Deepening of Lid Sulcus from Topical Bimatoprost Therapy

Purpose: To report a new adverse effect related to treatment with bimatoprost.

Case Reports: Serial clinical examination of three patients was performed. In each of the three reported patients, alteration of eyelid appearance with deepening of the lid sulcus was evident as the result of topical bimatoprost therapy.

Discussion: A comprehensive literature search of Medline using WebMd and MDConsult, was conducted to cross reference known side effects of topical prostaglandin analog treatment. The keywords utilized were prostaglandin analogs, prostaglandins, prostamide, glaucoma, ocular hypertension, intraocular pressure, side effects, adverse effects, bimatoprost, latanoprost, lumigan, and xalatan. This appears to be the first such report in the literature. Clinicians and patients should be made aware of this possible complication of topical bimatoprost therapy.

Bimatoprost (Lumigan, Allergan Inc., Irvine, CA) is a prostamide that lowers intraocular pressure (IOP) by enhancing uveoscleral outflow. Among medications used for glaucoma therapy, prostaglandin analogs and prostamides offer the advantages of good efficacy and potency as well as once daily dosing.¹ Adverse effects from topical prostaglandin analogs and prostamides have been reported, including conjunctival hyperemia, cystoid macular edema, and pigment changes in the periorbital skin, eyelashes, and iris.^2-5 When using these same agents, reports of iritis, herpes simplex keratitis reactivation, hypertrichosis, and headaches have also been made.^6,7 This report describes three patients who experienced ipsilateral deepening of the lid sulcus with the use of bimatoprost eye drops. To our knowledge, this is the first such report in the literature since bimatoprost was first introduced in 2001.

CASE REPORTS

Case 1

An 80-year-old male with a 5 year history of glaucoma was switched to monocular therapy with bimatoprost 0.03% qhs in his right eye in June 2001. At follow-up 3 months later, his pressure was controlled and no side effects were noted. He then missed a follow-up appointment and finally returned in April 2002, with his wife noting a different appearance of the treated right eye (Fig. 1A). The upper lid sulcus was now very prominent and dermatochalasis was not present in the treated eye (Fig. 1B), although the patient continued to demonstrate dermatochalasis with temporal hooding in the untreated eye (Fig. 1C), as had been previously documented.

Figure 1

The patient agreed to challenge the left eye with the same treatment of bimatoprost 0.03% qhs. Follow-up in May 2002 demonstrated deepening of the lid sulcus. No camera was available to document this change, but it was observed and recorded by one of the authors (LSP).

The patient then discontinued the bimatoprost in the left eye and continued the therapy in the right eye. Eyelid posture in the left eye returned to baseline with dermatochalasis and temporal hooding. The deeper lid sulcus continues in the right eye to present, and the patient has not discontinued treatment due to this adverse effect. This event was reported to the manufacturer in July 2002.

Case 2

A 77-year-old female presented in February 2003 for another opinion regarding her glaucoma, with concerns about the appearance of her left eye. She started on treatment with brimonidine twice a day OU in August 2000. In June 2002, bimatoprost 0.03% qhs was added to the left eye only. She complained that the eye now appeared swollen, dark, and very noticeable.

External examination revealed a deep and prominent upper lid sulcus OS with hypertrichosis of the lashes (Fig. 2A). Her glaucoma was otherwise controlled, with applanation IOPs of 15 mm Hg OD and 17 mm Hg OS.

Figure 2

The patient agreed to challenge the right eye with the same therapy of bimatoprost 0.03% qhs. She returned 1 month later (April 2003) noting that now both eyes were sunk in (Fig. 2B). IOP measured 14 mm Hg OD and 18 mm Hg OS. Bothered by the side effect, bimatoprost was discontinued from both eyes and the patient was continued on brimonidine only.

Follow-up in another month (May 2003) revealed lessening of the sulcus bilaterally with an anterior displacement of the lid fold and crease (Fig. 2C). IOP now measured 18 mm Hg OD and 22 mm Hg OS. The patient has not resumed bimatoprost and is undergoing alternate glaucoma therapy.

Case 3

A 51-year-old female has been treated for glaucoma since 1997. In July 2002, her therapy was changed to bimatoprost 0.03% qhs OU, with subsequent good IOP control of 14 to 16 mm Hg OU. This patient then underwent unilateral cataract surgery OD in August 2003. As a result of the surgery, the bimatoprost was discontinued OD but was still continued OS.

At a postoperative visit 6 weeks after surgery, the patient complained of a different appearance of her eyelids, thinking surgery caused her right eye to droop. A review of her records shows that dermatochalasis had been noted before 2002 (initiation of bimatoprost therapy), but none had been recorded since that time. Indeed, examination now showed some dermatochalasis of the right upper lid, but compared with a deeper, more prominent upper lid sulcus OS (Fig. 3A).

Figure 3

The patient was discontinued from bimatoprost and switched to alternate glaucoma therapy. At follow-up 6 weeks after discontinuing bimatoprost, her lid position has resumed its more natural appearance (Fig. 3B). Her IOP has now required multiple medications to reach the same goal pressure, but the patient prefers this regimen over the bimatoprost due to the improved cosmesis.

DISCUSSION

Prostaglandin analogs, including bimatoprost, have proven efficacy when used topically during glaucoma therapy to lower IOP.^8-10 It is believed that bimatoprost lowers IOP by increasing aqueous humor outflow through both the uveoscleral and trabecular meshwork routes by mimicking the action of naturally occurring prostamides.¹¹ These positive effects of bimatoprost are not without the balance of some adverse effects.¹²

A comprehensive literature search using WebMd and MDConsult was performed to identify all known and reported adverse effects from topical ocular prostaglandin therapy. This search included the phrases: prostaglandin analog, prostaglandins, prostamide, bimatoprost, lumigan, latanoprost, xalatan, glaucoma, ocular hypertension, IOPs, side effects, and adverse effects. Prostaglandins, endogenous fatty acids found throughout the body, are synthesized via the arachidonic acid pathway.¹³ As a drug class, prostaglandin analogs have a short plasma half life, which generates low systemic levels. Thus, they have no proven systemic side effects.¹⁴ Following ocular or surgical trauma, prostaglandin synthesis acts to create irritative reactions. Widely reported adverse effects of the topical prostaglandin analogs including iris color darkening, pigment changes in periorbital skin, eyelash changes, cystoid macular edema, and conjunctival hyperemia.^2-5,12 Some mechanisms of action have been proposed for several of these reported adverse effects.

Prostaglandins may contribute to cystoid macular edema by disrupting the blood-aqueous barrier in pseudophakes.³ It has been postulated that Bito's pump, which acts to actively transport prostaglandins, may not be working properly in individuals who develop cystoid macular edema while taking prostaglandin analogs.¹⁵ It is hypothesized that ocular irritation, caused operatively, creates a malfunction of Bito's pump. In this way, prostaglandins are not absorbed, allowing them to accumulate in the aqueous and vitreous. These additional prostaglandins act to break down the blood aqueous barrier and the blood-retinal barrier. A weakened blood-retinal barrier can lead to cystoid macular edema.³ For this reason, conditions that weaken the blood-retinal barrier, such as diabetes, hypertension, increased age, and uveitis, may increase the risk of developing cystoid macular edema when using prostaglandin analogs.³ Other research points to the preservative, benzalkonium chloride (found in prostaglandins), as the cause of the observed cystoid macular edema with antiglaucoma drops.¹⁶

Pigment changes in the periorbital skin, eyelashes, and iris due to prostaglandin analog use are thought to occur because of an increase in melanin granules in the melanocytes.¹⁷ Prostaglandins are known to be potent stimulators of melanogenesis.¹⁸ Iris pigment alteration appears to be more permanent than the pigment changes that may occur to the periorbital skin or eyelashes.¹⁸ Hair follicles, including those on the eyelids, have recurring cycles of involution and growth. It is hypothesized that latanoprost allows eyelashes to enter the anagen phase in the hair cycle,¹⁹ resulting in eyelash hypertrophy and an increased number of eyelashes.²⁰

It has been established that latanoprost makes certain strains of epithelial herpes simplex keratitis worse and increases the risk or epithelial recurrences in rabbit eyes.^21,22 The mechanism of this effect has not been proven. An association between latanoprost and anterior uveitis has been observed. It is speculated that increased prostaglandins cause an increased release of arachidonic acid, which leads to enhanced proinflammatory eicosanoid production.²³

Bimatoprost is a prostamide, a synthetic analog of fatty acid amides, rather than a true prostaglandin. It is unknown whether this slight structural difference is clinically apparent.¹³ The most common reported side effect of bimatoprost is conjunctival hyperemia.² The release of nitric oxide by the prostaglandin analog may cause this hyperemia.²⁴ However, this is neither well understood nor proven.

The proposed mechanisms for the known and studied side effects of Bimatoprost and the other prostaglandin analogs do not appear to be a factor in causing deepening of the lid sulcus in these reported patients. It is possible that Mueller's muscle is somehow affected by the prostamide, yet palpebral fissure measurements did not appear to change with the induction or removal of the drug. Two of our patients also had concomitant periocular pigmentary changes involving the lid, and this was noted by the patient in one instance (case 2). Exophthalmometry measurements were not obtained on these patients, but again, no change in the palpebral aperture was noted. Further investigation of this new side effect will be necessary to identify the true mechanism.

To our knowledge, deepening of the lid sulcus following topical bimatoprost therapy has yet to be reported. Perhaps this is a rare adverse effect. However, given the increase in the number of patients treated with bimatoprost in the past few years, it is more likely that the incidence of this effect is higher than has been reported. With bilateral treatment, which often occurs, this side effect may be less apparent to both the patient and clinician due to symmetrical lid involvement. It is our aim that clinicians and patients will both be aware of this previously unknown possible complication of topical bimatoprost therapy.

Lee S. Peplinski

4010 Dupont Circle, Suite 380

Louisville, KY 40207

e-mail: [e-mail]