Framing clinical questions and search for evidence
3. AED for generalized epilepsy
In patients with generalized epilepsy (tonic clonic type), which AED is most effective and safe?
Carbamazepine
We found no placebo-controlled trials of carbamazepine used as monotherapy in people with generalized epilepsy (tonic clonic type), but widespread consensus holds that these drugs are effective. We found three systematic reviews comparing carbamazepine versus sodium valproate, pheno-barbital, and phenytoin.
The first systematic review compared carbamazepine ver-sus sodium valproate [13] (5 RCTs, 4 of the RCTs included 395 people with generalized epilepsy, aged 3–79 years, follow-up 5 years). RCTs included in the review recruited people if they had generalized onset tonic clonic seizures with or without other generalized seizure types (e.g. absence or myoclonus). A meta-analysis of the generalized epilepsy 176 Part 3: Neurological diseases
subgroup found no significant difference between sodium valproate and carbamazepine for 12-month remission or first seizure. The review found no significant difference between sodium valproate and carbamazepine for treatment withdrawal. Although no difference was found in the system-atic review between sodium valproate and carbamazepine, the CI is wide and this result does not establish equivalence
of sodium valproate and carbamazepine. Also, the age distri-bution of people classified as having generalized epilepsy suggests errors in the classification of epilepsy type. Failure of the RCTs to document generalized seizures other than tonic clonic seizures is an important limitation.
The second systematic review (4 RCTs, 680 people, of whom 157 had generalized epilepsy) compared carbamazepine
Chapter 18: Epilepsy 177
Table 18.2 Comparisons of first-line AEDs in partial and generalized epilepsy.
SR (reference) Outcome Partial HR Generalized Both HR Comment (time to event) (95% CI) HR (95% CI) (95% CI)
PHB versus 12-month remission 1.03 0.61 Non-statistical significant difference
CBZ [14] (0.72–1.49) (0.36–1.03)
First seizure 0.71 1.50 Non-statistical significant difference for
(0.55–0.91) (0.95–2.35) generalized epilepsy
PHB better Advantage to PHB for partial seizures
Withdrawal 1.60 1.78 More withdrawals on PHB. Statistically
(1.18–2.17) (0.87–3.62) significant difference only for partial onset
PHB worse but with significant heterogeneity
VPA versus 12-month 0.82 0.96 Non-statistical significant difference
CBZ [13] remission (0.67–1.00) (0.75 to 1.24)
VPA worse
First seizure 1.22 0.86 Statistically significant difference only for
(1.04–1.44) (0.68–1.09) partial onset with advantage for CBZ VPA worse
Withdrawal 1.00 0.89 Non-statistical significant difference
(0.79–1.26) (0.62–1.29)
PHT versus 12-month remission 1.02 1.06 Non-statistical significant difference
VPA [17] (0.68–1.54) (0.71–1.57)
First seizure 0.81 1.03 Non-statistical significant difference
(0.59–1.10) (0.77–1.39)
Withdrawal 1.23 0.98 Non-statistical significant difference
(0.77–1.98) (0.60–1.58)
PHB versus 12-month remission 0.93 Non-statistical significant difference
PHT [16] (0.70–1.23)
First seizure 0.84 Non-statistical significant difference
(0.68–1.05)
Withdrawal 1.62 Statistically significant difference
(1.22–2.14) PHB worse
PHT versus 12-month remission 1.0 Non-difference
CBZ [15] (0.78–1.29)
First seizure 0.91 Non-statistical significant difference
(0.74–1.12)
Withdrawal 0.97 Non-statistical significant difference
(0.74–1.28)
12 month remission: HR 1 indicates first drug is better or more remission with first drug. First seizure 1 indicates first drug is better or less seizure recurrence with first drug. Withdrawals 1 worse for the first drug more withdrawals with the first drug.
PHT: phenytoin; PHB: phenobarbital; CBZ: carbamazepine; VDA: valproate.
versus phenobarbital [14]. Subgroup analysis in people with a generalized epilepsy found no significant differences for first seizure or 12-month remission. The review found no significant differences in treatment withdrawal between car-bamazepine and phenobarbital.
The third systematic review (3 RCTs, 552 people, of whom 121 had generalized epilepsy) compared carbamazepine ver-sus phenytoin [15]. It did not present results separately for people with generalized epilepsy. Overall, however, it found no significant difference between carbamazepine and pheny-toin for treatment withdrawal, first seizure, or 12-month remission.
Phenobarbital
We found no placebo-controlled trials of phenobarbital used as monotherapy in people with generalized epilepsy, but widespread consensus holds that it is effective.
We found one systematic review (4 RCTs, 680 people, of whom 157 had generalized epilepsy), which compared car-bamazepine versus phenobarbital [14]. Subgroup analysis in people with a generalized epilepsy found no significant dif-ferences for first seizure, or 12-month remission. The review found no significant difference for treatment withdrawal between carbamazepine and phenobarbital.
Phenytoin
We found no placebo-controlled trials of phenytoin used as monotherapy in people with generalized epilepsy, but wide-spread consensus holds that it is effective. We found two reviews comparing phenytoin versus carbamazepine and sodium valproate.
The first systematic review compared phenytoin and sodium valproate [17] (5 RCTs, 395 people aged 3–95 years with generalized epilepsy). RCTs included in the review recruited people if they had generalized onset tonic clonic seizures with or without other generalized seizure types (e.g. absence or myoclonus). A meta-analysis of the generalized epilepsy subgroup found no significant difference between sodium val-proate and phenytoin for 12-month remission or first seizure. The review found no significant difference between sodium valproate and phenytoin for time to treatment withdrawal. Although no difference was found in the sys-tematic reviews between sodium valproate and phenytoin, the CI is wide and this result does not establish equivalence of sodium valproate and phenytoin.
The second systematic review (3 RCTs, 552 people, of whom 121 had generalized epilepsy) compared carbamazepine ver-sus phenytoin [15]. It did not present results separately for people with generalized epilepsy. Overall, it found no significant difference between carbamazepine and pheny-toin for treatment withdrawal, first seizure, or 12-month remission.
Sodium valproate
We found no placebo-controlled trials of sodium valproate used as monotherapy in people with generalized epilepsy, but widespread consensus holds that it is effective. We found two systematic reviews comparing sodium valproate versus carbamazepine and phenytoin. The reviews were of RCTs that recruited people if they had generalized onset tonic clonic seizures with or without other generalized seizure types (e.g. absence or myoclonus).
The first systematic review compared carbamazepine ver-sus sodium valproate [13] (5 RCTs, 4 of the RCTs included 395 people with generalized epilepsy, aged 3–79 years, follow-up 5 years). A meta-analysis of the generalized epilepsy subgroup found no significant difference between sodium valproate and carbamazepine for 12-month remis-sion or first seizure. The review found no significant differ-ence between sodium valproate and carbamazepine for treatment withdrawal.
The second systematic review compared phenytoin and sodium valproate [17] (5 RCTs, 395 people aged 3–95 years with generalized epilepsy). A meta-analysis of the general-ized epilepsy subgroup found no significant difference between sodium valproate and phenytoin for 12-month remission or first seizure. The review found no significant difference between sodium valproate and phenytoin for time to treatment withdrawal.
Although no difference was found in the systematic reviews between sodium valproate and either carbamazepine or phenytoin, the CI are wide and these results do not establish equivalence of sodium valproate and carbamazepine or phenytoin. Also, the age distribution of people classified as having generalized epilepsy suggests errors in the classification of epilepsy type. Failure of the RCTs to document general-ized seizures other than tonic clonic seizures is an important limitation. The meta-analysis does not provide evidence to support or refute the use of sodium valproate for people with generalized tonic clonic seizures as part of generalized epilepsy.
Other AEDs
We found no placebo-controlled RCTs of other AEDs used as monotherapy in people with generalized epilepsy.
The details of the results of systematic reviews are given in Table 18.2.
Summary
We found no placebo-controlled trials of carbamazepine, phenobarbital, phenytoin, and sodium valproate used as monotherapy in people with generalized epilepsy (tonic clonic type), but widespread consensus holds that these drugs are effective. Systematic reviews found insufficient evidence on which to base a choice among AEDs in terms of 178 Part 3: Neurological diseases
seizure control. We found no RCTs of other AEDs used as monotherapy in people with generalized epilepsy.