Faculty Bibliography

Septal nuclei, components of basal forebrain, are strongly and reciprocally connected with hippocampus, and have been shown in animals to play a critical role in memory. In humans, the septal forebrain has received little attention. To examine the role of human septal forebrain in memory, we acquired high-resolution magnetic resonance imaging scans from 25 healthy subjects and calculated septal forebrain volume using recently developed probabilistic cytoarchitectonic maps. We indexed memory with the California Verbal Learning Test-II. Linear regression showed that bilateral septal forebrain volume was a significant positive predictor of recognition memory accuracy. More specifically, larger septal forebrain volume was associated with the ability to recall item source/context accuracy. Results indicate specific involvement of septal forebrain in human source memory, and recall the need for additional research into the role of septal nuclei in memory and other impairments associated with human diseases. (JINS, 2012, 18, 157-161)

A joint panel of the American Academy of Neurology (AAN) and the International League Against Epilepsy (ILAE) convened to develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. The literature was systematically reviewed to assess the global burden of relevant comorbid entities, to determine the number of patients who potentially utilize AEDs and antiretroviral agents (ARVs), and to address AED-ARV interactions. Key findings from this literature search included the following: AED-ARV administration may be indicated in up to 55% of people taking ARVs. Patients receiving phenytoin may require a lopinavir/ritonavir dosage increase of approximately 50% to maintain unchanged serum concentrations (Level C). Patients receiving valproic acid may require a zidovudine dosage reduction to maintain unchanged serum zidovudine concentrations (Level C). Coadministration of valproic acid and efavirenz may not require efavirenz dosage adjustment (Level C). Patients receiving ritonavir/atazanavir may require a lamotrigine dosage increase of approximately 50% to maintain unchanged lamotrigine serum concentrations (Level C). Coadministration of raltegravir/atazanavir and lamotrigine may not require lamotrigine dosage adjustment (Level C). Coadministration of raltegravir and midazolam may not require midazolam dosage adjustment (Level C). Patients may be counseled that it is unclear whether dosage adjustment is necessary when other AEDs and ARVs are combined (Level U). It may be important to avoid enzyme-inducing AEDs in people on ARV regimens that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors because pharmacokinetic interactions may result in virologic failure, which has clinical implications for disease progression and development of ARV resistance. If such regimens are required for seizure control, patients may be monitored through pharmacokinetic assessments to ensure efficacy of the ARV regimen (Level C).

Regulatory trials rigorously test the ability of a treatment to impact a known outcome, such as seizure frequency, as measured in well-controlled trials. Such outcomes are called efficacy outcomes. Sometimes these measured outcomes do not reflect the true effectiveness of the drug in the clinic. This article provides some examples of how this can happen and also discusses trials intended to measure effectiveness.

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. 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

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

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