by: EFMN's Professional Advisory Board Member Patricia Penovich, MD
Despite many more options for medical therapy, about 30% of patients with epilepsy fail to achieve adequate seizure control or seizure freedom.
These individuals should pursue consideration for a possible surgical treatment option. However, some of these folks will still not be able to have a surgical treatment for some of these potential reasons: 1. The epilepsy is a generalized epilepsy without a focal onset. 2. There is more than a single area from which the seizures begin. 3. The area of seizure onset controls an important function so that its resection would produce a permanent deficit such as loss of language or motor control if it were resected. Neurostimulation offers these individuals another option for improved seizure control.
Neurostimulation is approved and available for other illnesses such as Parkinson’s disease, tremor, depression, dystonia, pain. Neurostimulation of various brain areas for epilepsy treatment is not new. Research has been ongoing since the late 1960’s. The more recent experimental work and phase 3 device trials have led to three types of stimulation devices, 2 of which are FDA approved and available for patients.
Neurostimulation procedures are classified as either “closed loop” or “open loop” stimulation. Open loop stimulation means that the stimulation occurs at a pre-set defined and constant time interval and a preset stimulation current. Closed loop stimulation means that the stimulation current to the neural structures occurs only when a pre-defined pattern is detected by the stimulator. Neurostimulation may occur through stimulation techniques which are outside the actual brain, one example being the vagus nerve stimulation system. Stimulation of structures directly within the brain is done by deep brain stimulation or responsive neural stimulation techniques.
Interestingly, the effects of neurostimulation are not immediate but tend to increase gradually over time. The full effectiveness becomes evident over several years. The explanation for this phenomenon is not completely understood but is postulated to be a result of probable modulation (changing the structure or chemistry) of the actual cellular receptors and transmitters, cerebral blood flow, and neural pathways. Also there are reports that mood and cognition may improve with these methods as well.
VAGUS NERVE STIMULATOR (VNS)
VNS has been approved since 1997. The vagus nerve enter the brainstem and connections are distributed to multiple bilateral brain areas. The device is surgically placed under general anesthesia. The stimulation device is implanted under skin below the clavicle in the chest wall. This rounded or oval unit is a size between a quarter and a 50 cent piece. It contains the battery and the computer chip for setting the stimulation parameters. Wires or leads are wrapped around the vagus nerve in the neck and are tunneled under the skin and plugged into the stimulator in the chest wall. The neurologist sets the parameters and changes them gradually over time by using a “wand” that communicates with a computer program. The wand is placed over the unit in the chest wall. This is also used to check the battery life. When the battery life is nearing end, the unit in the chest wall is simply replaced as a day surgery procedure. The stimulator delivers a current to the vagus nerve on a repeating cycle for 24 hours per day every day. It is then “on” for a predetermined time (usually between 12-30 seconds) and then “off” for a predetermined period of time (usually 1.2 to 5 minutes and most often 5 minutes). This is called the duty cycle and determines the amount of energy that the nerve receives. Side effects may include a tickle or feeling in the throat, a hoarseness, or a cough during the “on” time. The patient or family also has a magnet that they may use should the patient have an aura or they see a seizure begin to develop. This magnet, when “swiped” over the chest wall, will set up a longer 60 second period of stimulation at higher current which is usually 0.25 mAmp greater than the usual ongoing stimulation. This magnet stimulation may or may not abort the seizure or shorten it. There are limitations on the types and locations of MRIs that may be utilized when the VNS is in place. The VNS needs to be programed to zero current during the test and turned back on after the test.
It has been approved for use in children older than 12 years and adults with medically intractable focal (partial) epilepsy and has been shown to be useful in other seizure types as well. Overall a reduction of 50% or more is reported in 55-80% of patients after 3-5 years therapy. New extension of the VNS system (Aspire) involves detecting an increase in heart rate that may occur in some patients that precedes a seizure and this results in the delivery of an automatic stimulation to the vagus nerve, hopefully to abort the seizure, much like the additional stimulation that magnet stimulation may do.
OTHER EXTRACRANIAL DEVICES
There are devices in development which are not FDA approved and are therefore not available. These include: 1. The TNS for stimulation of the trigeminal nerve in the scalp/face area; 2. The TMS device that delivers transcranial magnetic stimulation to the brain through the skull.
All of these devices will have contraindications to MRI, electrocautery, electroconvulsive therapy, TMS, or diathermy. This is due to a concern for heating of the intracranial electrodes by the procedure and possible brain damage from this.
Deep Brain Stimulation (DBS)
Although not yet FDA approved for epilepsy, the deep brain stimulation (DBS) system is approved for treatment of Parkinson’s disease since 1997. This is an open loop stimulation method. The electrode placement for occurs in specific areas of the thalamus - the anterior nucleus of the thalamus bilaterally. These nuclei are within the deep central area of the brain. The depth electrodes which are the leads of the system and deliver the stimuli are placed under stereotactic computer guidance. The stimulator is placed in the chest wall and delivers the stimulation in a repeated 24 hour a day “on and off cycle” or open loop method with settings that are programed into the stimulator. The Santé Trial involved a group of patients who were immediately begun on stimulation after the implantation and a group of patients who were not immediately stimulated but began stimulation later (placebo group). The outcome results showed seizures were reduced by 40% in the immediate group compared to 14% in the placebo. Late results at 26 months of treatment for all groups combined showed that seizures were reduced by 56%. The long term side effects have been minimal although there is a small initial risk for infection or bleeding at the time of insertion.
Responsive Neural Stimulation (RNS)
The responsive neurostimulation device (RNS) is a closed loop stimulation device. The FDA approved the system in 2013 for treatment of patients over the age of 18 with refractory focal (partial) epilepsy. This procedure is only available at Level 4 Epilepsy Centers.
The patient may have a focus in an area which is not able to be resected due to potential for severe deficit or may have two separate foci. The stimulating electrodes are either depth electrodes or strip electrodes (electrical contacts embedded in a plastic strip). They may be used in combination, with a maximum of 4 electrodes implanted, although only 2 are able to be stimulated at one time. They are inserted through stereotactic guidance. The electrode wires are connected to the stimulator which is implanted in a hollow carved into a small area of the skull .The device is then flush to the skull. The whole device is thus not visible and is intracranial. Initially it just records the brain activity and holds it into memory. The patient downloads the information every 1-7 days from the device in the skull using a wand and a remote monitor at home. This information is then available for the physician to study. The epileptologist evaluates the activity which is potentially there to cause a seizure (interictal activity) as well as actual seizure activity. This permits definition of the patterns which will be “learned” by the device. Recognition of these patterns by the computer then will trigger electrical pulses to the electrodes. This will hopefully stop the activity from evolving into a seizure. The physician sets the pattern recognition and stimulation settings when the patient returns to the office using a wand and a programming device. After the information is evaluated, it is actually turned on and the device will begin stimulation when the programed pattern occurs. The intracranial electrical signal of a seizure often precedes the actual seizure by many seconds. Thus when the device delivers the stimulating current to the brain area, the seizure may be stopped before it starts. This stimulation is not felt by the patient. It may be that prior to using the RNS, additional evaluation to more finely pinpoint an area of focal seizure onset must be done using a grid or stereo-electroencephalography (SEEG). Due to the craniotomy and insertion of the electrodes there is a small risk of infection or hemorrhage, comparable to that of the DBS. The battery life at the present time is 4-5 years and battery improvements are in process. Replacement involves a day surgery procedure to replace the stimulator unit in the skull. The seizure reduction reported in long term follow up increases from the initial 41% at 3 months up to a 72% reduction at 7 years.