Article

Know the systemic effects of ocular steroid therapy

Think outside the eye while using topical corticosteroids.

Know the systemic effects of ocular steroid therapy

Think outside the eye while using topical corticosteroids.

By Luke Moore, MD, Constance O. Okeke, MD, MSCE, and John Sheppard, MD, MMSc

The pituitary gland is one of several anatomical structures that can be affected by the introduction of topical corticosteroids. Use of these medications in some patients has been linked to pituitary gland conditions such as Cushing’s syndrome.

Topical corticosteroids are commonly used to treat a wide spectrum of ocular diseases and to control post-operative inflammation. Ophthalmologists generally prefer topical corticosteroid delivery over systemic steroid administration due to its favorable safety profile, efficacy, dosage versatility, and patient tolerability.1 However, numerous studies elucidate the various ocular complications attributed to topical corticosteroid use, including posterior subcapsular cataracts, glaucoma, delayed wound healing, potentiation of infection, viral reactivation and corneal stromal calcification.2

While practicing ophthalmologists are acutely aware of these potential adverse effects, evidence suggests certain patient populations require monitoring for systemic complications following the induction of topical corticosteroid therapy.

STEROIDS IN OPHTHALMOLOGY

Corticosteroid physiology

Corticosteroids, which include glucocorticoids and mineralocorticoids, are lipid-soluble hormones secreted by the cortex of the adrenal gland.3 Endogenous corticosteroids are regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids have anti-inflammatory and immunosuppressive effects, among other functions.3 The corticosteroids frequently used in ophthalmology (such as prednisolone, fluoromethalone, loteprednol etabonate, difluprednate and dexamethasone) have high glucocorticoid potency, making them effective in treating anterior segment ocular inflammation.

However, because these particular corticosteroids are administered topically, they have the potential to create systemic adverse effects via their absorption through ocular tissues, the nasolacrimal tract and when swallowed.3

Topical absorption

Several studies have detailed the systemic absorption of topical eyedrops with conflicting results. A 2002 study showed low serum levels of dexamethasone in patients who used a commonly administered drop regimen following pars plana vitrectomy;4 a 1998 study failed to detect measurable serum levels of loteprednol or its metabolite after chronic topical administration for 42 days.5

Loteprednol is broken down into inactive metabolites present in the eye and mucus membranes by endogenous tissue esterases, explaining its relatively low risk of systemic toxicity.6 Note that punctal occlusion was not routinely used in any of the aforementioned studies.

HPA axis

Although serum drug levels of topical corticosteroids may remain low or negligible during treatment, the HPA axis can still be affected. That 2002 study demonstrated partial adrenal suppression with decreased serum cortisol levels following a six-week regimen of 0.1% topical dexamethasone following vitrectomy.4

Debate exists over this issue. A 2012 study failed to show a change in adrenocorticotrophic hormone (ACTH) stimulation results in patients who had received at least six months of topical corticosteroid therapy following penetrating keratoplasty.7

ADVERSE EFFECTS

Beyond the eye

The adverse effects of systemic corticosteroid therapy have been widely documented and include weight gain, osteoporosis, systemic hypertension, diabetes mellitus, gastric ulceration, aseptic necrosis, impaired immune function, sleep disturbance, depression and psychosis. Due to the low absorption of topical corticosteroids, many of these adverse effects are typically avoided. However, solid evidence exists showing that ocular steroids could indeed bring about these serious extraocular side effects. We will discuss two here.

Prevention

The option of preventing adverse effects from topical steroids within the eye should not be forgotten. Cataract and glaucoma are potentially less common with reduced topical steroid dosage as well as with loteprednol etabonate. However, the most ideal approach to treatment of inflammation is to initiate intensive induction therapy with a potent steroid followed by a quick taper and judicious maintenance therapy if indicated. When there is an elevation in IOP, possible steps of action include discontinuing the medication, changing to a less potent steroid, changing to a non-steroidal agent (NSAID, mast cell stabilizer or antihistamine) or treatment for glaucoma (drops, laser or surgery).

Close monitoring of those at higher risk of IOP elevation is warranted. These patients may include children, primary open angle glaucoma patients and family members or poor wound-healing patients, such as those with diabetes or neurotrophy.

Effect on diabetic patients

Recent evidence suggests topical corticosteroids impair glucose tolerance in diabetic patients. A prospective study showed a statistically significant rise in the blood glucose levels of patients with diabetes receiving topical dexamethasone therapy after cataract extraction.8 Moreover, the study failed to show a significant difference in the blood glucose levels of patients without diabetes before and after topical corticosteroids. The authors proposed that the corticosteroid drops aggravated the diabetic patients’ pre-existing insulin resistance and exacerbated their hyperglycemia.

A large retrospective study showed a significant rise in hemoglobin A1c and fasting blood glucose levels in diabetic patients after treatment with topical corticosteroids for a variety of ocular diseases.1

Vigilant blood glucose monitoring and regular primary care follow-up for patients with diabetes receiving topical corticosteroids is warranted based on these findings.

Pediatric patients

Systemic evidence exists beyond the well-established predilection of children to develop elevated IOP. Physicians should be especially judicious when prescribing topical corticosteroids in the pediatric population. A published case shows iatrogenic Cushing’s syndrome and acanthosis nigricans in an 11-year-old patient after the child received 1% prednisolone acetate therapy for six months.9

Another case of iatrogenic Cushing’s syndrome was reported in an 18-year-old male being treated for chronic anterior uveitis with 1% prednisolone acetate.10 It is unclear what predisposed these patients to developing Cushing’s syndrome; however, it is important that ophthalmologists are aware of this potentially serious complication.

Signs consistent with Cushing’s syndrome include a moon-like face, truncal obesity and numerous body striae.

MANAGING COMPLICATIONS

Treatment collaboration

It is imperative, as prescribers, to remind patients of the important step of digital self-punctal occlusion. Furthermore, proactive mechanical punctal occlusion in appropriate patients using reversible collagen or silicone plugs, or permanent punctal cautery should be carefully considered. This step can significantly minimize the amount of steroid reaching the nasal mucosa to reduce systemic side effects.

Patients with diabetes who are receiving long-term topical corticosteroids should have regular blood glucose checks with the expectation that a more intensive diabetic regimen could be required with the addition of oral medications or insulin or both. These patients should have close follow-up with their primary care doctor to work collaboratively with the ophthalmologist to control their blood glucose levels.

In pediatric patients, the possible adverse effects of topical corticosteroids, besides the serious condition of iatrogenic Cushing’s syndrome, is possible bone demineralization. It is important to explore alternative therapies in pediatric patients and only use corticosteroids when absolutely necessary.

These patients should have close follow-up with their pediatrician who can monitor the signs and symptoms of these disease entities and refer the patient to a pediatric endocrinologist if necessary.

Punctal occlusion

Topical corticosteroids are a widely used and generally well-tolerated class of medications with limited systemic adverse effects in most patients. However, in pediatric patients or patients with diabetes, this medication class must be used more cautiously by utilizing collaboration with primary care providers, carefully orchestrated clinical observation to provide minimally sufficient efficacious dosage recommendations, and consideration of alternative medication options.

In these at-risk populations, punctal occlusion, either digital or mechanical, is encouraged when appropriate to limit the systemic absorption of topical corticosteroids and possible adverse effects. OM

REFERENCES

1. Bahar I, Vinker S, Kaiserman I. The effect of topical steroids on blood glucose profile in diabetic patients. J Clinic Experim Ophthalmol. 2011;2:doi:10.4172/2155-9570.1000133.

2. Carnahan, MC, Goldstein DA. Ocular complications of topical, peri-ocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11:478-483.

3. Gupta P, Bhatia V. Corticosteroid physiology and principles of therapy. Indian J Peds. 2008;75:1039-1044.

4. Weijtens O, Schoemaker RC, Romijn FP, et al. Intraocular penetration and systemic absorption after topical application of dexamethasone disodium phosphate. Ophthalmol. 2002;109:1887-1891.

5. Howes J, Novack GD. Failure to detect systemic levels, and effects of loteprednol etabonate and its metabolite, PJ-91, following chronic ocular administration. J Ocul Pharmacol Ther. 1998;14:153-158.

6. Samudre SS, Lattanzio FA, Williams PB, Sheppard JD. Comparison of topical steroids for acute anterior uveitis. J Ocul Pharmacol Ther. 2004;20:533-547.

7. Sandhu SS, Smith JM, Doherty M, James A, Figueiredo FC. Do topical ophthalmic corticosteroids suppress the hypothalmic-pituitary-adrenal axis in post-penetrating keratoplasty patients? Eye. 2012;26:699-702.

8. Bahar I, Rosenblat I, Erenberg M, et al. Effect of dexamethasone eyedrops on blood glucose profile. Current Eye Research. 2007;32:739-742.

9. Ozerdem U, Levi L, Cheng L, et al. Systemic toxicity of topical and periocular corticosteroid therapy in an 11-year-old male with posterior uveitis. Amer J Ophthalmol. 2000;130:240-241.

10. Chiang MY, Sarkar M, Koppens JM, et al. “Exogenous Cushing’s syndrome and topical ocular steroids. Eye. 2005:20:725-727.

About the Authors

Luke Moore, MD is a resident at Eastern Virginia Medical School. He plans on pursuing a fellowship when he completes his residency.

Constance O. Okeke, MD is a glaucoma specialist at Virginia Eye Consultants. She has designed and implemented numerous clinical trials and published extensively in the professional literature on glaucoma.

John Sheppard, MD is the president of Virginia Eye Consultants. He is listed in The Best Doctors in America and has received the American Academy of Ophthalmology Honor Award.