Mohammad Ayoub¹ and Tariq Ayoub²

1. Croydon University Hospital, 530LondonRoad,Thornton Heath, London CR7 7YE, UK
2. Western Eye Hospital, Imperial College Healthcare NHS Trust, 153-173 Marylebone Road, London NW1 5QH, UK

Summary

A lady in her 60s with primary open angle glaucoma was on latanoprost, dorzolamide/timolol combination and brimonidine drops for approximately three years. She presented to the eye casualty with a four-month history of worsening bilateral red, painful eyes with reduced vision. On examination, she had very poor vision, florid granulomatous anterior uveitis with posterior synechiae, mutton-fat keratic precipitates, and hypopyon in the left eye. Her intraocular pressures were very high despite her topical glaucoma medications. She also had bilateral follicular conjunctivitis. Investigations for systemic or infectious causes of anterior uveitis were negative.

All her topical glaucoma medications were stopped. Her intraocular pressure was controlled with oral acetazolamide and topical apraclonidine. Topical steroids and cycloplegic drops were used for her anterior uveitis. Over eight weeks, the uveitis and conjunctivitis resolved. Latanoprost and dorzolamide/timolol were restarted without recurrence of uveitis. Brimonidine was permanently discontinued, and this was considered the cause of her uveitis.

This case shows that brimonidine can rarely cause severe anterior uveitis. Stopping the drug promptly is essential to prevent permanent eye damage.

Introduction

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness worldwide, with management requiring long term intraocular pressure (IOP) reducing therapy (1). Brimonidine, a highly selective α2-adrenergic agonist, is prescribed as monotherapy or in combination with other agents for glaucoma and ocular hypertension. It lowers IOP by reducing aqueous humour production and increasing uveoscleral outflow (2).

While brimonidine is generally well tolerated, ocular allergic reactions such as follicular conjunctivitis are relatively common and may require discontinuing (2). Rarely, cases of anterior uveitis have occured, highlighting the importance of considering drug-induced causes when evaluating intraocular inflammation (3).

This case of severe granulomatous anterior uveitis associated with long-term brimonidine use is presented, highlighting the need for clinical awareness of this potentially sight-threatening adverse reaction.

Case

A woman in her 60s with primary open-angle glaucoma, treated for three years with latanoprost, brimonidine 0.2%, and a dorzolamide/timolol combination, presented with a four-month history of worsening bilateral painful red eyes and reduced vision. She had previously used brinzolamide and dorzolamide but were stopped due to allergic reactions. There was no other significant ocular or systemic history. She reported no travel history, skin rashes, ulcers, or musculoskeletal symptoms.

On examination, best corrected visual acuity was markedly reduced in both eyes. She had florid bilateral granulomatous anterior uveitis with posterior synechiae, diffuse mutton-fat keratic precipitates, fibrin, and a hypopyon in one eye. Intraocular pressures were very elevated despite topical therapy. Fundal examination was limited by anterior uveitis, posterior synechiae, and cataracts, but there was no vitritis or retinitis. The optic discs showed marked cupping.

Following reduction of intraocular pressure, a secondary examination revealed open angles and bilateral follicular conjunctivitis. Laboratory investigations, including full blood count, erythrocyte sedimentation rate, serum angiotensin-converting enzyme, HLA-B27 typing, and vasculitic screening, were unremarkable. Infectious workup for tuberculosis, syphilis, and Lyme disease was negative. Chest imaging was normal.

Treatment

On first presentation, the patient was treated with oral acetazolamide and a stat dose of topical apraclonidine to lower her raised intraocular pressure. She also received a subconjunctival injection of dexamethasone and was started on topical steroid and cycloplegic drops.

As bilateral follicular conjunctivitis was present, a working diagnosis of granulomatous anterior uveitis secondary to brimonidine was made. Brimonidine was stopped at presentation while investigations were ongoing. Latanoprost and dorzolamide/timolol combination were also temporarily stopped, and oral acetazolamide was continued.

Her intraocular pressures returned to normal. The anterior uveitis and conjunctivitis gradually resolved over approximately 2 months. There was no recurrence of uveitis after stopping topical steroids, and vision improved, limited by existing cataracts. Latanoprost and dorzolamide/timolol combination were restarted, and oral acetazolamide was stopped. Intraocular pressures remained stable on follow-up, with no recurrence of uveitis.

Given the high likelihood that brimonidine had caused the uveitis, the patient declined a rechallenge with the drug.

Discussion

Brimonidine is a highly selective alpha-2 adrenoceptor agonist that lowers IOP by reducing aqueous humour production and increasing uveoscleral outflow (4). It is used for the long-term treatment of ocular hypertension and glaucoma. Minor systemic side effects of brimonidine include dry mouth and fatigue. Ocular allergic reactions are more common and can be severe enough to require stopping the drug (5). Allergic conjunctivitis, allergic blepharitis, and follicular conjunctivitis have been reported and can lead to discontinuation in a notable proportion of patients (5, 6, 7). These allergic reactions usually occur after 6-9 months of treatment and resolve on stopping the drug (7).

Anterior uveitis can have many causes. Bilateral granulomatous anterior uveitis, however, is usually caused by a limited number of causes. Inflammatory causes include sarcoidosis, lymphoproliferative disorders, multiple sclerosis, and sympathetic ophthalmia. Infectious causes include tuberculosis, syphilis, and Lyme disease. Screening for known causes of anterior uveitis was negative in this patient.

A review of previously published cases of anterior uveitis secondary to brimonidine identified multiple reports (3, 8-13). All cases involved granulomatous anterior uveitis, often with mutton-fat keratic precipitates. Some reports described stellate keratic precipitates (14). The uveitis is almost always preceded by allergic or follicular conjunctivitis. It usually occurs after prolonged treatment, with time to presentation ranging from six months to several years (3, 8-14).

Stopping brimonidine, along with treatment using topical steroids, led to complete resolution of anterior uveitis in the patient. The uveitis did not recur after stopping steroids. There are reports of resolution of anterior uveitis after stopping brimonidine alone, without steroid treatment (14).

Other glaucoma medications, such as latanoprost, can cause anterior uveitis (15). In this patient, however, latanoprost and dorzolamide/timolol combination were restarted without recurrence of uveitis, making them unlikely causes. A rechallenge with brimonidine was not performed given the severity of the reaction.

The patient received apraclonidine to lower intraocular pressure on presentation. Apraclonidine was stopped once brimonidine was suspected as the cause. There are no known cases of uveitis due to apraclonidine. Apraclonidine can cause ocular allergy in many patients and is not licensed for long-term use (16). It is therefore unlikely to cause uveitis.

Conclusions

The mechanism by which brimonidine causes anterior uveitis is not fully understood. In reported cases, including this one, allergic conjunctivitis often precedes the uveitis. This suggests that continuing brimonidine in eyes with allergic reactions may trigger uveitis. Stopping the drug at the onset of an allergic reaction may explain why this side effect is rare.

Although uncommon, brimonidine-induced anterior uveitis can be sight-threatening. Clinicians should be aware of this potential side effect. Prompt cessation of the drug is essential to prevent permanent eye damage.

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