Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study.

INTRODUCTION: Markers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. METHODS: We measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. RESULTS: At baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. CONCLUSIONS: In this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

Catamenial epilepsy occurrence and patterns in a mixed population of women with epilepsy.

We evaluated the occurrence and distribution of patterns of catamenial epilepsy in a heterogenous cohort of women with epilepsy on no hormonal therapies, enrolled in a prospective, observational study. The primary aim of the study was pregnancy rate in women with epilepsy with no prior reproductive problems. In this analysis, we included women who recorded one or more menstrual cycles with one or more seizures. We measured progesterone concentrations for one to three cycles. We defined catamenial patterns as twofold or greater average daily seizure frequency around menstruation (C1), ovulation (C2), and for anovulatory cycles, from midcycle through menstruation (C3). Twenty-three of the 89 enrolled women with epilepsy were eligible for this analysis; 12 of 23 met criteria for catamenial epilepsy; five of 23 demonstrated only a C1 pattern, two of 23 only a C2 pattern, five of 23 a combined C1/C2 pattern, and the one woman with anovulatory cycles did not demonstrate a C3 pattern. There were no differences in likelihood of demonstrating a catamenial pattern between those who reported a prior catamenial pattern and those who did not (p = .855). This analysis demonstrates the utility of app-based tracking to determine a catamenial pattern. Larger prospective studies could confirm these findings and inform potential therapeutic trial designs for catamenial epilepsy.

Polypharmacy in US Medicare beneficiaries with antineutrophil cytoplasmic antibody vasculitis.

BACKGROUND: Treatment requirements of antineutrophil cytoplasmic autoantibody vasculitis (AV) and high comorbidity burden among patients with AV may lead to higher potential for polypharmacy and its associated adverse outcomes, including adverse drug events, nonadherence, drug-drug interactions, and higher costs. Medication burden and risk factors associated with polypharmacy in patients with AV have not been well-characterized. OBJECTIVE: To characterize medication burden and examine prevalence of and risk factors for polypharmacy in the first year after diagnosis with AV. METHODS: We conducted a retrospective cohort study using 2015-2017 Medicare claims to identify incident cases of AV. We counted the number of unique generic products dispensed to patients in each of the 4 quarters after diagnosis and categorized medication count as high (≥10 medications), moderate (5-9 medications), or minimal or no polypharmacy (<5 medications). We used multinomial logistic regression to examine associations of predisposing, enabling, and medical need factors with having high or moderate polypharmacy. RESULTS: In 1,239 Medicare beneficiaries with AV, high or moderate polypharmacy was most common in the first quarter after diagnosis (83.7%), with 43.2% taking 5 - 9 medications and 40.5% taking at least 10. The odds of high polypharmacy were greater in all quarters for patients with eosinophilic granulomatosis with polyangiitis compared with granulomatosis with polyangiitis, ranging from 2.02 (95% CI = 1.18 - 3.46) in the third quarter to 2.96 (95% CI = 1.64-5.33) in the second quarter. Older age, diabetes, chronic kidney disease, obesity, a higher Charlson Comorbidity Index score, coverage with Medicaid/Part D low-income subsidy, and living in areas with low education or persistent poverty were risk factors for high or moderate polypharmacy. CONCLUSIONS: Medicare beneficiaries with newly diagnosed AV experienced a high medication burden, with more than 40% taking at least 10 medications and the highest rates among those with eosinophilic granulomatosis with polyangiitis. Patients with AV may benefit from medication therapy management interventions to manage complex drug regimens and reduce risks associated with polypharmacy. DISCLOSURES: Dr Derebail receives personal fees from Travere Therapeutics, Pfizer, Bayer, Forma Therapeutics, UpToDate, outside of the submitted work. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or the Department of Veterans Affairs. Dr Thorpe receives royalties from SAGE Publishing for activities unrelated to the submitted work. This research is supported by internal funds from the University of North Carolina, as well as the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R21AI160606 (PI: C. Thorpe).

Variations in Seizure Frequency During Pregnancy and Postpartum by Epilepsy Type.

BACKGROUND AND OBJECTIVES: To assess whether increased seizure frequency during pregnancy and postpartum is influenced by epilepsy type, seizure location, and antiseizure medications. METHODS: Clinical data were collected in a longitudinal prospective database of pregnant women with epilepsy at Brigham and Women's Hospital. Within each individual participant, baseline seizure frequency was calculated for the 9 months before conception, and whether seizure frequency increased during pregnancy or the postpartum period was determined. Seizure frequency was calculated for each 4-week interval during pregnancy. Generalized estimating equations for logistic regression were applied. RESULTS: Ninety-nine patients contributing 114 pregnancies were included from 2013 to 2018. Increased seizure frequency occurred more often during pregnancies of women with focal vs generalized epilepsy (21.1% vs 5.3%, odds ratio [OR] 4.70, 95% confidence interval [CI] 1.00-22.00; p = 0.0497). Among women with focal epilepsy, increased seizure frequency occurred more often in those with frontal lobe epilepsy (OR 8.00, 95% CI 2.19-29.21; p = 0.0017). There was no difference in seizure worsening in the postpartum period between the focal and generalized (11.1% vs 9.1%; p = 0.4478) or frontal and other focal (18.8% vs 6.0%; p = 0.1478) epilepsy groups. Pregnancies on polytherapy had higher odds of seizure worsening compared to monotherapy (OR 8.36, 95% CI 2.07-33.84; p = 0.0029), regardless of the medication or epilepsy type. A lack of preconception seizure freedom was also associated with increased seizure frequency during pregnancy (OR 6.418; p = 0.0076). DISCUSSION: Women with focal epilepsy have higher likelihood of seizure worsening during pregnancy compared to women with generalized epilepsy; frontal lobe epilepsy poses an especially elevated risk. Polytherapy and lack of preconception seizure freedom are additional predictors for an increased likelihood of seizure worsening.

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.

BACKGROUND: Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear. OBJECTIVE: To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during ≥8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults. METHODS: We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors. RESULTS: Of 20 factors evaluated individually, only higher levels of plasmin-α2 -antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP ß = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI ß = -0.55, 95% CI: -0.90 to -0.19; FXc ß = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE. CONCLUSIONS: Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

Mindfulness-based therapy for psychogenic nonepileptic seizures.

BACKGROUND: Mindfulness-based therapies (MBTs) are effective in many neuropsychiatric disorders, and represent a potential therapeutic strategy for psychogenic nonepileptic seizures (PNES). OBJECTIVE: The objective of this study was to investigate the clinical effect of a manualized 12-session MBT for PNES in an uncontrolled trial. We hypothesized reductions in PNES frequency, intensity, and duration, and improvements in quality of life and psychiatric symptom severity at treatment completion. METHODS: Between August 2014 and February 2018, 49 patients with documented PNES (with video electroencephalography [EEG]) were recruited at Brigham and Women's Hospital to participate in the MBT for PNES treatment study. Baseline demographic and clinical information and self-rating scales were obtained during the diagnostic evaluation (T0). Baseline PNES frequency, intensity, and duration were collected at the first follow-up postdiagnosis (T1). Frequency was obtained at each subsequent MBT session and analyzed over time with median regression analysis. Outcomes for other measures were collected at the last MBT session (T3), and compared to baseline measures using linear mixed models. RESULTS: Twenty-six patients completed the 12-session MBT program and were included in the analysis. Median PNES frequency decreased by 0.12 events/week on average with each successive MBT session (p = 0.002). At session 12, 70% of participants endorsed a reduction in PNES frequency of at least 50%. Freedom from PNES was reported by 50% of participants by treatment conclusion. Seventy percent reported a 50% reduction in frequency from baseline and 50% reported remission at session 12. By treatment end, PNES intensity decreased (p = 0.012) and quality of life improved (p = 0.002). Event duration and psychiatric symptom severity were lower after treatment, but reductions were not statistically significant. CONCLUSIONS: Completion of a manualized 12-session MBT for PNES provides improvement in PNES frequency, intensity, and quality of life. The high dropout rate is consistent with adherence studies in PNES. Possible reasons for dropout are discussed. Randomized controlled trials and longer-term outcomes are needed to demonstrate the efficacy of MBT in PNES.

Antiepileptic Drug Management in Hospitalized Epilepsy Patients With Nil Per Os Diets: A Retrospective Review.

BACKGROUND AND PURPOSE: Antiepileptic drug (AED) management in patients with epilepsy who cannot take their usual oral medications is a common neurologic dilemma in the hospital setting. Strategies to maintain seizure control in patients with nil per os (NPO, nothing by mouth) diet orders include continuation of oral AEDs despite NPO nutrition orders, administration of intravenous AED(s), or temporary administration of benzodiazepines. The frequency with which these strategies are used and their effectiveness in preventing in-hospital seizures is unknown. METHODS: We conducted a retrospective cohort study to determine AED management strategies and seizure frequency in hospitalized epilepsy patients with NPO diet status admitted to an academic medical center between 2001 and 2016. Clinical documentation was reviewed. Antiepileptic drug selection (medication and route of administration) and presence or absence of seizures were recorded. RESULTS: We identified 199 admissions during which epilepsy patients had NPO diet orders. Antiepileptic drug management strategies included continuation of oral medications (50.3% of admissions), intravenous AED monotherapy (22.1%), intravenous AED polytherapy (12.6%), benzodiazepines (1.0%), holding AEDs (4.5%), or a combination (9.5%). Seizures occurred during 14 admissions. Treatment with AED polytherapy prior to admission and changing the patient's AED regimen during admission were associated with increased odds of seizures during admission (P = .0028; P = .0114). CONCLUSIONS: These results suggest that patients' home oral AED regimens should be continued when possible in order to minimize the frequency of seizures during hospitalizations.

The role of cEEG as a predictor of patient outcome and survival in patients with intraparenchymal hemorrhages.

PURPOSE: The objective of this study was to determine if continuous electroencephalography (cEEG) results are associated with functional outcome and survival in critically ill patients with intraparenchymal hemorrhages (IPH). METHODS: Patients diagnosed with IPH were selected using a Critical Care EEG Monitoring Consortium Database at Brigham and Women's Hospital in Boston. Functional Outcome in Patients with Primary Intracerebral Hemorrhage (FUNC) scores and Intracerebral Hemorrhage (ICH) scores were calculated as covariates. Outcomes of interest were functional outcome (modified Rankin scale [mRS] <3 vs ≥3) and mortality at hospital discharge. cEEG features, as defined by the American Clinical Neurophysiology Society standard terminology, were assessed for association with outcome after accounting for known clinical covariates. RESULTS: A total of 94 patients admitted between March 2013 and December 2015 were selected. Multivariate regression analysis revealed that the presence of Stage II Sleep is independently associated with good functional outcome at discharge after correcting for FUNC (p = 0.0080) and ICH (p = 0.0088). The absence of anteroposterior (AP) gradient in an EEG is associated with increased likelihood of mortality at discharge after correcting for FUNC (p = 0.013) and ICH (p = 0.019) scores. CONCLUSIONS: cEEG measures were significantly associated with functional and mortality outcome measures in patients with IPH even after accounting for known clinical and radiological covariates. Further research is needed to determine whether prediction models are improved by inclusion of cEEG features.

Administrative billing codes accurately identified occurrence of electrical cardioversion and ablation/maze procedures in a prospective cohort study of atrial fibrillation patients.

BACKGROUND: Administrative billing codes for electrical cardioversion and ablation/maze procedures may be useful for atrial fibrillation (AF) research if the codes are accurate relative to medical record documentation. HYPOTHESIS: Administrative billing codes accurately identify occurrence of electrical cardioversion and ablation/maze procedures in AF patients. METHODS: We studied adults ages 30 to 84 who experienced new-onset AF between October 2001 and December 2004 in Group Health Cooperative (acquired by Kaiser Permanente in 2017), an integrated healthcare system in Washington state and northern Idaho. Using medical record review as the gold standard, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for 3 administrative billing codes for electrical cardioversion and 3 codes for AF ablation/maze procedures. RESULTS: Of 1953 study participants, during a mean (SD) of 1.5 (0.7) years of follow-up after AF onset, 470 (24%) experienced electrical cardioversion and 44 (2%) experienced ablation/maze procedures, according to medical record review. For electrical cardioversion, individual codes had 7.7% to 76.4% sensitivity, >99% specificity, 83.7% to 96.5% PPV, and 77.3% to 93.0% NPV. Considering any of 3 codes (code 1 or code 2 or code 3) improved sensitivity to 84.9%. For ablation/maze, individual codes had 18.2% to 47.7% sensitivity, >99% specificity, 66.7% to 95.5% PPV, and >98% NPV. Considering any of 3 codes improved sensitivity to 84.1%. CONCLUSIONS: Administrative billing data accurately identified electrical cardioversion and ablation/maze procedures and can be used instead of medical record review. Our findings apply to healthcare settings with available administrative billing databases.