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Medication induced glaucoma
Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Medication induced glaucoma Elizabeth Martin, Thomas Patrianakos, Michael Giovingo n John H. Stroger, Jr. Hospital of Cook County, 1900 West Polk St. Ste. 617, Chicago, IL 60612, USA.
Glaucoma poses a significant public health problem. The World Health Organization (WHO) estimates the prevalence of blindness from glaucoma at more than 8 million, with 4 million cases caused by primary open angle glaucoma (POAG). Glaucoma is responsible for 12.3% of blindness, making it the second leading cause of blindness worldwide, after cataract.1 Glaucoma is an optic neuropathy where there is damage to the optic nerve and loss of neural tissue, as seen in the image below.2 The loss of nerve produces characteristic patterns of visual field loss. Risk factors for glaucoma include increasing age, elevated intraocular pressure (IOP), ethnicity, thin central corneas, and positive family history. Intraocular pressure is the only modifiable risk factor.1 There are many different types of glaucoma and these can all be divided into two broad categories; open and closed angle glaucoma. The difference between open and closed angle glaucoma refers to the status of the angle, or outflow channel of the eye, located near the junction of the iris and cornea (Fig. 1).2 In angle closure, the outflow is impaired by the apposition of the iris to the cornea. In open angle glaucoma, the impairment of outflow is due to a poorly function trabecular meshwork (Fig. 2). Angle closure can occur with or without pupillary block, which dictates the best course of treatment. Further subdivisions of glaucoma include primary, secondary acute and chronic. Each of these subdivisions can be seen in the open or closed angle variety. Primary open and closed angle glaucoma occur without an inciting source, while secondary glaucomas are subsequent to systemic disease or even medications. This chapter will focus on secondary glaucomas associated with medications. The symptoms for these conditions are highly variable so an understanding of possible side effects is crucial when prescribing these medications and monitoring patients using them.
Drug induced secondary open angle glaucoma (SOAG) The primary medication group known to cause secondary open angle glaucoma is the steroid family. SOAG has been caused by use of steroids though any route: topical, periocular, intravitreal, inhaled or systemic. The clinical presentation and course mimic POAG. Not all patients will develop glaucoma with steroids. Approximately one-third will develop an intraocular pressure increase, but only a small percentage of those will have clinically significant elevation in IOP ( Z10 mmHg).3 Length, frequency of administration, potency of the steroid and route of administration all play a factor in the onset and extent of IOP elevation.1 Topical and intravitreal use of corticosteroids are more likely to cause IOP elevations. Intravitreal injections of corticosteroids have been associated with transient elevation of IOP in more than 50% of patients, and up to 25% of these patients may require topical medication or incisional surgery to control IOP and prevent permanent loss of vision from glaucoma.3 For those on oral steroids, the risk of developing SOAG increased with higher doses of steroids and longer duration of use. However, IOP elevation as a response to corticosteroids may develop at any time during long-term use. Monitoring IOP in patients who need long term, high dose oral glucocorticoid therapy may be warranted. The risk of SOAG also increases with the use of high dose inhaled glucocorticoids when used for 3 months of longer. No increased risk was n
Corresponding author. E-mail address: [email protected] (M. Giovingo).
http://dx.doi.org/10.1016/j.disamonth.2016.09.007 0011-5029/ Published by Elsevier GmbH.
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
2
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 1. a: Normal optic nerve appearance b. glaucomatous nerve with enlarged cup to disc ratio.
Fig. 2. a: Trabecular meshwork obstruction b: Angle closure with pupillary block c: Angle closure without pupillary block.
seen in those with low to medium doses.4 Though the exact mechanism that causes the increase in IOP and SOAG with the use of glucocorticoids is unknown, it is generally believed that steroids raise IOP by increasing the resistance to aqueous humor outflow.1 Histopathologic studies have demonstrated morphologic changes in the trabecular meshwork of eyes with steroid-induced ocular hypertension (OHTN).
Drug induced acute angle closure glaucoma (AACG) Multiple classes of medications have been shown to induce AACG. Adrenergic agents cause mydriasis (dilation of the
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
pupil) and can precipitate an attack of acute angle closure by pupillary block. In pupillary block, the lens seals against the iris, inhibiting outflow. Patients that are predisposed to developing AACG are those with shallow anterior chambers, and are typically hyperopic (far-sighted). Examples of adrenergic medications include alpha adrenergic agonists like phenylephrine, epinephrine, ephedrine, and naphazoline. Beta2 adrenergic agents such as salbultamol, albuterol, and terbutaline can induce transient angle closure and increase IOP. These medications are used for bronchodilation in patients with asthma or COPD. They are often aerosolized and, with a poor fitting mask, can be absorbed through the cornea and conjunctiva. Properly fitted and positioned masks will help minimize ocular exposure of the nebulized medication.5 Indirect sympathomimetic agents can also induce angle closure. These include amphetamines, anti-depressant agents (imipramine, monoamine oxidase inhibitors) and cocaine, especially when used nasally.6 Anticholinergics have pupillary dilatation effects that can also induce AACG in patients who are predisposed. Tropicamide drops commonly administered for the ophthalmic fundus exam have been associated with AACG. Also longer acting anticholinergic eye drops including atropine and cyclopentolate. Tricyclic and tetracyclic antidepressants have weak anticholinergic side effects. Selective serotonin reuptake inhibitors (SSRIs) have lower incidence of cholinergic side effects, but there have been reports with paroxetine, venlafaxine, fluvoxamine, citalopram and escitalopram causing AACG.6 The underlying mechanism is pupillary block caused by pupil dilation from the anticholinergic and serotonergic side effects. Antipsychotics like trifluoperazine, perphenazine and fluphenazine also have weak anticholinergic effects, but weaker than those of tricyclic antidepressants.6 These will likely only induce AACG in those predisposed individuals when used in conjunction with another anticholinergic. Pupillary block AACG should be treated emergently with laser peripheral iridotomy to prevent permanent loss of vision. Sulfa-based drugs have been shown to cause a non-pupillary block AACG and have been reported with the use of trimethoprim-sulfamethoxazole, topiramate, acetazolamide, hydrochlorothiazide and cotrimoxazole.5 Topiramate, commonly used for migraines and weight loss, is a sulfa-based medication that has been well documented to induce AACG. Patients with topiramate induced AACG classically present with bilateral acute blurring of vision. This phenomenon is seen in both pediatric and adult patients. The majority of cases occur in females. Onset is typically soon after starting the drug, between days 1 and 49. Studies have reported that 85% of cases occurred in first 3 weeks of treatment.6 Unlike previously mentioned medication induced glaucomas, there are no identifying risk factors for this syndrome. Underlying pathophysiology is due to ciliary body edema which causes relaxation of zonules and ultimately allowing the lens to thicken. This rotation of the ciliary body leads to anterior displacement of the lens and iris, which causes a shallowing of the anterior chamber.1 This causes a secondary angle closure glaucoma. It also changes the patient′s refraction, which causes the blurry vision. There is no pupillary block present, so the typical laser peripheral iridotomy treatment approach is ineffective. The only treatment is cessation of the drug. Without the prompt evaluation and treatment, permanent vision loss has been reported.5 Anticoagulants can also cause acute angle closure after massive vitreous, choroidal or subretinal hemorrhage, but this is very rare. Risk factors for this complication include a supratherapeutic state while using an anticoagulant, history of exudative (or wet) age-related macular degeneration and nanophthalmos, a congenitally small eye.5 AACG occurs due to sudden forward displacement of the lens-iris diaphragm resulting from the detached retina or choroid. Because the mechanism of angle closure is non-pupillary block, peripheral iridotomy is again not effective. AACG has been reported with the use of heparin, enoxaparin and warfarin. Histamine H1 and H2 receptor antagonists also have weak anticholinergic effect which can induce mydriasis and subsequently AACG in predisposed patients. Promethazine has been reported to cause swelling of the lens that can in turn result in pupillary block. Ranitidine and cimetidine used for the treatment of gastroesophageal reflux have been shown to increase intraocular pressure in individuals who are known to have glaucoma.6
Management of prescribing these medications An understanding of the potential side effects of these medications is crucial when prescribing. It is not possible, nor is it necessary for clinicians prescribing these drugs to refer all patients for ophthalmic exams, but it is also important that the patients on these medications are sent for urgent evaluation if they experience pain or a decrease in vision. Identifying patients presenting with AACG can lead to urgent intervention and thus potentially save sight. It is also important to identify medications where longer treatments are associated with glaucoma such as steroids. These patients, if they have no complaints, should have a non-urgent evaluation if there is a plan for prolonged use. Patients who have undergone laser iridotomy should be able to safely take the medications that have the potential to induce AACG by pupillary block but these patients should already be in the regular care of an ophthalmologist. In any case, if there is a question of an ongoing issue or high risk, the clinician should always err on the side of caution and refer the patient to an ophthalmologist.
Disclaimer None. Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
References 1. Cantor L, Rapuano C, Cioffi G. Glaucoma, basic and clinical science course. Italy, Am Acad Ophthalmol 2014:27–137. 2. Kanski J, Bowling B. Clinical ophthalmology: a systematic approach.China: Elsevier; 2011. 3. Garbe E, Lelorier J, Boivin JF, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 1997;350: 979–82. 4. Garbe E, Lelorier J, Boivin JF, Suissa S. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997;277: 722–7. 5. Lachkar Yves, WalidBouassida. Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol 2007;18(2) 129–33 Web. 6. Ah-kee EY, Egong E, Shafi A, Lim LT, Li Yim JF. A review of drug-induced acute angle closure glaucoma for non-ophthalmologists. Qatar Med J 2015. http://dx.doi.org/10.5339/qmj.2015.6.
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
Contents lists available at ScienceDirect
Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth
Medication induced glaucoma Elizabeth Martin, Thomas Patrianakos, Michael Giovingo n John H. Stroger, Jr. Hospital of Cook County, 1900 West Polk St. Ste. 617, Chicago, IL 60612, USA.
Glaucoma poses a significant public health problem. The World Health Organization (WHO) estimates the prevalence of blindness from glaucoma at more than 8 million, with 4 million cases caused by primary open angle glaucoma (POAG). Glaucoma is responsible for 12.3% of blindness, making it the second leading cause of blindness worldwide, after cataract.1 Glaucoma is an optic neuropathy where there is damage to the optic nerve and loss of neural tissue, as seen in the image below.2 The loss of nerve produces characteristic patterns of visual field loss. Risk factors for glaucoma include increasing age, elevated intraocular pressure (IOP), ethnicity, thin central corneas, and positive family history. Intraocular pressure is the only modifiable risk factor.1 There are many different types of glaucoma and these can all be divided into two broad categories; open and closed angle glaucoma. The difference between open and closed angle glaucoma refers to the status of the angle, or outflow channel of the eye, located near the junction of the iris and cornea (Fig. 1).2 In angle closure, the outflow is impaired by the apposition of the iris to the cornea. In open angle glaucoma, the impairment of outflow is due to a poorly function trabecular meshwork (Fig. 2). Angle closure can occur with or without pupillary block, which dictates the best course of treatment. Further subdivisions of glaucoma include primary, secondary acute and chronic. Each of these subdivisions can be seen in the open or closed angle variety. Primary open and closed angle glaucoma occur without an inciting source, while secondary glaucomas are subsequent to systemic disease or even medications. This chapter will focus on secondary glaucomas associated with medications. The symptoms for these conditions are highly variable so an understanding of possible side effects is crucial when prescribing these medications and monitoring patients using them.
Drug induced secondary open angle glaucoma (SOAG) The primary medication group known to cause secondary open angle glaucoma is the steroid family. SOAG has been caused by use of steroids though any route: topical, periocular, intravitreal, inhaled or systemic. The clinical presentation and course mimic POAG. Not all patients will develop glaucoma with steroids. Approximately one-third will develop an intraocular pressure increase, but only a small percentage of those will have clinically significant elevation in IOP ( Z10 mmHg).3 Length, frequency of administration, potency of the steroid and route of administration all play a factor in the onset and extent of IOP elevation.1 Topical and intravitreal use of corticosteroids are more likely to cause IOP elevations. Intravitreal injections of corticosteroids have been associated with transient elevation of IOP in more than 50% of patients, and up to 25% of these patients may require topical medication or incisional surgery to control IOP and prevent permanent loss of vision from glaucoma.3 For those on oral steroids, the risk of developing SOAG increased with higher doses of steroids and longer duration of use. However, IOP elevation as a response to corticosteroids may develop at any time during long-term use. Monitoring IOP in patients who need long term, high dose oral glucocorticoid therapy may be warranted. The risk of SOAG also increases with the use of high dose inhaled glucocorticoids when used for 3 months of longer. No increased risk was n
Corresponding author. E-mail address: [email protected] (M. Giovingo).
http://dx.doi.org/10.1016/j.disamonth.2016.09.007 0011-5029/ Published by Elsevier GmbH.
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
2
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
Fig. 1. a: Normal optic nerve appearance b. glaucomatous nerve with enlarged cup to disc ratio.
Fig. 2. a: Trabecular meshwork obstruction b: Angle closure with pupillary block c: Angle closure without pupillary block.
seen in those with low to medium doses.4 Though the exact mechanism that causes the increase in IOP and SOAG with the use of glucocorticoids is unknown, it is generally believed that steroids raise IOP by increasing the resistance to aqueous humor outflow.1 Histopathologic studies have demonstrated morphologic changes in the trabecular meshwork of eyes with steroid-induced ocular hypertension (OHTN).
Drug induced acute angle closure glaucoma (AACG) Multiple classes of medications have been shown to induce AACG. Adrenergic agents cause mydriasis (dilation of the
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
3
pupil) and can precipitate an attack of acute angle closure by pupillary block. In pupillary block, the lens seals against the iris, inhibiting outflow. Patients that are predisposed to developing AACG are those with shallow anterior chambers, and are typically hyperopic (far-sighted). Examples of adrenergic medications include alpha adrenergic agonists like phenylephrine, epinephrine, ephedrine, and naphazoline. Beta2 adrenergic agents such as salbultamol, albuterol, and terbutaline can induce transient angle closure and increase IOP. These medications are used for bronchodilation in patients with asthma or COPD. They are often aerosolized and, with a poor fitting mask, can be absorbed through the cornea and conjunctiva. Properly fitted and positioned masks will help minimize ocular exposure of the nebulized medication.5 Indirect sympathomimetic agents can also induce angle closure. These include amphetamines, anti-depressant agents (imipramine, monoamine oxidase inhibitors) and cocaine, especially when used nasally.6 Anticholinergics have pupillary dilatation effects that can also induce AACG in patients who are predisposed. Tropicamide drops commonly administered for the ophthalmic fundus exam have been associated with AACG. Also longer acting anticholinergic eye drops including atropine and cyclopentolate. Tricyclic and tetracyclic antidepressants have weak anticholinergic side effects. Selective serotonin reuptake inhibitors (SSRIs) have lower incidence of cholinergic side effects, but there have been reports with paroxetine, venlafaxine, fluvoxamine, citalopram and escitalopram causing AACG.6 The underlying mechanism is pupillary block caused by pupil dilation from the anticholinergic and serotonergic side effects. Antipsychotics like trifluoperazine, perphenazine and fluphenazine also have weak anticholinergic effects, but weaker than those of tricyclic antidepressants.6 These will likely only induce AACG in those predisposed individuals when used in conjunction with another anticholinergic. Pupillary block AACG should be treated emergently with laser peripheral iridotomy to prevent permanent loss of vision. Sulfa-based drugs have been shown to cause a non-pupillary block AACG and have been reported with the use of trimethoprim-sulfamethoxazole, topiramate, acetazolamide, hydrochlorothiazide and cotrimoxazole.5 Topiramate, commonly used for migraines and weight loss, is a sulfa-based medication that has been well documented to induce AACG. Patients with topiramate induced AACG classically present with bilateral acute blurring of vision. This phenomenon is seen in both pediatric and adult patients. The majority of cases occur in females. Onset is typically soon after starting the drug, between days 1 and 49. Studies have reported that 85% of cases occurred in first 3 weeks of treatment.6 Unlike previously mentioned medication induced glaucomas, there are no identifying risk factors for this syndrome. Underlying pathophysiology is due to ciliary body edema which causes relaxation of zonules and ultimately allowing the lens to thicken. This rotation of the ciliary body leads to anterior displacement of the lens and iris, which causes a shallowing of the anterior chamber.1 This causes a secondary angle closure glaucoma. It also changes the patient′s refraction, which causes the blurry vision. There is no pupillary block present, so the typical laser peripheral iridotomy treatment approach is ineffective. The only treatment is cessation of the drug. Without the prompt evaluation and treatment, permanent vision loss has been reported.5 Anticoagulants can also cause acute angle closure after massive vitreous, choroidal or subretinal hemorrhage, but this is very rare. Risk factors for this complication include a supratherapeutic state while using an anticoagulant, history of exudative (or wet) age-related macular degeneration and nanophthalmos, a congenitally small eye.5 AACG occurs due to sudden forward displacement of the lens-iris diaphragm resulting from the detached retina or choroid. Because the mechanism of angle closure is non-pupillary block, peripheral iridotomy is again not effective. AACG has been reported with the use of heparin, enoxaparin and warfarin. Histamine H1 and H2 receptor antagonists also have weak anticholinergic effect which can induce mydriasis and subsequently AACG in predisposed patients. Promethazine has been reported to cause swelling of the lens that can in turn result in pupillary block. Ranitidine and cimetidine used for the treatment of gastroesophageal reflux have been shown to increase intraocular pressure in individuals who are known to have glaucoma.6
Management of prescribing these medications An understanding of the potential side effects of these medications is crucial when prescribing. It is not possible, nor is it necessary for clinicians prescribing these drugs to refer all patients for ophthalmic exams, but it is also important that the patients on these medications are sent for urgent evaluation if they experience pain or a decrease in vision. Identifying patients presenting with AACG can lead to urgent intervention and thus potentially save sight. It is also important to identify medications where longer treatments are associated with glaucoma such as steroids. These patients, if they have no complaints, should have a non-urgent evaluation if there is a plan for prolonged use. Patients who have undergone laser iridotomy should be able to safely take the medications that have the potential to induce AACG by pupillary block but these patients should already be in the regular care of an ophthalmologist. In any case, if there is a question of an ongoing issue or high risk, the clinician should always err on the side of caution and refer the patient to an ophthalmologist.
Disclaimer None. Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i
E. Martin et al. / Disease-a-Month ∎ (∎∎∎∎) ∎∎∎–∎∎∎
4
References 1. Cantor L, Rapuano C, Cioffi G. Glaucoma, basic and clinical science course. Italy, Am Acad Ophthalmol 2014:27–137. 2. Kanski J, Bowling B. Clinical ophthalmology: a systematic approach.China: Elsevier; 2011. 3. Garbe E, Lelorier J, Boivin JF, Suissa S. Risk of ocular hypertension or open-angle glaucoma in elderly patients on oral glucocorticoids. Lancet 1997;350: 979–82. 4. Garbe E, Lelorier J, Boivin JF, Suissa S. Inhaled and nasal glucocorticoids and the risks of ocular hypertension or open-angle glaucoma. JAMA 1997;277: 722–7. 5. Lachkar Yves, WalidBouassida. Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol 2007;18(2) 129–33 Web. 6. Ah-kee EY, Egong E, Shafi A, Lim LT, Li Yim JF. A review of drug-induced acute angle closure glaucoma for non-ophthalmologists. Qatar Med J 2015. http://dx.doi.org/10.5339/qmj.2015.6.
Please cite this article as: Martin E, et al. (2017), http://dx.doi.org/10.1016/j.disamonth.2016.09.007i