A case series of topiramate-induced angle closure crisis – an ophthalmic emergency

Abstract

Background

Topiramate is a drug commonly used by physicians. However, it has various systemic and ocular adverse effects. Bilateral angle closure crisis is a potentially blinding adverse reaction that is seldom reported in non-ophthalmic journals.

Objective

This article aims to report a case series of topiramate-induced angle closure crisis in the eyes.

Methods and material

Most patients presented to us with blurred vision and high intra-ocular pressure within days of starting topiramate tablet for headache. However, the attack resolved in those who presented early with prompt treatment, which included stopping topiramate.

Conclusions

Physicians prescribing topiramate must be well aware of this potentially blinding adverse effect. Educating the patient about this possible side effect is important. Timely referral and treatment can prevent blindness in these individuals.

Introduction

Topiramate is one of the drugs most commonly used by physicians since it has a wide variety of indications. It was used initially as an antiepileptic (1) and has now become more popular for migraine prophylaxis (2), trigeminal neuralgia, eating disorders, bipolar disorders, depression and idiopathic intracranial hypertension (3,4).

However, topiramate has many adverse drug reactions, which are dosage dependent. Up to 20% of patients using 100 mg tablets need a dosage reduction or change in therapy due to adverse drug reactions (5). There is also a clinical impression that there are more adverse effects reported by migraineurs than epileptics. With the growing “off label” use of this drug, it is important to raise awareness among physicians about its potentially blinding side effect. Among the various ocular adverse reactions of the drug, bilateral angle closure crisis is one of the most common and also most dreadful effects. Timely referral of such a patient by physicians to an ophthalmologist can prevent permanent blindness.

This case series includes the clinical course of six patients with topiramate-induced bilateral acute angle closure who presented to our institute between January 2018 and December 2019.

Case report

All six patients were young females with an age range of 25 to 45 years. They presented to our emergency services with sudden onset diminution of vision for 48 hours associated with mild pain in eyes except for cases 4 and 5, who presented after 48 hours of onset of symptoms. A diligent effort was made to obtain the treatment history from the patients and their caregivers. All of them gave a history of taking topiramate tablet, 25 mg per day for 1–2 weeks, prescribed by a general physician or neurologist for headache. On examination, they had poor vision ranging from 6/36 to counting fingers close to the face in both eyes. Refraction showed moderate to large myopia of 3 to 8 Dioptres except in the third patient, who showed slight hyperopic shift. Ocular examination showed edematous cornea due to high intraocular pressures and characteristically bilateral shallow anterior chamber (AC) (Figure 1(a)) in all patients. Intraocular pressures (IOP) were very high, even up to 60 mmHg (the normal range is 10–21 mmHg), except in those who were already receiving some form of anti-glaucoma medication from the referring hospital. Gonioscopy, which is used to visualise the angle of the AC; that is, the aqueous outflow pathway, showed a closed pathway in both eyes (BE) (Figure 2(a)), which was objectively confirmed with anterior segment optical coherence tomography (ASOCT) (Figure 3(a)). Fundus examination through a hazy media due to edematous cornea appeared to show a normal disc and macula except in the third case. This patient had disc edema in BE. Ultrasound B scan showed thickened retino-choroido-scleral (RCS) complex in all, and even choroidal detachments (Figure 4(a)) suggestive of ciliochoroidal effusion. Case 3 also had thickened peripapillary choroid.

Figure 1.

(a) Anterior segment photo showing shallow AC (no gap between the two beams of light), (b) anterior segment photo showing deepening of AC (significant gap between the two beams of light).

Figure 2.

(a) Gonioscopy showing closed angles, (b) gonioscopy showing angle structures since the angles have opened up.

Figure 3.

(a) AS OCT image. White arrow shows narrowed angle due to forward bowing of iris, (b) AS OCT image. White arrow shows opening up of angle and flattening of iris.

Figure 4.

(a) B scan image showing choroidal effusion, (b) B scan image showing resolution of the effusion.

All patients were asked to discontinue topiramate and started on antiglaucoma medications either only topically or along with systemic medications. Tablet acetazolamide, which is the most commonly prescribed oral antiglaucoma medication, was avoided in these patients as it is a sulpha derivative. They were also given topical anti-inflammatory agents in the form of steroids or non-steroidal anti-inflammatory drugs (NSAIDs). One patient required systemic steroid in tapering doses to tackle the ocular inflammation.

Within 3–10 days, the intraocular pressure had dropped down to normal, the cornea cleared, the anterior chamber deepened (Figure 1(b)), vision improved, and the myopic shift resolved. The previously closed angles opened up, which was confirmed with gonioscopy (Figure 2(b)) and ASOCT (Figure 3(b)). Choroidal effusion resolved (Figure 4(b)). The third patient had atypical presentation of hyperopic shift, disc edema and peripapillary choroid thickening, mimicking conditions like Vogt-Koyanagi-Harada disease causing posterior uveitis. However, this was ruled out after thorough examination by the uvea specialist with investigations such as fundus fluorescein angiography, and optical coherence tomography of the posterior segment.

The signs and symptoms were relieved in most of the patients. However, two patients who presented later than 48 hours showed permanent structural damage: One patient developed cataract in the form of glaucomflecken (anterior lenticular opacities that occur following an episode of acute elevated IOP), requiring a surgical intervention. Yet another patient developed glaucoma requiring anti-glaucoma medications and follow-up. The clinical features, refraction and IOP measurements of all the patients are summarised in Table 1.

Table 1.

Clinical features of topiramate-induced Angle Closure Crisis at presentation and after resolution. Table shows age, sex, duration of topiramate treatment, the vision, spherical refraction (in dioptre) and intraocular pressure (IOP) before and after resolution in the right eye (RE) and left eye (LE). Also included is the treatment received along with stopping topiramate tablet.

Case No.	Age (years)	Sex	Duration of topiramate treatment (days)	Vision		Spherical refraction (dioptre)		IOP (mmHg)		Choroidal effusion		Time taken for resolution (days)	Vision		Spherical refraction (dioptre)		IOP (mmHg)		Choroidal effusion		Treatment received
				At presentation									1–2 weeks after resolution
				RE	LE	RE	LE	RE	LE	RE	LE		RE	LE	RE	LE	RE	LE	RE	LE
1	31	F	7	6/60	6/60	−3	−3	56	53	Yes	Yes	4	6/6	6/6	Nil	Nil	14	14	No	No	A,B,C,D,F
2	31	F	9	4/60	4/60	−6	−6	14*	14*	Yes	Yes	6	6/6	6/6	Nil	Nil	12	12	No	No	B, G
3	44	F	7	6/36	6/24	+0.75	Nil	62	60	Yes	Yes	7	6/6	6/6	+1.5	+0.75	15	12	No	No	A,C, D,E,H
4	48	F	8	6/24	1/60	−1.5	−1.5	42	43	Yes	Yes	10	6/6	6/12	+0.5	+0.5	14	10	No	No	A,B, C, E, H, I
5	25	F	9	3/60	3/60	−8	−8	14*	14*	Yes	Yes	7	6/6	6/6	Nil	Nil	12	12	No	No	A,B
6	46	F	10	6/60	6/36	−3	−3	26	24	Yes	Yes	7	6/6	6/6	Nil	−0.5	14	16	No	No	A, B,C

A: steroid eye drops (dexamethasone/prednisolone) in tapering dose; B: timolol maleate eye drops, C: brimonidine eye drops; D: dorzolamide eye drops; E: intravenous mannitol; F: oral glycerol; G: nepafenac eye drops; H: dexamethasone injection; I: tablet prednisolone in tapering doses.

*Patients with normal IOP who had received antiglaucoma medications from the referring hospital.

Discussion

Our case series summarises the potentially blinding ocular adverse effect of topiramate. However, an accurate diagnosis and prompt initiation of treatment had prevented such eventuality with complete resolution in all patients except for two who had a delayed presentation.

Topiramate has many systemic adverse effects such as paraesthesia, fatigue, weight loss, nausea and diarrhoea (6). Various ocular adverse reactions include myopic shift, visual field defect, suprachoroidal effusions, peri-orbital oedema, scleritis, nystagmus and diplopia (7).

It has been postulated that topiramate and other sulpha-based medications can break the blood ocular barrier and cause an idiosyncratic reaction leading to an increase in the protein content in the ciliochoroidal extravascular space. This osmotic pressure difference causes choroidal expansion and anterior rotation of the ciliary body (8). This pushes the lens-iris diaphragm forward, inducing a myopic shift. Also, ciliary body edema relaxes the lens zonules, leading to anterior bulging of the lens (9). This also adds to the myopic shift. The resulting anatomical configuration causes significant shallowing of the anterior chamber and closes the angle.

All the patients in our series were young females who were prescribed topiramate for headache. Since the history of topiramate usage was reported by the patient/the prescription, a detailed case report on the type of headache for which the drug was started by the physician/neurologist was not available. Upon inquiry, we found that none of the patients were educated about this possible adverse reaction in the eyes. The female preponderance is probably either due to the fact that the incidence of migraine is higher in females (10) or that they have shorter eyes, contributing to higher chances of angle closure. All the patients presented to us within 2 weeks of initiating the therapy. All our patients received 25 mg per day of topiramate tablet, probably suggesting that the ocular side effects are not dose related (5). Literature also suggests that the ocular adverse effect, unlike the systemic ones, are not dose related (7). On the day of presentation, refraction showed a wide range of myopia with poor vision in both eyes except in the third patient, who had hypermetropia probably due to disc edema. Though these patients mostly have a typical presentation, such atypical features should also raise a suspicion in the ophthalmologist’s mind. Patients showed rapid improvement within a few days of treatment. All the patients regained normal to near-normal visual acuity after resolution of the attack, suggestive that there was no pre-existing refractive error.

The majority of the patients are in the younger age group. The condition might reverse once the drug is stopped if patients present at an early stage. Delaying the presentation and continuing the drug can lead to permanent structural damage in the eye, with a potential to cause blindness or compromise the quality of vision for life and might require lifelong follow-up and treatment. Sudden onset blurring of distant vision, especially within days of starting the treatment, must signal a red flag to the physician to ask the patient to stop the drug and consult an ophthalmologist immediately.

There are many such case reports and few case series (7) but mostly published in the ophthalmology journals across the globe, suggesting that probably there is no ethnic preponderance for the effect. As a precaution for practising physicians, a “black box” warning was therefore issued by the FDA (Food and Drug Administration) in 2004, regarding its potential to induce angle closure glaucoma (11). However, a prospective pilot study did not show angle narrowing in asymptomatic patients on topiramate (12). A routine screening of all patients receiving topiramate cannot be warranted, since “at risk” candidates cannot be identified.

Conclusion

Bilateral acute angle closure crisis associated with myopic shift is a rare but important cause of preventable blindness. If this condition can be diagnosed correctly at an appropriate time, it can be reversed by discontinuation of the causative drug. Physicians prescribing topiramate must be well aware of this potentially blinding adverse effect. Before initiating the treatment, the patient should be educated to stop topiramate and to consult an ophthalmologist in case of blurry vision or defective distant vision. Also, the treating ophthalmologist should carefully elicit the drug history and differentiate this condition from other causes of bilateral acute angle closure. However, it would be challenging for the ophthalmologist when there is atypical presentation. A small warning message will help to prevent blindness and preserve the quality of vision in these young patients.

Clinical implications

Topiramate has various ocular adverse reactions, with bilateral angle closure crisis being one of the most common and also most dreadful.

Physicians prescribing topiramate must be well aware of this potentially blinding adverse effect.

Before initiating topiramate, the patient should be educated to stop topiramate and to consult an ophthalmologist in case of blurry vision.

The treating ophthalmologist should carefully elicit the drug history, differentiate this condition from other causes, and be on the lookout for atypical presentation.