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Updates: First-line monotherapy in children with generalised tonic-clonic seizures with or without other generalised seizure types

This 2017 Cochrane review supports:

The use of sodium valproate as the first-line treatment for children with generalised tonic-clonic seizures (with or without other generalised seizure types).

Lamotrigine and levetiracetam as suitable alternatives, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. 


Management approach:
Treatment should be managed initially by a specialist neurologist trained in epilepsy. [37] Epilepsy may worsen the quality of life of a child and family, as well as causing serious hazards including physical injury and sudden death. Epilepsy also influences social aspects of everyday life. Because of these reasons, epilepsy requires treatment. However, despite successful treatment, some children may still have an impaired quality of life in relation to their own self-underestimation and adverse effects associated with therapy. The main treatment options include anticonvulsants, non-drug therapies such as a ketogenic diet and vagus nerve stimulation, and lifestyle measures (i.e., avoiding any precipitating stimuli such as sleep deprivation and alcohol consumption). Surgery is rarely recommended in generalised onset seizures.

Anticonvulsant drugs: principles of treatment
Anticonvulsants are the first-line treatment in most epilepsy syndromes and are used long term for prevention of seizures. Long-term therapy is indicated only when attacks are of a true epileptic nature and not a manifestation of another treatable disease process. Incorrect diagnosis leads to inadequate and potentially harmful treatment.

The main goal of treatment is to prevent further seizures. Where possible, diagnosis of a specific syndrome aids choice of anticonvulsant and guides length of treatment. Drug treatment is usually started after the second unprovoked seizure.

Choice of anticonvulsant is an important decision and depends equally on the efficacy in a specific syndrome and the potential adverse effects associated with the medicine. Studies have shown that only a few medicines can control idiopathic generalised epilepsies without potentially causing seizure aggravation. [38] Monotherapy is always preferred, as it decreases the risk of adverse effects and drug interactions, and allows the physician to find the right balance between symptom control and toxicity. [39] If monotherapy fails, combination therapy can be tried.

Newer anticonvulsants should be considered in patients who are not controlled on first-line agents (usually so-called 'old AEDs'), those in whom first-line drugs are contraindicated, those on other medicines where there is the potential for clinically significant drug interactions, and in women of child-bearing age. Importantly, few new AEDs are considered a first choice for the treatment of epilepsy in children, particularly because there is a lack of strong evidence that they induce fewer side effects. [39] [40] One study showed no significant differences with regard to efficacy and tolerability of levetiracetam and lamotrigine in newly diagnosed generalised epilepsy in patients aged 12 years and older despite more rapid titration in the levetiracetam arm. [41] A 2017 Cochrane review supports the use of sodium valproate as first-line treatment for children with generalised tonic-clonic seizures (with or without other generalised seizure types), and the use of lamotrigine and levetiracetam as suitable alternatives to sodium valproate, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]

Although most patients with epilepsy respond to medicine, a significant proportion prove refractory. This should change the course of management. Use of adjunctive perampanel was well tolerated and has improved control of drug-resistant primary generalised tonic-clonic seizures in idiopathic generalised epilepsy in patients aged 12 years or older. [43] After a patient has failed several medicine trials, the diagnosis needs to be reconsidered and options other than drugs explored such as a ketogenic diet, [44] vagus nerve stimulation, [45] [46] or surgery.

Increasingly, specialists are using lower starting doses than those traditionally recommended, with a more gradual increase in dose. This approach has resulted in good seizure response and tolerance. Local guidance on dosing should be consulted.

Generalised onset seizure in progress
When a seizure starts in a child, the child should be immediately placed on his or her side to prevent injury, and the airway cleared. If the seizure lasts for more than 5 minutes, or separate seizures happen in clusters, pharmacological intervention should be considered. First-line options include intravenous lorazepam, rectal diazepam, or buccal/intranasal midazolam, [47] [48] despite the fact that some evidence suggests midazolam may be more effective than diazepam. Evidence A Intravenous phenytoin is a second-line option if these therapies do not work. Rectal, intranasal, and buccal formulations may be given by the child's parent or carer if adequately trained. One study found no detectable differences in efficacy between intranasal midazolam and rectal diazepam as a rescue medicine for terminating seizures at home, although ease of administration makes intranasal midazolam more preferable. [49] Otherwise, paramedic intervention is required. Prolonged seizures or seizures that do not respond to this therapy require hospitalisation of the patient and the administration of intravenous anticonvulsants.

Status epilepticus is a complication that may occur with all types of epilepsy. It is defined as a continuous seizure or recurrent seizures without inter-ictal resumption of baseline CNS function. [50] There is no consensus about the duration of the seizure required for the diagnosis of status epilepticus; however, most specialists would say 10 minutes or longer.

Epilepsy syndromes
The concept of epilepsy syndromes represents the third level of epilepsy diagnosis and serves the purpose of guiding management. Epilepsy syndromes can be sub-divided depending on the usual age of onset. Each syndrome has a different natural history, and the choice of treatment for the prevention of seizures depends on the type of the epileptic syndrome. The more common epileptic syndromes with predominantly generalised onset seizures recognised in childhood will be discussed here. Sometimes an epileptic syndrome cannot be diagnosed in children; however, the patient will still require anticonvulsant therapy. The International League Against Epilepsy (ILAE) has noted that the concept of 'benign' can be misleading, and in the new classification and terminology paper this word is replaced by both 'self-limited' and 'pharmacoresponsive', each replacing different components of the meaning of 'benign'. It is expected that the word 'benign' in time will be replaced in the names of specific syndromes. [1]

Epilepsy syndromes in children <1 year old (excluding neonates)

  • 'Benign' familial or non-familial infantile epilepsy
    Because of benign outcome, the theoretical possibility of no treatment exists. But since the diagnosis is not always apparent, and repetitive clusters of seizures are known, empirical drug treatment is usually prescribed in the active seizure period and is effective. This is usually withdrawn after 1 to 3 years.


  • Myoclonic encephalopathy in non-progressive disorders (syndromes in development)
    In some cases, a good result may be obtained with valproate in association with ethosuximide or clonazepam. In some cases it may be necessary to use ACTH. If myoclonic status occurs, intravenous benzodiazepine is usually effective, but EEG-polygraphic recording is needed. Benzodiazepines may stop the myoclonias but not the continuous paroxysmal discharges.


  • Ohtahara syndrome
    This condition is a severe, very difficult to treat epileptic encephalopathy.
    Pyridoxine should be tried before any other treatment, especially when the early manifestation of epilepsy is status epilepticus.
    Sodium valproate, benzodiazepines, and ACTH (corticotropin) and/or corticosteroids are options for treatment, but their efficacy is limited.
    Zonisamide, vigabatrin, and high doses of phenobarbital have been reported to be of some value. [51] [52]
    A ketogenic diet is recommended in cases of severe drug resistance and may have a partial effect. [53]
    Surgery (i.e., hemispherectomy) may be effective in cases when focal cortical dysplasia is an aetiological factor.


  • Early myoclonic encephalopathy
    This condition is a severe, difficult to treat epileptic encephalopathy.
    Pyridoxine should be tried before any other treatment, especially when the early manifestation of epilepsy is status epilepticus.
    Sodium valproate, benzodiazepines, and ACTH (corticotropin) and/or corticosteroids are options for treatment, but their efficacy is limited.


  • Epileptic spasms (including West syndrome, previously known as infantile spasms)
    Epileptic spasms are resistant to most anticonvulsants. However, corticosteroids and/or ACTH (corticotropin), and vigabatrin (the treatment of choice in tuberous sclerosis) have all shown efficacy in studies. [54] [55] [56] [57] [58] [59]
    Recommendations regarding drug regimen, doses, and duration of treatment vary. The most common regimen is ACTH, followed by a corticosteroid (usually prednisolone). Treatment dose may need to be escalated quickly in an attempt to stop spasms and improve EEG. Vigabatrin has shown efficacy in studies for the treatment of epileptic spasms and is often used first line.
    Valproate may be effective in patients who do not respond to ACTH. Topiramate has been shown to be an effective and safe drug for epileptic spasms in children <2 years of age. [60] [61] Long-term effectiveness of zonisamide has also been reported. [62] [63]
    A ketogenic diet is an effective option for intractable epileptic spasms. [64]
    Surgery is a final option and is considered appropriate in children with drug-resistant epileptic spasms who have localised brain abnormalities, especially when they correlate with EEG localisation.


  • Myoclonic epilepsy in infancy
    Seizure control is usually favourable, with quick responders appearing to have a better outcome.
    Valproate monotherapy is generally considered effective in these patients. [65]
    Levetiracetam is a second-line alternative in patients who do not respond to valproate.
    There is a suggestion that delays in the start of treatment may cause cognitive problems later in life. [66] Many patients originally suspected to have this condition may develop other types of seizures, which often leads to a change of diagnosis. [67]


  • Severe myoclonic epilepsy in infancy (Dravet syndrome)
    Seizures respond poorly to standard anticonvulsants; however, valproate or benzodiazepines such as clonazepam may be useful. [68] [69]
    The addition of stiripentol (a cytochrome P450 inhibitor) has been shown to be effective when added to valproate and clobazam. [68] [69] It has been approved for use in conjunction with valproate and clobazam as adjunctive therapy of Dravet syndrome when seizures are not adequately controlled with clobazam and valproate. [68] [69] [70]
    The efficacy of topiramate when used as adjunctive therapy has also been reported. [71] Evidence B
    Lamotrigine is known to exacerbate seizures in these patients and is not recommended. [73] [74] However, in some patients with Dravet syndrome, lamotrigine may be beneficial. [75]
    A ketogenic diet has been reported to be partially effective in one study. [64] Children should be offered the ketogenic diet after 3 adequate trials of an anticonvulsant have failed. [76]

Epilepsy syndromes in early childhood

  • Epilepsy with myoclonic-atonic (previously astatic) seizures (Doose syndrome)
    Monotherapy with valproate is often effective, and approximately 50% of cases respond.
    Ethosuximide is also effective as a monotherapy or can be used in combination with valproate. Levetiracetam is an alternative option.
    A ketogenic diet is recommended if the patient does not respond to anticonvulsant therapy and is highly effective for this syndrome. [77] [78]


  • Lennox-Gastaut syndrome
    This syndrome is significantly resistant to therapy, and monotherapy with an anticonvulsant is rarely effective. This often means that polytherapy at high doses is required, which may lead to a paradoxical increase in seizure frequency.
    Valproate is the recommended first-line agent. Benzodiazepines may also be considered first line as monotherapy, or in combination with valproate.
    Second-line anticonvulsants include topiramate and lamotrigine. [72] [79] Evidence B Lamotrigine is particularly efficacious for atypical absences and falls, and may be used in combination with a benzodiazepine.
    Third-line anticonvulsants include phenobarbital, felbamate, ethosuximide, levetiracetam, and zonisamide. Felbamate may be used as a monotherapy or as an adjunctive therapy. [81] [82] Evidence B Rufinamide, topiramate, and clobazam may also be helpful as adjunctive therapies. [83] [84] [85] [86]
    Corticosteroids and/or ACTH (corticotropin) may be indicated for short-term treatment during a particularly difficult period.
    A ketogenic diet and vagus nerve stimulation are also frequently used for intractable cases.


  • Generalised epilepsy with febrile seizures plus (GEFS+), which includes febrile seizures plus (FS+)
    Valproate, lamotrigine, levetiracetam, or topiramate may be used for non-febrile generalised seizures, if these are frequent.

Epilepsy syndromes in middle childhood

  • Childhood absence epilepsy
    The goal of treatment is complete seizure control without drug-related adverse effects. It is important to note that generalised onset tonic-clonic seizures occur in some absence epilepsies, so treatment should be directed at treating both the tonic-clonic seizures and the absences.
    Valproate is the recommended first-line anticonvulsant, as it treats both absences and tonic-clonic seizures. In children with only absences, ethosuximide is a reasonable option. Evidence C
    A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to this first-line treatment, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]
    Lamotrigine may be added to valproate therapy in refractory cases. [87] [88] [89] [90] Evidence C Topiramate and zonisamide are effective third-line options.
    Gabapentin is not effective in these patients, [91] and evidence suggests that carbamazepine and vigabatrin may exacerbate absence seizures. [90] Therefore, the use of these agents is not recommended.


  • Epilepsy with myoclonic absences
    First-line treatment for these patients is valproate plus ethosuximide. High doses are usually required. The combination of valproate, phenobarbital, and a benzodiazepine is an alternative option.
    A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to this first-line treatment, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]


  • Eyelid myoclonia with absences
    This syndrome tends to be resistant to drug therapy.
    Valproate is usually used first line. Ethosuximide may also be effective.
    A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to this first-line treatment, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]

Epilepsy syndromes in late childhood/adolescence

  • Epilepsy with generalised tonic-clonic seizures alone
    This incorporates epilepsy with generalised onset tonic-clonic seizures on awakening.
    Lifestyle measures may need to be implemented to achieve freedom from seizures. Patients should be warned of common seizure precipitants including sleep deprivation and alcohol consumption.
    First-line treatment is valproate. A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to sodium valproate, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42] Topiramate and phenobarbital are also effective second-line options.
    Carbamazepine may aggravate seizures in patients with idiopathic generalised epilepsies and is therefore not recommended.
    Vagus nerve stimulation is a treatment option for patients with drug-resistant idiopathic generalised epilepsy. [46] [92]


  • Juvenile myoclonic epilepsy
    Lifestyle adjustments (avoiding sleep deprivation and alcohol consumption) and lifelong anticonvulsant therapy are required in these patients.
    First-line option is valproate. It may be used alone, or in combination with lamotrigine in resistant cases. [93] [80] Evidence B
    A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to sodium valproate, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]
    Monotherapy with lamotrigine is controversial as, despite its efficacy in controlling tonic-clonic seizures and absences, there is a very high risk of aggravation of myoclonic jerks. [94]
    Topiramate, phenobarbital, and zonisamide are good third-line options in patients whose seizures are not controlled by other anticonvulsants. [95] Levetiracetam is considered the most safe and efficacious of the newer anticonvulsants when used as monotherapy. [96] [97]
    Carbamazepine may aggravate seizures in patients with idiopathic generalised epilepsies and is therefore not recommended.

  • Juvenile absence epilepsy
    This condition is more likely to result in tonic-clonic seizures and is less likely to be outgrown than childhood absence epilepsy.
    Lifestyle adjustments (avoiding sleep deprivation and alcohol consumption) and lifelong anticonvulsant therapy are required in these patients.
    First-line anticonvulsant is valproate. A 2017 Cochrane review supports the use of lamotrigine and levetiracetam as suitable alternatives to sodium valproate, particularly for those of child-bearing potential, for whom sodium valproate may not be an appropriate therapy due to teratogenicity. [42]
    Third-line options include ethosuximide, topiramate, and zonisamide.
    Withdrawal of the treatment usually leads to relapse of seizures even in patients who have been seizure-free on treatment for many years.

Unidentified epilepsy syndrome
Sometimes an epileptic syndrome cannot be diagnosed in children. In these cases, anticonvulsant therapy must be tailored to the individual patient and is based on age, sex, and comorbidities. Monotherapy is preferable.
Good first-line options include valproate, lamotrigine, levetiracetam, carbamazepine, and topiramate. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and remains the drug of choice for many patients with generalised and unclassified epilepsies. [98] Evidence A Topiramate is well tolerated and effective for prolonged tonic-clonic seizures when used adjunctively with another anticonvulsant or for resistant tonic-clonic seizures when used as monotherapy. [99] [100] [101] [102] Evidence B
Other agents that may be tried include oxcarbazepine, phenobarbital, and phenytoin. Corticosteroids are generally not recommended. [103]

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References

Key articles

Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512-521.
Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:522-530.
Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia. 1997;38:1275-1282.
Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009;50:304-317.
Nordli DR Jr. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia. 2005;46(suppl s9):48-56.
French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.



Reference articles

1.  Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:512-521.
2.  Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:522-530.
3.  Eriksson KJ, Koivikko MJ. Prevalence, classification, and severity of epilepsy and epileptic syndromes in children. Epilepsia. 1997;38:1275-1282.
4.  Hauser WA. The prevalence and incidence of convulsive disorders in children. Epilepsia. 1994;35(suppl 2):S1-S6.
5.  Hauser WA, Hesdorffer DC. Epilepsy: frequency, causes, and consequences. New York, NY: Demos; 1990:18-21.
6.  Camfield CS, Camfield PR, Gordon K, et al. Incidence of epilepsy in childhood and adolescents: a population-based study in Nova Scotia from 1977 to 1985. Epilepsia. 1996;37:19-23.
7.  Hauser WA, Annegers JF, Kurland LT. Incidence of epilepsy and unprovoked seizures in Rochester, Minnesota: 1935-1984. Epilepsia. 1993;34:453-468.
8.  Berg AT. Risk of recurrence after a first unprovoked seizure. Epilepsia. 2008;49(suppl 1):13-18.
9.  Ramos Lizana J, Cassinello Garcia E, Carrasco Marina LL, et al. Seizure recurrence after a first unprovoked seizure in childhood: a prospective study. Epilepsia. 2000;41:1005-1013.
10.  Gardiner M. Genetics of idiopathic generalized epilepsies. Epilepsia. 2005;46(suppl s9):15-20.
11.  Weber YG, Lerche H. Genetic mechanisms in idiopathic epilepsies. Dev Med Child Neurol. 2008;50:648-654.
12.  Nakayama J, Arinami T. Molecular genetics of febrile seizures. Epilepsy Res. 2006;70(Suppl 1):S190-S198.
13.  Kramer MA, Cash SS. Epilepsy as a disorder of cortical network organization. Neuroscientist. 2012;18:360-372.
14.  Destexhe A, McCormick DA, Sejnowski TJ. Thalamic and thalamocortical mechanisms underlying 3 Hz spike-and-wave discharges. Prog Brain Res. 1999;121:289-307.
15.  Robinson R, Gardiner M. Genetics of childhood epilepsy. Arch Dis Child. 2000;82:121-125.
16.  Daoud AS, Batieha A, Bashtawi M, et al. Risk factors for childhood epilepsy: a case-control study from Irbid, Jordan. Seizure. 2003;12:171-174.
17.  Caravale B, Allemand F, Libenson MH. Factors predictive of seizures and neurologic outcome in perinatal depression. Pediatr Neurol. 2003;29:18-25.
18.  Appleton RE, Demellweek C. Post-traumatic epilepsy in children requiring inpatient rehabilitation following head injury. J Neurol Neurosurg Psychiatry. 2002;72:669-672.
19.  Giovanardi Rossi P, Posar A, Parmeggiani A. Epilepsy in adolescents and young adults with autistic disorder. Brain Dev. 2000;22:102-106.
20.  Steffenburg S, Steffenburg U, Gillberg C. Autism spectrum disorders in children with active epilepsy and learning disability: comorbidity, pre- and perinatal background, and seizure characteristics. Dev Med Child Neurol. 2003,45:724-730.
21.  Vestergaard M, Pedersen CB, Sidenius P, et al. The long-term risk of epilepsy after febrile seizures in susceptible subgroups. Am J Epidemiol. 2007;165:911-918.
22.  Wallace SJ. Febrile seizures. In: Wallace SJ, Farrell K, eds. Epilepsy in children, 2nd ed. London, UK: Arnold; 2004:123.
23.  Berg AT, Shinnar S, Levy SR, et al. Childhood-onset epilepsy with and without preceding febrile seizures. Neurology. 1999,53:1742-1748.
24.  Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child. 2004;89:751-756.
25.  Panayiotopoulos CP. A clinical guide to epileptic syndromes and their treatment. 2nd ed. London, UK: Springer; 2007.
26.  Lu Y, Waltz S, Stenzel K, et al. Photosensitivity in epileptic syndromes of childhood and adolescence. Epileptic Disord. 2008;10:136-143.
27.  Stephani U. The natural history of myoclonic astatic epilepsy (Doose syndrome) and Lennox-Gastaut syndrome. Epilepsia. 2006;47(suppl s2):53-55.
28.  Pressler R, Binnie CD, Cooper R, et al, eds. Neonatal and paediatric clinical neurophysiology. Edinburgh, UK: Churchill Livingstone; 2007.
29.  Winckler MI, Rotta NT. Clinical and electroencephalographic follow-up after a first unprovoked seizure. Pediatr Neurol. 2004;30:201-206.
30.  Ohtahara S, Yamatogi Y. Ohtahara syndrome: with special reference to its developmental aspects for differentiating from early myoclonic encephalopathy. Epilepsy Res. 2006;70(Suppl 1):S58-S67.
31.  Crespel A, Gelisse P, Bureau M, et al. Atlas of electroencephalography volume 2: the epilepsies, EEG and epileptic syndromes. Montrouge, France: John Libbey Eurotext; 2006.
32.  Joshi CN, Patrick J. Eyelid myoclonia with absences: routine EEG is sufficient to make a diagnosis. Seizure. 2007;16:254-260.
33.  Koutroumanidis M, Aggelakis K, Panayiotopoulos CP. Idiopathic epilepsy with generalized tonic-clonic seizures only versus idiopathic epilepsy with phantom absences and generalized tonic-clonic seizures: one or two syndromes? Epilepsia. 2008;49:2050-2062.
34.  Cross JH. Pitfalls in the diagnosis and differential diagnosis of epilepsy. Paediatr Child Health. 2009;19:199-202.
35.  Lai V, Mak HK, Yung AW, et al. Neuroimaging techniques in epilepsy. Hong Kong Med J. 2010;16:292-298.
36.  Bhatia MS. Pseudoseizures. Indian Pediatr. 2004;41:673-679.
37.  National Institute for Health and Care Excellence. QS27: Epilepsy in children and young people. February 2013. http://www.nice.org.uk/ (last accessed 18 September 2017).
38.  Hirtz D, Berg A, Bettis D, et al. Practice parameter: treatment of the child with a first unprovoked seizure. Neurology. 2003;60:166-175.
39.  Guerrini R, Zaccara G, la Marca G, et al. Safety and tolerability of antiepileptic drug treatment in children with epilepsy. Drug Saf. 2012;35:519-533.
40.  Verrotti A, Loiacono G, Coppola G, et al. Pharmacotherapy for children and adolescents with epilepsy. Expert Opin Pharmacother. 2011;12:175-194.
41.  Rosenow F, Schade-Brittinger C, Burchardi N, et al; LaLiMo Study Group. The LaLiMo Trial: lamotrigine compared with levetiracetam in the initial 26 weeks of monotherapy for focal and generalised epilepsy - an open-label, prospective, randomised controlled multicenter study. J Neurol Neurosurg Psychiatry. 2012;83:1093-1098.
42.  Nevitt SJ, Sudell M, Weston J, et al. Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data. Cochrane Database Syst Rev. 2017;(6):CD011412.
43.  French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: a randomized trial. Neurology. 2015;85:950-957.
44.  Martin K, Jackson CF, Levy RG, et al. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database Syst Rev. 2016;(2):CD001903.
45.  Robinson R. Vagal nerve stimulation is more effective than trials of further anti-epileptic drugs (AEDs) in children who have already tried >5 AEDs. Eur J Paediatr Neurol. 2011;15(suppl 1):89.
46.  Englot DJ, Chang EF, Auguste KI. Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response. J Neurosurg. 2011;115:1248-1255.
47.  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;366:205-210.
48.  Holsti M, Sill BL, Firth SD, et al. Prehospital intranasal midazolam for the treatment of pediatric seizures. Pediatr Emerg Care. 2007;23:148-153.
49.  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;164:747-753.
50.  Engel J Jr; International League Against Epilepsy. A proposed diagnostic scheme for people with epileptic seizures and with epilepsy: report of the ILAE Task Force on Classification and Terminology. Epilepsia. 2001;42:796-803.
51.  Ozawa H, Kawada Y, Noma S, et al. Oral high-dose phenobarbital therapy for early infantile epileptic encephalopathy. Pediatr Neurol. 2002;26:222-224.
52.  Ohno M, Shimotsuji Y, Abe J, et al. Zonisamide treatment of early infantile epileptic encephalopathy. Pediatr Neurol. 2000;23:341-344.
53.  Kossoff EH, Zupec-Kania BA, Amark PE, et al. Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group. Epilepsia. 2009;50:304-317.
54.  O'Callaghan FJ, Edwards S, Hancock E, et al. OP50 - 3017: The International Collaborative Infantile Spasms Study (ICISS) comparing hormonal therapies (prednisolone or tetracosactide depot) and vigabatrin versus hormonal therapies alone in the treatment of infantile spasms: Early clinical outcome. Abstract G59. 11th European Paediatric Neurology Society Congress, Vienna; 2015.
55.  Nelson GR. Management of infantile spasms. Transl Pediatr. 2015;4:260-270.
56.  Hancock EC, Osborne JP, Edwards SW. Treatment of infantile spasms. Cochrane Database Syst Rev. 2013;(6):CD001770.
57.  Glaze DG, Hrachovy RA, Frost JD Jr, et al. Prospective study of outcome of infants with infantile spasms treated during controlled studies of ACTH and prednisone. J Pediatr. 1988;112:389-396.
58.  Baram TZ, Mitchell WG, Tournay A, et al. High-dose corticotropin (ACTH) versus prednisone for infantile spasms: a prospective, randomized, blinded study. Pediatrics. 1996;97:375-379.
59.  Lux AL, Edwards SW, Hancock E, et al. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004;364:1773-1778.
60.  Zou LP, Ding CH, Fang F, et al. Prospective study of first-choice topiramate therapy in newly diagnosed infantile spasms. Clin Neuropharmacol. 2006;29:343-349.
61.  Korinthenberg R, Schreiner A. Topiramate in children with West syndrome: a retrospective multicenter evaluation of 100 patients. J Child Neurol. 2007;22:302-306.
62.  Suzuki Y, Imai K, Toribe Y, et al. Long-term response to zonisamide in patients with West syndrome. Neurology. 2002;58:1556-1559.
63.  Kluger G, Zsoter A, Holthausen H. Long-term use of zonisamide in refractory childhood-onset epilepsy. Eur J Paediatr Neurol. 2008;12:19-23.
64.  Hartman AL, Vining EP. Clinical aspects of the ketogenic diet. Epilepsia. 2007;48:31-42.
65.  Auvin S, Pandit F, De Bellecize J, et al. Benign myoclonic epilepsy in infants: electroclinical features and long-term follow-up of 34 patients. Epilepsia. 2006;47:387-393.
66.  Oguni H. Symptomatic epilepsies imitating idiopathic generalized epilepsies. Epilepsia. 2005;46(suppl s9):84-90.
67.  Nordli DR Jr. Idiopathic generalized epilepsies recognized by the International League Against Epilepsy. Epilepsia. 2005;46(suppl s9):48-56.
68.  Kassai B, Chiron C, Augier S, et al. Severe myoclonic epilepsy in infancy: a systematic review and a meta-analysis of individual patient data. Epilepsia. 2008;49:343-348.
69.  Chiron C, Marchand MC, Tran A, et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. Lancet. 2000;356:1638-1642.
70.  Brigo F, Igwe SC, Bragazzi NL. Antiepileptic drugs for the treatment of severe myoclonic epilepsy in infancy. Cochrane Database Syst Rev. 2017;(5):CD010483.
71.  Nieto-Barrera M, Candau R, Nieto-Jimenez M, et al. Topiramate in the treatment of severe myoclonic epilepsy in infancy. Seizure. 2000;9:590-594.
72.  Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology. 1999;52:1882-1887.
73.  Guerrini R, Dravet C, Genton P, et al. Lamotrigine and seizure aggravation in severe myoclonic epilepsy. Epilepsia. 1998;39:508-512.
74.  Crespel A, Genton P, Berramdane M, et al. Lamotrigine associated with exacerbation or de novo myoclonus in idiopathic generalized epilepsies. Neurology. 2005;65:762-764.
75.  Dalic L, Mullen SA, Roulet Perez E, et al. Lamotrigine can be beneficial in patients with Dravet syndrome. Dev Med Child Neurol. 2015;57:200-202.
76.  Caraballo RH, Cersosimo RO, Sakr D, et al. Ketogenic diet in patients with Dravet syndrome. Epilepsia. 2005;46:1539-1544.
77.  Kilaru S, Bergqvist AG. Current treatment of myoclonic astatic epilepsy: clinical experience at the Children's Hospital of Philadelphia. Epilepsia. 2007;48:1703-1707.
78.  Oguni H, Tanaka T, Hayashi K, et al. Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood. Neuropediatrics. 2002;33:122-132.
79.  Motte J, Trevathan E, Arvidsson JF, et al; Lamictal Lennox-Gastaut Study Group. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med. 1997;337:1807-1812.
80.  Trevathan E, Kerls SP, Hammer AE, et al. Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic-clonic seizures. Pediatrics. 2006;118:e371-e378.
81.  The Felbamate Study Group in Lennox-Gastaut Syndrome. Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). N Engl J Med. 1993;328:29-33.
82.  Dodson WE. Felbamate in the treatment of Lennox-Gastaut syndrome: results of a 12-month open-label study following a randomized clinical trial. Epilepsia. 1993;34(suppl 7):S18-S24.
83.  Hancock EC, Cross JH. Treatment of Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2013;(2):CD003277.
84.  Wier HA, Cerna A, So TY. Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview. Pediatr Drugs. 2011;13:97-106.
85.  Kim SH, Eun SH, Kang HC, et al. Rufinamide as an adjuvant treatment in children with Lennox-Gastaut syndrome. Seizure. 2012;21:288-291.
86.  Leahy JT, Chu-Shore CJ, Fisher JL. Clobazam as an adjunctive therapy in treating seizures associated with Lennox-Gastaut syndrome. Neuropsychiatr Dis Treat. 2011;7:673-681.
87.  French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62:1252-1260.
88.  Panayiotopoulos CP. Typical absence seizures and their treatment. Arch Dis Child. 1999;81:351-355.
89.  Coppola G, Auricchio G, Federico R, et al. Lamotrigine versus valproic acid as first-line monotherapy in newly diagnosed typical absence seizures: an open-label, randomized, parallel-group study. Epilepsia. 2004;45:1049-1053.
90.  National Institute for Health and Care Excellence. Epilepsies: diagnosis and management. February 2016. http://www.nice.org.uk/ (last accessed 18 September 2017).
91.  Trudeau V, Myers S, LaMoreaux L, et al. Gabapentin in naive childhood absence epilepsy: results from two double-blind, placebo-controlled, multicenter studies. J Child Neurol. 1996;11:470-475.
92.  Kostov H, Larsson PG, Roste GK. Is vagus nerve stimulation a treatment option for patients with drug-resistant idiopathic generalized epilepsy? Acta Neurol Scand Suppl. 2007;187:55-58.
93.  Covanis A, Gupta AK, Jeavons PM. Sodium valproate: monotherapy and polytherapy. Epilepsia. 1982;23:693-720.
94.  Tennis P, Eldridge RR; International Lamotrigine Pregnancy Registry Scientific Advisory Committee. Preliminary results on pregnancy outcomes in women using lamotrigine. Epilepsia. 2002;43:1161-1167.
95.  Berkovic SF, Knowlton RC, Leroy RF, et al; Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69:1751-1760.
96.  Sharpe DV, Patel AD, Abou-Khalil B, et al. Levetiracetam monotherapy in juvenile myoclonic epilepsy. Seizure. 2008;17:64-68.
97.  Verrotti A, Cerminara C, Coppola G, et al. Levetiracetam in juvenile myoclonic epilepsy: long-term efficacy in newly diagnosed adolescents. Dev Med Child Neurol. 2008;50:29-32.
98.  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;369:1016-1026.
99.  Wirrell E, Camfield C, Camfield P, et al. Prognostic significance of failure of the initial antiepileptic drug in children with absence epilepsy. Epilepsia. 2001;42:760-763.
100.  Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology. 1999;52:1330-1337.
101.  Wheless JW. Use of topiramate in childhood generalized seizure disorders. J Child Neurol. 2000;15(Suppl 1):S7-S13.
102.  Wheless JW, Neto W, Wang S; EPMN-105 Study Group. Topiramate, carbamazepine, and valproate monotherapy: double-blind comparison in children with newly diagnosed epilepsy. J Child Neurol. 2004;19:135-141.
103.  Mehta V, Ferrie CD, Cross JH, et al. Corticosteroids including ACTH for childhood epilepsy other than epileptic spasms. Cochrane Database Syst Rev. 2015;(6):CD005222.
104.  Panayiotopoulos CP. The epilepsies: seizures, syndromes and management. Oxford, UK: Bladon Medical Publishing; 2005:105.
105.  Henderson CB, Filloux FM, Alder SC, et al. Efficacy of the ketogenic diet as a treatment option for epilepsy: meta-analysis. J Child Neurol. 2006;21:193-198.
106.  Morris GL 3rd, Gloss D, Buchhalter J, et al. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy. Neurology. 2013;81:1453-1459.
107.  Medicines and Healthcare products Regulatory Agency (UK). Valproate and of risk of abnormal pregnancy outcomes: new communication materials. February 2016. https://www.gov.uk/ (last accessed 18 September 2017).
108.  Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res. 1998;29:147-154.
109.  Tjia-Leong E, Leong K, Marson AG. Lamotrigine adjunctive therapy for refractory generalized tonic-clonic seizures. Cochrane Database Syst Rev. 2010;(12):CD007783.
110.  Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst Rev. 2014;(3):CD009270.
111.  Wilner AN. Epilepsy notes. Marijuana for epilepsy: weighing the evidence. Medscape Neurology. WebMD. 25 March 2014.
112.  Hauser E, Freilinger M, Seidl R, et al. Prognosis of childhood epilepsy in newly referred patients. J Child Neurol. 1996;11:201-204.
113.  Sillanpää M, Schmidt D. Natural history of treated childhood-onset epilepsy: prospective, long-term population-based study. Brain. 2006;129:617-624.
114.  Leone MA, Solari A, Beghi E; FIRST Group. Treatment of the first tonic-clonic seizure does not affect long-term remission of epilepsy. Neurology. 2006;67:2227-2229.
115.  Beghi E, Leone M, Vallalta R, et al. Long-term mortality after a first unprovoked tonic-clonic seizure: risk factors and treatment effects. Oral presentations, abstract O6. Regional North American Annual Meeting of the World Federation of Neurology - Research Group on Neuroepidemiology, Toronto; 2010. Neuroepidemiology. 2010;34:274.
116.  Mitchell WG. Status epilepticus and acute serial seizures in children. J Child Neurol. 2002;17(suppl 1):S36-S43.
117.  Sofou K, Kristjánsdóttir R, Papachatzakis NE, et al. Management of prolonged seizures and status epilepticus in childhood: a systematic review. J Child Neurol. 2009;24:918-926.
118.  Neville BG, Chin RF, Scott RC. Childhood convulsive status epilepticus: epidemiology, management and outcome. Acta Neurol Scand Suppl. 2007;186:21-24.
119.  Shorvon S. The management of status epilepticus. J Neurol Neurosurg Psychiatry. 2001;70(Suppl II):ii22-ii27.
120.  Harden C, Tomson T, Gloss D, et al; American Academy of Neurology, American Epilepsy Society. Practice guideline summary: sudden unexpected death in epilepsy incidence rates and risk factors. Neurology. 2017;88:1674-1680.
121.  da Costa CRCM, Maia Filho HS, Gomes MM. Clinical and neuropsychological evaluation of attention in children and adolescents with epilepsy: a systematic review [in Portuguese]. J Epilepsy Clin Neurophysiol. 2009;15:77-82.
122.  Cheng LS, Prasad AN, Rieder MJ. Relationship between antiepileptic drugs and biological markers affecting long-term cardiovascular function in children and adolescents. Can J Clin Pharmacol. 2010;17:e5-e46.
123.  Strozzi I, Nolan SJ, Sperling MR, et al. Early versus late antiepileptic drug withdrawal for people with epilepsy in remission. Cochrane Database Syst Rev. 2015;(2):CD001902.
124.  Fleeman N, Bradley PM, Lindsay B. Care delivery and self-management strategies for children with epilepsy. Cochrane Database Syst Rev. 2015;(12):CD006245.