Many ocular and systemic conditions recognized by optometrists can be treated by the judicious use of corticosteroids, commonly known as steroids. This course serves to educate the reader about the mechanisms of steroid action, potential ocular and systemic effects, and side effects. It also provides information on indications and contraindications for use of steroids in optometric practice.
Mechanism of Action of Steroids
In the mid 1800s, Addison and Brown-Sequard studied the role of adrenal glands in regulating body function, and in the early 1900s several hormones termed glucocorticoids and mineralocorticoids were isolated from the cortex of the adrenal gland.
The mid-1900s brought the discovery of the link between the adrenal glands, the pituitary gland (responsible for secreting adrenocorticotropic hormone, or ACTH, which stimulates adrenal cortex steroid production), and the hypothalamus (responsible for secreting corticotropin-releasing factor, or CRF, which stimulates pituitary ACTH production). The hypothalamus, in turn, secretes more CRF in response to neural excitatory stimuli and reduced plasma corticosteroid concentration. This cascades to increasing pituitary ACTH production that ultimately increases adrenal cortex steroid production. This interdependent feedback mechanism is termed the H-P-A axis (Figure 1).
Figure 1. H-P-A (Hypothalamus-Pituitary-Adrenal Cortex) Axis
What is the benefit of this H-P-A axis? Simply put, it controls adaptation by the body to changing internal and external stimuli regulating corticosteroid secretion. The corticosteroids affect the body in many complex ways, some of which are shown in Table 1.
Table 1. Some corticosteroid effects on the body
In a normal individual, the adrenal glands normally secrete about 25mg of cortisol (hydrocortisone) and 5 mg corticosterone per day. Only about 5% of these steroids are biologically active, the remainder being bound to plasma protein. It is remarkable that such a small amount of active steroid can so dramatically modulate numerous metabolic activities. Because the natural steroids are so potent and affect so many systems, the use of synthetic steroids in clinical practice should be done conservatively.
The main use of steroids in practice is to reduce inflammatory action. Figure 2 displays the cellular synthesis of prostaglandins and leukotrienes from arachidonic acid. This synthesis is termed the inflammatory pathway, and is the main cascade to the inflammatory response:
Figure 2. The inflammatory pathway and its inhibition by steroids and non-steroidal anti-inflammatory drugs.
The synthesis products of prostaglandins (particularly PGE(1), PGE(Z), and PGF(Z-ALPHA)) and leukotrienes have been implicated in inflammatory responses such as vascular dilation and polymorphonuclear leukocyte migration, but their exact mechanisms of action are still not well understood. Steroids reduce prostaglandin and leukotriene production by inhibiting the enzyme phospholipase A(Z), which converts phospholipids into arachodonic acid.
As a side note, non-steroidal anti-inflammatory drugs (NSAIDs), such as salicylates (e.g., aspirin), indole derivatives (e.g.,indomethacin), pyrazolon derivatives (e.g., phenylbutazone), propionic acids (e.g., flurbiprofen), and the fenamates (e.g.,mefenamic acid) inhibit the enzyme cyclo-oxygenase from producing prostaglandins further along in the inflammatory pathway. Because steroids block the inflammatory pathway at a higher level, it makes sense that they are generally superior to NSAIDs in reducing inflammation.
Steroids Commonly Used in Clinical Practice
Several steroids have been made synthetically for clinical use. Table 2 shows the relative anti-inflammatory potencies of various corticosteroids, with hydrocortisone used as the standard with a value of 1.0.
Table 2. Anti-inflammatory potencies of various corticosteroids relative to hydrocortisone
The effect of reducing inflammation depends heavily on the type and dosage of steroid used. The most common steroid used by practitioners for oral use is prednisone.
Figure 3. Prednisone Tablets
Besides the oral route of administration, steroids can also be inhaled (such as in certain inhalers for asthma treatment), injected either locally or intravenously, and applied by the topical administration. Table 3 shows some commercially available injectable steroids and their typical route of administration. Table 4 lists the current commercially available topical steroids.
Table 3. Some commercially available injectable steroids and their typical administration routes
Table 4. Topical ocular steroids, listed from most potent (top) to least potent (bottom)
Note that most topical steroids (except for sodium phosphate forms of Prednisolone) are in suspension form. This requires that the patient shake the bottle to evenly distribute the steroid before instilling on the eye. Also of note, acetate forms of steroids generally have the greatest anti-inflammatory property, followed by alcohol, then phosphate forms. Hydrocortisone 1% ointment formulation, available over-the-counter but not available in ophthalmic formulation currently, is sometimes used for certain periocular skin conditions such as contact dermatitis. Likewise, triamcinolone (Kenalog) dermatological cream (available in 0.025%, 0.1% and 0.5% concentrations) and other combination steroid/antibiotic ointments such as Vasocidin, Blephamide, Cetapred, and Pred-G, could be considered as alternative treatments. However, the practitioner should always be aware if they are prescribing a drug in an off-label use.
Ocular Indications for Steroid Use
Ocular indications for steroids are numerous and include (but are not limited) to the following.
Eyelids blepharitis, chalazia, dermatitis, burns
Conjunctiva conjunctivitis (various types), mucocutaneous lesions, burns
Cornea edema, graft rejection, rosacea keratitis, interstitial keratitis, herpes simplex (stromal) keratitis, herpes zoster keratitis, post-herpes zoster neuralgia, infiltrates, marginal ulcers, burns
Uvea iridocyclitis, uveitis, traumatic hyphema, sympathetic ophthalmia
Sclera episcleritis, scleritis
Retina vasculitis, chorio-retinitis
Optic Nerve neuritis, temporal arteritis
Orbit endophthalmitis, pseudotumor cerebri, Grave's ophthalmopathy
Although optometrists frequently prescribe topical steroids for various ocular conditions as listed above, injected or orally administered steroids are used less often. Ocular indications for oral or injectable steroids include the following.
Uveitis not responding to topical therapy
Posterior uveitis and/or chorioretinitis
Orbital pseudotumor
Acute ocular allergic response not responding to topical therapy
Scleritis note subconjunctival injections are contraindicated
Temporal Arteritis/Arteritic Anterior Ischemic Optic Neuropathy
Optic Neuritis
Severe burns
Underlying autoimmune disease (collagen-vascular disorders)
Prednisone is available generically and is typically the least expensive of the steroids. Tablets available in several dosages, with the 10 mg tablets being commonly used. Methylprednisone is available in "Dosepak" packaging, consisting of six 4 mg tablets (totaling 24 mg) taken at once the first day, with the dosage reduced by one tablet per day over the course of a week:
Figure 4. Methylprednisone Dosepak blister package
Methylprednisone therapy is typically not as effective as Prednisone therapy, which is normally prescribed at between 40-80mg per day for a few days and then tapered gradually and evenly over one to three weeks.
Take Steroids with Food
It is recommended that oral steroids be taken during meals to reduce the potential of causing gastric ulcers. Amounts up to 60 mg can be taken at once, but higher dosages should be divided equally between breakfast and dinner. The maximum therapeutic effect can be achieved with the daily amount split equally into four dosages, with one dose taken every six hours.
Tapering Steroid Dosages
An important rule is that the higher the potency or starting dosage of a steroid, or the longer it is used, the longer the time period required for tapering. Since deaths have occurred from too sudden a withdrawal from oral steroids, this rule should not be taken lightly. Suppression of the H-P-A axis with steroid treatment is a serious concern, resulting in reduced adrenal production of the body's natural steroids. One study even demonstrated a reduction of natural plasma cortisol levels by as much as 50% with topical dexamethasone use. Sudden cessation of steroids heavily taxes the now atrophic adrenal cortex, potentially causing it to cease function. This can lead to hypotension and shock.
With long-term (several weeks or more) use of oral steroids, it is recommended that dosage should not be reduced by more than 0.5 to 1 mg every two to three weeks. Patients requiring long-term steroid use should ideally be managed by their primary physician in coordination with any specialists involved in treating their condition. In rare cases, however, such as an acute dermatitis from a known chemical burn, a dose of 40-60mg per day for 48 hours with immediate discontinuation may be safe.
Treatment of Ocular Conditions
Figure 5. Uveitis
Uveitis is probably the most common ocular indication for steroid treatment seen in optometric practices. A general rule of thumb is to "hit hard" (i.e., initially use a topical steroid at least every 2 hours then taper), and use a steroid with good anti-inflammatory potency (such as prednisone or dexamethosone) in combination with cycloplegia of the affected eye. Posterior uveitis, in which the patient may show haze and cells in the vitreous and/or chorioretinal inflammation, usually requires oral steroid treatment in addition to topical treatment. Determining the underlying etiology of uveitis is also essential.
Subconjunctival steroid injections are sometimes used in uveitis cases, but there is greater risk of ocular side effects such as posterior subcapsular cataract formation and ocular hypertension due to the bolus of steroid present. Regardless of route of administration, steroid dosages should be tapered appropriately once resolution begins.
Figure 6. Contact Dermatitis
Contact dermatitis is a type IV (cell-mediated) allergic reaction involving the eyelids and conjunctiva. It is typically caused by cosmetics as well as numerous antibiotics, preservatives, and other medications or chemicals. Removing the offensive substance is first priority, combined with cool compresses and possibly oral tetracycline or doxycycline.
Topical steroid ointments or creams such as 0.5% to 1% hydrocortisone or 0.1% dexamethasone three times a day for a few days may be very useful in reducing edema and inflammation. However, the practitioner should be aware that combination antibiotic/steroid drugs may worsen the condition if the patient is sensitive to the associated antibiotic (i.e., neomycin). Also, fluorinated steroids can cause persistent dermatitis.
Figure 7. Scleritis
Scleritis, typically involving inflammation of the scleral, episcleral, and conjunctival vessels, is another ocular condition in which steroids may be necessary. Their use may be indicated if NSAIDs are ineffective in treating the associated eye pain.
The presentation of scleritis is almost always raises the suspicion for underlying autoimmune disease such as rheumatoid arthritis or other connective tissue disorders, so steroid treatment may benefit both the ocular and systemic conditions concurrently.
Typical dosage is 60 to 100 mg of oral prednisone per day for one week, followed by no more than a 10 mg per day taper for two to three weeks. It should be noted that topical steroids have limited effectiveness with scleritis, and that subconjunctival steroid injections are contraindicated with scleritis due to the higher risk of tissue necrosis.
Figure 8. Chalazion
Chalazia are longstanding sterile granulomatous infiltrations of the meibomian glands resulting from a quiescent hordeola. They can also appear spontaneously. The patient reports a hard, immobile lump that is not painful to the touch. Most chalazia are simply an irritant or cosmetic inconvenience, and one in four resolve without treatment.
Persistent chalasia that do not respond to warm compresses, digital massage, and oral antibiotics may require curettage and excision or an intralesional injection of steroid such as triamcinolone (Kenalog). After local anesthesia, a dose of 0.05 to 0.3 ml of a 5 to 10 mg/ml suspension can be injected into the lesion using a 27-30 gauge needle. Resolution typically occurs in 1-2 weeks, but may require a second injection a few weeks later if the chalazion is large. The steroid serves to suppress the inflammatory cells that reside within the chalazion.
Depigmentation of the skin at the injection site may occur, but may be avoided by conjunctival versus transepithelial injection. The depigmentation usually reverses.
Figure 9. Arteritic Anterior Ischemic Optic Neuropathy
Arteritic Anterior Ischemic Optic Neuropathy (also known as temporal arteritis)is an indication for the immediate prescription of oral prednisone. Classic findings include jaw claudication, tenderness of the temporal scalp area and the head and neck areas, notably reduced vision in one eye, and an elevated Erythrocyte Sedimentation Rate (ESR).
This idiopathic vasculitis typically affects 1:1000 individuals over the age of 50, most often women. Up to 75% of patients who have reduced vision in one eye (the typical initial presentation) will develop reduced vision in the contralateral eye within days to weeks, resulting in bilateral blindness in up to half of untreated patients. Although prognosis for the initially involved eye is poor, prompt steroid treatment (either oral or intravenous) may prevent the incidence of contralateral eye involvement to less than 1% over a five-year duration.
Usually treatment with 80-120 mg/day of prednisone may be initiated, but, if significant visual reduction is present, 250 mg of intravenous hydrocortisone or 250 mg of methylprednisone every 6 hours for three days is preferred over oral treatment. The patient should be referred promptly for hospitalization and adjustment of steroid dosage according to symptoms and ESR levels. Oral prednisone 80-100 mg/day for 2-3 weeks typically follows the intravenous treatment with dosages tapered over several months to years.
Figure 10. Optic Neuritis
Optic neuritis is another condition in which steroids can play an important treatment role. Typically in younger patients (e.g., ages 18-45 years), optic neuritis may be associated with a relatively sudden onset of pain on eye movement, poor to no pupil response in the affected eye or eyes, variable visual field defects, desaturation of color vision, and/or loss of visual acuity. Causes range from idiopathic to infective to systemic conditions such as multiple sclerosis, so the practitioner must first try to determine the cause if possible before initiating treatment.
The Optic Neuritis Treatment Trial (ONTT) demonstrated that using oral steroids alone may actually exacerbate the condition. The preferred treatment is intravenous methylprednisolone for the first few days followed by oral prednisone tapered over a few weeks.
Determining and treating the underlying cause is the most important management approach. One must remember that steroids are considered palliative therapy that is, they suppress the inflammatory response but the underlying cause of the disease remains.
Figure 11. Herpetic Keratitis
Steroid treatment for herpetic keratitis has been a controversial subject. Steroids typically slow epithelial healing and suppress the host immune response, which may set the stage for worsening of the herpetic infection or lead to stomal keratitis.
Therefore, it is not recommended by this author to use steroids with epithelial dendritic keratitis. However, should the inflammation move to the stroma (e.g., disciform keratitis), topical steroids should be used alternating with antiviral medications several times per day to reduce the potential of stromal scarring and visual loss. Steroids also reduce stromal inflammation that impedes proper cornea epithelial migration.
Topical antibiotic/steroid ointment applied two to four times daily to vesicular lesions along the dermatome may be useful in cases of severe zoster-related post-herpetic neuralgia. Topical steroids can be also used to treat the many forms of herpes zoster keratitis.
Figure 12. Herpes Zoster Vesicular Lesions
Potential Ocular and Systemic Steroid Side Effects
Although steroids may be considered by some to be a panacea for many conditions, their ocular and systemic side effects are numerous and should be well understood by the optometrist.
Table 5. Ocular and systemic side effects of steroids
Posterior subcapsular cataracts and ocular hypertension are the classic potential ocular side effects of steroid use and may occur with any route of steroid administration. Long-term therapy (e.g., a year or more) can cause these problems, but children may manifest these sequelae more rapidly. Steroid type also plays a role, with prednisone and dexmethasone having greater propensity to cause increased intraocular pressure versus lotoprednol or florometholone which have less potential. Intraocular pressure measurement and lens condition should be checked regularly for patients using steroids.
For those patients who are "steroid responders," tapering off the steroid usually lowers the pressure back to baseline level. Mechanisms of action for the ocular side effects of steroid use are still not well known.
Reduced epithelial healing and reduced immunity can occur with steroid use, therefore these drugs should be avoided when treating acute bacterial or fungal infections or when there is a significant corneal epithelial defect over non-inflamed stroma. If steroid use is required, it should be done in combination with an anti-infective agent or agents.
The author has found that recent adenoviral infiltrative infections which show no epithelial compromise respond favorably to topical steroid treatment.
Various complications to ocular tissues can occur from injectable steroids, typically related to the injection itself rather than to the steroid. Subconjunctival injections can cause the greatest intraocular pressure rise due to proximity of the steroid to the trabeculum, whereas retrobulbar injections increase risk of physical damage to the optic nerve regardless of the agent being injected.
Figure 13. "Buffalo hump" resulting from prednisone use
Figure 14. Supraclavicular fat pads resulting from prednisone use
The 'Cushingoid' side effect of steroids mirrors Cushing's Syndrome (cortisol hypersecretion by the adrenal glands). In this condition, fat deposition on the back of the neck and face create the classic round "moon face" and "buffalo hump" typical of the condition. Weight gain, hirsutism (male-pattern hair growth), acne, hypertension and mood changes including psychosis and suicidal tendencies are also associated with steroid use.
Other potential systemic problems include gastric ulcers due to the steroid reducing protective prostaglandin secretions in the gut. Concurrent treatment with H2-receptor antagonists such as ranitidine (Zantac) 150 mg BID, famotidine (Pepcid) 20 mg BID, or a proton pump inhibitor such as omeprazole (Prilosec) or lansoprazole (Prevacid) as well as taking steroids with meals may help protect the gut.
Hyperglycemia potentially leading to steroid-induced diabetes may also occur, as well as electrolyte disturbances such as sodium retention and potassium depletion. Potassium supplements (e.g., Slow-K) may be necessary for the patient using steroids.
Retardation of skeletal growth in children has been reported, even with low dosages (e.g., 8 mg per day), and inhibition of osteoblast activity may affect ribs and vertebrae, causing osteoporosis.
Increased susceptibility to infection and poor wound healing are also points to note, and women should be cautioned of potential miscarriages, menstrual problems, and passage of the steroid in the breast milk to nursing babies.
Mood swings into psychosis, euphoria, or depression can occur with steroid treatment, and the patient should be made aware of this.
Contraindications to Using Steroids
As the side effects above indicate, steroids can precipitate or exacerbate a condition in at-risk individuals. Table 6 lists potential ocular and systemic conditions that may be relative or absolute contraindications to steroid use.
Table 6. Potential ocular and systemic contraindications to steroid use
Steroids may reduce the response to anticoagulant therapy, so combining steroid therapy with aspirin or other anticoagulants may be contraindicated. Rifampin, phenylbutazone, and phenytoin may also reduce the effect of systemic steroids
Summary
Optometric physicians should be knowledgeable of the mechanism, routes of administration, potential side effects, indications, and contraindications of steroid use. When patients are treated with steroids, judicious application is recommended, and communication with the patient's primary care provider and/or other specialists is recommended. However, even with these concerns and precautions, the power of steroids in managing a myriad of ocular diseases and underlying systemic conditions holds testament to their great value in patient care.
References
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Contact this author:
Lorne B. Yudcovitch, O.D., M.S., F.A.A.O.
Pacific University College of Optometry
2043 College Way
Forest Grove OR 97116
Note:
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