Faculty Bibliography

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.

Patient age can impact selection of the optimal antiepileptic drug for a number of reasons. Changes in brain physiology from neonate to elderly, as well as changes in underlying etiologies of epilepsy, could potentially affect the ability of different drugs to control seizures. Unfortunately, much of this is speculative, as good studies demonstrating differences in efficacy across age ranges do not exist. Beyond the issue of efficacy, certain drugs may be more or less appropriate at different ages because of differing pharmacokinetics, including changes in hepatic metabolism, absorption, and elimination. Lack of appropriate drug formulations (such as liquid forms) may be a barrier to using drugs in the very young. Finally, some serious adverse events are seen either exclusively or preferentially at different ages.

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.

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.

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).