +3 tein derivative test, syphilis sero-

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Figure 2. Multiple mutton-fat keratic precipitates in the right eye (A) and left eye (B) of patient 2.

logic test, and chest x-ray film were started and the brimonidine was dis- conjunctivitis preceded the devel- normal. continued. The conjunctivitis and opment of uveitis.1,2 As suggested The brimonidine was stopped uveitis resolved during the next 3 by Byles et al,1 up to 15% of the and the patient was treated with weeks. Three months later, 0.005% patients in clinical trials devel- 1% prednisolone acetate. One latanoprost was prescribed, and the oped allergic conjunctivitis and week later, her conjunctivitis had uveitis had not recurred in 3 years may have discontinued the bri- resolved, the eyelids were clear, of monitoring. monidine before uveitis devel- the bulbar follicles had resolved, oped.1,3 and the keratic precipitates were Comment. We have described 4 All of our patients were reduced. The corticosteroids were cases of a granulomatous anterior treated before the release of 0.15% tapered and the keratic precipi- uveitis and concurrent conjuncti- brimonidine tartrate (Alphagan P; tates resolved completely. She had vitis that appear to be related to Allergan Inc, Irvine, Calif), which no recurrences in 18 months. the use of 0.2% brimonidine tar- uses Purite, a preservative differ- Case 4. A 77-year-old man trate. All of the patients were 77 ent from the benzalkonium chlo- with a history of bilateral chronic years or older and had been using ride used in the original 0.2% open-angle glaucoma was referred 0.2% brimonidine tartrate for brimonidine tartrate. We are to the uveitis clinic with a more than 1 year. Uveitis recurred unaware of reports of uveitis asso- 6-month history of recurrent ante- in 1 eye rechallenged with bri- ciated with this more recent rior uveitis and papillary conjunc- monidine. In all cases, the uveitis re- preparation. tivitis affecting both eyes. Ocular solved only on cessation of bri- Overall, brimonidine is a medications included 0.2% brimonidine treatment. Although case well-tolerated topical glaucoma monidine tartrate for the past 16 2 describes recurrent uveitis in the medication. However, the 5 cases months and 0.5% loteprednol eta- right eye of a patient after bri- previously reported and the 4 bonate with 0.1% fluorometho- monidine had been discontinued, we cases described herein suggest lone ointment for the past several believe this was related to the his- that 0.2% brimonidine tartrate weeks in both eyes. tory of herpes zoster ophthalmi- should be considered as possible Bilateral papillary conjuncti- cus. The uveitis that occurred while cause of drug-induced uveitis. vitis with several mutton-fat the patient was using the bri- Furthermore, clinicians consider- keratic precipitates and +1 cell monidine was distinct in its bilat- ing continued use of brimonidine and flare were noted. A chest eral presentation and its granulo- in the face of conjunctivitis x-ray film, complete blood cell matous character. should monitor these patients count, fluorescent treponemal Medication-induced uveitis closely for signs and symptoms of antibody absorption test, and has been reported with a number uveitis. serum angiotensin-converting of drugs, including metipranolol enzyme level were normal. The and latanoprost, the bisphospho- Heidi I. Becker, MD loteprednol was discontinued and nates, rifabutin, cidofovir, and R. Christopher Walton, MD, MHA 1% prednisolone acetate was fomivirsen. Although such a con- Jonathan I. Diamant, MD begun. The uveitis resolved dur- nection was not reported in early Michael E. Zegans, MD ing the next 4 weeks and the cor- clinical studies, brimonidine has ticosteroids were tapered and dis- recently been associated with the The authors have no relevant finai- continued after 10 weeks of development of uveitis.1,2 The cial interest in this aricle. therapy. uveitis described in our report This study was supported in part Twelve weeks later, the uve- was seen with a concurrent aller- by grant 1 K08 EY13977-01 from the itis and conjunctivitis recurred. gic conjunctivitis. This contrasts National Eye Institute, Bethesda, Md Topical corticosteroids were re- with previous reports in which the (Dr Zegans).

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©2004 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 Correspondence: Dr Zegans, De- logically, the peripheral retinoschi- where.2 Few case reports describe partment of Surgery (Ophthalmol- sis is found in the nerve fiber layer. OCT imaging of this disease.2 We ogy) and Department of Microbiol- However, on review of recent lit- demonstrate the use of OCT ogy and Immunology, Dartmouth erature, it is not clear where the fo- to highlight unique foveal findings Medical School, 204 Vail Bldg, Han- veal split occurs. The progression in a patient with juvenile retinos- over, NH 03755-3842. of juvenile retinoschisis is asun- chisis. derlying retinal pigment epithe- 1. Byles DB, Frith P, Salmon JF. Anterior uveitis as 1 a side effect of topical brimonidine. Am J Oph- lium. Additional information may Report of a Case. A 26-year-old man thalmol. 2000;130:287-291. be gleaned from fluorescein angi- decreased vision and foveal schisis. 2. Goyal R, Ram AR. Brimonidine tartrate 0.2% (Al- ography, electroretinography, or This patient was previously exam- phagan) associated granulomatous anterior uveitis. Eye. 2000;14:908-910. genetic studies. ined and diagnosed when he was 10 3. Cantor LB. The evolving pharmacotherapeutic Optical coherence tomogra- years old. profile of brimonidine, an alpha 2-adrenergic agonist, after four years of continuous use. Expert phy (OCT) is a recent advance in The best-corrected visual acu- Opin Pharmacother. 2000;1:815-834. retinal imaging; the techniques of ity was 20/60 OD and 20/50 OS. Re- this modality are described else- fraction was +0.50 sphere OU. Pu-

A B Optical Coherence Tomography Findings in Foveal Schisis

Juvenile retinoschisis is a congenital X-linked recessive retinal disorder. Patients may develop nystag- mus, decreased central vision, or strabismus. Fundus findings vary considerably, from the absence of a foveal reflex to the presence of a large, elevated schisis cavity in- volving the fovea. The protean finding is a foveal schisis. Histo- Figure 1. Red-free photographs demonstrate foveomacular schisis in both eyes.

A B

C D

Figure 2. Two-dimensional optical coherence tomographic (OCT) scan of the right eye, with horizontal (A) and vertical (B) sections through the macula. Note the broad central area of flat foveal tissue surrounded by multiple levels of schisis. Horizontal (C) and vertical (D) sections reflect similar pathologic features in the left eye.

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