Trials Of Antiepileptic Drugs Research Articles

Joint modelling of longitudinal and competing risks data

Available methods for joint modelling of longitudinal and survival data typically have only one failure type for the time to event outcome. We extend the methodology to allow for competing risks data. We fit a cause-specific hazards sub-model to allow for competing risks, with a separate latent association between longitudinal measurements and each cause of failure.The method is applied to data from the SANAD trial of anti-epileptic drugs (AEDs), as a means of investigating the effect of drug titration on the relative effects of lamotrigine (LTG) and carbamazepine (CBZ) on treatment failure. Concern had been expressed that differential titration rates may have been to the disadvantage of CBZ. The beneficial effect of LTG on unacceptable adverse events leading to drug withdrawal did not lessen and indeed increased slightly when a calibrated dose was accounted for in the joint model. Adjustment for the titration rate of LTG relative to CBZ resulted in an unchanged effect of the former on drug withdrawals due to inadequate seizure control. LTG remains the AED of choice from this analysis.

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Digest

A survey of neurologists’ views on epilepsy surgery and medically refractory epilepsy

There is a 20-year delay between the diagnosis of epilepsy and surgical treatment. The aim of this study was to describe the different views held by neurologists regarding refractory epilepsy that may contribute to the delay in referring patients for epilepsy surgery. Neurologists in Michigan were mailed a 10-item survey inquiring about their definition of medically refractory epilepsy and their decision-making process in referring patients for epilepsy surgery. Eighty-four neurologists responded (20%). The majority defined medically refractory epilepsy as failure of three monotherapy antiepileptic drug (AEDs) trials and at least two polytherapy trials. Nineteen percent responded that all approved AEDs had to fail before a patient could be defined as medically refractory. Eighty-two percent of the respondents had referred patients for epilepsy surgery. Almost 50% were not satisfied with the level of communication from epilepsy centers. One-third reported serious complications resulting from surgery. These findings suggest that further education and improved communication from comprehensive epilepsy centers may shorten the time to referral and ultimately improve the lives of patients with epilepsy.

A pilot trial of levetiracetam in eyelid myoclonia with absences (Jeavons syndrome)

Eyelid myoclonia with absences (EMA) or Jeavons syndrome characterized by eyelid myoclonia (EM) (with or without absences), eye closure-induced EEG paroxysms, and photosensitivity. We conducted an open-label trial of levetiracetam in EMA. Patients were recruited in different Italian Epilepsy Centres. Levetiracetam was administrated at starting dose of 10 mg/kg/day up to 50-60 mg/kg/day in two doses. Treatment period included a 5-6 week up-titration phase and a 12-week evaluation phase. The number of days with EM (i.e., days with seizures, DwS) and number of generalized tonic-clonic seizures (GTCS) were evaluated. Analysis of intent-to-treat population was performed using Fisher's and Wilcoxon tests. Thirty-five patients (23 F) with a mean age of 19 +/- 6 years were recruited. Twenty-seven had previously undergone one to five adequate trials of antiepileptic drugs. The median number of DwS/month was 12 +/- 8.2. Twenty-one patients experienced GTCS (median number/month: 1 +/- 0.2). Thirty-four subjects completed the trial. Levetiracetam was well tolerated (mean dose: 1985 mg/day). Responders were 28/35 (80%) patients, nine taking levetiracetam as monotherapy. Six patients were seizure-free, 15 had > or =75% and seven >50% seizure reduction. GTCS remitted in 14 out of 21 (66.6%) patients. The number/month of DwS (median: 12 vs 5; p = 0.0001) and of GTCS (median: 1 vs 0; p = 0.0001) decreased compared to baseline period. Disappearance or clear reduction in paroxysmal abnormalities at eye closure occurred in 20 of the responders and photoparoxysmal response in 19. Mean follow-up was 23.9 +/- 18.5 months. Levetiracetam is effective and well tolerated in EMA. Placebo-controlled studies should confirm these findings.

Antiepileptic Drug Development in Children

The European Commission and the European Parliament have acknowledged the specific need for a proper evaluation of new drugs in children. The evaluation of the antiepileptic drugs (AEDs) available on the market illustrates the deficit in therapeutic trials for childhood epilepsy syndromes. Currently, the development of AEDs is mainly performed in children with focal epilepsy, whereas infants and the specific age-related epilepsy syndromes, particularly epileptic encephalopathies, are neglected. Infantile epilepsies remain 'therapeutic orphans', although they are the most frequent and deleterious disorders in the area of epilepsy. In order to circumvent the difficulties faced when conducting AED trials in children, we addressed the question of improving feasibility without decreasing quality, while optimally taking into account paediatric ethical requirements. For this review, we first raise the issues of paediatric epilepsies that require special considerations for randomized controlled trials (RCTs) in children. Then, we attempt to determine to what extent adult data could be extrapolated to children. Finally, we review innovative approaches that could be used in the evaluation of AEDs in children. The main specificities of paediatric epilepsies (heterogeneity, severity, cognitive impact, pharmacoresistance, syndrome-specific efficacy profile) are related to brain development and should be taken into consideration when establishing specific guidelines for the evaluation of AEDs in children. Extrapolating efficacy data from adults to children may be possible in focal epilepsy except in infants who need age-specific trials. Epileptic encephalopathies do not exist in adults and require specific trials. Pharmacokinetic data are required below a lower age limit for extrapolation of adult data to be determined in a case-to-case approach. Safety data are required at any paediatric age. RCTs in small but homogeneous populations in each paediatric-specific epileptic syndrome, the use of sequential or responder-enrichment designs, and population pharmacokinetics represent potentially promising approaches to evaluate drugs in children in an efficient way.

Epilepsy: randomised trials and genetic tribulations

The evidence base that underpins the pharmacological management of the epilepsies is not earth shattering. Most randomised, double-blind trials of the newer antiepileptic drugs (AEDs) have been done by the pharmaceutical industry for regulatory purposes with the primary aim of obtaining a licence. Add-on studies usually investigate a range of doses versus placebo for efficacy in patients with refractory epilepsy, but few patients become free from seizures. The results of head-to-head comparisons in patients with newly diagnosed epilepsy have been more interesting.

Monotherapy clinical trial design

Monotherapy of epilepsy is usually preferable to polytherapy for a variety of reasons. However, investigational or newer antiepileptic drugs (AEDs) are typically evaluated as add-on therapy in patients with refractory seizures. Because coadministered drugs are subject to drug interactions, add-on trials of AEDs do not necessarily address the utility of a new AED as monotherapy or its use in patients with newly diagnosed epilepsy, in whom monotherapy is usually sufficient. Monotherapy clinical trials are difficult to design because randomizing epilepsy patients to placebo or pseudoplacebo is considered unethical, and results from active-drug noninferiority designs are difficult to interpret. Active-drug superiority designs have been developed in an attempt to provide useful information about the monotherapeutic efficacy of new AEDs. The conversion to monotherapy trial design, introduced in the late 1970s, provides for initial add-on of an investigational agent to a preexisting drug in patients with uncontrolled seizures, followed by gradual discontinuation of the preexisting treatment and an eventual monotherapy phase of the investigational agent. Conversion to monotherapy trials are typically of short duration and have been criticized for failing to provide adequate time for titration to optimal dose, an inability to examine tolerance development or long-term safety, and possibly placing enrolled patients at increased risk for morbidity, but they have been used to obtain data about monotherapy efficacy sufficient for regulatory authority approval. Relevant clinical trial data are needed to guide treatment choices in patients who have failed previous monotherapy. To date, large-scale prospective trials comparing monotherapy with old and new AEDs have not shown superior efficacy of the new AEDs but have demonstrated their better tolerability and safety. It is hoped that use of appropriately designed monotherapy clinical trials will help to identify a new generation of AEDs in the future for monotherapy in epilepsy patients.

Monotherapy in children and infants

An expanding array of antiepileptic drugs (AEDs) is available to treat childhood epilepsy, offering the potential for improved seizure control and quality of life in this important patient population but also providing challenges in the selection of the best regimen for the individual patient. In addition to correct diagnosis of seizure type and general AED efficacy profile, other important treatment considerations in pediatric patients include age-specific organ toxicity, potential cognitive and behavioral or psychiatric effects of AEDs, compliance, and drug-drug interactions, since children commonly receive more medications than nonelderly adults. Drug dosing may be more difficult in pediatric than in adult epilepsy patients, and doses in children often require adjustment as the patient matures. Because many randomized controlled trials (RCTs) of newer AEDs have not included childhood epilepsy, physicians often have incomplete data on which to base treatment decisions. Therefore, despite the wider array of potential therapies, it is often unclear how to realize the potential they offer. Recently published guidelines from a number of organizations have provided strategies for the use of new AEDs in the treatment of childhood epilepsy. Additional RCTs of monotherapy options for childhood epilepsy are greatly needed. The ketogenic diet provides an alternative to pharmacologic control of seizures in some pediatric patients.

Seizures on hearing the alarm clock

In October, 2006, a 25-year-old trainee graphic designer was referred to us to establish whether her seizures were epileptic or dissociative. For 8 years, she had had seizures triggered by unexpected auditory stimuli, such as the ringing of her telephone or alarm clock. She would become startled and have a “turning feeling in her head”, palpitations, and anxiety. She would then hyperventilate, lose consciousness, and collapse, often with urinary incontinence. These episodes had occurred less frequently when she had avoided stress, not even attending school. However, she was now having seizures, with loss of consciousness, every day. Her electroencephalogram (EEG) and MRI of her head had been normal, as had several electrocardiograms (ECGs). She had no risk factors for epilepsy; she had never received a psychiatric assessment. Nonetheless, she had been diagnosed with complex partial and generalised epilepsy. Trials of antiepileptic drugs (valproic acid, carbamazepine, oxcarbazepine, topiramate, clobazam, and levetiracetam) had been unsuccessful.

Efficacité de la stimulation intermittente du nerf vague dans les épilepsies pharmaco-résistantes non chirurgicales de l’adolescent et de l’adulte

Vagus Nerve Stimulation (VNS) is recognized as an efficient procedure for controlling seizures in patients with drug-refractory epilepsies. It is used as a palliative procedure as a complement to conventional treatment by antiepileptic (AE) drugs and, according to literature, 40 to 50p.cent of patients report a decrease in seizures frequency >or=50p.cent, which is usually accepted to classify patients as responders in add on AE drug trials. The objectives of this study based on retrospective analysis of 50 consecutive patients with partial (39) or generalized (11) refractory epilepsy non eligible for surgery were; firstly to evaluate the global long term VNS efficacy and secondly to identify potential predictors of the VNS effects on seizure frequency. No patient has been seizure free at any moment of the follow up (2.8+/-1.8 years, max: 6 years) and the AE has been maintained in all. During follow up 44, 66, 61 and 58p.cent of patients were classified as responders at 6 months, 1, 2 and 3 years, respectively. Logistic regression analysis showed that: the percentage of responders at 6 months of follow up and later was significantly higher than that before 6 months (p=0.002); generalized epilepsy was predictive of a better outcome as compared to partial epilepsy (p=0.03); there was a trend for a better outcome in partial epilepsies symptomatic of a focal lesion than in those with normal brain MRI (p=0.06). These results are in line with previously published data in terms of global efficiency and confirm that seizures control does not reach its maximal level before at least one year of VNS. In severe generalized epilepsies (either secondary or cryptogenic) manifesting by frequent falls due to atonic or tonic-clonic generalized seizures VNS is a useful palliative procedure, which entails much les of surgical risk than callosotomy. The better VNS effects in patients with partial epilepsy possibly reflect the high incidence in our series of Malformations of Cortical Development, which have been identified as one the few variables possibly predictive of a response over 50p.cent of seizures frequency reduction.

A comparison of methods for fixed effects meta-analysis of individual patient data with time to event outcomes

Alternative methods for individual patient data (IPD) meta-analysis of time-to-event outcomes have been established and utilized in practice. The most common approach is a stratified log-rank analysis. The IPD approach is considered to be the gold standard approach for meta-analysis and is becoming increasingly more popular but the performance of different methods has not been studied previously. To compare commonly used methods for fixed effects meta-analysis of individual patient time-to-event data. The stratified log-rank analysis, an inverse variance weighted average of Cox model estimates, and the stratified Cox regression model are compared. First, a theoretical comparison of approaches is undertaken. Second, the bias and coverage are assessed for the pooled hazard ratio using simulated data under commonly encountered meta-analysis conditions. Finally, a comparison is presented using empirical data from four separate systematic reviews of anti-epileptic drug trials where IPD are available for two time-to-event outcomes. For hazard ratio close to 1 with minimal heterogeneity between trials, theoretical results suggest similar results should be expected from all the three methods. Results for empirical and simulated data are in keeping with the theoretical results and show all the three methods perform well under these conditions. When there is no heterogeneity and the proportional hazards assumption holds, the stratified Cox model and inverse variance weighted average produce similar estimates of the pooled treatment effect and are to be preferred to the stratified log-rank analysis when the underlying treatment effect is large. Coverage values diminish for all the three methods and are below 95% for low or moderate heterogeneity. The low coverage values highlight the need for models that appropriately account for or explore the between trial variation. Until larger simulations can be undertaken, conclusions based on the simulated and empirical data should only be applied to small meta-analyses of four or five trials. These investigations suggest that under normal conditions all three methods provide similar results. For moderate heterogeneity coverage for all the three fixed effects models depreciates.

Putting an end to DEND

This issue contains the first report in the neurologic literature of a potentially catastrophic infantile neurodevelopmental syndrome that, though rare, may turn out to be highly treatable.1 Shimomura et al. describe a male child, first encountered at 3.5 years of age, with a history of neonatal-onset diabetes mellitus and neonatal seizures that had progressed to infantile spasms, severe developmental delay, and medically refractory epilepsy. Attentive care (round-the-clock hourly glucose monitoring; insulin infusion by subcutaneous pump; multiple antiepileptic drug trials) had proven ineffective. Remarkably, the patient showed a dramatic response to treatment with oral glibenclamide, a sulfonylurea drug most often given to adult patients with noninsulin dependent diabetes. Glucose control improved, allowing discontinuation of insulin. In addition, electrographic signs of seizures and encephalopathy diminished, and neurodevelopmental progress resumed. Evidence from this case and others reported elsewhere2 suggests that early recognition and sulfonylurea treatment is essential for this treatment to be effective. Why did Shimomura et al. choose glibenclamide, and why did an oral agent work after insulin had failed? The authors recognized that their patient had delay, epilepsy, and neonatal …

Neonatal Seizures: Multicenter Variability in Current Treatment Practices

Standardized approaches to the treatment of neonatal seizures remain undeveloped. We assessed the type and number of anticonvulsants selected, blood levels attained, and postdischarge anticonvulsant treatment of neonatal seizures among five neonatal intensive care units in the United States between 2000-2003. Almost all of the 480 neonates (94%) with seizures were treated, initially with phenobarbital (82%), lorazepam (9%), phenytoin (2%), other anticonvulsants (1%), or a combination of the first two drugs (6%). While the majority of neonates were treated with one drug (59%), the number of anticonvulsants varied (P<0.0001), as did the peak serum phenobarbital levels (P<0.0001). The majority (75%) of survivors received anticonvulsant treatment after discharge. These neonates were more likely to have had abnormal electroencephalography or brain imaging, or to have needed a second anticonvulsant, compared with neonates whose drug therapy was discontinued. Anticonvulsant therapy is used in the majority of neonates with seizures, mostly with phenobarbital, and treatment is continued beyond discharge. The observed wide therapeutic variability may reflect a lack of standardized diagnostic and treatment approaches, particularly for seizures refractory to initial phenobarbital therapy. Trials of anticonvulsants with long-term neurodevelopmental follow-up are needed to develop evidence-based treatment guidelines.

Long-term prognosis in intractable epilepsy: Looking beyond a year

Introduction: There is good evidence to suggest that approximately one third of new-onset epilepsy patients will be refractory to medication and that further medication trials in these patients is unlikely to result in complete control, at least in the short term [1]. Information from trials of new antiepileptic drugs (AEDs) in refractory patients supports this notion. Patients in these trials have typically failed five or more other anticonvulsant drugs, with continued seizure frequency of at least three per month. The new drug is added to the patient’s baseline AEDs, with careful accounting of the impact on seizure frequency. Even in the relatively short period of 2 to 3 months typically included in the trials of new AEDs, fewer than 10% of patients typically become completely seizure free [2,3]. It is, therefore, clear that in patients with continued seizures after failure of several AEDs that the addition of another drug, or even simply continuing the present one, may result in improvement but not resolution of seizures in the short term. This important information is, appropriately, something of a rallying cry for awareness of intractability in epilepsy. Patients failing initial AED therapy should be referred to epilepsy centers for definitive diagnosis and evaluation for alternative treatments, especially epilepsy surgery, which (also in the short term) carries a much higher rate of seizure freedom [4,5]. But what about the long term? There is a relative paucity of prospective studies following patients for years or decades. An ongoing study of epilepsy surgery is addressing this question after surgical treatment, but what of the approximately 30% of epilepsy patients who are deemed refractory and who do not receive surgery? Two recent studies give tantalizing, though perhaps limited, information regarding long-term prognosis in refractory epilepsy [6,7].

Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s Pediatric Suicidal Risk Analysis of Antidepressants

To evaluate the link between antidepressants and suicidal behavior and ideation (suicidality) in youth, adverse events from pediatric clinical trials were classified in order to identify suicidal events. The authors describe the Columbia Classification Algorithm for Suicide Assessment (C-CASA), a standardized suicidal rating system that provided data for the pediatric suicidal risk analysis of antidepressants conducted by the Food and Drug Administration (FDA). Adverse events (N=427) from 25 pediatric antidepressant clinical trials were systematically identified by pharmaceutical companies. Randomly assigned adverse events were evaluated by three of nine independent expert suicidologists using the Columbia classification algorithm. Reliability of the C-CASA ratings and agreement with pharmaceutical company classification were estimated. Twenty-six new, possibly suicidal events (behavior and ideation) that were not originally identified by pharmaceutical companies were identified in the C-CASA, and 12 events originally labeled as suicidal by pharmaceutical companies were eliminated, which resulted in a total of 38 discrepant ratings. For the specific label of "suicide attempt," a relatively low level of agreement was observed between the C-CASA and pharmaceutical company ratings, with the C-CASA reporting a 50% reduction in ratings. Thus, although the C-CASA resulted in the identification of more suicidal events overall, fewer events were classified as suicide attempts. Additionally, the C-CASA ratings were highly reliable (intraclass correlation coefficient [ICC]=0.89). Utilizing a methodical, anchored approach to categorizing suicidality provides an accurate and comprehensive identification of suicidal events. The FDA's audit of the C-CASA demonstrated excellent transportability of this approach. The Columbia algorithm was used to classify suicidal adverse events in the recent FDA adult antidepressant safety analyses and has also been mandated to be applied to all anticonvulsant trials and other centrally acting agents and nonpsychotropic drugs.

Columbia Classification Algorithm of Suicide Assessment (C-CASA): Classification of Suicidal Events in the FDA’s Pediatric Suicidal Risk Analysis of Antidepressants

Objective: To evaluate the link between antidepressants and suicidal behavior and ideation (suicidality) in youth, adverse events from pediatric clinical trials were classified in order to identify suicidal events. The authors describe the Columbia Classification Algorithm for Suicide Assessment (C-CASA), a standardized suicidal rating system that provided data for the pediatric suicidal risk analysis of antidepressants conducted by the Food and Drug Administration (FDA). Method: Adverse events (N=427) from 25 pediatric antidepressant clinical trials were systematically identified by pharmaceutical companies. Randomly assigned adverse events were evaluated by three of nine independent expert suicidologists using the Columbia classification algorithm. Reliability of the C-CASA ratings and agreement with pharmaceutical company classification were estimated. Results: Twenty-six new, possibly suicidal events (behavior and ideation) that were not originally identified by pharmaceutical companies were identified in the C-CASA, and 12 events originally labeled as suicidal by pharmaceutical companies were eliminated, which resulted in a total of 38 discrepant ratings. For the specific label of “suicide attempt,” a relatively low level of agreement was observed between the C-CASA and pharmaceutical company ratings, with the C-CASA reporting a 50% reduction in ratings. Thus, although the C-CASA resulted in the identification of more suicidal events overall, fewer events were classified as suicide attempts. Additionally, the C-CASA ratings were highly reliable (intraclass correlation coefficient [ICC]=0.89). Conclusions: Utilizing a methodical, anchored approach to categorizing suicidality provides an accurate and comprehensive identification of suicidal events. The FDA’s audit of the C-CASA demonstrated excellent transportability of this approach. The Columbia algorithm was used to classify suicidal adverse events in the recent FDA adult antidepressant safety analyses and has also been mandated to be applied to all anticonvulsant trials and other centrally acting agents and nonpsychotropic drugs.

Etiology and management of refractory epilepsies

The epilepsies are an important, common and diverse group of symptom complexes characterized by recurrent spontaneous seizures. Although many patients with epilepsy have their seizures controlled effectively by antiepileptic drugs (AEDs), about one-third of patients continue to have seizures, despite trying a range of AEDs. Such patients bear the heaviest burden of epilepsy, with increased morbidity and risk of premature mortality. Our current understanding of the refractory epilepsies--the most common of which are focal--is limited; even their definition is problematic. Standard treatments for refractory epilepsies include optimization of existing AED regimens, trials of further AEDs, and, for some patients, therapeutic resective neurosurgery. Recent basic research has explored possible underlying causes of refractory epilepsy, and two main hypotheses have emerged to account for the failure of AED treatment. According to one hypothesis, AEDs might fail because of alterations in the properties of their usual targets. Alternatively, they might fail because multidrug transporter mechanisms limit concentrations of the drugs at their targets. The refractory epilepsies can be viewed as offering remarkable insights into biological processes in the epilepsies, and their effective treatment remains an important aim; treatment would potentially bring much-needed relief to hundreds of thousands of patients across the world.

Seizure‐Free Outcome in Randomized Add‐on Trials of the New Antiepileptic Drugs

The goal of this study is to (1) provide clinically useful, previously unpublished comparative analyses of seizure-freedom rates for newer antiepileptic drugs (AEDs), and (2) recommend a standard for data presentation and analysis. Data were reviewed from placebo-controlled adjunctive trials in refractory patients of gabapentin (GPN), lamotrigine (LTG), topiramate (TOP), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), zonisamide (ZNS), and pregabalin (PGB). Seizure-freedom analyses in these publications, if included at all, consistently included both patients who completed the trial, and those who dropped out prior to completion (last observation carried forward, LOCF). This has the potential to increase reported seizure-free outcomes. Pharmaceutical companies were contacted for the provision of unpublished seizure-free data in the patients who completed the entire study. In most cases, LOCF analysis produced a higher rate of seizure freedom compared to complete analysis. A total of 0%-1.1% of the LOCF population was seizure-free in the GPN trials (complete data not available). For the remaining AEDs, seizure-freedom results in the LOCF versus complete populations were: 0.7% versus 0.8% (LTG trial); 12% versus 2.6% (OXC trial); 3.6%-6.4% versus 3.9%-7.1% (LEV trial); 3.7%-7.9% versus 1.3%-1.4% (PGB trial); and 6.0% versus 3.0% (ZNS trial, minus titration period). By employing LOCF, a clinically unrealistic picture of seizure-free rates may be reported. Access to complete data is informative, as it includes only those patients who were able to tolerate the drug at doses that produced seizure freedom. Ideally, data from both ITT and complete analyses should be made available.

Tuberous sclerosis successfully treated with levetiracetam monotherapy: 18 months of follow-up

We present the case of a boy with tuberous sclerosis who was referred for evaluation and treatment of his intractable epileptic seizures, having failed multiple anti-epileptic drug trials. He was subsequently treated with Levetiracetam that was gradually titrated to an effective dose, achieving full suppression of his seizures. Thereafter, his concomitant anti-epileptic drugs were gradually reduced and eventually discontinued. He remained on monotherapy with Levetiracetam, which continued to fully control his seizures. His EEG tracings before and after treatment are presented and compared, showing normalization of the latter. Levetiracetam appears to be effective in treatment-resistant seizures which are symptomatic to tuberous sclerosis when used adjunctively as well as in monotherapy. This is the first report in the English literature regarding its use and efficacy in this condition.

Vagus nerve stimulation for treatment of epilepsy in Rett syndrome

This case series presents the outcomes of seven females with Rett syndrome and medically refractory epilepsy who were treated with adjunctive vagus nerve stimulation (VNS) therapy for a minimum of 12 months. Patients ranged in age from 1 to 14 years (median age 9y) at the time of implantation, had experienced seizures for a median period of approximately 6 years, and had failed at least two trials of antiepileptic drugs before receiving VNS. The median number of seizures per month was 150 (range 12–3600). At 12 months, six females had ≥50% reduction in seizure frequency. VNS was safe and well tolerated, with no surgical complications and no patients requiring explantation of the device. Quality of life outcomes of note among these patients included reports at 12 months of increased alertness among all seven patients. No change in mood or communication abilities was noted.