UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Seizures and epilepsy in children: Refractory seizures and prognosis

Author
Angus Wilfong, MD
Section Editor
Douglas R Nordli, Jr, MD
Deputy Editor
April F Eichler, MD, MPH

INTRODUCTION

Most children with epilepsy achieve reasonably good seizure control with antiseizure drug therapy, but some are refractory despite numerous medications. Medical treatment failure is often apparent early in the course of treatment. In these cases, referral to a comprehensive epilepsy center is appropriate to explore addition therapeutic options, including epilepsy surgery, vagus nerve stimulation, and the ketogenic diet.

There is no standardized definition of medically intractable epilepsy. A task force of the International League Against Epilepsy proposed that drug-resistant epilepsy be defined as failure of adequate trials of two tolerated and appropriately chosen and used antiseizure drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [1].

This topic discusses the management and prognosis of seizures and epilepsy in children who are not controlled with initial antiseizure drug therapy. The clinical features, diagnosis, and initial management of seizures and epilepsy in children are presented separately. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Clinical and laboratory diagnosis of seizures in infants and children" and "Seizures and epilepsy in children: Initial treatment and monitoring".)

EVALUATION

When seizures do not respond as expected to initial antiseizure drug therapy, it is important to reconsider the seizure classification and the appropriateness of the antiseizure drug regimens that have been tried. In addition, clinicians should consider whether the diagnosis of epilepsy is accurate, as misdiagnosis is common. Common mimics of seizures include psychogenic nonepileptic seizures and other nonepileptic paroxysmal disorders (table 1).

Additional reasons for apparent treatment failure that do not reflect true intractability include:

                            

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Fri Nov 11 00:00:00 GMT 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
References
Top
  1. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 2010; 51:1069.
  2. Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in children newly diagnosed with epilepsy. Pediatr Neurol 2009; 40:71.
  3. Sloan ME, Simard-Tremblay E, Shevell MI. Features of a subset of children with complex partial epilepsy requiring combination therapy for effective seizure control. J Child Neurol 2010; 25:43.
  4. Perucca E, Gram L, Avanzini G, Dulac O. Antiepileptic drugs as a cause of worsening seizures. Epilepsia 1998; 39:5.
  5. Labiner DM, Bagic AI, Herman ST, et al. Essential services, personnel, and facilities in specialized epilepsy centers--revised 2010 guidelines. Epilepsia 2010; 51:2322.
  6. McKee HR, Abou-Khalil B. Outpatient pharmacotherapy and modes of administration for acute repetitive and prolonged seizures. CNS Drugs 2015; 29:55.
  7. Wiznitzer M. Buccal midazolam for seizures. Lancet 2005; 366:182.
  8. McMullan J, Sasson C, Pancioli A, Silbergleit R. Midazolam versus diazepam for the treatment of status epilepticus in children and young adults: a meta-analysis. Acad Emerg Med 2010; 17:575.
  9. Pellock JM, Shinnar S. Respiratory adverse events associated with diazepam rectal gel. Neurology 2005; 64:1768.
  10. Rowland AG, Gill AM, Stewart AB, et al. Review of the efficacy of rectal paraldehyde in the management of acute and prolonged tonic-clonic convulsions. Arch Dis Child 2009; 94:720.
  11. Scott RC, Besag FM, Neville BG. Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomised trial. Lancet 1999; 353:623.
  12. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal midazolam versus rectal diazepam for emergency treatment of seizures in children: a randomised controlled trial. Lancet 2005; 366:205.
  13. Talukdar B, Chakrabarty B. Efficacy of buccal midazolam compared to intravenous diazepam in controlling convulsions in children: a randomized controlled trial. Brain Dev 2009; 31:744.
  14. Ahmad S, Ellis JC, Kamwendo H, Molyneux E. Efficacy and safety of intranasal lorazepam versus intramuscular paraldehyde for protracted convulsions in children: an open randomised trial. Lancet 2006; 367:1591.
  15. Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs rectal diazepam in acute childhood seizures. Pediatr Neurol 2006; 34:355.
  16. Holsti M, Dudley N, Schunk J, et al. Intranasal midazolam vs rectal diazepam for the home treatment of acute seizures in pediatric patients with epilepsy. Arch Pediatr Adolesc Med 2010; 164:747.
  17. Arya R, Gulati S, Kabra M, et al. Intranasal versus intravenous lorazepam for control of acute seizures in children: a randomized open-label study. Epilepsia 2011; 52:788.
  18. Wait S, Lagae L, Arzimanoglou A, et al. The administration of rescue medication to children with prolonged acute convulsive seizures in the community: what happens in practice? Eur J Paediatr Neurol 2013; 17:14.
  19. Cross JH, Wait S, Arzimanoglou A, et al. Are we failing to provide adequate rescue medication to children at risk of prolonged convulsive seizures in schools? Arch Dis Child 2013; 98:777.
  20. Hartman AL, Devore CD, Section on Neurology, American Academy of Pediatrics, et al. Rescue Medicine for Epilepsy in Education Settings. Pediatrics 2016; 137.
  21. Steinbok P, Gan PY, Connolly MB, et al. Epilepsy surgery in the first 3 years of life: a Canadian survey. Epilepsia 2009; 50:1442.
  22. Roulet-Perez E, Davidoff V, Mayor-Dubois C, et al. Impact of severe epilepsy on development: recovery potential after successful early epilepsy surgery. Epilepsia 2010; 51:1266.
  23. Oguni H, Olivier A, Andermann F, Comair J. Anterior callosotomy in the treatment of medically intractable epilepsies: a study of 43 patients with a mean follow-up of 39 months. Ann Neurol 1991; 30:357.
  24. Morrell F, Whisler WW, Smith MC, et al. Landau-Kleffner syndrome. Treatment with subpial intracortical transection. Brain 1995; 118 ( Pt 6):1529.
  25. Vigevano F, Bertini E, Boldrini R, et al. Hemimegalencephaly and intractable epilepsy: benefits of hemispherectomy. Epilepsia 1989; 30:833.
  26. Vining EP, Freeman JM, Pillas DJ, et al. Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996. Pediatrics 1997; 100:163.
  27. Vining EP, Freeman JM, Brandt J, et al. Progressive unilateral encephalopathy of childhood (Rasmussen's syndrome): a reappraisal. Epilepsia 1993; 34:639.
  28. Leach JP, Chadwick DW, Miles JB, Hart IK. Improvement in adult-onset Rasmussen's encephalitis with long-term immunomodulatory therapy. Neurology 1999; 52:738.
  29. Dunoyer C, Ragheb J, Resnick T, et al. The use of stereotactic radiosurgery to treat intractable childhood partial epilepsy. Epilepsia 2002; 43:292.
  30. Mizrahi EM, Kellaway P, Grossman RG, et al. Anterior temporal lobectomy and medically refractory temporal lobe epilepsy of childhood. Epilepsia 1990; 31:302.
  31. Maton B, Jayakar P, Resnick T, et al. Surgery for medically intractable temporal lobe epilepsy during early life. Epilepsia 2008; 49:80.
  32. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med 2001; 345:311.
  33. Wyllie E, Comair YG, Kotagal P, et al. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol 1998; 44:740.
  34. Cossu M, Lo Russo G, Francione S, et al. Epilepsy surgery in children: results and predictors of outcome on seizures. Epilepsia 2008; 49:65.
  35. Wyllie E, Lachhwani DK, Gupta A, et al. Successful surgery for epilepsy due to early brain lesions despite generalized EEG findings. Neurology 2007; 69:389.
  36. Duchowny M, Jayakar P, Resnick T, et al. Epilepsy surgery in the first three years of life. Epilepsia 1998; 39:737.
  37. Fish DR, Smith SJ, Quesney LF, et al. Surgical treatment of children with medically intractable frontal or temporal lobe epilepsy: results and highlights of 40 years' experience. Epilepsia 1993; 34:244.
  38. Jayakar P, Dunoyer C, Dean P, et al. Epilepsy surgery in patients with normal or nonfocal MRI scans: integrative strategies offer long-term seizure relief. Epilepsia 2008; 49:758.
  39. Mani J, Gupta A, Mascha E, et al. Postoperative seizures after extratemporal resections and hemispherectomy in pediatric epilepsy. Neurology 2006; 66:1038.
  40. Jonas R, Nguyen S, Hu B, et al. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes. Neurology 2004; 62:1712.
  41. Cukiert A, Cukiert CM, Argentoni M, et al. Outcome after hemispherectomy in hemiplegic adult patients with refractory epilepsy associated with early middle cerebral artery infarcts. Epilepsia 2009; 50:1381.
  42. Devlin AM, Cross JH, Harkness W, et al. Clinical outcomes of hemispherectomy for epilepsy in childhood and adolescence. Brain 2003; 126:556.
  43. Basheer SN, Connolly MB, Lautzenhiser A, et al. Hemispheric surgery in children with refractory epilepsy: seizure outcome, complications, and adaptive function. Epilepsia 2007; 48:133.
  44. Moosa AN, Gupta A, Jehi L, et al. Longitudinal seizure outcome and prognostic predictors after hemispherectomy in 170 children. Neurology 2013; 80:253.
  45. Delalande O, Bulteau C, Dellatolas G, et al. Vertical parasagittal hemispherotomy: surgical procedures and clinical long-term outcomes in a population of 83 children. Neurosurgery 2007; 60:ONS19.
  46. Kossoff EH, Vining EP, Pillas DJ, et al. Hemispherectomy for intractable unihemispheric epilepsy etiology vs outcome. Neurology 2003; 61:887.
  47. Schramm J, Kuczaty S, Sassen R, et al. Pediatric functional hemispherectomy: outcome in 92 patients. Acta Neurochir (Wien) 2012; 154:2017.
  48. Boshuisen K, van Schooneveld MM, Leijten FS, et al. Contralateral MRI abnormalities affect seizure and cognitive outcome after hemispherectomy. Neurology 2010; 75:1623.
  49. Hallbook T, Ruggieri P, Adina C, et al. Contralateral MRI abnormalities in candidates for hemispherectomy for refractory epilepsy. Epilepsia 2010; 51:556.
  50. Duchowny M. Hemispherectomy for epilepsy: when is one half better than two? Neurology 2004; 62:1664.
  51. Samargia SA, Kimberley TJ. Motor and cognitive outcomes in children after functional hemispherectomy. Pediatr Phys Ther 2009; 21:356.
  52. Honda R, Kaido T, Sugai K, et al. Long-term developmental outcome after early hemispherotomy for hemimegalencephaly in infants with epileptic encephalopathy. Epilepsy Behav 2013; 29:30.
  53. Graham D, Tisdall MM, Gill D. Corpus callosotomy outcomes in pediatric patients: A systematic review. Epilepsia 2016; 57:1053.
  54. Paglioli E, Martins WA, Azambuja N, et al. Selective posterior callosotomy for drop attacks: A new approach sparing prefrontal connectivity. Neurology 2016; 87:1968.
  55. Asadi-Pooya AA, Sharan A, Nei M, Sperling MR. Corpus callosotomy. Epilepsy Behav 2008; 13:271.
  56. Cukiert A, Burattini JA, Mariani PP, et al. Outcome after extended callosal section in patients with primary idiopathic generalized epilepsy. Epilepsia 2009; 50:1377.
  57. Smith ML, Elliott IM, Lach L. Cognitive, psychosocial, and family function one year after pediatric epilepsy surgery. Epilepsia 2004; 45:650.
  58. Sabaz M, Lawson JA, Cairns DR, et al. The impact of epilepsy surgery on quality of life in children. Neurology 2006; 66:557.
  59. Gleissner U, Clusmann H, Sassen R, et al. Postsurgical outcome in pediatric patients with epilepsy: a comparison of patients with intellectual disabilities, subaverage intelligence, and average-range intelligence. Epilepsia 2006; 47:406.
  60. Elliott IM, Lach L, Kadis DS, Smith ML. Psychosocial outcomes in children two years after epilepsy surgery: has anything changed? Epilepsia 2008; 49:634.
  61. Skirrow C, Cross JH, Cormack F, et al. Long-term intellectual outcome after temporal lobe surgery in childhood. Neurology 2011; 76:1330.
  62. Viggedal G, Kristjansdottir R, Olsson I, et al. Cognitive development from two to ten years after pediatric epilepsy surgery. Epilepsy Behav 2012; 25:2.
  63. de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet 2011; 378:1388.
  64. Boshuisen K, Arzimanoglou A, Cross JH, et al. Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study. Lancet Neurol 2012; 11:784.
  65. Boshuisen K, van Schooneveld MM, Uiterwaal CS, et al. Intelligence quotient improves after antiepileptic drug withdrawal following pediatric epilepsy surgery. Ann Neurol 2015; 78:104.
  66. Hoppe C, Poepel A, Sassen R, Elger CE. Discontinuation of anticonvulsant medication after epilepsy surgery in children. Epilepsia 2006; 47:580.
  67. Sinclair DB, Jurasek L, Wheatley M, et al. Discontinuation of antiepileptic drugs after pediatric epilepsy surgery. Pediatr Neurol 2007; 37:200.
  68. Lachhwani DK, Loddenkemper T, Holland KD, et al. Discontinuation of medications after successful epilepsy surgery in children. Pediatr Neurol 2008; 38:340.
  69. Geva-Dayan K, Shorer Z, Menascu S, et al. Immunoglobulin treatment for severe childhood epilepsy. Pediatr Neurol 2012; 46:375.
  70. Billiau AD, Witters P, Ceulemans B, et al. Intravenous immunoglobulins in refractory childhood-onset epilepsy: effects on seizure frequency, EEG activity, and cerebrospinal fluid cytokine profile. Epilepsia 2007; 48:1739.
  71. Mikati MA, Kurdi R, El-Khoury Z, et al. Intravenous immunoglobulin therapy in intractable childhood epilepsy: open-label study and review of the literature. Epilepsy Behav 2010; 17:90.
  72. Geng J, Dong J, Li Y, et al. Intravenous immunoglobulins for epilepsy. Cochrane Database Syst Rev 2011; :CD008557.
  73. Quek AM, Britton JW, McKeon A, et al. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. Arch Neurol 2012; 69:582.
  74. Wong-Kisiel LC, McKeon A, Wirrell EC. Autoimmune encephalopathies and epilepsies in children and teenagers. Can J Neurol Sci 2012; 39:134.
  75. Varadkar S, Bien CG, Kruse CA, et al. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances. Lancet Neurol 2014; 13:195.
  76. Lagarde S, Villeneuve N, Trébuchon A, et al. Anti-tumor necrosis factor alpha therapy (adalimumab) in Rasmussen's encephalitis: An open pilot study. Epilepsia 2016; 57:956.
  77. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev 2014; :CD009270.
  78. Koppel BS, Brust JC, Fife T, et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 2014; 82:1556.
  79. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016; 15:270.
  80. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015; 56:1246.
  81. Detyniecki K, Hirsch LJ. Cannabidiol for epilepsy: trying to see through the haze. Lancet Neurol 2016; 15:235.
  82. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci 2007; 80:1415.
  83. Yamaori S, Ebisawa J, Okushima Y, et al. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci 2011; 88:730.
  84. Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med 2014; 370:2219.
  85. Zalesky A, Solowij N, Yücel M, et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain 2012; 135:2245.
  86. Hess EJ, Moody KA, Geffrey AL, et al. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016; 57:1617.
  87. Chin RF, Cumberland PM, Pujar SS, et al. Outcomes of childhood epilepsy at age 33 years: a population-based birth-cohort study. Epilepsia 2011; 52:1513.
  88. Berg AT, Testa FM, Levy SR. Complete remission in nonsyndromic childhood-onset epilepsy. Ann Neurol 2011; 70:566.
  89. Berg AT, Shinnar S, Levy SR, et al. Two-year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia 2001; 42:1553.
  90. Sillanpää M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain 2006; 129:617.
  91. Geerts A, Brouwer O, van Donselaar C, et al. Health perception and socioeconomic status following childhood-onset epilepsy: the Dutch study of epilepsy in childhood. Epilepsia 2011; 52:2192.
  92. Marsh ED, Brooks-Kayal AR, Porter BE. Seizures and antiepileptic drugs: does exposure alter normal brain development? Epilepsia 2006; 47:1999.
  93. Berg AT, Zelko FA, Levy SR, Testa FM. Age at onset of epilepsy, pharmacoresistance, and cognitive outcomes: a prospective cohort study. Neurology 2012; 79:1384.
  94. Vasconcellos E, Wyllie E, Sullivan S, et al. Mental retardation in pediatric candidates for epilepsy surgery: the role of early seizure onset. Epilepsia 2001; 42:268.
  95. Cormack F, Cross JH, Isaacs E, et al. The development of intellectual abilities in pediatric temporal lobe epilepsy. Epilepsia 2007; 48:201.
  96. O'Callaghan FJ, Lux AL, Darke K, et al. The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. Epilepsia 2011; 52:1359.
  97. Hermann BP, Seidenberg M, Dow C, et al. Cognitive prognosis in chronic temporal lobe epilepsy. Ann Neurol 2006; 60:80.
  98. Hermann BP, Jones JE, Jackson DC, Seidenberg M. Starting at the beginning: the neuropsychological status of children with new-onset epilepsies. Epileptic Disord 2012; 14:12.
  99. Oostrom KJ, Smeets-Schouten A, Kruitwagen CL, et al. Not only a matter of epilepsy: early problems of cognition and behavior in children with "epilepsy only"--a prospective, longitudinal, controlled study starting at diagnosis. Pediatrics 2003; 112:1338.
  100. Rathouz PJ, Zhao Q, Jones JE, et al. Cognitive development in children with new onset epilepsy. Dev Med Child Neurol 2014; 56:635.
  101. Alfstad KÅ, Clench-Aas J, Van Roy B, et al. Psychiatric symptoms in Norwegian children with epilepsy aged 8-13 years: effects of age and gender? Epilepsia 2011; 52:1231.
  102. Stevanovic D, Jancic J, Lakic A. The impact of depression and anxiety disorder symptoms on the health-related quality of life of children and adolescents with epilepsy. Epilepsia 2011; 52:e75.
  103. Rantanen K, Eriksson K, Nieminen P. Cognitive impairment in preschool children with epilepsy. Epilepsia 2011; 52:1499.
  104. Taylor J, Jacoby A, Baker GA, Marson AG. Self-reported and parent-reported quality of life of children and adolescents with new-onset epilepsy. Epilepsia 2011; 52:1489.
  105. Russ SA, Larson K, Halfon N. A national profile of childhood epilepsy and seizure disorder. Pediatrics 2012; 129:256.
  106. Wagner JL, Wilson DA, Smith G, et al. Neurodevelopmental and mental health comorbidities in children and adolescents with epilepsy and migraine: a response to identified research gaps. Dev Med Child Neurol 2015; 57:45.
  107. Zhao Q, Rathouz PJ, Jones JE, et al. Longitudinal trajectories of behavior problems and social competence in children with new onset epilepsy. Dev Med Child Neurol 2015; 57:37.
  108. Lew AR, Lewis C, Lunn J, et al. Social cognition in children with epilepsy in mainstream education. Dev Med Child Neurol 2015; 57:53.
  109. Nicolai J, Ebus S, Biemans DP, et al. The cognitive effects of interictal epileptiform EEG discharges and short nonconvulsive epileptic seizures. Epilepsia 2012; 53:1051.
  110. Prasad V, Kendrick D, Sayal K, et al. Injury among children and young adults with epilepsy. Pediatrics 2014; 133:827.
  111. Hedström EM, Svensson O, Bergström U, Michno P. Epidemiology of fractures in children and adolescents. Acta Orthop 2010; 81:148.
  112. Cooper C, Dennison EM, Leufkens HG, et al. Epidemiology of childhood fractures in Britain: a study using the general practice research database. J Bone Miner Res 2004; 19:1976.
  113. Souverein PC, Webb DJ, Petri H, et al. Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General Practice Research Database. Epilepsia 2005; 46:304.
  114. Sillanpää M, Shinnar S. Long-term mortality in childhood-onset epilepsy. N Engl J Med 2010; 363:2522.
  115. Selassie AW, Wilson DA, Malek AM, et al. Premature deaths among children with epilepsy - South Carolina, 2000-2011. MMWR Morb Mortal Wkly Rep 2014; 63:989.
  116. Nesbitt V, Kirkpatrick M, Pearson G, et al. Risk and causes of death in children with a seizure disorder. Dev Med Child Neurol 2012; 54:612.
  117. Nickels KC, Grossardt BR, Wirrell EC. Epilepsy-related mortality is low in children: a 30-year population-based study in Olmsted County, MN. Epilepsia 2012; 53:2164.