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Year : 2021  |  Volume : 1  |  Issue : 3  |  Page : 509-511

Dangerous and deadly phenytoin-induced idiosyncratic mydriatic reaction in an epileptic patient precipitating a bilateral acute angle-closure attack

1 Medical Officer, Department of Glaucoma and Research, Mahathma Eye Hospital Private Limited, Trichy, Tamil Nadu, India
2 Medical Officer, Department of Cataract and Refractive Surgery, Mahathma Eye Hospital Private Limited, Trichy, Tamil Nadu, India
3 Chief Medical Officer, Mahathma Eye Hospital Private Limited, Trichy, Tamil Nadu, India
4 Head of Department of Cataract and Refractive Surgery. Mahathma Eye Hospital Private Limited, Trichy, Tamil Nadu, India

Date of Submission03-Sep-2020
Date of Acceptance06-Feb-2021
Date of Web Publication02-Jul-2021

Correspondence Address:
Dr. Prasanna Venkatesh Ramesh
Mahathma Eye Hospital Private Limited, No.6, Seshapuram, Thennur, Trichy - 620 017, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_2862_20

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A 52-year-old woman presented with acute bilateral ocular pain, headache and vomiting. Examination revealed bilateral circum-corneal congestion, 360° closed angles with a shallow chamber and sluggish mid-dilated pupil. Intraocular pressure was 40 and 42 mm Hg in OD and OS respectively. On vigilant history taking, patient revealed administration of Phenytoin for her epileptic event recently. The suspected drug was stopped and the symptoms reversed. YAG PI was performed, visual acuity improved to 20/20 with reduction of intraocular pressures to normal. This case highlights the risk of developing bilateral acute angle-closure attack after Phenytoin administration.

Keywords: Acute attack of angle closure, bilateral acute congestive glaucoma, deadly combination, idiosyncrasy, phenytoin

How to cite this article:
Ramesh PV, Ramesh SV, Rajasekaran R, Ramesh MK. Dangerous and deadly phenytoin-induced idiosyncratic mydriatic reaction in an epileptic patient precipitating a bilateral acute angle-closure attack. Indian J Ophthalmol Case Rep 2021;1:509-11

How to cite this URL:
Ramesh PV, Ramesh SV, Rajasekaran R, Ramesh MK. Dangerous and deadly phenytoin-induced idiosyncratic mydriatic reaction in an epileptic patient precipitating a bilateral acute angle-closure attack. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2021 Jul 28];1:509-11. Available from: https://www.ijoreports.in/text.asp?2021/1/3/509/320020

Several medications can induce a bilateral acute angle-closure glaucoma (AACG) event in predisposing patients (hypermetropics, narrow angles, short-axial length, and shallow anterior chamber). Bilateral drug-induced AACG is an ophthalmic emergency that may lead to persistent visual loss if not treated immediately.

In this report, a rare incidence of bilateral acute angle-closure attack is highlighted due to an idiosyncratic mydriatic reaction triggered by systemic Phenytoin administration.

  Case Report Top

A 52-year-old woman presented with severe acute bilateral ocular pain, decreased visual acuity, headache and vomiting. On evaluation, visual acuity was 20/60 with bilateral circum-corneal congestion, corneal epithelial edema, shallow anterior chamber, 360° closed angles and a sluggish mid-dilated pupil in both eyes [Figure 1]a and [Figure 1]b. Intraocular pressure was 40 and 42 mm Hg in OD and OS, respectively. Fundus examination was hazy but normal. Anterior segment optical coherence tomography (AS-OCT) and Scheimpflug imaging revealed peripheral closed angles and pupillary block phenomenon in both eyes [Figure 2]a, [Figure 2]c, [Figure 2]e and [Figure 2]g. B scan revealed no ciliary body or choroidal involvement [Figure 3]. On detailed history taking, it was noted that the patient had an epileptic event recently (five days back) and post that, was started on Phenytoin 100 mg tablet three times a day. The patient was also taking medication for her systemic hypertension (nifedipine 10 mg TDS) and insomnia (clonazepam 0.5 mg HS) for 15 years. The suspected medication phenytoin was discontinued and substituted later on, and patient was treated with topical anti-glaucoma therapy with intravenous mannitol 20% for the ocular hypertensive event. The symptoms and signs started to reverse [Figure 1]c and [Figure 1]d on removal of phenytoin. Once the cornea cleared, pilocarpine 2% drops were instilled in both eyes and a prophylactic YAG laser peripheral iridotomy (PI) was performed [Figure 4]a and [Figure 4]b. There was an improvement in visual acuity to 20/20, and intraocular pressures reduced to 10 mm Hg and 11 mm Hg, respectively, in OD and OS. Slit-lamp gonioscopic evaluation [Figure 4]c and [Figure 4]d, AS-OCT [Figure 2]b and [Figure 2]d and Scheimpflug imaging [Figure 2]f and [Figure 2]h revealed widening of the angle recess with resolution of the pupillary block phenomenon in both eyes.
Figure 1: (a and b) Angle evaluation on slit-lamp; Van Herickfs Grade 1 in OD and OS respectively. (c and d) Angle evaluation on slit lamp post Phenytoin removal and YAG peripheral iridotomy (PI) in OD and OS respectively; Van Herick fs Grade 3

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Figure 2: (a and c) Anterior segment optical coherence tomography (AS-OCT) of the angles revealing peripheral angle closure in OD and OS respectively. (b and d) AS-OCT revealing widened angle recess post Phenytoin removal and YAG PI in the OD and OS respectively. (e and g) Scheimpflug imaging of angles revealing peripheral angle closure in OD and OS respectively. (f and h) Scheimpflug imaging of the angles revealing widened angle recess post Phenytoin removal and YAG PI in the OD and OS respectively

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Figure 3: (a and b) B scan revealing normal thickness of the choroid in OD and OS respectively

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Figure 4: (a and b) Post . YAG PI (red arrows) slit lamp photography. (c and d) Post YAG PI gonioscopy reveals all the angle structures clearly

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  Discussion Top

The mechanism of bilateral AACG is either, pupillary block or due to nonpupillary block. In this scenario, idiosyncratic mydriatic reaction due to phenytoin triggered a cascade of events possibly by accentuating the already mild idiosyncratic mydriatic action of Clonazepam and Nifedipine, and eventually precipitated a bilateral pupillary block in this hypermetropic patient [Figure 5].
Figure 5: Biometric measurement of OD and OS of this hypermetropic patient revealing the possible predisposing factors such as small axial length, small anterior chamber depth with increased lens thickness (red arrows)

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Phenytoin-related bilateral mydriasis has been poorly reported in the literature, making it is a very rare idiosyncratic reaction.[1] However, according to our knowledge, there are no reports on phenytoin-induced bilateral angle-closure attack in the literature. The mechanism of action for mydriasis caused by it is poorly understood. It is however postulated that due to their weak anticholinergic effect, pupillary dilatation occurs, and increases the aqueous production secondary to increased ciliary body blood flow.[2] Though it can be argued that mydriasis caused by phenytoin alone did not precipitate the attack in the first place, and it could be just an idiosyncratic reaction to other agents such as Clonazepam and Nifedipine; the fact remains that the condition started showing reversal of symptoms after stopping Phenytoin, indicates a causal relationship and moreover the other medications were being taken for more than 15 years. Only Phenytoin was recently added. The best method to prove causality is to re-challenge. However, re-challenging may not be ethical and may sometimes fail to reproduce the event.

Clonazepam also can induce AACG by relaxing the sphincter muscle of the iris by its mild anticholinergic effect.[3],[4] Similarly, nifedipine has been reported to cause prolonged mydriasis and precipitate AACG in predisposed patients.[5] Also, tramadol which is a commonly prescribed opioid for severe pain was unfortunately given for this patient upon presentation to the emergency department with intolerable pain after the acute attack, possibly aggravating it. Tramadol usually causes miosis through stimulation of opioid receptors but rarely mydriasis also occurs through stimulation of the adrenergic receptors.[6],[7],[8] The ubiquitous pupillary response to Tramadol depends on an individual's metabolic abilities. Miosis is more likely to occur in extensive Tramadol metabolites while in intermediate and poor metabolizers, mydriasis develops, because of a delay in conversion of Tramadol to its active metabolite.[9] Unfortunately, this patient seems to be a poor metabolizer.

In this scenario, had the reversal of pupillary block phenomenon not happened after cessation of Phenytoin, then the immediate discontinuation of chronic medications such as Clonazepam and Nifedipine would have been advised, then and there, during the bilateral AACG phase. Also the rational for not stopping or changing the chronic medications (Clonazepam and Nifedipine) immediately was that; had they been the sole reason for the idiosyncratic mydriatic reaction to cause bilateral pupillary block, then the patient would have developed an episode of unilateral/bilateral AACG anytime during the past 15 year period. However, that was not the case for this patient as the patient never gave history of any such episodes in the past 15 years. Hence these chronic systemic medications were not stopped immediately; however, they were changed once the patient's ocular parameters stabilized, after thorough cardiac and psychiatric evaluation during the 1-month follow-up, in view of removing all triggers for dilatation, despite a YAG PI being performed.

One more point highlighted in this report is, though gonioscopy has served as the diagnostic standard for evaluating narrow angles, it requires contact which is not possible in acute attacks. So similar to AS-OCT, Scheimpflug imaging devices offer noncontact modality of angle-closure assessment in such difficult circumstances, where gonioscopy is poorly tolerated.[10]

This case report highlights the fact that drug-induced angle-closure should be suspected in any patient with features of bilateral AACG. Scheimpflug imaging, similar to AS-OCT is helpful in diagnosing this condition. Apart from IOP-lowering measures, a review of systemic medications and discontinuation of the most probable causative agent should be done to manage bilateral AACG for quick and complete visual recovery.

  Conclusion Top

Phenytoin administration may cause an idiosyncratic mydriatic reaction which can precipitate bilateral AACG in predisposed individuals. Also, all clinicians should make a special note of this dangerous and deadly synergistic combination of phenytoin along with nifedipine and clonazepam in predisposed individuals.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

  References Top

European Medicines Agency. European database of suspected adverse drug reactions reports. 2012-2016. Available from: http://www.adrreports.eu/en/index.html.  Back to cited text no. 1
Ioannidis K, Papachristos A, Athanassa Z, Skarlatinis I, Paskalis H. Concentration-related mydriasis in a patient with renal dysfunction treated with phenytoin. Hippokratia 2016;20:166-8.  Back to cited text no. 2
Lachkar Y, Bouassida W. Drug-induced acute angle closure glaucoma. Curr Opin Ophthalmol 2007;18:129-33.  Back to cited text no. 3
Hou RH, Scaife J, Freeman C, Langley RW, Szabadi E, Bradshaw CM. Relationship between sedation and pupillary function: Comparison of diazepam and diphenhydramine. Br J Clin Pharmacol 2006;61:752-60.  Back to cited text no. 4
Roos JC, Haridas AS. Prolonged mydriasis after inadvertent topical administration of the calcium channel antagonist amlodipine: Implications for glaucoma drug development. Cutan Ocul Toxicol 2015;34:84-7.  Back to cited text no. 5
Jaroudi M, Fadi M, Farah F, El Mollayess MG. GlycopyrrolateInduced bilateral angle closure glaucoma after cervical spine surgery. Middle East Afr J Ophtalmol 2013;20:182-4.  Back to cited text no. 6
Tashakori A, Afshari R. Tramadol overdose as a cause of serotonin syndrome: A case series. Clin Toxicol 2010;48:337-41.  Back to cited text no. 7
Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet 2004;43:879-923.  Back to cited text no. 8
Makris A, Matala ME, Tsirigotis A, Karmaniolou I. Apnea and mydriasis after postoperativetramadol administration: An unusual complication and possible underlying mechanisms. Anaesthesia 2012;67:73-84.  Back to cited text no. 9
Grewal D, Brar G, Jain R, Grewal S. Comparison of Scheimpflug imaging and spectral domain anterior segment optical coherence tomography for detection of narrow anterior chamber angles. Eye 2011:25:603-11.  Back to cited text no. 10


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]


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