Abstract
Antiepileptic drugs (AEDs) are used by millions of people worldwide for the treatment of epilepsy, as well as in many other neurological and psychiatric conditions. They are frequently associated with adverse effects (AEs), which have an impact on the tolerability and success of treatment. Half the people who develop intolerable AEs discontinue treatment early on after initiation, while the majority of people will continue to be exposed to their effects for long periods of time. The long-term safety of AEDs reflects their potential for chronic, cumulative dose effects; rare, but potentially serious late idiosyncratic effects; late, dose-related effects; and delayed, teratogenic or neurodevelopmental effects. These AEs can affect every body system and are usually insidious. With the exception of delayed effects, most other late or chronic AEs are reversible. To date, there is no clear evidence of a carcinogenic effect of AEDs in humans. While physicians are aware of the long-term AEs of old AEDs (the traditional liver enzyme-inducing AEDs and valproate), information about AEs of new AEDs (such as lamotrigine, levetiracetam, oxcarbazepine, topiramate or zonisamide), particularly of their teratogenic effects, has emerged over the years. Sporadic publications have raised issues about AEs of the newer AEDs eslicarbazepine, retigabine, rufinamide, lacosamide and perampanel but their long-term safety profiles may take years to be fully appreciated. Physicians should not only be aware of the late and chronic AEs of AEDs but should systematically enquire and screen for these according to the individual AED AE profile. Care should be taken for individuals with comorbid conditions that may render them more susceptible to specific AEs. Prevention and appropriate management of long-term AED AEs is expected to improve adherence to treatment, quality of life and control of epilepsy.
Similar content being viewed by others
References
Banerjee PN, Filippi D, Hauser WA. The descriptive epidemiology of epilepsy: a review. Epilepsy Res. 2009;85(1):31–45.
Perucca E, Tomson T. The pharmacological treatment of epilepsy in adults. Lancet Neurol. 2011;10(5):446–56.
D’Souza WJ, Quinn SJ, Fryer JL, et al. The prevalence and demographic distribution of treated epilepsy: a community-based study in Tasmania, Australia. Acta Neurol Scand. 2012;125(2):96–104.
Hsieh LP, Huang CY. Prevalence of treated epilepsy in western medicine among the adult population in Taiwan: a study conducted using antiepileptic drug prescription data. Epilepsy Res. 2008;80(2–3):114–8.
Johannessen Landmark C, Larsson PG, Rytter E, et al. Antiepileptic drugs in epilepsy and other disorders: a population-based study of prescriptions. Epilepsy Res. 2009;87(1):31–9.
Picot MC, Baldy-Moulinier M, Daures JP, et al. The prevalence of epilepsy and pharmacoresistant epilepsy in adults: a population-based study in a Western European country. Epilepsia. 2008;49(7):1230–8.
Purcell BG, Gaitatzis A, Sander JW, et al. Epilepsy prevalence and prescribing patterns in England and Wales. Health Stat Quart. 2002;15(Autumn 2002):23–30.
Johannessen Landmark C. Antiepileptic drugs in non-epilepsy disorders: relations between mechanisms of action and clinical efficacy. CNS Drugs. 2008;22(1):27–47.
Savica R, Beghi E, Mazzaglia G, et al. Prescribing patterns of antiepileptic drugs in Italy: a nationwide population-based study in the years 2000–2005. Eur J Neurol. 2007;14(12):1317–21.
Tsiropoulos I, Gichangi A, Andersen M, et al. Trends in utilization of antiepileptic drugs in Denmark. Acta Neurol Scand. 2006;113(6):405–11.
van de Vrie-Hoekstra NW, de Vries TW, van den Berg PB, et al. Antiepileptic drug utilization in children from 1997–2005: a study from the Netherlands. Eur J Clin Pharmacol. 2008;64(10):1013–20.
Neligan A, Bell GS, Sander JW, et al. How refractory is refractory epilepsy? Patterns of relapse and remission in people with refractory epilepsy. Epilepsy Res. 2011;96(3):225–30.
Raspall-Chaure M, Neville BG, Scott RC. The medical management of the epilepsies in children: conceptual and practical considerations. Lancet Neurol. 2008;7(1):57–69.
Sander JW. The use of antiepileptic drugs: principles and practice. Epilepsia. 2004;45(Suppl. 6):28–34.
Bootsma HP, Ricker L, Hekster YA, et al. The impact of side effects on long-term retention in three new antiepileptic drugs. Seizure. 2009;18(5):327–31.
Chung S, Wang N, Hank N. Comparative retention rates and long-term tolerability of new antiepileptic drugs. Seizure. 2007;16(4):296–304.
Bautista RE, Rundle-Gonzalez V. Effects of antiepileptic drug characteristics on medication adherence. Epilepsy Behav. 2012;23(4):437–41.
Greenwood RS. Adverse effects of antiepileptic drugs. Epilepsia. 2000;41(Suppl. 2):42–52.
Marson AG, Al-Kharusi AM, Alwaidh M, et al. The SANAD study of effectiveness of carbamazepine, gabapentin, lamotrigine, oxcarbazepine, or topiramate for treatment of partial epilepsy: an unblinded randomised controlled trial. Lancet. 2007;369(9566):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(9566):1016–26.
Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2006;47(7):1094–120.
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.
Simister RJ, Sander JW, Koepp MJ. Long-term retention rates of new antiepileptic drugs in adults with chronic epilepsy and learning disability. Epilepsy Behav. 2007;10(2):336–9.
Perucca E, Beghi E, Dulac O, et al. Assessing risk to benefit ratio in antiepileptic drug therapy. Epilepsy Res. 2000;41(2):107–39.
Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000;356(9237):1255–9.
Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):792–802.
Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia. 1988;29(6):794–804.
Rosenfield RL. Clinical practice: hirsutism. N Engl J Med. 2005;353(24):2578–88.
Jeavons PM. Non-dose-related side effects of valproate. Epilepsia. 1984;25(Suppl. 1):50–5.
Mattson RH, Cramer JA, Collins JF. A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic-clonic seizures in adults: the Department of Veterans Affairs Epilepsy Cooperative Study No. 264 Group. N Engl J Med. 1992;327(11):765–71.
Smith MC, Centorrino F, Welge JA, et al. Clinical comparison of extended-release divalproex versus delayed-release divalproex: pooled data analyses from nine trials. Epilepsy Behav. 2004;5(5):746–51.
Koch-Weser J, Browne TR. Drug therapy: valproic acid. N Engl J Med. 1980;302(12):661–6.
Shapiro J. Clinical practice: hair loss in women. N Engl J Med. 2007;357(16):1620–30.
Tengstrand M, Star K, van Puijenbroek EP, et al. Alopecia in association with lamotrigine use: an analysis of individual case safety reports in a global database. Drug Saf. 2010;33(8):653–8.
Lefebvre EB, Haining RG, Labbe RF. Coarse facies, calvarial thickening and hyperphosphatasia associated with long-term anticonvulsant therapy. N Engl J Med. 1972;286(24):1301–2.
Chow KM, Szeto CC. Cerebral atrophy and skull thickening due to chronic phenytoin therapy. CMAJ. 2007;176(3):321–3.
Angelopoulos AP, Goaz PW. Incidence of diphenylhydantoin gingival hyperplasia. Oral Surg Oral Med Oral Pathol. 1972;34(6):898–906.
Aarli JA. Phenytoin-induced depression of salivary IgA and gingival hyperplasia. Epilepsia. 1976;17(3):283–91.
Correa JD, Queiroz-Junior CM, Costa JE, et al. Phenytoin-induced gingival overgrowth: a review of the molecular, immune, and inflammatory features. ISRN Dent. 2011;2011:497850.
Beghi E. Adverse reactions to antiepileptic drugs: a follow-up study of 355 patients with chronic antiepileptic drug treatment. Collaborative Group for Epidemiology of Epilepsy. Epilepsia. 1988;29(6):787–93.
Cerminara C, Seri S, Bombardieri R, et al. Hypohidrosis during topiramate treatment: a rare and reversible side effect. Pediatr Neurol. 2006;34(5):392–4.
Leppik IE. Practical prescribing and long-term efficacy and safety of zonisamide. Epilepsy Res. 2006;68(Suppl. 2):S17–24.
Critchley EM, Vakil SD, Hayward HW, et al. Dupuytren’s disease in epilepsy: result of prolonged administration of anticonvulsants. J Neurol Neurosurg Psychiatry. 1976;39(5):498–503.
De Santis A, Ceccarelli G, Cesana BM, et al. Shoulder-hand syndrome in neurosurgical patients treated with barbiturates: a long term evaluation. J Neurosurg Sci. 2000;44(2):69–75.
Mattson RH, Cramer JA, McCutchen CB. Barbiturate-related connective tissue disorders. Arch Intern Med. 1989;149(4):911–4.
Strzelczyk A, Vogt H, Hamer HM, et al. Continuous phenobarbital treatment leads to recurrent plantar fibromatosis. Epilepsia. 2008;49(11):1965–8.
Tripoli M, Cordova A, Moschella F. Dupuytren’s contracture as result of prolonged administration of phenobarbital. Eur Rev Med Pharmacol Sci. 2011;15(3):299–302.
Isojärvi J. Disorders of reproduction in patients with epilepsy: antiepileptic drug related mechanisms. Seizure. 2008;17(2):111–9.
Verrotti A, D’Egidio C, Mohn A, et al. Antiepileptic drugs, sex hormones, and PCOS. Epilepsia. 2011;52(2):199–211.
Brodie MJ, Mintzer S, Pack AM, et al. Enzyme induction with antiepileptic drugs: cause for concern? Epilepsia. 2013;54(1):11–27.
Galimberti CA, Magri F, Copello F, et al. Changes in sex steroid levels in women with epilepsy on treatment: relationship with antiepileptic therapies and seizure frequency. Epilepsia. 2009;50(Suppl. 1):28–32.
Herzog AG, Drislane FW, Schomer DL, et al. Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy. Neurology. 2005;65(7):1016–20.
Pennell PB. Hormonal aspects of epilepsy. Neurol Clin. 2009;27(4):941–65.
Lossius MI, Tauboll E, Mowinckel P, et al. Reversible effects of antiepileptic drugs on reproductive endocrine function in men and women with epilepsy: a prospective randomized double-blind withdrawal study. Epilepsia. 2007;48(10):1875–82.
Kaufman KR, Struck PJ. Gabapentin-induced sexual dysfunction. Epilepsy Behav. 2011;21(3):324–6.
Labbate LA, Rubey RN. Gabapentin-induced ejaculatory failure and anorgasmia. Am J Psychiatry. 1999;156(6):972.
Perloff MD, Thaler DE, Otis JA. Anorgasmia with gabapentin may be common in older patients. Am J Geriatr Pharmacother. 2011;9(3):199–203.
Mikkonen K, Vainionpaa LK, Pakarinen AJ, et al. Long-term reproductive endocrine health in young women with epilepsy during puberty. Neurology. 2004;62(3):445–50.
Rasgon NL, Altshuler LL, Fairbanks L, et al. Reproductive function and risk for PCOS in women treated for bipolar disorder. Bipolar Disord. 2005;7(3):246–59.
Morrell MJ, Hayes FJ, Sluss PM, et al. Hyperandrogenism, ovulatory dysfunction, and polycystic ovary syndrome with valproate versus lamotrigine. Ann Neurol. 2008;64(2):200–11.
Isojärvi JI, Rattya J, Myllyla VV, et al. Valproate, lamotrigine, and insulin-mediated risks in women with epilepsy. Ann Neurol. 1998;43(4):446–51.
Fitzpatrick LA. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav. 2004;5(Suppl. 2):S3–15.
Souverein PC, Webb DJ, Weil JG, et al. Use of antiepileptic drugs and risk of fractures: case–control study among patients with epilepsy. Neurology. 2006;66(9):1318–24.
Tsiropoulos I, Andersen M, Nymark T, et al. Exposure to antiepileptic drugs and the risk of hip fracture: a case–control study. Epilepsia. 2008;49(12):2092–9.
Beniczky SA, Viken J, Jensen LT, et al. Bone mineral density in adult patients treated with various antiepileptic drugs. Seizure. 2012;21(6):471–2.
Heo K, Rhee Y, Lee HW, et al. The effect of topiramate monotherapy on bone mineral density and markers of bone and mineral metabolism in premenopausal women with epilepsy. Epilepsia. 2011;52(10):1884–9.
Mintzer S, Boppana P, Toguri J, et al. Vitamin D levels and bone turnover in epilepsy patients taking carbamazepine or oxcarbazepine. Epilepsia. 2006;47(3):510–5.
Pack AM, Morrell MJ, Marcus R, et al. Bone mass and turnover in women with epilepsy on antiepileptic drug monotherapy. Ann Neurol. 2005;57(2):252–7.
El-Hajj Fuleihan G, Dib L, Yamout B, et al. Predictors of bone density in ambulatory patients on antiepileptic drugs. Bone. 2008;43(1):149–55.
Coppola G, Fortunato D, Auricchio G, et al. Bone mineral density in children, adolescents, and young adults with epilepsy. Epilepsia. 2009;50(9):2140–6.
Morrell MJ. Reproductive and metabolic disorders in women with epilepsy. Epilepsia. 2003;44(Suppl. 4):11–20.
Gough H, Goggin T, Bissessar A, et al. A comparative study of the relative influence of different anticonvulsant drugs, UV exposure and diet on vitamin D and calcium metabolism in out-patients with epilepsy. Q J Med. 1986;59(230):569–77.
Pack AM, Morrell MJ, Randall A, et al. Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy. Neurology. 2008;70(18):1586–93.
Awumey EM, Mitra DA, Hollis BW, et al. Vitamin D metabolism is altered in Asian Indians in the southern United States: a clinical research center study. J Clin Endocrinol Metab. 1998;83(1):169–73.
Pack AM, Morrell MJ. Adverse effects of antiepileptic drugs on bone structure: epidemiology, mechanisms and therapeutic implications. CNS Drugs. 2001;15(8):633–42.
Sheth RD, Hermann BP. Bone mineral density with lamotrigine monotherapy for epilepsy. Pediatr Neurol. 2007;37(4):250–4.
Ali II, Herial NA, Horrigan T, et al. Measurement of bone mineral density in patients on levetiracetam monotherapy. Epilepsia. 2006;47(Suppl. s4):276.
Koo DL, Joo EY, Kim D, et al. Effects of levetiracetam as a monotherapy on bone mineral density and biochemical markers of bone metabolism in patients with epilepsy. Epilepsy Res. 2013;104(1–2):134–9.
Isojärvi JI, Turkka J, Pakarinen AJ, et al. Thyroid function in men taking carbamazepine, oxcarbazepine, or valproate for epilepsy. Epilepsia. 2001;42(7):930–4.
Verrotti A, Laus M, Scardapane A, et al. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol. 2009;160(1):81–6.
Lossius MI, Tauboll E, Mowinckel P, et al. Reversible effects of antiepileptic drugs on thyroid hormones in men and women with epilepsy: a prospective randomized double-blind withdrawal study. Epilepsy Behav. 2009;16(1):64–8.
Vainionpää LK, Mikkonen K, Rattya J, et al. Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication. Epilepsia. 2004;45(3):197–203.
Biton V, Mirza W, Montouris G, et al. Weight change associated with valproate and lamotrigine monotherapy in patients with epilepsy. Neurology. 2001;56(2):172–7.
Isojärvi JI, Laatikainen TJ, Knip M, et al. Obesity and endocrine disorders in women taking valproate for epilepsy. Ann Neurol. 1996;39(5):579–84.
Freitag FG, Collins SD, Carlson HA, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58(11):1652–9.
Privitera MD, Brodie MJ, Mattson RH, et al. Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy. Acta Neurol Scand. 2003;107(3):165–75.
DeToledo JC, Toledo C, DeCerce J, et al. Changes in body weight with chronic, high-dose gabapentin therapy. Ther Drug Monit. 1997;19(4):394–6.
Arroyo S, Anhut H, Kugler AR, et al. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia. 2004;45(1):20–7.
Ryvlin P. Defining success in clinical trials: profiling pregabalin, the newest AED. Eur J Neurol. 2005;12(Suppl. 4):12–21.
Siddall PJ, Cousins MJ, Otte A, et al. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67(10):1792–800.
Ben-Menachem E. Weight issues for people with epilepsy: a review. Epilepsia. 2007;48(Suppl. 9):42–5.
Jallon P, Picard F. Bodyweight gain and anticonvulsants: a comparative review. Drug Saf. 2001;24(13):969–78.
Meister B. Neurotransmitters in key neurons of the hypothalamus that regulate feeding behavior and body weight. Physiol Behav. 2007;92(1–2):263–71.
Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010;75(20):1817–24.
Uludag IF, Kulu U, Sener U, et al. The effect of carbamazepine treatment on serum leptin levels. Epilepsy Res. 2009;86(1):48–53.
Biton V. Effect of antiepileptic drugs on bodyweight: overview and clinical implications for the treatment of epilepsy. CNS Drugs. 2003;17(11):781–91.
Perez J, Chiron C, Musial C, et al. Stiripentol: efficacy and tolerability in children with epilepsy. Epilepsia. 1999;40(11):1618–26.
Verrotti A, Scaparrotta A, Agostinelli S, et al. Topiramate-induced weight loss: a review. Epilepsy Res. 2011;95(3):189–99.
Ben-Menachem E, Axelsen M, Johanson EH, et al. Predictors of weight loss in adults with topiramate-treated epilepsy. Obes Res. 2003;11(4):556–62.
Mourand I, Crespel A, Gelisse P. Dramatic weight loss with rufinamide. Epilepsia. 2013;54(1):e5–8.
Wheless JW, Conry J, Krauss G, et al. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol. 2009;24(12):1520–5.
Coppola G. Update on rufinamide in childhood epilepsy. Neuropsychiatr Dis Treat. 2011;7:399–407.
Eirís J, Novo-Rodriguez MI, Del Rio M, et al. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbital therapy in children with epilepsy. Epilepsy Res. 2000;41(1):1–7.
Mintzer S. Metabolic consequences of antiepileptic drugs. Curr Opin Neurol. 2010;23(2):164–9.
Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet. 2002;360(9340):1155–62.
Chuang YC, Chuang HY, Lin TK, et al. Effects of long-term antiepileptic drug monotherapy on vascular risk factors and atherosclerosis. Epilepsia. 2012;53(1):120–8.
Mintzer S, Skidmore CT, Abidin CJ, et al. Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein. Ann Neurol. 2009;65(4):448–56.
Tan TY, Lu CH, Chuang HY, et al. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia. 2009;50(6):1579–86.
Chang HH, Yang YK, Gean PW, et al. The role of valproate in metabolic disturbances in bipolar disorder patients. J Affect Disord. 2010;124(3):319–23.
LoPinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Options Neurol. 2010;12(4):300–8.
Pylvänen V, Pakarinen A, Knip M, et al. Insulin-related metabolic changes during treatment with valproate in patients with epilepsy. Epilepsy Behav. 2006;8(3):643–8.
Verrotti A, Manco R, Agostinelli S, et al. The metabolic syndrome in overweight epileptic patients treated with valproic acid. Epilepsia. 2010;51(2):268–73.
Belcastro V, Striano P, Gorgone G, et al. Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. Epilepsia. 2010;51(2):274–9.
den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126(Pt 1):170–5.
Sachdev PS, Valenzuela M, Wang XL, et al. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology. 2002;58(10):1539–41.
Spence JD. Homocysteine-lowering therapy: a role in stroke prevention? Lancet Neurol. 2007;6(9):830–8.
Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs interact with folate and vitamin B12 serum levels. Ann Neurol. 2012;69(2):352–9.
Hernandez-Diaz S, Werler MM, Walker AM, et al. Folic acid antagonists during pregnancy and the risk of birth defects. N Engl J Med. 2000;343(22):1608–14.
Apeland T, Mansoor MA, Strandjord RE. Antiepileptic drugs as independent predictors of plasma total homocysteine levels. Epilepsy Res. 2001;47(1–2):27–35.
Reynolds EH. Chronic antiepileptic toxicity: a review. Epilepsia. 1975;16(2):319–52.
Verrotti A, Pascarella R, Trotta D, et al. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy Res. 2000;41(3):253–7.
Belcastro V, Striano P. Antiepileptic drugs, hyperhomocysteinemia and B-vitamins supplementation in patients with epilepsy. Epilepsy Res. 2012;102(1–2):1–7.
Linnebank M, Moskau S, Semmler A, et al. Antiepileptic drugs and vitamin B6 plasma levels in adult patients. Epilepsy Res. 2012;101(1–2):182–4.
Mintzer S, Skidmore CT, Sperling MR. B-vitamin deficiency in patients treated with antiepileptic drugs. Epilepsy Behav. 2012;24(3):341–4.
Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol. 2006;5(11):949–60.
Katayama F, Miura H, Takanashi S. Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies. Brain Dev. 2002;24(3):150–4.
Mahmoud AA, Rizk T, El-Bakri NK, et al. Incidence of kidney stones with topiramate treatment in pediatric patients. Epilepsia. 2011;52(10):1890–3.
Resor SR Jr, Resor LD. Chronic acetazolamide monotherapy in the treatment of juvenile myoclonic epilepsy. Neurology. 1990;40(11):1677–81.
Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia. 1996;37(Suppl. 2):18–22.
Wroe S. Zonisamide and renal calculi in patients with epilepsy: how big an issue? Curr Med Res Opin. 2007;23(8):1765–73.
Zaccara G, Tramacere L, Cincotta M. Drug safety evaluation of zonisamide for the treatment of epilepsy. Expert Opin Drug Saf. 2011;10(4):623–31.
Goldfarb DS. A woman with recurrent calcium phosphate kidney stones. Clin J Am Soc Nephrol. 2012;7(7):1172–8.
Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009;68(5):655–61.
Brickel N, Gandhi P, VanLandingham K, et al. The urinary safety profile and secondary renal effects of retigabine (ezogabine): a first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. Epilepsia. 2012;53(4):606–12.
Gil-Nagel A, Elger C, Ben-Menachem E, et al. Efficacy and safety of eslicarbazepine acetate as add-on treatment in patients with focal-onset seizures: integrated analysis of pooled data from double-blind phase III clinical studies. Epilepsia. 2013;54(1):98–107.
Letmaier M, Painold A, Holl AK, et al. Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme. Int J Neuropsychopharmacol. 2012;15(6):739–48.
Buggy Y, Layton D, Fogg C, et al. Safety profile of oxcarbazepine: results from a prescription-event monitoring study. Epilepsia. 2010;51(5):818–29.
Dong X, Leppik IE, White J, et al. Hyponatremia from oxcarbazepine and carbamazepine. Neurology. 2005;65(12):1976–8.
Asconapé JJ, Penry JK, Dreifuss FE, et al. Valproate-associated pancreatitis. Epilepsia. 1993;34(1):177–83.
Binek J, Hany A, Heer M. Valproic-acid-induced pancreatitis: case report and review of the literature. J Clin Gastroenterol. 1991;13(6):690–3.
Pellock JM, Wilder BJ, Deaton R, et al. Acute pancreatitis coincident with valproate use: a critical review. Epilepsia. 2002;43(11):1421–4.
Luef G, Rauchenzauner M, Waldmann M, et al. Non-alcoholic fatty liver disease (NAFLD), insulin resistance and lipid profile in antiepileptic drug treatment. Epilepsy Res. 2009;86(1):42–7.
Verrotti A, Agostinelli S, Parisi P, et al. Nonalcoholic fatty liver disease in adolescents receiving valproic acid. Epilepsy Behav. 2011;20(2):382–5.
Pellock JM. Felbamate. Epilepsia. 1999;40(Suppl. 5):57–62.
Koenig SA, Buesing D, Longin E, et al. Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003. Epilepsia. 2006;47(12):2027–31.
Gram L, Bentsen KD. Hepatic toxicity of antiepileptic drugs: a review. Acta Neurol Scand Suppl. 1983;97:81–90.
Iivanainen M, Savolainen H. Side effects of phenobarbital and phenytoin during long-term treatment of epilepsy. Acta Neurol Scand Suppl. 1983;97:49–67.
Aarli JA. Drug-induced IgA deficiency in epileptic patients. Arch Neurol. 1976;33(4):296–9.
Ranua J, Luoma K, Auvinen A, et al. Serum IgA, IgG, and IgM concentrations in patients with epilepsy and matched controls: a cohort-based cross-sectional study. Epilepsy Behav. 2005;6(2):191–5.
Seager J, Jamison DL, Wilson J, et al. IgA deficiency, epilepsy, and phenytoin treatment. Lancet. 1975;2(7936):632–5.
Crespel A, Velizarova R, Agullo M, et al. Ethosuximide-induced de novo systemic lupus erythematosus with anti-double-strand DNA antibodies: a case report with definite evidence. Epilepsia. 2009;50(8):2003.
De Giorgio CM, Rabinowicz AL, Olivas RD. Carbamazepine-induced antinuclear antibodies and systemic lupus erythematosus-like syndrome. Epilepsia. 1991;32(1):128–9.
Drory VE, Korczyn AD. Hypersensitivity vasculitis and systemic lupus erythematosus induced by anticonvulsants. Clin Neuropharmacol. 1993;16(1):19–29.
Jain KK. Systemic lupus erythematosus (SLE)-like syndromes associated with carbamazepine therapy. Drug Saf. 1991;6(5):350–60.
Ross S, Ormerod AD, Roberts C, et al. Subacute cutaneous lupus erythematosus associated with phenytoin. Clin Exp Dermatol. 2002;27(6):474–6.
Rubin RL. Drug-induced lupus. Toxicology. 2005;209(2):135–47.
Scheinfeld N. Phenytoin in cutaneous medicine: its uses, mechanisms and side effects. Dermatol Online J. 2003;9(3):6.
Askmark H, Wiholm BE. Epidemiology of adverse reactions to carbamazepine as seen in a spontaneous reporting system. Acta Neurol Scand. 1990;81(2):131–40.
Handoko KB, Souverein PC, van Staa TP, et al. Risk of aplastic anemia in patients using antiepileptic drugs. Epilepsia. 2006;47(7):1232–6.
Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia. 2007;48(7):1223–44.
Hart RG, Easton JD. Carbamazepine and hematological monitoring. Ann Neurol. 1982;11(3):309–12.
Delgado MR, Riela AR, Mills J, et al. Thrombocytopenia secondary to high valproate levels in children with epilepsy. J Child Neurol. 1994;9(3):311–4.
Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia. 2008;49(3):438–45.
Acharya S, Bussel JB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22(1):62–5.
Ganick DJ, Sunder T, Finley JL. Severe hematologic toxicity of valproic acid: a report of four patients. Am J Pediatr Hematol Oncol. 1990;12(1):80–5.
Gerstner T, Teich M, Bell N, et al. Valproate-associated coagulopathies are frequent and variable in children. Epilepsia. 2006;47(7):1136–43.
Köse G, Arhan E, Unal B, et al. Valproate-associated coagulopathies in children during short-term treatment. J Child Neurol. 2009;24(12):1493–8.
May RB, Sunder TR. Hematologic manifestations of long-term valproate therapy. Epilepsia. 1993;34(6):1098–101.
So CC, Wong KF. Valproate-associated dysmyelopoiesis in elderly patients. Am J Clin Pathol. 2002;118(2):225–8.
Choi TS, Doh KS, Kim SH, et al. Clinicopathological and genotypic aspects of anticonvulsant-induced pseudolymphoma syndrome. Br J Dermatol. 2003;148(4):730–6.
Sevcencu C, Struijk JJ. Autonomic alterations and cardiac changes in epilepsy. Epilepsia. 2010;51(5):725–37.
Boesen F, Andersen EB, Jensen EK, et al. Cardiac conduction disturbances during carbamazepine therapy. Acta Neurol Scand. 1983;68(1):49–52.
Faisy C, Guerot E, Diehl JL, et al. Carbamazepine-associated severe left ventricular dysfunction. J Toxicol Clin Toxicol. 2000;38(3):339–42.
Kasarskis EJ, Kuo CS, Berger R, et al. Carbamazepine-induced cardiac dysfunction: characterization of two distinct clinical syndromes. Arch Intern Med. 1992;152(1):186–91.
Nizam A, Mylavarapu K, Thomas D, et al. Lacosamide-induced second-degree atrioventricular block in a patient with partial epilepsy. Epilepsia. 2011;52(10):e153–5.
Weig SG, Pollack P. Carbamazepine-induced heart block in a child with tuberous sclerosis and cardiac rhabdomyoma: implications for evaluation and follow-up. Ann Neurol. 1993;34(4):617–9.
Puletti M, Iani C, Curione M, et al. Carbamazepine and the heart. Ann Neurol. 1991;29(5):575–6.
Saetre E, Abdelnoor M, Amlie JP, et al. Cardiac function and antiepileptic drug treatment in the elderly: a comparison between lamotrigine and sustained-release carbamazepine. Epilepsia. 2009;50(8):1841–9.
DeGiorgio CM. Atrial flutter/atrial fibrillation associated with lacosamide for partial seizures. Epilepsy Behav. 2010;18(3):322–4.
Zaccara G, Perucca P, Loiacono G, et al. The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2013;54(1):66–74.
Danielsson BR, Lansdell K, Patmore L, et al. Phenytoin and phenobarbital inhibit human HERG potassium channels. Epilepsy Res. 2003;55(1–2):147–57.
Danielsson BR, Lansdell K, Patmore L, et al. Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005;63(1):17–25.
Dixon R, Job S, Oliver R, et al. Lamotrigine does not prolong QTc in a thorough QT/QTc study in healthy subjects. Br J Clin Pharmacol. 2008;66(3):396–404.
Surges R, Taggart P, Sander JW, et al. Too long or too short? New insights into abnormal cardiac repolarization in people with chronic epilepsy and its potential role in sudden unexpected death. Epilepsia. 2010;51(5):738–44.
Stephen LJ, Brodie MJ. Antiepileptic drug monotherapy versus polytherapy: pursuing seizure freedom and tolerability in adults. Curr Opin Neurol. 2012;25(2):164–72.
Schimpf R, Veltmann C, Papavassiliu T, et al. Drug-induced QT-interval shortening following antiepileptic treatment with oral rufinamide. Heart Rhythm. 2012;9(5):776–81.
Singh G, Driever PH, Sander JW. Cancer risk in people with epilepsy: the role of antiepileptic drugs. Brain. 2005;128(Pt 1):7–17.
Olsen JH, Boice JD Jr, Jensen JP, et al. Cancer among epileptic patients exposed to anticonvulsant drugs. J Natl Cancer Inst. 1989;81(10):803–8.
Olsen JH, Schulgen G, Boice JD Jr, et al. Antiepileptic treatment and risk for hepatobiliary cancer and malignant lymphoma. Cancer Res. 1995;55(2):294–7.
Stettner M, Kramer G, Strauss A, et al. Long-term antiepileptic treatment with histone deacetylase inhibitors may reduce the risk of prostate cancer. Eur J Cancer Prev. 2012;21(1):55–64.
Hallas J, Friis S, Bjerrum L, et al. Cancer risk in long-term users of valproate: a population-based case–control study. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1714–9.
Jammoul F, Wang Q, Nabbout R, et al. Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity. Ann Neurol. 2009;65(1):98–107.
Plant GT, Sergott RC. Understanding and interpreting vision safety issues with vigabatrin therapy. Acta Neurol Scand Suppl. 2011;192:57–71.
Eke T, Talbot JF, Lawden MC. Severe persistent visual field constriction associated with vigabatrin. BMJ. 1997;314(7075):180–1.
Maguire MJ, Hemming K, Wild JM, et al. Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia. 2010;51(12):2423–31.
Arndt CF, Salle M, Derambure PH, et al. The effect on vision of associated treatments in patients taking vigabatrin: carbamazepine versus valproate. Epilepsia. 2002;43(8):812–7.
Nielsen NV, Syversen K. Possible retinotoxic effect of carbamazepine. Acta Ophthalmol (Copenh). 1986;64(3):287–90.
Gatzonis S, Karadimas P, Bouzas EA. Clonazepam associated retinopathy. Eur J Ophthalmol. 2003;13(9–10):813–5.
López L, Thomson A, Rabinowicz AL. Assessment of colour vision in epileptic patients exposed to single-drug therapy. Eur Neurol. 1999;41(4):201–5.
Nousiainen I, Kalviainen R, Mantyjarvi M. Color vision in epilepsy patients treated with vigabatrin or carbamazepine monotherapy. Ophthalmology. 2000;107(5):884–8.
Verrotti A, Lobefalo L, Tocco AM, et al. Color vision and macular recovery time in epileptic adolescents treated with valproate and carbamazepine. Eur J Neurol. 2006;13(7):736–41.
Abtahi MA, Abtahi SH, Fazel F, et al. Topiramate and the vision: a systematic review. Clin Ophthalmol. 2012;6:117–31.
Lovelace RE, Horwitz SJ. Peripheral neuropathy in long-term diphenylhydantoin therapy. Arch Neurol. 1968;18(1):69–77.
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;45(7):620–6.
So EL, Penry JK. Adverse effects of phenytoin on peripheral nerves and neuromuscular junction: a review. Epilepsia. 1981;22(4):467–73.
Ghatak NR, Santoso RA, McKinney WM. Cerebellar degeneration following long-term phenytoin therapy. Neurology. 1976;26(9):818–20.
Haberland C. Cerebellar degeneration with clinical manifestation in chronic epileptic patients. Psychiatr Neurol (Basel). 1962;143:29–44.
McLain LW Jr, Martin JT, Allen JH. Cerebellar degeneration due to chronic phenytoin therapy. Ann Neurol. 1980;7(1):18–23.
Rapport RL 2nd, Shaw CM. Phenytoin-related cerebellar degeneration without seizures. Ann Neurol. 1977;2(5):437–9.
Lindvall O, Nilsson B. Cerebellar atrophy following phenytoin intoxication. Ann Neurol. 1984;16(2):258–60.
Luef G, Chemelli A, Birbamer G, et al. Phenytoin overdosage and cerebellar atrophy in epileptic patients: clinical and MRI findings. Eur Neurol. 1994;34(Suppl. 1):79–81.
Zadikoff C, Munhoz RP, Asante AN, et al. Movement disorders in patients taking anticonvulsants. J Neurol Neurosurg Psychiatry. 2007;78(2):147–51.
Armon C, Shin C, Miller P, et al. Reversible parkinsonism and cognitive impairment with chronic valproate use. Neurology. 1996;47(3):626–35.
Jamora D, Lim SH, Pan A, et al. Valproate-induced Parkinsonism in epilepsy patients. Mov Disord. 2007;22(1):130–3.
Eriksson SH. Epilepsy and sleep. Curr Opin Neurol. 2011;24(2):171–6.
Pearl PL, Vezina LG, Saneto RP, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia. 2009;50(2):184–94.
Wheless JW, Carmant L, Bebin M, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009;50(2):195–205.
Brodie MJ, Covanis A, Gil-Nagel A, et al. Antiepileptic drug therapy: does mechanism of action matter? Epilepsy Behav. 2011;21(4):331–41.
Eddy CM, Rickards HE, Cavanna AE. The cognitive impact of antiepileptic drugs. Ther Adv Neurol Disord. 2011;4(6):385–407.
Bromley RL, Leeman BA, Baker GA, et al. Cognitive and neurodevelopmental effects of antiepileptic drugs. Epilepsy Behav. 2011;22(1):9–16.
Riss J, Cloyd J, Gates J, et al. Benzodiazepines in epilepsy: pharmacology and pharmacokinetics. Acta Neurol Scand. 2008;118(2):69–86.
Farwell JR, Lee YJ, Hirtz DG, et al. Phenobarbital for febrile seizures: effects on intelligence and on seizure recurrence. N Engl J Med. 1990;322(6):364–9.
Meador KJ, Loring DW, Moore EE, et al. Comparative cognitive effects of phenobarbital, phenytoin, and valproate in healthy adults. Neurology. 1995;45(8):1494–9.
Ding D, Zhang Q, Zhou D, et al. Cognitive and mood effects of phenobarbital treatment in people with epilepsy in rural China: a prospective study. J Neurol Neurosurg Psychiatry. 2012;83(12):1139–44.
Cumbo E, Ligori LD. Levetiracetam, lamotrigine, and phenobarbital in patients with epileptic seizures and Alzheimer’s disease. Epilepsy Behav. 2010;17(4):461–6.
Arif H, Buchsbaum R, Weintraub D, et al. Patient-reported cognitive side effects of antiepileptic drugs: predictors and comparison of all commonly used antiepileptic drugs. Epilepsy Behav. 2009;14(1):202–9.
White JR, Walczak TS, Marino SE, et al. Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case–control study. Neurology. 2010;75(6):513–8.
Bootsma HP, Vos AM, Hulsman J, et al. Lamotrigine in clinical practice: long-term experience in patients with refractory epilepsy referred to a tertiary epilepsy center. Epilepsy Behav. 2008;12(2):262–8.
Marino SE, Meador KJ, Loring DW, et al. Subjective perception of cognition is related to mood and not performance. Epilepsy Behav. 2009;14(3):459–64.
Vermeulen J, Aldenkamp AP. Cognitive side-effects of chronic antiepileptic drug treatment: a review of 25 years of research. Epilepsy Res. 1995;22(2):65–95.
Lossius MI, Hessen E, Mowinckel P, et al. Consequences of antiepileptic drug withdrawal: a randomized, double-blind study (Akershus Study). Epilepsia. 2008;49(3):455–63.
Grünewald RA, Thompson PJ, Corcoran R, et al. Effects of vigabatrin on partial seizures and cognitive function. J Neurol Neurosurg Psychiatry. 1994;57(9):1057–63.
Kanner AM, Kozak AM, Frey M. The use of sertraline in patients with epilepsy: is it safe? Epilepsy Behav. 2000;1(2):100–5.
Matsuura M. Epileptic psychoses and anticonvulsant drug treatment. J Neurol Neurosurg Psychiatry. 1999;67(2):231–3.
Faught E, Ayala R, Montouris GG, et al. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology. 2001;57(10):1774–9.
Miller JM, Kustra RP, Vuong A, et al. Depressive symptoms in epilepsy: prevalence, impact, aetiology, biological correlates and effect of treatment with antiepileptic drugs. Drugs. 2008;68(11):1493–509.
Mula M, Trimble MR, Yuen A, et al. Psychiatric adverse events during levetiracetam therapy. Neurology. 2003;61(5):704–6.
Brent DA, Crumrine PK, Varma RR, et al. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics. 1987;80(6):909–17.
Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia. 1999;40(Suppl. 10):65–70.
Cramer JA, De Rue K, Devinsky O, et al. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav. 2003;4(2):124–32.
Brodie MJ, Richens A, Yuen AW. Double-blind comparison of lamotrigine and carbamazepine in newly diagnosed epilepsy: UK Lamotrigine/Carbamazepine Monotherapy Trial Group. Lancet. 1995;345(8948):476–9.
Ketter TA, Malow BA, Flamini R, et al. Felbamate monotherapy has stimulant-like effects in patients with epilepsy. Epilepsy Res. 1996;23(2):129–37.
Beyenburg S, Mitchell AJ, Schmidt D, et al. Anxiety in patients with epilepsy: systematic review and suggestions for clinical management. Epilepsy Behav. 2005;7(2):161–71.
Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology. 1999;53(5 Suppl. 2):S53–67.
Kossoff EH, Bergey GK, Freeman JM, et al. Levetiracetam psychosis in children with epilepsy. Epilepsia. 2001;42(12):1611–3.
Trimble MR, Rusch N, Betts T, et al. Psychiatric symptoms after therapy with new antiepileptic drugs: psychopathological and seizure related variables. Seizure. 2000;9(4):249–54.
Katz R. Briefing document for the July 10, 2008 Advisory Committee meeting to discuss antiepileptic drugs (AEDs) and suicidality: memorandum 2008 [online]. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4372b1-01-FDA-Katz.pdf (Accessed 4 Dec 2012).
Hesdorffer DC, Kanner AM. The FDA alert on suicidality and antiepileptic drugs: fire or false alarm? Epilepsia. 2009;50(5):978–86.
Patorno E, Bohn RL, Wahl PM, et al. Anticonvulsant medications and the risk of suicide, attempted suicide, or violent death. JAMA. 2010;303(14):1401–9.
Arana A, Wentworth CE, Ayuso-Mateos JL, et al. Suicide-related events in patients treated with antiepileptic drugs. N Engl J Med. 2010;363(6):542–51.
Mula M, Kanner AM, Schmitz B, et al. Antiepileptic drugs and suicidality: an expert consensus statement from the Task Force on Therapeutic strategies of the ILAE Commission on Neuropsychobiology. Epilepsia. 2013;54(1):199–203.
Harden CL, Meador KJ, Pennell PB, et al. Management issues for women with epilepsy: focus on pregnancy (an evidence-based review). II. Teratogenesis and perinatal outcomes: Report of the Quality Standards Subcommittee and Therapeutics and Technology Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009;50(5):1237–46.
Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology. 2008;71(14):1109–17.
Adab N, Kini U, Vinten J, et al. The longer term outcome of children born to mothers with epilepsy. J Neurol Neurosurg Psychiatry. 2004;75(11):1575–83.
Holmes LB, Harvey EA, Coull BA, et al. The teratogenicity of anticonvulsant drugs. N Engl J Med. 2001;344(15):1132–8.
Artama M, Auvinen A, Raudaskoski T, et al. Antiepileptic drug use of women with epilepsy and congenital malformations in offspring. Neurology. 2005;64(11):1874–8.
Morrow J, Russell A, Guthrie E, 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(2):193–8.
Wide K, Winbladh B, Kallen B. Major malformations in infants exposed to antiepileptic drugs in utero, with emphasis on carbamazepine and valproic acid: a nation-wide, population-based register study. Acta Paediatr. 2004;93(2):174–6.
Wyszynski DF, Nambisan M, Surve T, et al. Increased rate of major malformations in offspring exposed to valproate during pregnancy. Neurology. 2005;64(6):961–5.
Tomson T. Which drug for the pregnant woman with epilepsy? N Engl J Med. 2009;360(16):1667–9.
Holmes LB, Mittendorf R, Shen A, et al. Fetal effects of anticonvulsant polytherapies: different risks from different drug combinations. Arch Neurol. 2011;68(10):1275–81.
Tomson T, Battino D, Bonizzoni E, et al. Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lancet Neurol. 2011;10(7):609–17.
Cunnington MC, Weil JG, Messenheimer JA, et al. Final results from 18 years of the International Lamotrigine Pregnancy Registry. Neurology. 2011;76(21):1817–23.
Jentink J, Dolk H, Loane MA, et al. Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case–control study. BMJ. 2010;341:c6581.
Holmes LB, Hernandez-Diaz S. Newer anticonvulsants: lamotrigine, topiramate and gabapentin. Birth Defects Res A Clin Mol Teratol. 2012;94(8):599–606.
Tomson T, Battino D. Teratogenic effects of antiepileptic drugs. Lancet Neurol. 2012;11(9):803–13.
Hernandez-Diaz S, Smith CR, Shen A, et al. Comparative safety of antiepileptic drugs during pregnancy. Neurology. 2012;78(21):1692–9.
Hvas CL, Henriksen TB, Ostergaard JR, et al. Epilepsy and pregnancy: effect of antiepileptic drugs and lifestyle on birthweight. BJOG. 2000;107(7):896–902.
Viinikainen K, Heinonen S, Eriksson K, et al. Community-based, prospective, controlled study of obstetric and neonatal outcome of 179 pregnancies in women with epilepsy. Epilepsia. 2006;47(1):186–92.
Mawer G, Briggs M, Baker GA, et al. Pregnancy with epilepsy: obstetric and neonatal outcome of a controlled study. Seizure. 2010;19(2):112–9.
Banach R, Boskovic R, Einarson T, et al. Long-term developmental outcome of children of women with epilepsy, unexposed or exposed prenatally to antiepileptic drugs: a meta-analysis of cohort studies. Drug Saf. 2010;33(1):73–9.
Harden CL, Hopp J, Ting TY, et al. Management issues for women with epilepsy: focus on pregnancy (an evidence-based review). I. Obstetrical complications and change in seizure frequency: Report of the Quality Standards Subcommittee and Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Epilepsia. 2009;50(5):1229–36.
Bromley RL. Foetal exposure to antiepileptic drugs: outcomes in the child. Liverpool: University of Liverpool; 2009.
Bromley RL, Mawer G, Love J, et al. Early cognitive development in children born to women with epilepsy: a prospective report. Epilepsia. 2010;51(10):2058–65.
Meador KJ, Baker GA, Browning N, et al. Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. N Engl J Med. 2009;360(16):1597–605.
Shallcross R, Bromley RL, Irwin B, et al. Child development following in utero exposure: levetiracetam vs sodium valproate. Neurology. 2011;76(4):383–9.
Meador KJ, Baker GA, Browning N, et al. Foetal antiepileptic drug exposure and verbal versus non-verbal abilities at three years of age. Brain. 2011;134(Pt 2):396–404.
Bromley RL, Mawer G, Clayton-Smith J, et al. Autism spectrum disorders following in utero exposure to antiepileptic drugs. Neurology. 2008;71(23):1923–4.
Moore SJ, Turnpenny P, Quinn A, et al. A clinical study of 57 children with fetal anticonvulsant syndromes. J Med Genet. 2000;37(7):489–97.
Nilsson L, Farahmand BY, Persson PG, et al. Risk factors for sudden unexpected death in epilepsy: a case–control study. Lancet. 1999;353(9156):888–93.
Walczak TS, Leppik IE, D’Amelio M, et al. Incidence and risk factors in sudden unexpected death in epilepsy: a prospective cohort study. Neurology. 2001;56(4):519–25.
Aurlien D, Tauboll E, Gjerstad L. Lamotrigine in idiopathic epilepsy: increased risk of cardiac death? Acta Neurol Scand. 2007;115(3):199–203.
Hesdorffer DC, Tomson T, Benn E, et al. Combined analysis of risk factors for SUDEP. Epilepsia. 2011;52(6):1150–9.
Tomson T, Nashef L, Ryvlin P. Sudden unexpected death in epilepsy: current knowledge and future directions. Lancet Neurol. 2008;7(11):1021–31.
Hesdorffer DC, Tomson T, Benn E, et al. Do antiepileptic drugs or generalized tonic-clonic seizure frequency increase SUDEP risk? A combined analysis. Epilepsia. 2012;53(2):249–52.
Ryvlin P, Cucherat M, Rheims S. Risk of sudden unexpected death in epilepsy in patients given adjunctive antiepileptic treatment for refractory seizures: a meta-analysis of placebo-controlled randomised trials. Lancet Neurol. 2011;10(11):961–8.
Tomson T, Hirsch LJ, Friedman D, et al. Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials. Epilepsia. 2013;54(1):135–40.
Gaitatzis A, Trimble MR, Sander JW. The psychiatric comorbidity of epilepsy. Acta Neurol Scand. 2004;110(4):207–20.
Gaitatzis A, Sisodiya SM, Sander JW. The somatic comorbidity of epilepsy: a weighty but often unrecognised burden. Epilepsia. 2012;53(8):1282–93.
Mezuk B, Morden NE, Ganoczy D, et al. Anticonvulsant use, bipolar disorder, and risk of fracture among older adults in the Veterans Health Administration. Am J Geriatr Psychiatry. 2010;18(3):245–55.
Gaitatzis A, Carroll K, Majeed A, et al. The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia. 2004;45(12):1613–22.
Löscher W, Schmidt D. Experimental and clinical evidence for loss of effect (tolerance) during prolonged treatment with antiepileptic drugs. Epilepsia. 2006;47(8):1253–84.
Baker GA, Jacoby A, Buck D, et al. Quality of life of people with epilepsy: a European study. Epilepsia. 1997;38(3):353–62.
Bonnett L, Smith CT, Smith D, et al. Prognostic factors for time to treatment failure and time to 12 months of remission for patients with focal epilepsy: post-hoc, subgroup analyses of data from the SANAD trial. Lancet Neurol. 2012;11(4):331–40.
Davis KL, Candrilli SD, Edin HM. Prevalence and cost of nonadherence with antiepileptic drugs in an adult managed care population. Epilepsia. 2008;49(3):446–54.
Ettinger AB, Manjunath R, Candrilli SD, et al. Prevalence and cost of nonadherence to antiepileptic drugs in elderly patients with epilepsy. Epilepsy Behav. 2009;14(2):324–9.
Faught E, Duh MS, Weiner JR, et al. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology. 2008;71(20):1572–8.
Hovinga CA, Asato MR, Manjunath R, et al. Association of non-adherence to antiepileptic drugs and seizures, quality of life, and productivity: survey of patients with epilepsy and physicians. Epilepsy Behav. 2008;13(2):316–22.
Manjunath R, Davis KL, Candrilli SD, et al. Association of antiepileptic drug nonadherence with risk of seizures in adults with epilepsy. Epilepsy Behav. 2009;14(2):372–8.
Gilliam F. Optimizing health outcomes in active epilepsy. Neurology. 2002;58(8 Suppl. 5):S9–20.
Uijl SG, Uiterwaal CS, Aldenkamp AP, et al. A cross-sectional study of subjective complaints in patients with epilepsy who seem to be well-controlled with anti-epileptic drugs. Seizure. 2006;15(4):242–8.
Uijl SG, Uiterwaal CS, Aldenkamp AP, et al. Adjustment of treatment increases quality of life in patients with epilepsy: a randomized controlled pragmatic trial. Eur J Neurol. 2009;16(11):1173–7.
Goldstein DB, Need AC, Singh R, et al. Potential genetic causes of heterogeneity of treatment effects. Am J Med. 2007;120(4 Suppl. 1):S21–5.
Zhou BT, Zhou QH, Yin JY, et al. Comprehensive analysis of the association of SCN1A gene polymorphisms with the retention rate of carbamazepine following monotherapy for new-onset focal seizures in the Chinese Han population. Clin Exp Pharmacol Physiol. 2012;39(4):379–84.
Arcas J, Ferrer T, Roche MC, et al. Hypohidrosis related to the administration of topiramate to children. Epilepsia. 2001;42(10):1363–5.
Low PA, James S, Peschel T, et al. Zonisamide and associated oligohidrosis and hyperthermia. Epilepsy Res. 2004;62(1):27–34.
Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res. 1993;14(2):165–73.
Boneva N, Brenner T, Argov Z. Gabapentin may be hazardous in myasthenia gravis. Muscle Nerve. 2000;23(8):1204–8.
Finsterer J, Zarrouk Mahjoub S. Epilepsy in mitochondrial disorders. Seizure. 2012;21(5):316–21.
Gordon N. Ornithine transcarbamylase deficiency: a urea cycle defect. Eur J Paediatr Neurol. 2003;7(3):115–21.
Ruiz-Gimenez J, Sanchez-Alvarez JC, Canadillas-Hidalgo F, et al. Antiepileptic treatment in patients with epilepsy and other comorbidities. Seizure. 2010;19(7):375–82.
Jennings HR, Romanelli F. The use of valproic acid in HIV-positive patients. Ann Pharmacother. 1999;33(10):1113–6.
Routy JP, Tremblay CL, Angel JB, et al. Valproic acid in association with highly active antiretroviral therapy for reducing systemic HIV-1 reservoirs: results from a multicentre randomized clinical study. HIV Med. 2012;13(5):291–6.
Acknowledgments
The authors report no conflict of interest in relation to this work. It was partly undertaken at University College Hospitals/University College London, which receives a proportion of funding from the Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme. No other sources of funding were used in the preparation of this review. JWS has received honoraria for consulting and lecturing from GSK, UCB and Viropharma; serves on the editorial boards for the Lancet Neurology and Epileptic Disorders; and has received research support from the Epilepsy Society, the Marvin Weil Epilepsy Research Fund, The European Union FP7 Programme, Eisai, GSK, UCB, the World Health Organization, National Institutes of Health and Nationaal Epilepsie Fonds Nederland. The authors are grateful to Dr. Gail Bell for her thorough review of the manuscript and valuable comments.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Gaitatzis, A., Sander, J.W. The Long-Term Safety of Antiepileptic Drugs. CNS Drugs 27, 435–455 (2013). https://doi.org/10.1007/s40263-013-0063-0
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-013-0063-0