Corneal endothelial toxicity secondary to Asclepias fruticosa

Sir,

A single layer of endothelial cells covers the posterior surface of Descemet's membrane of the cornea. Corneal hydration and consequently transparency is primarily a function of the sodium–potassium adenosine triphosphatase (Na⁺/K⁺-ATPase) pump, expressed in the basolateral membrane of corneal endothelial cells. If this pump is impaired, corneal oedema results.¹

Cardenolides, also known as cardiac glycosides, are a group of C₂₃ steroids produced in nature by several plant families. These natural toxins protect plants and insects from predation. In humans, they have a cardiotonic activity, which is the basis for much of their pharmacological uses. A receptor for cardenolides is the integral membrane protein Na⁺/K⁺-ATPase. Cardenolides bind the enzyme region of this protein at the endothelial cell surface and inhibit the pump's activity.²

Asclepias fruticosa is a small perennial shrub about 1–1.5 m in height, containing a milky latex with cardiac glycosides and proteolytic activity (Figure 1).³ Plants of the genus Asclepias (milkweed family) are widely distributed, mainly in the tropics and subtropics, and are well known causes of death in sheep and cattle in open-range grazing.^{4, 5} It is common in grassland and is often planted in gardens because it attracts butterflies.

Figure 1

Asclepias fruticosa (copyright permission given by Karlheinz Knoch at the Botanical Garden of Karlsruhe).

There has been one previous case report describing painless blurring of vision and corneal oedema following contact with the milky latex of A. curassavica.¹ Herein, we describe the self-limited effects of A. fruticosa latex components on the cornea. We also discuss the mechanism of endothelial cell toxicity and provide an update on the current literature on the regulation of the Na⁺/K⁺-ATPase activity and pump function in corneal endothelial cells.

Case report

A previously healthy 73-year-old farmer presented to our clinic complaining of redness and blurred vision in both eyes (right worse than left). The previous day, he handled the milky latex of an Asclepias shrub and then rubbed his eyes. He did not have any ocular discomfort. On examination, best-corrected visual acuity was counting fingers on the right and 20/40 on the left. Slit-lamp microscopy showed conjunctival hyperemia, stromal corneal oedema with Descemet's folds greater on the right, and a moderate cataract in both eyes (Figures 2a and b). The corneal epithelium was intact. Anterior chamber was quiet with no appreciable flare. Intraocular pressure and posterior segment examination were within normal limits. Both eyes were flushed with saline. Topical dexamethasone 0.1% eye drops and artificial tears (four times a day) were prescribed. At 3 days after exposure, symptoms and clinical signs showed marked improvement. At 2 weeks after presentation, corneal oedema resolved with a best-corrected vision of 20/40 on the right and 20/30 on the left, consistent with moderate nuclear sclerotic changes. At 9 months after presentation, the patient's corneas remained clear with stable vision (Figure 3).

Figure 2

(a and b). Anterior segment photograph of the patient's right eye 1 day after contact with traces of latex from Asclepias fruticosa. Descemet's membrane folds are seen on slit-lamp biomicroscopy.

Figure 3

Anterior segment photograph of the patient's right eye 9 months after resolution of corneal oedema following exposure to the milky latex of Asclepias fruticosa.

Discussion

The plants of the Asclepiadaceae family are known to contain toxic cardiac glycosides in their latex, stems, leaves, and roots. Cardiac glycosides function clinically by inhibiting the enzyme Na⁺/K⁺-ATPase.⁶ Normal functioning of corneal endothelial Na⁺/K⁺-ATPase pump is needed to maintain corneal transparency.⁷ Cardenolides are capable of penetrating the human cornea without major injury to the epithelium.¹ Topical administration of digitoxin has been shown to cause corneal oedema by inhibiting endothelial Na⁺/K⁺-ATPase.⁸ Similar ocular changes were noted in a patient with systemic digoxin toxicity.⁹

Isolated corneal oedema developed in our patient several hours after the ocular surface had come into contact with traces of the milky latex of an Asclepias shrub. The delay in visual blurring is seen with the appearance of digitalis keratopathy after topical administration of digitoxin drops.⁶ There was no epithelial defect. Therefore, these glycosides seem able to penetrate the intact epithelium and to be toxic mainly to the corneal endothelium by inhibiting the endothelial Na⁺/K⁺-ATPase.

Steroidal treatment is often administered to reduce ocular inflammatory symptoms. Recently, a study demonstrated that dexamethasone results in increases in Na⁺/K⁺-ATPase pump activity in cultured corneal endothelial cells.¹⁰ The use of topical steroids may result in an increase of the pump activity in the remaining receptors that have not been blocked by the cardenolides. This may serve to compensate for some of the lost activity caused by the inhibitory action of the cardenolides and help in the recovery process. Corneal oedema may also disappear spontaneously when inhibition by the cardenolide has ceased. The harm caused by the cardenolides appears to be a temporary dysfunction of corneal endothelial cells that have been exposed to the toxic agent. A previous case involving A. curassavica reported an effect lasting 24–48 hours,¹ whereas our case (A. fruticosa) was resolved by day 3 with supportive treatment. As such, these conditions are typically self-limiting over a few days and associated with a full recovery without sequelae.

Toxic exposures to the cornea are not uncommon. As Asclepias plants are widely distributed, patients presenting with corneal oedema should be asked about possible exposures to plant sap. Knowledge of these toxic plants and their sap constituents may aid in the diagnosis and appropriate management of such cases.