Ocular dysfunctions and toxicities induced by antiepileptic medications: Types, pathogenic mechanisms, and treatment strategies

ABSTRACT

Introduction: Ocular dysfunctions and toxicities induced by antiepileptic drugs (AEDs) are rarely reviewed and not frequently received attention by treating physicians compared to other adverse effects (e.g. endocrinologic, cognitive and metabolic). However, some are frequent and progressive even in therapeutic concentrations or result in permanent blindness. Although some adverse effects are non-specific, others are related to the specific pharmacodynamics of the drug.

Areas covered: This review was written after detailed search in PubMed, EMBASE, ISI web, SciELO, Scopus, and Cochrane Central Register databases (from 1970 to 2019). It summarized the reported ophthalmologic adverse effects of the currently available AEDs; their risks and possible pathogenic mechanisms. They include ocular motility dysfunctions, retinopathy, maculopathy, glaucoma, myopia, optic neuropathy, and impaired retinal vascular autoregulation. In general, ophthalmo-neuro- or retino-toxic adverse effects of AEDs are classified as type A (dose-dependent), type B (host-dependent or idiosyncratic) or type C which is due to the cumulative effect from long-term use.

Expert opinion: Ocular adverse effects of AEDs are rarely reviewed although some are frequent or may result in permanent blindness. Increasing knowledge of their incidence and improving understanding of their risks and pathogenic mechanisms are crucial for monitoring, prevention, and management of patients’ at risk.

KEYWORDS:

• Antiepileptic drugs
• gamma-aminobutyric acid (GABA)
• glaucoma
• glutamate
• myopia
• nystagmus
• ocular toxicity
• sodium channels
• visual field defects

Article highlights

• Ocular adverse effects of AEDs do not receive much attention by the treating physicians and researchers compared to other adverse effects as endocrinologic, cognitive and metabolic which are the focus of hundreds of researches and reviews.

• The severities of ocular adverse effects of AEDs vary from asymptomatic or subclinical (detected by quantitative or qualitative techniques) to clinically manifest ocular motility disorders, visual deficiencies or visual loss.

• The ocular adverse reactions of AEDs are classified into three types: type A or dose-dependent which improve with dose reduction or withdrawal, type B or host-dependent (idiosyncratic) which resolve with immediate drug discontinuation and type C which is due to the cumulative drug effect from long-term use and this type needs regular monitoring of patients’ at risk.

• Ocular motility dysfunctions (e.g. impaired saccadic and/or pursuit eye movements, diplopia, nystagmus, gaze palsy, and ophthalmoplegia) are common with some AEDs (e.g. PHT and CBZ). They are type A adverse reactions. However, they may occur with therapeutic drug concentrations in susceptible individuals. They may be a consequence of the negative effect of sodium channel blockade activity of these drugs on brainstem and/or cerebellum functions.

• Retinal toxicities (e.g. color deficiencies, impaired contrast sensitivity, visual field defects, and retinal fiber nerve loss) are common with GABA-ergic AEDs (e.g. VGB, VPA, TPM and TGB). VGB induced visual field loss occurs in 1/3-1/2 of treated adults. They are type C adverse drug reaction. These drugs enhance the levels or activity of GABA in the retina resulting in prolonged depolarization of retinal cells, excitotoxicity, and oxidative stress.

• Secondary acute angle closure glaucoma, acute myopia, and maculopathy may occur with TPM and ZNC. They are type B adverse drug reaction. They are due to cilioeffusion syndrome, an idiosyncratic immune-mediated inflammatory reaction, in response to their sulfonamide molecules.

• Subclinical optic neuropathy occurs with CBZ and VPA. It may be due to the negative effect of sodium channel blockade on ganglion cell axons and optic nerve fibers.

• Increasing knowledge about the incidence of ocular adverse effects of AEDs, improving understanding of their risks and pathogenic mechanisms and increasing awareness of the treating physicians by the ocular adverse effects of AEDs are needed for monitoring of patients’ at risk and their proper management.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.