Faculty Bibliography

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: 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

Blurring of the cortical gray and white matter border on MRI is associated with normal aging, pathological aging, and the presence of focal cortical dysplasia. However, it remains unclear whether normal variations in signal intensity contrast at the gray and white matter junction reflect the functional integrity of subjacent tissue. This study explores the relationship between verbal abilities and gray and white matter contrast (GWC) in healthy human adults. Participants were scanned at 3 T MRI and administered standardized measures of verbal expression and verbal working memory. GWC was estimated by calculating the non-normalized T1 image intensity contrast above and below the cortical gray/white matter interface. Spherical averaging and whole-brain correlational analyses were performed. Sulcal regions exhibited higher contrast compared to gyral regions. We found a strongly lateralized and regionally specific profile with reduced verbal expression abilities associated with blurring in left hemisphere inferior frontal cortex and temporal pole. Reduced verbal working memory was associated with blurring in widespread left frontal and temporal cortices. Such lateralized and focal results provide support for GWC as a measure of regional functional integrity and highlight its potential role in probing the neuroanatomical substrates of cognition in healthy and diseased populations

Experimental and clinical findings have shown in the past decade that specific proinflammatory mediators and their cognate receptors are upregulated in epileptic brain tissue. In particular, the IL-1 receptor (R)/Toll-like receptor (TLR) signaling pathways are activated in experimental models of seizures and in human epileptic tissue from drug-resistant patients. Pharmacological targeting of these proinflammatory pathways using selective receptor antagonists, or the use of transgenic mice with perturbed cell signaling, demostrated that the activation of IL-1R type 1 and TLR4 by their respective endogenous ligands, i.e., interleukin (IL)-1b and High Mobility Group Box 1, is implicated in the precipitation and recurrence of experimentally induced seizures in rodents. This evidence highlights a new target system for pharmacological intervention to inhibit seizures by interfering with mechanisms involved in their genesis and recurrence.

Using data from NIH Research Portfolio Online Reporting Tools (RePORT) and recently assembled prevalence estimates of 6 major neurologic diseases, we compared the relative prevalences and the annual NIH support levels for 6 major neurologic disorders: Alzheimer disease, amyotrophic lateral sclerosis (ALS), epilepsy, multiple sclerosis, Parkinson disease, and stroke. Compared to these other major neurologic disorders, epilepsy research is funded at a persistently lower rate based on relative disease prevalences. Relative NIH funding for these other disorders in 2010 adjusted for prevalence ranged from 1.7x (stroke) to 61.1x (ALS) greater than epilepsy. The disparity cannot be explained by differences in the overall impact of these diseases on US citizens. Greater transparency in the review and funding process is needed to disclose the reason for this disparity