Journal of Pediatric Epilepsy 2017; 06(01): 003-018
DOI: 10.1055/s-0036-1584935
Review Article
Georg Thieme Verlag KG Stuttgart · New York

The Effects of Antiepileptic Drugs on Pediatric Cognition, Mood, and Behavior

Khalid I. Afzal
1   Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois, United States
,
Seeba Anam
1   Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois, United States
,
Scott J. Hunter
1   Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois, United States
2   Department of Pediatrics, The University of Chicago, Chicago, Illinois, United States
› Author Affiliations
Further Information

Publication History

01 February 2015

21 March 2016

Publication Date:
01 July 2016 (online)

Abstract

In the past three decades, several new antiepileptic drugs (AEDs) have been marketed across the world, although with a surprisingly modest improvement in overall seizure control. During the same period, the use of AEDs as mood stabilizing or impulse control agents has been trending upwards, due to a notable increase in comorbid mood and behavior disorders in children, and a desire to address these pharmacologically. AEDs have been frequently associated with adverse mood and behavior changes, along with neuropsychiatric effects on attention, memory, and cognition. In this review, we discuss the use and adverse effects of the first- (e.g., barbiturates, carbamazepine, ethosuximide, phenytoin, valproate), second- (e.g., clobazam, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, stiripentol, vigabatrin, zonisamide), and third- (e.g., brivaracetam, eslicarbazepine acetate, lacosamide, perampanel, retigabine, rufinamide) generation AEDs in pediatric mood and behavior disorders. We also address what is currently known about the potential long-term neuropsychiatric consequences of AEDs. The distinction between the U.S. Food and Drug Administration-approved drugs versus off-label use of these drugs in the pediatric population is also examined.

 
  • References

  • 1 Wolf P. History of epilepsy: nosological concepts and classification. Epileptic Disord 2014; 16 (03) 261-269
  • 2 Chaudhary UJ, Duncan JS, Lemieux L. A dialogue with historical concepts of epilepsy from the Babylonians to Hughlings Jackson: persistent beliefs. Epilepsy Behav 2011; 21 (02) 109-114
  • 3 Brodie MJ. Antiepileptic drug therapy the story so far. Seizure 2010; 19 (10) 650-655
  • 4 Clouston TS. Experiments to determine the precise effect of bromide of potassium in epilepsy. Br J Psychiatry 1868; 14 (67) 305-321
  • 5 The Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Association; 2013
  • 6 U.S. Food and Drug Administration (FDA). Available at: http://www.fda.gov/drugs/drugsafety/informationbydrugclass/default.htm . Accessed January 8, 2016
  • 7 Haymarket Media, Inc. Mood disorders. Available at: http://www.empr.com/mood-disorders/category/17/0/ . Accessed January 7, 2016
  • 8 Perucca P, Mula M. Antiepileptic drug effects on mood and behavior: molecular targets. Epilepsy Behav 2013; 26 (03) 440-449
  • 9 LaRoche SM. A new look at the second-generation antiepileptic drugs: a decade of experience. Neurologist 2007; 13 (03) 133-139
  • 10 Potschka H. Pharmacological treatment strategies: Mechanisms of antiepileptic drugs. Epileptology 2013; 1 (01) 31-37
  • 11 Brodie MJ, Covanis A, Gil-Nagel A. , et al. Antiepileptic drug therapy: does mechanism of action matter?. Epilepsy Behav 2011; 21 (04) 331-341
  • 12 Afzal KI, Drossos T, Hunter S. Mood and behavior disorder in pediatric epilepsy-A review of literature. J Pediatr Epilepsy 2013; 2 (03) 157-172
  • 13 Zaccara G, Perucca E. Interactions between antiepileptic drugs, and between antiepileptic drugs and other drugs. Epileptic Disord 2014; 16 (04) 409-431
  • 14 Tran AR, Zito JM, Safer DJ, Hundley SD. National trends in pediatric use of anticonvulsants. Psychiatr Serv 2012; 63 (11) 1095-1101
  • 15 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders: DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000
  • 16 Italiano D, Capuano A, Alibrandi A. , et al. Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005-2011. Br J Clin Pharmacol 2015; 79 (06) 1010-1019
  • 17 Drug safety update. Off-label or unlicensed use of medicines: prescribers' responsibilities. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON087990 . Accessed January 24, 2016
  • 18 "Off-label" and investigational use of marketed drugs, biologics, and medical devices-information sheet. Available at: http://www.fda.gov/RegulatoryInformation/Guidances/ucm126486.htm . Accessed March 14, 2016
  • 19 Stafford RS. Regulating off-label drug use—rethinking the role of the FDA. N Engl J Med 2008; 358 (14) 1427-1429
  • 20 Wittich CM, Burkle CM, Lanier WL. Ten common questions (and their answers) about off-label drug use. Mayo Clin Proc 2012; 87 (10) 982-990
  • 21 Leslie DL, Mohamed S, Rosenheck RA. Off-label use of antipsychotic medications in the department of Veterans Affairs health care system. Psychiatr Serv 2009; 60 (09) 1175-1181
  • 22 Zito JM, Derivan AT, Kratochvil CJ, Safer DJ, Fegert JM, Greenhill LL. Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring. Child Adolesc Psychiatry Ment Health 2008; 2 (01) 24 . Doi: 10.1186/1753-2000-2-24
  • 23 Kwan P, Brodie MJ. Phenobarbital for the treatment of epilepsy in the 21st century: a critical review. Epilepsia 2004; 45 (09) 1141-1149
  • 24 Findling RL, Ginsberg LD. The safety and effectiveness of open-label extended-release carbamazepine in the treatment of children and adolescents with bipolar I disorder suffering from a manic or mixed episode. Neuropsychiatr Dis Treat 2014; 10: 1589-1597
  • 25 Schneider MR, Klein CC, Weber W. , et al. The effects of carbamazepine on prefrontal activation in manic youth with bipolar disorder. Psychiatry Res 2014; 223 (03) 268-270
  • 26 Leucht S, Helfer B, Dold M, Kissling W, McGrath J. Carbamazepine for schizophrenia. Cochrane Database Syst Rev 2014; 5: CD001258 . Doi: 10.1002/14651858.CD001258.pub2
  • 27 Vajda FJ, Eadie MJ. The clinical pharmacology of traditional antiepileptic drugs. Epileptic Disord 2014; 16 (04) 395-408
  • 28 Bersudsky Y. Phenytoin: an anti-bipolar anticonvulsant?. Int J Neuropsychopharmacol 2006; 9 (04) 479-484
  • 29 Gallagher P, Reid KS, Watson S. Phenytoin, an anti-bipolar anticonvulsant: a potential anti-glucocorticoid mechanism?. Int J Neuropsychopharmacol 2006; 9 (05) 627-628
  • 30 Sitges M, Chiu LM, Reed RC. Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na(+) and Ca(2+) Channels Permeability. Neurochem Res 2016; 41 (04) 758-769
  • 31 Masuch A, Shieh CH, van Rooijen N, van Calker D, Biber K. Mechanism of microglia neuroprotection: Involvement of P2 × 7, TNFα, and valproic acid. Glia 2016; 64 (01) 76-89
  • 32 Liu HY, Potter MP, Woodworth KY. , et al. Pharmacologic treatments for pediatric bipolar disorder: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry 2011; 50 (08) 749-762.e39
  • 33 Pavuluri MN. Pharmacologic treatments for pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2011; 50 (12) 1290 , author reply 1290–1291. Doi: 10.1016/j.jaac.2011.09.002
  • 34 Pavuluri MN, Passarotti AM, Fitzgerald JM, Wegbreit E, Sweeney JA. Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry 2012; 51 (02) 157-170.e5
  • 35 Padhy R, Saxena K, Remsing L, Huemer J, Plattner B, Steiner H. Symptomatic response to divalproex in subtypes of conduct disorder. Child Psychiatry Hum Dev 2011; 42 (05) 584-593
  • 36 Sankar R. GABA(A) receptor physiology and its relationship to the mechanism of action of the 1,5-benzodiazepine clobazam. CNS Drugs 2012; 26 (03) 229-244
  • 37 Shi LL, Dong J, Ni H, Geng J, Wu T. Felbamate as an add-on therapy for refractory epilepsy. Cochrane Database Syst Rev 2014; 7: CD008295 . Doi: 10.1002/14651858.CD008295.pub3
  • 38 Reinares M, Rosa AR, Franco C. , et al. A systematic review on the role of anticonvulsants in the treatment of acute bipolar depression. Int J Neuropsychopharmacol 2013; 16 (02) 485-496
  • 39 Bialer M. Chemical properties of antiepileptic drugs (AEDs). Adv Drug Deliv Rev 2012; 64 (10) 887-895
  • 40 Fullerton CA, Busch AB, Frank RG. The rise and fall of gabapentin for bipolar disorder: a case study on off-label pharmaceutical diffusion. Med Care 2010; 48 (04) 372-379
  • 41 Chace MJ, Zhang F, Fullerton CA, Huskamp HA, Gilden D, Soumerai SB. Intended and unintended consequences of the gabapentin off-label marketing lawsuit among patients with bipolar disorder. J Clin Psychiatry 2012; 73 (11) 1388-1394
  • 42 Schaffer LC, Schaffer CB, Miller AR, Manley JL, Piekut JA, Nordahl TE. An open trial of pregabalin as an acute and maintenance adjunctive treatment for outpatients with treatment resistant bipolar disorder. J Affect Disord 2013; 147 (01/03) 407-410
  • 43 Ketter TA, Manji HK, Post RM. Potential mechanisms of action of lamotrigine in the treatment of bipolar disorders. J Clin Psychopharmacol 2003; 23 (05) 484-495
  • 44 Peruzzolo TL, Tramontina S, Rohde LA, Zeni CP. Pharmacotherapy of bipolar disorder in children and adolescents: an update. Rev Bras Psiquiatr 2013; 35 (04) 393-405
  • 45 Himmerich H, Bartsch S, Hamer H. , et al. Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro. J Psychiatr Res 2013; 47 (11) 1751-1759
  • 46 Munkholm K, Braüner JV, Kessing LV, Vinberg M. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. J Psychiatr Res 2013; 47 (09) 1119-1133
  • 47 Öncü B, Er O, Çolak B, Nutt DJ. Lamotrigine for attention deficit-hyperactivity disorder comorbid with mood disorders: a case series. J Psychopharmacol 2014; 28 (03) 282-283
  • 48 Cerullo MA, Strakowski SM. A systematic review of the evidence for the treatment of acute depression in bipolar I disorder. CNS Spectr 2013; 18 (04) 199-208
  • 49 Saricicek A, Maloney K, Muralidharan A. , et al. Levetiracetam in the management of bipolar depression: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2011; 72 (06) 744-750
  • 50 Ambrósio AF, Soares-Da-Silva P, Carvalho CM, Carvalho AP. Mechanisms of action of carbamazepine and its derivatives, oxcarbazepine, BIA 2-093, and BIA 2-024. Neurochem Res 2002; 27 (01/02) 121-130
  • 51 Macmillan CM, Gonzalez-Heydrich JM. Oxcarbazepine is no more effective than placebo for reducing manic symptoms of bipolar I disorder in children and adolescents. Evid Based Ment Health 2007; 10 (02) 59 . Doi: 10.1136/ebmh.10.2.59
  • 52 Wagner KD, Kowatch RA, Emslie GJ. , et al. A double-blind, randomized, placebo-controlled trial of oxcarbazepine in the treatment of bipolar disorder in children and adolescents. Am J Psychiatry 2006; 163 (07) 1179-1186
  • 53 Vasudev A, Macritchie K, Vasudev K, Watson S, Geddes J, Young AH. Oxcarbazepine for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev 2011; (12) CD004857 . Doi: 10.1002/14651858.CD004857.pub2
  • 54 Angehagen M, Ben-Menachem E, Rönnbäck L, Hansson E. Novel mechanisms of action of three antiepileptic drugs, vigabatrin, tiagabine, and topiramate. Neurochem Res 2003; 28 (02) 333-340
  • 55 Hertzman M. Tiagabine for treatment of bipolar disorder with severe anxiety. Psychiatry (Edgmont) 2005; 2 (05) 11-11
  • 56 Vasudev A, Macritchie K, Rao SK, Geddes J, Young AH. Tiagabine for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev 2012; 12: CD004694 . Doi: 10.1002/14651858.CD004694.pub3
  • 57 Correll CU, Sheridan EM, DelBello MP. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord 2010; 12 (02) 116-141
  • 58 Wozniak J, Mick E, Waxmonsky J, Kotarski M, Hantsoo L, Biederman J. Comparison of open-label, 8-week trials of olanzapine monotherapy and topiramate augmentation of olanzapine for the treatment of pediatric bipolar disorder. J Child Adolesc Psychopharmacol 2009; 19 (05) 539-545
  • 59 Greenfield Jr LJ. Molecular mechanisms of antiseizure drug activity at GABAA receptors. Seizure 2013; 22 (08) 589-600
  • 60 Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 2007; 30 (04) 230-240
  • 61 Haw C, Stubbs J. A survey of the off-label use of mood stabilizers in a large psychiatric hospital. J Psychopharmacol 2005; 19 (04) 402-407
  • 62 Glauser TA. Behavioral and psychiatric adverse events associated with antiepileptic drugs commonly used in pediatric patients. J Child Neurol 2004; 19 (Suppl. 01) S25-S38
  • 63 Wolf SM, Carr A, Davis DC. , et al. The value of phenobarbital in the child who has had a single febrile seizure: a controlled prospective study. Pediatrics 1977; 59 (03) 378-385
  • 64 Knudsen FU, Vestermark S. Prophylactic diazepam or phenobarbitone in febrile convulsions: a prospective, controlled study. Arch Dis Child 1978; 53 (08) 660-663
  • 65 Domizio S, Verrotti A, Ramenghi LA, Sabatino G, Morgese G. Anti-epileptic therapy and behaviour disturbances in children. Childs Nerv Syst 1993; 9 (05) 272-274
  • 66 Herranz JL, Armijo JA, Arteaga R. Effectiveness and toxicity of phenobarbital, primidone, and sodium valproate in the prevention of febrile convulsions, controlled by plasma levels. Epilepsia 1984; 25 (01) 89-95
  • 67 Vining EP, Mellitis ED, Dorsen MM. , et al. Psychologic and behavioral effects of antiepileptic drugs in children: a double-blind comparison between phenobarbital and valproic acid. Pediatrics 1987; 80 (02) 165-174
  • 68 Brent DA, Crumrine PK, Varma R, Brown RV, Allan MJ. Phenobarbital treatment and major depressive disorder in children with epilepsy: a naturalistic follow-up. Pediatrics 1990; 85 (06) 1086-1091
  • 69 Brent DA, Crumrine PK, Varma RR, Allan M, Allman C. Phenobarbital treatment and major depressive disorder in children with epilepsy. Pediatrics 1987; 80 (06) 909-917
  • 70 Pal DK. Phenobarbital for childhood epilepsy: systematic review. Paediatr Perinat Drug Ther 2006; 7 (01) 31-42
  • 71 Banu SH, Jahan M, Koli UK, Ferdousi S, Khan NZ, Neville B. Side effects of phenobarbital and carbamazepine in childhood epilepsy: randomised controlled trial. BMJ 2007; 334 (7605): 1207 . Doi: 10.1136/bmj.39022.436389.BE
  • 72 Herranz JL, Armijo JA, Arteaga R. Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia 1988; 29 (06) 794-804
  • 73 Thilothammal N, Banu K, Ratnam RS. Comparison of phenobarbitone, phenytoin with sodium valproate: randomized, double-blind study. Indian Pediatr 1996; 33 (07) 549-555
  • 74 de Silva M, MacArdle B, McGowan M. , et al. Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy. Lancet 1996; 347 (9003): 709-713
  • 75 Smith DB, Mattson RH, Cramer JA, Collins JF, Novelly RA, Craft B. Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone. Epilepsia 1987; 28 (Suppl. 03) S50-S58
  • 76 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 (01) 44-50
  • 77 Canadian Study Group for Childhood Epilepsy. Clobazam has equivalent efficacy to carbamazepine and phenytoin as monotherapy for childhood epilepsy. Epilepsia 1998; 39 (09) 952-959
  • 78 McLellan DL, Swash M. Choreo-athetosis and encephalopathy induced by phenytoin. BMJ 1974; 2 (5912): 204-205
  • 79 Chua HC, Venketasubramanian N, Tan CB, Tjia H. Paradoxical seizures in phenytoin toxicity. Singapore Med J 1999; 40 (04) 276-277
  • 80 Schmitz B. Psychiatric syndromes related to antiepileptic drugs. Epilepsia 1999; 40 (Suppl. 10) S65-S70
  • 81 Marín LL, García-Peñas JJ, Herguedas JL. , et al. Phenytoin-induced visual disturbances mimicking Delirium Tremens in a child. Eur J Paediatr Neurol 2010; 14 (05) 460-463
  • 82 Meador KJ, Loring DW, Hulihan JF, Kamin M, Karim R. ; CAPSS-027 Study Group. Differential cognitive and behavioral effects of topiramate and valproate. Neurology 2003; 60 (09) 1483-1488
  • 83 Sherard Jr ES, Steiman GS, Couri D. Treatment of childhood epilepsy with valproic acid: results of the first 100 patients in a 6-month trial. Neurology 1980; 30 (01) 31-35
  • 84 Coulter DL, Wu H, Allen RJ. Valproic acid therapy in childhood epilepsy. JAMA 1980; 244 (08) 785-788
  • 85 Berg I, Butler A, Ellis M, Foster J. Psychiatric aspects of epilepsy in childhood treated with carbamazepine, phenytoin or sodium valproate: a random trial. Dev Med Child Neurol 1993; 35 (02) 149-157
  • 86 Glauser TA, Cnaan A, Shinnar S. , et al; Childhood Absence Epilepsy Study Team. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy: initial monotherapy outcomes at 12 months. Epilepsia 2013; 54 (01) 141-155
  • 87 Marson AG, Al-Kharusi AM, Alwaidh M. , et al; SANAD Study group. The SANAD study of effectiveness of valproate, lamotrigine, or topiramate for generalised and unclassifiable epilepsy: an unblinded randomised controlled trial. Lancet 2007; 369 (9566): 1016-1026
  • 88 Silverstein FS, Parrish MA, Johnston MV. Adverse behavioral reactions in children treated with carbamazepine (Tegretol). J Pediatr 1982; 101 (05) 785-787
  • 89 Kang HC, Eun BL, Lee CW. , et al; Korean Pediatric Topiramate Study Group. The effects on cognitive function and behavioral problems of topiramate compared to carbamazepine as monotherapy for children with benign rolandic epilepsy. Epilepsia 2007; 48 (09) 1716-1723
  • 90 Kälviäinen R, Aikiä M, Saukkonen AM, Mervaala E, Riekkinen Sr PJ. Vigabatrin vs carbamazepine monotherapy in patients with newly diagnosed epilepsy. A randomized, controlled study. Arch Neurol 1995; 52 (10) 989-996
  • 91 Zamponi N, Cardinali C. Open comparative long-term study of vigabatrin vs carbamazepine in newly diagnosed partial seizures in children. Arch Neurol 1999; 56 (05) 605-607
  • 92 Chadwick D. ; Vigabatrin European Monotherapy Study Group. Safety and efficacy of vigabatrin and carbamazepine in newly diagnosed epilepsy: a multicentre randomised double-blind study. Lancet 1999; 354 (9172): 13-19
  • 93 Shehata GA, Bateh Ael-A, Hamed SA, Rageh TA, Elsorogy YB. Neuropsychological effects of antiepileptic drugs (carbamazepine versus valproate) in adult males with epilepsy. Neuropsychiatr Dis Treat 2009; 5: 527-533
  • 94 Lee SA, Lee HW, Heo K. , et al. Cognitive and behavioral effects of lamotrigine and carbamazepine monotherapy in patients with newly diagnosed or untreated partial epilepsy. Seizure 2011; 20 (01) 49-54
  • 95 Seidel WT, Mitchell WG. Cognitive and behavioral effects of carbamazepine in children: data from benign rolandic epilepsy. J Child Neurol 1999; 14 (11) 716-723
  • 96 Glauser TA, Cnaan A, Shinnar S. , et al; Childhood Absence Epilepsy Study Group. Ethosuximide, valproic acid, and lamotrigine in childhood absence epilepsy. N Engl J Med 2010; 362 (09) 790-799
  • 97 Mandelbaum DE, Burack GD, Bhise VV. Impact of antiepileptic drugs on cognition, behavior, and motor skills in children with new-onset, idiopathic epilepsy. Epilepsy Behav 2009; 16 (02) 341-344
  • 98 Ijff DM, Aldenkamp AP. Cognitive side-effects of antiepileptic drugs in children. Handb Clin Neurol 2013; 111: 707-718
  • 99 Wolf P. The clinical syndromes of forced normalisation. Folia Psychiatr Neurol Jpn 1984; 38: 187-192
  • 100 Chien J. Ethosuximide-induced mania in a 10-year-old boy. Epilepsy Behav 2011; 21 (04) 483-485
  • 101 Bawden HN, Camfield CS, Camfield PR. , et al; Canadian Study Group for Childhood Epilepsy. The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Epilepsy Res 1999; 33 (02/03) 133-143
  • 102 Sheth RD, Ronen GM, Goulden KJ, Penney S, Bodensteiner JB. Clobazam for intractable pediatric epilepsy. J Child Neurol 1995; 10 (03) 205-208
  • 103 Sheth RD, Goulden KJ, Ronen GM. Aggression in children treated with clobazam for epilepsy. Clin Neuropharmacol 1994; 17 (04) 332-337
  • 104 Chu-Shore CJ, Thiele EA. New drugs for pediatric epilepsy. Semin Pediatr Neurol 2010; 17 (04) 214-223
  • 105 Ketter TA, Post RM, Theodore WH. Positive and negative psychiatric effects of antiepileptic drugs in patients with seizure disorders. Neurology 1999; 53 (05) (Suppl. 02) S53-S67
  • 106 Gay PE, Mecham GF, Coskey JS, Sadler T, Thompson JA. Behavioral effects of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). Psychol Rep 1995; 77 (3 Pt 2): 1208-1210
  • 107 Zupanc ML, Roell Werner R, Schwabe MS. , et al. Efficacy of felbamate in the treatment of intractable pediatric epilepsy. Pediatr Neurol 2010; 42 (06) 396-403
  • 108 Theodore WH, Albert P, Stertz B. , et al. Felbamate monotherapy: implications for antiepileptic drug development. Epilepsia 1995; 36 (11) 1105-1110
  • 109 Heyman E, Levin N, Lahat E, Epstein O, Gandelman-Marton R. Efficacy and safety of felbamate in children with refractory epilepsy. Eur J Paediatr Neurol 2014; 18 (06) 658-662
  • 110 Pellock JM, Faught E, Leppik IE, Shinnar S, Zupanc ML. Felbamate: consensus of current clinical experience. Epilepsy Res 2006; 71 (02/03) 89-101
  • 111 Bourgeois BF. Felbamate. Semin Pediatr Neurol 1997; 4 (01) 3-8
  • 112 Eddy CM, Rickards HE, Cavanna AE. Behavioral adverse effects of antiepileptic drugs in epilepsy. J Clin Psychopharmacol 2012; 32 (03) 362-375
  • 113 Mikati MA, Choueri R, Khurana DS, Riviello J, Helmers S, Holmes G. Gabapentin in the treatment of refractory partial epilepsy in children with intellectual disability. J Intellect Disabil Res 1998; 42 (Suppl. 01) 57-62
  • 114 Morris GL. Gabapentin. Epilepsia 1999; 40 (Suppl. 05) S63-S70
  • 115 Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ, Mikati MA. Behavioral side effects of gabapentin in children. Epilepsia 1996; 37 (01) 87-90
  • 116 Besag FM, Dulac O, Alving J, Mullens EL. Long-term safety and efficacy of lamotrigine (Lamictal) in paediatric patients with epilepsy. Seizure 1997; 6 (01) 51-56
  • 117 Eriksson AS, Nergårdh A, Hoppu K. The efficacy of lamotrigine in children and adolescents with refractory generalized epilepsy: a randomized, double-blind, crossover study. Epilepsia 1998; 39 (05) 495-501
  • 118 Cardenas JF, Rho JM, Ng YT. Reversible lamotrigine-induced neurobehavioral disturbances in children with epilepsy. J Child Neurol 2010; 25 (02) 182-187
  • 119 McKee JR, Sunder TR, FineSmith R. , et al. Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation. Epilepsy Behav 2003; 4 (04) 386-394
  • 120 Marson AG, Al-Kharusi AM, Alwaidh M. , et al; SANAD Study group. 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): 1000-1015
  • 121 Beran RG, Gibson RJ. Aggressive behaviour in intellectually challenged patients with epilepsy treated with lamotrigine. Epilepsia 1998; 39 (03) 280-282
  • 122 Barron TF, Hunt SL, Hoban TF, Price ML. Lamotrigine monotherapy in children. Pediatr Neurol 2000; 23 (02) 160-163
  • 123 Vigneswari G, Sofiah A, Hussain IH. Lamotrigine as an add-on therapy in intractable paediatric epilepsy—the Kuala Lumpur Hospital experience. Med J Malaysia 2001; 56 (03) 359-364
  • 124 Brodbeck V, Jansen V, Fietzek U, Muehe C, Weber G, Heinen F. Long-term profile of lamotrigine in 119 children with epilepsy. Eur J Paediatr Neurol 2006; 10 (03) 135-141
  • 125 Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology 2006; 66 (10) 1495-1499
  • 126 Khurana DS, Kothare SV, Valencia I, Melvin JJ, Legido A. Levetiracetam monotherapy in children with epilepsy. Pediatr Neurol 2007; 36 (04) 227-230
  • 127 Giroux PC, Salas-Prato M, Théorêt Y, Carmant L. Levetiracetam in children with refractory epilepsy: lack of correlation between plasma concentration and efficacy. Seizure 2009; 18 (08) 559-563
  • 128 Krief P, Li Kan, Maytal J. Efficacy of levetiracetam in children with epilepsy younger than 2 years of age. J Child Neurol 2008; 23 (05) 582-584
  • 129 Obeid M, Pong AW. Efficacy and tolerability of high oral doses of levetiracetam in children with epilepsy. Epilepsy Res 2010; 91 (01) 101-105
  • 130 Peake D, Mordekar S, Gosalakkal J. , et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. Seizure 2007; 16 (02) 185-189
  • 131 Callenbach PM, Arts WF, ten Houten R. , et al. Add-on levetiracetam in children and adolescents with refractory epilepsy: results of an open-label multi-centre study. Eur J Paediatr Neurol 2008; 12 (04) 321-327
  • 132 Fujikawa M, Kishimoto Y, Kakisaka Y. , et al. Obsessive-compulsive behavior induced by levetiracetam. J Child Neurol 2015; 30 (07) 942-944
  • 133 Camacho A, Espín JC, Nuñez N, Simón R. Levetiracetam-induced reversible autistic regression. Pediatr Neurol 2012; 47 (01) 65-67
  • 134 Perry MS, Benatar M. Efficacy and tolerability of levetiracetam in children younger than 4 years: a retrospective review. Epilepsia 2007; 48 (06) 1123-1127
  • 135 Helmstaedter C, Witt JA. The effects of levetiracetam on cognition: a non-interventional surveillance study. Epilepsy Behav 2008; 13 (04) 642-649
  • 136 Ben-Menachem E, Gilland E. Efficacy and tolerability of levetiracetam during 1-year follow-up in patients with refractory epilepsy. Seizure 2003; 12 (03) 131-135
  • 137 Levisohn PM, Mintz M, Hunter SJ, Yang H, Jones J. ; N01103 Levetiracetam Study Group. Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial. Epilepsia 2009; 50 (11) 2377-2389
  • 138 Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial. Seizure 2005; 14 (01) 66-71
  • 139 de la Loge C, Hunter SJ, Schiemann J, Yang H. Assessment of behavioral and emotional functioning using standardized instruments in children and adolescents with partial-onset seizures treated with adjunctive levetiracetam in a randomized, placebo-controlled trial. Epilepsy Behav 2010; 18 (03) 291-298
  • 140 Piña-Garza JE, Espinoza R, Nordli D. , et al. Oxcarbazepine adjunctive therapy in infants and young children with partial seizures. Neurology 2005; 65 (09) 1370-1375
  • 141 Kothare SV, Khurana DS, Mostofi N. , et al. Oxcarbazepine monotherapy in children and adolescents: a single-center clinical experience. Pediatr Neurol 2006; 35 (04) 235-239
  • 142 Seo JG, Lee DI, Hwang YH. , et al. Comparison of cognitive effects of lamotrigine and oxcarbazepine in epilepsy patients. J Clin Neurol 2007; 3 (01) 31-37
  • 143 Eun SH, Eun BL, Lee JS. , et al. Effects of lamotrigine on cognition and behavior compared to carbamazepine as monotherapy for children with partial epilepsy. Brain Dev 2012; 34 (10) 818-823
  • 144 Donati F, Gobbi G, Campistol J. , et al; Oxcarbazepine Cognitive Study Group. Effects of oxcarbazepine on cognitive function in children and adolescents with partial seizures. Neurology 2006; 67 (04) 679-682
  • 145 Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011; 52 (04) 826-836
  • 146 Ciesielski AS, Samson S, Steinhoff BJ. Neuropsychological and psychiatric impact of add-on titration of pregabalin versus levetiracetam: a comparative short-term study. Epilepsy Behav 2006; 9 (03) 424-431
  • 147 Chiron C, Marchand MC, Tran A. , et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 2000; 356 (9242): 1638-1642
  • 148 Vossler DG, Morris III GL, Harden CL. , et al; Postmarketing Antiepileptic Drug Survey (PADS) group study investigators. Tiagabine in clinical practice: effects on seizure control and behavior. Epilepsy Behav 2013; 28 (02) 211-216
  • 149 Pellock JM. Tiagabine (gabitril) experience in children. Epilepsia 2001; 42 (Suppl. 03) 49-51
  • 150 Leppik IE. Tiagabine: the safety landscape. Epilepsia 1995; 36 (Suppl. 06) S10-S13
  • 151 Dodrill CB, Arnett JL, Shu V, Pixton GC, Lenz GT, Sommerville KW. Effects of tiagabine monotherapy on abilities, adjustment, and mood. Epilepsia 1998; 39 (01) 33-42
  • 152 Suppes T, Chisholm KA, Dhavale D. , et al. Tiagabine in treatment refractory bipolar disorder: a clinical case series. Bipolar Disord 2002; 4 (05) 283-289
  • 153 Rosenthal M. Tiagabine for the treatment of generalized anxiety disorder: a randomized, open-label, clinical trial with paroxetine as a positive control. J Clin Psychiatry 2003; 64 (10) 1245-1249
  • 154 Kerr MP, Baker GA, Brodie MJ. A randomized, double-blind, placebo-controlled trial of topiramate in adults with epilepsy and intellectual disability: impact on seizures, severity, and quality of life. Epilepsy Behav 2005; 7 (03) 472-480
  • 155 Yeung S, Ferrie CD, Murdoch-Eaton DG, Livingston JH. Topiramate for drug-resistant epilepsies. Eur J Paediatr Neurol 2000; 4 (01) 31-33
  • 156 Coppola G, Verrotti A, Resicato G. , et al. Topiramate in children and adolescents with epilepsy and mental retardation: a prospective study on behavior and cognitive effects. Epilepsy Behav 2008; 12 (02) 253-256
  • 157 Moreland EC, Griesemer DA, Holden KR. Topiramate for intractable childhood epilepsy. Seizure 1999; 8 (01) 38-40
  • 158 Martin P, Schreiner A, Rettig K, Schäuble B. Topiramate in patients with epilepsy and intellectual disability. Epilepsy Behav 2009; 14 (03) 496-502
  • 159 Brandl U, Kurlemann G, Neubauer B, Rettig K, Schäuble B, Schreiner A. Seizure and cognitive outcomes in children and adolescents with epilepsy treated with topiramate. Neuropediatrics 2010; 41 (03) 113-120
  • 160 Pandina GJ, Ness S, Polverejan E. , et al. Cognitive effects of topiramate in migraine patients aged 12 through 17 years. Pediatr Neurol 2010; 42 (03) 187-195
  • 161 Witt JA, Elger CE, Helmstaedter C. Impaired verbal fluency under topiramate—evidence for synergistic negative effects of epilepsy, topiramate, and polytherapy. Eur J Neurol 2013; 20 (01) 130-137
  • 162 Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia 2008; 49 (07) 1186-1191
  • 163 Kluger G, Berz K, Holthausen H. The long-term use of vigabatrin and lamotrigine in patients with severe childhood onset epilepsy. Eur J Paediatr Neurol 2001; 5 (01) 37-40
  • 164 Ferrie CD, Robinson RO, Panayiotopoulos CP. Psychotic and severe behavioural reactions with vigabatrin: a review. Acta Neurol Scand 1996; 93 (01) 1-8
  • 165 Thomas L, Trimble M, Schmitz B, Ring H. Vigabatrin and behaviour disorders: a retrospective survey. Epilepsy Res 1996; 25 (01) 21-27
  • 166 Wong IC. Retrospective study of vigabatrin and psychiatric behavioural disturbances. Epilepsy Res 1995; 21 (03) 227-230
  • 167 Weber P, Dill P, Datta AN. Vigabatrin-induced forced normalization and psychosis—prolongated termination of behavioral symptoms but persistent antiepileptic effect after withdrawal. Epilepsy Behav 2012; 24 (01) 138-140
  • 168 Guberman A, Bruni J. ; The Canadian Vigabatrin Study Group. Long-term open multicentre, add-on trial of vigabatrin in adult resistant partial epilepsy. Seizure 2000; 9 (02) 112-118
  • 169 Bhaumik S, Branford D, Duggirala C, Ismail IA. A naturalistic study of the use of vigabatrin, lamotrigine and gabapentin in adults with learning disabilities. Seizure 1997; 6 (02) 127-133
  • 170 Veggiotti P, De Agostini G, Muzio C. , et al. Vigabatrin use in psychotic epileptic patients: report of a prospective pilot study. Acta Neurol Scand 1999; 99 (03) 142-146
  • 171 Gaily E, Appelqvist K, Kantola-Sorsa E. , et al. Cognitive deficits after cryptogenic infantile spasms with benign seizure evolution. Dev Med Child Neurol 1999; 41 (10) 660-664
  • 172 White JR, Walczak TS, Marino SE, Beniak TE, Leppik IE, Birnbaum AK. Zonisamide discontinuation due to psychiatric and cognitive adverse events: a case-control study. Neurology 2010; 75 (06) 513-518
  • 173 Kim HL, Aldridge J, Rho JM. Clinical experience with zonisamide monotherapy and adjunctive therapy in children with epilepsy at a tertiary care referral center. J Child Neurol 2005; 20 (03) 212-219
  • 174 Faught E, Ayala R, Montouris GG, Leppik IE. ; Zonisamide 922 Trial Group. Randomized controlled trial of zonisamide for the treatment of refractory partial-onset seizures. Neurology 2001; 57 (10) 1774-1779
  • 175 Cavanna AE, Seri S. Psychiatric adverse effects of zonisamide in patients with epilepsy and mental disorder comorbidities. Epilepsy Behav 2013; 29 (02) 281-284
  • 176 Thampratankul L, Khongkhatithum C, Visudtibhan A. Efficacy and safety of zonisamide in Thai children and adolescents with intractable seizures. J Child Neurol 2015; 30 (04) 527-531
  • 177 Pack AM. Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial. Epilepsy Curr 2014; 14 (04) 196-198
  • 178 UCB BIOSCIENCES, Inc. Brivaracetam safety and efficacy follow-up study in subjects with epilepsy (BRITE™). Available at: https://clinicaltrials.gov/ct2/show/NCT01339559 . Accessed March 14, 2016
  • 179 McCormack PL, Robinson DM. Eslicarbazepine acetate. CNS Drugs 2009; 23 (01) 71-79
  • 180 Almeida L, Minciu I, Nunes T. , et al. Pharmacokinetics, efficacy, and tolerability of eslicarbazepine acetate in children and adolescents with epilepsy. J Clin Pharmacol 2008; 48 (08) 966-977
  • 181 Porter RJ, Partiot A, Sachdeo R, Nohria V, Alves WM. ; 205 Study Group. Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007; 68 (15) 1197-1204
  • 182 French JA, Abou-Khalil BW, Leroy RF. , et al; RESTORE 1/Study 301 Investigators. Randomized, double-blind, placebo-controlled trial of ezogabine (retigabine) in partial epilepsy. Neurology 2011; 76 (18) 1555-1563
  • 183 Chhim RF, Shelton CM, Christensen ML. Recent new drug approvals, part 2: drugs undergoing active clinical studies in children. J Pediatr Pharmacol Ther 2013; 18 (01) 14-38
  • 184 Pasha I, Kamate M, Didagi SK. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy. Pediatr Neurol 2014; 51 (04) 509-514
  • 185 Pasha I, Kamate M, Didagi SK. Reversible inattention and hyperactivity in a child on lacosamide - in south Indian subpopulation. IOSR. J Pharm Biol Sci. 2014; 9: 66-67
  • 186 Guilhoto LM, Loddenkemper T, Gooty VD. , et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol 2011; 44 (06) 414-419
  • 187 Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav 2011; 20 (04) 691-693
  • 188 Verrotti A, Loiacono G, Pizzolorusso A. , et al. Lacosamide in pediatric and adult patients: comparison of efficacy and safety. Seizure 2013; 22 (03) 210-216
  • 189 Kim JS, Kim H, Lim BC. , et al. Lacosamide as an adjunctive therapy in pediatric patients with refractory focal epilepsy. Brain Dev 2014; 36 (06) 510-515
  • 190 Heyman E, Lahat E, Levin N, Berkovitch M, Gandelman-Marton R. Preliminary efficacy and safety of lacosamide in children with refractory epilepsy. Eur J Paediatr Neurol 2012; 16 (01) 15-19
  • 191 Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol 2012; 27 (04) 492-495
  • 192 Grosso S, Parisi P, Spalice A, Verrotti A, Balestri P. Efficacy and safety of lacosamide in infants and young children with refractory focal epilepsy. Eur J Paediatr Neurol 2014; 18 (01) 55-59
  • 193 French JA, Krauss GL, Biton V. , et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012; 79 (06) 589-596
  • 194 Steinhoff BJ, Ben-Menachem E, Ryvlin P. , et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013; 54 (08) 1481-1489
  • 195 Krauss GL, Serratosa JM, Villanueva V. , et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology 2012; 78 (18) 1408-1415
  • 196 Wheless JW, Conry J, Krauss G, Mann A, LoPresti A, Narurkar M. Safety and tolerability of rufinamide in children with epilepsy: a pooled analysis of 7 clinical studies. J Child Neurol 2009; 24 (12) 1520-1525
  • 197 Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology 2008; 70 (21) 1950-1958
  • 198 Vendrame M, Loddenkemper T, Gooty VD. , et al. Experience with rufinamide in a pediatric population: a single center's experience. Pediatr Neurol 2010; 43 (03) 155-158
  • 199 Moavero R, Cusmai R, Specchio N. , et al. Rufinamide efficacy and safety as adjunctive treatment in children with focal drug resistant epilepsy: the first Italian prospective study. Epilepsy Res 2012; 102 (01/02) 94-99
  • 200 Lee EH, Yum MS, Ko TS. Effectiveness and tolerability of rufinamide in children and young adults with Lennox-Gastaut syndrome: a single center study in Korea. Clin Neurol Neurosurg 2013; 115 (07) 926-929
  • 201 Grosso S, Coppola G, Dontin SD. , et al. Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies. Eur J Paediatr Neurol 2014; 18 (05) 641-645
  • 202 Kaufman KR, Struck PJ. Activation of suicidal ideation with adjunctive rufinamide in bipolar disorder. Epilepsy Behav 2011; 20 (02) 386-389
  • 203 Cusmai R, Verrotti A, Moavero R. , et al. Rufinamide for the treatment of refractory epilepsy secondary to neuronal migration disorders. Epilepsy Res 2014; 108 (03) 542-546
  • 204 Johannessen SI, Landmark CJ. Value of therapeutic drug monitoring in epilepsy. Expert Rev Neurother 2008; 8 (06) 929-939
  • 205 Mula M, Sander JW. Suicide risk in people with epilepsy taking antiepileptic drugs. Bipolar Disord 2013; 15 (05) 622-627
  • 206 Fountoulakis KN, Gonda X, Baghai TC. , et al. Report of the WPA section of pharmacopsychiatry on the relationship of antiepileptic drugs with suicidality in epilepsy. Int J Psychiatry Clin Pract 2015; 19 (03) 158-167
  • 207 Machado RA, Espinosa AG, Melendrez D, González YR, García VF, Rodríguez YQ. Suicidal risk and suicide attempts in people treated with antiepileptic drugs for epilepsy. Seizure 2011; 20 (04) 280-284
  • 208 Andersohn F, Schade R, Willich SN, Garbe E. Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior. Neurology 2010; 75 (04) 335-340
  • 209 Jones JE, Siddarth P, Gurbani S, Shields WD, Caplan R. Screening for suicidal ideation in children with epilepsy. Epilepsy Behav 2013; 29 (03) 521-526
  • 210 Caplan R, Siddarth P, Gurbani S, Hanson R, Sankar R, Shields WD. Depression and anxiety disorders in pediatric epilepsy. Epilepsia 2005; 46 (05) 720-730