Vagus nerve stimulation is currently the only approved stimulation therapy in the United States, but stimulation has been proposed at sites as varied as (see 64,65
for citations) cerebellum, anterior thalamus, centromedian thalamus, subthalamic nucleus, hippocampus, caudate, locus coeruleus, corpus callosum, mammillothalamic tract and the cortical seizure focus.
Vagus and Peripheral Nerve Stimulation
Vagus nerve stimulation was approved in Europe in 1994 and in the United States and Canada in 1997 for therapy of epilepsy, based upon pivotal trials in patients with partial and secondarily generalized seizures in patients over 12 years of age 66,67,68
. Retrospective studies of 440 patients implanted for 2–3 years 69
and for greater than ten years 70
. VNS has been shown to be effective for partial and secondarily generalized seizures in pediatric populations 71,72,73
. Small trials 74
have suggested efficacy of VNS for some generalized seizures.
The clinical VNS device allows a noninvasive paddle held near the device to program current intensity, individual pulse duration, pulse frequency, on-off cycle time and intensity and duration of an extra pulse triggered by a magnet held over the stimulator. Tecoma and Iragui 75
reviewed value of varying these stimulation parameters. Pulse width of 0.25 ms may be better tolerated than those of 0.5, with similar efficacy, but 0.13 ms pulses are less effective. Stimulation at frequencies below 20 per second may allow increased stimulation of unmyelinated C-fibers, with more autonomic side effects. A controlled study of on-off cycle durations (DeGiorgio 76
showed no differences in efficacy; however, some non-responders improved when the on-cycle was later increased. No stimulation parameter set has yet been shown conclusively to be better than those used in the pivotal trials, recognizing that individual patients may respond to various parameter changes.
Vagus nerve stimulation technology continues to be under development. Size of the device is decreasing, such that the Demipulse device is smaller and has improved monitoring of battery life 77
. High-field MRI has recently been shown safe, with a 3T GE Signa scanner using a specific T/R head coil 78
, but more experience with safety is needed for other systems. Externally rechargeable devices are under development, so the battery need not be replaced every few years. Development of remote monitoring and telemedicine capabilities for the vagus stimulator is in progress. The ADNS-300 stimulator system 79
can record VNS compound action potentials, affording possible enhancement of understanding of the physiology of vagus stimulation for epilepsy and perhaps better individualization of stimulation parameters. Recording from the VNS also holds the possibility of early detection or even anticipation of seizures. In rats with pentylenetetrazol-induced tonic seizures 80
, a measure of energy in the nerve could be used to predict behavioral seizures. Some patients benefit from using a magnet to turn VNS on at start of a seizure. A trial has begun at Ghent University in Belgium of using ictal tachycardia to trigger stimulation 81
One retrospective study 82
found that unilateral interictal discharges, cortical dysplasia and younger age were predictive of better outcomes. However, most reviews have concluded that it is difficult to predict who will benefit from VNS 70,75
. For that reason, external stimulation paradigms are of interest as noninvasive screens for whether an implanted stimulating device is likely to be of value. An auricular branch, called the Arnold nerve has been hypothesized to be a potentially useful test stimulation site prior to device implantation 83
. A randomized study of electroacupuncture for pain effectively used stimulation at this superficial vagal auricular site 84
. Transcutaneous stimulation of the left vagus nerve under the tragus of the ear was shown to influence MRI BOLD signals in the left locus coeruleus, left thalamus, left cingulate, left insula, left prefrontal cortex, and bilateral postcentral gyrus 85
. DeGiorgio 86
used superficial stimulation of the supraorbital nerve to identify responders, who are implanted with a subcutaneous supraorbital nerve stimulator. In an unblinded paradigm, seizure frequency was reduced relative to baseline by 66% at 3 months, 56% at 6 months and 59% at 12 months. Efficacy will need to be validated in a larger controlled, blinded study.
Transcranial Magnetic Brain Stimulation
Electrical shocks to the scalp can activate cortical neurons, but the stimulation tends to hurt 87
; transcutaneous magnetic stimulation (TMS) is less painful. Magnetic field induced brain currents fall off rapidly with distance from the magnetic stimulator coil, so great efforts have been made to produce coils that can stimulate focally and relatively deeply into brain tissue 88
. Figure-of-eight coils are widely in use by virtue of these characteristics.
Early case series of TMS for epilepsy generally were favorable 89
. Nine patients with partial or secondarily generalized seizures, two from temporal and seven from extra-temporal regions were given TMS 90
. A round magnetic coil stimulated the vertex head region at one pulse every 3 seconds, for two trains of 500 pulses per day. Weekly seizure frequency declined from 10.3 ± 6.6 before stimulation to 5.8 ± 6.4, significant at p=0.048. Subsequent case series of TMS showed benefit for seizures in some 91,92,93,94,95
and little or no benefit in others 96,97
. Positioning of the stimulating coil over the seizure focus might be important in determination of success, according to one study that compared vertex stimulation to targeted TMS 98
Three controlled trials of TMS for epilepsy have been accomplished. In a positive trial, Fregni and associates 99
targeted TMS to sites of cortical dysplasia in 21 patients with medication-resistant seizures. Patients were subjected to five consecutive daily 20-minute sessions of stimulation at 1 per second, using either a figure-of-eight real stimulation coil or a fabricated coil looking and sounding similar to a real coil but delivering no stimulation. The epileptogenic focus was targeted as the site of stimulation, except in four patients with diffuse abnormalities, in whom stimulation was delivered to the vertex. By 2, 4 and 8 weeks after stimulation, seizure frequency was reduced respectively to 72%, 53% and 58% of baseline, each of which was statistically significant. EEG epileptiform discharges also were reduced. Two other controlled studies were negative. Cantello and associates 100
stimulated 43 patients with medication-resistant predominantly focal cortical epilepsies. After a 12-week baseline TMS was initiated via two stacked stimulating coils over the vertex. Active treatment was stimulation with the one near the scalp, and sham with stimulation by the upper coil distant from the scalp. Stimulation was set at two daily series of 500 stimuli at 0.3 Hz, separated by a 30-s interval. The stimulus intensity was 100% of the motor-evoked threshold. Although the study showed trends in favor of stimulation, neither seizure frequency nor EEG epileptiform activity changed significantly with active versus sham stimulation. Theodore and coworkers 101
evaluated TMS in 21 patients with localization-related epilepsy. TMS was given at 120% of the motor-evoked threshold at 1 pulse per second for 15 minutes twice daily for 1 week at 120%. The coil was positioned over the best estimate of the region of the seizure focus. Sham stimulation was given with the coil angled away from the head. The patients were then observed on a stable drug regimen for two months. Neither partial nor generalized seizures improved significantly with TMS active stimulation in comparison to sham stimulation. A trend toward short-term benefit was noted in patients with lateral temporal seizure foci, where magnetic fields would best penetrate the focus.
Experience collectively leaves open the question of effectiveness of TMS for epilepsy. One of three controlled studies showed efficacy. That study targeted stimulation to superficial regions of cortical dysplasia, which may have been a factor in efficacy. Other differences in stimulation parameters, such as frequency, intensity, duration of the train and other factors could have contributed to different study outcomes. In addition, compared to other trials of neurostimulation, TMS trials have stimulated only during a small fraction of each trial day.
Magnetic stimulation is not entirely benign, in that it inadvertently can instigate seizures, even with single pulses 102
. A systematic literature review 94
found 16 cases of seizures with TMS. This is a low percentage, given the thousands of patients exposed to TMS 103
. A consensus conference on safety of TMS 94
concluded that TMS was contraindicated when metallic hardware, such as a cochlear implant or medication pump, was in close proximity to the stimulation site. Special care is required with untested stimulation parameters, patients with a seizure history or brain lesions or medications that lower seizure thresholds, or pregnancy or heart disease.
The first devices used to treat epilepsy were forms of electrical stimulation. Electrical stimulation to map human brain function may have started in 1884, when the Cincinnati surgeon Robert Bartholow observed contralateral movements with electrical stimulation of cortex during repair of cranial osteomyelitis 104
. Wilder Penfield and Herbert Jasper pioneered the technique of mapping cortex with electrical stimulation, and Spiegel and Wycis of mapping and sometimes stimulating deep structures 104
; however, these investigators did not use stimulation as treatment. The first therapeutic brain stimulation efforts were in the field of psychiatry, by Heath 105
and Delgado 106
in the early 1950’s. Some of Heath’s patients had epilepsy as well as psychiatric problems, and epileptiform spikes were observed at septal nuclei and other stimulation sites 105
Deep brain electrical stimulation to reduce seizures is credited to the New York Neurosurgeon, Irving Cooper, who reported improvement in seizure frequency with stimulation either of cerebellum 107
or the anterior thalamus 108
. Cooper’s positive results were qualitative and uncontrolled with little detail on individual degrees of improvement and comorbid conditions . In subsequent years, about a dozen uncontrolled studies showed benefit of cerebellar stimulation to treat epilepsy, but two small blinded studies were negative 109
. DBS for epilepsy fell out of favor for many years and came back to interest with the success of vagus nerve stimulation for epilepsy and DBS for movement disorders. After cerebellum, centromedian thalamus was the primary target of stimulation, pioneered by the Velasco’s in Mexico City 110,111
, but a small cross-over trial was negative 112
A series of studies showed benefit of DBS of anterior thalamus in experimental models of epilepsy 113
. Based upon promising animal experimentation and the early work of Cooper, six small unblinded trials of anterior nucleus stimulation for medication-resistant epilepsy were published 64
, showing a conglomerate mean 47% reduction in seizures compared to baseline. Uncontrolled stimulation studies are subject to several types of potential bias, including placebo effect, regression to the mean, micro-lesion effects from electrode placement and other unknown confounding factors. Therefore, Fisher and associates 114
performed a randomized, placebo-controlled, multi-center trial of anterior nucleus stimulation in patients with medication-resistant partial and secondarily generalized seizures, called SANTE, for stimulation of the anterior nucleus of thalamus for epilepsy. Randomization was performed on 110 patients either to 5 V or 0 V (placebo) stimulation of bilateral anterior nuclei of thalamus, at 145 pulses per second, 0.9 ms pulses referential to the stimulation case, with stimulation on for 1 minute and off for 5 minutes. The group had a median of about 20 seizures per month and a mean of 57 seizures per month at baseline. Stimulation was begun one month after implantation of the deep brain leads, and continued for a three-month blinded phase. shows seizure frequency relative to baseline.
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 (more ...)
Seizure frequency declined 20% in the month after implantation prior to initiation of electrical stimulation, either to nonspecific or micro-lesion effects. By the end of the blinded phase, the treated group continued to improve, to a median level 40.5% less than baseline, compared to only 14.5% in the 0 V group (p=0.038). The control group received 5V stimulation at the end of the blinded phase. Seizures declined over the next two months to levels encountered in the initially stimulated group. Improvement was sustained, with seizures in the terminal three months of stimulation at three years measuring a median 58% reduction compared to baseline. In the blinded phase, stimulation produced significant reduction in injuries due to seizures, frequency of complex partial seizures, seizures originating from the temporal lobes and seizures pre-designated as “most severe” by the patient. Responder rates for 50% improvement and quality of life did not significantly improve during the three-month blinded phase, but did in the open-label and long-term follow-up stages from 1 to 3 years after implantation. In the long-term phase, 14% of patients became seizure-free for at least 6 months. Patients who previously had not benefitted from vagus nerve stimulation or epilepsy surgery had the same favorable response to DBS as did the overall group.
Complications of stimulation consisted of occasional chest or other paresthesias, need for repositioning leads, and superficial infections. No symptomatic brain hemorrhages were seen, though neuroimaging showed asymptomatic blood in five patients. Neuropsychological tests showed no difference in cognitive or profiles of mood scores, but more stimulated patients reported symptoms of depression and memory impairment. Five patients had status epilepticus, two related to initiation of stimulation, and resolving with reduction of voltage. Rates of depression, status epilepticus, depression, suicide and sudden unexpected death in epilepsy (SUDEP) all were within the expected ranges for a population of people with refractory epilepsy.
The conclusion of the SANTE study was that stimulation of the anterior nuclei of thalamus reduced the number of seizures in patients with medication-resistant epilepsy. Complications were similar to those encountered with DBS for movement disorders, with additional concerns raised about possible subjective symptoms of depression and memory impairment.
A second randomized trial of neurostimulation employed a strategy to stimulate subdural strips or depth electrodes placed near seizure foci, in response to electroencephalographically-detected epileptiform activity 115
. A total of 191 patients with medication-resistant partial or secondarily generalized seizures were implanted with a responsive neurostimulator (RNS) affixed within a craniotomy, and connected subcutaneously to a subclavicular stimulator ().
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 (more ...)
Patients were randomized to receive active or sham stimulation. Stimulation was begun one month after implantation, and the three-month blinded test phase began two months after implantation. Improvement was similar to that seen in the SANTE study, with 37.9% mean change in seizure frequency relative to baseline for the actively stimulated group, versus 17.3% in the sham stimulated group, significant by generalized estimating equations at p=0.012. In the third month of the blinded evaluation period, the reduction in seizures in the treatment group reached 41.5% and in the sham stimulation group was 9.4% (p = 0.008). The seizure reduction was sustained, and even improved, over time. The median % reduction in seizures and responder rates at 1 year were 44% each and at 2 years were −53% and 55%. There were statistically significant improvements in overall quality of life (QOL) and in 9/16 QOLIE-89 scales at 1 and 2 years after implantation. There was no deterioration in any neuropsychological measure and there were statistically significant improvements at 1 and 2 years post-implant in verbal function, visual-spatial processing, memory and mood. Stimulation was well-tolerated.
At the time of this writing, based upon the SANTE trial, DBS is approved for clinical use in Europe and several other countries, but the US FDA is still evaluating the risk-benefit balance. The RNS System is under evaluation by the US FDA. Is a median 40% improvement in seizures (during the blinded phase) sufficient to justify the risks of implanted stimulators? Each patient and clinician will ultimately need to individualize this answer. However, improvements in this range can be clinically meaningful, especially where all else has failed, and when some improve markedly with stimulation. Experience is currently insufficient to recommend when to use thalamic or responsive neurostimulation in relation to vagus nerve stimulation. The latter clearly is less invasive. Responsive stimulation requires knowing where to place the stimulators. Clinical trials are underway for hippocampal stimulation and testing at other CNS sites are in planning.