Clinical aspects

Description

A substantial portion of patients does not achieve seizure control without adverse effects using antiseizure medication (39). A portion of these medication-resistant patients are candidates for curative surgery that could result in long-term seizure freedom without disabling deficits (15; 28; 61). However, there is a substantial number of patients who have medication-resistant epilepsy and are not candidates for epilepsy surgery. Based on the fundamental principle that epilepsy is a disorder of abnormal electrical activity, neurostimulation aims to directly modify the abnormal electrical activity that is associated with epilepsy.

Neurostimulation can take 2, not-mutually-exclusive approaches: continuous stimulation or responsive stimulation. In continuous stimulation, there is a baseline cycle of stimulation with the goal of reducing the long-term likelihood of seizure. The provider can modify various settings of the stimulation technology with the goal of maximizing seizure frequency reduction and minimizing unintended adverse effects. In responsive stimulation, the stimulator monitors for particular objective conditions to be met before providing stimulation. This can reduce the quantity of stimulations and thereby prolong battery life while reducing adverse effects incurred by stimulations that have a low likelihood of improving seizure control.

After placement, each neurostimulation device has titratable parameters of stimulation that can be personalized to each individual based on seizure response and adverse effects. The initial seizure response to neurostimulation can be low, with 40% of patients experiencing at least 50% reduction (09). Prolonged neurostimulation is thought to modify the underlying network resulting in as high as 80% of patients who had at least 50% reduction in seizure frequency in prolonged follow up; however, these results do not include a control group so the effect of natural history is not known.

This article provides a clinical description of the use of neurostimulation for medication-resistant epilepsy. Due to this clinical focus, this article focuses on discussion of the FDA-approved technologies of vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation system. Although other technologies are emerging, they are not widely clinically available and therefore are outside of the scope of this work.

Vagus nerve stimulation. The vagus nerve stimulator is a coiled electrode that is placed on the vagus nerve in the neck. Placement of the vagus nerve stimulator is a relatively low-risk procedure. However, once placed, scar tissue can form around the stimulation coil. This significantly complicates removal, therefore, if the vagus nerve stimulator is ineffective and the patient desires for the device to be removed, this coil can be left in place while the remainder of the hardware is removed. The placement of conductive material in the neck can complicate the acquisition of MRI due to potential for local heating and unintended ablation of the vagus nerve or injury to the carotid artery (69). Comprehensive epilepsy centers often have specific MRI parameters to ensure safety and image quality so MRIs can be obtained both at 1.5T and 3T (17).

If removed according to the standard of leaving less than 2 cm of the lead, the MRI risk is reduced.

The stimulation provided by the vagus nerve has a typical duty cycle of 30 Hz stimulation with a current of 1.5 to 2.25 mA for 30 seconds, then 5 minutes of no stimulation (75). Higher amplitude of stimulation is associated with more activation and potentially more antiseizure activity up to currents of about 2.0 to 2.5 mA. However, higher amplitude of stimulation is associated with more side effects of hoarseness and cough due to stimulation of the recurrent laryngeal nerve. Similar to a medication, some patients acclimate to this effect over time. Starting at a low level of stimulation and slowly titrating up may allow patients to achieve a higher amplitude of stimulation without this adverse effect. In addition to titration of the amplitude, the on- and off-times also can be titrated. An increase in the total duration of stimulation leads to shorter battery life. Rapid cycling also shortens battery life; therefore, it should be minimized unless clinical benefit is evident (49). At typical settings, the battery needs to be replaced every 3 to 8 years (06).

In addition to this chronic stimulation, there are 2 types of responsive stimulation. When a patient feels an aura or preseizure warning, the patient can place a magnet over the device. This provides stimulation with the goal of aborting or shortening that individual seizure (75). Additionally, more recent versions of the vagus nerve stimulator include an autostimulation function that provides automated monitoring of the patient’s heart rate. Based on reports that 82% of epileptic seizures may be preceded by an abrupt increase in heart rate (12), the vagus nerve stimulator monitors a titratable, abrupt increase in heart rate, and additional stimulation is provided when the threshold is surpassed with the goal of either aborting or shortening the seizure. In order to avoid false-positive stimulation, there are safeguards against prolonged stimulation (and stimulation for normal heart rate patterns, eg, exercise) (45). The parameters for autostimulation also can be modified if the patient or provider notes excessive false-positive stimulation.

Deep brain stimulation. Deep brain stimulation also provides chronic stimulation but has an intracranial target. The only FDA-approved target in the United States is the anterior nucleus of the thalamus but other targets have been explored including the centromedian nucleus of the thalamus, thought to be effective in generalized-onset seizures, as well as other targets including the subthalamic nucleus (used in Parkinson disease), hippocampus, inferior caudate, cerebellum, parafascicular nucleus of the thalamus, or patient’s specific seizure-onset zone.

Placement of the device has similar surgical technique and procedure compared to depth electrodes for surgical evaluation of epilepsy or responsive neurostimulation. Surgical targeted techniques can be used to create a hole in the cranium that allows the stimulation electrode to pass with minimal trauma to surrounding structures. One of the main concerns about placement is avoidance of cerebral arterial and venous vasculature, as well as other eloquent structures. Asymptomatic clinically insignificant hemorrhages occurred in 4.5% of participants in the pivotal trial, SANTE (18). Once placed, the electrodes are fixed and stabilized using the skull and stimulation wires are tracked down to the stimulation device which is placed on the chest. Tracking of the wires down to the stimulation device is similar to the techniques used for ventricular-peritoneal drains. The stimulation device and battery are placed similar to a cardiac pacemaker.

After placement and time for healing, stimulation begins (18). The standard stimulation settings in the pivotal trial were 5 V amplitude at 145 Hz with a cycle of 1 minute on and 5 minutes off. Alternate stimulation parameters include increasing voltage to 7.5 V and increasing frequency to 185 Hz but these were not studied rigorously in trials. Typical settings range from 1 to 10 V and frequencies from 100 to 250 Hz, with different targets of deep brain stimulation having different canonical settings. Based on experiences with hoarseness from vagus nerve stimulation, one would presume that the adverse effect of paresthesias reported in 18.2% of patients may be related to direct stimulation of the thalamus; therefore, changing the amplitude or frequency of the signal may reduce this adverse effect but this is not well studied. Rarely, patients have transient acute stimulation-associated seizures when the deep brain stimulation is turned on. In this case, the deep brain stimulation should be turned off and restarted at a lower voltage. Acute stimulation-associated seizures have not been associated with poor treatment response or prognosis (53).

Responsive neurostimulation system. In comparison to vagus nerve stimulation and deep brain stimulation that have a standard approach for most patients, with some personalization, the stimulation target of each patient with a responsive neurostimulation system is personalized to the exact localization of the patient’s seizure onset zone (67). This localization is determined based on an epilepsy surgical evaluation for medication-resistant epilepsy that may include intracranial monitoring with depth or strip electrodes. Some patients may have responsive neurostimulation system placed without depth or strip electrode monitoring. Despite completion of a surgical evaluation, the responsive neurostimulation system is FDA-approved as an adjunctive therapy for patients who are not candidates for resective or ablative epilepsy surgery. There are multiple reasons why a patient is not a candidate for resective or ablative epilepsy surgery.

The patient may not have been a candidate because resection of the target area would result in intolerable neurologic deficits (eg, aphasia or paresis). Although continuous stimulation or ablation of the area may result in these intolerable neurologic deficits, the responsive neurostimulation system only stimulates when a preictal or early ictal EEG signature is detected.

Alternatively, the patient may have multifocal epilepsy including but not limited to bilateral anterior temporal lobes. In this case, resection or ablation of both anterior temporal lobes would cause loss of declarative memory similar to patient HM (57). However, the patient may benefit from 2 responsive neurostimulation system electrodes placed with 1 in each seizure-onset zone to reduce seizure frequency and severity – (the current generation responsive neurostimulation system is limited to 2 strip or depth electrodes and each has 4 contacts.) In addition to these direct effects on seizures both acutely and through neuromodulation, the responsive neurostimulation system records snippets of the electrocorticography based on features concerning for seizures. These electrocorticography data can be uploaded via the internet for review by the treating epileptologist.

In addition to guiding selection of responsive neurostimulation system parameters, the relative burden of seizures associated with each responsive neurostimulation system could guide future curative epilepsy surgery. Data from these ultra-long-term recordings have demonstrated that although inpatient intracranial monitoring for a week or 2 may observe a small and different number of seizures, this short-term seizure count may not reflect the patient’s chronic burden (32). Consider a hypothetical patient that experienced 1 left temporal-onset and 6 right temporal-onset during inpatient intracranial monitoring and bilateral temporal responsive neurostimulation system was placed. If after 12 months of follow-up all seizures were observed by the right temporal responsive neurostimulation system, then it could be reasonable to propose a potentially curative right temporal lobe resection.

As compared to vagus nerve stimulation and deep brain stimulation that are continuously stimulating with chosen parameters, the responsive nature of the responsive neurostimulation system allows for more flexibility. As suggested by figure 1, if all seizures could be detected and aborted early without changing the underlying normal neural activity, then patients theoretically would achieve seizure freedom without side effects. In this way, the responsive neurostimulation system is a closed-loop system that uses electrocorticography to detect preictal or early ictal features and provide stimulation to halt the seizure or stop propagation. When the device is placed, the provider selects the electrocorticographic features that will trigger data to be saved, with 3 default triggers: magnet swipe by the patient, high amplitude saturation of the electrocorticography data, or sustained changes in the electrocorticography, called long episodes. Each of these events could indicate a seizure. The latter 2 triggers also can be modified by the provider after placement to, for example, change the bandpass filter or reduce the line length detector to detect smaller changes in the electrocorticogram.

There are 5 stimulation settings, 3 of which are personalized. Stimulation frequency typically is set at 200 Hz and burst duration is set at 100 ms (values based on recommendations of NeuroPace physician manual).

In addition to these stimulation parameters, the provider can select which electrodes provide the stimulation. As both the strip and depth electrodes include both stimulation and recording electrodes, this can be changed after implantation.

When changing parameters and stimulation locations, providers should evaluate for evidence of after-discharges from stimulation both in clinic and through the patient data management system. After-discharges are associated with stimulation-induced seizures as compared to the desired effect of stimulation-aborted seizures.

There is a significant variation in estimated battery life based on stimulation parameters. NeuroPace estimates that 5% of batteries last less than 5.1 years and 5% last more than 9.4 years, with the median battery lasting 8.4 years. Increased current, frequency, and bursts per day all can reduce battery life, as well as prolonged interrogation of the device more than 10 minutes per day.

To guide modification of these seizure detection and stimulation parameters, patients are trained to interrogate their device daily and sync with the remote patient data management system weekly. Although patients are typically seen every 3 months by their responsive neurostimulation system provider, any responsive neurostimulation system provider can log into this system remotely between visits to review the records.

In selecting the appropriate stimulation parameters, the provider can select a balance of sensitivity and specificity. If trigger detection has low sensitivity but high specificity, then patients may experience seizures that could be aborted, if stimulated (false negatives). In contrast, if the triggers are set with high sensitivity but low specificity, there may be multiple stimulations that reduce battery life and potentially produce stimulation-related adverse effects (false positives). However, due to the observation that chronic neurostimulation may result in neuromodulation and progressive improvements in seizure frequency, the provider may opt to have more false positive stimulations that may result in neuromodulation, as compared to favoring a high false negative rate with low stimulation frequency. Each of these choices can be individualized in discussion with the patient and caregivers.

Indications

Patients with epilepsy are defined as medication-resistant if 2 or more appropriately chosen antiseizure medications have failed in adequate trials (39). Approximately 70% of patients with epilepsy will be medication responsive and, unless there are unique situations, these patients should not be considered for neurostimulation because the risks and efficacy of neurostimulation are likely inferior to tolerated pharmacotherapy (67; 11; 09; 66). For patients with medication-resistant epilepsy that are good candidates for resective, ablative, or disconnection surgery, the rates of seizure freedom in these surgical approaches is superior to neurostimulation (16; 28; 10; 03). Therefore, unless there is evidence that surgery would result in an intolerable neurologic deficit in that specific patient, then surgery should not be delayed in favor of neurostimulation. This is because epilepsy surgery is potentially curative and the success of epilepsy surgery is associated with reduced time from seizure onset to curative surgery (44; 41; 43; 74; 14).

Although vagus nerve stimulation does not require localization of the seizure-onset zone, responsive neurostimulation system requires precise localization and deep brain stimulation covers a broad area that should contain the seizure-onset zone. Deep brain stimulation of the anterior nucleus of the thalamus allows for effects that project onto larger areas of cortex that likely will contain the epileptogenic zone and thereby reduce the propensity for epileptic seizures. Responsive neurostimulation system requires the identification of no more than 2 lead placements that are similar in specificity to the field of view of recording electrodes.

Contraindications

Each neurostimulation technology addresses a unique population of patients with epilepsy and has unique cautions.

Vagus nerve stimulation has the fewest contraindications. However, a vagus nerve stimulation is a coil around the vagus nerve that is intended to conduct electricity. Consequently, vagus nerve stimulation can cause complications with acquisition of magnetic resonance images of the neck and chest. The MRI restrictions for vagus nerve stimulation depend on the generator model. The artifact from vagus nerve stimulation also can influence magnetoencephalography but not electroencephalography or electrocardiogram (ECG or EKG) (36). Vagus nerve stimulation has been associated with development of central and obstructive sleep apnea; therefore, patients and providers may avoid vagus nerve stimulation placement in patients with preexisting, untreated sleep apnea (77; 20).

As discussed in indications, responsive neurostimulation system requires precise localization of the seizure onset zone. If the hypothesis for this zone is too broad to be captured by 1 or 2 responsive neurostimulation system electrodes, then responsive neurostimulation system may be ineffective.

For both deep brain stimulation and responsive neurostimulation system, if a patient’s skull does not have the structural integrity for the electrodes to be mounted and affixed, then they are not a candidate for these therapies. This includes but is not limited to patients that are too young for their skull to be ossified, patients with prior neurotrauma, or patients with destructive skull lesions (eg, Paget disease).

Although it is theoretically possible to use multiple neurostimulation technologies in conjunction, this has not been studied well.

In addition to these listed contraindications, one must consider the risks of the specific procedure to implant the devices including but not limited to perioperative cardiovascular risk, local infection, and the prognosis of other comorbidities.

Outcomes

A primary goal of neuromodulation is to reduce seizure frequency. Just as some antiseizure medications have fortuitous side effects that benefit common comorbidities of epilepsy, there is some evidence that neuromodulation can address these comorbidities. As compared to resective or ablative surgery for epilepsy, the goal is not seizure freedom, although seizure freedom does occur rarely (5% to 16% of patients) (08; 40; 02; 48). For vagus nerve stimulation and deep brain stimulation, the mechanism of action is not to directly abort a detected seizure, although there is some evidence that vagus nerve stimulation can and the use of auto-stimulation based on heart rate changes is intended to abort seizures. Instead, the stimulation changes the underlying network to transition towards a state that is less likely to generate epileptic seizures.

This perspective is based on the finding that the initial reduction in seizure frequency is moderate and improves over time both within individual patients and across patients. The initial reduction in seizure frequency is likely due to the stimulation itself and the delayed response over years is thought to be from neuromodulation (09).

The caveat to this interpretation is that the duration of the randomized trials of each technology is short. After the blinded phase, providers can personalize the stimulation parameters based on the individual patient’s response and adverse effects. Similar to titration of an antiseizure medication, this personalization can balance reductions in seizure frequency with adverse effects or practical considerations like battery life. This personalization may be another cause for improved outcome over time. Once placed, however, the surgical risk of removing neurostimulation devices frequently outweighs the benefit of removal. Therefore, if the device is ineffective, the device is typically turned off but not removed.

In addition, the indication for placement of vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation system differ; therefore, the rates of seizure reduction may not be comparable directly across technologies.

Vagus nerve stimulation. In the pivotal trials of vagus nerve stimulation (01; 50), the mean seizure reduction in the high-stimulation arm of the over the 12-week trial was moderate (25%) but mean seizure reduction improved to 56% after 5 years. Reported a different way, 44% and 65% of patients had an at least 50% reduction in seizure frequency after 1 and 5 years, respectively (22). In a metaanalysis including 3321 patients, seizures were reduced by at least 50% in about 50% of patients at last follow-up (16).

Of note, vagus nerve stimulation may be used for both focal and generalized epilepsies, including Lennox-Gastaut syndrome (25). The response to vagus nerve stimulation may vary based on indication.

Deep brain stimulation. SANTE, the pivotal trail of anterior nucleus of the thalamus for epilepsy, demonstrated a 40% reduction in seizure frequency in the active stimulation arm and a 15% reduction in the off group. The median seizure reduction improved to 69% after implantation. This corresponded to 43% and 68% of patients experiencing at least a 50% reduction in seizure frequency after 1 and 5 years, respectively.

Responsive neurostimulation system. The seizure frequency improvement expected from responsive neurostimulation system is similar to vagus nerve stimulation and deep brain stimulation. In the pivotal trial, there was a mean seizure reduction of 38% in the treatment and 17% in the sham (47). When all patients had stimulation, seizure frequencies were reduced by 50% and 66% at 1 and 6 years, respectively. This corresponded to 44% and 55% of patients having an at least 50% reduction in seizure frequency after 1 and 6 years, respectively (02; 48).

Although some patients note improvement of mood and cognition associated with improved seizure control, there is not thought to be an independent effect of responsive neurostimulation system on comorbidities of epilepsy or other nonseizure aspects of quality of life.

In addition to its influence on seizures, the responsive neurostimulation system serves as an ultra-long term intracranial EEG monitoring device. In selected patients, this function can guide future curative treatment of epilepsy. For instance, in patients with bilateral temporal lobe epilepsy or other multifocal epilepsy, bilateral responsive neurostimulation system can monitor seizure counts from each side to identify the lateralization asymmetry (32; 04). Long-term studies of these patients have demonstrated that short-term intracranial monitoring may not reflect the relative burden of seizures association with each temporal lobe. If a large portion of seizures are found with responsive neurostimulation system to come from a single temporal lobe that, if resected or ablated, would not generate disabling deficits in language or memory, these results can motivate unilateral temporal lobe epilepsy surgery.

Adverse effects

The placement of each neurostimulation device is a surgical procedure with immediate surgical risks of infection and bleeding. Local bleeding is easily controlled when placing a vagus nerve stimulator, but the deep brain stimulation and responsive neurostimulation system devices involve placement of intracranial electrodes. To reduce the risk of intracranial hemorrhage, the surgical approach can be tailored specifically to a patient’s vascular anatomy to avoid this potentially fatal complication. Intracranial hemorrhage occurred in 4.7% of patients with responsive neurostimulation system. Similarly, responsive neurostimulation system and deep brain stimulation were associated with a 5% and 13% risk of intracranial infection (59). In the deep brain stimulation trial, 8.2% of leads were misplaced (18; 59) but subsequent technological advances have improved the accuracy of lead placement. Less severe adverse events associated with placement of deep brain stimulation and responsive neurostimulation system included implant site pain (16%), headache (11%), and abnormal sensations (6%) (23).

After placement, the adverse effects of vagus nerve stimulation pertain to stimulation of other portions of the vagus nerve (07). Stimulation of the recurrent laryngeal nerve from high intensity stimulation can result in hoarseness or coughing that is phase locked with the duty cycle of the device. This can be remarkably common (hoarseness in 66% and coughing in 45% of early studies) (37). These adverse effects are direct results of stimulation parameters and therefore stimulation can be titrated to maximize efficacy while minimizing adverse effects, similar to an antiseizure medication. Consequently, after 2 years of stimulation, hoarseness was reported in only 20% of patients (37). Injury to the recurrent laryngeal nerve rarely can result in vocal cord paralysis in 1% of patients, with its associated sequelae (37). Additionally, vagus nerve stimulation has been associated with central and obstructive sleep apnea; therefore, providers should have caution when placing vagus nerve stimulation in patients with premorbid sleep apnea and monitor for sleep apnea after placement (77; 20).

Similarly, adverse effects from deep brain stimulation after placement pertain to collateral stimulation of the thalamus. Due to the thalamus’ central role in sensation, 23% of patients reported paresthesia that was associated with stimulation (59). This paresthesia was not disabling. Due to the role of the thalamus and Papez circuit in memory, 13% of patients also reported memory dysfunction. Alteration of limbic activity also can influence mood, as 15% of patients in the active group in SANTE reported depression (2% of inactive group) (65). These neurocognitive and mood effects were not sustained at 5-year follow-up and patients did not discontinue stimulation due to these adverse effects (70). In fact, the average patient with deep brain stimulation may experience small improvements in memory and cognition (54; 68; 42).

After placement of responsive neurostimulation system, the targeted and responsive nature of the stimulation limits the adverse effects related to stimulation. Therefore, the long-term risks are similar to patients with other implanted devices like pacemakers.

Special considerations

There is a relative paucity of high-quality evidence for the use of neurostimulation in pediatric epilepsies. In part, this can be due to practical considerations that children’s brains and skulls continue to develop, potentially resulting in shifting of stimulator locations and other embedded hardware in deep brain stimulation and responsive neurostimulation system. Although there are an increasing number of case reports of efficacy, these technologies have not been FDA-approved in children (35; 62; 76; 31; 30).

As a result, vagus nerve stimulation is the most well-studied neurostimulation technique in pediatrics and it has been approved to age 4 years. Studies that have compared to efficacy of vagus nerve stimulation in pediatrics have found similar seizure frequency responses to adults (50; 13; 55; 27). Vagus nerve stimulation also has been effective for some medication-resistant pediatric epilepsies with severe effects on development including Lennox-Gastaut syndrome (25; 49).

Scientific basis

Although the exact mechanism of action of each neurostimulation technology is not completely understood, there are some principles that guide the understanding of why neurostimulation is effective.

Vagus nerve stimulation. Through the nucleus tractus solitarius and locus coeruleus, the vagus nerve is one of the major drivers of norepinephrine and serotonin within the brain, including to the thalamus and hippocampus (29). Due to the mechanism of vagus nerve stimulation involving the thalamus (24), there may be an overlap in the mechanism of deep brain stimulation and vagus nerve stimulation but this is poorly understood and only studied in small samples (38). In animal studies, increases in norepinephrine in the hippocampus were in association with suppression of seizures and reduced seizure frequency (58). In humans, the P300 evoked potential is a marker for this increase in norepinephrine (52). It was found that patients whose seizures were reduced with vagus nerve stimulation had more change in P300. There are investigations to see if the change in P300 after noninvasive vagus nerve stimulation could predict future response to permanent vagus nerve stimulation, but these studies are forthcoming. A concern regarding this prediction of future response is that if one of the mechanisms of action of vagus nerve stimulation is long-term neuromodulation, then short-term noninvasive stimulation may not capture patients who would respond in the long-term.

Although vagus nerve stimulation has been approved for about 25 years, there have been multiple generations of devices that have addressed limitations in prior devices. With the demonstration of the efficacy of closed-loop systems like responsive neurostimulation system, vagus nerve stimulation also has explored modification of stimulation based on patient monitoring. It was reported that 82% of patients with epilepsy have preictal heart rate increases (12); therefore, modern vagus nerve stimulation devices have an option for heart rate monitoring to trigger additional stimulation (45).

Deep brain stimulation. Although there are multiple targets for deep brain stimulation implantation, the only FDA-approved target for epilepsy is the anterior nucleus of the thalamus. The centromedian nucleus of the thalamus may have an effect on generalized-onset epilepsy (19; 72; 71; 40; 60; 33; 76). Other targets include the hippocampus, subthalamic nucleus, inferior caudate nucleus, cerebellum, and parafascicular nucleus of the thalamaus (18; 47; 21; 64). As a reminder of neuroanatomy, the anterior nucleus of the thalamus is core part of Papez circuit and includes projections to the frontal cortex, cingulate, and hippocampal formation (26). Bilateral high-frequency stimulation or lesions of the anterior nucleus of the thalamus suppressed the spread of seizures in the motor cortex, as well as modified the levels of glutamate and GABA in the hippocampus. This is thought to be similar to the mechanism of action of some antiseizure medications (46). This suggests that although stimulation of the anterior nucleus of the thalamus may not cause seizure cessation, it may inhibit spread of the seizure to symptomatic areas of cortex (05).

Due to the broad distribution of the projections of the anterior nucleus of the thalamus, anterior nucleus of the thalamus-deep brain stimulation is effective for a broad range of hypothesized or demonstrated localizations of seizures. However, there are not clear methods to predict response to anterior nucleus of the thalamus-deep brain stimulation. There is emerging literature from essential tremor and Parkinson disease that individualized profiles of functional connectivity may predict response (73) but these have yet to be demonstrated in epilepsy.

Responsive neurostimulation system. As compared to vagus nerve stimulation and deep brain stimulation that influence neural activity throughout large areas of cortex, the responsive neurostimulation system is local therapy targeted at each patient’s seizure focus. Direct cortical stimulation has been shown to abort after-discharges, which are a type of epileptiform discharges (56; 51). Based on these observations, the responsive neurostimulator system was designed as a closed-loop system that used limited intracranial EEG to monitor for epileptiform activity or the preictal period. When this abnormal activity is detected, the system automatically stimulates in this local area to disrupt the seizure. In addition to this direct effect, longer-term stimulation may alter the neural network of the seizure by suppressing cortical synchronization distal from direct stimulation, resulting in both direct and indirect seizure reduction (63; 34).