Control of inflammation may be crucial to refractive cataract surgery success

Novel drug formulations aim at bypassing the side effects associated with corticosteroids.

John D. Sheppard

Ocular surface preparation before surgery and accurate measurement and control of inflammation after surgery are necessary for successful outcomes of cataract procedures, according to a specialist.

“Meetings in the last 2 years have been very much centered on premium IOL technology, and more recently, the greatest buzz has been generated by femtosecond laser cataract surgery. Cataract surgery is evolving in exciting directions and patients can expect refractive results that are potentially near to perfection in many cases,” John D. Sheppard, MD, said in an interview at the annual joint meeting of Ocular Surgery News and the Italian Society of Ophthalmology.

“More than ever, an absolutely compulsive management of the ocular surface is mandatory, because it truly improves the accuracy and predictability of our measurements. Even 0.5 D of myopia, hyperopia or cylinder can render patient and doctor quite dissatisfied,” Dr. Sheppard said.

Prevention, management

Corticosteroids are the gold standard for preventing and managing inflammation after cataract surgery and most other ocular procedures, including transplantations, LASIK, glaucoma drainage operations and vitreoretinal work.

Dr. Sheppard said he uses Lotemax (loteprednol etabonate ophthalmic ointment 0.5%, Bausch + Lomb) preoperatively because it is effective against all three major types of ocular surface disease that impact cataract surgery results: allergy, blepharitis and dry eye. Each of these conditions requires a specific therapeutic approach, but loteprednol adequately addresses the inflammation component, he said.

Loteprednol etabonate can be continued throughout the perioperative convalescence with minimal concern for IOP spikes, particularly in patients with ocular hypertension and glaucoma, according to Dr. Sheppard.

“It is also an outstanding agent for perioperative management of trabeculectomy, Trabectome (NeoMedix) and pterygium patients, and essential for long-term pharmacologic prevention of allograft rejection,” Dr. Sheppard said. “In fact, all of my transplant patients — [Descemet’s stripping endothelial keratoplasty], [deep anterior lamellar keratoplasty] and traditional PK — receive lifetime Lotemax to avoid the tragedy of rejection.”

In patients with blepharitis, after the induction phase of treatment with loteprednol, Dr. Sheppard relies on warm compress, Azasite (azithromycin ophthalmic solution 1%, Merck) or a lower dose of loteprednol for maintenance. For dry eye patients with other concomitant ocular surface disease, he induces with loteprednol and then maintains with preservative-free Restasis (cyclosporine ophthalmic emulsion 0.05%, Allergan).

“I found that in many cases, long-term maintenance therapy with Restasis was ideal while recommending supplemental pulse therapy with loteprednol in lower doses for acute exacerbations of concomitant ocular surface disease,” Dr. Sheppard said. “In the treatment of allergies, the mechanism of the steroid molecule is such that it controls all aspects of the inflammatory cascade, producing a very rapid diminution of the allergic symptoms. For difficult dry eye cases, loteprednol is the ideal induction agent and Restasis the ideal long-term maintenance agent.”

Patients with severe allergies that are not environmentally or pharmacologically controlled by medications have a higher incidence of cystoid macular edema after cataract surgery, according to Dr. Sheppard. Studies show that they also have a threefold risk of LASIK flap inflammation, Sands of the Sahara syndrome or diffuse lamellar keratitis, if LASIK is performed without pre-treatment.

After the induction phase with corticosteroids for allergic ocular surface disease, antihistamines may be adequate for long-term maintenance prior to surgery, Dr. Sheppard said.

Equally mandatory is the postoperative management of the ocular surface to minimize inflammation.

“When we perform cataract surgery, we insult the eye with the speculum, severe convection drying, bright lights, aggressive topical therapy, repeated preservative exposure and incisions that cut the corneal nerve plexus. A certain amount of inflammation is expected, no matter how good we are as surgeons, no matter how small our incision might be, and an appropriate therapeutic intervention with corticosteroids is often crucial,” Dr. Sheppard said. “All of these preoperative, perioperative and postoperative considerations are even more critical when recommending premium or lifestyle IOLs, since patient expectations have become astronomically demanding.”

High safety profile

With its high safety profile, loteprednol etabonate can be administered for long periods of time without causing IOP spikes and lens opacification, Dr. Sheppard said. The medication is synthesized through modification of the prednisolone molecule.

“In the loteprednol molecule, the position 20 ketone group is replaced by an ester group,” he said. “This allows useless unbound active ingredient to be hydrolyzed and inactivated by tissue esterases immediately after bound drug has carried out its anti-inflammatory effect by saturating available glucocorticoid receptors. This reduces the incidence of the side effects that are typically associated with the presence of residual, unbound active ketone-based drug, such as IOP elevation and cataract.”

According to Dr. Sheppard, Durezol (difluprednate ophthalmic emulsion 0.05%, Alcon) has proven to be a versatile perioperative steroid for patients with a high risk for corneal complications, including Fuchs’ dystrophy, previous transplants, previous ocular surgery, ocular trauma, uveitis, or challenging cases with dense cataracts, pseudoexfoliation or intraoperative floppy iris syndrome.

“Although not recommended for [ocular surface disease], Durezol provides superior anti-inflammatory control when compared to prednisolone acetate, particularly the generic version so frequently substituted by pharmacists,” he said.

Difluprednate does not require shaking because it is an emulsion rather than a suspension and does not contain benzalkonium chloride preservative. Its potency, a result of several biochemical modifications of the basic prednisolone molecule, including fluoride moieties at both the 3 and 6 positions, enables lower-frequency dosing.

“It is recommended for postoperative use up to 3 weeks after ocular surgery. Beyond that time frame, astute surgeons should carefully evaluate IOP on a case by case basis if necessary,” Dr. Sheppard said.

Further biochemical attempts to alter steroid biochemistry and bypass the steroid side effects are under way. A selective glucocorticoid receptor agonist (SEGRA) licensed by Bausch + Lomb is undergoing evaluation as a novel anti-inflammatory medication with an improved safety profile.

“Current steroid drugs bind to glucocorticoid receptors on the surface, and the receptor complex enters the inside of the cell and activates messenger RNA production in the nucleus. The SEGRA completely bypasses this process, enters the nucleus directly and produces the same anti-inflammatory effect, hopefully without any miscellaneous binding to lens tissue or to trabecular meshwork, without inhibition of wound healing, without reactivation of herpes virus or a decrease in the immune response, and without potentiation of pseudomonas, acanthamoeba or fungal infections,” Dr. Sheppard said.

“SEGRA is an idealized magic bullet. We have great hope, and clinical trials for cataract and dry eye are under way at this time. We are very excited by that prospect,” he said. – by Michela Cimberle

• John D. Sheppard, MD, can be reached at Virginia Eye Consultants, 241 Corporate Blvd., Norfolk, VA 23502; 757-622-2200; fax: 757-622-4866; email: docshep@hotmail.com.
• Disclosure: Dr. Sheppard is an advisor and does research work for Alcon, Allergan and Bausch + Lomb.