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Clinicians find success with off-label therapy for persistent epithelial defect

A 2-week course of DHEA drops and retinoic acid ointment promoted healing in this case report

Issue: July 2012

ByLee Azpiroz, OD

ByJohn G. Dodd, DO

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An 89-year-old female had an ocular history of enucleation of the left eye, cataract extraction in the right eye, bilateral blepharoplasty with ptosis repair, conjunctival resection for conjunctivochalasis and punctoplasty.

Her medical history is significant for progressive dysphagia, which led to the placement of a permanent feeding tube. While hospitalized, she developed right-sided herpes zoster virus ophthalmicus. She had a complicated course including uveitis, trabeculitis, postherpetic neuralgia and neurotrophic keratopathy.

The patient was initially started on steroid drops, pressure lowering drops, lubricant eye drops, gel drops, gels and ointments. Restasis (topical cyclosporine A 0.05%, Allergan) and Lotemax (loteprednol etabonate, Bausch + Lomb) were prescribed to optimize the ocular surface. Despite aggressive treatment, her condition worsened with the development of band keratopathy (BK).

The patient was fit with a 15-mm Jupiter mini-scleral gas-permeable lens in an effort to create a fluid reservoir to protect the epithelium and limbal stem cells from mechanical insult.

After several weeks, all topical treatments were discontinued. At this time, slit lamp exam revealed stromal thinning.

Images: Azpiroz L

A superficial keratectomy was performed for the BK, and her early postoperative period was uncomplicated with full re-epithelialization. Two weeks postop, central irregularity was noted in spite of good compliance with therapy. Three weeks postop, acuity had decreased to 20/40, and a central defect was noted.

We added 1,000 mg of vitamin C to promote corneal healing. Despite aggressive treatment, the chronic defect continued to persist. Doxycycline 100 mg was added twice per day to decrease metalloproteinase activity. Over the next 3 months, the patient’s acuity fluctuated between 20/30 and 20/60, and recurrent bouts of epithelial defects and uveitis were noted. The entire time, the patient wore a bandage contact lens with replacement every 2 weeks.

Six-and-a-half months postoperatively, the patient spontaneously developed a 2-mm by 4-mm persistent paracentral epithelial defect that did not improve over the next 2 months. The cornea was culture-negative. The patient was fit with a 15-mm Jupiter mini-scleral gas-permeable lens in an effort to create a fluid reservoir to protect the epithelium and limbal stem cells from mechanical insult. The lens would also compensate for the distorted optics of the irregular cornea.

Topical therapy was limited to 1% dehydroepiandrosterone (DHEA) drops three times daily, 0.1% vitamin A ointment at bedtime and preservative-free Refresh Optive (Allergan) drops. (The DHEA and retinoic acid were compounded at a local pharmacy.)Acuity immediately improved from 20/60 to 20/30 with the switch from a soft bandage to the mini-scleral lens. The epithelium remained intact with trace edema, and the patient’s vision improved to 20/25.

After several weeks, all topical treatments were discontinued. At this time, slit lamp exam revealed stromal thinning. Over the next 3 months, the patient remained stable with pulsed dose topical steroids to control inflammation. She currently wears the Jupiter lens continuously and uses only preservative-free Optive.

Aqueous deficiency, evaporative dry eye

Dry eye syndrome (DES), also known as dysfunctional tear syndrome (DTS), is a chronic multifactorial disease with a number of risk factors. It can be categorized as primary autoimmune aqueous deficiency, from causes such as Sjögren’s syndrome. Other categories include non-autoimmune dry eye with or without meibomian gland dysfunction. Medications such as birth control pills, diuretics and smooth muscle relaxants are some of the causes of non-autoimmune dry eye without meibomian gland dysfunction.

Non-autoimmune dry eye with meibomian gland dysfunction is also known as evaporative dry eye. Depleted androgen serum levels may be responsible for inflammatory changes in the meibomian glands, leading to altered sebum secretions and rapid tear break-up. A diet high in omega-6 and low in omega-3 oils has been implicated in these inflammatory changes. Involutional changes from aging and trauma can alter the normal lid architecture and lead to tear instability and exposure. Surgical correction is the most effective treatment in these cases.

Perhaps most important is the fact that chronic dry eye syndrome leads to progression of the disease. Loss of goblet cells over time leads to more inflammation and further damage. These patients are in a vicious cycle of dryness leading to damage, which leads to more dryness, which leads to more damage. Studies have shown that both cyclosporine and retinoic acid reverse squamous metaplasia and increase goblet cell density (Tseng, Tseng et al., Ubels et al.).

In our case, dryness led to loss of limbal stem cells, calcification of tissue and eventual non-healing epithelial defect. Left untreated, it could have led to complete band keratopathy and severe loss of vision.

Both the DEWS report and the MGD Workshop Report outline appropriate treatments for mild, moderate and severe DES/DTS. The recommendations focus on commercially available therapies approved by the U.S. Food and Drug Administration, which are the mainstay of therapy.

Off-label dry eye treatments

Studies certainly support the use of off-label and experimental therapies in the treatment of all forms of DES/DTS. Tetracyclines and macrolides concentrate in the sebaceous glands and exert an anti-inflammatory effect, improving the quantity and quality of sebum, which in turn prolongs tear break-up times. DHEA has anabolic properties that upregulate cell division and repair. Autologous serum eye drops are rich in growth factors that accelerate cell division and repair. Albumin is a naturally occurring protein in serum that speeds up healing. Drops can be compounded from albumin powder, eliminating the need to handle blood products. Retinoic acid is critical in cell membrane repair and speeds epithelial growth. Vitamin C has been shown to aid in collagen repair and stability.

In our case, a 2-week course of DHEA drops and retinoic acid ointment helped heal a persistent epithelial defect. A mini-scleral lens created a fluid reservoir, which stabilized the corneal surface and prevented recurrence of the epithelial defect. It also significantly improved vision by neutralizing irregular astigmatism induced by the corneal thinning.

There is certainly a place for both FDA-approved and off-label therapies in the management of chronic dry eye syndrome. Most compounding pharmacies have access to formulas for compounding these products. Serum for autologous serum eye drops can be drawn and spun by most laboratories and diluted and packaged in a sterile fashion by most compounding pharmacies.