C.W. Dewey, DVM, MS, DACVIM (Neurology), DACVS
Deep brain stimulation (DBS) has proven to be a very effective surgical treatment option for people with Parkinson's disease. In recent years, evidence has accumulated attesting to the potential effectiveness of DBS for a variety of other brain disorders in people, including idiopathic epilepsy refractory to medical therapy. To date, all of the reports concerning DBS in human epileptics have been small uncontrolled case series. However, the positive preliminary results of these small reports (40%-90% seizure reduction) have prompted a large double-blinded, randomized prospective investigation of DBS for human epilepsy which is currently ongoing. As with the field of human seizure management, refractory canine epilepsy remains an important challenge for veterinarians despite the addition of several new drugs over the last 10-15 years. Impediments to adapting human surgical treatment options for seizure control to canine epileptics include cost, required expertise for application of such therapies, and potential morbidity associated with such procedures. The goals of this presentation are to review the current state of knowledge concerning DBS for seizure management in people and to discuss the possibility of evaluating this mode of therapy for the treatment of dogs with refractory epilepsy.
How DBS Provides an Anticonvulsant Effect
Nobody really knows how this happens. Deep brain stimulation involves the application of high frequency (90-180 Hz) current to specific brain structures via surgically-implanted electrodes. The four general (but not mutually exclusive) hypotheses by which DBS may provide an anticonvulsant effect include: 1) depolarization blockade, 2) synaptic inhibition, 3) synaptic depression, and 4) stimulus-induced disruption/modulation of pathologic network activity (i.e., desynchronization of depolarizing shift). That any or all of the proposed mechanisms may be involved in seizure suppression can be explained by the complex local environment surrounding a stimulation electrode. In a specific focal area of the brain, a DBS electrode may influence several types of cell populations: local cells, afferent inputs, and fibers of passage. Local cells are neurons whose cell bodies are very close to the stimulating electrode. Afferent inputs refer to axonal processes from neurons outside of the immediate vicinity of the electrode that are making synaptic contact with local cells. Fibers of passage refer to the axonal processes that traverse the vicinity of the stimulating electrode, the cell bodies and axon terminals of which are not in the immediate vicinity of the electrode. Several studies have documented alterations in brain neurotransmitter levels (e.g., GABA, glutamate, serotonin) associated with high-frequency DBS, alterations that may have both regional and remote effects on seizure suppression. Finally, there is evidence that simply placing DBS electrodes may provide an anticonvulsant effect via a "microthalamotomy".
Targets of DBS
Numerous parts of the brain have been targeted for DBS electrode insertion for the purpose of improved seizure control, including several thalamic regions, the cerebellum, the hippocampus, and the caudate nucleus. The thalamus, and specifically the rostral (anterior) thalamus, has been targeted for DBS most frequently, due to the widespread connectivity of thalamic centers and the cerebral cortex.
Technical Aspects of DBS
Unilateral or (more commonly) bilateral DBS stimulating electrodes are placed through burr holes under stereotactic guidance (CT or MRI) and secured to the skull. The DBS electrodes are then connected to a surgically implanted, battery-powered pulse generator (internal pulse generator, or IPG) by lead extensions. The IPG can be activated or inactivated remotely following implantation, and stimulation parameters can also be adjusted as needed. The majority of cases reported in which DBS was used to control epilepsy utilized open-loop systems, in which the stimulation from the DBS unit is scheduled independent of seizure activity occurring in the patient. In other words, most DBS systems deliver high frequency impulses on a predetermined schedule-such as one minute on, 5 minutes off, alternating from one side to the next. More recent work has focused on closed-loop or responsive systems, in which the DBS unit is triggered when a sensor (located over cerebral convexities, similar to an EEG recorder) picks up seizure spikes.
Morbidity Associated with DBS
DBS implantation and treatment in people is considered a very safe therapeutic modality, with few serious side effects, many of which are transient and can be abolished by manipulating stimulation parameters. However, a small percentage of patients have been reported with DBS electrode-associated intracranial hemorrhage (typically minor-identified on imaging but not a clinical problem) and IPG-associated post-operative infection.
Potential Adaptability of DBS to Epileptic Dogs
The major barriers to adapting DBS technology to epileptic dogs are lack of availability and expertise in stereotactic surgery, and exorbitant expense associated with commercially-available DBS hardware. Despite these impediments, there is potential for applying DBS therapy to canine epilepsy in a less technically demanding (e.g., stereotactic surgery) and less expensive way. The author has been collaborating with a group of engineers and radiologists at Cornell University in attempts to investigate the feasibility of non-stereotactic CT guided DBS electrode placement into the canine rostral thalamus and the possibility of creating a dog-specific implantable open loop DBS system. The dog has a very prominent thalamus, which should be a reasonable target for electrode implantation, even without stereotactic equipment. In addition, the basic components of a DBS system can be assembled at a cost far less than the cost of commercially available human DBS systems. Potential designs for canine DBS systems, modes of implantation of such systems, and methods to evaluate efficacy/inefficacy of DBS therapy will be discussed.
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