Daniela Markovic

Randomized controlled trial of trigeminal nerve stimulation for drug-resistant epilepsy

Objective: To explore the safety and efficacy of external trigeminal nerve stimulation (eTNS) in patients with drug-resistant epilepsy (DRE) using a double-blind randomized controlled trial design, and to test the suitability of treatment and control parameters in preparation for a phase III multicenter clinical trial. Methods: This is a double-blind randomized active-control trial in DRE. Fifty subjects with 2 or more partial onset seizures per month (complex partial or tonic-clonic) entered a 6-week baseline period, and then were evaluated at 6, 12, and 18 weeks during the acute treatment period. Subjects were randomized to treatment (eTNS 120 Hz) or control (eTNS 2 Hz) parameters. Results: At entry, subjects were highly drug-resistant, averaging 8.7 seizures per month (treatment group) and 4.8 seizures per month (active controls). On average, subjects failed 3.35 antiepileptic drugs prior to enrollment, with an average duration of epilepsy of 21.5 years (treatment group) and 23.7 years (active control group), respectively. eTNS was well-tolerated. Side effects included anxiety (4%), headache (4%), and skin irritation (14%). The responder rate, defined as >50% reduction in seizure frequency, was 30.2% for the treatment group vs 21.1% for the active control group for the 18-week treatment period (not significant, p = 0.31, generalized estimating equation [GEE] model). The treatment group experienced a significant within-group improvement in responder rate over the 18-week treatment period (from 17.8% at 6 weeks to 40.5% at 18 weeks, p = 0.01, GEE). Subjects in the treatment group were more likely to respond than patients randomized to control (odds ratio 1.73, confidence interval 0.59–0.51). eTNS was associated with reductions in seizure frequency as measured by the response ratio (p = 0.04, analysis of variance [ANOVA]), and improvements in mood on the Beck Depression Inventory (p = 0.02, ANOVA). Conclusions: This study provides preliminary evidence that eTNS is safe and may be effective in subjects with DRE. Side effects were primarily limited to anxiety, headache, and skin irritation. These results will serve as a basis to inform and power a larger multicenter phase III clinical trial. Classification of evidence: This phase II study provides Class II evidence that trigeminal nerve stimulation may be safe and effective in reducing seizures in people with DRE.

Trigeminal nerve stimulation for epilepsy: long-term feasibility and efficacy.

Neurostimulation has emerged as a viable alternative for intractable epilepsy. Trigeminal nerve stimulation (TNS), a novel form of neurostimulation, has an antiepileptic effect in a rodent model.1 The superficial location of trigeminal branches allows for minimally invasive approaches, allowing assessment of response prior to a permanent device.2 We report the long-term safety and efficacy of external TNS for epilepsy. ### Methods. Research committee approval was obtained for an open study of external TNS in epilepsy. Informed consent was obtained before enrollment. Inclusion/exclusion criteria were age 18–65 years, ≥3 complex-partial/generalized tonic-clonic seizures/month, no progressive medical conditions, and exposure to ≥2 antiepileptic drugs (AEDs). Subjects enrolled in a 4-week pretreatment baseline, and were evaluated at 1, 2, 3, 6, and 12 months. AEDs remained unchanged unless essential for patient safety. Neurostimulation was initially supplied using the analog EMS Model 400, and later a digital EMS model 7500.2 Stimulation settings were as follows: frequency 120 Hz, 250 μs, ≤30 seconds on, ≤30 seconds off for 12–24 hours/day, and 1.25-inch disposable, silver-gel, adhesive electrodes were utilized, spaced 2 inches …

Predictive Index for Tumor Recurrence after Liver Transplantation for Locally Advanced Intrahepatic and Hilar Cholangiocarcinoma

BACKGROUND Current criteria for orthotopic liver transplantation (OLT) for cholangiocarcinoma (CCA) remain restricted to early stage and small hilar tumors, excluding patients with locally advanced intrahepatic and hilar CCA for potential cure. The present study was undertaken to define a prognostic scoring system for risk stratification of patients with intrahepatic and hilar CCA who might benefit from OLT and to allow expansion of current OLT criteria. STUDY DESIGN We conducted a retrospective review of 40 patients who underwent OLT for locally advanced intrahepatic and hilar CCA at our center between February 1985 and June 2010. Median follow-up was 3 years. Independent risk factors for tumor recurrence after OLT were identified using the Cox model and were assigned risk score points. Points were summed and assigned to predictive index categories: 0 to 3 for low risk, 4 to 7 for intermediate risk, and 8 to 15 for high risk. RESULTS Seven multivariate factors predictive for tumor recurrence included multifocal tumor, perineural invasion, infiltrative growth pattern, lack of neoadjuvant and adjuvant therapy, history of primary sclerosing cholangitis, hilar tumors, and lymphovascular invasion. The 5-year tumor recurrence-free patient survival was significantly higher in low-risk (78%) compared with intermediate- (19%) and high-risk (0%) groups (p < 0.001); survival benefit was also seen in intermediate- compared with high-risk groups. CONCLUSIONS This model was highly predictive of long-term outcomes after OLT for locally advanced intrahepatic and hilar CCA and can be applied clinically for risk stratification of patients considered for OLT. Long-term disease recurrence-free survival was excellent in low-risk and acceptable in intermediate-risk groups, justifying the expansion of liver transplant criteria for treatment of this challenging malignancy.

Impact of a healthy lifestyle on all-cause and cardiovascular mortality after stroke in the USA

Background Little is known about the effects of a healthy lifestyle on mortality after stroke. This study assessed whether five healthy lifestyle factors had independent and dose dependent associations with all-cause and cardiovascular mortality after stroke. Methods In a nationally representative sample of the US population (n=15 299) with previous stroke (n=649) followed from survey participation (1988–1994) through to mortality assessment (2000), the relationship between five factors (eating ≥5 servings of fruits/vegetables per day, exercising >12 times/month, having a body mass index of 18.5–29.9 mg/kg2, moderate alcohol use [1 drink/day for women and 2 drinks/day for men] and not smoking) and all-cause and cardiovascular mortality was assessed. Results Mean age was 67.0 years (SE 1.1 years) and 53% were women. After adjusting for covariates, abstaining from smoking (HR 0.57, CI 0.34 to 0.98) and exercising regularly (HR 0.66, CI 0.44 to 0.99) were associated with lower all-cause mortality but no individual factors had independent associations with cardiovascular mortality. All-cause mortality decreased with higher numbers of healthy behaviours (1–3 factors vs none: HR 0.12, CI 0.03 to 0.47; 4–5 factors vs none: HR 0.04, CI 0.01 to 0.20; 4–5 factors vs 1–3 factors: HR 0.38, CI 0.22 to 0.66; trend p=0.04). Similar effects were observed for cardiovascular mortality (4–5 factors vs none: HR 0.08, CI 0.01 to 0.66; 1–3 factors vs none: HR 0.15, CI 0.02 to 1.15; 4–5 factors vs 1–3 factors: HR 0.53, CI 0.28 to 0.98; trend p=0.18). Conclusions Regular exercise and abstinence from smoking were independently associated with lower all-cause mortality after stroke. Combinations of healthy lifestyle factors were associated with lower all-cause and cardiovascular mortality in a dose dependent fashion.

Complete pathologic response to pretransplant locoregional therapy for hepatocellular carcinoma defines cancer cure after liver transplantation: analysis of 501 consecutively treated patients.

OBJECTIVES To evaluate the rate, effect, and predictive factors of a complete pathologic response (cPR) in patients with hepatocellular carcinoma (HCC) undergoing locoregional therapy (LRT) before liver transplantation (LT). BACKGROUND Eligible patients with HCC receive equal model for end-stage liver disease prioritization, despite variable risks of tumor progression, waitlist dropout, and posttransplant recurrence. Pretransplant LRT mitigates these risks by inducing tumor necrosis. METHODS Comparisons were made among HCC recipients with cPR (n = 126) and without cPR (n = 375) receiving pre-LT LRT (1994-2013). Multivariable predictors of cPR were identified. RESULTS Of 501 patients, 272, 148, and 81 received 1, 2, and 3 or more LRT treatments. The overall, recurrence-free, and disease-specific survival at 1-, 3-, and 5 years was 86%, 71%, 63%; 84%, 67%, 60%; and 97%, 90%, 87%. Compared with recipients without cPR, cPR patients had significantly lower laboratory model for end-stage liver disease scores, pretransplant alpha fetoprotein, and cumulative tumor diameters; were more likely to have 1 lesion, tumors within Milan/University of California, San Francisco (UCSF) criteria, LRT that included ablation, and a favorable tumor response to LRT; and had superior 1-, 3-, and 5-year recurrence-free survival (92%, 79%, and 73% vs 81%, 63%, and 56%; P = 0.006) and disease-specific survival (100%, 100%, and 99% vs 96%, 89%, and 86%; P < 0.001) with only 1 cancer-specific death and fewer recurrences (2.4% vs 15.2%; P < 0.001). Multivariate predictors of cPR included a favorable post-LRT radiologic/alpha fetoprotein tumor response, longer time interval from LRT to LT, and lower model for end-stage liver disease score and maximum tumor diameter (C-statistic 0.75). CONCLUSIONS Achieving cPR in patients with HCC receiving LRT strongly predicts tumor-free survival. Factors predicting cPR are identified, allowing for differential prioritization of HCC recipients based on their variable risks of post-LT recurrence. Improving LRT strategies to maximize cPR would enhance posttransplant cancer outcomes.

Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy.

Trigeminal nerve stimulation (TNS) is a novel therapy for drug-resistant epilepsy. We report in detail the safety of external TNS (eTNS), focusing on acute and long-term heart rate and systolic and diastolic blood pressure in response to TNS from the pilot feasibility study. The data indicate that eTNS of the infraorbital and supraorbital branches of the trigeminal nerve is safe and well tolerated.

Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: A nationwide study

BACKGROUND Although the original homocysteine hypothesis for atherothrombotic disease is falling out of favor, prior studies did not comprehensively adjust for confounders or explore specific subgroups of patients who may benefit from serum homocysteine-lowering. We aimed to determine (1) if elevated total homocysteine (tHcy) affects odds of prevalent stroke after adjusting for a broad array of pertinent covariates and (2) whether particular vascular risk factors amplify the effect of high homocysteine on prevalent stroke. METHODS The independent and interactive effects of elevated tHcy (≥10 μmol/L) on likelihood of prevalent stroke was assessed in the National Health and Nutrition Examination Survey, a nationally representative cross-sectional sample of the US population conducted from 1999 to 2004 (n=12,683). RESULTS After adjusting for 17 covariates, those with elevated tHcy were more likely to have prevalent stroke vs. those without elevated tHcy (OR 1.52, 95% CI 1.01-2.29; p=0.045). Individuals with a combination of elevated tHcy and hypertension were substantially more likely to have prevalent stroke compared to individuals without either condition (OR 12.02, 95% CI 6.36-22.73 for men and OR 17.34, 95% CI 10.49-28.64 for women). The association of tHcy with prevalent stroke was strongest in younger individuals and declined linearly with increasing age. CONCLUSIONS Elevated tHcy independently increases odds of prevalent stroke. Younger individuals and those with concomitant hypertension may particularly benefit from tHcy-lowering.

Current National Patterns of Comorbid Diabetes among Acute Ischemic Stroke Patients

Background: Type 2 diabetes rates in the general population have risen with the growing obesity epidemic. Knowledge of temporal patterns and factors associated with comorbid diabetes among stroke patients may enable health practitioners and policy makers to develop interventions aimed at reducing diabetes rates, which may consequently lead to declines in stroke incidence and improvements in stroke outcomes. Methods: Using the Nationwide Inpatient Sample (NIS), a nationally representative data set of US hospital admissions, we assessed trends in the proportion of acute ischemic stroke (AIS) patients with comorbid diabetes from 1997 to 2006. Independent factors associated with comorbid diabetes were evaluated using multivariable logistic regression. Results: Over the study period, the absolute number of AIS hospitalizations declined by 17% (from 489,766 in 1997 to 408,378 in 2006); however, the absolute number of AIS hospitalizations with comorbid type 2 diabetes rose by 27% [from 97,577 (20%) in 1997 to 124,244 (30%) in 2006, p < 0.001]. The rise in comorbid diabetes over time was more pronounced in patients who were relatively younger, Black or ‘other’ race, on Medicaid, or admitted to hospitals located in the South. Factors independently associated with higher odds of diabetes in AIS patients were Black or ‘other’ versus White race, congestive heart failure, peripheral vascular disease, history of myocardial infarction, renal disease and hypertension. Conclusions: Although hospitalizations for AIS in the US decreased from 1997 to 2006, there was a steep rise in the proportion with comorbid diabetes (from 1 in 5 to almost 1 in 3). Specific patient populations may be potential targets for mitigating this trend.

National Gender-Specific Trends in Myocardial Infarction Hospitalization Rates Among Patients Aged 35 to 64 Years

In recent years, the prevalence of myocardial infarction (MI) has increased among women and decreased among men aged 35 to 54 years. To determine the extent to which changes in incidence account for recent variations in prevalence, we assessed the temporal trends in gender-specific hospitalization rates for MI. Using the Nationwide Inpatient Sample, we identified patients aged 35 to 64 years admitted to United States hospitals with a primary discharge diagnosis of MI from 1997 to 2006 (n = 2,824,615). The age-standardized MI hospitalization rates per 100,000 subjects were assessed for men and women aged 35 to 44, 45 to 54, and 55 to 64 years. The MI hospitalization rates per 100,000 subjects decreased by 26% from 168 to 126 for men and by 18% from 56 to 46 for women (both p <0.001). The reductions in the MI hospitalization rates were greatest among men aged 45 to 54, men aged 55 to 64, and women aged 55 to 64 years (standardized rates of change -3%, -4%, and -3% annually, p <0.001). The MI hospitalization rates decreased slightly for women aged 45 to 54 years and men aged 35 to 44 years (standardized rate of change -2% annually, p <0.001) and increased for women aged 35 to 44 years (standardized rate of change 2% annually, p = 0.008). In conclusion, from 1997 to 2006, men and women aged 35 to 64 years experienced an overall decrease in MI hospitalization rates; the reductions were more pronounced in men than in women. The slight increase in MI hospitalizations among women aged 35 to 44 years might have played a small role in the previously noted increases in MI prevalence among middle-age women.

Recent Age-and Gender-Specific Trends in Mortality during Stroke Hospitalization in the United States:

Background Advancements in diagnosis and treatment have resulted in better clinical outcomes after stroke; however, the influence of age and gender on recent trends in death during stroke hospitalization has not been specifically investigated. We assessed the impact of age and gender on nationwide patterns of in-hospital mortality after stroke. Methods Data were obtained from all US states that contributed to the Nationwide Inpatient Sample. All patients admitted to hospitals between 1997 and 1998 (n = 1 351 293) and 2005 and 2006 (n = 1 202 449), with a discharge diagnosis of stroke (identified by the International Classification of Diseases, Ninth Revision procedure codes), were included. Time trends for in-hospital mortality after stroke were evaluated by gender and age group based on 10-year age increments (<55, 55–64, 65–74, 75–84, >84) using multivariable logistic regression. Results Between 1997 and 2006, in-hospital mortality rates decreased across time in all sub-groups (all P < 0·01), except in men > 84 years. In unadjusted analysis, men aged > 84 years in 1997–1998 had poorer mortality outcomes than similarly aged women (odds ratio 0·93, 95% confidence interval = 0·88–0·98). This disparity worsened by 2005–2006 (odds ratio 0·88, 95% confidence interval = 0·84–0·93). After adjusting for confounders, compared with similarly aged women, the mortality outcomes among men aged >84 years were poorer in 1997–1998 (odds ratio 0·97, 95% confidence interval = 0·92–1·02) and were poorer in 2005–2006 (odds ratio 0·92, 95% confidence interval = 0·87–0·96), P = 0·04, for gender × time trend. Conclusions Over the last decade, in-hospital mortality rates after stroke in the United States have declined for every age/gender group, except men aged > 84 years. Given the rapidly ageing US population, avenues for boosting in-hospital survival among very elderly men with stroke need to be explored.