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ERSET (Early Surgery for MTLE)

Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy: A Randomized Trial

Year of Publication: 2012

Authors: Jerome Engel Jr, Michael P. McDermott, Samuel Wiebe, ..., for the Early Randomized Surgical Epilepsy Trial (ERSET) Study Group

Journal: JAMA

Citation: JAMA. 2012;307(9):922-930

Link: https://doi.org/10.1001/jama.2012.220

PDF: https://public.websites.umich.edu/~gusb/...T-2012-JAMA.pdf

Clinical Question

Is surgery soon after failure of 2 antiepileptic drug (AED) trials superior to continued medical management in controlling seizures and improving quality of life in patients with newly intractable mesial temporal lobe epilepsy (MTLE)?

Bottom Line

Among patients with newly intractable disabling mesial temporal lobe epilepsy (within 2 years of failing 2 AED trials), anteromesial temporal resection plus AED treatment resulted in significantly higher seizure freedom rates during year 2 of follow-up compared to continued AED treatment alone (73% vs 0%, P<0.001). Surgery also improved quality of life, driving ability, and socialization, though the trial was terminated prematurely due to slow enrollment.

        Major Points
        Only 38 of planned 200 patients enrolled due to slow accrual; trial terminated early on DSMB recommendation based on feasibility
Primary outcome: 73% seizure freedom in surgical group vs 0% in medical group during year 2 (P<0.001)
85% seizure-free rate in surgical group when restricted to those with complete year 2 data (11/13 vs 0/19)
Quality of life (QOLIE-89) significantly better in surgical group at months 6, 12, and 18 (P≤0.009); trend at 24 months (P=0.08 ITT, P=0.01 excluding crossovers)
Driving ability dramatically improved: 80% surgical vs 22% medical at 24 months (OR 14.4, P<0.001)
Socialization improved: surgical group gained 6.5 days/month socializing vs medical group lost 1.0 day/month (P=0.002)
30% crossover from medical to surgical group before 2-year visit
Memory decline in 36% of surgical participants on verbal recall measures, consistent with expected postsurgical rates

      

Design

Study Type: Multicenter, randomized controlled trial, parallel-group

Randomization: 1

Blinding: Unblinded for participants and treating physicians; seizure adjudication committee and pharmacotherapy monitoring panel blinded to treatment assignment

Enrollment Period: 2003-2007

Follow-up Duration: 24 months

Centers: 16

Countries: United States

Sample Size: 38

Analysis: Intention-to-treat; sensitivity analysis with multiple imputation (OR 12.4, 95% CI 2.6-59.2, P=0.002)

Inclusion Criteria

Age ≥12 years
Mesial temporal lobe epilepsy (MTLE) diagnosis
Disabling seizures persisting for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs
Considered candidates for anteromesial temporal resection based on standardized presurgical evaluation
Positive MRI and PET findings consistent with MTLE
Concordant EEG and imaging data localizing seizure focus

Exclusion Criteria

Normal MRI findings
Normal PET scan results
Discordant EEG and imaging data
Extratemporal ictal EEG onsets
Bilateral, independent ictal EEG onsets
Nonlocalizing ictal EEG onsets
Not meeting criteria for anteromesial temporal resection candidacy
More than 2 consecutive years of disabling seizures after failure of 2 AED trials

Baseline Characteristics

Characteristic	Control	Active
Age (mean±SD)	30.9 ± 10.1 years	37.5 ± 11.1 years
Female	39.1%	73.3%
Sample Size	23	15
Duration of Epilepsy (median)	5.3 years (IQR 2.8-13.4)	5.2 years (IQR 3.2-15.8)
Left Side Ictal Onset	60.9%	60.0%
Mean Number of AEDs	1.9 (SD 0.9)	1.6 (SD 0.7)
Driving	30.4%	6.7%
Median Seizures Per Month	3.0 (IQR 2.0-7.0)	2.0 (IQR 1.0-3.3)
QOLIE-89 Overall T-Score	45.7 (SD 10.0)	41.3 (SD 12.2)

Arms

Field	Control	Anteromesial Temporal Resection + AED
Intervention	Optimized AED pharmacotherapy with 4-stage protocol (monotherapy → ditherapy → rarely used AEDs → multiple AEDs); brand-name only; monitored by blinded independent panel	En bloc resection of anterior 3.5-4 cm of lateral temporal lobe (sparing superior temporal gyrus) plus removal of hippocampus, parahippocampal gyrus, and part of amygdala, followed by continued AED pharmacotherapy
Duration	24 months	24 months

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Freedom from disabling seizures during year 2 of follow-up	Primary	0/23 (0%)	11/15 (73%)	73%	<0.001
QOLIE-89 overall T-score change at 24 months (ITT)	Secondary	+4.0 points	+12.6 points		0.08
QOLIE-89 overall T-score change at 24 months (excluding crossovers)	Secondary	+2.8 points	+12.8 points		0.01
Driving at 24 months	Secondary	5/23 (22%)	12/15 (80%)	14.4	<0.001
Socialization (median change in days/month with friends)	Secondary	-1.0 day	+6.5 days		0.002
Serious Adverse Events (Medical Group)	Adverse	7 SAEs in 4 patients (including 3 status epilepticus episodes)
Serious Adverse Events (Surgical Group)	Adverse		6 SAEs in 5 patients (3 postop MRI ischemic changes, 1 hydrocephalus requiring VP shunt, 1 postop vomiting)
Memory Decline (RAVLT Delayed Recall at 12 months)	Adverse	0%	36%		0.03
Boston Naming Test Decline (12 months)	Adverse	7%	55%		0.02

Subgroup Analysis

Complete-data-only analysis: 0/19 (0%) vs 11/13 (85%) seizure-free (P<0.001). Multiple imputation sensitivity analysis: OR 12.4 (95% CI 2.6-59.2, P=0.002).

Criticisms

Trial terminated prematurely due to slow accrual; only 38 of planned 200 participants enrolled
Small sample size limits statistical power and generalizability, particularly for cognitive outcomes
Unblinded for participants and treating physicians, potentially biasing self-reported outcomes
Baseline imbalance in sex distribution and age between groups
30% crossover from medical to surgical group before 2-year visit, complicating ITT analysis
Required both MRI and PET to be diagnostic, excluding patients who might benefit from invasive monitoring
Relatively short follow-up (24 months) may not capture long-term employment and psychosocial outcomes
Adverse events of surgery greater in number than previously reported in literature
No cost-effectiveness analysis provided

Funding

National Institutes of Health (NINDS grants R21 NS37897 and U01 NS42372)

Based on: ERSET (Early Surgery for MTLE) (JAMA, 2012)

Authors: Jerome Engel Jr, Michael P. McDermott, Samuel Wiebe, ..., for the Early Randomized Surgical Epilepsy Trial (ERSET) Study Group

Citation: JAMA. 2012;307(9):922-930

Content summarized and formatted by NeuroTrials.ai.

ERSET (Early Surgery for MTLE)

(2012)

Objective

To compare early surgical intervention with continued medical therapy in patients with newly intractable mesial temporal lobe epilepsy (MTLE).

Study Summary

• This multicenter RCT demonstrated that surgery shortly after failure of two AEDs led to superior seizure control and improved psychosocial outcomes compared to continued pharmacotherapy.

Intervention

Standardized anteromesial temporal resection (AMTR) plus AEDs vs. continued AED therapy alone.

Inclusion Criteria

Patients aged ≥12 with disabling seizures ≤2 years after failure of 2 brand-name AEDs, and meeting criteria for AMTR based on standardized presurgical evaluation.

Study Design

Arms: AMTR + AED vs. Continued AED Only

Patients per Arm: Surgical: 15; Medical: 23 (total 38 randomized)

Outcome

• Seizure freedom during year 2: 73% (11/15) surgery vs. 0% (0/23) medical (OR ∞, 95% CI: 11.8–∞, p<0.001). • QOL improvement (QOLIE-89 T-score at 24 months): +12.8 surgery vs. +2.8 medical (p=0.01, when excluding crossover). • Driving at 24 months: 80% surgical vs. 22% medical (p<0.001). • Median increase in socialization: +6.5 days/month surgery vs. −1 day/month medical (p=0.002). • Memory decline observed in 36% of surgical patients on RAVLT delayed recall and 55% on Boston Naming Test. • Serious adverse events: 6 surgical (1 stroke, 2 hydrocephalus/gastrostomy, 3 MRI ischemic changes), 7 medical (including 3 status epilepticus) [oai_citation:0‡ERSET.pdf](file-service://file-1wfyYy2569RwvCG7WyD2zv).

Bottom Line

Major Points

Only 38 of planned 200 patients enrolled due to slow accrual; trial terminated early on DSMB recommendation based on feasibility
Primary outcome: 73% seizure freedom in surgical group vs 0% in medical group during year 2 (P<0.001)
85% seizure-free rate in surgical group when restricted to those with complete year 2 data (11/13 vs 0/19)
Quality of life (QOLIE-89) significantly better in surgical group at months 6, 12, and 18 (P≤0.009); trend at 24 months (P=0.08 ITT, P=0.01 excluding crossovers)
Driving ability dramatically improved: 80% surgical vs 22% medical at 24 months (OR 14.4, P<0.001)
Socialization improved: surgical group gained 6.5 days/month socializing vs medical group lost 1.0 day/month (P=0.002)
30% crossover from medical to surgical group before 2-year visit
Memory decline in 36% of surgical participants on verbal recall measures, consistent with expected postsurgical rates

Study Design

Study Type: Multicenter, randomized controlled trial, parallel-group
Randomization: Yes
Blinding: Unblinded for participants and treating physicians; seizure adjudication committee and pharmacotherapy monitoring panel blinded to treatment assignment
Sample Size: 38
Follow-up: 24 months
Centers: 16
Countries: United States

Primary Outcome

Definition: Freedom from disabling seizures during year 2 of follow-up

Control	Intervention	HR/OR	P-value
0/23 (0%)	11/15 (73%)	- (11.8 to infinity)	<0.001

Limitations & Criticisms

Trial terminated prematurely due to slow accrual; only 38 of planned 200 participants enrolled
Small sample size limits statistical power and generalizability, particularly for cognitive outcomes
Unblinded for participants and treating physicians, potentially biasing self-reported outcomes
Baseline imbalance in sex distribution and age between groups
30% crossover from medical to surgical group before 2-year visit, complicating ITT analysis
Required both MRI and PET to be diagnostic, excluding patients who might benefit from invasive monitoring
Relatively short follow-up (24 months) may not capture long-term employment and psychosocial outcomes
Adverse events of surgery greater in number than previously reported in literature
No cost-effectiveness analysis provided

Citation

JAMA. 2012;307(9):922-930

View Original Publication →

ERSET (Early Surgery for MTLE)

Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy: A Randomized Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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