The syndrome of primary generalized-onset tonic–clonic seizures presents the clinician with nosologic, diagnostic and treatment difficulties. Some patients with IGE appear to have generalized-onset tonic–clonic seizures alone and the 1989 ILAE epilepsy classification individualized epilepsy with grand mal seizures on awakening and epilepsies with specific modes of precipitation. The evolving classification of IGE uses more inclusive terms such as IGE with generalized-onset tonic–clonic seizures only and IGE with pure grand mal seizures. This common syndrome is typically characterized by generalized-onset tonic–clonic seizures only and is probably the same as generalized-onset tonic–clonic seizures on awakening, in which seizures are not limited to the morning. When other seizure types exist in these IGEs, the seizures can clinically include mixed features, giving rise to confusing names.
The assumption is that such generalized-onset tonic–clonic seizures will respond to anti-epileptic drugs that have been demonstrated to be of benefit in partial and secondary generalized seizures. It is difficult to assess the evidence for this group, because many studies for generalized-onset tonic–clonic seizures have not specifically included patients with IGE or have included patients with IGE who, in addition to generalized-onset tonic–clonic seizures, had other seizure types and probably a variety of IGE syndromes. Because generalized-onset tonic–clonic seizures overlap with other IGE syndromes, the use of some drugs, for example phenytoin or carbamazepine, could result in suboptimal control. This view is reflected in the recently released guidelines from the ILAE. Greater understanding of this syndrome as an entity and subsequent drug studies will improve evidence for optimum treatment.
ILAE Guidelines (Newly Diagnosed Epilepsy)
ILAE guidelines state that carbamazepine, lamotrigine, oxcarbazepine, PH, phenytoin, topiramate and valproate are possibly efficacious / effective as initial monotherapy for adults with generalized-onset tonic–clonic seizures and may be considered for initial therapy in selected situations (recommendation level C). In children with generalized-onset tonic–clonic seizures, carbamazepine, phenobarbital, phenytoin, topiramate, and valproate are possibly efficacious / effective and may be considered for initial monotherapy. No clear first choice exists; individualized prescription is encouraged. However, the guidelines state that carbamazepine, oxcarbazepine and phenytoin may also precipitate or aggravate generalized-onset tonic–clonic seizures and, more commonly, other generalized seizure types in patients with primary generalized-onset tonic–clonic seizures and therefore these drugs should be used with caution in these patients.
AAN Guidelines (New Anti-Epileptic Drugs Only)
The AAN guidelines state that topiramate is effective for the treatment of refractory generalized-onset tonic–clonic seizures in adults and children (recommendation level A). A small study with lamotrigine used as add-on therapy in patients with refractory IGE and a combination of seizure types is mentioned in the guidelines. However, lamotrigine is not mentioned in the ‘summary of evidence’ of the guidelines.
A recent review of generalized epilepsy with generalized-onset tonic–clonic seizures only suggested that counselling to patients with primary generalized-onset tonic–clonic seizures should be the same as in juvenile myoclonic epilepsy. The patient needs to avoid clear triggering factors such as sleep deprivation, photic stimulation and excessive alcohol intake. The pharmacological sensitivity is probably the same as in juvenile myoclonic epilepsy, with a selective efficacy of valproate. One review on treatment options in IGE does not clearly separate this syndrome from juvenile myoclonic epilepsy and other IGE syndromes and stresses the first-line place of valproate. One meta-analysis found no evidence to support the use of valproate vs. carbamazepine as the treatment of choice for patients with generalized-onset tonic–clonic seizures as part of generalized epilepsy. However, the number of patients in the generalized-onset tonic–clonic seizure subgroup was small and confidence intervals were wide, so the authors considered that they had not been able to exclude the existence of an important therapeutic difference.
There is one case series suggesting efficacy for phenobarbital for patients with idiopathic generalized-onset tonic–clonic seizures that began in childhood and persisted into adulthood.
Lamotrigine showed potential in the treatment of primary generalized-onset tonic–clonic seizures on the basis of pre-clinical data, case reports and case series, open-label and randomized, double-blind, active-comparator clinical trials that enrolled patients with newly diagnosed primary or secondarily generalized-onset tonic–clonic seizures. Biton et al. evaluated the efficacy and tolerability of adjunctive lamotrigine in primary generalized-onset tonic–clonic seizures in a randomized, double-blind, placebo-controlled trial. Patients with a diagnosis of epilepsy with generalized-onset tonic–clonic seizures (with or without other types of generalized seizures) who were receiving one or two anti-epileptic drugs at study entry were eligible. Patients were required to have at least three primary generalized-onset tonic–clonic seizures during the 8-week baseline period. Patients with partial seizures were excluded on the basis of seizure history and screening EEGs. The study comprised a baseline phase, an escalation phase, during which study medication was titrated to a target dose, and a 12-week maintenance phase, during which doses of lamotrigine / placebo and concomitant anti-epileptic drugs were maintained. Of the 121 randomized patients aged between 2 and 55 years, 117 (58 lamotrigine, 59 placebo) entered the escalation phase and received study medication. It is important to mention that 31% of patients had absence seizures, 29% had myoclonic seizures and 9% had tonic seizures in addition to generalized-onset tonic–clonic seizures.
During the escalation and maintenance phases combined, median per cent reduction in primary generalized-onset tonic–clonic seizure frequency was 66.5% with lamotrigine compared with 34.2% with placebo (P = 0.006). The corresponding numbers for lamotrigine and placebo were 60.6% and 32.8% (P = 0.038) during the escalation phase and 81.9% and 43.0% (P = 0.006) during the maintenance phase. During the maintenance phase, 72% of lamotrigine-treated patients compared with 49% of placebo-treated patients experienced a >50% reduction in frequency of primary generalized-onset tonic–clonic seizures (P = 0.014). A similar pattern of results was observed for all generalized seizures. The most common drug-related adverse events were dizziness (5% lamotrigine, 2% placebo), somnolence (5% lamotrigine, 2% placebo) and nausea (5% lamotrigine, 3% placebo).
The efficacy of topiramate in primary generalized-onset tonic–clonic seizures was shown in a double-blind, randomized, placebo-controlled trial. Eighty patients (aged 3-59 years) with a diagnosis of primary generalized-onset tonic–clonic seizures (with or without other types of generalized seizures), who had at least three generalized-onset tonic–clonic seizures during an 8-week baseline phase (in spite of treatment with one or two anti-epileptic drugs) were randomly assigned to treatment with either topiramate (n = 39) or placebo (n = 41). Approximately 70% of patients had other types of generalized seizures (absence, myoclonic or tonic seizures). A more detailed syndromic classification was not made, but EEG findings suggestive of generalized epilepsy, without other significant findings, were required to be included in the study. topiramate was titrated to target doses of approximately 6 mg / kg / day over 8 weeks and maintained for another 12 weeks. The median percentage reduction from baseline in primary generalized-onset tonic–clonic seizure rate was 56.7% for topiramate and 9.0% for placebo (P = 0.019). The proportion of patients with 50% or higher reduction in primary generalized-onset tonic–clonic seizure rate was 22 / 39 (56%) and 8 / 40 (20%) for the topiramate and placebo groups respectively (P = 0.001). The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (P = 0.003). The proportions of patients with 50% or higher reduction in generalized seizure rate were 18 / 39 (46%) and 7 / 41 (17%) for the topiramate and placebo groups respectively (P = 0.003). Thirteen per cent of topiramate-treated patients and 5% of placebo-treated patients became free of generalized-onset tonic–clonic seizures, but this difference was not statistically significant. The most common adverse events were somnolence, fatigue, weight loss, difficulty with memory and nervousness.
In an open label study, topiramate was administered to 131 adults and children with refractory generalized-onset tonic–clonic seizures of non-focal origin who had completed double-blinded trials. The mean duration of open-label topiramate treatment was 387 days (range 14-909 days); the mean topiramate dose was 7 mg / kg / day (range l-16 mg / kg / day). At the last study visit, the frequency of generalized-onset tonic–clonic seizures was reduced by >50% from baseline in 63% of patients and by >75% in 44%. Among patients treated >6 months, 16% were free of generalized-onset tonic–clonic seizures for >6 months despite a pre-treatment seizure frequency of one generalized-onset tonic–clonic seizures / week (median). Treatment with topiramate was being continued in 82% of patients (n = 107) at the last visit. During treatment periods of up to 2.5 years, 11 (8%) patients discontinued topiramate because of adverse events and seven (5%) because of inadequate seizure control.
A recent study explored the efficacy of levetiracetam to treat refractory primary generalized-onset tonic–clonic seizures. The trial included 164 patients with a diagnosis of IGE and refractory primary generalized-onset tonic–clonic seizures in spite of treatment with stable doses of one or two anti-epileptic drugs. A minimum number of three generalized-onset tonic–clonic seizures during the 8-week baseline period was required to be included in the study. It was a double-blind, randomized, placebo-controlled, parallel-group and multicentre study. Patients were randomized to received add-on levetiracetam (80 patients) or placebo (84 patients). There was a 4-week titration phase, followed by a 20-week maintenance phase and a 6-week down-titration phase. Mean percentage reduction in number of generalized-onset tonic–clonic seizures per week was 77.6% in the levetiracetam group compared with 44.6% in the placebo group (P = 0.004). The percentage of responders (patients who experienced a reduction of at least 50% in frequency of seizures per week) during the treatment period was 72.2% in the levetiracetam group compared with 45.2% in the placebo group (P = 0.0005). A significant number of patients (24.1%) became seizure free in the levetiracetam group, compared with 8.3% in the placebo group (P = 0.009). The safety profile of levetiracetam was similar to that observed in previous studies, with 1.3% withdrawing from the study because of adverse effects compared with 4.8% in the placebo group.
In a preliminary report on patients with refractory primary generalized epilepsy treated with zonisamide, two of four patients with tonic-clonic seizures had a greater than 50% reduction in seizures. No mention was made of whether any patients became seizure free. In summary, although there are suggestions that zonisamide may have efficacy for primary generalized-onset tonic–clonic seizures, there are no well-controlled studies and the published reports include small numbers of patients.
Common Clinical Practice
When clear triggering factors such as sleep deprivation, photic stimulation or excessive alcohol intake have been identified, specific measures to avoid them should be adopted by the patient, as in juvenile myoclonic epilepsy. The pharmacological sensitivity is probably the same as in juvenile myoclonic epilepsy, with valproate being the first-line treatment, together with lamotrigine, topiramate and possibly levetiracetam. Zonisamide may be another option in the future.