Faculty Bibliography

Transmeningeal pharmacotherapy for cerebral cortical disorders requires drug delivery through the subdural/subarachnoid space, ideally with a feedback controlled mechanism. We have developed a device suitable for this function. The first novel component of the apparatus is a silicone rubber strip equipped with (a) fluid-exchange ports for both drug delivery and local cerebrospinal fluid (CSF) removal, and (b) EEG recording electrode contacts. This strip can be positioned between the dura and pia maters. The second novel component is an implantable dual minipump that directs fluid movement to and from the silicone strip and is accessible for refilling and emptying the drug and CSF reservoirs, respectively. This minipump is regulated by a battery-powered microcontroller integrating a bi-directional radiofrequency (RF) communication module. The entire apparatus was implanted in 5 macaque monkeys, with the subdural strip positioned over the frontal cortex and the minipump assembly secured to the cranium under a protective cap. The system was successfully tested for up to 8months for (1) transmeningeal drug delivery using acetylcholine (ACh) and muscimol as test compounds, (2) RF-transmission of neocortical EEG data to assess the efficacy of drug delivery, and (3) local CSF removal for subsequent diagnostic analyses. The device can be used for (a) monitoring neocortical electrophysiology and neurochemistry in freely behaving nonhuman primates for more than 6months, (b) determining the neurobiological impact of subdural/subarachnoid drug delivery interfaces, (c) obtaining novel neuropharmacological data on the effects of central nervous system (CNS) drugs, and (d) performing translational studies to develop subdural pharmacotherapy devices

OBJECTIVE: To develop guidelines for selection of antiepileptic drugs (AEDs) among people with HIV/AIDS. METHODS: 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. Results and Recommendations: 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 ~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, as 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.

Depression in patients with temporal lobe epilepsy (TLE) is highly prevalent and carries significant morbidity and mortality. Its neural basis is poorly understood. We used quantitative, surface-based MRI analysis to correlate brain morphometry with severity of depressive symptoms in 38 patients with TLE and 45 controls. Increasing severity of depressive symptoms was associated with orbitofrontal cortex (OFC) thinning in controls, but with OFC thickening in TLE patients. These results demonstrate distinct neuroanatomical substrates for depression with and without TLE, and suggest a unique role for OFC, a limbic region for emotional processing strongly interconnected with medial temporal structures, in TLE-related depressive symptoms

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)

The efficacy and safety of lamotrigine extended-release tablets (LTG XR) as monotherapy for partial seizures were evaluated using the conversion-to-monotherapy design, and historical data as the control. This methodology was recently approved by the United States Food and Drug Administration, and this study is the first historical control design in epilepsy to complete enrollment. Patients >/=13 years old with uncontrolled partial epilepsy receiving monotherapy with valproate or a noninducing antiepileptic drug were converted to once-daily LTG XR (250 mg or 300 mg) as monotherapy and were followed up for 12 additional weeks. Efficacy was measured by the proportion of patients meeting predefined escape criteria for seizure worsening compared with aggregated pseudoplacebo control data from 8 previously conducted conversion-to-monotherapy trials. Nonoverlap of the 95% confidence limit for LTG XR and the 95% prediction interval of the historical control denotes efficacy. Of 226 randomized patients, 174 (93 in 300 mg/day group and 81 in 250 mg/day group) started withdrawal of the background AED and were evaluated for escape. In the historical control analysis population, the lower 95% prediction interval of the historical control (65.3%) was not overlapped by the upper 95% confidence limit of either LTG XR (300 mg/day; 37.2%) or LTG XR (250 mg/day; 43.4%). Adverse events were reported in 53% and 61% of patients receiving LTG XR (300 mg/day and 250 mg/day, respectively). LTG XR (250 mg or 300 mg once daily) is effective for conversion-to-monotherapy treatment of partial seizures in patients >/=13 years old.

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).

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