Development of an antiepileptogenesis drug screening platform: Effects of everolimus and phenobarbital.

OBJECTIVE: The kainic acid (KA)-induced status epilepticus (SE) model in rats is a well-defined model of epileptogenesis. This model closely recapitulates many of the clinical and pathological characteristics of human temporal lobe epilepsy (TLE) that arise following SE or another neurological insult. Spontaneous recurrent seizures (SRS) in TLE can present after a latent period following a neurological insult (traumatic brain injury, SE event, viral infection, etc.). Moreover, this model is suitable for preclinical studies to evaluate the long-term process of epileptogenesis and screen putative disease-modifying/antiepileptogenic agents. The burden of human TLE is highly variable, similar to the post-KA SE rat model. In this regard, this model may have broad translational relevance. This report thus details the pharmacological characterization and methodological refinement of a moderate-throughput drug screening program using the post-KA-induced SE model of epileptogenesis in male Sprague Dawley rats to identify potential agents that may prevent or modify the burden of SRS. Specifically, we sought to demonstrate whether our protocol could prevent the development of SRS or lead to a reduced frequency/severity of SRS. METHODS: Rats were administered either everolimus (2-3 mg/kg po) beginning 1, 2, or 24 h after SE onset, or phenobarbital (60 mg/kg ip) beginning 1 h after SE onset. All treatments were administered once/day for 5-7 days. Rats in all studies (n = 12/treatment dose/study) were then monitored intermittently by video-electroencephalography (2 weeks on, 2 weeks off, 2 weeks on epochs) to determine latency to onset of SRS and disease burden. RESULTS: Although no adverse side effects were observed in our studies, no treatment significantly modified disease or prevented the presentation of SRS by 6 weeks after SE onset. SIGNIFICANCE: Neither phenobarbital nor everolimus administered at several time points after SE onset prevented the development of SRS. Nonetheless, we demonstrate a practical and moderate-throughput screen for potential antiepileptogenic agents in a rat model of TLE.

A needs assessment of pediatric epilepsy surgery in Haiti.

OBJECTIVE: Epilepsy disproportionately affects low- and/or middle-income countries (LMICs). Surgical treatments for epilepsy are potentially curative and cost-effective and may improve quality of life and reduce social stigmas. In the current study, the authors estimate the potential need for a surgical epilepsy program in Haiti by applying contemporary epilepsy surgery referral guidelines to a population of children assessed at the Clinique d'Épilepsie de Port-au-Prince (CLIDEP). METHODS: The authors reviewed 812 pediatric patient records from the CLIDEP, the only pediatric epilepsy referral center in Haiti. Clinical covariates and seizure outcomes were extracted from digitized charts. Electroencephalography (EEG) and neuroimaging reports were further analyzed to determine the prevalence of focal epilepsy or surgically amenable syndromes and to assess the lesional causes of epilepsy in Haiti. Lastly, the toolsforepilepsy instrument was applied to determine the proportion of patients who met the criteria for epilepsy surgery referral. RESULTS: Two-thirds of the patients at CLIDEP (543/812) were determined to have epilepsy based on clinical and diagnostic evaluations. Most of them (82%, 444/543) had been evaluated with interictal EEG, 88% of whom (391/444) had abnormal findings. The most common finding was a unilateral focal abnormality (32%, 125/391). Neuroimaging, a prerequisite for applying the epilepsy surgery referral criteria, had been performed in only 58 patients in the entire CLIDEP cohort, 39 of whom were eventually diagnosed with epilepsy. Two-thirds (26/39) of those patients had abnormal findings on neuroimaging. Most patients (55%, 18/33) assessed with the toolsforepilepsy application met the criteria for epilepsy surgery referral. CONCLUSIONS: The authors' findings suggest that many children with epilepsy in Haiti could benefit from being evaluated at a center with the capacity to perform basic brain imaging and neurosurgical treatments.

Cost-Utility of Intermediate Obstetric Critical Care in a Resource-Limited Setting: A Value-Based Analysis.

Background: Sierra Leone faces among the highest maternal mortality rates worldwide. Despite this burden, the role of life-saving critical care interventions in low-resource settings remains scarcely explored. A value-based approach may be used to question whether it is sustainable and useful to start and run an obstetric intermediate critical care facility in a resource-poor referral hospital. We also aimed to investigate whether patient outcomes in terms of quality of life justified the allocated resources. Objective: To explore the value-based dimension performing a cost-utility analysis with regard to the implementation and one-year operation of the HDU. The primary endopoint was the quality-adjusted life-years (QALYs) of patients admitted to the HDU, against direct and indirect costs. Secondary endpoints included key procedures or treatments performed during the HDU stay. Methods: The study was conducted from October 2, 2017 to October 1, 2018 in the obstetric high dependency unit (HDU) of Princess Christian Maternity Hospital (PCMH) in Freetown, Sierra Leone. Findings: 523 patients (median age 25 years, IQR 21-30) were admitted to HDU. The total 1 year investment and operation costs for the HDU amounted to €120,082 - resulting in €230 of extra cost per admitted patient. The overall cost per QALY gained was of €10; this value is much lower than the WHO threshold defining high cost effectiveness of an intervention, i.e. three times the current Sierra Leone annual per capita GDP of €1416. Conclusion: With an additional cost per QALY of only €10.0, the implementation and one-year running of the case studied obstetric HDU can be considered a highly cost-effective frugal innovation in limited resource contexts. The evidences provided by this study allow a precise and novel insight to policy makers and clinicians useful to prioritize interventions in critical care and thus address maternal mortality in a high burden scenario.

Behavioural, electrocorticographic, and electromyographic alterations induced by Nerium oleander ethanolic extract: Anticonvulsant therapeutics assessment.

Nerium oleander Linn. is an Apocynaceae shrub which is among the most toxic ornamental plants. Although seizures are one of the symptoms associated with N. Oleander poisoning in humans, only a few studies are available on the behavioural and electrophysiological alterations caused by this plant poisoning. This study aimed at providing a thorough description of the electroencephalographic (EEG) and electromyographic (EMG) profiles throughout the experimental poisoning of Wistar rats (200-250 g) using ethanolic extract of N. oleander (EENO). Further, seizure control was assessed using different anticonvulsants. Male Wistar rat's behaviour was assessed upon EENO (150 mg/kg) administration and the animals were evaluated for muscle and neural activities through EMG and EEG recordings, respectively. The behavioural test showed two distinct phases of CNS activity: Phase I - myorelaxation and depression, and Phase II - excitability (agitated behaviour and seizures). Such phases were consistent with the EEG and EMG tracing patterns attained. Within the first 400 s of the recordings, during Phase I, the EMG showed no tracing amplitude variation. Later, the tracing pattern was changed and an intensification of the muscle contraction power in higher frequencies was observed during Phase II. The EEG showed initially a slight flattening in the tracings with a reduction in the intensity of the signal as per spectrogram of frequency attained. Thereafter, during Phase II, much higher amplitude tracings could be noted with an intensification of the signal, compatible with seizures. Seizure control was evaluated using four agents: phenytoin, phenobarbital, diazepam and scopolamine (at 10 mg/kg in all cases). While scopolamine was not effective in the seizure control, diazepam was the most efficient drug for the attenuation of the poisoning. Our results indicate the possibility of including phenytoin, phenobarbital and diazepam, mainly the latter, in the poisoning therapeutic protocol, including for those individuals who could be more susceptible to the poisoning by Nerium oleander as in the case of epileptic patients.

Effect of prophylactic treatment with levetiracetam on the incidence of postattenuation seizures in dogs undergoing surgical management of single congenital extrahepatic portosystemic shunts.

OBJECTIVE: To report the incidence of postattenuation seizures (PAS) in dogs that underwent single congenital extrahepatic portosystemic shunt (cEHPSS) attenuation and to compare incidence of PAS in dogs that either did or did not receive prophylactic treatment with levetiracetam (LEV). STUDY DESIGN: Multi-institutional retrospective study. POPULATION: Nine hundred forty dogs. METHODS: Medical records were reviewed to identify dogs that underwent surgical attenuation of a single cEHPSS from January 2005 through July 2017 and developed PAS within 7 days postoperatively. Dogs were divided into 3 groups: no LEV (LEV-); LEV at ≥15 mg/kg every 8 hours for ≥24 hours preoperatively or a 60 mg/kg intravenous loading dose perioperatively, followed by ≥15 mg/kg every 8 hours postoperatively (LEV1); and LEV at <15 mg/kg every 8 hours, for <24 hours preoperatively, or continued at <15 mg/kg every 8 hours postoperatively (LEV2). RESULTS: Seventy-five (8.0%) dogs developed PAS. Incidence of PAS was 35 of 523 (6.7%), 21 of 188 (11.2%), and 19 of 228 (8.3%) in groups LEV-, LEV1, and LEV2, respectively. This difference was not statistically significant (P = .14). No differences between groups of dogs that seized with respect to investigated variables were identified. CONCLUSION: The overall incidence of PAS was low (8%). Prophylactic treatment with LEV according to the protocols that were investigated in our study was not associated with a reduced incidence of PAS. CLINICAL SIGNIFICANCE: Prophylactic treatment with LEV does not afford protection against development of PAS. Surgically treated dogs should continue to be monitored closely during the first 7 days postoperatively for seizures.

Active Epilepsy and Seizure Control in Adults - United States, 2013 and 2015.

Approximately 3 million American adults reported active epilepsy* in 2015 (1). Active epilepsy, especially when seizures are uncontrolled, poses substantial burdens because of somatic, neurologic, and mental health comorbidity; cognitive and physical dysfunction; side effects of antiseizure medications; higher injury and mortality rates; poorer quality of life; and increased financial cost (2). Thus, prompt diagnosis and seizure control (i.e., seizure-free in the 12 months preceding the survey) confers numerous clinical and social advantages to persons with active epilepsy. To obtain recent and reliable estimates of active epilepsy and seizure control status in the U.S. population, CDC analyzed aggregated data from the 2013 and the 2015 National Health Interview Surveys (NHISs). Overall, an annual estimated 2.6 million (1.1%) U.S. adults self-reported having active epilepsy, 67% of whom had seen a neurologist or an epilepsy specialist in the past year, and 90% of whom reported taking epilepsy medication. Among those taking epilepsy medication, only 44% reported having their seizures controlled. A higher prevalence of active epilepsy and poorer seizure control were associated with low family income, unemployment, and being divorced, separated, or widowed. Use of epilepsy medication was higher among adults who saw an epilepsy specialist in the past year than among those who did not. Health care and public health should ensure that adults with uncontrolled seizures have appropriate care and self-management support in order to promote seizure control, improve health and social outcomes, and reduce health care costs.

Assessment of the Anticonvulsant Potency of Ursolic Acid in Seizure Threshold Tests in Mice.

Ursolic acid (UA) is a plant derived compound which is also a component of the standard human diet. It possesses a wide range of pharmacological properties, i.e., antioxidant, anti-inflammatory, antimicrobial and antitumor, which have been used in folk medicine for centuries. Moreover, influence of UA on central nervous system-related processes, i.e., pain, anxiety and depression, was proved in experimental studies. UA also revealed anticonvulsant properties in animal models of epilepsy and seizures. The aim of the present study was to investigate the influence of UA on seizure thresholds in three acute seizure models in mice, i.e., the 6 Hz-induced psychomotor seizure threshold test, the maximal electroshock threshold (MEST) test and the timed intravenous pentylenetetrazole (iv PTZ) infusion test. We also examined its effect on the muscular strength (assessed in the grip strength test) and motor coordination (estimated in the chimney test) in mice. UA at doses of 50 and 100 mg/kg significantly increased the seizure thresholds in the 6 Hz and MEST tests. The studied compound did not influence the seizure thresholds in the iv PTZ test. Moreover, UA did not affect the motor coordination and muscular strength in mice. UA displays only a weak anticonvulsant potential which is dependent on the used seizure model.

New-onset seizure during and after brain tumor excision: a risk assessment analysis.

OBJECTIVE Prophylactic use of antiepileptic drugs (AEDs) in seizure-naïve brain tumor patients remains a topic of debate. This study aimed to characterize a subset of patients at highest risk for new-onset perioperative seizures (i.e., intraoperative and postoperative seizures occurring within 30 days of surgery) who may benefit from prophylactic AEDs. METHODS The authors conducted a retrospective case-control study of all adults who had undergone tumor resection or biopsy at the authors' institution between January 1, 2004, and June 31, 2015. All patients with a history of preoperative seizures, posterior fossa tumors, pituitary tumors, and parasellar tumors were excluded. A control group was matched to the seizure patients according to age (± 0 years). Demographic data, clinical status, operative data, and postoperative course data were collected and analyzed. RESULTS Among 1693 patients who underwent tumor resection or biopsy, 549 (32.4%) had never had a preoperative seizure. Of these 549 patients, 25 (4.6%) suffered a perioperative seizure (Group 1). A total of 524 patients (95.4%) who remained seizure free were matched to Group 1 according to age (± 0 years), resulting in 132 control patients (Group 2), at an approximate ratio of 1:5. There were no differences between the patient groups in terms of age, sex, race, relationship status, and neurological deficits on presentation. Histological subtype (infiltrating glioma vs meningioma vs other, p = 0.041), intradural tumor location (p < 0.001), intraoperative cortical stimulation (p = 0.004), and extent of resection (less than gross total, p = 0.002) were associated with the occurrence of perioperative seizures. CONCLUSIONS While most seizure-naïve brain tumor patients do not benefit from perioperative seizure prophylaxis, such treatment should be considered in high-risk patients with supratentorial intradural tumors, in patients undergoing intraoperative cortical stimulation, and in patients in whom subtotal resection is likely.

Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour.

BACKGROUND: Cardiotocography (CTG) records changes in the fetal heart rate and their temporal relationship to uterine contractions. The aim is to identify babies who may be short of oxygen (hypoxic) to guide additional assessments of fetal wellbeing, or determine if the baby needs to be delivered by caesarean section or instrumental vaginal birth. This is an update of a review previously published in 2013, 2006 and 2001. OBJECTIVES: To evaluate the effectiveness and safety of continuous cardiotocography when used as a method to monitor fetal wellbeing during labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 November 2016) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving a comparison of continuous cardiotocography (with and without fetal blood sampling) with no fetal monitoring, intermittent auscultation intermittent cardiotocography. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, quality and extracted data from included studies. Data were checked for accuracy. MAIN RESULTS: We included 13 trials involving over 37,000 women. No new studies were included in this update.One trial (4044 women) compared continuous CTG with intermittent CTG, all other trials compared continuous CTG with intermittent auscultation. No data were found comparing no fetal monitoring with continuous CTG. Overall, methodological quality was mixed. All included studies were at high risk of performance bias, unclear or high risk of detection bias, and unclear risk of reporting bias. Only two trials were assessed at high methodological quality.Compared with intermittent auscultation, continuous cardiotocography showed no significant improvement in overall perinatal death rate (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.59 to 1.23, N = 33,513, 11 trials, low quality evidence), but was associated with halving neonatal seizure rates (RR 0.50, 95% CI 0.31 to 0.80, N = 32,386, 9 trials, moderate quality evidence). There was no difference in cerebral palsy rates (RR 1.75, 95% CI 0.84 to 3.63, N = 13,252, 2 trials, low quality evidence). There was an increase in caesarean sections associated with continuous CTG (RR 1.63, 95% CI 1.29 to 2.07, N = 18,861, 11 trials, low quality evidence). Women were also more likely to have instrumental vaginal births (RR 1.15, 95% CI 1.01 to 1.33, N = 18,615, 10 trials, low quality evidence). There was no difference in the incidence of cord blood acidosis (RR 0.92, 95% CI 0.27 to 3.11, N = 2494, 2 trials, very low quality evidence) or use of any pharmacological analgesia (RR 0.98, 95% CI 0.88 to 1.09, N = 1677, 3 trials, low quality evidence).Compared with intermittent CTG, continuous CTG made no difference to caesarean section rates (RR 1.29, 95% CI 0.84 to 1.97, N = 4044, 1 trial) or instrumental births (RR 1.16, 95% CI 0.92 to 1.46, N = 4044, 1 trial). Less cord blood acidosis was observed in women who had intermittent CTG, however, this result could have been due to chance (RR 1.43, 95% CI 0.95 to 2.14, N = 4044, 1 trial).Data for low risk, high risk, preterm pregnancy and high-quality trials subgroups were consistent with overall results. Access to fetal blood sampling did not appear to influence differences in neonatal seizures or other outcomes.Evidence was assessed using GRADE. Most outcomes were graded as low quality evidence (rates of perinatal death, cerebral palsy, caesarean section, instrumental vaginal births, and any pharmacological analgesia), and downgraded for limitations in design, inconsistency and imprecision of results. The remaining outcomes were downgraded to moderate quality (neonatal seizures) and very low quality (cord blood acidosis) due to similar concerns over limitations in design, inconsistency and imprecision. AUTHORS' CONCLUSIONS: CTG during labour is associated with reduced rates of neonatal seizures, but no clear differences in cerebral palsy, infant mortality or other standard measures of neonatal wellbeing. However, continuous CTG was associated with an increase in caesarean sections and instrumental vaginal births. The challenge is how best to convey these results to women to enable them to make an informed decision without compromising the normality of labour.The question remains as to whether future randomised trials should measure efficacy (the intrinsic value of continuous CTG in trying to prevent adverse neonatal outcomes under optimal clinical conditions) or effectiveness (the effect of this technique in routine clinical practice).Along with the need for further investigations into long-term effects of operative births for women and babies, much remains to be learned about the causation and possible links between antenatal or intrapartum events, neonatal seizures and long-term neurodevelopmental outcomes, whilst considering changes in clinical practice over the intervening years (one-to-one-support during labour, caesarean section rates). The large number of babies randomised to the trials in this review have now reached adulthood and could potentially provide a unique opportunity to clarify if a reduction in neonatal seizures is something inconsequential that should not greatly influence women's and clinicians' choices, or if seizure reduction leads to long-term benefits for babies. Defining meaningful neurological and behavioural outcomes that could be measured in large cohorts of young adults poses huge challenges. However, it is important to collect data from these women and babies while medical records still exist, where possible describe women's mobility and positions during labour and birth, and clarify if these might impact on outcomes. Research should also address the possible contribution of the supine position to adverse outcomes for babies, and assess whether the use of mobility and positions can further reduce the low incidence of neonatal seizures and improve psychological outcomes for women.

Assessment of luteolin isolated from Eclipta alba leaves in animal models of epilepsy.

CONTEXT: Eclipta alba (Linn) Hassk. (Asteraceae) has been reported to be a nerve tonic and has been used to treat epilepsy in folk medicine. OBJECTIVE: The present study isolates and characterizes luteolin from E. alba and evaluates its antiepileptic potential in chemically induced acute and chronic models in mice. MATERIALS AND METHODS: The methanol extract (16.85% w/w) of E. alba leaves was subjected to fractionation for isolation of luteolin. In acute pentylenetetrazole (PTZ) model, luteolin (5, 10, 20 mg/kg, i.p.) was administered 30 min prior to PTZ injection (100 mg/kg) in Swiss albino mice. Kindling was induced by chronic administration of PTZ (35 mg/kg) on every alternate day (48 days). Luteolin was investigated on the course of kindling development and oxidative stress markers [reduced glutathione (GSH) and malondialdehyde (MDA)] in kindled mice. RESULTS: Single-dose pretreatment with luteolin (10 and 20 mg/kg, i.p.) was found to be effective in an acute PTZ model (100% protection from mortality) and it did not exhibit any effect on motor coordination at the same doses. PTZ-induced kindling was significantly (p < 0.001) prevented by luteolin (5, 10, 20 mg/kg, i.p.) in a dose-dependent manner. Luteolin restored levels of reduced GSH (p < 0.001) and decreased the level of MDA (p < 0.001), a marker of lipid peroxidation. DISCUSSION AND CONCLUSION: The results of the present study demonstrated that luteolin had an anticonvulsant effect in an acute PTZ model. Luteolin exhibited and inhibitory effect on the course of kindling and associated oxidative stress and hence could be a potential molecule in the treatment of epilepsy.

Switching generic antiepileptic drug manufacturer not linked to seizures: A case-crossover study.

OBJECTIVE: With more antiepileptic drugs (AED) becoming available in generic form, we estimated the risk of seizure-related events associated with refilling generic AEDs and the effect of switching between different manufacturers of the same generic drug. METHODS: We designed a population-based case-crossover study using the Medicaid Analytic eXtract and a US commercial health insurance database. We identified 83,001 generic AED users who experienced a seizure-related hospital admission or emergency room visit between 2000 and 2013 and assessed whether they received a refill of the same AED from the same manufacturer or a different manufacturer. Patients served as their own controls and conditional logistic regression was used to compare exposure to a refill during the hazard period, defined as days 2-36 preceding the seizure-related event, to exposure during the control period, defined as days 51-85 preceding the seizure-related event. RESULTS: Generic AED refilling was associated with an 8% increase in the odds of seizure-related events (odds ratio [OR] 1.08; 95% confidence interval [CI] 1.06-1.11). The OR following a switch to a different manufacturer of the same AED was 1.09 (95% CI 1.03-1.15); however, after adjusting for the process of refilling, there was no association between switching and seizure-related hospital visits (OR 1.00; 95% CI 0.94-1.07). CONCLUSIONS: Among patients on a generic AED, refilling the same AED was associated with an elevated risk of seizure-related event; however, there was no additional risk from switching during that refill to a different manufacturer. Generic AEDs available to US patients, with Food and Drug Administration-validated bioequivalence, appear to be safe clinical choices.

Variation in Anticonvulsant Selection and Electroencephalographic Monitoring Following Severe Traumatic Brain Injury in Children-Understanding Resource Availability in Sites Participating in a Comparative Effectiveness Study.

OBJECTIVES: Early posttraumatic seizures may contribute to worsened outcomes after traumatic brain injury. Evidence to guide the evaluation and management of early posttraumatic seizures in children is limited. We undertook a survey of current practices of continuous electroencephalographic monitoring, seizure prophylaxis, and the management of early posttraumatic seizures to provide essential information for trial design and the development of posttraumatic seizure management pathways. DESIGN: Surveys were sent to site principal investigators at all 43 sites participating in the Approaches and Decisions in Acute Pediatric TBI trial at the time of the survey. Surveys consisted of 12 questions addressing strategies to 1) implement continuous electroencephalographic monitoring, 2) posttraumatic seizure prophylaxis, 3) treat acute posttraumatic seizures, 4) treat status epilepticus and refractory status epilepticus, and 5) monitor antiseizure drug levels. SETTING: Institutions comprised a mixture of free-standing children's hospitals and university medical centers across the United States and Europe. SUBJECTS: Site principal investigators of the Approaches and Decisions in Acute Pediatric TBI trial. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Continuous electroencephalographic monitoring was available in the PICU in the overwhelming majority of clinical sites (98%); however, the plans to operationalize such monitoring for children varied considerably. A similar majority of sites report that administration of prophylactic antiseizure medications is anticipated in children (93%); yet, a minority reports that a specified protocol for treatment of posttraumatic seizures is in place (43%). Reported medication choices varied substantially between sites, but the majority of sites reported pentobarbital for refractory status epilepticus (81%). The presence of treatment protocols for seizure prophylaxis, early posttraumatic seizures, posttraumatic status epilepticus, and refractory status epilepticus was associated with decreased reported medications (all p < 0.05). CONCLUSIONS: This study reports the current management practices for early posttraumatic seizures in select academic centers after pediatric severe traumatic brain injury. The substantial variation in continuous electroencephalographic monitoring implementation, choice of seizure prophylaxis medications, and management of early posttraumatic seizures across institutions was reported, signifying the areas of clinical uncertainty that will help provide focused design of clinical trials. Although sites with treatment protocols reported a decreased number of medications for the scenarios described, completion of the Approaches and Decisions in Acute Pediatric TBI trial will be able to determine if these protocols lead to decreased variability in medication administration in children at the clinical sites.

Assessment of the Combined Treatment with Umbelliferone and Four Classical Antiepileptic Drugs Against Maximal Electroshock-Induced Seizures in Mice.

BACKGROUND/AIMS: The aim of this study was to determine the effects of umbelliferone (7-hydroxycoumarin; UMB) on the anticonvulsant potency of four classical antiepileptic drugs (carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB) and valproate (VPA)) in the mouse maximal electroshock-induced seizure (MES) model. RESULTS: UMB administered systemically intraperitoneally (ip) in a dose of 150 mg/kg significantly elevated the threshold for maximal electroconvulsions (p < 0.05) in mice. Moreover, UMB (150 mg/kg) co-administered with PB and VPA significantly enhanced the anticonvulsant potency of these drugs by reducing their median effective doses (ED50 values) from 35.39 to 21.78 mg/kg (p < 0.01) for PB, and from 281.4 to 215.5 mg/kg (p < 0.01) for VPA. In contrast, UMB (150 mg/kg, ip) had no significant effect on the antiseizure activity of CBZ and PHT in the mouse MES model. Neither total brain PB, nor total brain VPA concentrations were altered after ip administration of UMB, indicating a pharmacodynamic nature of interactions between the tested drugs. CONCLUSIONS: The selective potentiation of the anticonvulsant potency of PB and VPA by UMB, and lack of any pharmacokinetic interactions between drugs, make the combinations of UMB with PB or VPA worthy of consideration for epileptic patients who are refractory to standard antiepileptic treatment.

[ZONISAMIDE: FIRST CHOICE AMONG THE FIRST-LINE ANTIEPILEPTIC DRUGS IN FOCAL EPILEPSY]. / ZONISAMID: AZ ELSOKÉNT VÁLASZTANDÓ ANTIEPILEPTIKUMOK KÖZÖTT FOKÁLIS EPILEPSZIÁBAN.

Chronic administration of antiepileptic drugs without history of unprovoked epileptic seizures are not recommended for epilepsy prophylaxis. Conversely, if the patient suffered the first unprovoked seizure, then the presence of epileptiform discharges on the EEG, focal neurological signs, and the presence of epileptogenic lesion on the MRI are risk factors for a second seizure (such as for the development of epilepsy). Without these risk factors, the chance of a second seizure is about 25-30%, while the presence of these risk factors (for example signs of previous stroke, neurotrauma, or encephalitis on the MRI) can predict >70% seizure recurrence. Thus the International League Against Epilepsy (ILAE) re-defined the term 'epilepsy' which can be diagnosed even after the first seizure, if the risk of seizure recurrence is high. According to this definition, we can start antiepileptic drug therapy after a single unprovoked seizure. There are four antiepileptic drugs which has the highest evidence (level "A") as first-line initial monotherapy for treating newly diagnosed epilepsy. These are: carbamazepine, phenytoin, levetiracetam, and zonisamide (ZNS). The present review focuses on the ZNS. Beacuse ZNS can be administrated once a day, it is an optimal drug for maintaining patient's compliance and for those patients who have a high risk for developing a non-compliance (for example teenagers and young adults). Due to the low interaction potential, ZNS treatment is safe and effective in treating epilepsy of elderly people. ZNS is an ideal drug in epilepsy accompanied by obesity, because ZNS has a weight loss effect, especially in obese patients.

Surgical versus medical treatment for refractory epilepsy: outcomes beyond seizure control.

Nearly one third of patients with epilepsy become medically intractable, and the likelihood of achieving seizure freedom decreases with each additional medication trial. For appropriately chosen patients, epilepsy surgery affords the opportunity to achieve seizure freedom and potentially wean off medications. Epilepsy surgery, as with medical management, is not without adverse effects; to counsel patients wisely, practitioners need to understand the advantages and disadvantages of both. Randomized controlled trials in temporal lobe epilepsy reveal that epilepsy surgery achieves superior outcome compared to continued medical management. Although seizure freedom is the ultimate goal of any therapy, it represents a single outcome measure among a variety of other domains that affect patient welfare. It is imperative that providers understand the patient variables that affect these outcome measures and how these measures impact each other. Because the data comparing surgical therapy versus medical management for refractory epilepsy are limited, we review the available evidence comparing outcomes beyond seizure freedom including quality of life, cognition, psychosocial function, mortality, and financial costs.

Continuous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labour.

BACKGROUND: Cardiotocography (known also as electronic fetal monitoring), records changes in the fetal heart rate and their temporal relationship to uterine contractions. The aim is to identify babies who may be short of oxygen (hypoxic), so additional assessments of fetal well-being may be used, or the baby delivered by caesarean section or instrumental vaginal birth. OBJECTIVES: To evaluate the effectiveness of continuous cardiotocography during labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 December 2012) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials involving a comparison of continuous cardiotocography (with and without fetal blood sampling) with (a) no fetal monitoring, (b) intermittent auscultation (c) intermittent cardiotocography. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, quality and extracted data from included studies. MAIN RESULTS: Thirteen trials were included with over 37,000 women; only two were judged to be of high quality.Compared with intermittent auscultation, continuous cardiotocography showed no significant improvement in overall perinatal death rate (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.59 to 1.23, n = 33,513, 11 trials), but was associated with a halving of neonatal seizures (RR 0.50, 95% CI 0.31 to 0.80, n = 32,386, nine trials). There was no significant difference in cerebral palsy rates (RR 1.75, 95% CI 0.84 to 3.63, n = 13,252, two trials). There was a significant increase in caesarean sections associated with continuous cardiotocography (RR 1.63, 95% CI 1.29 to 2.07, n = 18,861, 11 trials). Women were also more likely to have an instrumental vaginal birth (RR 1.15, 95% CI 1.01 to 1.33, n = 18,615, 10 trials).Data for subgroups of low-risk, high-risk, preterm pregnancies and high-quality trials were consistent with overall results. Access to fetal blood sampling did not appear to influence the difference in neonatal seizures nor any other prespecified outcome. AUTHORS' CONCLUSIONS: Continuous cardiotocography during labour is associated with a reduction in neonatal seizures, but no significant differences in cerebral palsy, infant mortality or other standard measures of neonatal well-being. However, continuous cardiotocography was associated with an increase in caesarean sections and instrumental vaginal births. The challenge is how best to convey these results to women to enable them to make an informed choice without compromising the normality of labour.

Survey of prophylactic antiseizure drug use for non-traumatic intracerebral hemorrhage.

OBJECTIVE: Prophylactic antiseizure drugs (PAD) are commonly prescribed for non-traumatic intracerebral hemorrhage (ICH) despite limited evidence for this indication. We sought to determine the current prescribing patterns of the use of a PAD for ICH. METHODS: A 36-item survey was distributed to physicians who manage ICH patients soliciting details of PAD prescription in their practice. RESULTS: A total of 199 physicians responded to the survey, all of who manage 50 or more ICH patients per year. The respondents were neurologists (32%), neurosurgeons (11%), and intensivists (57%) in academia (69%) and private practice (31%). Prophylactic antiseizure drugs prescriptions used: never (33%), 1-33% (35%), 34-66% (14%), 67-99% (9%) of the time, or always (9%). Most respondents performed electroencephalographic and serum level monitoring in at least some patients. Levetiracetam was used most often (60%), followed by fosphenytoin (37%), for a usual duration of days (36%), weeks (47%), or months (17%). Prophylactic antiseizure drugs prescription varied by patient characteristics and physician specialty. Perception of physician community consensus regarding PAD use for ICH among respondents ranged from strongly (7%) or weakly (23%) against the practice, to a fairly equal division of opinion (41%), to weakly (27%) or strongly (4%) in favor of the practice. CONCLUSIONS: We found variability of multiple aspects of the current prescribing patterns and opinions regarding the use of a PAD for ICH. This variability is likely secondary to insufficient data. Clinical equipoise exists for this issue, and controlled trials would be both justified and useful.

Dalfampridine prior authorization program: a cohort study.

BACKGROUND: Dalfampridine (Ampyra) is indicated to improve walking in patients with multiple sclerosis (MS) and was found to be effective in 35%-43% of individuals with MS in clinical trials. Dalfampridine may increase seizure risk, particularly in patients with renal impairment. A U.S. managed care expert consensus panel agreed that patient access to dalfampridine is best managed by a prior authorization (PA) in accordance with the FDA-approved labeling. To ensure safe and appropriate dalfampridine use, a health plan developed and implemented a 2-phase point-of-sale PA program. OBJECTIVES: To evaluate dalfampridine PA review decisions, utilization, and pharmacy expenditures following the implementation of a dalfampridine safety and clinical PA program compared with a group of dalfampridine utilizers unexposed to a PA program. METHODS: The study utilized retrospective administrative pharmacy claims data from a commercial health plan averaging 1.3 million members per month. The plan implemented a 2-phase dalfampridine safety and effectiveness PA program on August 1, 2010. A comparison group that did not implement the dalfampridine PA program was identified from a commercially insured population with approximately 350,000 members per month. Members in both groups were required to be continuously enrolled from August 1, 2010, through January 31, 2011. A member's earliest paid or rejected claim found from August 1, 2010, through October 31, 2010, was defined as the index claim. Dalfampridine-weighted 30-day supply claims were summed and compared between groups from index date through January 31, 2011. A pharmacy cost avoidance estimate was calculated using the difference in average claims per member from index claim through January 31, 2011, multiplied by dalfampridine wholesale acquisition cost. Overall, dalfampridine utilization was evaluated between the intervention and comparison populations from August 2010 (implementation of PA in intervention group) through December 2011. Linear regression and Poisson models were used to test the trend differences. RESULTS: The 60 PA-exposed dalfampridine members' average follow-up was 157 days. Phase 1 approval was obtained by 32 (53.3%) members; 4 (6.7%) members received a denial because of renal impairment; 8 (13.3%) members received a denial due to inability to obtain walking time; 1 (1.7%) member with relapse-remitting MS was denied a PA due to no concomitant disease-modifying agent; and 15 (25.0%) members did not initiate the PA process. Phase 2 approval was obtained by 23 (38.3%) of the 60 members. The 60 PA members had a total of 126 claims and an average utilization of 2.1 (SD 1.8) claims per member. The 20 non-PA dalfampridine members' average follow-up was 157 days. The comparison group members had a total of 84 claims and an average utilization of 4.2 (SD 2.0) claims per member. The PA program resulted in an average of 2.1 (P less than 0.001) fewer claims per member in the PA group. The total dalfampridine cost avoidance estimate was $143,010 or $0.03 per member per month. The overall measure of a monthly claims utilization difference over time was statistically significantly different at P less than 0.001, using the linear regression slope trend test. The trend line slope was not statistically significantly different, P = 0.841, between the intervention and comparison populations. CONCLUSIONS: The study indicates that a dalfampridine PA program potentially improved safety and minimized dalfampridine costs. A PA program is effective in selecting appropriate utilizers for initial therapy. Addition of care management may further optimize use by encouraging adherence and tracking patient response.

Uninformed clinical decisions resulting from lack of adherence assessment in children with new-onset epilepsy.

This study examined the relationship between nonadherence to antiepileptic drug (AED) therapy and clinical decision making in a cohort of 112 children with newly diagnosed epilepsy. Antiepileptic drug adherence was monitored using electronic monitoring over the first six months of therapy. The primary outcome measure was rate of uninformed clinical decisions as defined by the number of participants with AED dosage or drug changes to address continued seizures who demonstrated nonadherence prior to the seizure. Among the 52 (47%) participants who had an AED change for continued seizures, 30 (27% of the overall cohort) had imperfect medication adherence prior to their seizures. A quarter of the children with new-onset epilepsy had uninformed medication changes because adherence was not rigorously assessed in clinical practice. The results highlight the importance of routinely assessing medication adherence in this population.