Medical Treatment of Epilepsy
by Michael Wong, MD, PhD
“Traditional” AEDs: Open-Label and Placebo-Controlled Trials
- The earliest reports documenting the efficacy of the older AEDs, such as phenytoin, consisted of uncontrolled, open-label studies, comparing seizure-frequency before and during AED treatment (e.g. Merritt and Putman 1940).
- Except for first seizure (not epilepsy) studies, the traditional AEDs (PHT, PB, CBZ, VPA) have never been assessed in placebo-controlled monotherapy trials (Marson and Chadwick 1996). This absence of documented efficacy of the traditional AEDs in placebo-controlled monotherapy trials lies at the root of the FDA’s refusal to accept equivalence of “new” and “old” AEDs in comparative trials as evidence of efficacy of the new AED.
- In a few small placebo-controlled add-on trials, traditional AEDs, such as CBZ and VPA, have been shown to more effective than placebo as add-on therapy (Crawford and Chadwick 1986, Rodin et al. 1974).
“Traditional” AEDs: Comparative Monotherapy Trials
Most studies of traditional AEDs have compared the efficacy of the various AEDs among themselves and have found minimal differences.
- Mixed Primary and Secondary Generalized Seizures
- Many studies found no significant difference between VPA, CBZ, and PHT for treatment of both partial or generalized tonic-clonic seizures, but a definite distinction between primary and secondarily GTCs was not clearly made.
- ~40-80% of patients became seizure-free in each of these studies (Callaghan 1985, deSilva et al. 1996, Heller et al. 1995, Richens et al. 1994, Turnbull et al. 1985).
- Partial Seizures: The VA Cooperative Studies only tested partial epilepsy.
- Overall, all traditional AEDs tested were equally effective for secondary GTCs, but CBZ was superior to the others for simple or complex partial seizures without secondary GTCs.
- CBZ = PHT = PB = PRM = ~45% seizure-free for secondary GTCs. CBZ (43% seizure-free) > PHT (28%) > PHB (16%) = PRM (15%) for simple and complex partial seizures (Mattson et al. 1985).
- CBZ = VPA = ~45% seizure-free for secondary GTC. CBZ (32% seizure-free) > VPA (23%) and several other measures for complex partial seizures (Mattson et al. 1992).
- Primary Generalized Seizures
- VPA was slightly better (64% seizure-free) than PHT (53%) for primary GTC seizures, but the difference was not statistically significant (Ramsey et al. 1992).
- No study has directly compared VPA and CBZ exclusively for primary generalized epilepsy (?), but CBZ has been reported to exacerbate some patients with primary generalized epilepsy (Snead and Hosey 1985). In one study, almost 50% of patients on CBZ who had pre- and post-treatment EEGs experienced a worsening of the EEG with new generalized spike-and-wave and/or worsening of seizures (Talwar et al. 1994).
“New” AEDs: Placebo-Controlled Add-On Trials in Refractory Patients with Partial Epilepsy
- Meta-Analysis: A meta-analysis (Marson et al. 1997) compared the placebo-controlled add-on trials of several new AEDs in refractory partial epilepsy.
- The overall odds ratios (OR) for >50% sz reduction and for discontinuation from the studies compared to placebo for each AED
- GBP LTG TPM TGB VGB
- OR 50% sz reduction 2.29 2.32 4.07 3.03 3.67
- OR discontinuation 1.36 1.19 2.56 1.81 2.58
- Although the AED with the highest OR was almost twice the lowest OR for both 50% sz reduction and discontinuation, these
differences were not statistically significant. Therefore, while each AED was shown to be more effective than placebo, the meta-
analysis did not find conclusive evidence for differences in efficacy or tolerability between AEDs.
- The overall odds ratios (OR) for >50% sz reduction and for discontinuation from the studies compared to placebo for each AED
- Gabapentin (GBP):
- In several parallel add-on studies (Anhut et al. 1994, Sivenius et al. 1991, UK GBP Study Group 1990, US GBP Study Group 1993), overall ~20% of patients on GBP had >50% sz reduction compared to ~10% of placebo.
- A linear dose-response relationship was observed throughout the entire range of dose tested (300-1800 mg) without evidence of plateauing, suggesting that doses used in the studies were suboptimal.
- Lamotrigine (LTG):
- In multiple parallel or cross-over studies (Binnie et al. 1989, Jawad et al. 1989, Louiseau et al. 1990, Matsuo et al. 1993, Messenheimer et al. 1994, Schapel et al. 1993, Smith et al. 1993), overall ~21% of patients on LTG had >50% sz reduction compared to ~9% of placebo.
- Topiramate (TPM):
- In several parallel add-on studies (Ben-Menachem et al. 1996, Faught et al. 1996, Privitera et al. 1996, Tassinari et al. 1996), overall ~44% of patients on TPM had >50% sz reduction compared to ~11% of placebo.
- Tiagabine (TGB):
- In three unpublished and published (Kalviainen et al. 1998) parallel add-on studies, overall ~21% of patients on TGB had >50% sz reduction compared to 6% of placebo.
- A dose-response relationship was observed with increasing efficacy with increasing doses and no sign of plateauing, suggesting that doses used in the studies were suboptimal.
- Vigabatrin (VGB):
- In several parallel add-on studies (French et al. 1996, Grunewald et al. 1994, Penry et al. 1993), overall ~40% of patients on VGB had >50% sz reduction compared to ~14% of placebo.
- Zonisamide (ZNS):
- In a placebo-controlled add-on trial in adults with refractory partial epilepsy (Schmidt et al. 1993), ZNS had superior responder rates (~30% with >50% sz reduction) compared to placebo (~10%).
- Levetiracetam (LVT)
- In placebo-controlled add-on trials in adults with refractory partial epilepsy (Cereghino et al. 2000, Shorvon et al. 2000), LVT had superior responder rates (30-40% with >50% sz reduction) compared to placebo (~10%).
“New” AEDs: Placebo-Controlled Add-On Trials in Refractory Patients with Generalized Epilepsy
- Lennox-Gastaut syndrome: In a parallel add-on trial of 169 patients with Lennox-Gastaut, 33% of patients on LTG had >50% sz reduction compared to 16% of placebo (Motte et al. 1997).
- Other Refractory Generalized Epilepsy (including Lennox-Gastaut): In cross-over trials, LTG has also been shown to significantly reduce seizure frequency and make some patients seizure-free (Beran et al. 1998, Eriksson et al. 1998).
- Lennox-Gastaut syndrome: In a parallel add-on study of patients with Lennox-Gastaut, 33% of patients on TPM had >50% seizure reduction compared to 8% of placebo (Sachdeo et al. 1999).
- Refractory Primary Generalized Epilepsy (excluding Lennox-Gastaut): In a parallel add-on study of patients with refractory generalized epilepsy on 1 or 2 other AEDs, 56% of patients on TPM had >50% sz reduction compared to 20% of placebo (Biton et al. 1999).
- Lennox-Gastaut syndrome: In a parallel add-on study of 73 patients with Lennox-Gastaut, there was a small but significant decrease with FBM in total seizure frequency (19%) and atonic seizure frequency (34%) compared to placebo (4% and 9%) (Felbamate Study Group 1993).
- Primary Generalized Seizures: Gabapentin was no different than placebo for primary generalized tonic-clonic seizures (Chadwick et al. 1996).
“New” AEDs: Comparative Monotherapy Trials versus “Traditional” AEDs
- Established Partial Epilepsy: LTG monotherapy was significantly more effective than VPA monotherapy in prolonging time to meet study exit criteria in patients with known partial epilepsy who were withdrawn off CBZ or PHT monotherapy (Gilliam et al. 1998).
- Newly-Diagnosed Partial or Generalized Epilepsy: LTG and CBZ monotherapy were equally efficacious for both partial (35% vs 37% seizure-free) and primary GTC (both 47% seizure-free) seizures in patients with newly-diagnosed epilepsy, but LTG was better tolerated with a higher study completion rate (Brodie et al. 1995, Reunanen et al. 1996). LTG and PHT monotherapy were
also equally efficacious, but LTG better tolerated, in newly-diagnosed epilepsy (Steiner et al. 1999).
- Newly-Diagnosed Partial Epilepsy: GBP and CBZ monotherapy had similar efficacy as measured by time to meet study exit criteria in patients with newly-diagnosed partial epilepsy (Chadwick et al. 1998).
- Refractory Partial Epilepsy: GBP monotherapy at low, medium, and high doses was not significantly different in meeting exit criteria between different doses in patients with refractory partial epilepsy who were withdrawn off their previous AEDs (Beydoun et al. 1997).
- Refractory Partial Epilepsy: High-dose TPM monotherapy was more effective than low-dose in prolonging time to meeting exit criteria in patients with refractory partial epilepsy who were withdrawn off their previous AEDs (Sachdeo et al. 1997).
- Refractory Partial Epilepsy: FBM monotherapy was significantly more effective than VPA monotherapy in prolonging time to meet study exit criteria in patients with refractory partial epilepsy who were withdrawn off their previous AED (Faught et al. 1993, Sachdeo et al. 1992).
- Newly-Diagnosed Partial or Generalized Epilepsy: VGB and CBZ monotherapy were equally effective for partial and GTC seizures in patients with newly-diagnosed epilepsy (Kalviainen et al. 1995, Zamponi and Cardinali 1999).
- Oxcarbazepine (OXC)
- In several comparative monotherapy trials in adults and children (Bill et al. 1997, Dam et al. 1989, Guerreiro et al. 1997, Reinikainen et al. 1987), OXC had equivalent efficacy to CBZ or PHT in monotherapy, but OXC had superior tolerability in some trials.
Placebo-controlled Monotherapy Trials
- In a single study (Schacter et al. 1999) involving patients with refractory partial epilepsy during inpatient presurgical evaluation, OXC was superior to placebo in monotherapy during a 10 day trial. Due to ethical concerns, this is one of the only placebo-controlled monotherapy trials for any AED in epilepsy.
Comparison of the “Traditional” AEDs: A review of comparative AED studies compared the adverse effects and tolerability of CBZ, PHT, and VPA (Ramsay and DeToledo 1997).
- Comparison of the “Traditional” AEDs: A review of comparative AED studies compared the adverse effects and tolerability of CBZ, PHT, and VPA (Ramsay and DeToledo 1997).
- Side effect profiles showed some drug specificity:
- CBZ: dizziness
- PHT: ataxia, gum hypertrophy
- VPA: weight gain, tremor
- Discontinuation rates due to adverse effects were lower for VPA (6%) compared to CBZ (13%) and PHT (13%). Discontinuation due to rash was lower for VPA (1%) compared to CBZ (7%) and PHT (6%).
Comparison of the “New” AEDs: A meta-analysis of 29 placebo-controlled add-on trials of AEDs in refractory partial epilepsy compared the adverse effects and discontinuation rates (for any reason – a measure of efficacy and tolerability) of the new AEDs (except FBM) (Marson et al. 1997).
- Side effects significantly more common with GBP than placebo were (Odds Ratio (OR)): dizziness (2.25), fatigue (2.25), somnolence (2.04).
- OR for discontinuation was 1.36, which is not significantly different than placebo.
- Side effects significantly more common with LTG than placebo were: ataxia (2.98), diplopia (3.39), dizziness (2.38), fatigue (2.25), nausea (1.70).
- OR for discontinuation was 1.19, which is not significantly different than placebo.
- Side effects significantly more common with TPM than placebo were: dizziness (1.99), fatigue (2.52), somnolence (2.86), thinking/concentration problems (3.95).
- OR for discontinuation was 2.56, which is significantly more than placebo.
- Side effects significantly more common with TGB than placebo were: dizziness (1.88), tremor (3.17).
- OR for discontinuation was 1.81, which is significantly more than placebo.
- There were no side effects that were significantly more common than placebo.
- OR for discontinuation was 2.58, which is significantly more than placebo.
Incidence of Rare or Idiosyncratic Reactions
- VPA: ~ 1/10,000 overall, but higher risk in infants and patients on polytherapy or with preexisting metabolic disorder (1/500 in children < 2 years on polytherapy, 1/40,000 for older patients on monotherapy) (Dreifuss et al. 1987).
- FBM: up to 1/25,000, but this estimate may be high due to a biased sample of high risk patients.
- rash/Stevens Johnson
- LTG: allergic rash seen in up to 10% of patients, but highly dependent on rate of dose increase; Stevens-Johnson ~0.1-0.5% (Guberman et al. 1999, Messenheimer 1998).
- CBZ: allergic rash in ~2-5%.
- cognitive impairment: PB and possibly other AEDs may cause cognitive impairment and be associated with lower IQ scores by ~5 points compared to controls, but technical complications make the significance of these differences unclear and controversial (Farwell et al. 1990).
- visual field constriction: ~10-30% of patients on VGB (Krauss et al. 1998).
- Multicenter Study: In an uncontrolled prospective multicenter study of 51 children with intractable epilepsy, 40% of patients on the ketogenic diet had >50% decrease in seizures and 10% were seizure-free at 1 year (Vining et al. 1998).
- Johns Hopkins Study: In an uncontrolled prospective single center study of 150 children with intractable epilepsy, 30% of patients on the ketogenic diet had >90% decrease in seizure frequency (Freeman et al. 1998).
- In both of the above studies, ~50% of patients initially enrolled remained on the diet for one year.
- Side effects: renal calculi (~3%), hyperuricemia, hypocalcemia, hypoproteinemia, hypercholesterolemia, hepatotoxicity (Ballaban-Gil et al. 1998).
Vagal Nerve Stimulator
- Partial Seizures: Two multicenter trials of >300 adult patients with refractory partial epilepsy compared high stimulation with low stimulation rate. High stimulation caused a 25-28% reduction in total seizure frequency compared to 6-15% reduction with low stimulation for up to one year. In one of the studies, 31% of patients in the high stim group had >50% sz reduction compared to 13% of the low stim group (Handforth et al. 1998, Salinsky et al. 1996, VNS Study Group 1995).
- Generalized Seizures: In an uncontrolled trial of 24 patients with refractory generalized epilepsy, VNS caused a median seizure reduction of 46%, with 46% of patients having >50% reduction (Labar et al. 1999).
- Side effects: hoarseness (~35%), cough, throat pain, surgical complications (infection), equipment malfunction.
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