SEATTLE—Levetiracetam has similar efficacy and tolerability to long-acting valproate (VPA-ER) and long-acting carbamazepine (CBZ-CR) among patients with newly diagnosed partial or generalized epilepsy, according to results of an open-label, parallel-group study presented by Bernhard Pohlmann-Eden, MD, and colleagues.

A total of 1,688 patients 16 or older from 269 centers in Europe and Australia were randomized first to “best recommended treatment” (either VPA-ER or CBZ-CR) and then to levetiracetam (n = 841; median dosage, 986.6 mg/day), VPA-ER (n = 347; median dosage, 986.5 mg/day), or CBZ-CR (n = 500; median dosage, 588.5 mg/day), for 52 weeks.

Inclusion criteria were newly diagnosed epilepsy (within the past year), at least two unprovoked seizures in the past two years, and at least one seizure in the past six months. Patients were not eligible if they had been treated previously with levetiracetam, valproate, or carbamazepine. Extended-release levetiracetam was not available at the time of the study but is now FDA approved.

“The primary outcome measure—time to withdrawal—which assesses both efficacy and tolerability, was similar for all three drugs. There was no difference in the seizure freedom rates at six months or 12 months,” said Dr. Pohlmann-Eden, a neurologist at Dalhousie University in Halifax, Nova Scotia.

The frequency of treatment-emergent adverse events was 45.6% for levetiracetam, 45.9% for VPA-ER, and 52.3% for CBZ-CR. Headache and fatigue were two of the most common side effects for all three drugs. Total discontinuation rates were similar between levetiracetam (24%) and both standard antiepileptic drugs (26.1%). However, the time to first seizure was significantly longer for VPA-ER and CBZ-CR than for levetiracetam (hazard ratio, 1.20).

Dr. Pohlmann-Eden concluded that “levetiracetam is at least as effective as standard antiepileptic drugs and slightly better for adverse events, with no significant difference for seizure freedom. In addition, it appears that levetiracetam is effective in generalized as well as partial epilepsy.”

Lacosamide Is Well Tolerated as Adjunctive Therapy
Lacosamide is well tolerated in patients with partial-onset seizures when combined with up to three concomitant antiepileptic drugs, reported Victor Biton, MD, Director of the Arkansas Epilepsy Program in Little Rock, and colleagues. The researchers presented findings from three similarly designed trials of lacosamide.

The pooled safety analysis included 1,308 subjects (944 on lacosamide, 364 on placebo) from a 21-week phase II study, a 21-week phase III study, and an 18-week phase III study. The most frequent adverse events occurring with lacosamide versus placebo were dizziness (31% vs 8%), headache (13% vs 9%), nausea (11% vs 4%), and diplopia (11% vs 2%).

The investigators observed a small, dose-related increase in the PR interval on ECG, which was not associated with second- or third-degree AV block. The percentage of patients discontinuing treatment due to an adverse event was 17% with lacosamide and 5% with placebo.

“Side effects mostly occurred in the titration phase,” said Dr. Biton. “We start with lacosamide 50 mg by mouth twice daily and increase by 100 mg/week to the maintenance phase of 200 to 400 mg/day.”

Although the recent FDA approval classifies lacosamide as a “controlled substance,” Dr. Biton said he “did not notice a euphoric factor.” Lacosamide does not induce physical dependency, and a withdrawal effect has not been documented.

“Lacosamide is effective, well tolerated, and will be available in an IV form,” concluded Dr. Biton.

Investigational Device Reduces Disabling Seizures
The RNS System, an investigational device, was safe and reduced disabling seizures when used as adjunctive therapy in adults with medically intractable partial-onset seizures participating in a two-year, multicenter feasibility study, reported Martha Morrell, MD, and colleagues.

Dr. Morrell, who is Chief Medical Officer of Neuropace, Inc (Mountain View, California), the manufacturer of the device, explained that the RNS System includes a cranially implanted, battery-powered responsive neurostimulator that detects the onset of electric seizures and responds with an electric stimulus to abort the seizure. The stimulator is connected to two leads (depth and/or subdural), each with four electrode contacts. A programmer sets detection and stimulation parameters, and EEG data are transmitted to a secure Web-based file. Dr. Morrell is also Clinical Professor of Neurology at Stanford University in Palo Alto, California.

The feasibility investigation was designed to demonstrate safety and provide preliminary evidence for efficacy. The study enrolled 65 subjects (ages 18 to 57; 52% female) who had four or more disabling simple partial, complex partial, or secondarily generalized tonic clonic seizures per month in one or two localized epileptogenic zones; participants had been treated unsuccessfully with two or more antiepileptic drugs. The mean age at seizure onset was 14 years, 28% had prior vagus nerve stimulation, and 82% had intracranial monitoring. Thirty-seven percent had had unsuccessful epilepsy surgery.

The RNS System neurostimulator and leads were implanted by a neurosurgeon. The neurostimulator was programmed to detect and, in those subjects assigned to receive stimulation, to stimulate in response to those detections. Evaluation for efficacy began 28 days after implantation, over three 28-day periods. Subjects were followed for 24 months postimplant. After two years, patients could transition to a long-term treatment trial for an additional five years.

The responder rate (≥ 50% seizure reduction) for the initial three 28-day periods, compared with baseline, was 24% for all disabling seizures, 27% for complex partial seizures, and 65% for generalized tonic clonic seizures. Seizure response appeared to be durable, as the responder rate for all disabling seizures was 48% at 18 months and 50% at 36 months. An analysis by seizure onset location revealed that the responder rate for hippocampal seizures (68%) was higher than the rate for neocortical seizures (38%).

Device-related serious adverse events included focal status epilepticus, an increase in seizure frequency, erosion, tissue infection, cranial reconstruction, fall injury, and wound infection, all of which were resolved.

A multicenter, double-blind, controlled pivotal trial is now under way at 29 sites across the United States.

Ambulatory Device Detects Sleep Apnea
A wearable sleep-monitoring device demonstrated high sensitivity and specificity for detecting apnea, according to data presented by John Duncan, MD, and colleagues. The research team has tested several prototypes of the device, with the current version consisting of a microphone, sensor dome, and adhesive that affixes to skin over the trachea.

According to Dr. Duncan, current ambulatory respiratory monitoring devices have several drawbacks: They tend to be too bulky to be comfortable, the sensor picks up too many movement artifacts, and they may require a large power source. The new system fits in the suprasternal notch and is designed to trigger an alarm in the event of more than 25 seconds of apnea. “We tried respiratory bands, electromyography, and axillary and chest wall placement, but the trachea is the best. The respiratory signal is very strong, it’s comfortable, you can get the cardiac signal at the same time, and it doesn’t come off when you roll over,” commented Dr. Duncan, Head of the Department of Clinical and Experimental Epilepsy at the Institute of Neurology at University College London.

Initial testing from 13 subjects (11 male; ages 18 to 33; weight, 50 to 100 kg) included 630 minutes of breathing data and 182 minutes of “voluntary apnea,” which were recorded by a computer and processed by an apnea detection algorithm. Despite ambient music and continuous head movement, the sensitivity and specificity were 99.2% and 99.92%, respectively. This translated into one false alarm for every 13.5 hours of monitoring and three missed apnea events from a total of 363 voluntary 30-second apnea episodes.

“Testing so far has been in volunteers. The next phase of trials will include overnight recordings in the sleep laboratory, using the sleep lab apnea data as the gold standard for comparison,” said Dr. Duncan.

Omega-3 Fatty Acids Improve Risk Factors for SUDEP
High-dose omega-3 fatty acids may improve cardiac risk factors and heart rate variability (HRV), a marker for the risk of sudden unexpected death in epilepsy (SUDEP), according to results of a randomized crossover pilot study reported by Christopher DeGiorgio, MD, Vice Chair and Professor in Residence of Neurology at the University of California, Los Angeles, and colleagues.

After a four-week baseline period, 11 subjects received high-dose omega-3 fatty acids, in the form of fish oil (9,600 mg/day), or placebo (soybean oil) for 12 weeks. A six-week washout period ensued, during which no drug was taken, followed by a crossover period. HRV was measured as SDNN (standard deviation of all normal R-R intervals for one hour) and SDANN (standard deviation of all R-R intervals in each successive five-minute epoch) and determined after one-hour ambulatory EKG monitoring at both the initial and last visits.

Overall, treatment with fish oil did not significantly affect seizure frequency or increase HRV. However, in four of five subjects with below-average HRV prior to treatment, the mean SDNN improved from 38.8 to 46.6 ms. Similarly, in the same subgroup, the SDANN improved from 17.5 to 21.2 ms. The researchers also found that the lower the baseline HRV, the better the improvement with fish oil.

In addition, the median HDL cholesterol level increased from 52 to 60 mg/dL, and the median triglyceride level decreased from 91 to 68 mg/dL.

“The results are preliminary, but this study provides the first evidence that risk factors for SUDEP, specifically low HRV, can be modified and improved,” Dr. DeGiorgio concluded. “We have begun a larger randomized trial of low- and high-dose omega-3 fatty acids versus corn oil placebo to test the hypothesis that omega-3 fatty acids improve risk factors associated with SUDEP.

—Andrew N. Wilner, MD

Study Data Support Levetiracetam Monotherapy