Faculty Bibliography

Clinical trials as part of antiepileptic drug development are increasingly expensive and complex, with many pitfalls that can derail even promising drugs and devices. Although a third of patients remain resistant to treatment, the availability of more than 20 approved antiepileptic drugs can reduce the incentive to enrol in trials of unproven agents, for which safety is not assured. The challenge of recruiting patients drives investigators to regions of the world where treatment options are more limited. This increases complexity and has potential implications for quality of the trial data. Furthermore, the availability of so many approved treatments raises questions about the ethics and safety of placebo-controlled trials in patients with epilepsy. Novel trial designs, such as time-to-event adjunctive therapy and historical-control monotherapy, might be more acceptable to patients and their doctors because they restrict exposure to placebo or ineffective treatments.

Rationale: Resective surgical treatment can be curative in a large subset of patients with treatment resistant epilepsy. Despite the potential for seizure freedom following surgery, many patients do not progress to epilepsy surgery. It is presumed that the reasons for this are multifactorial and often stem from poor prognostic factors within the presurgical workup. This study was designed to explore potential barriers (both medical and social) to resective epilepsy surgery in a population of patients with a high likelihood of seizure freedom based upon initial MRI, EEG, and semiology data. Methods: Chart review of patients admitted to the New York University Langone Medical Center epilepsy monitoring unit from 1/1/2007 to 7/31/2008 identified 1,105 unique patients. Of these, 455 met inclusion criteria: age >=18, focal epilepsy diagnosis>=2 years, failed >=1 medication, and >=1 seizure three months prior to admission. Utilizing the Epilepsy Surgery Grading Scale (ESGS; Table 1), a score was calculated from MRI, EEG, semiology, and IQ data. Patients with scores categorizing them as Grade 1 (best likelihood of seizure freedom) were included for analysis. Patients with follow-up periods less than 6 months and those with previous resective surgeries were excluded (32 patients). Outcomes were assessed based upon last available follow-up up through June 1, 2011. Patients were classified as either seizure free or not seizure free. For patients not undergoing surgery, medical and surgical outpatient notes were reviewed to ascertain the reason(s) for not pursuing surgery. Results: Of the 423 patients, a total of 110 were Grade 1. Of all Grade 1 patients, 43 (39.1%) underwent resective epilepsy surgery. Two patients had less than one year of follow-up; 35/41 (85.4%) were seizure free. An additional 11 (10%) patients underwent intracranial EEG monitoring without resection. Of the 56 (50.9%) patients that did not undergo invasive monitoring or resective surgery within the period of follow-up, 15 (26.8%) were reported as seizure free at the time of last follow-up. For the remaining patients, multiple reasons were identified for not pursuing surgery. These findings are presented in Table 2. In brief, 2% are presently awaiting surgery, 21% the patient declined surgery, 7% reported adequate seizure control and declined surgery, 16% had no identifiable reason (unknown), 25% were lost to follow up, and 2% had insurance denials precluding surgery. Conclusions: These results indicate that multiple factors can contribute to patients failing to pursue epilepsy surgery, with over 1/2 of patients declining surgery due to seizure freedom, "adequate" seizure control or no desire to further pursue surgery despite continued seizures. In addition, 25% of patients were lost to follow-up, which does not preclude them having had resective surgery at another institution

Early withdrawal of patients from a clinical trial can compromise the robustness of the data by introducing bias into the analysis. This is most commonly addressed by using the "intent to treat" (ITT) population and "last observation carried forward" (LOCF) methodology, where a patient's last assessment is carried forward. This can lead to overstatement of treatment efficacy especially if events indicative of treatment failure are infrequent. An alternative methodology, labeled "pragmatic ITT" (P-ITT), requires patients to have a positive outcome and to complete the trial in order to be considered a treatment success by that outcome measure. Data from 3 randomized multicenter lamotrigine extended-release (LTG XR) trials were analyzed and response (proportions seizure-free and with 50% response) were compared using LOCF and P-ITT methodologies. In 2 of the 3 trials, a lower response for both seizure freedom and 50% response was seen during the Maintenance phase using the P-ITT methodology. In the trial that did not show a difference, only a small number of patients withdrew early, thus negating the benefit brought by the P-ITT method. Differences between methodologies were not noted when evaluation was applied to the entire treatment period, most likely a reflection of the fact that a therapeutic dose of lamotrigine is not rapidly achieved. We propose that the P-ITT may be a simpler, more informative method for evaluating the effectiveness of a drug, especially in comparison to another active drug(s).

Rationale: In patients with refractory focal epilepsy, surgery remains an important treatment option for achieving seizure freedom. However, the existing data suggest that for patients with normal neuroimaging, the likelihood of achieving seizure freedom is significantly reduced compared to patients with lesional neuroimaging. This study assesses the utilization of resective surgery versus medical management in patients with normal neuroimaging. Specifically, the study aims to determine how frequently patients with normal brain MRIs are referred for epilepsy surgery and whether there is a difference in outcome (i.e. seizure control) between medically managed and surgically managed patients. Methods: Following approval through the Institutional Review Board at New York University School of Medicine, patients were retrospectively identified by querying the surgical multidisciplinary case (MDC) conference registry. The records were reviewed from January 1, 2007 - July 31, 2008 to identify patients. Inclusion criteria were: age >=18 years, focal epilepsy diagnosis >=2 years, failed >=1 medication, and >=1 seizure three months prior to admission. Of all patients meeting these criteria, 193 were presented at the MDC conference and 33 had normal MRIs upon review. Seizure frequency data were collected by chart review, and when data were incomplete, the patient's primary epileptologist at the NYU Comprehensive Epilepsy Center was contacted. Comparisons were made between the two groups (surgical versus nonsurgical treatment) utilizing the Student's t-test and Fisher's exact test. Results: Of the 33 patients with normal neuroimaging who were presented at MDC, 19 went on to epilepsy surgery (9 women) and 14 were managed medically (7 women); all patients undergoing invasive monitoring underwent resective surgery. The mean age at the time of MDC did not differ between groups (surgery: 30.1+/-10.4, medical: 29+/-10.6; p>0.76). Although a trend for a younger mean age at seizure onset was seen for medically managed patients (surgery: 16.6+/-9.3, medical: 10.9+/-8.8; p>0.09), no significant difference was seen for duration (in years) of epilepsy at the time of MDC (surgery: 13.6+/-10.2, medical: 18.1+/-12.5; p>0.26). At the time of last follow-up, 7 (36.8%) surgical patients were seizure free and 3 (21.4%) medically managed patients were seizure free (p=0.46). Conclusions: Across one and a half years, only 33 of 193 (17.1%) patients reviewed at MDC had normal neuroimaging and focal epilepsy. Ten (30.3%) of the 33 patients were completely seizure free (Engel IA) at last follow-up (with either medical or surgical management). Nineteen of the patients with normal neuroimaging went on to resective surgery with seven (36.8%) becoming seizure free, whereas three (21.4%) of the 14 who were managed medically became seizure free. These data demonstrate that patients with normal neuroimaging represent a minority of those presented at MDC. Although not seen in the majority of cases with normal neuroimaging, seizure freedom can be achieved through either surgical or medical management

Rationale: The purpose of this study is to evaluate the use of an electronic diary system with a mobile application tool in an epilepsy trial. Clinical trials in epilepsy can be compromised by inaccurate reporting of seizures and other clinical events. Paper diaries, which are the standard, do not assess whether data was entered in a timely fashion. Electronic diaries (particularly coupled with mobile devices) may not only facilitate reporting by subjects, but also enable monitoring of the interval from occurrence of event to entry time as a marker of validity and accuracy, and allow real-time monitoring of adherence with study procedures. The WEPOD (Women with Epilepsy: Pregnancy Outcomes and Deliveries) study is a 3-site prospective, observational study evaluating fertility, hormones, AED concentrations, and seizure frequency as women with epilepsy (WWE) transition from preconception planning through pregnancy and delivery. We assessed the ability of subjects to use electronic data entry and the timeliness of data entry. Methods: Women with epilepsy and controls, ages 18-40 years, seeking pregnancy are enrolled within 6 months of stopping birth control. A customized iPod Touch Application (the WEPOD App) was developed for daily tracking of primary clinical data. The WEPOD App is connected to a web-based program utilizing the infrastructure of "My Epilepsy Diary" by epilepsy.com. All subjects were given an iPod Touch 4, but they could also elect to use the web-based program or a paper diary. All subjects were asked to track menstrual flow and sexual activity daily (fertility diary). WWE also tracked AED adherence and seizure occurrence. The WEPOD App includes an alarmed daily reminder asking the subject if she tracked today. Results: At this interim analysis, 16 WWE and 21 controls were enrolled and provided diary data for 1402 days and 1186 days, respectively. All subjects used the WEPOD app and/or the web; no subjects chose paper diaries. No significant differences were found between the WWE and controls for age, race, ethnicity, education, and employment (Table 1) (p>0.05). Average days of data entry was 86.6 +/-60.4 (range 2- 189) for WWE, and 57.2 +/-50.4 (range 1-180) for controls. On average the completion of the fertility diary was 100% +0.3 for WWE and 100% +0.3 for controls (minimum 48% and 65%, respectively). Time stamps for 89 seizures revealed that 83.2% were entered <24 hours of reported seizure occurrence. Mean time to report was 14.5 +/-23.7 hours. Conclusions: Use of a customized mobile App for daily tracking of clinical data has been an effective tool in the WEPOD trial. Use of an iPod Touch could serve as a positive recruiting tool in the young adult population targeted for this study, but did not cause an imbalance between the two groups. Time to seizure entry was excellent. Additional benefits include a daily reminder alarm, ability to monitor protocol compliance, and immediate information to schedule study visits, especially if timed to an event such as menstrual flow. Future directions include evaluation of this tool across a variety of populations, trial designs, and diseases

Rationale: Resective surgical treatment can be curative in a large subset of patients with treatment resistant epilepsy. There is a need for a simple surgical grading scale that can be used by the referring neurologist using information obtained prior to diagnostic hospitalization. Such a tool would provide a simple, systematic method for identifying a patient's likelihood of positive outcome following surgical treatment and would offer a uniform means to improve epidemiology and tracking. Our hypothesis was that a model using interictal EEG, brain MRI, seizure semiology and IQ could stratify patients with treatment resistant epilepsy based upon their likelihood of achieving seizure freedom following assessment for resective epilepsy surgery. Methods: Chart review of patients admitted to the New York University Langone Medical Center epilepsy monitoring unit from 1/1/2007 to 7/31/2008 identified 1,105 unique patients. Of these, 455 met inclusion criteria: age >=18, focal epilepsy diagnosis >=2 years, failed >=1 medication, and >=1 seizure three months prior to admission. Calculation of the Epilepsy Surgery Grading Scale (ESGS) score was based upon MRI, EEG, semiology, IQ (Table 1). Patients with follow-up periods <6 months and those with prior resective surgeries were excluded (32 patients). Outcomes were assessed at the study's conclusion (3/31/2010); patients were classified as either seizure free following resective surgery or not seizure free following surgery/no resection. Three cohorts were used in this study: 1) the full cohort, 2) only patients undergoing surgical multidisciplinary case (MDC) conference evaluation, 3) only patients who underwent resective surgery. Results: Our data demonstrate that of 423 patients initially identified as presurgical admissions to the EMU, only 193 (45.6%) were ultimately considered for surgical management and presented in surgical MDC. Eighty-four (19.9%) then underwent resective surgery. Analysis of the MDC cohort reveals that 53.2% of ESGS Grade 1 patients, 34.1% of Grade 2 patients, and 17.2 % of Grade 3 patients became seizure free from resective surgery. For this cohort, significant differences between Grades 1 and 3 (p=0.0001), and between Grades 2 and 3 (p=0.0463) were seen, and a trend was seen between Grades 1 and 2 (p=0.0743). Analysis of the resection only cohort showed that 89.2% of ESGS Grade 1 patients, 83.3% of Grade 2 patients, and 44.8% of Grade 3 patients became seizure free from resective surgery (Table 2). Significant differences between Grades 1 and 3 (p=0.0009), and between Grades 2 and 3 (p=0.0343) were seen; the difference between Grades 1 and 2 was not statistically significant (p=0.6713). Conclusions: These results indicate that, using basic information obtainable in a doctor's office, patients with treatment resistant epilepsy may be stratified into clinically meaningful groups based upon their likelihood of achieving seizure freedom as a result of resective surgery

Object The authors evaluated the extent to which the Subdural Pharmacotherapy Device (SPD), chronically implanted over the frontal cortex to perform periodic, localized muscimol-delivery/CSF removal cycles, affects overall behavior, motor performance, electroencephalography (EEG) activity, and blood and CSF neurochemistry in macaque monkeys. Methods Two monkeys were used to adjust methodology and 4 monkeys were subjected to comprehensive testing. Prior to surgery, the animals' behavior in a large test chamber was monitored, and the motor skills required to remove food pellets from food ports located on the walls of the chamber were determined. The monkeys underwent implantation of the subdural and extracranial SPD units. The subdural unit, a silicone strip integrating EEG electrodes and fluid-exchange ports, was positioned over the right frontal cortex. The control unit included a battery-powered, microprocessor-regulated dual minipump and radiofrequency module secured to the cranium. After implantation, the SPD automatically performed periodic saline or muscimol (1.0 mM) deliveries at 12-hour intervals, alternating with local CSF removals at 6-hour intervals. The antiepileptic efficacy of this muscimol concentration was verified by demonstrating its ability to prevent focal acetylcholine-induced seizures. During SPD treatment, the monkeys' behavior and motor performance were again monitored, and the power spectrum of their radiofrequency-transmitted EEG recordings was analyzed. Serum and CSF muscimol levels were measured with high-performance liquid chromatography electrochemical detection, and CSF protein levels were measured with turbidimetry. Results The SPD was well tolerated in all monkeys for up to 11 months. The behavioral study revealed that during both saline and muscimol SPD treatment, the monkeys could achieve the maximum motor performance of 40 food-pellet removals per session, as before surgery. The EEG study showed that local EEG power spectra were not affected by muscimol treatment with SPD. The neurochemical study demonstrated that the administration of 1.0 mM muscimol into the neocortical subarachnoid space led to no detectable levels of this compound in the blood and cisternal CSF, as measured 1-125 minutes after delivery. Total protein levels were within the normal range in the cisternal CSF, but protein levels in the cortical-site CSF were significantly higher than normal: 361 +/- 81.6 mg/dl. Abrupt discontinuation of 3-month, periodic, subdural muscimol treatments induced withdrawal seizures, which could be completely prevented by gradually tapering off the subdural muscimol concentration from 1.0 mM to 0.12-0.03 mM over a period of 2 weeks. The monkeys' general health and weight were maintained. Infection occurred only in one monkey 9 months after surgery. Conclusions Long-term, periodic, transmeningeal muscimol delivery with the SPD is essentially a safe procedure. If further improved and successfully adapted for use in humans, the SPD can be used for the treatment of intractable focal neocortical epilepsy affecting approximately 150,000 patients in the US.

PURPOSE: An NINDS-sponsored conference in April of 2011 reviewed issues in epilepsy clinical trials. One goal was to clarify new electronic methods for recording seizure information and other data in clinical trials. METHODS: This selective literature review and compilation of expert opinion considers advantages and limitations of traditional paper-based seizure diaries in comparison to electronic diaries. KEY FINDINGS: Seizure diaries are a type of patient-reported outcome. All seizure diaries depend first on accurate recognition and recording of seizures, which is a problem since about half of seizures recorded during video-EEG monitoring are not known to the patient. Reliability of recording is another key issue. Diaries may not be at hand after a seizure, lost or not brought to clinic visits. On-line electronic diaries have several potential advantages over paper diaries. Smartphones are increasingly accessible as data entry gateways. Data are not easily lost and are accessible from clinic. Entries can be time-stamped and provide immediate feedback, validation or reminders. Data can also can be graphed and pasted into an EMR. Disadvantages include need for digital sophistication, higher cost, increased setup time, and requiring attention to potential privacy issues. The Epilepsy Diary by epilepsy.com and Irody, Inc. has over 13,000 registrants and SeizureTracker over 10,000, and both are used for clinical and research purposes. Some studies have documented patient preference and increased compliance for electronic versus paper diaries. Seizure diaries can be challenging in the pediatric population. Children often have multiple seizure types and limited reporting of subjective symptoms. Multiple caregivers during the day require more training to produce reliable and consistent data. Diary-based observational studies have the advantages of low cost, allowing locus-of-control by the patient and testing in a "real-world" environment. Diary-based studies can also be useful as descriptive "snapshots" of a population. However, the type of information available is very different from that obtained by prospective controlled studies. The act of self-recording observations may itself influence the observation, for example, by causing the subject to attend more vigilantly to seizures after changing medication. Pivotal anti-seizure drug or device trials still mostly rely on paper-based seizure diaries. Industry is aware of the potential advantages of electronic diaries, particularly, the promise of real-time transmission of data, time-stamping of entries, reminders to subjects, and potentially automatic interfaces to other devices. However, until diaries are validated as research tools and the regulatory environment becomes clearer, adoption of new types of diaries as markers for a primary study outcome will be cautious. SIGNIFICANCE: Recommendations from the conference included: further studies of validity of epilepsy diaries and how they can be used to improve adherence; use and further development of core data sets, such as the one recently developed by NINDS; encouraging links of diaries to electronic sensors; development of diary privacy and legal policies; examination of special pediatric diary issues; development of principles for observational research from diaries; and work with the FDA to make electronic diaries more useful in industry-sponsored clinical trials.

Idiopathic generalized epilepsy (IGE) is associated with widespread cortical network abnormalities on electroencephalography. Resting state functional connectivity (RSFC), based on fMRI, can assess the brain's global functional organization and its disruption in clinical conditions. We compared RSFC associated with the 'default mode network' (DMN) between people with IGE and healthy controls. Strength of functional connectivity within the DMN associated with seeds in the posterior cingulate cortex (PCC) and medial prefrontal cortices (MPFC) was compared between people with IGE and healthy controls and was correlated with seizure duration, age of seizure onset and age at scan. Those with IGE showed markedly reduced functional network connectivity between anterior and posterior cortical seed regions. Seizure duration positively correlates with RSFC between parahippocampal gyri and the PCC but negatively correlates with connectivity between the PCC and frontal lobe. The observed pattern of disruption provides evidence for integration- and segregation-type network abnormalities and supports aberrant network organization among people with IGE.