Abstract
A variety of newer antiepileptic drugs (AEDs) are now available for treating patients with epilepsy in addition to the ‘conventional’ drugs that have been available throughout a large part of the last century. Since these drugs act to suppress the pathological neuronal hyperexcitability that constitutes the final substrate in many seizure disorders, it is not surprising that they are prone to causing adverse reactions that affect the CNS.
Information on adverse effects of the older AEDs has been mainly observational. Equally, whilst the newer drugs have been more systematically studied, their long-term adverse effects are not clearly known. This is illustrated by the relatively late emergence of the knowledge of visual field constriction in the case of vigabatrin, which only became known after several hundred thousand patient-years of use. However, older drugs continue to be studied and there has been more recent comment on the possible effect of valproate (valproic acid) on cognition following exposure to this drug in utero.
With most AEDs, there are mainly dose-related adverse effects that could be considered generic, such as sedation, drowsiness, incoordination, nausea and fatigue. Careful dose titration with small initial doses can reduce the likelihood of these adverse effects occurring. Adverse effects such as paraesthesiae are more commonly reported with drugs such as topiramate and zonisamide that have carbonic anhydrase activity. Weight loss and anorexia can also be peculiar to these drugs. Neuropsychiatric adverse effects are reported with a variety of AEDs and may not be dose related. Some drugs, such as carbamazepine when used to treat primary generalized epilepsy, can exacerbate certain seizure types. Rare adverse effects such as hyperammonaemia with valproate are drug specific. There are relatively very few head-to-head comparisons of AEDs and limited information is available in this regard.
In this review, we discuss the available literature and provide a comprehensive summary of adverse drug reactions of AEDs affecting the CNS.
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References
Femer RE, Aronson JK. Communicating information about drug safety. BMJ 2006; 333: 143–5
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamo-trigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1000–15
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369: 1016–26
Perucca E, Alexandre Jr V, Tomson T. Old versus new antiepileptic drugs: the SANAD study [letter]. Lancet 2007; 370: 313
Twyman RE, Rogers CJ, Macdonald RL. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 1989; 25: 213–20
Koeppen D. A review of clobazam studies in epilepsy. In: Hindmarch I, Stonier PD, Trimble MR, editors. Clobazam, human psychopharmacology and clinical applications. London: Royal Society of Medicine; 1985: 1207–15
Cull CA, Trimble MR. Anticonvulsant benzodiazepines and performance. In: Hindmarch I, Stonier PD, Trimble MR, editors. Clobazam, human psychopharmacology and clinical applications. London: The Royal Society of Medicine, 1985: 121–8
Bawden HN, Camfield CS, Camfield PR, et al. The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy. Epilepsy Res 1999; 33(2–3): 133–43
Naito H, Wachi M, Nishida M. Clinical effects and plasma concentrations of long-term clonazepam monotherapy in previously untreated epileptics. Acta Neurologica Scandinavica 1987; 76: 58–63
Rothschild AJ, Shindul-Rothschild, Vinguera A, et al. Comparison of the frequency of behavioural disinhibition on alprazolam, clonazepam, or no benzodiazepine in hospitalized psychiatric patients. J Clin Psychopharmacol 2000; 20: 7–11
Sato S, Penry JK, Dreifuss FE, et al. Clonazepam in the treatment of absence seizures. Neurology (Minneap) 1977; 27: 371
Colasanti BK, Craig CR. Reduction of seizure frequency by clonazepam during cobalt experimental epilepsy. Brain Res Bull 1992; 28: 329–31
Specht U, Boenigk HE, Wolf P. Discontinuation of clonazepam after long-term treatment. Epilepsia 1989; 30: 458–63
Wong T, Tiessen E. Scizure in gradual clonazepam withdrawal. Psychiatr J Univ Ottawa 1989; 14: 484
Bittencourt PRM, Richens A. Anticonvulsant-induced status epilepticus in Lennox-Gastaut syndrome. Epilepsia 1981; 22: 129–34
Bladin PF. The use of clonazepam as an anticonvulsant-clinical evaluation. Med J Aust 1973; 1: 683–8
Munthe-Kaas AW, Strandjord RE. Clonazepam in the treatment of epileptic seizures. Acta Neurol Scand 1973; 49: 97–102
Rosebuch PI, Mazurek MF. Catatonia after benzodiazepine withdrawal. J Clin Psychopharmacol 1996; 16: 315–9
Schwartz JR, Grigat G. Phenytoin and carbamazepine: potential and frequency-dependent block of Na currents in mammalian myelinated nerve fibres. Epilepsia 1989; 30: 286–94
Collaborative Group for Epidemiology of Epilepsy. Adverse reactions to antiepileptic drugs: a follow-up study of 355 patients with chronic antiepileptic drug treatment. Epilepsia 1988; 29: 787–93
Smith DB, Mattson RH, Cramer J, et al. Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbitone, phenytoin and primidone. Epilepsia 1987; 28 Suppl. 3: S50–8
Chadwick DW, Shaw MDM, Foy P, et al. Serum anticonvulsant concentrations and the risk of drug-induced skin eruptions. J Neurol Neurosurg Psychiatry 1984; 47: 642–4
Brent DA, Crumrine PK, Varma RR, et al. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987; 80: 909–17
Pellock JM. Carbamazepine side effects in children and adults. Epilepsia 1987; 28 Suppl. 3: S64–70
Schmitz B, Trimble MR. PIP-syndrome in temporal lobe epilepsy. Epilepsy Res 1995; 22: 215–20
Dalby MA. Behavioural effects of carbamazepine. In: Penry JK, Daly DD, editors. Complex partial seizures and their treatment. Advances in neurology. Vol. 11. New York: Raven Press, 1975: 331–43
Drake ME, Peruzzi WT. Manic state with carbamazepine therapy of seizures. J Natl Med Assoc 1986; 78: 1105–10
Gorman M, Barkley GL. Oculogyric crisis induced by carbamazepine. Epilepsia 1995; 36(11): 1158–60
Jacome D. Carbamazepine-induced dystonia [letter]. JAMA 1979; 241(21): 2263
Thomas P, Valton L, Genton P. Absence and myoclonic status epilepticus precipitated by antiepileptic drugs in idiopathic generalized epilepsy. Brain 2006; 129(5): 1281–92
Perucca E, Gram L, Avanzini G, et al. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39(1): 5–17
Snead OC, Hosey LC. Exacerbation of seizures in children by carbamazepine. New Engl J Med 1985; 313: 916–21
Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann Neurol 1989; 25: 582–93
Browne T. Ethosuximide (Zarontin) and other succinimides. In: Browne T, Feldman R, editors. Epilepsy, diagnosis and management. Boston (MA): Little, Brown, 1983: 215–24
Sato S, White BG, Penry JK, et al. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology 1982; 32(2): 157–63
Martinovic Z. Comparison of ethosuximide with sodium valproate as monotherapies of absence seizures. In: Parsonage M, Grant R, Craig A, et al., editors. Advances in epileptology: XIVth Epilepsy International Symposium. New York: Raven Press, 1983: 301–5
Callaghan N, O’Hare J, O’Driscoll D, et al. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol 1982; 24(6): 830–6
Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia 1999; 40 Suppl. 10: S65–70
Dreifuss F. Ethosuximide: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. New York: Raven Press, 1995: 675–9
Todorov A, Lenn N, Gabor A. Exacerbation of generalized non-convulsive seizures with ethosuximide therapy. Arch Neurol 1978; 35: 389–91
Snead OC. Scizure aggrevation: clinical assessment and role of AEDs. Antiepileptic Therapy Symposium, 2005; Washington, DC
Goldensohn E, Hardie J, Borea E. Ethosuximide in the treatment of epilepsy. JAMA 1962; 180: 840–2
Wang WZ, Wu JZ, Ma GY, et al. Efficacy assessment of phenobarbital in epilepsy: a large community-based intervention trial in rural China. Lancet Neurol 2006; 5(1): 46–52
Nimaga K, Desplats D, Duoumbo O, et al. Treatment with phenobarbital and monitoring of epileptic patients in rural Mali. Bull World Health Organ 2002; 80(7): 532–7
Pal DK, Das T, Chaudhury G, et al. Randomised controlled trial to assess acceptability of phenobarbital for childhood epilepsy in rural India. Lancet 1998; 351(9095): 19–23
Theodore WH. Rational use of antiepileptic drug levels. Pharmacol Ther 1992; 54: 297–305
Pritchard JW, Mattson RA. Barbiturates: an update. In: Pedley TA, Meldrum BS, editors. Recent advances in epilepsy. Edinburgh: Churchill Livingstone, 1986: 261–77
Vining EP, Mellitis ED, Dorsen MM, et al. Psychological and behavioural effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. Pediatrics 1987; 80: 165–74
Cramer J, Mattson RH. Phenobarbital: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 409–20
Farwell JR, Lee YJ, Hirtz DG, et al. Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence [published erratum appears in N Engl J Med 1992 Jan 9; 326 (2): 144]. New Engl J Med 1990; 322(6): 364–9
Reinisch JM, Sanders SA, Mortensen EL, et al. In utero exposure to phenobarbital and intelligence deficits in adult men. JAMA 1995; 274: 1518–25
Heller AJ, Chesterman P, Elwes RD, et al. Phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed adult epilepsy: a randomised comparative monotherapy trial. J Neurol Neurosurg Psychiatry 1995; 58(1): 44–50
Taylor S, Tudor SC, Williamson PR, et al. Phenobarbitone versus phenytoin monotherapy for partial-onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev 2001; (4): CD002217
Mattson RH, Cramer J, Collins JF, et al. Comparison of carbamazepine, phenobarbital phenytoin, and primidone in partial and secondarily generalised tonic-clonic seizures. New Engl J Med 1985; 313: 145–51
Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia 2004; 45(9): 1141–9
Meador KJ, Loring DW, Huh K, et al. Comparative cognitive effects of anticonvulsants. Neurology 1990; 40: 391–4
Vandam LD, Collins WL. Recovery from acute phenobarbital intoxication after prolonged coma. JAMA 1963 Apr 20; 184: 239–41
Guerrini R, Belmonte A, Strumia S, et al. Exacerbation of epileptic negative myoclonus by carbamazepine or phenobarbital in children with atypical benign rolandic epilepsy. Epilepsia 1995; 36 Suppl. 3: S65
Wilder BJ, Rangel RJ. Clinically relevant antiepileptic drug interactions. In: WH Pitlick, editor. Antiepileptic drug interactions. New York: Demos Publications, 1989: 65–75
Kutt H, Winters W, Kokenge R, et al. Diphenylhydantoin metabolism, blood levels and toxicity. Arch Neurol 1964; 11: 642–8
Chua HC, Venketasubramanian N, Tan CB, et al. Paradoxical seizures in phenytoin toxicity. Singapore Med 1999; 40: 276–7
McLellan DL, Swash M. Choreo-athetosis and encephalopathy induced by phenytoin. BMJ 1974; 2: 204–5
Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J Neurol Neurosurg Psychiatry 1982; 47: 621–6
Bayer AU, Thiel HJ, Zrenner E, et al. Color vision tests for early detection of antiepileptic drug toxicity. Neurology 1997; 48: 1394–7
Trimble MR. Anticonvulsant drugs and cognitive function: a review of the literature. Epilepsia 1987; 28 Suppl. 3: S37–45
Aldenkamp AP, Alpherts WC, Diepman L, et al. Cognitive side effects of phenytoin compared with carbamazepine in patients with localization-related epilepsy. Epilepsy Res 1994; 19: 37–43
Kalviainen R, Aikia M, Riekkinen P. Cognitive adverse effects of antiepileptic drugs: incidence, mechanisms and therapeutic implications. CNS Drugs 1996; 5: 358–68
Tudur SC, Marson AG, Williamson PR. Phenytoin versus valproate monotherapy for partial-onset seizures and generalized onset tonic-clonic seizures. Cochrane Database Syst Rev 2001; (4): CD001769
Tudur SC, Marson AG, Clough HE, et al. Carbamazepine versus phenytoin monotherapy for epilepsy. Cochrane Database Syst Rev 2002; (2): CD001911
Ney GC, Lantos G, Barr WB, et al. Cerebellar atrophy in patients with long-term phenytoin exposure. Arch Neurol 1994; 51(8): 767–71
Leppick I, Cloyd JC. Primidone: toxicity. In: Levy RH, Mattson RH, Meldrum BS, editors. Antiepileptic drugs. 4th ed. New York: Raven Press, 1995: 487–90
Randomised study of antiepileptic drug withdrawal in patients in remission. Medical Research Council Antiepileptic Drug Withdrawal Study Group. Lancet 1991; 337(8751): 1175–80
McLean MJ, Macdonald RL. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237: 1001–11
Kelly KM, Gross RA, Macdonald RL. Valproic acid selectivity reduces the low-threshold calcium current in rat nodose neurons. Neurosci Lett 1990; 116: 233–8
Goulden KJ, Dooley JM, Camfield PR, et al. Clinical valproate toxicity induced by acetylsalicylic acid. Neurology 1987; 37: 1392–4
Trimble MR, Thompson PJ. Sodium valproate and cognitive function. Epilepsia 1984; 25: S60–4
Meador KJ, Loring DW, Hulihan JF, et al. Differential cognitive and behavioural effects of topiramate and valproate. Neurology 2003; 60(9): 1483–8
Keranen T, Sivenius J. Side effects of carbamazepine, valproate and clonazepam during long-term treatment of epilepsy. Acta Neurol Scand Suppl 1983; 97: 69–80
Masmoudi K, Gras-Champel V, Mason H, et al. Parkinsonism and/or cognitive impairment with valproic acid therapy: a report of ten cases. Pharmacopsychiatry 2006; 39(1): 9–12
Murphy JV, Marquardt K. Asymptomatic hyperammonemia in patients receiving valproic acid. Arch Neurol 1982; 39: 591–3
Vossler DG, Wilensky AJ, Cawthorn DF, et al. Serum and CSF glutamine levels in valproate-related hyperammonemic encephalopathy. Epilepsia 2002; 43: 154–9
Verrotti A, Trotta D, Morgese G, et al. Valproate-induced hyperammonemic encephalopathy. Metab Brain Dis 2002; 17: 367–73
Triggs WJ, Bohan TP, Lin S, et al. Valproate-induced coma with ketosis and carnitine insufficiency. Arch Neurol 1990; 47: 1131–3
Rottach KG, Weiss-Brummer J, Wieland U, et al. Valproic acid in prophylaxis of bipolar disorder: a case of valproate-induced encephalopathy. Nervenarzt 2000; 71: 401–3
Reif A, Leonhard C, Mossner R, et al. Encephalopathy and myoclonus triggered by valproic acid. Prog Neuropsycho-pharmacology Biol Psychiatry 2004; 28: 1061–3
Vinten J, Adab N, Kini U, et al. Neuropsychological effects of exposure to anticonvulsant medication in utero. Neurology 2005; 64(6): 949–54
Motamedi GK, Meador KJ. Antiepileptic drugs and neurodevelopment. Curr Neurol Neurosci Rep 2006; 6(4): 341–6
Lhatoo SD, Wong IC, Polizzi G, et al. Long-term retention rates of lamotrigine, gabapentin, and topiramate in chronic epilepsy. Epilepsia 2000; 41(12): 1592–6
Depondt C, Yuen AW, Bell GS, et al. The long term retention of levetiracetam in a large cohort of patients with epilepsy. J Neurol Neurosurg Psychiatry 2006; 77(1): 101–3
Pellock JM, Watermberg N. New antiepileptic drugs in children: present and future. Semin Pediatr Neurol 1997; 4: 9–18
Pisani A, Spadoni F, Bernadi G. Electrophysiological actions of felbamate on rat striatal neurones. Br J Pharmacol 1995; 116: 2053–61
McCabe RT, Wasterlain CG, Kucharezyk N, et al. Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors. J Pharmacol Exp Ther 1993; 26: 1248–52
Leppick I. Felbamate. Epilepsia 1995; 36 Suppl. 2: S66–72
Bourgeois B. Felbamate. Semin Pediatr Neurol 1997; 4: 3–8
O’Neil MG, Perdun CS, Wilson MB, et al. Felbamate-associated fatal acute hepatic necrosis. Neurology 1996; 46: 1457–9
Wamil AW, McLean MJ. Limitation by gabapentin of high frequency action potential firing by mouse central neurons in cell culture. Epilepsy Res 1994; 17(1): 1–11
Gotz E, Feuerstein TJ, Lais A, et al. Effects of gabapentin on release of gamma-amminobutyric acid from slices of rat neostriatum. Arzneimittelforschung 1993; 43(6): 636–8
Gee NS, Brown JP, Dissanayake VU, et al. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 1996; 271(10): 5768–76
Hill DR, Suman-Chauhan N, Woodruff GN. Localization of [3H]gabapentin to a novel site in rat brain: autoradiographic studies. Eur J Pharmacology 1993; 244(3): 303–9
Cramer J, Fisher R, Ben-Menachem E, et al. New antiepileptic drugs: a comparison of key clinical trials. Epilepsia 1999; 40: 590–600
Devinsky O, Cramer J. Safety and efficacy of standard and new antiepileptic drugs. Neurology 2000; 55Suppl. 3: 5–10
Marson AG, Kadir ZA, Hutton JL, et al. The new antiepileptic drugs: a systematic review of their efficacy and tolerability. Epilepsia 1997; 38(8): 859–80
Gabapentin as add-on therapy in refractory partial epilepsy: a double-blind, placebo-controlled, parallel-group study. The US Gabapentin Study Group. Neurology 1993; 43(11): 2292–8
Gabapentin in partial epilepsy. UK Gabapentin Study Group. Lancet 1990; 335(8698): 1114–7
Anhut H, Ashman P, Feuerstein TJ, et al. Gabapentin (Neurontin) as add-on therapy in patients with partial seizures: a double-blind, placebo-controlled study. The International Gabapentin Study Group. Epilepsia 1994; 35(4): 795–801
Sivenius J, Kalviainen R, Ylinen A, et al. Double-blind study of gabapentin in the treatment of partial seizures. Epilepsia 1991; 32(4): 539–42
Litzinger MJ, Wiscombe N, Hanny A, et al. Increased seizures and aggression seen in persons with mental retardation and epilepsy treated with Neurontin [abstract]. Epilepsia 1995; 36Suppl. 4: 71
Doherty KP, Gates JR, Penovich PE, et al. Gabapentin in a medically refractory epilepsy population: seizure response and unusual side effects [abstract]. Epilepsia 1995; 36Suppl. 4: 71
Asconape J, Diedrich A, DellaBadia J. Myoclonus associated with the use of gabapentin. Epilepsia 2000; 41: 479–81
Leach JP, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neuro-chemical studies on the mechanism of action. Epilepsia 1986; 27: 490–7
Cheung H, Kamp D, Harris E. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 1992; 13: 107–12
Morrow J, Russell A, Guthrie L, et al. Malformation risks of antiepileptic drugs in pregnancy: a prospective study from the UK Epilepsy and Pregnancy Register. J Neurol Neurosurg Psychiatry 2006; 77: 193–8
Biton V, Sackellares JC, Vuong A, et al. Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. Neurology 2005; 65(11): 1737–43
Gamble C, Williamson PR, Chadwick DW, et al. A meta-analysis of individual patient responses to lamotrigine or car-bamazepine therapy. Neurology 2006; 66(9): 1310–7
Gamble C, Williamson PR, Marson AG. Lamotrigine versus carbamazepine monotherapy for epilepsy. Cochrane Database Syst Rev 2006; (1): CD001031
Matsuo F, Bergen D, Faught E, et al. Placebo-controlled study of the efficacy and safety of lamotrigine in patients with partial seizures. US Lamotrigine Protocol 0.5 Clinical Trial Group. Neurology 1993; 43(11): 2284–91
Binnie CD, Debets RM, Engelsman M, et al. Double-blind crossover trial of lamotrigine (Lamictal) as add-on therapy in intractable epilepsy. Epilepsy Res 1989; 4(3): 222–9
Jawad S, Richens A, Goodwin G, et al. Controlled trial of lamotrigine (Lamictal) for refractory partial seizures. Epilepsia 1989; 30(3): 356–63
Loiseau P, Yuen AW, Duche B, et al. A randomized double-blind placebo controlled crossover add-on trial of lamotrigine in patients with treatment resistant partial seizures. Epilepsy Res 1990; 7(2): 136–45
Messenheimer J, Ramsay RE, Willmore LJ, et al. Lamotrigine therapy for partial seizures: a multicenter, placebo-controlled, double-blind, crossover trial. Epilepsia 1994; 35(1): 113–21
Schapel GJ, Beran RG, Vajda FJ, et al. Double blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant partial seizures. J Neurol Neurosurg Psychiatry 1993; 56(5): 448–53
Smith D, Baker G, Davies G, et al. Outcomes of add on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34(2): 312–22
Committee on Safety of Medicines and the MHRA (medicines). Reminder: lamotrigine (Lamictal) and serious skin reactions. Curr Probl Pharmacovigilance 1996; 22: 12
Messenheimer J, Mullens EL, Giorgi L, et al. Safety review of adult clinical trial experience with lamotrigine. Drug Saf 1998; 18(4): 281–96
Beran RG, Gibson RJ. Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia 1998; 39(3): 280–2
Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Drug Saf 2000; 23(1): 35–56
Aldenkamp AP, Arends J, Bootsman PR, et al. Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers. Epilepsia 2002; 43(1): 19–26
Smith D, Baker G, Davies G, et al. Outcomes of add-on treatment with lamotrigine in partial epilepsy. Epilepsia 1993; 34: 312–22
Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia 1998; 39(5): 508–12
Biraben A, Allain H, Scarabin JM, et al. Exacerbation of juvenile myoclonic epilepsy with lamotrigine. Neurology 2000; 55(11): 1757–8
Lynch AA, Lamberg N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci 2004; 101(26): 9861–6
Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomised, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000; 41(9): 1179–86
Ramael S, Daoust A, Otoul C, et al. Levetiracetam intravenous infusion: a randomised, placebo-controlled safety and pharma-cokinetic study. Epilepsia 2006; 47(7): 1128–35
Mula M, Trimble MR, Yuen AW, et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003; 61(5): 704–6
Brodtkorb E, Klees TM, Nakken KO, et al. Levetiracetam in adult patients with and without learning disability: focus on behavioural adverse effects. Epilepsy Behav 2004; 5(2): 231–5
Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Scizure 2004; 13(1): 55–7
Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia 2001; 42(12): 1611–3
Glauser TA, Pellock JM, Bebin EM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open label trial. Epilepsia 2002; 43(5): 518–24
Houtkooper MA, Lammertsma A, Meyer JWA. et al. Oxcarbazepine (GP 47.680): a possible alternative to carbamazepine. Epilepsia 1987; 28: 693–8
Dam M, Ekberg R, Løyning Y, et al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Res 1989; 3: 70–6
Van Amelsvoort T, Bakshi R, Devaux CB, et al. Hyponatremia associated with carbamazepine and oxcarbazepine therapy: a review. Epilepsia 1994; 35: 181–8
Schmidt D, Elger CE. What is the evidence that oxcarbazepine and carbamazepine are distinctly different antiepileptic drugs? Epilepsy Behaviour 2004; 5(5): 627–35
Gram L. Oxcarbazepine. In: Engel S, Pedley T, editors. Epilepsy: a comprehensive textbook. Philadelphia (PA): Lippincott-Raven, 1997: 1541–6
Muller M, Marson AG, Williamson PR. Oxcarbazepine versus phenytoin monotherapy for epilepsy (review). Cochrane Database Syst Rev 2006; (3): CD003615
Gelisse P, Genton P, Kuate C, et al. Worsening of seizures by oxcarbazepine in juvenile idiopathic generalized epilepsies. Epilepsia 2004; 45: 282–6
Taylor CP, Vartanian MG. Profile of anticonvulsant activity of CI-1008 (pregabalin) in animal models. Epilepsia 1997; 38Suppl. 8: 8
Arroyo S, Anhut H, Kugler AR, et al. Pregabalin add-on treatment: a randomised, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 2004; 45(1): 20–7
Elger CE, Brodie MJ, Anhut H, et al. Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study. Epilepsia 2005; 46(12): 1926–36
White SH. Clinical significance of animal seizure models and mechanism of action studies of potential antiepileptic drugs. Epilepsia 1997; 38(1): S9–17
Meldrum BS. Update on the mechanism of action of new antiepileptic drugs. Epilepsia 1996; 37(6): S4–11
Macdonald RL, Greenfield LJ. Mechanisms of action of new antiepileptic drugs. Curr Opin Neurol 1997; 10: 121–8
Crawford P, Meinardi H, Brown S, et al. Tiagabine: efficacy and safety in adjunctive treatment of partial seizures. Epilepsia 2001; 42(4): 531–8
Schachter SC. Tiagabine. Epilepsia 1999; 40 Suppl. 5: S17–22
Knake S, Hammer HM, Schomburg U, et al. Tiagabine-induced absence status in idiopathic generalised epilepsy. Scizure 1999; 8(5): 314–7
Koepp MJ, Edwards M, Collins JF, et al. Status epilepticus and tiagabine therapy revisited. Epilepsia 2005; 46(10): 1625–32
Fulton JA, Hoffman RS, Nelson LSN. Tiagabine overdose: a case of status epilepticus in a non-epileptic patient. Clin Toxicol 2005; 43(7): 869–71
Wolanczyk T, Grabowska-Grzyb A. Transient dystonias in three patients treated with tiagabine. Epilepsia 2001; 42(7): 944–6
Sorri I, Kalviainen R, Mantyjarvi M. Color vision and contrast sensitivity in epilepsy patients treated with initial tiagabine monotherapy. Epilepsy Res 2005; 67(3): 101–7
White HS, Brown SD, Woodhead JH, et al. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 1997; 23: 167–79
Glauser TA. Topiramate. Epilepsia 1999; 40Suppl. 5: 71–80
Privitera MD. Topiramate: a new antiepileptic drug. Ann Pharmacother 1997; 31: 1164–73
Reife RA, Lim P, Pledger G. Topiramate: side effect profile in double-blind studies. Epilepsia 1995; 36Suppl. 4: 34
Lee S, Sziklas V, Andermann F, et al. The effects of adjunctive topiramate on cognitive function in patients with epilepsy. Epilepsia 2003; 44(3): 339–47
Lee HW, Jung DK, Suh CK, et al. Cognitive effects of low-dose topiramate monotherpay in epilepsy patients: a one-year follow up. Epilepsy Behav 2006; 8(4): 736–41
Sander JWAS. Practical aspects of the use of topiramate in patients with epilepsy. Epilepsia 1997; 38 Suppl. 1: S56–8
Gogol LM, Morris HH. The office use of topiramate:a review of seizure control and side effect profile [abstract]. Epilepsia 1998; 39Suppl. 6: 55
Meador KJ, Loring DW, Vahle VJ, et al. Cognitive and behavioural effects of lamotrigine and topiramate in healthy volunteers. Neurology 2005; 64: 2108–14
Majkowski J, Neto W, Wapenaar R, et al. Time course of adverse events in patients with localisation-related epilepsy receiving topiramate added to carbamazepine. Epilepsia 2005; 46(5): 648–53
Traub SJ, Howland MA, Hoffman RS, et al. Acute topiramate toxicity. J Toxicol Clin Toxicol 2003; 41(7): 987–90
Fakhoury T, Murray L, Seger D, et al. Topiramate overdose: clinical and laboratory features. Epilepsy Behav 2002; 3: 185–9
Chiron C, Dulac O, Beaumont D. Therapeutic trial of vigabatrin in refractory infantile spasms. J Child Neurol 1991; 6 Suppl. 2: S52–9
Chiron C, Dumas C, Jambaque I, et al. Randomized trial comparing vigabatrin and hydrocortisone in infantile spasms due to tuberous sclerosis. Epilepsy Res 1997; 26: 389–95
Livingston JH, Beaumont D, Arzimanoglou A, et al. Vigabatrin in the treatment of epilepsy in children. Br J Clin Pharmacol 1989; 27 Suppl. 1: S109–12
Dulac O, Chiron C, Luna D, et al. Vigabatrin in childhood epilepsy. J Child Neurol 1991; 6 Suppl. 2: S30–7
Gibbs J, Appleton RE, Rosenbloom L. Vigabatrin in intractable childhood epilepsy: a retrospective study. Paediatr Neurol 1992; 8: 338–40
Appleton RE. The role of vigabatrin in the management of infantile epileptic syndromes. Neurology 1993; 43: 21–3
Curatolo P. Vigabatrin for refractory partial seizures in children with tuberous sclerosis [letter]. Neuropediatrics 1994; 25: 55
Constable S, Pirmohamed M. Drugs and the retina. Expert Opin Drug Saf 2004; 3: 249–59
van der Torren K, Graniewski-Wijnands HS, Polak BC. Visual field and electrophysiological abnormalities due to vigabatrin. Doc Ophthalmol 2002; 104(2): 181–8
Besch D, Kurtenbach A, Apfelstedt-Sylla E, et al. Visual field constriction and electrophysiological changes associated with vigabatrin. Doc Ophthalmol 2002; 104(2): 151–70
Krauss GL, Johnson MA, Mitler NR. Vigabatrin-associated retinal cone system dysfunction: electroretinogram and ophthalmologic findings. Neurol 1998; 50: 614–8
Tassinari CA, Michelucci R, Ambrosetto G, et al. Double-blind study of vigabatrin in the treatment of drug-resistant epilepsy. Arch Neurol 1987; 44: 907–10
Browne TR, Mattson RH, Penry JK. Vigabatrin for refractory complex partial seizures: multicenter, single-blind study with long-term follow-up. Neurology 1987; 37: 184–9
Remy C, Beaumont D. Efficacy and safety of vigabatrin in the long-term treatment of refractory epilepsy. Br J Clin Pharmacol 1989; 27 Suppl. 1: S125–9
Mumford J, Cannon DJ. Vigabatrin. Epilepsia 1994; 35 Suppl. 5: S25–8
Mumford J, Dam M. Meta-analysis of European placebo-controlled studies of vigabatrin in drug resistant epilepsy. Br J Clin Pharmacol 1989; 27: S101–7
Shovorn SD, Stefan H, Overview of the safety of newer antiepileptic drugs. Epilepsia 1997; 38(1): S45–51
Guberman A. Vigabatrin. Can J Neurol Sci 1996; 23(4): S13–7
Ferrie CD, Robinson MK, Panayiotopolous CP. Psychotic and severe behavioural reactions with vigabatrin: a review. Acta Neurologica Scandinavica 1996; 93: 1–8
Tanganelli P, Regesta G. Vigabatrin vs carbamazepine mono-therapy in newly diagnosed epilepsy: a randomised response conditional crossover study. Epilepsy Res 1996; 25: 257–62
Kaelviaeinen R, Aeikiae M, Saukkonen AM, et al. Vigabatrin vs carbamazepine in patients with newly diagnosed epilepsy: a randomised, controlled study. Arch Neurol 1995; 52: 989–96
Robinson MK, Richens A, Oxley R. Vigabatrin and behaviour disturbances [letter]. Lancet 1990; 336: 504
Ring HA, Reynolds EH. Vigabatrin and psychosis [letter]. Lancet 1990; 335: 970
Sander JW, Hart YM, Trimble MR, et al. Vigabatrin and psychosis. J Neurol Neurosurg Psychiatry 1991; 54: 435–9
Sander JW, Hart YM. Vigabatrin and behaviour disturbances [letter]. Lancet 1990; 335(8680): 57
Vigabatrin and behaviour disturbances [letter]. Lancet 1990; 335(8689): 605
Brodie MJ, McKee PJW. Vigabatrin and psychosis [letter]. Lancet 1990; 335: 1279
French JA, Mosier M, Walker S, et al. A double-blind placebo-controlled study of vigabatrin three g/day in patients with uncontrolled partial complex seizures. Neurology 1996; 46: 54–61
Wong ICK, Tavernor S, Tavernor R. Psychiatric adverse effects of anticonvulsant drugs: incidence and therapeutic implications. CNS Drugs 1997; 8(6): 492–509
Chadwick DW, Marson AG. Zonisamide add-on for drug-resistant epilepsy (review). Cochrane Database Syst Rev 2005; (4): CD001416
Wilder BJ, Ramsay RE, Guterman A, et al. A double-blind multicenter placebo-controlled study of the efficacy and safety of zonisamide in the treatment of complex partial seizures in medically refractory patients. Osaka: Internal report of Dainippon Pharmaceutical Co. Ltd, 1986
Schmidt D, Jacob R, Loiseau P, et al. Zonisamide for add-on treatment of refractory partial epilepsy: a European double-blind trial. Epilepsy Res 1993; 15: 67–73
Zaccara G, Messori A, Cincotta M, et al. Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long-term studies? Acta Neurol Scand 2006; 114(3): 157–68
Acknowledgements
No sources of funding were used to assist in the preparation of this review. Dr S.D. Lhatoo has acted as a consultant for and received educational and travel grants from Janssen Cilag, Eisai Ltd, UCB Pharmaceuticals and Glaxo Wellcome. Dr G.M. Kennedy has no conflicts of interest that are directly relevant to the content of this review.
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Kennedy, G.M., Lhatoo, S.D. CNS Adverse Events Associated with Antiepileptic Drugs. CNS Drugs 22, 739–760 (2008). https://doi.org/10.2165/00023210-200822090-00003
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DOI: https://doi.org/10.2165/00023210-200822090-00003