Lois G. Kim

Immediate versus deferred antiepileptic drug treatment for early epilepsy and single seizures: a randomised controlled trial

BACKGROUND The relative risks and benefits of starting or withholding antiepileptic drug treatment in patients with few or infrequent seizures are unclear. We sought to compare policies of immediate versus deferred treatment in such patients and to assess the effects of these policies on short-term recurrence and long-term outcomes. METHODS We undertook an unmasked, multicentre, randomised study of immediate and deferred antiepileptic drug treatment in 1847 patients with single seizures and early epilepsy. Outcomes comprised time to first, second, and fifth seizures; time to 2-year remission; no seizures between years 1 and 3 and between years 3 and 5 after randomisation; and quality of life. Analysis was by intention to treat. FINDINGS 404 patients invited to join the trial did not consent to randomisation; 722 were subsequently assigned immediate treatment with antiepileptic drugs and 721 were assigned deferred treatment. Immediate treatment increased time to first seizure (hazard ratio 1.4 [95% CI 1.2 to 1.7]), second seizure (1.3 [1.1 to 1.6]), and first tonic-clonic seizure (1.5 [1.2 to 1.8]). It also reduced the time to achieve 2-year remission of seizures (p=0.023). At 5-years follow-up, 76% of patients in the immediate treatment group and 77% of those in the deferred treatment group were seizure free between 3 and 5 years after randomisation (difference -0.2% [95% CI -5.8% to 5.5%]). The two policies did not differ with respect to quality of life outcomes or serious complications. INTERPRETATION Immediate antiepileptic drug treatment reduces the occurrence of seizures in the next 1-2 years, but does not affect long-term remission in individuals with single or infrequent seizures.

Prediction of risk of seizure recurrence after a single seizure and early epilepsy: further results from the MESS trial

BACKGROUND The MRC Multicentre trial for Early Epilepsy and Single Seizures (MESS) showed a reduced risk of further seizures in patients, for whom treatment with antiepileptic drugs was uncertain, who were randomly assigned immediate treatment compared with delayed treatment. However, there was no evidence of an effect on [corrected] long-term remission rates. This study was undertaken to assess the role of patient characteristics and treatment in the prediction of seizure recurrence. This will enable decision-making on the basis of the perceived risk of treatment compared with the benefit of reducing the risk of further seizures in the initial years after diagnosis. METHODS A prognostic model was developed based on individual patient data from MESS to enable identification of patients at low, medium, or high risk of seizure recurrence. A split-sample approach was used in which the model was developed on a subsample of the full data and validated on the remainder of the sample. Distinction of the prognostic groups and predictive accuracy of the model were assessed. FINDINGS Number of seizures of all types at presentation, presence of a neurological disorder, and an abnormal electroencephalogram (EEG) were significant factors in indicating future seizures. Individuals with two or three seizures, a neurological disorder, or an abnormal EEG were identified as the medium-risk group, those with two of these features or more than three seizures as the high-risk group, and those with a single seizure only as the low-risk group. INTERPRETATION The model shows that there is little benefit to immediate treatment in patients at low risk of seizure recurrence, but potentially worthwhile benefits are seen in those at medium and high risk.

A sustained mortality benefit from screening for abdominal aortic aneurysm

Context Is it cost-effective to screen older adults for abdominal aortic aneurysm (AAA)? Contribution This 7-year follow-up report of a large randomized trial in the United Kingdom found that men age 65 to 74 years who were invited to have ultrasonography and surveillance for AAA had lower mortality rates than did those who were not invited (hazard ratio, 0.53 [CI, 0.42 to 0.68]). Cost-effectiveness for AAA-related deaths, based on costs applied to the events experienced by the men, was estimated at

Systematic review and meta-analysis of the growth and rupture rates of small abdominal aortic aneurysms: implications for surveillance intervals and their cost-effectiveness

19500 (CI,

Atrophy patterns in Alzheimer's disease and semantic dementia: A comparison of FreeSurfer and manual volumetric measurements

12400 to

Cost-effectiveness of the National Health Service abdominal aortic aneurysm screening programme in England

39800) per life-year gained. Cautions Only men were studied. Actual costs of screening and surveillance may vary substantially in different settings. The Editors A fast-growing body of literature is providing evidence in favor of screening men for abdominal aortic aneurysm (AAA). Several large, randomized trials published in the past few years (14) have consistently shown that screening reduces AAA-related mortality. A few observational studies of programs under way in localized areas have established the feasibility of systematic screening and have explored its practical implementation (57). In addition to the mortality benefit, evidence indicating that screening is highly cost-effective is increasing (811). In light of this evidence, national screening programs are now being considered in many countries (1214). However, there is little evidence regarding long-term outcomes after AAA screening; almost all of the evidence from randomized trials is limited to the first 4 years after screening (14). Moreover, long-term cost-effectiveness has been estimated only through health economic modeling (10). We describe cost-effectiveness based on 7-year follow-up from the largest of the 4 trials of AAA screeningthe Multicentre Aneurysm Screening Study (MASS) (2). The trial randomly assigned approximately 67800 men age 65 to 74 years to receive an invitation to screening or to not receive an invitation. At 4-year follow-up, the trial reported a substantial relative reduction of 42% (95% CI, 22% to 58%) in AAA-related mortality and an incremental cost-effectiveness ratio of

Measuring disease progression in frontotemporal lobar degeneration: A clinical and MRI study

44900 (CI,

How cost-effective is screening for abdominal aortic aneurysms?

24000 to

Uncertainty and validation of health economic decision models

231000) per life-year gained (9), which is at the borderline of the commonly accepted threshold for interventions. All values are reported in U.S. dollars (U.K. 1 = U.S.

Acceleration of cortical thinning in familial Alzheimer's disease

1.58) (15). The costs of AAA screening are primarily incurred at the start of the program, but benefits continue to accrue in terms of life-years gained in patients in whom AAA rupture is avoided through elective surgery. It is therefore expected that cost-effectiveness of screening will improve over time. The mid-term results of MASS provide reliable, trial-based information regarding clinical outcomes and cost-effectiveness over a longer period. Methods The details of the MASS protocol were described previously (2), but a brief summary is provided (Figure 1). Between 1997 and 1999, a population-based sample of 70495 men age 65 to 74 years from 4 centers in the United Kingdom was identified by obtaining records for every man in this age range who was registered with a family physician (registered persons account for approximately 98% of the population). Persons who were ineligible for the trial (incorrect details, known AAA, previous AAA surgery, or terminal illness) were excluded before randomization. The remaining 67770 men were randomly assigned to receive an invitation to ultrasonography for AAA or to not receive an invitation to ultrasonography. At screening, men with an aortic diameter of 3.0 cm or greater were defined as having an AAA and were subsequently invited for recall scans to monitor growth of the aneurysm. Men with an aortic diameter of 3.0 to 4.4 cm were rescreened every year, and those with an aortic diameter of 4.5 to 5.4 cm were rescreened every 3 months. Participants were considered for elective surgery when the aortic diameter reached 5.5 cm, aortic expansion was 1.0 cm or more in 1 year, or they experienced symptoms attributable to the aneurysm. Men with an aortic diameter less than 3.0 cm on the initial scan were not rescreened. Blood pressure was also measured; although family physicians were informed of these measurements, no further intervention was provided through the screening program. We obtained approval from local ethics committees at each center, and all patients who had screening provided signed informed consent. Figure 1. Study flow diagram. Additional data on follow-up scans and AAA surgeries were collected from hospital records. Deaths up to 31 March 2005 were confirmed by the U.K. Office of National Statistics after matching of the unique National Health Service number for each person. Follow-up ranged from 5.9 to 8.2 years (mean, 7.1 years). The primary outcome of interest, AAA-related mortality, is defined as all deaths within 30 days of any AAA surgery (elective or emergency) plus all deaths with International Classification of Diseases, Ninth Revision, codes 441.3 (ruptured abdominal aortic aneurysm), 441.4 (abdominal aortic aneurysm without mention of rupture), 441.5 (ruptured aortic aneurysm at unspecified site), or 441.6 (aortic aneurysm at unspecified site without mention of rupture). The use of codes 441.5 and 441.6 may result in inclusion of some thoracic aortic aneurysm deaths. Investigation of the accuracy of cause-of-death coding on the death certificates was done by an independent mortality working party that was blinded to group allocation. The results of this analysis showed that inaccuracies in coding did not have an important impact on study outcomes (2). Statistical Analysis All analyses were done by using Stata, version 9 (Stata Corp., College Station, Texas). Deaths related to AAA (primary analysis) and all-cause mortality (secondary analysis) were compared between the 2 randomized groups by using unadjusted Cox regression by intention-to-treat analysis. Adjustment for age at baseline did not influence the results. The proportional hazards assumption was tested by using Schoenfeld residuals. An unbiased randomization-based estimate of the benefit of screening was also obtained (16). This estimate is calculated by subtracting from the control group a subgroup that is equivalent in terms of survival to the nonadherent subgroup in the invited group. Thus, the remaining controls are comparable to the group of invited patients who attended screening. Life-years gained are estimated as the area between the KaplanMeier curves for both groups (17). The cost-effectiveness of screening is estimated from a health service perspective for follow-up truncated at 7 years, with adjustment for censoring (18). Details of the costing exercise in the trial at 20002001 prices were reported previously (9). The unit costs obtained (U.K. 1 = U.S.