Hurricane keratopathy is a condition in which a whorl-like pattern appears on the corneal epithelium. It was first reported after penetrating keratoplasty (PKP). It is characterized by whorl-like epithelial changes highlighted by fluorescein staining, reflecting increased turnover of the corneal epithelium.
The term “vortex keratopathy” is also an alias for cornea verticillata. To avoid confusion, some distinguish between fluorescein-positive cases as hurricane keratopathy and fluorescein-negative cases as cornea verticillata. When the pattern is more irregular (random) but has the same etiology, it is called blizzard keratopathy.
Drug-induced corneal epithelial disorders can also produce similar whorl-like patterns, and it is important to notice them at the stage of vortex keratopathy and discontinue the causative drug. If left untreated, it can progress through epithelial crack lines to persistent epithelial defects.
In typical cases, symptoms are mild. Patients complain of mild foreign body sensation and eye irritation. Increased tearing may be observed. Photophobia and mild blurred vision may also occur.
On the other hand, in severe drug-related cases, symptoms can be pronounced. In a reported case related to apremilast (PDE4 inhibitor), after 5 months of oral administration, severe pain, photophobia, and redness appeared in both eyes, and corrected visual acuity decreased to 20/70 in the right eye and 20/60 in the left eye 1).
The most characteristic feature is a whorl-like pattern on the cornea. It appears as white or gray-brown lines, and in most cases shows a clockwise direction. It is clearly delineated by fluorescein staining as a cluster of punctate epithelial erosions.
It is confined to the epithelial layer and is not accompanied by stromal infiltration or infiltrates 1). Anterior chamber inflammation (cell/flare) is also usually absent 1).
The cornea has a positive potential relative to the posterior pole of the eye, and the eyeball functions as a dipole. The electromagnetic field generated by this current is distributed concentrically and clockwise on the cornea, and is thought to influence the direction of epithelial cell migration.
Penetrating Keratoplasty (PKP)
First reported cause: Occurs in association with penetrating keratoplasty.
Role of postoperative steroids: Steroid eye drops used after surgery affect epithelial healing.
Prevalence: Observed in 15–30% of cases after penetrating keratoplasty.
Hard Contact Lenses
Mechanical irritation: Contact of the lens apex causes microabrasions.
Increased epithelial turnover: Appears as a repair response to mechanical irritation.
Longer duration: After contact lens use, the average duration is 42.8 weeks, tending to be longer than after penetrating keratoplasty (29.9 weeks).
Chronic Steroid Eye Drops
Can occur alone: Develops with long-term steroid use even without a history of surgery.
Improves with discontinuation: The pattern disappears when steroid eye drops are stopped.
A type of drug toxicity: Involves inhibition of epithelial basal cell division.
Other reported causes include after cataract surgery (steroid use + postoperative dryness). Drug-related cases include hurricane keratopathy caused by apremilast (PDE4 inhibitor for psoriasis) 1). The oral anticancer drug TS-1 (tegafur combination) can cause hurricane keratopathy over the entire cornea, and is characterized by frequent involvement of limbal stem cell damage.
Risk factors after full-thickness corneal transplantation include preoperative eyelid disease, decreased corneal sensation, prolonged donor tissue preservation time, and use of hyaluronic acid preparation (Healon).
In many cases, improvement or resolution occurs within 3 weeks to 6 months after discontinuing steroid eye drops. The whorl pattern begins to disappear from the periphery and recedes toward the center.
Diagnosis is based on slit-lamp microscopy with fluorescein staining. If a whorl-like punctate staining pattern is seen on the corneal epithelium, hurricane keratopathy is suspected.
The time of onset after full-thickness corneal transplantation ranges from 1 week to 18 months postoperatively, with the most common period being 6 to 12 months. Prevalence varies from 15% to 30% depending on the report.
| Differential Diagnosis | Features |
|---|---|
| Cornea verticillata | Fluorescein staining negative. Caused by drug deposits or Fabry disease. |
| Mild limbal stem cell deficiency (LSCD) | May present with whorl-like epithelial thinning 2). Accompanied by vascular invasion or conjunctival epithelial ingrowth. |
| Superficial punctate keratitis (SPK) | Lacks a whorl pattern. Diffuse punctate staining. |
In mild cases of LSCD, fluorescein staining may show a vortex pattern or whorl-like epitheliopathy 2), and differentiation is made by the presence or absence of superficial neovascularization or corneal pannus.
The principle of treatment for hurricane keratopathy is removal of the cause. If the stimulus causing increased epithelial turnover is removed, it will resolve spontaneously. The whorl pattern begins to disappear from the periphery and recedes toward the center.
Steroid-related cases: discontinue steroid eye drops. Improvement is seen within 3 weeks to 6 months after discontinuation. Contact lens-related cases: discontinue lens wear.
Drug-related cases require discontinuation of the causative drug. In an apremilast-related case, in addition to drug discontinuation, prednisolone eye drops once daily and preservative-free artificial tears were used, resulting in complete recovery in 10 weeks 1). Recurrence occurred with low-dose rechallenge (positive rechallenge), strongly suggesting a causal relationship 1).
Preservative-free artificial tears are useful for relieving foreign body sensation and ocular irritation, and also contribute to promoting epithelial healing.
In typical cases after full-thickness corneal transplantation or contact lens-related hurricane keratopathy, the impact on vision is mild and resolves with removal of the cause. However, in severe drug-related cases, corrected visual acuity has been reported to decrease to around 20/70, so early intervention is important.
Stem cells located in the corneal limbus are responsible for epithelial regeneration and maintenance. In normal epithelial turnover, epithelial cells migrate centripetally from the limbus toward the center of the cornea.
Initially, it was thought that corneal sutures after full-thickness transplantation impeded cell migration, forming a whorl pattern. However, Dua observed the same pattern in corneas without surgical history and proposed that during periods of accelerated epithelial regeneration, intercellular adhesion decreases, increasing fluorescein permeability.
The direction of the whorl pattern has an electromagnetic field hypothesis. The eye functions as a dipole, with the cornea having a positive potential relative to the posterior pole. The electromagnetic field generated by this current forms a concentric clockwise pattern on the cornea. Cultured corneal epithelial cells have been shown to change their migration direction in response to magnetic fields, suggesting that electromagnetic fields may promote the formation of whorl patterns.
In drug-related hurricane keratopathy, inhibition of epithelial basal cell division is involved. The condition where the proliferation of basal cells cannot keep up with the shedding rate of superficial cells is interpreted as the essence of vortex keratopathy. For apremilast, it has been pointed out that the increase in cAMP due to PDE4 inhibition may affect epithelial cell adhesion and migration1). In mouse models, it has been suggested that the genotoxicity of apremilast (chromosomal abnormalities, micronucleus formation) may act on limbal progenitor cells1).
Vortex keratopathy is caused by drug (e.g., amiodarone) or Fabry disease-related deposits in the corneal epithelium, and fluorescein staining is negative. Hurricane keratopathy is a cluster of punctate epithelial erosions that are positive on fluorescein staining, and the essence is increased epithelial turnover.
In 2023, Wolfel et al. reported the first case of hurricane keratopathy caused by apremilast (PDE4 inhibitor)1).
A 49-year-old woman developed bilateral severe punctate corneal epithelial erosions 5 months after starting oral apremilast for psoriasis. Complete recovery occurred 10 weeks after drug discontinuation and prednisolone eye drops, and recurrence was confirmed upon re-administration at a lower dose (positive rechallenge).1)
This report raises awareness for the entire class of PDE4 inhibitors1). Although the mechanism of action of this drug on the corneal epithelium is unknown, there is also a report that a nanoemulsion gel of apremilast promoted wound healing in a rat model1), suggesting involvement in corneal epithelial proliferation and remodeling.
In the future, accumulation of reports of hurricane keratopathy due to new drugs and elucidation of the pharmacological effects on epithelial cell migration and adhesion are required.
