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Drug Induced Glaucoma –A Review

Miscellaneous

Ravi Chandil

Glaucoma is an optic neuropathy with characteristic structural damage to the optic nerve and visual field

loss. It is usually associated with raised Intra ocular pressure (IOP).

The glaucoma has traditionally been divided on the basis of primary and secondary forms. Drug-induced glaucoma is a form of secondary glaucoma induced by topical and systemic medications. Although most common one is glucocorticoid1, but it is not the only one. Drug induced glaucoma is not synonymous to steroid induced glaucoma. There are many other non-steroidal systemic medicines (Table 1) as well as ophthalmic medicines which (Table 2) have the potential to raise IOP, even anti glaucoma drugs…. YES antiglaucoma drugs.

Mechanisms of IOP elevation in drug-induced glaucomaIOP elevation can occur via an open-angle or angle-closure mechanism (Table 1 and 2).

Open-angleCorticosteroid is a group of drugs that may produce IOP elevation by open-angle mechanism. Not all the patients taking steroid will develop IOP elevation. The risk factors include preexisting primary open-angle glaucoma (OAG), a family history of glaucoma, high myopia, diabetes mellitus and young age and rheumatoid arthritis2,3,4.

It has been shown that 18-36% of the general population respond to topical ocular administration of corticosteroids with an elevation of IOP. IOP rises usually within 2-4 weeks after therapy has been instituted. Topically applied eye drops and creams to the periorbital area and intravitreal injections are more likely to cause IOP elevation than intravenous, parenteral and inhaled forms.

Closed-angleSome drugs may produce IOP elevation acutely by angle-

closure mechanism. These are topical anticholinergic or sympathomimetic pupil dilating drops, tricyclic anti-depressants, monoamine oxidase inhibitors, antihistamines, anti-Parkinson drugs, antipsychotic medications and antispasmolytic agents. These drugs will incite an attack in individuals with very narrow anterior chamber angles that are prone to occlusion, especially when the pupils are dilated.

Idiosyncratic reaction Sulfonamide-containing medications may induce an angle closure glaucoma (ACG) by a different mechanism, involving the anterior rotation of the cilliary-body5,6,7,8,9,10.

Typically, the angle-closure is bilateral and occurs within the first few doses. Patients with narrow or wide open angles are susceptible to this rare idiosyncratic reaction.

Pathophysiology of Drug-induced Glaucoma (Figure 1)

Open-angle

The exact pathophysiology of steroid-induced glaucoma is unknown. It is known that steroid-induced IOP elevation is

Figure 1: Mechanism of Drug Induced Glaucoma

Ravi Chandil DOMS

Consultant Glaucoma, Ratan Jyoti Netralaya, Gwalior, M.P

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secondary to increased resistance to aqueous outflow11,12. But the following observations and theories have been reported.

1. Some evidence shows that there could be increased accumulation of glycosaminoglycans producing biological oedema13,14 or increased production of trabecular meshwork-inducible glucocorticoid response (TIGR) protein, which could mechanically obstruct the aqueous outflow.

2. Other evidence suggests that the corticosteroid-induced cytoskeletal changes could inhibit pinocytosis of aqueous humour or inhibit the clearing of glycosaminoglycans, resulting in the accumulation of this substance and blockage of the aqueous outflow15.

3. Direct physical obstruction of the trabecular meshwork with crystalline steroid particles16,17.

Pathophysiology of Non Steroidal drugs e.g dicyclomine causing open-angle glaucoma are much more varied including the release of pigment during the pupillary dilation with subsequent obstruction of the trabecular meshwork, and a possible increase of inflow during pupillary dilation.

Closed-angleThe pathophysiology of angle-closure glaucoma is usually due to pupillary blockage, i.e. iris-lens contact at the pupillary border resulting from pupillary dilation. Medications have a direct or secondary effect, either in stimulating sympathetic or inhibiting parasympathetic activation causing pupillary dilation, which can precipitate acute angle-closures in patients with occludable anterior chamber angles.

Sulfa-containing medications result in acute angle-closures in a different mechanism18,19. This involves the anterior

rotation of the ciliary body with or without choroidal effusions, resulting in a shallow anterior chamber and blockage of the trabecular meshwork by the iris. The exact reason causing ciliary body swelling is unknown in susceptible individuals.

Clinical Assessment for Drug-induced Glaucoma

HistoryThe patient’s detailed history regarding systemic illness which could require chronic corticosteroid use like uveitis, collagen vascular disease, asthma, dermatitis should be asked. History of neurological disease and medications should be carefully elicited.

Patient’s risk factor to be steroid responders like preexisting primary open-angle glaucoma, a family history of primary open-angle glaucoma, diabetes mellitus, high myopia, or connective tissue diseases should be elicited.

SymptomsIn drug induced open angle glaucoma, the pressure elevation is gradual. Therefore, there are very few symptoms during the early stage of disease. Some time patient may complain of coloured haloes. At a later stage, patients may complain of loss of the peripheral visual field. At the more advanced stage, when the central vision is also affected, patients may complain of blurring of vision.

In drug-induced acute angle-closure glaucoma, the symptoms are the same as in primary acute angle-closure glaucoma. These include sudden eye pain, headache associated with nausea and/ or vomiting, blurring of vision and halos around bright objects.

Physical ExaminationA complete ophthalmic examination should be performed including:

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Visual acuity, pupil reaction, intraocular pressure measurement, anterior chamber examination for assessment of anterior chamber depth. Signs of other secondary glaucoma such as uveitic, pigment dispersion and pseudoexfoliation glaucoma should looked for. Posterior subcapsular cataract may present in chronic steroid users.

Gonioscopic examination

Gonioscopy for evaluation of angle anatomy i.e. open or narrow and to determine whether the angle is occludable during pupil dilation.

Optic disc evaluation

Stereoscopic examination of the optic disc (Figure 2) is necessary to document glaucomatous damage. This can be done by slit lamp biomicroscopy (78D & 90D).

Investigations

Perimetry

Visual Field testing such as Humphrey (Figure 3) is used to evaluate the severity of optic neuropathy. Even when optic nerve damage not present, baseline documentation of visual field is essential.

Optical Coherence Tomography (OCT)

OCT is an optical signal acquisition and processing method. It is used to evaluate the retinal nerve fibre thickness around the optic disc (Figure 4) in glaucoma patients. Serial scans can be used to demonstrate any progression of disease.

Ultrasound Biomicroscopy (UBM)

UBM is an imaging technique that uses high frequency ultrasound to produce images of the eye at near microscopic

resolution. This technique is used to evaluate the anterior chamber angle configuration i.e. open or closed and the position of the cilliary body e.g. anterior rotation (Figure 5)

Anterior Segment OCT (ASOCT)

It applies the same principle as OCT but it provides images of the anterior chamber including the angle and the lens.

Treatment of Drug-induced GlaucomaIf the patient’s underlying medical condition can tolerate discontinuation of drugs, then cessation of the medication will usually result in normalization of IOP.

Medical management for Open-angle drug induced glaucoma

In the case of topical corticosteroid drops, using a lower potency steroid medication, such as the phosphate forms of prednisolone, loteprednol or fluorometholone should be considered. These drugs have a lesser chance of IOP rise20,21,22, but they are usually not as effective as an anti-inflammatory drug. Topical NSAID medications can be considered, but they may not have enough anti-inflammatory activity to treat the patient’s underlying condition23,24.

Figure 2: Optic disc changes in steroid induced glaucoma case

Figure 3: Humphery visual field changes in steroid induced glaucoma case

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Figure 5: Anterior rotation of the ciliary body with choroidal effusion

IOP rise can be asymptomatic initially especially in open-angle type. General practitioners should be aware of the risk factors for glaucoma before prescribing a drug that has the potential to cause, precipitate or exacerbate glaucoma whenever in doubt, an ophthalmologist should be consulted. When prescribing such medicines for long term, regular and complete eye checkup should be done.

References1. Tripathi RC, Parapuram SK, Tripathi BJ, et al. Corticosteroids and

glaucoma risk. Drugs Aging 1999;15:439-450.2. Podos SM, Becker B, Morton WR. High myopia and primary open-

angle glaucoma. Am J Ophthalmol. 1966; 62(6):1038-1043.3. Becker B. Diabetes mellitus and primary open-angle glaucoma. Am

J. Ophthalmol. 1971; 1-16.4. Gaston H, Absolon MJ, Thurtle OA, et al. Steroid responsiveness in

connective tissue diseases. Br J Ophthalmol. 1983; 67(7):487-490.5. Kakaria V, Chalam, Tillis T, Farhana S, Brar SA. Acute bilateral

simultaneous angle closure glaucoma Topiramate administration: a case report. J Med Case Reports 2008;2:1.

In cases in which the patient’s IOP does not normalize upon cessation of the steroid or in those patients who must continue to be on corticosteroid medications, topical antiglaucoma medications are considered.

Medical management for Closed-angle drug induced glaucoma

If the aetiology is because of sulfa-containing medications, the increase in IOP generally will resolve upon stopping the medication. However, severe cases of sulfonamide-induced angle-closure may not respond to simply discontinuing the offending medication. These cases may respond to intravenous mannitol.

For other aetiologies of drug-induced angle-closure, they are treated similar to primary acute angle-closure glaucoma by using antiglaucoma medications including topical beta blockers, prostaglandin analogues, cholinergic agonists and often oral acetazolamide.

Laser treatment

For open-angle glaucoma, Argon laser trabeculoplasty or selective laser trabeculoplasty can be applied in the absence of ocular inflammation if the IOP is suboptimal with medication25,26.

In closed-angle glaucoma, argon laser peripheral iridoplasty (ALPI) may be applied to deepen the anterior chamber and widen the angle. Laser iridotomy (LI) can be performed to reverse pupillary block or to prevent further pupillary block.

Laser iridotomy is not effective in cases of acute ACG caused by sulfa drug like topiramate because secondary angle closure glaucoma occurs without pupillary block.

Surgical treatment for Open-angle and Closed angle casesIndication

1. Medical therapy is ineffective in lowering the IOP to target pressure or

2. The patient is intolerant of medical therapy or

3. In patients whom both medical and laser therapy have failed to lower the IOP adequately.

Usually, trabeculectomy, a guarded filtration procedure, with or without intraoperative antimetabolites, is the primary procedure.

In case of posterior subtenon steroid and in intravitreal steroid, vitrectomy is helpful to lower the load of steroid and IOP.

ConclusionUncontrolled increase in IOP can lead to permanent optic nerve damage and permanent blindness. Drug-induced

Figure 4: OCT RNFL changes in steroid induced glaucoma case

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6. GuMHP, Thiagalingam S, Ong P, Goldberg I. Bilateral acute angle closure caused by supraciliary effusion associated with Velafaxine intake. MJA 2005; 182:121- 123.

7. Nemet A, Nesher R, Almog Y, Assia E. Bilateral acute angle closure glaucoma following Topiramate treatment. Harefuah 2002; 141:597-9.

8. Singh SK, Thapa SS, Badhu BP. Topiramate induced bilateral angle-closure glaucoma. Kathmandu University Medical Journal 2007; 5:234.

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10. Levy J, Yagev R, Petrova A, Lifshitz T. Topiramate – induced bilateral angle-closure glaucoma. Can J Ophthalmol. 2006; 41:221-5.

11. Jones R III, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol. 2006; 17(2):163-167.

12. Kersey JP, Broadway DC. Corticosteroid-induced glaucoma: a review of the literature. Eye 2006; 20(4):407-416.

13. François J. The importance of the mucopolysaccharides in intraocular pressure regulation. Invest Ophthalmol. 1975; 14(3):173-176.

14. François J, Victoria-Troncoso V. Mucopolysaccharides and pathogenesis of cortisone glaucoma [in German]. Klin Monatsbl Augenheilkd. 1974; 165(1):5-10.

15. Bill A. The drainage of aqueous humor [editorial]. Invest Ophthalmol. 1975;14(1):1-3

16. Singh I P, Ahmad SI, Yeh D, et al. Early rapid rise in intraocular pressure after intravitreal triamcinolone acetonide injection. Am J Ophthalmol. 2004;138(2):286-287.

17. Im L, Allingham RR, Singh I, et al. A prospective study of early

intraocular pressure changes after a single intravitreal triamcinolone injection. J Glaucoma 2008;17(2):128-132.

18. Tripathi RC, Triathi BJ, Haggerty C. Drug-induced glaucomas: mechanism and management. Drug 2003; 26:749–767.

19. Geanon JD, Perkins TW. Bilateral acute angle-closure glaucoma associated with drug sensitivity to hydrochlorothiazide. Arch Ophthalmol. 1995; 113:1231–1232.

20. Leibowitz HM, Ryan WJ Jr, Kupferman A. Comparative anti-inflammatoryefficacyoftopicalcorticosteroidswithlowglaucoma-inducing potential. Arch Ophthalmol. 1992;110(1):118-120.

21. Mindel JS, Tavitian HO, Smith H Jr, et al. Comparative ocular pressure elevation by medrysone, fluorometholone, and dexamethasonephosphate. Arch Ophthalmol. 1980;98(9):1577-1578.

22. Morrison E, Archer DB. Effect of fluorometholone (FML) on theintraocular pressure of corticosteroid responders. Br J Ophthalmol. 1984;68(8):581-584.

23. Gieser DK, Hodapp E, Goldberg I, et al. Flurbiprofen and intraocular pressure. Ann Ophthalmol. 1981;13(7):831-833.

24. Strelow SA, Sherwood MB, Broncato LJ, et al. The effect of diclofenac sodium ophthalmic solution on intraocular pressure following cataract extraction. Ophthalmic Surg 1992;23(3):170-175.

25. Ricci F, Missiroli F, Parravano M. Argon laser trabeculoplasty in triamcinolone acetonide induced ocular hypertension refractory to maximal medical treatment. Eur J Ophthalmol. 2006;16(5):756-757.

26. Rubin B, Taglienti A, Rothman RF, et al. The effect of selective laser trabeculoplasty on intraocular pressure in patients with intravitreal steroid induced elevated intraocular pressure. J Glaucoma 2008;17(4):287-292.