Seizure 2004; 13: 113–128 doi:10.1016/S1059–1311(03)00082-7 View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector The effect of antiepileptic drugs on visual performance EMMA J. ROFF HILTON †, SARAH L. HOSKING † & TIM BETTS ‡ †Neurosciences Research Institute, School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK; ‡Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital, Birmingham B15 2QZ, UK Correspondence to: Dr Sarah Hosking, Neurosciences Research Institute, School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK. E-mail: [email protected] Visual disturbances are a common side-effect of many antiepileptic drugs. Non-specific retino- and neurotoxic visual abnormal- ities, that are often reported with over-dosage and prolonged AED use, include diplopia, blurred vision and nystagmus. Some anticonvulsants are associated with specific visual problems that may be related to the mechanistic properties of the drug, and occur even when the drugs are administered within the recommended daily dose. Vigabatrin, a GABA-transaminase inhibitor, has been associated with bilateral concentric visual field loss, electrophysiological changes, central visual function deficits including reduced contrast sensitivity and abnormal colour perception, and morphological alterations of the fundus and retina. Topiramate, a drug that enhances GABAergic transmission, has been associated with cases of acute closed angle glaucoma, while tiagabine, a GABA uptake inhibitor, has been investigated for a potential GABAergic effect on the visual field. Only mild neurotoxic effects have been identified for patients treated with gabapentin, a drug designed as a cyclic analogue of GABA but exhibiting an unknown mechanism while carbamazepine, an inhibitor of voltage-dependent sodium channels, has been linked with abnormal colour perception and reduced contrast sensitivity. The following review outlines the visual disturbances associated with some of the most commonly prescribed anticonvulsants. For each drug, the ocular site of potential damage and the likely mechanism responsible for the adverse visual effects is described. © 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved. Key words: GABA; antiepileptic drugs; visual fields; colour perception; contrast sensitivity. INTRODUCTION process3, or the anticonvulsant therapy prescribed to control the seizures. While many mild visual dis- Epileptologists administer antiepileptic drugs with turbances such as diplopia, nystagmus and blurred the combined aim of managing seizures, minimising vision may simply be an early neurotoxic compli- side-effects and maintaining an acceptable quality cation of extended treatment or dosage, other, more of life for the patient. All of the antiepileptic drugs specific ocular complaints may be related to the (AEDs) commonly used to control seizures in the UK unique mechanistic properties of the drug and can are associated with some adverse effects; these range occur even when administered at therapeutic levels. from mild effects such as nausea and weight gain, to Steinhoff et al.4 recommended the retina as a parallel more serious life-threatening complications including model to study the mechanistic properties of anti- renal, hepatic and cardiovascular changes1. The num- convulsant therapy on cortical and cerebral function. ber of marketed AEDs has increased considerably over The retina is ontogenically part of the brain, and the last decade, with many of the newer agents elicit- studies have shown that epileptogenic mechanisms ing fewer side-effects2; visual disturbances, however, including GABAergic and glutamatergic neurotrans- remain a relatively common occurrence (Table 1). mission and ion-dependent membrane conductance Visual disruption in patients diagnosed with are mediators of retinal signal transmission4, 5. The epilepsy may be attributable to either the disease following review will outline the main visual effects 1059–1311/$30.00 © 2003 BEA Trading Ltd. Published by Elsevier Science Ltd. All rights reserved. 114 E. J. Roff Hilton et al. Table 1: Antiepileptic drugs (listed alphabetically), their mechanism of action and visual side-effects. AED Main mechanism of action Visual side-effects Acetazolamide (old) Carbonic anhydrase inhibitor Enhanced ocular blood flow Decreased IOP Benzodiazepine Enhanced GABA-mediated inhibition via Blurred vision, ERG and VEP changes, AEDs (old) benzodiazepine receptor maculopathy, improved nystagmus Carbamazepine (old) Inhibition of voltage-dependent Na+ channels Blurred vision, diplopia, abnormal colour perception, nystagmus, oscillopsia, photosensitivity, altered VEPs Ethosuximide (old) Altered neurotransmitter release Dyskinesia, photophobia, myopia Control of Ca2+ into nerve terminals Modulation of Na+, and Cl− conductance Felbamate (new, but Uncertain mechanism Diplopia, nystagmus little used) Blocks NMDA currents facilitating a GABAergic response Gabapentin (new) Designed as GABA agonist (?) Blurred vision, nystagmus, diplopia, some visual Possible GABA mechanism (?) electrophysiological changes. Impaired critical Glutamate receptor effect (?) flicker frequency, improved post-adaptation thresholds and nystagmus Lamotrigine (new) Reduced glutamate release by inhibiting Blurred vision, diplopia, some visual voltage-sensitive Na+ channels electrophysiological disturbances, nystagmus Levetiracetam (new) Unknown mechanism Diplopia May selectively prevent hypersynchronisation Oxcarbmazepine Block voltage-sensitive Na+ channels Diplopia, blurred vision (new in the UK) Increased K+ conductance and modulation of high-voltage Ca2+ channels Phenobarbitone (old) Potentiation of GABA-A receptor activation No major visual effects reported Phenytoin (old) Inhibition of voltage-dependent Na+ channels Dyskinesia, nystagmus, ophthalmoplegia, blurred vision, disturbed colour perception Primidone (old) Unclear mechanism related to drug metabolism Diplopia, nystagmus Potentiation of GABAergic synaptic activity Sodium valproate (old) Enhanced GABAergic inhibition (?) Some reports of abnormal colour perception and Inhibition of voltage-dependent sodium channels altered VEPs Topiramate (new) Enhances GABA Cl− channels Diplopia, acute myopia and angle closure glaucoma Positive effect on GABA-A receptor Kainite inhibition Carbonic-anhydrase inhibition State-dependent sodium channel-blocking action Tiagabine (new) GABA reuptake inhibitor Abnormal colour perception, blurred vision, nystagmus, diplopia Vigabatrin (new) GABA-transaminase inhibitor enhances inhibitory Diplopia, nystagmus, peripheral visual field loss, neurotransmission colour perception abnormalities, retinal abnormalities, optic nerve pallor, visual electrophysiological changes, reduced contrast sensitivity, reduced ocular blood flow associated with anticonvulsant therapy; the drugs between 60 and 70% of all synapses7. Investigations will be grouped by their mechanisms of action, have revealed that GABA is similarly important in with special attention to the new GABAergic acting retinal neural inhibition where approximately 40% of drugs. all retinal cells are immunoreactive to it8. Tradition- ally, light microscopic findings have led to the human retina being described as 10 functional layers of cells GABAergic CELLS OF THE RETINA (Fig. 1). Of these, subpopulations of amacrine and hor- izontal cells, bipolar cells, interplexiform cells, Müller ␥-Aminobutyric acid (GABA) is the main inhibitory cells and retinal ganglion cells have been described as neurotransmitter in the mammalian brain6 influencing GABAergic8–11. The effect of antiepileptic drugs on visual performance 115 Fig. 1: Anatomy of the human retina. GABA is synthesised in the presynaptic nerve ter- There are several ways in which anticonvulsant minal from glutamate by the enzyme glutamic acid drugs may enhance inhibitory neurotransmission decarboxylase (GAD). GABA containing vesicles (Fig. 2): GABA-mediated increases in chloride con- release the neurotransmitter into the synaptic cleft ductance may be enhanced; GABA levels may be where it diffuses across to bind with GABA recep- raised by stimulating the enzyme GAD; the release tors on the post-synaptic neuron. Three heterogenous of GABA may be enhanced; and, the reuptake and receptors are known to exist in the vertebrate retina degradation of GABA may be inhibited. and central nervous system; GABA-A, GABA-B and GABA-C subtypes10. GABA-A and GABA-C re- ceptors are particularly abundant in the retina12, 13 AEDs UTILISING GABAergic MECHANISMS where receptor binding triggers the opening of chlo- ride channels which is inhibitory to neuronal firing. Vigabatrin GABA-C receptors differ markedly from the other subtypes in two main ways: (1) they are highly sen- Visual field loss sitive to GABA14, thus even at low concentrations the neurotransmitter can initiate a response; and (2) Vigabatrin (␥-vinyl GABA) elicits an antiepileptic ef- they initiate a sustained response to GABA, rather fect by binding irreversibly to GABA-transaminase17, than a transient response which is true for GABA-A thereby increasing GABA levels and enhancing in- receptors10. The inhibitory action of GABA is lim- hibitory neurotransmission in the brain. Vigabatrin ited via active reuptake into the presynaptic nerve has been targeted largely at the management of par- terminals and surrounding glial cells. To date, four tial seizures and infantile spasms and was