- 1 Treatment Of Partial Epilepsy
- 2 Treatment Of Generalized Epilepsy Idiopathic Generalized Epilepsy
- 3 Treatment Of Symptomatic Generalized Epilepsy
- 4 Treatment Of Epileptic Encephalopathies
- 5 Abortive Therapy In Newly Diagnosed Patients
- 6 Table Food and Drug Administration-approved indications for anti-epileptic drugs in patients under 16 years of age
- 7 Related Posts
Paediatric epilepsy is amazingly diverse. In some children, basic diagnosis, seizure classification and treatment are straightforward. Other patients have difficult-to-diagnose seizures, complicated seizure classification and a variable response to treatment. Some seizures are subclinical, others are barely noticeable, and occasionally they are life threatening. Many children with epilepsy have no associated disabilities, but all children with epilepsy are at increased risk for learning and behavioural difficulties. In many patients, even those with well-controlled seizures, epilepsy is only one element of a complex neurodevelopmental problem.
In children, epilepsy is typically defined as a tendency toward recurrent seizures, with a history of at least two unprovoked seizures. The first task when confronting a child with suspected seizures is to confirm that the episodes of concern are epileptic seizures, as there are many other conditions in children that may mimic seizures. The second task is to ensure that the seizures are unprovoked. Unprovoked seizures occur without an immediate trigger, such as fever, acute metabolic disturbance, acute head trauma or acute central nervous system (CNS) infection. Seizures associated with an immediate precipitant are provoked seizures. Since many children with a single unprovoked seizure will not have recurrent seizures, it is important to limit the diagnosis of paediatric epilepsy to those children who have had at least two unprovoked seizures. This is distinctly different from adults, in whom even a single seizure may have a significant impact on employment and driving.
Table First-line anti-epileptic drugs (anti-epileptic drugs) by spectrum of action
|Partial epilepsy (with or without second generalization): ‘narrow-spectrum anti-epileptic drugs’||Partial and generalized epilepsy: ‘broad-spectrum anti-epileptic drugs’||Full spectrum not yet defined||Syndrome-specific use|
|Carbamazepine||Clobazam||Zonisamide||Ethosuximide – childhood absence epilepsy|
|Gabapentin||Lamotrigine||Adrenocorticotropic hormone (ACTH) – infantile spasms|
|Oxcarbazepine||Levetiracetam||Vigabatrin – infantile spasms in patients with tuberous sclerosis|
Treatment Of Partial Epilepsy
Symptomatic or Cryptogenic Partial Epilepsy
Initial treatment of partial epilepsy is typically with a ‘narrow-spectrum’ anti-epileptic drug, but some broad-spectrum anti-epileptic drugs can also be used (see Table First-line anti-epileptic drugs (anti-epileptic drugs) by spectrum of action). The strongest evidence supports oxcarbazepine as initial monotherapy. Among the traditional anti-epileptic drugs, there is evidence to support the use of valproate, carbamazepine, phenobarbital and phenytoin. However, these anti-epileptic drugs may have more side-effects than some of the newer medications. Clobazam, levetiracetam, lamotrigine and topiramate can also be used in the initial treatment of childhood partial epilepsy. The patient’s seizure frequency, seizure severity, co-morbid conditions, ability to swallow the dosing formulation and insurance status / prescription plan all influence the choice of anti-epileptic drug.
Idiopathic Partial Epilepsy
There is a paucity of research evaluating treatment regimens for these syndromes. Gabapentin and sulthiame have both been shown to be more effective than placebo for treatment of BECTS. In addition, anti-epileptic drugs which are effective for partial-onset seizures, in general can be considered as first-line therapies for BECTS. Many patients with idiopathic partial epilepsy, especially those with BECTS, do not require anti-epileptic drugs. For those who request treatment, single nocturnal doses of an appropriate anti-epileptic drug (e.g. gabapentin) may be sufficient. Although the approach is not evidence based and is not typically recommended, some children with BECTS choose to take anti-epileptic drugs on an intermittent basis, such as when going away to camp or sleeping at a friend’s home.
Treatment Of Generalized Epilepsy Idiopathic Generalized Epilepsy
Childhood Absence Epilepsy
There is evidence to support the use of valproate, ethosuximide (), and lamotrigine as initial monotherapy for CAE. No evidence currently suggests that any of these has superior efficacy or effectiveness. There is, however, an ongoing multicentre trial, supported by the United States National Institutes of Health, to address this question.
Juvenile Myoclonic Epilepsy
Ideally, the goal in treating juvenile myoclonic epilepsy is to eliminate all seizure types. When this is not possible, targeting the most disabling seizure type, while avoiding obvious triggers (sleep deprivation and alcohol) is reasonable. While valproate has traditionally been used as the first-line anti-epileptic drug in juvenile myoclonic epilepsy, there are no controlled trials to support this. In fact, no controlled trials have studied any anti-epileptic drug as initial monotherapy for patients with juvenile myoclonic epilepsy. There is evidence from case series and open-label trials to support the use of valproate, lamotrigine, levetiracetam, topiramate and zonisamide (). However, lamotrigine has also been reported to exacerbate myoclonic seizures in juvenile myoclonic epilepsy. Therefore, in a patient for whom the myoclonus is the primary concern, with infrequent convulsions, lamotrigine may not be the anti-epileptic drug of choice.
Additional consideration should be given to the fact that juvenile myoclonic epilepsy patients typically require lifelong anti-epileptic drug therapy. For adolescent females, concerns regarding teratogenicity may argue against valproate as a first-line agent. Interactions with oral contraceptives should also be considered ().
Primary Generalized Epilepsy with Tonic-Clonic Seizures Alone
There are few data to support evidence-based selection of anti-epileptic drugs for primary generalized tonic-clonic seizures alone. The available choices are the same as those discussed for juvenile myoclonic epilepsy: valproate, lamotrigine, levetiracetam, topiramate and zonisamide.
Treatment Of Symptomatic Generalized Epilepsy
Lennox-Gastaut Syndrome (Lennox–Gastaut syndrome)
The classic triad of Lennox–Gastaut syndrome is frequent seizures with multiple seizure types, interictal slow spike-wave and delayed mental development. The Food and Drug Administration (FDA) has approved felbamate (), lamotrigine and topiramate for use in the treatment of Lennox–Gastaut syndrome. topiramate was shown to decrease drop attacks and convulsions when compared with placebo (33% of topiramate patients had greater than 50% reduction in seizures, compared with 8% of placebo). Of patients treated with lamotrigine vs. placebo, 33% vs. 16% had greater than 50% seizure reduction. Patients treated with felbamate had a 34% decrease in seizures, compared with a 16% decrease in placebo-treated patients.
Other anti-epileptic drugs often used in treatment of Lennox–Gastaut syndrome, without data from controlled trials, include: valproate, vigabatrin (), zonisamide, phenobarbital, benzodiazepines and adrenocorticotropic hormone (ACTH) or prednisolone. Additional options include the ketogenic diet, vagus nerve stimulator or corpus callosotomy.
As with other epilepsy syndromes with multiple seizure types, targeting the most disabling seizures is important. In patients with Lennox–Gastaut syndrome, tonic seizures cause injuries and are often the most disabling. Simple interventions, such as providing a helmet with face protection, can also be helpful.
Treatment Of Epileptic Encephalopathies
West syndrome is the triad of infantile spasms (ISs), profoundly abnormal interictal EEG (hypsarrhythmia), and developmental arrest or regression. This is one of the classic catastrophic epilepsies of childhood. The prognosis and treatment of a child with IS often depends on the underlying aetiology of the disorder. For many infants, an extensive diagnostic work-up is required ().
While prompt treatment of IS is typically viewed as important, there are remarkably few data available to support the various treatment choices. A recent practice parameter by the American Academy of Pediatrics and the Child Neurology Society concluded that ACTH is ‘probably effective’ for the short-term treatment of infantile spasms and resolution of hypsarrhythmia, but there is insufficient evidence to recommend optimal ACTH dosage or duration of treatment. High-dose ACTH (150 units / m2 daily) may have a slightly higher response rate than low-dose regimens, but there are increased side-effects with the increased steroid dose. Recent work has suggested that doses as low as 0.2-1.0 units / kg / day can be effective and have fewer serious side-effects.
In most current protocols, infants are started on a relatively low-dose ACTH regimen and monitored for response. If, by 2 weeks of treatment, the ISs resolve and the EEG improves, ACTH is tapered over approximately 4 weeks. If the seizures have not improved and side-effects are tolerable, the dose can be increased in an attempt to control the ISs. Ranitidine, or a similar agent, is used to avoid gastritis. Regular monitoring of blood pressure and routine stool guaiac testing may prevent serious adverse events. Some epilepsy centres also recommend co-trimazole as prophylaxis against Pneumocystis carinii pneumonia. Parents should be counselled that irritability is a common, but reversible, side-effect from this treatment regimen.
For patients who do not respond to ACTH, there are other options. vigabatrin can be effective in doses of 25-150 mg / kg / day. However, vigabatrin may take longer to produce a positive effect than ACTH, and the duration of IS and hypsarrhythmia may have implications for developmental outcome, especially in patients with cryptogenic IS.
Several studies have shown that patients whose ISs are caused by tuberous sclerosis have particularly good responses to vigabatrin. For these patients, vigabatrin is considered the most appropriate first-line therapy, despite risks of irreversible peripheral vision loss. vigabatrin is not approved by the FDA for use in the United States.
Other second- or third-line anti-epileptic drug choices for IS include valproate, pyridoxine, topiramate, zonisamide and lamotrigine. In many cases, infants with newly diagnosed IS should be given a trial of 100- mg intravenous pyridoxine while an EEG is being recorded, to rule out pyridoxine dependency. High-dose pyridoxine has also been used as an ongoing treatment for IS, sometimes combined with low-dose ACTH. topiramate and zonisamide have shown efficacy in small case series of IS.
Abortive Therapy In Newly Diagnosed Patients
The option of prescribing an abortive medication, such as rectal diazepam (), may be a good one for the primary care physician who is caring for a child with a first unprovoked seizure or newly diagnosed epilepsy who must wait for several weeks prior to consultation with a neurologist. This may circumvent unnecessary prescription of a daily anti-epileptic drug for a child who might not need such treatment. Additionally, it will avoid the situation in which an inappropriate medication is selected, which could exacerbate seizures in a patient with generalized epilepsy.
Discontinuing Anti-Epileptic Drugs
About half of all children with epilepsy will eventually outgrow their disorder. For patients who are seizure free for a period of time (usually 2 years), a trial-off of anti-epileptic drug is almost always reasonable. In this scenario, approximately 70% of children are successfully weaned from anti-epileptic drugs. Risk factors for recurrence of seizures after weaning anti-epileptic drugs include: (i) onset of epilepsy during adolescence; (ii) epileptiform discharges on EEG; and (iii) symptomatic (vs. idiopathic) epilepsy syndrome. While none of these risk factors is an absolute contraindication for weaning anti-epileptic drugs, the patient and family must be made aware that the chances of success are reduced. Regardless, the risk of developing intractable epilepsy after withdrawing an anti-epileptic drug in an appropriate clinical context is very low.
There is concern that rapid withdrawal of anti-epileptic drugs may precipitate status epilepticus. Therefore, slow tapering of anti-epileptic drugs is recommended. Generally, a taper of 6 weeks is appropriate for the child who is seizure free and is on monotherapy. There appears to be little or no advantage to using a longer taper.
As mentioned above, typical patients with juvenile myoclonic epilepsy require lifelong anti-epileptic drug treatment because of recurrent convulsions when anti-epileptic drug tapers are attempted. Usually, by the time they achieve a period of seizure freedom, these patients are of driving age and prefer to continue the anti-epileptic drug rather than give up their driving privileges.
Adults with a history of childhood-onset epilepsy are less likely than controls to obtain a driver’s licence. Because driving is so important for social functioning, if at all possible we recommend a trial off of anti-epileptic drugs prior to the age of obtaining a licence. Doing this at age 12-14 years allows an adequate trial-off of anti-epileptic drugs, as well as enough time to regain seizure control should the wean be unsuccessful. Requirements of seizure freedom vary between states and countries, but most specify 6 months’ to 2 years’ remission prior to granting licences.
It is important that patients and care-givers have a plan of action in the case of recurrent seizures as anti-epileptic drugs are tapered and discontinued. They should know their specific epilepsy syndrome diagnosis and seizure type(s), anti-epileptic drug dose at which the child was seizure free and whom to call in the case of a seizure. Plans should be clear regarding the need for emergency medical services in the case of recurrent seizures (care-giver knowledge of cardiopulmonary resuscitation [CPR] and a prescription for an emergency abortive medication are important). In addition, patients and care-givers should pay attention to any cognitive or behavioural changes that may occur when the child is off anti-epileptic drugs, as this could alter future treatment plans in the case of relapse.
Table Food and Drug Administration-approved indications for anti-epileptic drugs in patients under 16 years of age
|Drug||Monotherapy indication in children||Adjunctive therapy indication in children||Paediatric-friendly formulation|
|Phenobarbital||Generalized and partial epilepsy||Suspension 20 mg / 5ml|
|Phenytoin (Dilantin)||GTCs and complex partial seizures||Chewable tablets 50 mgSuspension 125 mg / 5ml|
|Carbamazepine (Tegretol, Tegretol XR, Carbatrol)||Complex partial seizures, GTCs, mixed seizure patterns||Chewable tablets 100 mgSuspension 100 mg / 5mExtended release sprinkle capsule 100 mg, 200 mg, 300 mg|
|Valproate (Depakote, Depakene)||Complex partial seizures in patients 10 years and older; simple and complex absence seizures||Sprinkle capsule 125 mgSuspension 250 mg / 5ml|
|Gabapentin (Neurontin)||No||Partial seizures in patients 3 years and over||Suspension 250 mg / 5ml|
|Lamotrigine (Lamictal)||Primary GTCs in patients 2 years and older||Partial seizures and generalized seizures in Lennox–Gastaut syndrome in patients 2 years and older||Chewable tablet 2 mg, 5 mg, 25 mg|
|Levetiracetam (Keppra)||No||Partial seizures in patients 4 years and older; myoclonic seizures in juvenile myoclonic epilepsy patients 12 years and older||Suspension 500 mg / 5ml|
|Oxcarbazepine (Trileptal)||Partial seizures in patients 4 years and older||Partial seizures in patients 4 years and older||Suspension 300 mg / 5ml|
|Topiramate (Topamax)||Partial onset or primary GTCs in patients 10 years and older||Partial seizures, primary GTCs and generalized seizures in Lennox–Gastaut syndrome in patients 2 years and over||Sprinkle capsule 15 mg, 25 mg|
|Vigabatrin (Sabril)||No||No||500-mg powder sachet|
Selections from the book: “Therapeutic Strategies in Epilepsy” (2008).