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Antiepileptic Drugs and Ophthalmologic Problems 

Antiepileptic Drugs and Ophthalmologic Problems
Chapter:
Antiepileptic Drugs and Ophthalmologic Problems
Author(s):

Ali A. Asadi-Pooya

and Michael R. Sperling

DOI:
10.1093/med/9780190214968.003.0027
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Ophthalmologic problems in patients with epilepsy may be due to either the disease process or therapy with antiepileptic drugs (AEDs). Visual disturbances such as blurred vision, diplopia, and oscillopsia are generally benign, reversible, dose-dependent neurotoxic side effects of AEDs (Table 27.1). The dose of medication simply needs to be reduced or the dosing frequency increased to abolish this complaint in most instances. However, some patients have visual complaints at relatively low serum levels, and the offending AED must be stopped and replaced with another.

Table 27.1 Visual Adverse Effects of Antiepileptic Drugs

Antiepileptic Drug

Visual Adverse Effects

Acetazolamide

Enhanced ocular blood flow, decreased intra-ocular pressure

Benzodiazepine

Blurred vision, visual electrophysiological changes, maculopathy

Carbamazepine

Blurred vision, diplopia, abnormal color perception, nystagmus, oscillopsia (illusionary movements of objects), altered visual evoked potentials (VEPs), ophthalmoplegia

Eslicarbazepine acetate

Diplopia, blurred vision, impaired vision, nystagmus

Ethosuximide

Photophobia, myopia

Ezogabine

Retinal pigmentary abnormalities, blurred vision, diplopia, nystagmus

Felbamate

Blurred vision, diplopia, miosis, hemianopia, conjunctivitis

Gabapentin

Amblyopia, blurred vision, nystagmus, diplopia, visual electrophysiological changes, impaired critical flicker frequency

Lacosamide

Diplopia, blurred vision, nystagmus

Lamotrigine

Blurred vision, diplopia, visual electrophysiological disturbances, nystagmus

Levetiracetam

Blurred vision, diplopia

Oxcarbazepine

Diplopia, blurred vision

Perampanel

Diplopia, blurred vision

Phenobarbital

Blurred vision, miosis, mydriasis, ophthalmoplegia

Phenytoin

Nystagmus, ophthalmoplegia, blurred vision, diplopia, disturbed color perception

Pregabalin

Blurred vision, diplopia, nystagmus, conjunctivitis

Primidone

Blurred vision, diplopia, nystagmus, ophthalmoplegia

Rufinamide

Diplopia, blurred vision, nystagmus

Tiagabine

Abnormal color perception, blurred vision, nystagmus, diplopia

Topiramate

Blurred vision, diplopia, acute myopia, acute angle closure glaucoma, suprachoroidal effusions, nystagmus, conjunctivitis

Valproate

Abnormal color perception, altered VEPs, blurred vision, diplopia, nystagmus

Vigabatrin

Diplopia, nystagmus, peripheral visual field loss, color perception abnormalities, retinal abnormalities, optic nerve pallor, visual electrophysiological changes, reduced contrast sensitivity, reduced ocular blood flow

Zonisamide

Blurred vision, diplopia, nystagmus

Other ocular complaints may be related to the unique mechanistic properties of the drug and can occur when they are administered at therapeutic levels. This is true of vigabatrin and ezogabine, which have special retinal toxicity that has greatly limited their use.

Ezogabine

Ezogabine can cause abnormalities of the retina. These abnormalities have funduscopic features similar to those seen in retinal pigment dystrophies that are known to result in damage to photoreceptors and vision loss. Approximately, one-third of the patients who had ophthalmologic examinations performed after 4 years of treatment were found to have retinal pigmentary abnormalities. Funduscopic abnormalities have most commonly been described as perivascular pigmentation (bone spicule pattern) in the retinal periphery and/or as areas of focal retinal pigment epithelium clumping. The rate of progression of retinal abnormalities and the reversibility after drug discontinuation are unknown.

Because of the observed ophthalmologic adverse reactions, ezogabine should only be used in patients who have responded inadequately to several alternative AEDs and for whom the benefits outweigh the risks. Patients who fail to show substantial clinical benefit after adequate titration should be discontinued from ezogabine. Patients should have baseline ophthalmologic testing and follow-up testing every 6 months. The ophthalmologic monitoring program should include visual acuity testing and dilated fundus photography. Additional testing may include fluorescein angiograms (FA), ocular coherence tomography (OCT), perimetry, and electroretinograms (ERG). If retinal pigmentary abnormalities or vision changes are detected, ezogabine should be discontinued unless no other suitable treatment options are available and the benefits of treatment outweigh the potential risk of vision loss.

Vigabatrin

A drug that acts on the GABAergic pathway, vigabatrin causes a visual disturbance (Hilton et al., 2004; Bhattacharyya & Basu, 2005). This is due to the concentration of this drug in retinal glial cells that results in toxicity, ultimately affecting foveal and peripheral cone cells. Other AEDs that act on GABAergic pathways do not accumulate in the retina to the same extent as vigabatrin and do not have retinal toxicity.

The onset of vision loss from vigabatrin is unpredictable and can occur at any time after starting treatment. Symptoms of vision loss from vigabatrin are unlikely to be recognized by patients or caregivers before vision loss is severe. Vigabatrin-associated visual disturbances can be identified with electroretinograms and visual field perimetry. Perimetry defects characteristically present as bilateral concentric nasal constriction with temporal and central sparing, a pattern rarely seen in other conditions. Approximately, 30% (20%–50%) of epilepsy patients receiving the drug at normal therapeutic doses have visual field abnormalities (You et al., 2006). Men receiving vigabatrin are more susceptible to visual field constriction than are women, and adults are probably more susceptible than are children. The vast majority of patients with vigabatrin-associated visual field constriction are asymptomatic. In clinical practice, patients with visual field defects often remain asymptomatic until the defect impinges on, or is close to, fixation; this is particularly likely in the case of binasal defects where the preserved temporal visual field in each eye enables patients to retain good mobility. Longitudinal investigations of vigabatrin-associated visual field loss have reported the defects to be permanent, persisting even after patients are withdrawn from the drug (Hilton et al., 2004). However, visual field defects were found to be reversible in two children treated with vigabatrin when the drug was withdrawn (Nabbout, 2001).

For this reason, vigabatrin is reserved for situations when no other drug offers hope or when a short-term course of therapy is planned. For children with tuberous sclerosis who have infantile spasms, the benefits of vigabatrin monotherapy appear to outweigh the risks (Nabbout, 2001; Hilton et al., 2004; You et al., 2006). It is not clear that other conditions warrant the use of this agent. When treatment with vigabatrin is indicated, visual field testing (e.g., perimetry) should be carried out at the start of treatment (within 4 weeks of the start of treatment) and at regular time intervals (every 3 months); electroretinography may help detect abnormalities as well, perhaps before field loss appears (Figure 27.1). Finally, vigabatrin should be withdrawn from patients with refractory complex partial seizures within 3 months of initiation and within 2 to 4 weeks of initiation for patients with infantile spasms, who fail to show substantial clinical benefit.


Figure 27.1 Recommended screening algorithm for patients with (a) complex partial seizures and (b) infantile spasms, taking vigabatrin.

Figure 27.1 Recommended screening algorithm for patients with (a) complex partial seizures and (b) infantile spasms, taking vigabatrin.

ERG: Electroretinography; OCT: Optical coherence tomography; VGB: Vigabatrin; pVFD: Peripheral visual field defect.

Adapted from: Sergott RC, Wheless JW, Smith MC, Westall CA, Kardon RH, Arnold A, Foroozan R, Sagar SM. Evidence-based review of recommendations for visual function testing in patients treated with Vigabatrin. Neuro-Ophthalmology 2010;34(1): 20–35.

Because of the risk of permanent vision loss, vigabatrin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Support, Help and Resources for Epilepsy (SHARE) program.

Other Antiepileptic Drugs

Ocular pathology is rarely provoked by topiramate. This drug can cause acute myopia and secondary closed angle glaucoma without pupillary block. These findings are more common in females, occur when serum levels are within a normal therapeutic range, and usually appear within the first month of therapy. The symptoms include an acute onset of decreased visual acuity and/or ocular pain. Ophthalmologic examination may reveal myopia, ocular hyperemia, shallowing of the anterior chamber, and elevated intraocular pressure, with or without pupil dilation; choroidal effusions have also been described. It has been suggested that supraciliary effusion and ciliary body swelling may displace the lens and iris anteriorly, secondarily resulting in angle closure glaucoma (Hilton et al., 2004; Bhattacharyya & Basu, 2005).

Benzodiazepines are reportedly contraindicated in patients with acute closed-angle glaucoma according to recommendations of official drug information materials. However, a systematic review of the literature reveals that this contraindication is based on only one published case, while 22 other investigations, some of them controlled, found that benzodiazepines reduce intraocular pressure (Fritze et al., 2002). Hence, this recommendation is probably not valid, and benzodiazepines may be used in patients with glaucoma.

Ophthalmoplegia has been reported consequent to administration of phenytoin, phenobarbital, primidone, and carbamazepine. Phenytoin can induce external ophthalmoplegia whether administered orally or intravenously. Incomplete as well as complete ophthalmoplegia has been reported with phenytoin even within therapeutic range (Fredericks et al., 1986; Spector and Davidoff, 1976; Puri and Chaudhry, 2004; Drugs’ websites).

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