Impact of Aspirin and Clopidogrel Hyporesponsiveness in Patients Treated With Drug-Eluting Stents: 2-Year Results of a Prospective, Multicenter Registry Study.

OBJECTIVES: In this analysis of 2-year outcomes in the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) study, the authors sought to examine the independent associations between platelet reactivity to both aspirin and clopidogrel and subsequent outcomes. BACKGROUND: The relationship between platelet reactivity and long-term adverse events following implantation of drug-eluting stents (DES) has been incompletely characterized. METHODS: The ADAPT-DES study was a multicenter registry of patients undergoing routine platelet function testing following percutaneous coronary intervention with DES. The primary study endpoint was definite or probable stent thrombosis (ST); other endpoints were all-cause mortality, myocardial infarction, and clinically relevant bleeding. RESULTS: A total of 8,582 patients were enrolled between 2008 and 2010; 46.3% of patients were on dual antiplatelet therapy at 2 years without discontinuation. At 2 years, definite or probable ST occurred in 92 patients (1.07%). In patients treated with dual antiplatelet therapy continuously for 2 years, high platelet reactivity on clopidogrel was independently associated with definite or probable ST (adjusted hazard ratio [HR]: 2.16; 95% confidence interval [CI]: 1.27 to 3.67; p = 0.003), myocardial infarction (adjusted HR: 1.35; 95% CI: 1.05 to 1.74; p = 0.02), freedom from clinically relevant bleeding (adjusted HR: 0.74; 95% CI: 0.62 to 0.90; p = 0.002), and all-cause mortality (adjusted HR: 1.36; 95% CI: 1.01 to 1.85; p = 0.04). Between years 1 and 2, high platelet reactivity was not associated with the very late ST and in patients on aspirin monotherapy, aspirin hyporesponsiveness was not associated with adverse outcomes. CONCLUSIONS: The present study confirms the strong relationship of high platelet reactivity on clopidogrel to 2-year ischemic and bleeding outcomes after DES. The majority of stent-related events occurred within the first year.

Effect of Short Procedural Duration With Bivalirudin on Increased Risk of Acute Stent Thrombosis in Patients With STEMI: A Secondary Analysis of the HORIZONS-AMI Randomized Clinical Trial.

Importance: Bivalirudin has been associated with reduced bleeding and mortality during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). However, increased rates of acute stent thrombosis (AST) have been noted when bivalirudin is discontinued at the end of the procedure, which is perhaps related to this medication's short half-life. Objectives: To evaluate the clinical effect of procedure duration on AST when either bivalirudin or heparin plus glycoprotein IIb/IIIa receptor inhibitor (GPI) is used. Design, Setting, and Participants: An ad hoc analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) clinical trial was performed between March 1, 2015, and April 30, 2016, on patients who underwent primary percutaneous coronary intervention with stents and were randomized 1:1 to bivalirudin or heparin plus GPI. Defined as the difference between the patient's arrival at the catheterization laboratory and the patient's final angiogram. Participants included 3602 patients with STEMI, aged 18 years or older, who were undergoing primary percutaneous coronary intervention and presenting less than 12 hours from symptom onset. Main Outcomes and Measures: Clinical events committee-adjudicated definite AST (occurring ≤24 hours after percutaneous coronary intervention). Results: Among patients included in this analysis, procedure time was identified in 1286 receiving bivalirudin and 1412 receiving heparin plus GPI. Shorter procedures were defined as the lowest quartile of duration (<45 minutes). Patients undergoing shorter procedures were younger and less likely to be hypertensive and smokers. Shorter procedures were less complicated with fewer stents implanted, less multivessel stenting, less thrombus, and less no-reflow. An increased risk of definite AST was associated with shorter than with longer procedures with bivalirudin (7 [2.1%] vs 7 [0.7%]; relative risk, 2.87; 95% CI, 1.01-8.17; P = .04) but not with heparin plus GPI (0 vs 3 [0.3%]; P = .30). Conclusions and Relevance: Despite less procedural complexity, shorter primary percutaneous coronary intervention time was associated with an increased risk of AST in patients treated with bivalirudin but not patients treated with heparin plus GPI, possibly because of the rapid offset of bivalirudin's antithrombotic effect during a window of limited oral antiplatelet action. Trial Registration: clinicaltrials.gov Identifier: NCT00433966.

Relation Between Renal Function and Coronary Plaque Morphology (from the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents Virtual Histology-Intravascular Ultrasound Substudy).

We sought to examine the relation between various degrees of renal function and coronary plaque morphology by grayscale and virtual histology intravascular ultrasound (IVUS). ADAPT-DES was a prospective, multicenter registry of 8,582 consecutive patients treated using coronary drug-eluting stents with a prespecified grayscale and virtual histology-IVUS substudy. A lesion-level analysis of study participants was performed by comparing IVUS parameters of culprit and nonculprit lesions across tertiles of estimated creatinine clearance (CrCl). Preintervention IVUS imaging of 762 patients identified 898 culprit and 752 nonculprit native coronary artery lesions. Patients in the lowest CrCl tertile were older, more often women, and more often presented with stable angina. Compared with the middle and upper tertiles, the lowest tertile was significantly associated with culprit lesion smaller mean external elastic membrane cross-sectional area (12.9 vs 14.2 mm3/mm vs 14.9 mm3/mm, p <0.0001), smaller mean lumen cross-sectional area (5.5 mm3/mm vs 5.8 mm3/mm vs 6.1 mm3/mm, p = 0.002), and more dense calcium volume (11.5% vs 10.2% vs 9.7%, p = 0.02). Similar trends were found in the nonculprit lesions. Plaque rupture was least common in patients in the lowest tertile. On multivariable analysis, independent predictors of greater dense calcium volume were lower CrCl, hyperlipidemia, female gender, and presentation without ST-segment elevation myocardial infarction. In conclusion, in the present large-scale IVUS study diminishing renal function was associated with increased coronary calcification and decreased coronary vessel and lumen sizes, with a graded response according to the reduction in CrCl. In addition, these patients were more likely to present with stable angina versus patients with normal renal function who were more likely to present with an acute coronary syndrome.

Comparison of Dabigatran and Warfarin in Patients With Atrial Fibrillation and Valvular Heart Disease: The RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulant Therapy).

BACKGROUND: The RE-LY trial (Randomized Evaluation of Long-Term Anticoagulant Therapy) compared dabigatran 150 and 110 mg twice daily with warfarin in 18 113 patients with atrial fibrillation. Those with prosthetic heart valves, significant mitral stenosis, and valvular heart disease (VHD) requiring intervention were excluded. Others with VHD were included. METHODS: This is a post hoc analysis of the RE-LY trial. RESULTS: There were 3950 patients with any VHD: 3101 had mitral regurgitation, 1179 with tricuspid regurgitation, 817 had aortic regurgitation, 471 with aortic stenosis, and 193 with mild mitral stenosis. At baseline, patients with any VHD had more heart failure, coronary disease, renal impairment, and persistent atrial fibrillation. Patients with any VHD had higher rates of major bleeds (hazard ratio [HR], 1.32; 95% confidence interval [CI], 1.16-1.5) but similar stroke or systemic embolism event rates (HR, 1.09; 95% CI, 0.88-1.33). For patients receiving dabigatran 110 mg, major bleed rates were lower than for patients taking warfarin (HR, 0.73; 95% CI, 0.56-0.95 with VHD; HR, 0.84; 95% CI, 0.71-0.99 without VHD), and major bleed rates for dabigatran 150 mg were similar to those for warfarin in patients with VHD (HR, 0.82; 95% CI, 0.64-1.06) or without VHD (HR, 0.98; 95% CI, 0.83-1.15). For dabigatran 150 mg, stroke/systemic embolic event rates were lower compared with warfarin in those with VHD (HR, 0.59; 95% CI, 0.37-0.93) and those without VHD (HR, 0.67; 95% CI, 0.52-0.86), and stroke/systemic embolic event rates were similar for warfarin and dabigatran 110 mg regardless of the presence of VHD (HR, 0.97; 95% CI, 0.65-1.45; and HR, 0.88; 95% CI, 0.70-1.10). Intracranial bleeds and death rates for dabigatran 150 and 110 mg were lower compared with warfarin independently of the presence of VHD. CONCLUSIONS: The presence of any VHD did not influence the comparison of dabigatran with warfarin. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00262600.

Relation Between Platelet Count and Platelet Reactivity to Thrombotic and Bleeding Risk: From the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents Study.

Whether the association between platelet count (PC) and thrombotic and bleeding risk is independent of or varies by residual platelet reactivity to antiplatelet therapies is unclear. We sought to investigate the independent and combined effects of PC and platelet reactivity on thrombotic and bleeding risk after coronary artery implantation of drug-eluting stents (DES). Patients enrolled in the prospective, multicenter Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents study were stratified by PC tertiles. The study cohort comprised 8,402 patients. By linear regression analysis, lower PC was strongly and independently associated with higher platelet reactive units (PRUs) on clopidogrel. After multivariable adjustment (including PRU and aspirin reactive units), high, but not low, PC tertile was independently associated with higher risk of thrombotic complications, including spontaneous myocardial infarction and stent thrombosis. Although no independent association was observed between PC tertiles and hemorrhagic risk, both high and low PC tertiles were associated with increased risk for all-cause mortality. After stratification of PC tertiles by tertiles of PRUs, the crude risk of thrombotic complications was highest in patients in the high PC and high PRU tertiles. By multivariable adjustment, PRU increases were uniformly associated with higher risk of thrombotic events across PC tertiles, without evidence of interaction. In conclusion, higher PCs and higher PRUs act independently and synergistically in determining thrombotic risk. Alongside PRU, PCs could be a simple hematological parameter to consider for risk stratification and in tailoring duration and potency of pharmacologic platelet inhibition after DES implantation.

Coronary Thrombosis and Major Bleeding After PCI With Drug-Eluting Stents: Risk Scores From PARIS.

BACKGROUND: Dual-antiplatelet therapy with aspirin and clopidogrel after percutaneous coronary intervention reduces the risk for coronary thrombotic events (CTEs) at the expense of increasing risk for major bleeding (MB). Metrics to accurately predict the occurrence of each respective event and inform clinical decision making are lacking. OBJECTIVES: The aim of this study was to develop and validate separate models to predict risks for out-of-hospital thrombotic and bleeding events after percutaneous coronary intervention with drug-eluting stents. METHODS: Using data from 4,190 patients treated with drug-eluting stents and enrolled in the PARIS (Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients) registry, separate risk scores were developed to predict CTE (defined as the composite of stent thrombosis or myocardial infarction) and MB (defined as the occurrence of a Bleeding Academic Research Consortium type 3 or 5 bleed). External validation was performed in the ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) registry. RESULTS: Over 2 years, CTEs occurred in 151 patients (3.8%) and MB in 133 (3.3%). Independent predictors of CTEs included acute coronary syndrome, prior revascularization, diabetes mellitus, renal dysfunction, and current smoking. Independent predictors of MB included older age, body mass index, triple therapy at discharge, anemia, current smoking, and renal dysfunction. Each model displayed moderate levels of discrimination and adequate calibration. CONCLUSIONS: Simple risk scores of baseline clinical variables may be useful to predict risks for ischemic and bleeding events after PCI with DES, thereby facilitating clinical decisions surrounding the optimal duration of DAPT. (Patterns of Non-Adherence to Anti-Platelet Regimen in Stented Patients [PARIS]; NCT00998127).

Risk stratification of patients undergoing medical therapy after coronary angiography.

AIM: We sought to investigate the prognostic impact of the SYNTAX (Synergy between PCI with TAXUS and Cardiac Surgery) score (SS) on 1-year clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) undergoing medical therapy only. METHODS AND RESULTS: Among the 13 819 patients enrolled in the ACUITY trial and undergoing coronary angiogram, 4491 patients were treated with medical therapy as the initial strategy. Of those, baseline SS and complete angiographic analysis were available in 1275 patients. Patients were divided in four groups based on the presence or absence of coronary artery disease (CAD) and subsequently, among patients with CAD, by SS. Major adverse cardiac events (MACE) and its individual components (death, myocardial infarction, and unplanned revascularization) were compared between groups. Among the 1275 patients, the mean SS was 3.5 ± 7.0 (range 0-45). SYNTAX score was 0 in 842 patients, >0 and ≤5 in 170, >5 and ≤11 in 119, and >11 in 144 patients. The 1-year rates of MACE were higher in patients with CAD and higher SS. By multivariable analysis, the SS was a strong predictor of all adverse ischaemic events, including mortality. By receiver operator characteristic analysis, an SS cut-off of 8 showed the best prognostic accuracy for death and MACE. CONCLUSION: In patients with NSTE ACS undergoing medical therapy, the SS, especially when >8, was shown to be a strong predictor of 1-year MACE, including mortality. This finding has important clinical implications for risk stratification of patients with NSTE ACS undergoing medical therapy after an initial angiogram.

Impact of Hemoglobin A1c Levels on Residual Platelet Reactivity and Outcomes After Insertion of Coronary Drug-Eluting Stents (from the ADAPT-DES Study).

An increasing hemoglobin A1c (HbA1c) level portends an adverse cardiovascular prognosis; however, the association between glycemic control, platelet reactivity, and outcomes after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) is unknown. We sought to investigate whether HbA1c levels are associated with high platelet reactivity (HPR) in patients loaded with clopidogrel and aspirin, thereby constituting an argument for intensified antiplatelet therapy in patients with poor glycemic control. In the prospective, multicenter Assessment of Dual Antiplatelet Therapy With Drug Eluting Stents registry, HbA1c levels were measured as clinically indicated in 1,145 of 8,582 patients, stratified by HbA1c <6.5% (n = 551, 48.12%), 6.5% to 8.5% (n = 423, 36.9%), and >8.5% (n = 171, 14.9%). HPR on clopidogrel and aspirin was defined after PCI as P2Y12 reaction units (PRU) >208 and aspirin reaction units >550, respectively. HPR on clopidogrel was frequent (48.3%), whereas HPR on aspirin was not (3.9%). Patients with HbA1c >8.5% were younger, more likely non-Caucasian, had a greater body mass index, and more insulin-treated diabetes and acute coronary syndromes. Proportions of PRU >208 (42.5%, 50.2%, and 62.3%, p <0.001) and rates of definite or probable stent thrombosis (ST; 0.9%, 2.7%, and 4.2%, p = 0.02) increased progressively with HbA1c groups. Clinically relevant bleeding was greatest in the intermediate HbA1c group (8.2% vs 13.1% vs 9.5%, p = 0.04). In adjusted models that included PRU, high HbA1c levels (>8.5) remained associated with ST (hazard ratio 3.92, 95% CI 1.29 to 12.66, p = 0.02) and cardiac death (hazard ratio 4.24, 95% CI 1.41 to 12.70) but not bleeding at 2-year follow-up. There was no association between aspirin reaction units >550 and HbA1c levels. In conclusion, in this large-scale study, HbA1c and HPR were positively associated, but the clinical effect on adverse outcome was driven by poor glycemic control, which predicted ST and cardiac death after PCI regardless of PRU levels, warranting efforts to improve glycemic control after DES implantation in patients with diabetes mellitus.

Etiology, Frequency, and Clinical Outcomes of Myocardial Infarction After Successful Drug-Eluting Stent Implantation: Two-Year Follow-Up From the ADAPT-DES Study.

BACKGROUND: The frequency, causes, and impact of myocardial infarction (MI) after successful percutaneous coronary intervention have not been well studied. METHODS AND RESULTS: The Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) study was a prospective, multicenter registry study of 8582 patients undergoing successful drug-eluting stent implantation at 11 centers in the United States and Germany. After excluding 128 patients with periprocedural MI, we investigated the pathogenesis, frequency, and long-term consequences of non-periprocedural MI in 8454 patients. MI during 2-year follow-up developed in 263 patients (3.3%) at a median (25th and 75th percentiles) time of 318 (129, 503) days. The 263 MIs were subclassified as spontaneous MI (n=78; 29.7%), secondary or indeterminate MI (n=64; 24.3%), stent thrombosis-related MI (n=63; 24.0%), and in-stent restenosis-related MI (n=58; 22.1%). Multivariable predictors of MI included clinical and angiographic factors (acute coronary syndromes presentation, diabetes mellitus, current smoker, multivessel disease, treatment of an in-stent restenotic lesion), laboratory findings (low baseline hemoglobin and reduced creatinine clearance), antiplatelet agent-related factors (higher on-treatment platelet P2Y12 receptor reactivity and premature thienopyridine discontinuation), and not being on a statin at discharge. Patients who experienced an MI during the follow-up period had significantly greater 2-year mortality than those without MI (17.3% [42 deaths] versus 3.4% [265 deaths], P<0.001). By multivariable analysis, the adjusted hazard ratio (95% confidence interval) for subsequent mortality during follow-up was 2.17 (1.06, 4.45) in patients with versus without a non-periprocedural MI (P=0.03). CONCLUSIONS: The occurrence of a non-periprocedural MI within 2 years after successful drug-eluting stent implantation is relatively infrequent, but has numerous etiologies and is significantly associated with subsequent mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Hippocampal Malrotation Is Associated With Prolonged Febrile Seizures: Results of the FEBSTAT Study.

OBJECTIVE: Hippocampal malrotation is characterized by incomplete hippocampal inversion with a rounded shape and blurred internal architecture. There is still debate about whether hippocampal malrotation has pathologic significance. We present findings from the Consequences of Prolonged Febrile Seizures in Childhood (FEBSTAT) study on the frequency of and risk factors for hippocampal malrotation. SUBJECTS AND METHODS: FEBSTAT is a prospective multicenter study investigating the consequences of febrile status epilepticus in childhood. MRI studies of 226 patients with febrile status epilepticus were analyzed visually by two board-certified neuroradiologists blinded to clinical details and were compared with MRI studies of 96 subjects with first simple febrile seizure. Quantitative analysis of hippocampal volume was performed by two independent observers. RESULTS: Hippocampal malrotation was present in 20 of 226 (8.8%) patients with febrile status epilepticus compared with two of 96 (2.1%) control subjects (odds ratio [OR], 4.56; 95% CI, 1.05-19.92). Hippocampal malrotation was exclusively left-sided in 18 of 22 (81.8%) patients and bilateral in the remaining four patients (18.2%). There was no case of exclusively right-sided hippocampal malrotation. Hippocampal malrotation was more common in boys than in girls (OR, 6.1; 95% CI, 1.7-21.5). On quantitative volumetric MRI analysis, the left hippocampal volume was smaller in patients with hippocampal malrotation than in control subjects with simple febrile seizure (p = 0.004), and the right-to-left hippocampal volume ratio was higher in the hippocampal malrotation group than in the simple febrile seizure group (p < 0.001). CONCLUSION: Hippocampal malrotation is a developmental malformation that predominantly affects the left hippocampus in male patients and is more frequently found in children with prolonged febrile status epilepticus than in control subjects. These data provide further evidence that hippocampal malrotation represents a pathologic error in brain development rather than a normal variant.

Incidence, Predictors, and Impact of Post-Discharge Bleeding After Percutaneous Coronary Intervention.

BACKGROUND: The incidence, predictors, and prognostic impact of post-discharge bleeding (PDB) after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation are unclear. OBJECTIVES: This study sought to characterize the determinants and consequences of PDB after PCI. METHODS: The prospective ADAPT-DES (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) study was used to determine the incidence and predictors of clinically relevant bleeding events occurring within 2 years after hospital discharge. The effect of PDB on subsequent 2-year all-cause mortality was estimated by time-adjusted Cox proportional hazards regression. RESULTS: Among 8,582 "all-comers" who underwent successful PCI with DES in the ADAPT-DES study, PDB occurred in 535 of 8,577 hospital survivors (6.2%) at a median time of 300 days (interquartile range: 130 to 509 days) post-discharge. Gastrointestinal bleeding (61.7%) was the most frequent source of PDB. Predictors of PDB included older age, lower baseline hemoglobin, lower platelet reactivity on clopidogrel, and use of chronic oral anticoagulation therapy. PDB was associated with higher crude rates of all-cause mortality (13.0% vs. 3.2%; p < 0.0001). Following multivariable adjustment, PDB was strongly associated with 2-year mortality (hazard ratio [HR]: 5.03; p < 0.0001), with an effect size greater than that of post-discharge myocardial infarction (PDMI) (HR: 1.92; p = 0.009). CONCLUSIONS: After successful PCI with DES in an unrestricted patient population, PDB is not uncommon and has a strong relationship with subsequent all-cause mortality, greater that that associated with PDMI. Efforts to reduce PDB may further improve prognosis after successful DES implantation. (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents [ADAPT-DES]; NCT00638794).

Age-related effects of smoking on culprit lesion plaque vulnerability as assessed by grayscale and virtual histology-intravascular ultrasound.

BACKGROUND: Although smoking is a risk factor for coronary atherosclerosis, the age-related impact on lesion characteristics and plaque instability remains unclear. PATIENTS AND METHODS: In ADAPT-DES, 780 patients with 916 culprit lesions were evaluated by preprocedural grayscale and virtual histology-intravascular ultrasound. RESULTS: Current smokers (smoking within 1 month) more often presented with acute coronary syndrome (67 vs. 51 vs. 51%, P<0.05) compared with former smokers (no smoking for >1 month) or nonsmokers. In patients 65 or more years of age, current smokers (vs. nonsmokers) showed larger normalized volumes of plaque and media [8.6 (7.8-9.4) vs. 7.2 (6.8-7.7) mm/mm, P=0.016] and external elastic membrane [14.4 (13.2-15.5) vs. 12.8 (12.2-13.4) mm/mm, P=0.05]. At the minimal lumen area site, despite a greater plaque burden, the larger external elastic membrane area [14.4 (13.1-15.7) vs. 12.0 (11.3-12.7) mm, P=0.003] contributed toward preserving the minimal lumen area [2.6 (2.4-2.7) vs. 2.6 (2.5-2.7) mm, P=0.91] in current smokers (vs. nonsmokers) 65 or more years of age. Moreover, current smokers (vs. nonsmokers) 65 or more years of age showed a greater normalized necrotic core volume [1.19 (0.96-1.46) vs. 0.75 (0.66-0.85) mm/mm, P=0.0007], more thin-cap fibroatheromas (61 vs. 48%, P=0.04), and plaque ruptures (38 vs. 26%, P=0.051). Conversely, in patients younger than 65 years of age, there was no significant difference in culprit lesion morphology among current, former, and nonsmokers. CONCLUSION: In patients 65 or more years (not in patients<65 years), smoking increased culprit lesion plaque instability (greater plaque with more necrotic core, thin-cap fibroatheromas, positive remodeling, and plaque ruptures).

Hippocampal sclerosis after febrile status epilepticus: the FEBSTAT study.

OBJECTIVE: Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine whether FSE produces acute hippocampal injury that evolves to HS. METHODS: FEBSTAT and 2 affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute magnetic resonance imaging (MRI), and follow-up MRI was obtained approximately 1 year later in the majority. Visual interpretation by 2 neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intrahippocampal distribution of T2 signal, and apparent diffusion coefficients. RESULTS: Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRI obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRI had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially, and reduced hippocampal growth. INTERPRETATION: Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after 1 year. Furthermore, impaired growth of normal-appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE.

Risk factors for febrile status epilepticus: a case-control study.

OBJECTIVE: To identify risk factors for developing a first febrile status epilepticus (FSE) among children with a first febrile seizure (FS). STUDY DESIGN: Cases were children with a first FS that was FSE drawn from the Consequences of Prolonged Febrile Seizures in Childhood and Columbia cohorts. Controls were children with a first simple FS and separately, children with a first complex FS that was not FSE. Identical questionnaires were administered to family members of the 3 cohorts. Magnetic resonance imaging protocol and readings were consistent across cohorts, and seizure phenomenology was assessed by the same physicians. Risk factors were analyzed using logistic regression. RESULTS: Compared with children with simple FS, FSE was associated with younger age, lower temperature, longer duration (1-24 hours) of recognized temperature before FS, female sex, structural temporal lobe abnormalities, and first-degree family history of FS. Compared with children with other complex FS, FSE was associated with low temperature and longer duration (1-24 hours) of temperature recognition before FS. Risk factors for complex FS that was not FSE were similar in magnitude to those for FSE but only younger age was significant. CONCLUSIONS: Among children with a first FS, FSE appears to be due to a combination of lower seizure threshold (younger age and lower temperatures) and impaired regulation of seizure duration. Clinicians evaluating FS should be aware of these factors as many episodes of FSE go unnoticed. Further work is needed to develop strategies to prevent FSE.

Design and phenomenology of the FEBSTAT study.

PURPOSE: Febrile status epilepticus (FSE) has been associated with hippocampal injury and subsequent hippocampal sclerosis (HS) and temporal lobe epilepsy. The FEBSTAT study was designed to prospectively examine the association between prolonged febrile seizures and development of HS and associated temporal lobe epilepsy, one of the most controversial issues in epilepsy. We report on the baseline phenomenology of the final cohorts as well as detailed aims and methodology. METHODS: The "Consequences of Prolonged Febrile Seizures in Childhood" (FEBSTAT) study is a prospective, multicenter study. Enrolled are children, aged 1 month to 6 years of age, presenting with a febrile seizure lasting 30 min or longer based on ambulance, emergency department, and hospital records, and parental interview. At baseline, procedures included a magnetic resonance imaging (MRI) study and electroencephalography (EEG) recording done within 72 h of FSE, and a detailed history and neurologic examination. Baseline development and behavior are assessed at 1 month. The baseline assessment is repeated, with age-appropriate developmental testing at 1 and 5 years after enrollment as well as at the development of epilepsy and 1 year after that. Telephone calls every 3 months document additional seizures. Two other groups of children are included: a "control" group consisting of children with a first febrile seizure ascertained at Columbia University and with almost identical baseline and 1-year follow-up examinations and a pilot cohort of FSE from Duke University. KEY FINDINGS: The FEBSTAT cohort consists of 199 children with a median age at baseline of 16.0 months (interquartile range [IQR] 12.0-24.0) and a median duration of FSE of 70.0 min (IQR 47.0-110.0). Seizures were continuous in 57.3% and behaviorally intermittent (without recovery in between) in 31.2%; most were partial (2.0%) or secondary generalized (65.8%), and almost all (98.0%) culminated in a generalized tonic-clonic seizure. Of the 199 children, 86.4% had normal development and 20% had prior febrile seizures. In one third of cases, FSE was unrecognized in the emergency department. The Duke existing cohort consists of 23 children with a median age of FSE onset of 18.0 months (IQR 14.0-28.0) and median duration of FSE of 90.0 min (IQR 50.0-170.0). The Columbia control cohort consists of 159 children with a first febrile seizure who received almost the same workup as the FEBSTAT cohort at baseline and at 1 year. They were followed by telephone every 4 months for a median of 42 months. Among the control cohort, 64.2% had a first simple FS, 26.4% had a first complex FS that was not FSE, and 9.4% had FSE. Among the 15 with FSE, the median age at onset was 14.0 months (IQR 12.0-20.0) and the median duration of FSE was 43.0 min (IQR 35.0-75.0). SIGNIFICANCE: The FEBSTAT study presents an opportunity to prospectively study the relationship between FSE and acute hippocampal damage, the development of mesial temporal sclerosis, epilepsy (particularly temporal lobe epilepsy), and impaired hippocampal function in a large cohort. It is hoped that this study may illuminate a major mystery in clinical epilepsy today, and permit the development of interventions designed to prevent the sequelae of FSE.