Combination Of Antiepileptic Drugs Research Articles

Conversion to lacosamide monotherapy in the treatment of focal epilepsy: results from a historical-controlled, multicenter, double-blind study.

ObjectiveTo evaluate the efficacy and safety of conversion to lacosamide 400 mg/day monotherapy in adults with focal epilepsy.MethodsThis historical-controlled, double-blind study (NCT00520741) enrolled patients aged 16–70 years on stable doses of 1–2 antiepileptic drugs (AEDs) and experiencing 2–40 partial-onset seizures per 28 days during the 8-week prospective Baseline. Patients were randomized to lacosamide 400 or 300 mg/day (3:1 ratio), starting at 200 mg/day and titrated over 3 weeks to randomized dose. Patients then withdrew background AEDs over 6 weeks and entered a 10-week Monotherapy Phase. The primary assessment was the Kaplan-Meier–predicted percentage of patients on 400 mg/day in the full analysis set (FAS) meeting ≥1 predefined seizure-related exit criterion by day 112, compared with the historical-control threshold (65.3%).ResultsFour hundred twenty-five patients were enrolled and were eligible for safety analyses (400 mg/day, n = 319; 300 mg/day, n = 106). A total of 271 (63.8%) of 425 patients completed the Lacosamide Maintenance Phase (combined AED Withdrawal and Monotherapy Phases). Among 284 patients in the 400 mg/day group in the FAS, 82 (28.9%) met ≥1 exit criterion; the Kaplan-Meier–predicted exit percentage at day 112 for 400 mg/day (30.0%; 95% confidence interval [CI] 24.6–35.5%) was lower than the historical control. When exit events, withdrawal due to treatment-emergent adverse events (TEAEs), and withdrawal due to lack of efficacy were summed (n = 90), the predicted exit percentage (32.3%; 95% CI 26.8–37.8%) was also lower than the historical control. Most patients receiving 400 mg/day reported some improvement on the Clinical Global Impression of Change (75.4%) and Patient Global Impression of Change (74.3%). Overall, the most common (>10%) TEAEs were dizziness (24.0%), headache (14.4%), nausea (13.4%), convulsion (11.5%), somnolence (10.4%), and fatigue (10.1%); most (74.1%) were mild-to-moderate in intensity. Seventy-two patients (16.9%) discontinued due to TEAEs. Seventeen patients (4%, all receiving 400 mg/day) experienced serious AEs.SignificanceLacosamide 400 mg/day monotherapy was effective, with a favorable safety profile in patients with focal epilepsy.

Management of focal epilepsy in adults treated with polytherapy in France: The direct cost of drug resistance (ESPERA study)

PurposeTo estimate the direct costs associated with the current management of focal epilepsy in adults treated with a combination of antiepileptic drugs (AEDs) in France and the supplementary costs of drug resistant epilepsy as defined by the International League Against Epilepsy (ILAE) in 2009. MethodsESPERA was a multicentre, observational, cross-sectional study conducted in France in 2010. A random sample of neurologists, including specialists in epilepsy, prospectively enrolled adults with focal epilepsy treated with a combination of AEDs. Investigators classified their patients according to the 2009 ILAE criteria for drug resistance and this classification was then reviewed by two experts. All items of healthcare resource use associated with epilepsy over the previous year were documented retrospectively and valued from a societal perspective. ResultsSeventy-one neurologists enrolled 405 patients. After experts’ review, 70.6% of patients were classified with drug-resistant epilepsy, 22.4% with drug-responsive epilepsy and 7% with undefined epilepsy. The mean annual epilepsy-related direct costs per patient were €4485±€4313 in patients with drug-resistant epilepsy compared to €1926±€1795 in patients with drug-responsive epilepsy. In these two groups, costs of AEDs were estimated at €2603 and €1544, respectively. Patients with drug-resistant epilepsy were more often hospitalised (mean annual cost: €1270 vs. €97) and underwent more additional tests (mean annual cost: €194 vs. €53). ConclusionThe direct cost of focal epilepsy in adults on AED combinations was estimated at €3850/patient/year. Drug resistance, as defined by the 2009 ILAE criteria, resulted in significant extra costs which varied with seizure frequency.

A child with uncontrollable bursts of laughter

Hypothalamic hamartomas (HH) are rare (1:200,000), nonneoplastic heterotopic congenital malformations formed by neurons and glial cells located close to the posterior hypothalamus, tuber cinereum, or mammillary bodies [1]. The condition was first described in 1873 as a seizure presenting with laughter [2]. Later, Daly and Mulder named this condition ‘‘gelastic epilepsy’’ [3]. Gelastic seizures, central precocious puberty, and cognitive impairment are the predominant manifestations of HH in infancy [4]. The typical MRI features of HH are isoor hypo-intensity on T1weighted images and isoor slight hyper-intensity on T2-weighted images. A lack of contrast enhancement in the tuber cinereum region is valuable for radiological diagnosis to distinguish tumors from other lesions in this field, such as third-ventricular ependymomas, hypothalamic astrocytomas, germ cell tumors, Langerhans cell histiocytosis, and papillomas. Our patient was diagnosed with HH due to the similarity with previous case reports. The electroencephalogram showed interictal focal (mostly right frontal and temporal) paroxysmal activity (more frequently slow spike-andwave complexes) consistent with HH lateralization. Recent reports have demonstrated the intrinsic epileptogenicity of HH. The mechanism of gelastic epilepsy may be the spontaneous firing of gamma-aminobutyric acid (GABA)-ergic small HH neurons, which project synaptic connections onto the larger adjacent pyramidal-like HH neurons. The combination of these neurons acts as a pacemaker that synchronizes the numerous output neurons to mediate seizure activity in the brain, and this action results in the observed clinical symptoms. This groupof lesionshas been classifiedbyDelalandeas I through IV, based onmorphology onMRI [5]. Type I has a horizontal orientation and may be lateralized to one side. Type II has a vertical orientation and an intraventricular location. Type III is a combination of types I and IIwith a vertical plane of attachmentwithin the ventricle and a horizontal plane of attachment on the underside of the hypothalamus. Type IV is a giant hamartoma. In our patient, the lesion was located in its entirety in the third ventricle (Fig. 2 of Images in Neuroscience: Question) and was thus classified as type II. Due to the insufficient number of clinical reports, there is no consensus regarding the various therapeutic options. Despite the use of higher doses and several combinations of antiepileptic drugs, freedom from seizures or good seizure control is rarely achieved in HH patients [6]. At present, surgical resection, stereotactic endoscopic disconnection, Gamma Knife radiosurgery (Elekta AB, Stockholm, Sweden), and radiofrequency thermocoagulation appear to be useful and safe approaches, particularly for the treatment of small HH [7–9]. In our patient, numerous antiepileptic drugs were utilized in various combinations for approximately 4 years; however, none of these treatments exhibited any efficacy. Subsequently, the patient underwent Gamma Knife radiosurgery and long-term follow-up. Further studies are needed to assess the prognosis.

Medical Treatment in Childhood Epilepsies

Summary The majority of epileptic seizures are controlled with antiepileptic drugs (AEDs). Whether or not to start treatment following an initial unprovoked seizure should be decided on an individualized basis; and, the risk of seizure recurrence versus possible side-effects and social conse quences of chronic AED treatment should be evaluated. Main risk factors for seizure recurrence can be summarized as the presence of focal seizure types, organic brain lesion, focal neurologic abnormality, previous neurodevelopmental retardation, specific EEG abnormality and positive family history of epilepsy. The AED chosen for initial therapy should be one that is highly effective for a particular seizure type and epilepsy syndrome, as also, that is safe and well tolerated. Monotherapy is the goal in epilepsy treatment. If the first two monotherapies fail, combinations of AEDs should be tried. Withdrawal of AED therapy should be considered in most children after two years without seizures. AEDs should be tapered slowly rather than halted abruptly.

Therapeutic approach to epileptic encephalopathies

Epileptic encephalopathies (EEs) are electroclinical entities with a peculiar course of disease; seizures and electroencephalographic (EEG) epileptiform abnormalities, ictal and interictal, contribute to progressive disturbance of cerebral functions. Frequently EEs are drug resistant, and consequences may be catastrophic. The main goal of treatment is to stop the peculiar course of epilepsy, operating on three parameters: seizure control, reduction of EEG abnormalities, and developmental outcome. For a correct therapeutic approach it is mandatory to have an as accurate as possible syndromic and etiologic diagnosis. Given the poor efficacy of conventional antiepileptic drugs (AEDs), the use of specific drugs for EEs, such as adrenocorticotropic hormone (ACTH) and corticosteroids or stiripentol is suggested. In some cases the choice of treatment is strictly related to the etiology: vigabatrin in tuberous sclerosis, ketogenic diet in glucose transporter type 1 (GLUT-1) deficiency, and pyridoxine in pyridoxine deficiency. Some AEDs combinations, such as sodium valproate with lamotrigine, have also provided interesting results, for example, in Lennox-Gastaut syndrome, although controlled studies are lacking. Finally, early surgery can be an option in children with focal structural abnormalities responsible for EEs preferably before irreversible damage on developmental outcome. Multispecialist support is recommended in EE. Management should be global from the onset, integrating not only seizure control but also all issues related to comorbidities, particularly neuropsychological and psychiatric.

Meta-analyses of antiepileptic drugs for refractory partial (focal) epilepsy: an observation

Meta-analyses of antiepileptic drugs for refractory partial (focal) epilepsy: an observation

A Comparison of the Efficacy and Tolerability of Oxcarbazepine Oral Suspension Between Infants and Children with Epilepsy: A Retrospective Chart Review at a Single Medical Center in Taiwan

Few clinical studies have assessed the efficacy and safety of oxcarbazepine (OXC) oral suspension in Asian pediatric patients and particularly in infants. The aim of this study was to investigate and compare the efficacy, tolerability, and side effects of OXC oral suspension in Taiwanese infants and children with various types of epilepsy. A retrospective review of the efficacy, tolerability, and side effects of OXC oral suspension in a tertiary medical center in Taiwan was conducted and included children (1-9 years old) and infants (<1 year old) diagnosed with epilepsy, which was classified into idiopathic partial, symptomatic partial, or multifocal subtypes. The OXC oral suspension (Trileptal(®); Novartis) was given in a gradual dose titration, from an initial 7.5 mg/kg/day to 30 mg/kg/day within 1 month in all cases. A total of 20 infants and 38 children were identified. There were no statistically significant differences between the children and infants in efficacy (75 vs. 82 %, p = 0.734) and adverse effects (30 vs. 21 %, p = 0.525) after OXC oral suspension treatment. The efficacy was significantly correlated with the epilepsy subtype (p < 0.01) and the number of combined antiepileptic drugs (AEDs) before OXC treatment (p < 0.01) in both groups. The patients with idiopathic and symptomatic partial epilepsy responded better to OXC oral suspension than those with multifocal epilepsy. OXC oral suspension is effective and well tolerated in both infants and children with partial epilepsy in Taiwan. Treatment efficacy was related to epilepsy subtype and number of combined AEDs before OXC treatment. Monotherapy had an excellent therapeutic response in partial epilepsy but not in multifocal epilepsy.

Control of seizures in different stages of partial epilepsy: LACO-EXP, a Spanish retrospective study of lacosamide

Lacosamide is approved as adjunctive therapy for focal epilepsies. The number of antiepileptic drugs (AEDs) tried is associated with prognosis. This multicenter, retrospective, observational study (LACO-EXP) in Spain in 500 adult patients with focal epilepsies examined the efficacy and tolerability of add-on lacosamide. Factors associated with better efficacy/tolerability were analyzed. After 12months, the responder rate (≥50% reduction in seizure frequency) was 57.1%, and the seizure-free rate was 14.9%. Efficacy was better when lacosamide was the first or second add-on AED, although there was a small chance to be seizure-free even for patients who had received ≤10 prior AEDs. The mechanism of action of concomitant AEDs is important in all the stages, but differences are smaller in the early stages. Lacosamide was generally well tolerated. A slower dosage–titration schedule was associated with a lower adverse event rate. Further investigation of the timing of initiation of lacosamide add-on therapy and ideal combinations of AEDs is required.

Possible effect of perampanel on focal status epilepticus after generalized tonic–clonic status epilepticus

Since in refractory status epilepticus (SE), additional glutamate receptors such as alpha-amino-3-hydroxy-5-methyl4-isoxazolepropionic acid (AMPA) and N-methyl-Daspartate (NMDA) receptors are built up in the synaptic membrane [1], perampanel, a novel noncompetitive AMPA-receptor antagonist, may be effective in this condition. During the treatment of refractory SE, usually a combination therapy of several antiepileptic drugs (AEDs) is established. Therefore, the drug, which has terminated the SE, cannot easily be identified. A possible effect of an AED on the termination of a SE may be supposed, when the termination of a SE is associated with the introduction of an AED in the therapy or an increased dose of an AED in combination with other changes in the antiepileptic medication at the same time [2]. Here we present a case where perampanel was the last AED introduced in the treatment of a focal SE before its termination 24 h later.

Does Mechanism of Drug Action Matter to Inform Rational Polytherapy in Epilepsy?

When monotherapy for epilepsy fails, add-on therapy is an alternative option. There are several possible antiepileptic drug combinations based on their different and multiple mechanisms of action and pharmacokinetic interactions. However, only when benefits of drug combinations outweigh the harms, polytherapy can be defined as "rational". In the past 20 years, second generation AEDs have been marketed, some of which have better defined mechanisms of action and better pharmacokinetic profile. The mechanisms of action of AEDs involve, among others, blockade of voltage-gated sodium channels, blockade of voltage-gated calcium channel, activation of the ionotropic GABAA receptor and increase of GABA levels at the synaptic cleft, blockade of glutamate receptors, binding to synaptic vesicle protein 2A, and opening of KCNQ (Kv7) potassium channels. Aim of this review was to examine published reports on AEDs combinations in animal models and humans focusing on mechanisms of action and pharmacokinetic interactions. Studies in animals have shown that AED combinations are more effective when using drugs with different mechanisms of action. The most effective combination was found using a drug with a single mechanism of action and another with multiple mechanisms of action. In humans some combinations between a blocker of voltage-gated sodium channels and a drug with multiple mechanisms of action may be synergistic. Future studies are necessary to better define rational combinations and complementary mechanisms of action, considering also pharmacokinetic interactions and measures of toxicity and not only drug efficacy.

Challenges in Diagnosing a Metabolic Disorder

Certain drugs are known to cause metabolic changes resulting in altered metabolic profiles. We report here a case where a combination of antiepileptic drugs resulted in a profile that mimicked a metabolic disorder. A 16month-old female child on antiepileptic drugs (valproate and topiramate) was suspected to have the inherited metabolic disorder, dihydrolipoamide dehydrogenase deficiency, based on clinical symptoms and metabolic profile showing hyperalaninemia, elevated branched-chain amino acids, and lactate-pyruvate ratio. Suspecting that the observed metabolic changes could have also arised from medication, current medication was weaned off and replaced with levetiracetam, clonazepam, and levocarnitine (supportive therapy). Metabolic profiling conducted after 47 days showed normal alanine, branched-chain amino acids, ornithine, and lactate-pyruvate ratio, suggesting that the earlier abnormalities could have been medication induced. We stress that metabolic changes resulting from chronic medication should be considered while interpreting a positive result when investigating an inherited metabolic disorder.

Effectiveness and Healthcare Utilization with Newly Initiated Antiepileptic Drug Combination Therapy for Partial Onset Seizures According to Mechanisms of Action (PD4.009)

Effectiveness and Healthcare Utilization with Newly Initiated Antiepileptic Drug Combination Therapy for Partial Onset Seizures According to Mechanisms of Action (PD4.009)

Impact of stigma on the quality of life of patients with refractory epilepsy

PurposeTo assess the impact of perceived stigma on the quality of life of Bulgarian patients with refractory epilepsy. MethodsWe studied 70 adult patients with refractory epilepsy, without cognitive impairment, progressive somatic, neurological disease or recent seizures, and 70 patients with pharmacosensitive epilepsy. All participants completed a 3-item stigma scale, the patients with refractory epilepsy also completed a Health Related Quality of Life measure (the QOLIE-89). ResultsThe patients with refractory epilepsy had a mean disease duration 25.1±1.3 years. 40.0% of patients (±5.9) had symptomatic epilepsy. Seventeen patients (24.2%±5.1) had partial seizures, 16 (22.8%±5.0) had generalized seizures and 37 (52.9±6.0) had a mixture of partial and generalized seizures. Most participants had several seizures per week (45.7%) or month (30.0%) despite the fact that 90% were taking combination antiepileptic drug treatment. We found perceived stigma in 43.6% of patients with refractory epilepsy, and 28.7% self-reported severe stigmatization. Only 4 (5.7%) patients with pharmacosensitive epilepsy reported stigmatization which was mild or moderate in all cases. Perceived stigma had a negative impact on the overall score of the QOLIE-89 (T-score 47.8), as well as on all subscales of QOLIE-89, with the exception of “change in health” and “sexual relations”. Patients with refractory epilepsy reporting stigmatization most commonly had very low and low scores on the subscales “health perceptions” (82.9%), “emotional well-being” (71.5%), “memory” (63.4%) and “health discouragement” (62.5%). There was a negative correlation of all QOLIE-89 subscales with perceived stigma severity. ConclusionAll aspects of the quality of life of Bulgarian patients with refractory epilepsy correlate negatively with the severity of perceived stigma.

Utilization patterns of antiepileptic drugs among adult epileptic patients at a tertiary hospital in Oman

To describe utilization patterns of antiepileptic drugs (AEDs) among adult epileptic patients at a tertiary hospital in Oman. Data were collected retrospectively from January 2006 to December 2009. The study included all adult (>18 years) epileptic patients on AEDs and followed up at a neurology clinic at Sultan Qaboos University Hospital in Oman. All reported therapeutic drug monitoring (TDM) requests for serum AED concentrations were also collected. Institutional ethical approval was sought and obtained. The study included a total of 372 patients with a mean age of 34 ± 15 years. Monotherapy AEDs accounted for 53% of the prescriptions, whereas polytherapy with two or three AED combinations accounted for 27% and 20% respectively. The most frequently prescribed AED was sodium valproate (27%) followed by carbamazepine (23%). The commonly prescribed AED combinations were sodium valproate with clonazepam (12%) followed by sodium valproate with lamotrigine (12%). Evaluation of 574 TDM requests for three AEDs showed that 57% of carbamazepine, 78% of phenytoin and 54% of valproic acid requests were either above or below the recommended therapeutic threshold. Most of these requests were ordered from the hospital's emergency department for suspected insufficient serum concentrations. Antiepileptic drug monotherapy is still the most frequently employed therapeutic strategy in adult patients with epilepsy in keeping with the standard therapeutic guidelines. Sodium valproate is commonly used for different types of seizures reflecting its wide spectrum of anticonvulsant potential. Newer AED utilizations are becoming increasingly popular in our subjects particularly as add-on with other standard AEDs.

Pseudohypoparathyroidism: A Case Report of a Rare Disease with Uncommon Presentation Producing Diagnostic Dilemma

Pseudohypoparathyroidism (PHP) is a rare hereditary disorder having the prevalence of 3.4 per million. It is characterized by symptoms and signs of hypoparathyroidism, typically in association with distinctive skeletal and developmental defects. The features of hypoparathyroidism are due to tissue resistance to the effect of parathyroid hormone (PTH). We will describe a 32-yearold woman who had recurrent convulsion for 16 years, infertility, cataract, psychosis, candidiasis and typical features of Albright’s hereditary osteodystrophy (AHO), which include a round face, short neck, short stature and brachydactyly. Laboratory investigations showed hypocalcemia, hyperphosphatemia with high PTH level. Computed tomography scan of head revealed wide spread calcification in basal ganglia and cerebral hemispheres. X ray of left foot showed short left 4th metatarsal bone. The patient was diagnosed as a case of PHP on the basis of somatic features of AHO with typical biochemical abnormalities and uncontrolled convulsion with combined antiepileptic drugs for 16 years. The unusual features in our case are long delay in clinical diagnosis and absence of family history. She was treated with calcium salt and vitamin D. With this treatment patient’s condition was improved and she experiences no attack of convulsion and carpal spasm. Anticonvulsants were withdrawn gradually. We recommend that hypocalcaemia should be excluded before commencing anticonvulsant therapy in all epileptic patients and those patients whose seizures are refractory to anticonvulsant drugs DOI: http://dx.doi.org/10.3329/jbcps.v29i4.11331 J Bangladesh Coll Phys Surg 2011; 29: 227-230

Effect of ACEA—a selective cannabinoid CB1 receptor agonist on the protective action of different antiepileptic drugs in the mouse pentylenetetrazole-induced seizure model

Endogenous cannabinoid ligands and cannabinoid CB1 receptor agonists have been shown to exert anticonvulsant effects in various experimental models of epilepsy. The purpose of this study was to determine the effects of arachidonyl-2'-chloroethylamide (ACEA-a highly selective cannabinoid CB1 receptor agonist) on the protective action of clonazepam, ethosuximide, phenobarbital, and valproate against pentylenetetrazole (PTZ)-induced clonic seizures in mice. To ascertain any pharmacokinetic contribution of ACEA to the observed interactions between tested drugs, free (non-protein bound) plasma and total brain concentrations of the antiepileptic drugs were estimated. Additionally, acute adverse-effect profiles of the combination of ACEA and different classical antiepileptic drugs (clonazepam, ethosuximide, phenobarbital and valproate) with respect to motor performance, long-term memory and skeletal muscular strength were measured. Results indicated that ACEA (10mg/kg, i.p.) co-administered with phenylmethylsulfonyl fluoride (PMSF-a substance protecting ACEA against degradation by the fatty-acid hydrolase; 30mg/kg, i.p.) significantly potentiated the anticonvulsant activity of ethosuximide, phenobarbital and valproate in the mouse PTZ-induced clonic seizure model by reducing their median effective doses (ED(50) values) from 122.8mg/kg to 71.7mg/kg (P<0.01; for ethosuximide), from 13.77mg/kg to 5.26mg/kg (P<0.05; for phenobarbital), and from 142.7mg/kg to 87.3mg/kg (P<0.05; for valproate), respectively. In contrast, ACEA (10mg/kg, i.p.) in combination with PMSF (30mg/kg, i.p.) had no impact on the protective action of clonazepam against PTZ-induced seizures in mice. However, ACEA (10mg/kg)+PMSF (30mg/kg) considerably increased free plasma and total brain concentrations of ethosuximide and valproate in mice suggesting a pharmacokinetic nature of interaction between drugs. In contrast, free plasma and total brain concentrations of clonazepam and phenobarbital remained unchanged after ACEA+PMSF administration and thus, indicating pharmacodynamic interactions. Moreover, none of the examined combinations of ACEA (10mg/kg, i.p.)+PMSF (30mg/kg, i.p.) with clonazepam, ethosuximide, phenobarbital, and valproate (at their ED(50) values from the PTZ-induced seizure test) affected motor coordination in the chimney test, long-term memory in the passive avoidance task, and muscular strength in the grip-strength test in mice, indicating no possible acute adverse effects in animals. In conclusion, pharmacodynamic enhancement of the anticonvulsant potency of phenobarbital by ACEA+PMSF is worthy of recommendation for further clinical settings. Pharmacokinetic interactions of ACEA+PMSF with ethosuximide and valproate seem to be responsible for a significant suppression of PTZ-induced seizures in mice. The combination of ACEA+PMSF with clonazepam seems to be neutral from a preclinical viewpoint.

PIH77 Annual Overall and Epilepsy-Related Health Care Utilization in Adult Epilepsy Patients in the United States

There are multiple drug options for the treatment of epilepsy. Some patients may be refractory to treatment and require combination antiepileptic drug (AED) treatment. We compared healthcare utilization of refractory and stable epilepsy patients. Using a claims database covering 2007-2009, we identified adults (age≥18years) with epilepsy who were either stable on therapy (no change in AED over 12 months) or were refractory (defined as adding AED therapy to an existing regimen). An index date in 2008 was selected: the date on which an additional AED was started for refractory patients; and a convenience date for stable patients. All pharmacy and medical claims in the post-index year were used to estimate overall utilization. Claims with epilepsy in any diagnosis field were used to estimate epilepsy-related utilization. Logistic regression models were used to adjust for baseline differences. There were 1536 refractory and 8571 stable patients (age: 41.8 vs. 43years; 50.7% vs. 47.6% female; mean Charlson comorbidity index: 0.7 vs. 0.5). Refractory patients were hospitalized more often than stable patients, both for any diagnosis (18.3% vs. 9.8% had ≥1 hospitalization) and for epilepsy-related diagnoses (15.7% vs. 7%). Refractory patients had greater mean hospital length of stay (any diagnosis: 10.9 vs. 7.1 and epilepsy-related: 8.9 vs. 5.6 days). They also had more physician office visits than stable patients (any diagnosis: 12 vs. 9 and epilepsy-related: 3.6 vs. 2.2). After adjusting for demographics, region, usual-care physician specialty, and risk factors, the odds of hospitalization (OR:1.8; 95% CI:1.6-2.1), emergency department visit (OR:1.6; CI:1.5-1.8), epilepsy-related hospitalization (OR:2.2; CI:1.9-2.6), and epilepsy-related emergency department visit (OR:1.9; CI:1.7-2.2) were greater in the refractory group. Patients with refractory epilepsy use significantly more health care services than those with stable disease. As new and more effective AEDs become available, it may be possible to reduce utilization in the refractory group.

Trends in antiepileptic drug utilisation in UK primary care 1993–2008: Cohort study using the General Practice Research Database

PurposeTo describe changes in utilisation of antiepileptic drugs (AED) by people with epilepsy in the United Kingdom during 1993–2008. MethodsCohort study of 63,586 participants with epilepsy and prescribed AEDs from 434 UK family practices. Prescriptions for different AEDs and AED combinations were evaluated by calendar year, gender and age group. ResultsTotal follow-up was 361,207 person-years, with 282,080 person-years treated with AEDs and 79,126 person-years untreated. AED monotherapy accounted for 72.6% of treated person years of follow-up. Carbamazepine and valproates were among the most commonly used medications throughout 1993–2008. Phenytoin accounted for 39.5% of treated person-years in 1993 declining to 18.3% by 2008. Use of barbiturates declined from 14.3% in 1993 to 6.0% in 2008. In contrast between 1993 and 2008 there were substantial increases in the use of lamotrigine (2.0% to 17.0%) and to a lesser extent levetiracetam (0% to 8.6%). Newer AEDs were more frequently prescribed to younger participants, especially women aged 15–44 years, while older adults were more likely to be prescribed longer established AEDs. In 1993, 201 different AED combinations were prescribed, increasing to 500 different combinations in 2008. Combinations of sodium valproate and carbamazepine were frequent throughout, while sodium valproate and lamotrigine was frequent in 2008. ConclusionsUtilisation of newer AEDs in UK primary care has increased between 1993 and 2008 with increasing use of diverse combinations of AEDs. The data quantify exposure to AEDs relevant to planning analytical pharmaco-epidemiological studies, as well as providing information to inform prescribing policies.

Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update.

In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs.

Efficacy of Adjunctive Perampanel in Phase III Clinical Trials: Subanalysis of Change in Seizure Frequency and Responder Rates by Concomitant Antiepileptic Drug Use (S56.006)

Objective: Assess effect of concomitant antiepileptic drugs (AEDs) on seizure frequency and responder rate in a pooled analysis of perampanel phase III studies. Background In phase III trials, adjunctive perampanel was efficacious in reducing uncontrolled partial-onset seizures (4-12 mg/day). Design/Methods: Following Baseline, patients (≥12 years, receiving 1-3 AEDs) were randomized to once-daily double-blind treatment with placebo or perampanel 2, 4, 8, or 12 mg. Efficacy endpoints were analyzed with respect to concomitant use of the most frequently taken AEDs (in any combination) to test if addition of these AEDs with other mechanisms of action affected the efficacy of perampanel. Endpoints analyzed were: percent change in seizure frequency/28 days (Double-blind Phase vs Baseline) and 50% responder rate (Maintenance vs Baseline). Results: Across the phase III studies, 1478 patients were randomized and treated (placebo, n=441; perampanel 2 mg, n=180; 4 mg, n=172; 8 mg, n=431; 12 mg, n=254), and were taking an average of 2.2 concomitant AEDs. The most common AEDs (≥45 patients/treatment group), used in combinations of 1-3 concomitant AEDs, were: carbamazepine (n=491), valproate (n=478), lamotrigine (n=457), and levetiracetam (n=435). Median differences (Hodges-Lehmann) in median percent change in seizure frequency/28 days in patients receiving concomitant AED combinations including carbamazepine, valproate, lamotrigine, or levetiracetam compared with placebo ranged from: 7.7% to -7.8% with perampanel 2 mg; -3.0% to -12.7% with 4 mg; -8.9% to -20.8% with 8 mg; and -12.4% to -16.7% with 12 mg. Responder rate ranges for these patients were: 13.6-23.1% with placebo; 13.8-21.4% with perampanel 2 mg; 19.6-34.7% with 4 mg; 29.7-38.3% with 8 mg; and 30.6-43.0% with 12 mg. Conclusions: Perampanel (4-12 mg/day) decreased seizure frequency and increased responder rates in patients concomitantly taking at least one of the four most common AEDs. The presence of another AED mechanism did not appear to reduce the efficacy of perampanel. Supported by: Eisai Inc. Disclosure: Dr. French has nothing to disclose. Dr. Ben-Menachem has received personal compensation for activities with Eisai Inc, UCB Pharma, Cyberonics, Inc., GlaxoSmithKline, Inc. and Lundbeck Research USA as an advisory board participant and/or speaker. Dr. Ben-Menachem has received personal compensation in an editorial capacity for Acta Neurologica Scandinovica. Dr. Ben-Menachem has received research support from Eisai Inc, UCB Pharma and Bial. Dr. Brodie has received personal compensation for activities with Pfizer Inc, UCB Pharma, Eisai Inc., GlaxoSmithKline, Inc., Sanofi-Aventis Pharmaceuticals, Inc., and Lundbeck Research USA, Inc. Dr. Brodie has received research support from Eisai Inc. Dr. Squillacote has received personal compensation for activities with Eisai as an employee. Dr. Yang has received personal compensation for activities with Eisai, Inc. as an employee. Dr. Kumar has received personal compensation for activities with Eisai Inc. as an employee. Dr. Laurenza has received personal compensation for activities with Eisai as an employee.