MESS
(2005)Objective
To compare immediate versus deferred antiepileptic drug treatment after a first or early unprovoked seizure.
Study Summary
• The early advantage disappeared by 4-6 years: seizure-free between years 3-5 was 76% (immediate) vs 77% (deferred); 2-year remission rates converged (~95-96% by 8 years)
• Immediate treatment increased adverse events (39% vs 31%), supporting individualized treatment rather than mandatory therapy after a first seizure
Intervention
Immediate clinician-selected AED (mostly carbamazepine or valproate) vs deferred treatment until patient and clinician agreed; N=1443
Inclusion Criteria
Age ≥1 month with ≥1 clinically definite unprovoked seizure where clinician and patient were uncertain (equipoise) about starting treatment.
Study Design
Arms: Immediate Treatment vs Deferred Treatment (control)
Patients per Arm: Immediate: 722, Deferred: 721
Outcome
• At 2 years, seizure recurrence 37% vs 48%; by 8 years 52% vs 61%
• Seizure-free years 3-5: 76% vs 77% (no difference)
• Any adverse event 39% vs 31% (difference 8.6%, 95% CI 3.6-13.6)
Bottom Line
Immediate AED treatment significantly reduced time to first seizure (HR 1.4, p<0.0001) and time to first tonic-clonic seizure (HR 1.5, p<0.0001) compared to deferred treatment. However, this early advantage disappeared by 4-6 years, with no difference in long-term 2-year remission rates (95% vs 96% at 8 years) or seizure-free periods between years 3-5 (76% vs 77%). Immediate treatment increased adverse events (39% vs 31%). These findings support shared decision-making after first seizure rather than mandatory immediate treatment.
Major Points
- Immediate treatment after first seizure reduces early recurrence (51% vs 39% seizure-free at 2 years) but NOT long-term remission.
- By 5 years: no significant difference in seizure-free rates between immediate and deferred treatment.
- 1443 patients randomized. UK multicenter, pragmatic. Published Lancet 2005 (Marson et al.).
- Immediate: start AED after first/second seizure. Deferred: delay treatment until patient/physician agree.
- Quality of life: no significant difference at 2 years between groups.
- Driving: immediate treatment group had earlier return to driving eligibility.
- Key message: treating after first seizure prevents early recurrence but doesn't alter natural history.
- Supports individualized approach — not all patients need treatment after a single seizure.
- Influenced AAN practice parameter on when to start AEDs.
- Established that antiseizure drugs are symptomatic, not disease-modifying.
Study Design
- Study Type
- Pragmatic, multicenter, unmasked (open-label), randomized controlled trial
- Randomization
- Yes
- Blinding
- Open-label (unmasked)
- Sample Size
- 1443
- Follow-up
- Up to 8 years (median not specified)
- Centers
- Multiple (50% UK, 50% non-UK)
- Countries
- United Kingdom, Multiple international centers
Primary Outcome
Definition: Time to first seizure (all types)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Deferred: 53% had a seizure (382/721) | Immediate: 43% had a seizure (311/722) | 1.4 (deferred vs immediate) (1.2 to 1.7) | <0.0001 |
Limitations & Criticisms
- Open-label (unmasked) design could bias seizure reporting
- Equipoise-based enrollment selects population with lower seizure burden, may not generalize to high-risk patients
- No placebo control: 46% of deferred group eventually started treatment, creating significant contamination
- Predominantly older AEDs (92% CBZ or VPA): may not generalize to newer AEDs with better tolerability
- QOL assessment limited to UK adults only (527 of 1,443 patients)
- Under-recruitment: only 48% of planned 3,000 patients enrolled
- Self-reported seizure outcomes inherently imprecise, subject to recall bias
Citation
Marson A et al. Lancet. 2005;365(9476):2007-2013. DOI: 10.1016/S0140-6736(05)66694-9