- 1 International League Against Epilepsy Guidelines (Newly Diagnosed Epilepsy)
- 2 American Academy Of Neurology Guidelines
- 3 Treatment Of Juvenile Absence Epilepsy
- 4 Treatment Of IGE With GTC Seizures Only
- 5 Treatment Of Juvenile Myoclonic Epilepsy
- 6 Aggravation Of Seizures In IGE
- 7 Clinical Evidence For Aggravation Of Generalized Epilepsies
- 8 Medically Intractable Idiopathic Generalized Epilepsy
- 9 Related Posts
International League Against Epilepsy Guidelines (Newly Diagnosed Epilepsy)
According to the ILAE guidelines, the absence of class I and class II randomized controlled trials (RCTs) for children with absence seizures implies a marked deficiency in adequately powered, seizure type-specific, published studies for this category, and no anti-epileptic drugs reach the highest level of evidence (level A or B) for efficacy / effectiveness for children with absence seizures (level C).
Based on RCT efficacy and effectiveness evidence, ethosuximide, lamotrigine and valproate are possibly efficacious / effective for children with absence seizures (level C):
- ethosuximide had similar efficacy / effectiveness to valproate.
- lamotrigine had superior efficacy to placebo and slower onset of efficacy compared with valproate.
- valproate had similar efficacy / effectiveness to ethosuximide and faster onset of efficacy compared with lamotrigine.
Based on these data, the ILAE recommends that ethosuximide, lamotrigine and valproate may be considered as candidates for initial monotherapy in children with newly diagnosed or untreated absence seizures. Among these three anti-epileptic drugs, no clear first-choice anti-epileptic drug exists based only on efficacy or effectiveness criteria.
Treatment Of Juvenile Absence Epilepsy
Trial data regarding juvenile absence epilepsy (JAE) are scarce; however, JAE is regarded as similar to CAE, and valproate and ethosuximide are suggested as effective treatments. One case series of patients with JAE and childhood absence epilepsy found that 85% of the JAE patients responded to valproate, ethosuximide or both. In this series, the response was better in JAE than in CAE. Combination with myoclonic seizures did not affect the response to therapy. As generalized-onset tonic–clonic seizures are common in patients with JAE, valproate is usually considered the drug of choice. In the rare instances where the absences in this syndrome do not respond to valproate, or when there is concern about teratogenicity, lamotrigine can be given, as shown in a study including patients with absence seizures starting during both childhood and adolescence, although onset of action may be slower compared with valproate.
Aggravation Of Seizures In IGE
Unlike partial seizures, seizures in IGE seem to be more vulnerable to aggravation by anti-epileptic drugs. Aggravation may consist of increase in seizure frequency or appearance of new seizure types. Many patients with IGE who are not controlled with anti-epileptic drugs are not truly intractable, but instead have been treated with appropriate anti-epileptic drugs (pseudo-refractoriness). Before seizure exacerbation can be attributed to an anti-epileptic drug, one has to exclude other possible factors such as spontaneous fluctuations in the number of seizures, poor compliance, co-morbid illnesses and medications, increase in precipitating factors and development of tolerance to a previously efficacious anti-epileptic drug:
Clinical Evidence For Aggravation Of Generalized Epilepsies
To support the hypothesis that seizure aggravation is due to the effect of one or several anti-epileptic drugs, certain conditions need to be fulfilled:
- Seizure aggravation is seen soon after initiation of therapy.
- An increase in dosage is followed by further seizure exacerbation.
- When the dose is lowered, seizure frequency decreases or new seizure types disappear.
- A rechallenge with the drug results again in seizure aggravation.
Most often these conditions are not fulfilled; in particular a rechallenge is usually not done, as it is deemed unethical. Evidence of seizure aggravation can also be provided by objective data, including seizure quantification in placebo-controlled trials aimed at demonstrating efficacy and tolerability of a drug. However, most controlled trials are performed in partial epilepsies, and most data on aggravation of generalized seizures are based on anecdotal case reports, case series or uncontrolled, open-label or retrospective studies. For all these reasons, one has to be cautious when interpreting these data. ILAE guidelines also make some statements regarding seizure aggravation by certain anti-epileptic drugs.
Class IV evidence suggests that carbamazepine may precipitate or aggravate generalized-onset tonic–clonic seizures and more commonly other generalized seizure types in patients with IGE and therefore should be used with caution in these patients. Based solely on scattered reports (class IV), carbamazepine may precipitate or aggravate absence seizures. Class IV studies indicate that carbamazepine may precipitate or aggravate myoclonic seizures.
Carbamazepine may worsen absence seizures and may trigger status epilepticus in patients with absence epilepsy. Absence seizures may also reappear or appear de novo with carbamazepine.
Carbamazepine has also been implicated in the aggravation of generalized convulsive seizures and in precipitating absence, myoclonic and generalized status in patients with IGE. Carbamazepine also aggravates myoclonic seizures. In a retrospective, uncontrolled study, carbamazepine was said to aggravate seizures in over 65% of patients with juvenile myoclonic epilepsy.
Based on class IV studies, phenytoin may precipitate or aggravate generalized-onset tonic–clonic seizures, absence and myoclonic seizures and should be used with caution in these patients. Phenytoin may worsen absence and myoclonic seizures, and may provoke absence and generalized status in patients with IGE. In one retrospective study, aggravation of seizures was reported in one-third of patients with juvenile myoclonic epilepsy to whom phenytoin was prescribed.
Oxcarbazepine is similar to carbamazepine and has been reported to cause exacerbation or appearance of new seizure types in IGE, mainly absence and myoclonus. In spite of class IV evidence, cautious use in patients with IGE is recommended in the ILAE guidelines.
Phenobarbital (phenobarbital) has been reported to induce de novo atypical absence seizures.
ILAE guidelines include phenobarbital in the list of anti-epileptic drugs which may worsen absence seizures based on scattered, class IV reports.
Vigabatrin (vigabatrin) aggravates absence and myoclonic seizures; de novo myoclonic seizures, absence and convulsive status induced by vigabatrin have been reported. ILAE guidelines recommend cautious use in absence epilepsy based on class IV scattered reports.
Although lamotrigine is effective in IGE and in most epileptic myoclonus, some reports have suggested that it may occasionally worsen or trigger de novo myoclonic seizures. In open-label studies of lamotrigine monotherapy for juvenile myoclonic epilepsy, some patients experienced a worsening in myoclonus, which was transient in some. This study is mentioned in the ILAE guidelines. Five patients with IGE treated with lamotrigine experienced exacerbation or de novo appearance of myoclonic jerks. In three patients, lamotrigine exacerbated myoclonus in a dose-dependent manner with early aggravation during titration. Myoclonus disappeared when lamotrigine dose was decreased by 25% to 50%. In two patients, lamotrigine exacerbated myoclonic jerks in a delayed but more severe manner, with the appearance of myoclonic status that only ceased after lamotrigine withdrawal.
Gabapentin (gabapentin) has been implicated in worsening and de novo appearance of new-onset myoclonus. In an open-label study of gabapentin as add-on therapy, new-onset myoclonus was seen in around 10% of cases. However, this series included patients with focal epilepsy. Thomas et al., in their series of status epilepticus induced by anti-epileptic drugs, included one patient with atypical absence status with eyelid myoclonia when gabapentin was started and carbamazepine increased. Gabapentin is included in the list of anti-epileptic drugs which may precipitate or aggravate absence seizures and myoclonic seizures according to class IV evidence in the ILAE guidelines.
As with other GABA-ergic anti-epileptic drugs, seizure exacerbation induced by tiagabine () has been reported, mainly in IGE. This includes aggravation and de novo appearance of absence seizures and even absence status. Tiagabine may also aggravate myoclonic seizures. Tiagabine may precipitate or aggravate myoclonic seizures according to the ILAE guidelines (class IV studies).
Common Clinical Practice
In spite of poor-quality data, when treating patients with IGE, the possibility of seizure aggravation induced by anti-epileptic drugs has to be considered. It is critical to make a correct syndromic diagnosis and identify all seizure types. If this is not possible, a broad-spectrum anti-epileptic drug should be used. Patients with multiple seizure types seem to be especially prone to seizure aggravation. Drugs that block Na+ channels, in addition to GABA-ergic drugs, may exacerbate absence and myoclonic seizures, so they should be avoided in these seizure types.
Medically Intractable Idiopathic Generalized Epilepsy
Many patients who appear to have medically intractable IGE are not truly intractable, but have been treated with inappropriate anti-epileptic drugs. Another possibility is that frontal lobe epilepsy with secondary bilateral synchrony is mistaken for IGE. Once these possibilities have been ruled out, a small minority of patients with IGE remain refractory to medical treatment. These patients may benefit from different drug combinations including valproate, lamotrigine, clonazepam, topiramate, levetiracetam and zonisamide, as shown in trials which have included patients with refractory generalized seizure types. For some patients, vagal nerve stimulation (VNS) can be a good option. It seems that VNS has similar or greater efficacy in IGE than in partial epilepsy, but this is still an off-label use. Ketogenic diet could also be an option, although no solid data are available to support this.
Selections from the book: “Therapeutic Strategies in Epilepsy” (2008).