Therapeutic devices for epilepsy

Abstract

Therapeutic devices provide new options for treating drug-resistant epilepsy. These devices act by a variety of mechanisms to modulate neuronal activity. Only vagus nerve stimulation (VNS), which continues to develop new technology, is approved for use in the United States. Deep brain stimulation of anterior thalamus for partial epilepsy recently was approved in Europe and several other countries. Responsive neurostimulation, which delivers stimuli to 1 or 2 seizure foci in response to a detected seizure, recently completed a successful multicenter trial. Several other trials of brain stimulation are in planning or underway. Transcutaneous magnetic stimulation (TMS) may provide a noninvasive method to stimulate cortex. Controlled studies of TMS are split on efficacy, which may depend on whether a seizure focus is near a possible region for stimulation. Seizure detection devices in the form of shake detectors via portable accelerometers can provide notification of an ongoing tonic-clonic seizure, or peace of mind in the absence of notification. Prediction of seizures from various aspects of electroencephalography (EEG) is in early stages. Prediction appears to be possible in a subpopulation of people with refractory seizures, and a clinical trial of an implantable prediction device is underway. Cooling of neocortex or hippocampus reversibly can attenuate epileptiform EEG activity and seizures, but engineering problems remain in its implementation. Optogenetics is a new technique that can control excitability of specific populations of neurons with light. Inhibition of epileptiform activity has been demonstrated in hippocampal slices, but use in humans will require more work. In general, devices provide useful palliation for otherwise uncontrollable seizures, but with a different risk profile than with most drugs. Optimizing the place of devices in therapy for epilepsy will require further development and clinical experience.

Figure 1

A. A Peltier cooling device (cool side down) is situated over a left frontal seizure focus in an anesthetized rat. The seizure focus was induced by placement of the GABA antagonist, bicuculline methiodide 2 mM. B. Upper panel shows spikes at 37° C. The middle panel shows attenuation of spikes with cooling of cortex. The lower panel shows reversible return of spiking with rewarming to 37° C.

Figure 2

A. In an organotypic hippocampal culture, a yellow-orange light (marked by orange bar) activates channel rhodopsin, opens chloride channels, hyperpolarizes transfected neurons and inhibits firing. B. Stimulus-train-induced bursting in hippocampal culture slices is inhibited by halorhodopsin mediated response to orange light (marked by orange bar, middle panel). Region of expanded insets is marked by dotted rectangles. Adapted with permission from Tønnesen et al. .

Figure 3

A. The GABA antagonist drug, bicuculline methiodide 4 mM, is placed via cannula a twist drill skull opening onto the left parietal cortex of an anesthetized rat. Bone screws record EEG at left anterior (LA), right anterior (RA), left mid-cortex (LM), right mid-cortex (RM), left parietal (LP) and right parietal (RP) with respect to a reference (Ref) over the frontal midline sinus. B. Bipolar EEG at baseline. C. Epileptiform spikes are seen over the LM electrode after placement of bicuculline methiodide (BMI) 4 mM. D. Epileptiform spiking disappears seconds after administration of diazepam via the catheter. Adapted with permission from Eder et al. Eder .

Figure 4

In the SANTE trial of anterior nucleus stimulation, patients receiving active stimulation (green solid line) have fewer median seizures as a percentage of baseline than do those receiving sham stimulation (red dashed line). Adapted with permission from Fisher et al. .

Figure 5

Diagrammatic view of a responsive neurostimulator implanted in right temporal skull, with a recording-stimulating strip over the right frontal region and a stimulating-recording depth wire in the right occipital region. With permission, courtesy of Martha Morrell of NeuroPace®.