MESS
Immediate Versus Deferred Antiepileptic Drug Treatment for Early Epilepsy and Single Seizures: A Randomised Controlled Trial
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.
Design
Study Type: Pragmatic, multicenter, unmasked (open-label), randomized controlled trial
Randomization: 1
Blinding: Open-label (unmasked)
Enrollment Period: January 1, 1993 to December 31, 2000
Follow-up Duration: Up to 8 years (median not specified)
Centers: Multiple (50% UK, 50% non-UK)
Countries: United Kingdom, Multiple international centers
Sample Size: 1443
Analysis: Intention-to-treat; minimisation randomization balanced by center and number of seizures; target 1,500 (originally 3,000)
Inclusion Criteria
- Age at least 1 month
- Adequately documented history of one or more clinically definite, spontaneous, unprovoked epileptic seizures (excluding febrile convulsions or acute symptomatic seizures)
- Both the clinician AND the patient were in equipoise (uncertain whether to proceed with treatment)
Exclusion Criteria
- Already treated with antiepileptic drugs (other than short-acting drug for serial seizures/status, or previous prophylactic treatment for acute symptomatic seizures)
- Progressive disease
Arms
| Field | Immediate Treatment | Control |
|---|---|---|
| Intervention | Clinician-selected AED started immediately. Drugs chosen: carbamazepine 328 (46%), valproate 325 (46%), phenytoin 25 (3%), lamotrigine 19 (3%). Doses: CBZ >=16yr: 400 mg/day (IQR 300-600); VPA >=16yr: 900 mg/day (IQR 500-1000) | No drugs until clinician and patient agreed treatment necessary. 332 (46%) eventually started AEDs: CBZ 134 (40%), VPA 142 (43%), PHT 20 (6%), LTG 17 (5%) |
| Duration | Continuous; at 5 years, 60% still receiving AEDs | Deferred; at 5 years, 41% had started treatment |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first seizure (all types) | Primary | Deferred: 53% had a seizure (382/721) | Immediate: 43% had a seizure (311/722) | 1.4 (deferred vs immediate) | <0.0001 |
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| Adverse | 214 (31%); difference 8.6% (95% CI 3.6-13.6%) | 270 (39%) | |||
| Adverse | 31 | 40 | |||
| Adverse | 32 | 37 | |||
| Adverse | 24 | 41 | |||
| Adverse | 23 | 41 | |||
| Adverse | 13 | 37 | |||
| Adverse | 14 | 31 | |||
| Adverse | 6 | 17 | |||
| Adverse | 23 (6 sudden unexplained deaths: 4 immediate, 2 deferred) | 31 |
Subgroup Analysis
Single seizure patients: lower recurrence, NNT 14 at 2 years; Multiple seizure patients: higher recurrence, NNT 5 at 2 years; both subgroups showed long-term remission convergence
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
Funding
UK Medical Research Council (non-industry)
Based on: MESS (The Lancet, 2005)
Authors: Marson A, Jacoby A, Johnson A, ..., Chadwick D; Medical Research Council MESS Study Group
Citation: Marson A et al. Lancet. 2005;365(9476):2007-2013. DOI: 10.1016/S0140-6736(05)66694-9
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