Neurostimulators in Epilepsy

Vicenta Salanova, MD, and Robert Worth, MD, PhD

Corresponding author
Vicenta Salanova, MD
Department of Neurology, Indiana University, University Hospital,
Room 1711, 550 University Boulevard, Indianapolis, IN 46202, USA.
E-mail: vsalanov@iupui.edu
Current Neurology and Neuroscience Reports 2007, 7:315319
Current Medicine Group LLC ISSN 1528-4042
Copyright 2007 by Current Medicine Group LLC

A review of electrical stimulation in patients with refractory epilepsy, including animal and human data, shows
that there is anatomic and physiologic evidence supporting the role of the thalamus in epilepsy. The most recent
reports in patients with refractory epilepsy suggest that
deep brain stimulation and cortical electrical stimulation of the anterior thalamic nucleus and hippocampus
may reduce seizure frequency in patients with refractory
partial and secondarily generalized seizures. This has led
to a multicenter, prospective randomized trial called the
Stimulation of the Anterior Nucleus of the Thalamus for
Epilepsy (SANTE trial) that is currently being conducted
at several centers in the United States. There is also a
multicenter clinical trial for patients with refractory partial epilepsy treated with a cranially implanted responsive
neurostimulator (RNS) system. Preliminary reports from
the RNS system feasibility trial (the NeuroPace trial) suggest that electrographic seizures can be detected before
they evolve into clinical seizures, and that electrical stimulation of the epileptogenic zone can then terminate the
electrographic seizures. The preliminary data in patients
using deep brain stimulation of the anterior thalamic
nucleus and hippocampus, and cortical stimulation studies of the epileptogenic zone are promising and suggest
a reduction in seizure frequency in some patients with
refractory partial and secondarily generalized seizures.
The exact mechanism of action and the best parameters
used during electrical stimulation remain unknown and
are the subject of ongoing research.

Introduction
Epilepsy affects close to 3 million people in the United
States and more than 50 million people worldwide, and
at least 30% of these patients are refractory to medical
treatment [1]. Many of these patients benefit from resective epilepsy surgery; however, there are a large number
of patients who are not surgical candidates. Vagal nerve

stimulation (VNS) was approved for the treatment of

patients with refractory partial epilepsy who are not candidates for surgical resection. In clinical trials, 30% to
40% of patients with medically refractory partial seizures
had a reduction in seizures of at least 50% [2].
There is anatomic and physiologic evidence supporting
the role of the thalamus in epilepsy. The thalamus has
general effects on cortical excitability mediated by diffusely projecting nonspecific thalamic nuclei such as the
anterior and intralaminar nuclei [3].
Mirski et al. [4] reported that high-frequency stimulation (50100 Hz) of the anterior nucleus (AN) of the
thalamus increased the seizure threshold in rats with
pentylenetetrazol-induced seizures. They also demonstrated the anticonvulsant effect of anterior thalamic
high-frequency stimulation in the rat and found that
low-frequency stimulation (8 Hz) was proconvulsant
[4]. The high-frequency stimulation was believed to have
inhibitory effects similar to the injection of the gammaaminobutyric acid agonist muscinol. They postulated
that the disruption of corticothalamic transmission with
AN stimulation would prevent normal recruitment and
synchronization into a generalized seizure [4].
Human studies also support the role of the thalamus
in epilepsy. Henry [5] reported changes in the thalamus
using positron emission tomography (PET) scanning in
patients with refractory epilepsy and showed that seizures
improved most in patients who had bilateral thalamic
activation induced by VNS in long-term PET studies. He
stated these results supported earlier evidence from acute
VNS-activation PET studies that altered thalamic processing
contributes to antiseizure effects of VNS [5].

Deep Brain Stimulation in Epilepsy

In 2002, Hodaie et al. [6] reported five patients with
medically refractory epilepsy who had stereotactic placement of bilateral deep brain stimulation (DBS) electrodes
in the AN of the thalamus. The patients received intermittent high-frequency stimulation. Bipolar stimulation was
initiated by using 100 Hz, 90-microsecond pulse width,
cycling 1 minute on with 5 minutes off, alternating left
and right. At the time of activation of the pulse generators, voltage was increased by 1 V/min to a maximum of
10 V. The authors stated that these initial parameters
were chosen based on the available experimental evidence, indicating high frequency (100 Hz) stimulation to

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Epilepsy

Lead/
extension
connections
Extension

r
(battery)

Figure 1. A model of the Intercept Epilepsy Control System.

(Courtesy off Medtronic, Minneapolis, MN.)

be the most important parameter, and on previous clinical

experience with stimulation of the central median nucleus
of the thalamus (CM) for epilepsy at our institution (two
patients, unpublished data) and elsewhere [6]. Electroencephalogram (EEG) recording through the thalamic
electrodes showed interictal spikes in all patients and ictal
electrographic changes shortly after seizure onsets. The
authors reported a mean reduction in seizure frequency of
54%, and that two of the patients had a seizure reduction
greater than 75% (mean follow-up of 15 months). They
observed no adverse effects after DBS electrode insertion or stimulation, and there was no emergence of new
seizure types. They reported that the benefits did not differ between stimulation-on and stimulation-off periods.
Patients had a decrease in seizure frequency immediately
after the implantation of the DBS electrodes, although
stimulation did not start until 4 weeks after implantation.
They postulated that there may be an initial lesioning or
so called microthalamotomy effect, similar to that seen
with DBS implantation in other thalamic nuclei [6].
Recently Andrade et al. [7] reported on the long-term
follow-up (2 to 7 years) of these five patients plus one new
patient receiving AN stimulation and two patients who
had centro-median thalamic stimulation. Three patients
had symptomatic generalized epilepsy with tonic-clonic
seizures, and the rest had multifocal/partial epilepsy with
secondarily generalized seizures. Five patients with AN
implantation had greater than 50% seizure reduction.

DBS electrode implantation in AN patients was followed by seizure reduction 1 to 3 months before active
stimulation, raising the possibility of a beneficial microthalamotomy effect [7]. The authors reported that
implantation of the DBS electrodes was followed by
seizure reduction in all patients. Activation of the pulse
generators and the multiple subsequent changes made to
stimulation parameters or contacts stimulated over the
subsequent months and years could not be linked to any
further benefit in seizure control [7].
Kerrigan et al. [8] reported an open-label pilot study
of intermittent electrical stimulation of the AN of the thalamus in five patients with intractable partial epilepsy; four
of these patients also had secondarily generalized seizures.
Stimulation was delivered by bilateral implantable, programmable devices using an intermittent high-frequency
protocol. The stimulation parameters were 100 cycles per
second with charge-balanced alternating current, pulse
width of 90 microseconds, and voltages ranging between
1 and 10 V. Four of the five patients showed significant
improvement with respect to the severity of their seizures,
specifically with respect to the frequency of secondarily
generalized seizures. The authors noted that in four
patients in whom ANT stimulation was stopped, an immediate increase in seizure frequency and intensity occurred.
These patients improved when stimulation was resumed.
These observations tend to argue that intermittent electrical
stimulation of ANT is the active factor in achieving the
therapeutic effect rather than a lesion effect within ANT
caused by physical placement of the electrode [8].
The mechanism of thalamic DBS and the best parameters during electrical stimulation in patients with epilepsy
are unknown. Zumsteg et al. [9] investigated the effects
of high-frequency anterior thalamic DBS in a patient with
intractable seizures undergoing presurgical evaluation with
depth electrodes in both temporal lobes and reported that
the hippocampal inhibition was clearly related to the voltage (> 7) and frequency (> 70 Hz) of the thalamic stimulus
and occurred with a delay of approximately 60 seconds
after stimulus onset. The authors stated that our findings
that inhibition of ipsilateral hippocampal structures was
positively related to the voltage (increasing inhibition with
increasing voltage) and frequency (reaching a plateau at
about 70 Hz) of the AN stimulus are in accordance with
the results from previous investigations in movement disorders [9]. They further stated that their findings were in
keeping with the assumption that the effects of DBS are
a stimulation-induced modulation of pathologic network
activity, and that DBS of AN might override the activity within a pathologic thalamocortical or corticocortical
network in patients with epilepsy, thus resulting in an inhibition of distant cortical or limbic structures [9].
Fisher and the SANTE study group [10] presented an
interim report of the Stimulation of the anterior Nucleus
of Thalamus for Epilepsy (SANTE) clinical trial at the
American Epilepsy Society annual meeting in San Diego

Neurostimulators in Epilepsy Salanova and Worth

in December, 2006. The patients were 18 to 65 years of

age with partial-onset seizures with or without secondarily generalized seizures. Seizures had to be documented
by video-EEG monitoring. Patients averaged at least six
seizures per month and had failed at least three antiepileptic drugs. After a 3-month baseline period, the patients
received bilateral anterior thalamic nuclei implantation
(Fig. 1). One month later, stimulation was initiated at either
0 (placebo) or 5 V (active treatment), with pulse width of
90 microseconds, 145 pulses per second on for 1 minute
and off for 5 minutes. The double-blind period continued
for 3 months, after which there was 9 months of systematic
variation of certain stimulation parameters. As of March
27, 2006, 98 patients were enrolled and 58 implanted at 15
medical centers in the United States. A VNS device had previously been implanted in 42.4% of patients and 20% had
undergone prior epilepsy resective surgery. Twelve patients
had both epilepsy surgery and VNS. Dr. Fisher stated that
The SANTE trial is proceeding satisfactorily. Efficacy
and safety data will be analyzed and presented after 102
patients have completed the blinded phase [10].

317

Figure 2. An illustration of the Responsive Neurostimulator (RNS)

system. This gure shows one possible implant situation, with two
leads (one depth and one cortical strip). (Courtesy off NeuroPace,
Mountain View, CA.)

Cortical Stimulation in Epilepsy

Animal data and preliminary reports of patients with
refractory partial epilepsy have demonstrated reduction in
seizure frequency following cortical stimulation. Velasco
et al. [11] reported that subacute hippocampal stimulation
(SAHCS) blocks intractable temporal lobe epileptogenesis
with no additional damage to the stimulated hippocampal
tissue. SAHCS was applied to 10 patients with nonlesional temporal lobe epilepsy and unilateral focus, before
an anterior temporal lobectomy [12]. They reported that
the most evident and fastest antiepileptic response was
found in 5 patients in whom the stimulation contacts were
located at either the anterior pes-hippocampus near the
amygdaloid nucleus or at the anterior parahippocampal
gyrus near the entorhinal cortex. They also reported that
chronic hippocampal stimulation persistently blocked
temporal lobe epileptogenesis in one patient under open
protocol during 24 months with no apparent additional
alterations in recent memory [12].
Vonck et al. [13] evaluated long-term amygdalohippocampal stimulation in three patients with complex partial
seizures and reported that after a mean follow-up of 5
months all patients had a greater than 50% reduction in
seizure frequency, none of the patients reported adverse
effects. The authors concluded that This study clearly
shows the feasibility of recording amygdalohippocampal
EEG and subsequent DBS in medial temporal lobe structures using DBS electrodes implanted during a single
surgical procedure [13]. They also found that electrical
stimulation was safe and significantly reduced interictal
EEG abnormalities and seizures.
Tellez-Zenteno et al. [14] reported four patients with
refractory mesial temporal lobe epilepsy (MTLE) who

underwent implantation of a chronic stimulating depth

electrode along the axis of the left hippocampus. They
found that hippocampal stimulation produced a median
reduction in seizures of 15% and that all but one patients
seizures improved; however, the results did not reach significance [14]. There were no adverse effects.
A cranially implanted responsive neurostimulator (the
RNS system) is being evaluated for safety and efficacy in a
multicenter pivotal investigation in adults with medically
refractory partial epilepsy. The system includes a cranially
implanted device, depth and subdural leads, a telemetry
wand, a programmer and a remote patient monitor, and
a Web-based patient data management system. Leads are
surgically implanted in the region of seizure onset (Fig.
2). The device records electrocorticographic signals and is
programmed by the physician to detect specific electrocorticographic patterns and deliver responsive stimulation.
Preliminary results from the RNS system feasibility
investigation to assess safety and preliminary evidence for
efficacy were presented at the American Epilepsy Society
meeting in 2006 by Barkley et al. [15]. Patients with more
than 12 simple partial (SP) sensory or motor seizures,
complex partial (CP) seizures, or generalized tonicclonic (GTC) seizures over an 84-day baseline period
participated in the study. Efficacy was reported during
two times periods, the 84-day period beginning 28 days
post-implant (primary) and the most recent 84 days for
which a subject could have received therapy (secondary)
[15]. The responder rate (> 50% reduction in seizures) for
the primary evaluation period in 50 patients was 32% for
CP seizures and 63% for GTC seizures. For the secondary
evaluation period the responder rate for 62 patients was

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Epilepsy

40% for CP seizures, 55% for GTC seizures, and 41% for
total disabling seizures (n = 62 for SP, CP seizures, and
GTC seizures). The authors reported that seizure reduction
was significant for CP seizures (P < 0.05), GTC seizures
(P < 0.005), and total disabling seizures (P < 0.001). The
authors concluded that preliminary results indicated that
the RNS system may provide a safe and effective treatment for adults with intractable onset seizures [15].
Chabolla et al. [16] presented data from a subset of 18
adults participating in the RNS system feasibility investigation who had unilateral or bilateral MTLE, did not have a
suspected extrahippocampal seizure focus, and had not had
prior resective surgery. The mean follow-up period was 481
days. Patients with leads placed in or on the hippocampus
unilaterally had a 43% seizure reduction during the most
recent 84-day period during which a patient could receive
therapy, and patients with bilateral hippocampal leads had
53% reduction during the most recent 84-day period. One
anticipated serious adverse event was reported (depression) in a patient with bilateral leads, but the relationship
to the RNS system was uncertain. The author concluded
that Preliminary results suggest that RNS is safe and may
have efficacy in treating seizures in patients with MTLE.
Results also suggest that the RNS system may be a treatment option for patients with intractable bilateral MTLE
for whom resective surgery is not an option [16].
Drazkowski et al. [17], at the American Epilepsy Society
meeting in 2006, reported on the health-related quality of life
(HRQOL) results of the RNS system feasibility investigation.
The Quality of Life in Epilepsy Inventory (QOLIE-89) was
administered to each patient prior to the implantation of the
RNS device and at 1 year and 2 years after the implantation.
Data for 41 patients were available for the 1-year analysis.
The authors concluded that In this preliminary analysis,
self reported HRQOL shows a trend towards improvement
at one year in those with reduced seizures. HRQOL scores
in this cohort are similar to those reported in patients with
medically intractable partial epilepsy. Longer follow-up may
be required to demonstrate HRQOL improvements in association with seizure reduction [17].
Morrell [18] recently reviewed brain stimulation for
epilepsy and stated that in order to terminate clinical seizures by responsive stimulation, the seizure must be detected
and treated prior to the onset of clinical symptoms. She
also reviewed the safety of DBS and cortical neurostimulation therapy for epilepsy. Based on previous experience with
DBS in the treatment of movement disorders, complications
of DBS are mainly associated with the implantation procedure (including 5% risk of intracerebral hemorrhage), and
for devices implanted in the skull for treatment of hearing
loss the main complications are infection and scalp necrosis.
She also stated that experience with DBS for treatment of
Parkinsons disease suggest that chronic stimulation can be
delivered safely. Tissue damage can be avoided by observing
appropriate charge density [18].

Conclusions
Animal studies and preliminary human data suggest that
DBS and cortical stimulation may reduce the frequency
of disabling seizures in patients with refractory partial
epilepsy. There are currently two ongoing multicenter
studies of brain stimulation in patients with refractory
partial seizures: 1) the SANTE, sponsored by Medtronic
(Minneapolis, MN), which hopes to determine the safety
and efficacy of DBS in adults with refractory epilepsy
(open loop); and 2) the NeuroPace (Mountain View, CA)
RNS system clinical investigation, which hopes to assess
the safety and efficacy of responsive neurostimulation
(closed loop) in adults with refractory epilepsy. The
mechanism of action and the best stimulation parameters are the subject of ongoing research. The SANTE
and NeuroPace trials may lead to important new treatment modalities that may be used in patients who do not
qualify for resective surgery because of more than one
epileptogenic focus or because they have epileptogenic
zones adjacent to the eloquent cortex, patients at risk for
verbal memory deficits following temporal resections,
and patients who have had epilepsy resective surgery but
continue to have seizures.

Acknowledgment
Dr. Salanova is currently involved in both the SANTE and
NeuroPace trials and is the Principal Investigator for the
Indiana University site.

References and Recommended Reading

Papers of particular interest, published recently,
have been highlighted as:

Of importance

Of major importance
1.

Engel JR: Surgery for seizures. N Engl J Med 1996,

334:647652.
2.
The Vagus Nerve Stimulation Study Group: A randomized
controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995,
45:224230.
3.
Fisher RS, Mirski M, Krauss GL: Brain stimulation. In
Epilepsy, A Comprehensive Textbook, vol 2. Edited by
Engel JR, Pedley TA. Philadelphia-New York: Lippincott
Raven; 1998:18671875.
4.
Mirski MA, Rossell LA, Terry JB, Fisher RS: Anticonvulsant
effect of anterior thalamic high frequency electrical stimulation in the rat. Epilepsy Res 1997, 28:89100.
5.
Henry TR: Therapeutic mechanisms of vagus nerve stimulation.
Neurology 2002, 59 (Suppl 4):S3S14
6.
Hodaie M, Wennberg RA, Dostrovsky JO, Lozano AM:
Chronic anterior thalamus stimulation for intractable
epilepsy. Epilepsia 2002, 43:603608.
7.
Andrade DM, Zumsteg D, Hamani C, et al.: Long term
follow-up of patients with thalamic deep brain stimulation
for epilepsy. Neurology 2006, 66:15711573.
Reviews the long-term follow-up (up to 7 years) of patients
treated with anterior thalamic stimulation from the Toronto
Epilepsy program.

Neurostimulators in Epilepsy Salanova and Worth

8.

Kerrigan JF, Litt B, Fisher RS, et al.: Electrical stimulation

of the anterior nucleus of the thalamus for the treatment of
intractable epilepsy. Epilepsia 2004, 45:346354.
Reviews the results of anterior thalamic stimulation in five patients
with refractory epilepsy and showed that five patients had significant improvement.
9.
Zumsteg D, Lozano AM, Wennberg RA: Mesial temporal
inhibition in a patient with deep brain stimulation of the
anterior thalamus for epilepsy. Epilepsia 2006, 47:19581962.
10.
Fisher RS, SANTE study group: Interim report. Abstract
#4.122. Presented at American Epilepsy Society Annual
Meeting. San Diego, CA; December, 2006.
11.
Velasco M, Velasco F, Velasco AL: Centromedian-Thalamic
and hippocampal electrical stimulation for the control of
intractable epileptic seizures. J Clin Neurophysiol 2001,
18:495513
12.
Velasco F, Velasco M, Velasco AL, et al.: Subacute electrical
stimulation of the hippocampus blocks intractable temporal
lobe seizures and paroxysmal EEG activities. Epilepsia
2000, 41:158169.
13.
Vonck K, Boon P, Achten E, et al.: Long term amygdalohippocampal stimulation for refractory temporal lobe
epilepsy. Ann Neurol 2002, 52:556565.

14.

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Tellez-Zenteno JF, McLachlan RS, Parrent A, et al.: Hippocampal electrical stimulation in mesial temporal lobe
epilepsy. Neurology 2006, 66:14901494.
15.
Barkley GL, Smith B, Bergey G, et al.: Safety and preliminary efficacy of the RNS responsive neurostimulators for
the treatment of intractable epilepsy in adults [abstract].
Presented at the Annual Meeting of the American Epilepsy
Society. San Diego, CA; December 2006.
16.
Chabolla DR, Murro AM, Goodman RR, et al.: Treatment
of mesial temporal lobe epilepsy with responsive hippocampal stimulation by the RNS neurostimulator [abstract].
Presented at the Annual Meeting of the American Epilepsy
Society. San Diego, CA; December, 2006.
17.
Drazkowski J, Barkley G, Bergey G, et al.: Health related
quality of life results in adults with intractable epilepsy
implanted with the cranially based programmable RNS
responsive neurostimulator [abstract]. Presented at the
Annual Meeting of the American Epilepsy Society. San
Diego, CA; December 2006.
18. Morrell M: Brain stimulation for epilepsy: can scheduled
or responsive neurostimulation stop seizures? Curr Opin
Neurol 2006, 19:164168.
Excellent review of DBS and cortical stimulation in epilepsy.