Treatment of Childhood Epilepsy - What’s New?

A third of patients with epilepsy are refractory to current treatment options. Thus, new agents are a welcome addition. Antiepileptic drugs usually constitute first-line therapy, although treatment with these agents is usually not initiated after the first event. This reflects the fact that the recurrence rate after the first seizure is relatively low (15% to 20%), when no other risk factors are evident. Other treatment options include dietary regimens, vagus nerve stimulation, and surgery. 

A brief overview of recent advances in each of these areas is outlined below.

ANTIEPILEPTIC DRUGS

Three novel antiepileptic medications have been introduced in the past 2 years after a long hiatus.

Vigabatrin (Sabril) was approved in 2009 for add-on use in refractory partial epilepsy in adults in the United States. Off-label use in pediatric patients is becoming fairly common. In 2005, a survey of child neurologists revealed that vigabatrin was the primary drug for the treatment of infantile spasms, especially when tuberous sclerosis was the underlying disease.¹ This agent remains the first line treatment for pediatric patients.

Vigabatrin is an irreversible inhibitor of GABA transaminase that increases levels of the inhibitory neurotransmitter GABA in the brain. It is available as a 500 mg pill and a powder sachet of 500 mg. The usual initiation dose is 50 mg/kg/d; the maximum recommended dose is 150 mg/kg/d. The time to peak concentration is 1.3 to 2.4 hours; the half-life is 5.5 hours. The major drug interaction is a reduction in phenytoin serum levels.

A significant side effect is the development of a permanent peripheral visual field defect, most commonly in the nasal field. The prevalence of this side effect is lower in children than in adults (15% vs 25% to 50% in adults). The condition may progress to involve both visual fields, leaving intact a concentric area of central vision.² Most patients with visual impairments are asymptomatic, at least initially. Therefore, age-appropriate visual field testing is vital.

Rufinamide (Banzel) was approved in 2009 by the FDA for treatment of children over 4 years old with Lennox-Gastaut syndrome (LGS)-- a rare but potentially devastating form of childhood epilepsy that is commonly refractory to treatment. The drug has also received approval for treatment of seizures in adolescents over 12 years old.

Rufinamide regulates the activity of sodium channels in the brain. Rufinamide is available as scored tablets of 200 mg and 400 mg and as a suspension of 40mg/ml.³ The initial prescribing dose is 10 mg/kg/d; the maximum dose is 45 mg/kg/d (upper dose of 3200 mg/d) in 2 divided doses. It has a half-life of 6 to 10 hours. 

Drug interactions may occur with valproic acid, phenobarbital, and phenytoin.

Rufinamide is contraindicated in children with familial short QT syndrome. It is prudent to obtain a baseline ECG before initiating treatment with this drug.

Lacosamide (Vimpat) received FDA approval in the latter half of 2008 as adjuvant treatment for partial epilepsy in adolescents older than 17 years. It enhances slow inactivation of sodium channels in the brain and hence affects action potentials that lead to seizures. The elimination half life is 13 hours.⁴

The major side effects of locosamide are dizziness and ataxia. A dose-dependent prolongation of the PR interval has been documented; thus the drug should be avoided in patients with cardiac conduction disturbances. 

Locosamide is usually started at a dose of 50 mg twice daily and increased to a maximum of 400 mg/d in 2 divided doses. It is marketed as 50 mg, 100 mg, 150 mg, and 200 mg pills; a 200 mg/20 ml vial is also available for IV administration.⁵

Other drugs that have received FDA approval over the past decade include oxcarbazepin (Trileptal, 2000); levetiracetam (Keppra, 1999); tiagabine (Gabatril, 1997); topiramate (Topomax, 1996); and felbamate (1993).

DIETARY REGIMENS
The ketogenic diet has been used as a treatment modality for intractable epilepsy since the 1920s. The basic principle is to include 3 to 4 parts fat to 1 part carbohydrate/protein. However, the modified Atkin’s diet-- which is less restrictive and more child-friendly-has been recently shown to be efficacious as well.⁶ It has proven effective in several types of epilepsy, including myoclonic epilepsy, infantile spasms, and myoclonic-astatic seizures.

Adverse effects of the ketogenic diet include acidosis, hypoglycemia, nephrolithiasis, elevated liver enzymes levels, hyperlipidemia, bone deminerilazation, cardiomyopathy, and deficiencies of vitamins and trace minerals.⁷ These effects occur less frequently with the modified Atkin’s diet than with the ketogenic diet. Multiple aspects need to be discussed with the family and child before dietary modifications are made because significant parental involvement and commitment is mandatory.

VAGUS NERVE STIMULATION

VNS has been used in children since 1997, for children with epilepsy refractory to drug treatment, and in those unlikely to be surgical candidates. The device is surgically implanted beneath the skin of the left chest and connects to the vagus nerve via an electrode. VNS prevents seizures but also can have an immediate abortive effect when a hand held magnet is “swiped” over it to produce a surge of electric current.

VNS has been shown to be helpful in both partial and generalized epilepsy types, especially LGS. A significant reduction in seizure frequency can be expected in about a third of those who opt for this treatment regimen. The exact mechanism of action is not clear, although it is hypothesized that it can interfere with thalamic circuitry that has a role in seizure generation.⁸

SURGERY

Surgical options were previously reserved for those whose seizures were refractory to medical interventions. However, focal resection for temporal lobe epilepsy has emerged as a viable early alternative. Success rates range from 66% to 88%.^9,10 Similar results elude those with extratemporal epilepsy (eg, occipital or frontal lobe epilepsy).

Deep brain stimulation involving the thalamus, subthalamic nucleus, pallidum, and medial temporal lobe is also being actively investigated as a treatment alternative in children, but currently no formal recommendations can be made.¹¹ For those children in whom focal resection is unlikely to provide much benefit, palliative procedures such as corpus callosotomy and multiple subpial transections can be considered.

References
1. Wheless JW, Clarke DF, Carpenter D. Treatment of pediatric epilepsy: expert opinion. J Child Neurol. 2005;20(suppl 1):S1-S56.
2. Willmore LJ, Abelson MB, Ben-Menachem E, et al. Vigabatrin: 2008 update. Epilepsia. 2009;50(2):163-173.
3. Wier HA, Cerna A, So TY. Rufinamide for pediatric patients with Lennox-Gastaut syndrome: a comprehensive overview. Pediatr Drugs. 2011;13(2):97-106.
4. Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial onset seizures. Epilepsia. 2007;48(7):1308-1317.
5. Cada DJ, Levien TL, Baker DE. Lacosamide. Hospital Pharmacy. 2009;44 (6):497–508.
6. Kossoff EH, McGrogan JR, Bluml RM, et al. A  modified Atkins diet is effective for the treatment of intractable pediatric epilepsy. Epilepsia. 2006;47(2):421-424.
7. Nordli D. Ketogenic diet uses and abuses. Neurology. 2002;58(12):S21-S24.
8. Vonck K, De Herdt V, Bosman T, et al. Thalamic and limbic involvement in the mechanism of action of vagus nerve stimulation, a SPECT study. Seizure. 2008;17(8):699-706.
9. Tellez-Zenteno JF, Dhar R, Wiebe S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain. 2005;(128):1188-1198.
10. Kim SK, Wang KC, Hwang YS. Epilepsy surgery in children: outcome and complications. J Neurosurg Pediatrics. 2008;1(4):277-283.
11. Lipsman N, Ellis M, Lozano AM. Current and future indications for deep brain stimulation in pediatric populations. Neurosurg Focus. 2010;29(2):E2.