Second antiseizure medication monotherapy in patients with adult-onset epilepsy: A register-based analysis.

OBJECTIVE: Revision of therapy is fundamental in epilepsy care, since only half of patients achieve seizure freedom and tolerate the first antiseizure medication (ASM). We studied the selection and retention of second antiseizure medication monotherapy in adults who discontinued treatment with one of the three most frequently prescribed first ASMs, and the impact of age or brain comorbidities. METHODS: Using Swedish national registers, we conducted a population-based, retrospective cohort study from 2007 to 2019 on patients age ≥ 30 at the epilepsy diagnosis that had switched to a second monotherapy after the three most common initial monotherapies (n = 7369). Retention rates (RR) were estimated via Kaplan-Meier. Discontinuation of the second monotherapy was defined as 12-month prescription gap or initiation of a third ASM. Analyses were stratified by sex, age, and presence of stroke or dementia. RESULTS: The three most commonly prescribed second ASMs were carbamazepine, levetiracetam, and lamotrigine. The 1-year retention rate was 63-76% in all patients. For groups with stroke or dementia, the maximal 1-year RRs were 77% and 87%, respectively. After five years, retention rates ranged from 12% to 39%. There were no major differences between ASMs, apart from in patients discontinuing carbamazepine, where lamotrigine had a superior retention compared to levetiracetam as second monotherapy. SIGNIFICANCE: The three most often prescribed second ASMs seem to be suitable treatment options according to present guidelines. The second ASMs' retention rates were initially high in all studied patient groups but dropped to approximately the expected proportion of second monotherapy responders over the next five years. This suggests that therapy revision could be expedited.

Antiseizure medication selection and retention for adult onset focal epilepsy in a Swedish health service region: A population-based cohort study.

OBJECTIVE: Historically, approximately half of those with newly diagnosed epilepsy have responded to and tolerated the first antiseizure medication (ASM), but there are few contemporary real-world data. Third-generation ASMs have improved tolerability and are increasingly used according to prescription data. We aimed to describe current ASM selection and retention in adult onset focal epilepsy in western Sweden. METHODS: A multicenter retrospective cohort study was performed at five public neurology care providers in western Sweden (nearly complete coverage in the area). We reviewed 2607 medical charts and included patients diagnosed with nongeneralized epilepsy after January 1, 2020 who had a seizure onset after age 25 years (presumed focal onset) and were started on ASM monotherapy. RESULTS: A total of 542 patients (median age at seizure onset = 68 years, interquartile range = 52-77) were included. Most patients received levetiracetam (62%) or lamotrigine (35%), with levetiracetam being more common among men and those with structural causes or short epilepsy duration. During follow-up (median = 471.5 days), 463 patients (85%) remained on the first ASM. Fifty-nine (18%) patients discontinued levetiracetam, and 18 (10%) ended treatment with lamotrigine (p = .010), most commonly because of side effects. In a multivariable Cox regression model, the discontinuation risk was higher for levetiracetam than lamotrigine (adjusted hazard ratio = 2.01, 95% confidence interval = 1.16-3.51). SIGNIFICANCE: Levetiracetam and lamotrigine were the dominating first ASMs for adult onset focal epilepsy in our region, indicating good awareness of problems with enzyme induction or teratogenicity of older drugs. The most striking finding is the high retention rates, perhaps reflecting a shift toward an older epilepsy population, higher tolerability of newer ASMs, or suboptimal follow-up. The finding that treatment retention differed among patients receiving levetiracetam and lamotrigine aligns with the recent SANAD II results. It suggests lamotrigine may be underutilized in our region and that education efforts are needed to ensure it is considered the first choice more often.

Potential for improved retention rate by personalized antiseizure medication selection: A register-based analysis.

OBJECTIVE: The first antiseizure medication (ASM) is ineffective or intolerable in 50% of epilepsy cases. Selection between more than 25 available ASMs is guided by epilepsy factors, but also age and comorbidities. Randomized evidence for particular patient subgroups is seldom available. We asked whether register data could be used for retention rate calculations based on demographics, comorbidities, and ASM history, and quantified the potential improvement in retention rates of the first ASM in several large epilepsy cohorts. We also describe retention rates in patients with epilepsy after traumatic brain injury and dementia, patient groups with little available evidence. METHODS: We used medical, demographic, and drug prescription data from epilepsy cohorts from comprehensive Swedish registers, containing 6380 observations. By analyzing 381 840 prescriptions, we studied retention rates of first- and second-line ASMs for patients with epilepsy in multiple sclerosis (MS), brain infection, dementia, traumatic brain injury, or stroke. The rank of retention rates of ASMs was validated by comparison to published randomized control trials. We identified the optimal stratification for each brain disease, and quantified the potential improvement if all patients had received the optimal ASM. RESULTS: Using optimal stratification for each brain disease, the potential improvement in retention rate (percentage points) was MS, 20%; brain infection, 21%; dementia, 14%; trauma, 21%; and stroke, 14%. In epilepsy after trauma, levetiracetam had the highest retention rate at 80% (95% confidence interval [CI] = 65-89), exceeding that of the most commonly prescribed ASM, carbamazepine (p = .04). In epilepsy after dementia, lamotrigine (77%, 95% CI = 68-84) and levetiracetam (74%, 95% CI = 68-79) had higher retention rates than carbamazepine (p = .006 and p = .01, respectively). SIGNIFICANCE: We conclude that personalized ASM selection could improve retention rates and that national registers have potential as big data sources for personalized medicine in epilepsy.

Emergency Department Chest Pain Patients With or Without Ongoing Pain: Characteristics, Outcome, and Diagnostic Value of the Electrocardiogram.

BACKGROUND: In emergency department (ED) chest pain patients, it is believed that the diagnostic accuracy of the electrocardiogram (ECG) for acute coronary syndrome (ACS) is higher during ongoing than abated chest pain. OBJECTIVES: We compared patient characteristics and the diagnostic performance of the ECG in ED patients presenting with ongoing, vs. abated, chest pain. METHODS: In total, 1132 unselected ED chest pain patients were analyzed. The patient characteristics and diagnostic accuracy for index visit ACS of the emergency physicians' interpretation of the ECG was compared in patients with and without ongoing chest pain. Logistic regression analysis was performed to control for possible confounders. RESULTS: Patients with abated chest pain (n = 508) were older, had more comorbidities, and had double the risk of index visit ACS (15%) and major adverse cardiac events (MACE) at 30 days (15.6%) compared with patients with ongoing pain (n = 631; ACS 7.3%, 30-day MACE 7.4%). Sensitivity of the ECG for ACS was 24% in patients with ongoing pain and 35% in those without, specificity was 97% in both groups, negative predictive value was 94% and 89%, respectively, and positive likelihood ratio 10.6 and 7.8, respectively. When the diagnostic performance was controlled for confounders, there was no significant difference between the groups. CONCLUSION: Our results indicate that ED chest pain patients with ongoing pain at arrival are younger, healthier, and have less ACS and 30-day MACE than patients with abated pain, but that there is no difference in the diagnostic accuracy of the ECG for ACS between the two groups.

Diagnostic Accuracy of History and Physical Examination for Predicting Major Adverse Cardiac Events Within 30 Days in Patients With Acute Chest Pain.

BACKGROUND: The cornerstones in the assessment of emergency department (ED) patients with suspected acute coronary syndrome (ACS) are patient history and physical examination, electrocardiogram, and cardiac troponins. Although there are several prior studies on this subject, they have in some cases produced inconsistent results. OBJECTIVE: The aim of this study was to evaluate the diagnostic and prognostic accuracy of elements of patient history and the physical examination in ED chest pain patients for predicting major adverse cardiac events (MACE) within 30 days. METHODS: This was a prospective observational study that included 1167 ED patients with nontraumatic chest pain. We collected clinical data during the initial ED assessment of the patients. Our primary outcome was 30-day MACE. RESULTS: Pain radiating to both arms increased the probability of 30-day MACE (positive likelihood ratio [LR+] 2.7), whereas episodic chest pain lasting seconds (LR+ 0.0) and >24 h (LR+ 0.1) markedly decreased the risk. In the physical examination, pulmonary rales (LR+ 3.0) increased the risk of 30-day MACE, while pain reproduced by palpation (LR+ 0.3) decreased the risk. Among cardiac risk factors, a history of diabetes (LR+ 3.0) and peripheral arterial disease (LR+ 2.7) were the most predictive factors. CONCLUSIONS: No clinical findings reliably ruled in 30-day MACE, whereas episodic chest pain lasting seconds and pain lasting more than 24 h markedly decreased the risk of 30-day MACE. Consequently, these two findings can be adjuncts in ruling out 30-day MACE.

The objective CORE score allows early rule out in acute chest pain patients.

OBJECTIVES: Chest pain is a common complaint in the emergency department (ED), and it is a challenge to identify low-risk chest pain patients eligible for early discharge. We aimed to develop a simple objective decision rule to exclude 30-day major adverse cardiac events (MACE) in ED chest pain patients. DESIGN: We analyzed prospectively included patients presenting with chest pain. Low risk patients were identified with the clinical objective rule-out evaluation (CORE). CORE was based on high sensitivity cardiac troponin T (hs-cTnT) tests at ED presentation (0 h) and 2 h later together with a simplified risk score consisting of four objective variables: age ≥65 years and a history of arterial disease, hypertension or diabetes. For the patient to be classified as low risk in the CORE rule, hs-cTnT had to be ≤14 ng/L both at 0 and 2 h, and the sum of the risk score had to be 0. The primary outcome was MACE within 30 days. RESULTS: Among the 751 patients in the final analysis, 90 (11.9%) had a MACE. CORE identified 248 (33%) of patients as low risk with a sensitivity of 98.9% (CI 93.1-99.9) and a negative predictive value of 99.6% (95% CI 97.4-100) for 30-day MACE. Adding the ED physician's interpretation of the ECG to CORE did not improve diagnostic performance. CONCLUSION: A simple objective decision rule (CORE) identified one-third of all patients as having a very low 30-day risk of MACE. These patients may potentially be discharged without additional investigations for acute coronary syndrome.

Orthogonal P-wave morphology is affected by intra-atrial pressures.

BACKGROUND: It has previously been shown that the morphology of the P-wave neither depends on atrial size in healthy subjects with physiologically enlarged atria nor on the physiological anatomical variation in transverse orientation of the left atrium. The present study aimed to investigate if different pressures in the left and right atrium are associated with different P-wave morphologies. METHODS: 38 patients with isolated, increased left atrial pressure, 51 patients with isolated, increased right atrial pressure and 76 patients with biatrially increased pressure were studied. All had undergone right heart catheterization and had 12-lead electrocardiographic recordings, which were transformed into vectorcardiograms for detailed P-wave morphology analysis. RESULTS: Normal P-wave morphology (type 1) was more common in patients with isolated increased pressure in the right atrium while abnormal P-wave morphology (type 2) was more common in the groups with increased left atrial pressure (P = 0.032). Moreover, patients with increased left atrial pressure, either isolated or in conjunction with increased right atrial pressure, had significantly more often a P-wave morphology with a positive deflection in the sagittal plane (P = 0.004). CONCLUSION: Isolated elevated right atrial pressure was associated with normal P-wave morphology while left-sided atrial pressure elevation, either isolated or in combination with right atrial pressure elevation, was associated with abnormal P-wave morphology.

Fracture epidemiology in male elite football players from 2001 to 2013: 'How long will this fracture keep me out?'.

BACKGROUND: Determining fracture risk and rehabilitation periods after specific fractures in professional football is essential for team planning. AIM: To identify fracture epidemiology and absences after different types of fractures in male professional football players. METHODS: 2439 players from 41 professional male teams in 10 countries were followed prospectively from 2001 to 2013. Team medical staff registered fractures, absences after fractures and player exposure. RESULTS: 364 fractures were recorded, with an incidence of 0.27/1000 h of exposure (95% CI 0.25 to 0.30). The incidence of traumatic fractures was 0.25 (0.22 to 0.27) and that of stress fractures was 0.03 (0.02 to 0.04). 45% of traumatic fractures and 86% of stress fractures affected the lower extremities. Absence after a fracture was 32 days (1-278) (median (range)), compared to that after a traumatic fracture of 30 days (1-278) and a stress fracture of 65 days (6-168) (p<0.001). Annual fracture incidence was stable during the study period (R(2)=0.051, b=-0.011 (95% CI -0.043 to 0.021)). Young players had a relative risk of 10.9 (3.3 to 35.6) of sustaining stress fractures compared to old players (p<0.01). The fracture incidence did not differ between individuals in different playing positions (p=0.10). SUMMARY: A male professional football team can expect 1 to 2 fractures per season. There are more traumatic fractures than stress fractures; while most fractures affect the lower extremities, stress fractures yield longer absences than traumatic fractures and young players have more stress fractures than old players. There is no difference in risk among players at different playing positions.

Cardiovascular risk factor assessment in late-onset seizures: A study protocol to assess the value of structured intervention.

OBJECTIVE: A growing body of evidence suggests patients with late-onset seizures are at an increased risk of stroke, but the potential for reducing cardiovascular morbidity through risk factor screening and management is unknown. We aim to determine whether individuals with new-onset unprovoked seizures after middle age should undergo vascular risk assessment. The long follow-up needed to assess stroke risk and the known benefit of vascular risk factor modification make a standard RCT logistically and ethically challenging. Instead, we propose and have developed a protocol for a cluster project assessing the effect of vascular risk factor screening in an intervention trial as well as a cohort study. METHODS: Participating neurology clinics will implement standard cardiovascular risk factor assessment into the routine evaluation for individuals aged ≥50 years attending their first specialized consultation after an unprovoked seizure, excluding those with progressive brain disease. The project has two interlinked components: a prospective single group trial, in which risk factor assessment is performed and subsequent management is followed for one year; and a register-based cohort study examining the long-term effects of the intervention on a system level by comparing patients attending initial consultations in the 2 years after start of the study, with patients seen in the four preceding years at the same clinics. ANALYSIS: The primary outcome of the intervention trial is the proportion of patients receiving subsequent pharmacological treatment. The primary outcome of the cohort study is the incidence of acute stroke in the Swedish Stroke Register. ETHICS AND DISSEMINATION: Swedish Ethical Review Authority approval (which is valid for 2 years only) will be sought when funding is obtained. The results will be disseminated through peer-reviewed scientific publications. REGISTRATION DETAILS: The study will be registered at clinicaltrials.gov. PLAIN LANGUAGE SUMMARY: A first seizure in a middle-aged or older person indicates a higher risk of stroke. It is not known whether investigating and treating blood pressure, blood cholesterol, or similar risk factors after a first seizure is an effective way to prevent stroke. A traditional clinical study would need too many patients and it would be unethical not to treat the control group. We have designed a study in which participating neurology departments change their practice to test and treat vascular risk factors. Patients are then compared to historic controls using registered data.

Adherence to anti-seizure medications in the Swedish Prospective Regional Epilepsy Database and Biobank for Individualized Clinical Treatment (PREDICT).

The aim of this study was to describe the extent of, and risk factors for, non-adherence to anti-seizure medications (ASMs) in adult people with epilepsy (PWE) in Sweden. A cross-sectional multi-centre study was performed of PWEs in western Sweden, with data from medical records, and a questionnaire filled in by the participants including self-reports on how often ASM doses had been forgotten during the past year. Participants were categorized into adherent if they forgot at 0-1 occasion, and non-adherent if they forgot at 2-10 or >10 occasions. Demographic and clinical factors were compared by Chi2- or Fisher's test and a logistic regression model was used to find risk factors for non-adherence. In the cohort of 416 PWE aged median 43, IQR 29-62 years, 398 patients were prescribed ASM treatment at inclusion, and 39 % (n = 154) were in the non-adherent group. Significant factors in the multivariable analysis were: younger age, seizure freedom the past year, valproate treatment and experiencing side effects. The rate of self-reported non-adherence was high, illustrating a need for continuous focus on fundamental aspects of epilepsy care. The identified risk factors could enable quality improvement projects and patient education to be directed to those at risk of non-adherence.

Prevalence and nature of patient-reported antiseizure medication side effects in a Swedish regional multi-center study.

PURPOSE: Side effects is one of the major clinical problems in epilepsy care. We assessed the prevalence of ASM side effects in participants in a large regional multicenter observational study in western Sweden and aimed to identify risk factors and inventory the nature of side effects with different ASM regimes. METHODS: Cross-sectional analysis of survey answers and clinical characteristics of 406 adult participants recruited to a regional observational study between December 2020 and March 2023. Half of the participants had been seizure free for one year. Second-generation or newer ASMs were the most common. RESULTS: A total of 164 (40 %, 95 %CI: 36-45) patients reported side effects. Patients reporting side effects were younger (median 41 vs 47 years, p = 0.015), had more frequently experienced a seizure in the last year (p = 0.02), and were more often on ASM polytherapy (p < 0.01). ASM polytherapy and age were significant risk factors in regression models, but the explanatory value was low. The most common side effect was tiredness followed by cognitive symptoms. CONCLUSIONS: Our findings show that side effects are still common in epilepsy care and suggests that unnecessary polypharmacy should be avoided. Apart from number or ASMs, predicting who will experience side effects is difficult and more research on individual vulnerability is needed.

Association Between Antiseizure Drug Monotherapy and Mortality for Patients With Poststroke Epilepsy.

Importance: There is little evidence to guide the choice of antiseizure medication (ASM) for patients with poststroke epilepsy. Theoretical concerns about detrimental effects of ASMs on survival exist. Enzyme-inducing drugs could interfere with secondary stroke prevention. The US Food and Drug Administration recently issued a safety announcement about the potential proarrhythmic properties of lamotrigine. Objective: To investigate whether mortality varies with specific ASMs among patients with poststroke epilepsy. Design, Setting, and Participants: A cohort study was conducted using individual-level data from linked registers on all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and subsequent onset of epilepsy before December 31, 2014. A total of 2577 patients receiving continuous ASM monotherapy were eligible for the study. Data were analyzed between May 27, 2019, and April 8, 2021. Exposures: The dispensed ASM (Anatomical Therapeutic Chemical code N03A) determined exposure status, and the first dispensation date marked the start of treatment. Main Outcomes and Measures: The primary outcome, all-cause death, was analyzed using Cox proportional hazards regression with carbamazepine as the reference. Cardiovascular death (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes I0-I99 as the underlying cause) was assessed using Fine-Gray competing risk regression models. Results: A total of 2577 patients (1400 men [54%]; median age, 78 years [IQR, 69-85 years]) were included. The adjusted hazard ratio of all-cause death compared with carbamazepine was 0.72 (95% CI, 0.60-0.86) for lamotrigine, 0.96 (95% CI, 0.80-1.15) for levetiracetam, 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.81-1.66) for oxcarbazepine. The adjusted hazard ratio of cardiovascular death compared with carbamazepine was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine. Conclusions and Relevance: This cohort study's findings suggest differences in survival between patients treated with different ASMs for poststroke epilepsy. Patients receiving lamotrigine monotherapy had significantly lower mortality compared with those receiving carbamazepine. The opposite applied to patients prescribed valproic acid, who had a higher risk of cardiovascular and all-cause death. Levetiracetam was associated with a reduced risk of cardiovascular death compared with carbamazepine, but there was no significant difference in overall mortality.

Quantitative proteomic analysis to identify differentially expressed proteins in patients with epilepsy.

There is a great need for biomarkers in epilepsy, particularly markers of epileptogenesis. A first seizure will lead to epilepsy in 20-45 % of cases, but biomarkers that can identify these individuals are missing. The purpose of this study was to identify potential biomarkers of epilepsy/epileptogenesis in a cohort of adults with new-onset seizures, using quantitative proteomic analysis. Plasma was collected from 55 adults with new-onset seizures and sufficient follow-up to identify epilepsy. After a follow up period of two years, 63.6 % of the cohort had a diagnosis of epilepsy, whereas 36.4 % of patients only had a single seizure. Plasma proteins were extracted and labelled with tandem mass tags, then analyzed using mass spectrometry approach. Proteins that were up- or downregulated by ≥20 % and with a p-value of <0.05 were considered as differentially expressed and were also annotated to their processes and pathways. Several proteins were differentially expressed in the epilepsy group compared to controls. A total of 1075 proteins were detected, out of which 41 proteins were found to be significantly dysregulated in epilepsy patients. Many of these have been identified in experimental studies of epilepogenesis. We report plasma proteome profiling in new-onset epilepsy in a pilot study with 55 individuals. The identified proteins could be involved in pathways associated with epileptogenesis. The results should be seen as hypothesis-generating and targeted, confirmatory studies are needed.

Brain injury markers in new-onset seizures in adults: A pilot study.

BACKGROUND: Biochemical markers of brain pathology could potentially contribute to diagnosis and prediction in epilepsy. We describe levels of five brain injury markers in adults with new-onset seizures, and assess group differences in patients with a single seizure, epilepsy, and poststroke epilepsy. METHODS: In this prospective observational study, adults with new-onset seizures were recruited at Sahlgrenska University Hospital, Sweden, and concentrations of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), microtubule-associated protein tau (tau), S100 calcium-binding protein (S100B), and neuron-specific enolase (NSE) were measured. Participants were categorized as epilepsy, poststroke epilepsy (PSE), or single seizure (no additional seizures). Patients were followed until a diagnosis of epilepsy or PSE, or for at least two years in single seizure cases. RESULTS: The cohort included 23 (37%) individuals with a single seizure, 24 (39%) with epilepsy, and 15 (24%) with PSE. The concentrations of S100B were higher in patients with epilepsy and PSE than in single seizures (p = 0.0023 and p = 0.0162, respectively). The concentrations of NfL were higher in patients with PSE than in single seizures (p=0.0027). After age-normalization, levels of S100B were higher in patients with epilepsy and levels of NfL were higher in patients with PSE (p = 0.0021 and p = 0.0180). CONCLUSION: Levels of S100B and NfL were higher in patients with epilepsy or PSE than patients with single seizures. Further studies are needed to investigate the biomarker potential of brain injury markers as predictors of epilepsy course or indicators of epileptogenesis.

Risk of stroke after new-onset seizures.

PURPOSE: Observational cohort studies have reported a potentially increased risk of stroke in patients with epileptic seizures. Whether late-onset seizures merit primary stroke prophylaxis is not known, and more information on stroke risk is needed for the planning of RCTs. We performed a case-control study based on Swedish national registers to quantify the risk of stroke after epileptic seizures. METHODS: Cases ≤100 years of age with a first-ever stroke 2001-2009 were identified through the Swedish Stroke Register, and stroke-free controls (matched for age and sex) were obtained from the Population Register. The National Patient Register provided information on diagnostic codes for seizures, epilepsy and comorbidities. 123 105 stroke cases and 250 506 controls were included. RESULTS: Epileptic seizures prior to index stroke date were detected in 1559 (1.27 %) cases and 1806 (0.72 %) controls, yielding an odds ratio (95 % confidence interval) for stroke of 1.77 (1.65-1.89). ORs were similar in men and women, but higher below the age of 75. An onset of seizures in the year preceding stroke date resulted in a higher risk for stroke (OR = 2.21, 95 % CI = 1.79-2.72) compared to when more than 5 years had passed since the first seizure (OR = 1.57, 95 % CI = 1.43-1.72). CONCLUSION: A history of epileptic seizures was associated with an increased risk of subsequent stroke. The risk seems to be particularly high in the first year following seizure diagnosis, which supports the notion that unexplained late-onset seizures may merit swift assessment of vascular risk profile. The nature of stroke prevention requires further study.

[Swedish emergency physicians can safely sedate patients with propofol prior to cardioversion]. / Akutläkardriven propofolsedering är säker vid elkonvertering.

Emergency Medicine became a full-fledged speciality in Sweden in 2015. This prospective study analyzed the safety and implementation of Emergency Physician-administered propofol to sedate patients with hemodynamically stable atrial fibrillation prior to cardioversion. During the first 1.5 years, 321 sedations were carried out at Lund's Emergency Department by Emergency Physicians or senior residents. In two cases, the oxygen saturation dipped below 90% before responding to simple measures. In 12 cases, the systolic blood pressure dipped below 90 mmHg, and in two cases patients were administered a push-dose pressor. No patient required hospitalization due to sedation-induced complications. The majority of eligible specialists and senior residents voluntarily participated in an Emergency Physician-driven certification process. This study demonstrates the safety and feasibility of a locally implemented process for Emergency Physician-driven procedural sedation.

Retention rate of first antiepileptic drug in poststroke epilepsy: A nationwide study.

PURPOSE: To describe the retention rates of first antiepileptic drugs (AEDs) in patients with poststroke epilepsy on a nationwide scale. METHODS: The Swedish Stroke Register, which has 94% coverage and high-resolution data on stroke, comorbidities, and disability, was cross-referenced to the National Patient Register, Drug Register, and Cause-of-Death Register. Patients with onset of AED-treated epilepsy after stroke in 2005-2010 were included. An algorithm based on prescription renewal intervals was used to analyze treatment data until the end of 2014. RESULTS: A total of 4991 patients were included. First AEDs analyzed were carbamazepine (n = 2373), valproic acid (n = 943), levetiracetam (n = 555), lamotrigine (n = 519), phenytoin (n = 176), and oxcarbazepine (n = 89). The five-year retention rate was highest for lamotrigine (75%, 95%CI:70.4-79.4), followed by levetiracetam (69%, 95%CI:62.9-74.3), oxcarbazepine (68%, 95%CI:55.2-79.8), valproic acid (62%, 95%CI:57.8-66.4), carbamazepine (60%, 95%CI:57.6-62.4), and phenytoin (55%, 95%CI:45.2-64.0). There were minor differences in baseline characteristics with low levels of disability being slightly more common in patients treated with lamotrigine and levetiracetam. Atrial fibrillation and hypertension were more common in patients treated with levetiracetam, and atrial fibrillation was less common in patients treated with carbamazepine. In a Cox model adjusted for baseline characteristics, the risk of discontinuation was lower for lamotrigine (HR 0.53, 95%CI:0.43-0.67) and levetiracetam (HR 0.75, 95%CI:0.60-0.94) when compared to carbamazepine. CONCLUSIONS: Lamotrigine and levetiracetam have higher retention rates than carbamazepine in poststroke epilepsy. This is in agreement with existing small RCTs in this patient group.

Biomodulation of an implant for enhanced bone-implant anchorage.

Aseptic loosening of implants is the major cause for revision surgery. By modulating the bone-implant interface, early bone-implant anchorage could be improved. Implant surface manipulation by the addition of osteopromotive molecules locally and systemically to promote implant integration has been described with limited success. This study describes a novel approach by making the implant capable of biologically modulating its surroundings. It was hypothesized that the early implant fixation would improve by filling the interior of the implant with a carrier providing spatio-temporal release of bone active drugs with known osteogenic effect. The implant consisted of a threaded polyether ether ketone (PEEK) hollow chamber with holes at the bottom. The implant was filled with a calcium sulphate (CaS)/hydroxyapatite (HA) carrier, delivering two bone active molecules; zoledronic acid (ZA) and bone morphogenic protein-2 (BMP-2). At first, a rat abdominal muscle pouch model indicated a sustained in-vivo release of both 125I-rhBMP-2 (57%) and 14C-ZA (22%) from the CaS/HA carrier over a period of 4-weeks. The biomodulated implant was then inserted in the proximal tibia in rats with the following experimental groups: G1) Empty implant, G2) Implant + CaS/HA, G3) Implant + CaS/HA + ZA and G4) Implant + CaS/HA + ZA + rhBMP-2. Significantly higher bone volume (BV) was seen around the implant in groups G3 (3.3 ±â€¯0.7 mm3) and G4 (3.1 ±â€¯0.7 mm3) compared to the control (1.3 ±â€¯0.4 mm3) using micro-computed tomography and qualitative histology. Group G3, also exhibited significantly higher pull-out force and absorbed energy when compared to the control group G1. These findings indicate that a low dose of ZA alone, released in a controlled manner from within a fenestrated implant is enough to improve implant anchorage without the need of adding rhBMP-2. This simple method of using a fenestrated implant containing a ceramic carrier releasing bone active molecules improved bone anchorage and could clinically reduce prosthetic failure. STATEMENT OF SIGNIFICANCE: Aseptic loosening remains as a major cause for implant revisions and early reaction of surrounding bone to the prosthesis is important for longevity. A novel approach to enhance early bone-implant anchorage is presented. The implant is filled with a carrier providing controlled release of bone active molecules. In an animal model, a calcium sulphate (CaS)/hydroxyapatite (HA) carrier was used to provide a spatio-temporal release of bone morphogenic protein-2 (BMP-2) and zoledronic acid (ZA). Significantly better bone-implant integration was achieved using ZA alone, thereby eliminating the need for adding BMP-2. The developed method of implant biomodulation holds potential to prevent implant loosening and is an alternative to prosthetic coatings or systemic drug treatment. Importantly, all constituents are approved for clinical use.

Guided tissue engineering for healing of cancellous and cortical bone using a combination of biomaterial based scaffolding and local bone active molecule delivery.

A metaphyseal bone defect due to infection, tumor or fracture leads to loss of cancellous and cortical bone. An animal model separating the cancellous and cortical healing was used with a combination of a macroporous gelatin-calcium sulphate-hydroxyapatite (Gel-CaS-HA) biomaterial as a cancellous defect filler, and a thin collagen membrane (CM) guiding cortical bone regeneration. The membrane was immobilized with bone morphogenic protein-2 (rhBMP-2) to enhance the osteoinductive properties. The Gel-CaS-HA cancellous defect filler contained both rhBMP-2 and a bisphosphonate, (zoledronate = ZA) to prevent premature callus resorption induced by the pro-osteoclast effect of rhBMP-2 alone. In the first part of the study, the CM delivering both rhBMP-2 and ZA was tested in a muscle pouch model in rats and the co-delivery of rhBMP-2 and ZA via the CM resulted in higher amounts of bone compared to rhBMP-2 alone. Secondly, an established tibia defect model in rats was used to study cortical and cancellous bone regeneration. The defect was left empty, filled with Gel-CaS-HA alone, Gel-CaS-HA immobilized with ZA or Gel-CaS-HA immobilized with rhBMP-2+ZA. Functionalization of the Gel-CaS-HA scaffold with bioactive molecules produced significantly more bone in the cancellous defect and its surroundings but cortical defect healing was delayed likely due to the protrusion of the Gel-CaS-HA into the cortical bone. To guide cortical regeneration, the cortical defect was sealed endosteally by a CM with or without rhBMP-2. Subsequently, the cancellous defect was filled with Gel-CaS-HA containing ZA and rhBMP-2+ZA. In the groups where the CM was doped with rhBMP-2, significantly higher number of cortices bridged. The approach to guide cancellous as well as cortical bone regeneration separately in a metaphyseal defect using two bioactive molecule immobilized biomaterials is promising and could improve the clinical care of patients with metaphyseal defects.