Uses and Effects of Ocular Steroids
A comprehensive look at the applications and side effects of different ocular steroids.
By Leonid Skorin, Jr., O.D., D.O., F.A.A.O., F.A.O.C.O., Albert Lea, Minn.

The mainstay of ocular anti-inflammatory therapy is the category of corticosteroids. We mainly use steroids because of their ability to suppress inflammatory, allergic and immune reactions.

Inflammatory manifestations

The anti-inflammatory effects of corticosteroids are nonspecific, but if we use them promptly, we can help avert protracted and devastating tissue damage. Acute and chronic inflammation can manifest locally in five ways, known as the cardinal signs of inflammation. They are:

1. Rubor or redness resulting from arteriolar vasodilation and the increased blood flow in the microcirculation at the site of injury.

2. Calor or heat from the increased localized blood flow.

3. Tumor or swelling is localized edema from increased permeability and the accumulation of inflammatory exudates with its increase of interstitial fluid.

4. Dolor is pain in the involved site and has been attributed to pressure on sensory nerve endings resulting from exudation. Beyond this simplistic view, chemical mediators also appear to be involved.

5. The inflamed tissue loses its function. This is known as functio laesa. A combination of pain and tissue destruction come to play in function loss. The hyperemia of inflammation raises the temperature in the microenvironment of the cells, impairing enzyme function, or the increased metabolic activity of an inflammatory focus might lower the pH and interfere with function in that way.

Mechanistic examples of loss of ocular function from inflammation include loss of pupillary function from synechiae formation, loss of optic nerve function from prolonged elevated intraocular pressure (IOP) from inflammatory debris blocking the trabecular outflow or the optic neuropathy that results from the enlargement of the extraocular muscles and other inflammatory orbital debris in Grave's disease.

Regardless of the initiating factors, the gross characteristics of manifestation remain uniformly the same. The pathophysiology of most of these cardinal signs is easily verifiable and generally accepted.

Steroid mechanisms

As potent anti-inflammatory agents, steroids prevent the inflammatory response by complex mechanisms. These mech anisms involve the alteration of cell-mediated immune function by increasing the quantity of blood neutrophils while decreasing the numbers of circulating lymphocytes, eosinophils and monocytes. Because of the inhibition of chemotaxis and adherence to blood vessel walls, neutrophils are prevented from accumulating at an inflammatory focus.

Other beneficial anti-inflammatory effects include decreased vascular permeability, interference with histamine, prostaglandin synthesis blockade and the reduction of antibody formation by lymphocytes. Steroids also suppress the late inflammatory responses of capillary proliferation (neovascularization), fibroblast proliferation, collagen deposition and scarring.

Acute conditions

In general, steroids are most effective at treating acute inflammatory conditions than chronic conditions. Therefore it's just as important to know when not to use these medications, as it is to know when they're beneficial. When the disease has reached a chronic stage (as in degenerative diseases), complications of steroid therapy are often worse than the disease process itself.

Signs of chronic disease where steroids are of little value include: chronic flare with no cells in the anterior chamber, old inflammatory cells or blood in the vitreous, chronic pars planitis without cystoid macular edema and small, peripheral toxoplasmosis lesions that aren't threatening the macula or optic disc.

Steroids are effective against a large number of primary ocular and systemic conditions that have ophthalmic consequences (see table at left). They're also effective as a secondary therapeutic approach when used in a post-op setting. Use steroids to prevent or suppress corneal graft rejection, anterior chamber reaction after anterior segment surgery, such as cataract extraction and filtering bleb scarring. They're also beneficial in cases of traumatic iritis and uveitis.

Taking the therapeutic approach

The therapeutic approach to treating ocular diseases with steroids depends on the location and the extent of the disease. You may prescribe therapy topically, systemically, anteriorly, posteriorly as repository periocular injection and intravitreally.

Topical therapy. Topical application of any drug brings the advantages of the therapeutic agent being administered directly to the tissue in need of treatment. This also minimizes systemic exposure to the topically applied agent. Additionally, ophthalmic steroids vary in their ability to penetrate the cornea, which consists of both hydrophobic and hydrophilic layers, so the ideal steroid should be biphasic in its polarity.

Epithelial integrity. If the corneal epithelium is compromised, prednisolone sodium phosphate solution, being relatively water soluble, penetrates the stroma effectively resulting in its increased bioavailability within the anterior chamber. If the epithelium is intact, lipophilicity is more important and results in better corneal penetration with a prednisolone acetate suspension product.

Comparing formulations. Suspensions are also superior to solutions because of the persistence of particles in the conjunctival cul-de-sac, which enhance contact time with the cornea and promote higher concentrations in corneal tissues. Finally, ointments have less bioavailability than suspensions or solutions.

This occurs because of the affinity of the petrolatum base used with the active ingredient, which hinder the drug's release (see table right).

Topical steroid therapy is usually sufficient for most anterior segment diseases that involve inflammation. In severe forms of anterior uveitis it may be desirable to supplement the local application with subconjunctival and systemic administration. No matter what treatment modality you employ, start them as soon as possible and dose it high enough to suppress the inflammatory response.

Treating inflammatory conditions. For inflammatory diseases that mainly affect the external ocular and periocular structures, use topical steroids that don't produce increases in IOP by virtue of their poor penetration into the eye such as medrysone (HMS) or site specific (soft) steroids such as loteprednol etabonate (Lotemax 0.5%, Alrex 0.2%) or rimexolone (Vexol 1%), which convert to an inactive metabolite (see table below).

In patients who are susceptible, this rise in IOP is rarely seen in less than 2 weeks of therapy. Because some patients will have late responses, after 6 weeks of treatment or even longer, IOP monitoring is required at periodic intervals during the entire course of chronic steroid therapy. Steroid-induced IOP rises are nearly always reversible by stopping the drug.

If you need to continue a steroid for optimal result, then either continue with the same treatment and closely monitor the status of the optic nerve, change to one of the site-specific steroid agents or reduce the potency, concentration or frequency of the steroid you're using. Adding a glaucoma drug to lower the IOP may also be advised.

Periocular steroids. Administer periocular steroids by subconjunctival, sub-Tenon's capsule or retrobulbar injection (see table on pg. 00). You can administer them independently or use them as supplemental treatment to topical or systemic therapy. You can achieve high local tissue levels of cortico-steroids with such injection.

Repository preparations such as methyl-prednisolone acetate (Depo-Medrol) and triamcin-olone acetonide (Kenalog) provide effective concentrations of the drug in the anterior segment of the eye from 1 to 5 weeks. You can use both of these drugs in the treatment of chalazia.

In cases where a long-term effect isn't indicated, you can use injectable corticosteroid solutions such as beta-methasone sodium phosphate (Celestone). Retrobulbar or posterior sub-Tenon's injection of steroids is quite appropriate to deliver the drug to the posterior pole in high concentration. There is, however, a distinct danger in perforating the globe and placing the steroid intraocularly.

Systemic therapy. Oral or intravenous systemic administration of steroids is most effective for severe inflammations of the posterior segment, orbit and optic nerve. Diseases which benefit from this approach include optic neuritis, temporal arteritis, orbital pseudotumor and Grave's ophthalmopathy.

Most corticosteroids are well absorbed when given orally. Prednisone is commonly prescribed in the oral tablet or syrup forms because of its flexibility in dosing and its low cost. Another formulation consisting of methylprednisolone (Medrol DosePak) is commercially available in a package of programmed delivery of oral steroid tapered over 6 days of therapy. This is a convenient method to increase patient compliance when used for short-term treatment.

Intravitreal therapy. Use intravenous "pulse" therapy with methylprednislone in the treatment of acute optic neuritis as per the guidelines of the Optic Neuritis Treatment Trial and for arteritic ischemic optic neuropathy (temporal arteritis).

When long-term therapy is necessary with systemic steroids, it's important to maintain the patient on as small a dose as possible. Frequently the dose of systemically administered cortico steroids in continued therapy can be reduced if local steroids are used in conjunction with the systemic drug, as in the treatment of sympathetic ophthalmia.

When prolonged therapy is required, it's imperative that you observe the patient regularly for the onset of any side effects.

Steroid side effects

The most serious side effect of prolonged steroid use on the endocrine system is the suppression of pituitary adrenocorticotropic hormone (ACTH) secretion, which results in adrenal cortical atrophy. The degree of adrenal atrophy is dose dependent but may be severe if moderate or high doses of a steroid are given for more than 2 to 4 weeks.

Any patient who has received more than 10mg of prednisone or the equivalent for more than several weeks may have this suppression following cessation of the therapy. Therefore it's critical to withdraw the steroid slowly. The rate of reduction is then determined by the length of steroid therapy, clinical response and course of the disease being treated and any flare-up of inflammation.

If exacerbation of the disease process follows a given dose reduction, immediately raise the dose of the steroid to the prereduction level. As long as evidence of active disease persists, continue therapy at a level that permits control of signs or symptoms.

Various other ocular or systemic side effects can occur with steroid use. Ocular compli-cations are more familiar to most O.D.s and include posterior subcapsular cataracts, ocular hypertension or glaucoma, secondary ocular infection, keratitis, corneal and scleral thinning and corneal melting.

Just as serious are the systemic side effects. These include changes in the patient's physical appearance such as redistribution of fat ("moon face" and "buffalo hump"), acne, purplish striae, hirsutism, easy bruisability and other cushingoid features.

Mental reactions range from mild nervousness, euphoria and insomnia to severe depression or psychosis. Sodium retention and hypokalemia are electrolyte abnormalities induced by steroids.

Hyperglycemia may occur or diabetes in a patient may become more difficult to manage. Resistance to systemic infections also decreases. Osteoporosis, myopathy and aseptic necrosis of the hip joint may result from long-term systemic steroid use.

Other undesirable effects include menstrual irregularities, night sweats, hypercholester-olemia, acute pancreatitis and pseudotumor cerebri. To prevent the possible development of peptic ulcers during oral steroid use, patients may take antacids or histamine H2-receptor antagonists such as cimetidine (Tagamet) or ranitidine (Zantac) concurrently. This is particularly important if the patient has a previous history of ulcers.

Know what to look for

Because ocular steroids can have so many different effects, it's important to know how to use them properly and what possible side effects to keep a look out for. Understanding these basic factors will help you considerably when faced with your next patient who presents with inflammatory, allergic or immune reactions.

Dr. Skorin is adjunct professor of neuro-ophthalmology at Midwestern University in Chicago. He is a staff ophthalmologist at the Albert Lea Eye Clinic Mayo Health System.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.