Download Vagus Nerve Stimulation Therapy for Seizures

REVIEW ARTICLE
Vagus Nerve Stimulation Therapy for Seizures
Ramachandran Ramani, MD
Abstract: Of the 3 million patients with seizures in North
America approximately 70% have effective seizure control with
medications. In the group refractory to medical treatment only a
minority fit the criteria for surgical therapy. Vagus nerve
stimulation therapy seems to be a suitable nonpharmacologic
therapy for reducing seizure frequency in these cases. It is a
simple device with 2 electrodes and an anchor loop implanted on
the midcervical portion of left vagus nerve and the impulse
generator is implanted subcutaneously in the left infraclavicular
region. The left vagus is the preferred site as the right vagus
innervates the sinoatrial node and influences the heart rate. Data
from laboratory studies suggest that it most probably works by
increasing the release of norepinephrine in the locus ceruleus,
which in turn increases the seizure threshold. More than 32,000
devices have been implanted since it was approved in 1997.
There is class I evidence that vagus nerve stimulator reduces the
frequency of seizures. In addition it also elevates the patients’
mood—independent of seizure control. In one of the studies
50% reduction in seizure frequency was 37% in the first year
and 44% in the second and third year. The side effects
commonly reported are constriction in the throat, change in
voice, and throat pain which most patients are able to tolerate
and continue the use of the device. In conclusion VNS seems to
be an effective nonpharmacologic therapy for medically
refractory partial onset seizures.
Key Words: vagus nerve stimulator, VNS therapy, brain
stimulation, seizure therapy, locus ceruleus
(J Neurosurg Anesthesiol 2008;20:29–35)
T
he word ‘‘epilepsy’’ is derived from the Greek word
epilepsia—which means ‘‘seizure’’ (attack). It is a
chronic disorder characterized by paroxysmal brain
dysfunction due to excessive neuronal discharge.1 There
are E3 million patients with epilepsy in North America.2
It is the second most common neurologic disorder (after
stroke) and is the most prevalent neurologic disorder
involving all age groups. Despite the advances in
neuropharmacology and the advent of new antiepileptic
drugs, seizure control is ineffective in E30% of epilepsy
cases.3,4 Roughly half of these are partial onset seizures.5,6
Received for publication August 5, 2006; accepted September 18, 2007.
From the Department of Anesthesia, Yale University School of
Medicine, New Haven, CT.
Reprints: Dr Ramachandran Ramani, MD, Yale University School of
Medicine, 333 Cedar Street, PO Box 208051, New Haven, CT 065208051 (e-mail: [email protected]).
Copyright r 2007 by Lippincott Williams & Wilkins
J Neurosurg Anesthesiol
Volume 20, Number 1, January 2008
Partial onset seizures are those in which the first clinical
and electroencephalogram (EEG) changes indicate initial
activation of a system of neurons limited to part of one
cerebral hemisphere.7 Only a minority of these patients
benefit from surgical treatment. Antiepileptic drugs also
have cognitive, psychologic, and behavioral side effects.
Thus, the present day pharmacologic management of
epilepsy is far from satisfactory and this underscores the
importance of effective nonpharmacologic treatment
measures for epilepsy.
In 1997, the United States Food and Drug Administration (FDA) approved the vagus nerve stimulator
(VNS) therapy (manufactured by Cyberonics Inc,
Houston, TX) as an adjunct therapy for reducing seizure
frequency in patients over 12 years of age with partial
onset seizures refractory to antiepileptic medications. The
VNS device intermittently stimulates the vagus nerve and
transmits afferent stimuli to the central nervous system
(CNS) and increases the seizure threshold in the patient.
The VNS device is the first such device for seizure control
approved by the FDA and is a significant departure from
the conventional manner in which seizure is treated
(somatic activation for a CNS disease). This review will
address the neuroanatomy, physiologic basis of VNS, its
mechanism of action and its anesthetic implications.
TREATMENT OPTIONS FOR EPILEPSY
Presently the treatment options available for a
patient with seizure disorder are medical treatment first
followed by surgical resection, if the patient is refractory
to medical treatment. With antiepileptic medications
seizure control is effective in E70% of the cases.8 Most
patients who do not respond to 3 antiepileptic drugs
(given separately or in combination) do not ultimately
respond to pharmacotherapy.3 In the group refractory to
medical management (E30% of patients with seizure
disorder) 50% have partial onset seizures.5,6 These are the
patients suitable for seizure surgery workup. However,
only 10% to 30% of these partial onset seizure patients
refractory to medical management are appropriate
candidates for seizure surgery and eventually only 1%
undergo the procedure.9 Surgical options include focal
cortical resection, temporal lobectomy, corpus callosotomy, subpial resection, and hemispherectomy. In the
temporal lobe amygdalo-hippocampectomy is one of
the most common surgical procedures carried out.10 The
outcome after surgery depends on the degree of sclerosis
in the amygdala and the hippocampus—in patients with
severe sclerosis 88.7% are seizure free and when sclerosis
is mild 59.6% are seizure free after surgery.10,11 In a
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Volume 20, Number 1, January 2008
comparison between surgery and medical management in
temporal lobe epilepsy, after 4.8 years of follow-up 44.6%
in the surgical group and 4.3% in the medical management group were seizure free. However, for those patients
where surgery is not indicated (or the patient is unwilling
to undergo surgery) and those who do not respond to
surgical resection, there is a big void in treatment option.
In addition there are patients in the medical management
group who are noncompliant with medication because of
the intolerable side effects to antiepileptic drugs.12 VNS is
a therapeutic option when medical and surgical treatments of epilepsy either fail or are not feasible.
VAGUS NERVE STIMULATION
History
VNS is an example of treating neuro-psychiatric
diseases by somatic stimulation. Other techniques include
electroconvulsive therapy for depression and deep brain
stimulation for Parkinson disease and essential tremor.
Corning,13 back in 1883, was the first to propose the idea
of VNS for seizures—based on his theory that seizure
activity is caused by venous hyperemia in the brain and
that vagus nerve activation will treat seizures by decreasing the heart rate and the cerebral blood flow (CBF),
thereby correcting the cerebral hyperemia. However,
Bailey and Bremer14 in 1938 recognized the direct CNS
effects of vagus nerve activation (in contrast to the
cardiovascular effects as proposed by Corning).15 Dell
and Olson16 in their study on awake cats with high
cervical lesion, observed a slow wave activity in the
anterior rhinal sulcus with vagus nerve activation.
Consolidating all this basic information, Zabara17,18
created experimental seizures in dogs and demonstrated
the antiepileptic effect of VNS therapy. He hypothesized
that VNS therapy can ‘‘control/prevent the motor,
autonomic and conscious components of epilepsy.’’
He also observed that the inhibitory effect on seizures
outlasts the period of VNS activation (at least 4 times
FIGURE 2. VNS leads with the 3 helical loops (A and C are the
positive and negative leads and B is the anchor).
longer in the acute experimental epilepsy models and
much longer in the chronic models). The first VNS was
implanted in 1988 by Penry and Dean.19
Indications for VNS
VNS therapy is recommended in patients over 12
years of age with partial onset seizures refractory to
antiepileptic medications. In the earlier studies where
efficacy of the VNS was evaluated the defining criteria for
medically refractory seizure was 6 seizures or more per
month and seizure-free interval of no more than 2 to
3 weeks despite therapy with multiple medications.20
However, now multiple factors are taken into account
before advising the VNS therapy such as—uncontrolled
seizures despite 2 drug trials, compromised quality of life,
noncompliance with antiepileptic medication, intolerable
side effects to antiepileptic medications, and patients not
suitable for surgery or not willing to undergo surgery.
Decision to implant VNS is made on a case-by-case basis.
Off label use of VNS has been reported in children as
young as 3 years of age and in patients with generalized
seizures.21
Anatomy of Vagus Nerve
FIGURE 1. VNS device.
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Vagus nerve gets its name from the Latin word
‘‘vagus’’ which means ‘‘wandering.’’1 This refers to the
extensive distribution of the vagus nerve to the head,
neck, thoracic, and abdominal viscera. In the vagus nerve,
80% of the fibers are afferent carrying both somatic and
visceral afferents. The vagus nerve carries afferent fibers
from the head, neck, thoracic, and abdominal viscera and
parasympathetic efferents to the heart, lung, and major
part of the gastrointestinal tract. The motor efferents to
the pharynx and larynx also arise from the vagus. The cell
bodies of the afferent sensory component of vagus are
located in the nodose ganglion. The nodose ganglion
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relays the afferent input to the nucleus tractus solitarius
(NTS). From the NTS there are 3 major outflows22:
(1) Autonomic feed back loop.
(2) Direct projection to the reticular formation in the
medulla.
(3) Ascending projection to the parabrachial nucleus
(PB) and locus ceruleus (LC).
LC is one of the primary norepinephrine (NE)
secreting nuclei in the CNS. The release of NE in response
to VNS seems to determine the antiepileptic action of
VNS.23 The PB and LC also have efferent connections to
the amygdala and the stria terminalis.24 The antidepressant and mood elevation effect observed with the VNS
(which may or may not be associated with seizure control)
could be related to the effect of the vagus nerve activation
on the amygdala. The amygdala controls emotional
behavior and mood.
The midcervical portion of the vagus nerve is devoid
of any branches.25 In the neck, the superior and inferior
cardiac branches arise rostral to the midcervical part of
the vagus nerve. Branches from the right vagus supply the
sinoatrial node whereas the branches from left vagus
innervate the atrioventricular node. Hence the right
vagus influences the heart rate much more than the left
vagus. Because of this reason the VNS electrodes are
almost always placed on the left vagus in its midcervical
portion (caudal to the origin of the cardiac branches).
Despite this, occasionally because of retrograde stimulation
there can be bradycardia with the activation of the left
vagus nerve. The branches to the pharynx, carotid sinus,
and the superior laryngeal nerve also arise rostral to the
midcervical portion of the vagus nerve. The recurrent
laryngeal nerve is the only branch caudal to the midcervical
part of the vagus. Hence with the midcervical placement of
the VNS, the recurrent laryngeal nerve does get activated
and hoarseness of voice is a common occurrence. Retrograde activation of the superior laryngeal nerve can cause a
feeling of tightness and pain in the throat.
Theoretical Basis of VNS Therapy
Although the mechanism of the antiepileptic efficacy
of the VNS therapy remains to be elucidated in humans,
there is compelling evidence that the modulation of
afferent vagal nerve activity increases the seizure threshold. The vagal afferents from the viscera relay impulses to
multiple regions in the CNS many of which are potential
sites for epileptogenesis. This includes the hippocampus,
amygdala, cerebellum, diencephalon (includes the thalamus and hypothalamus), and insular cortex. As described
in the section on anatomy, the vagal afferents project to
the NTS and from NTS sensory afferents are relayed to
the PB and LC. The hippocampus and the amygdala also
get afferent input from the LC. LC is one of the major NE
secreting regions of the CNS. Activation of the LC has
been implicated as one of the possible mechanisms by
which the VNS works.23 As a proof, in laboratory seizure
models (rats) if the LC is destroyed then VNS is no longer
effective in controlling seizure activity. Infusion of
6-hydroxydopamine can deplete NE level in the LC and
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this has been shown to neutralize the efficacy of VNS.26 It
has been suggested that the LC activation releases NE
and serotonin which in turn modulates the seizure
threshold by releasing g-amino butyric acid or by
inhibiting the release of glutamate in the regions with
afferent connectivity to the LC.27 Injection of g-amino
butyric acid or glutamate antagonist in the NTS (which is
connected to the LC) blocks seizure activity. Yet another
mechanism suggested is the change in heart rate and
cardiac contractility associated with the VNS therapy,
which alters the CBF in specific regions of the CNS
resulting in a rise in seizure threshold.28 However, the
argument against this theory is the VNS is not associated
with any primary change in cardiovascular function
and the changes in CBF observed are more likely to be
secondary to the alteration in neuronal activity induced
by the VNS.
VNS Device (http://www.vnstherapy.com/
epilepsy/hcp)29
The VNS device is manufactured by Cyberonics Inc
(Houston, TX). The device primarily consists of a pulse
generator (Fig. 1) and implantable leads. The patient end of
the lead has 3 discrete helical coils (Fig. 2), which wrap
around the left vagus nerve. The proximal and distal coils
are the positive and negative leads whereas the middle coil
is an anchor. This anchor ensures that undue tension is not
exerted on the vagus nerve with movements of the neck.
It is meant to snugly fit around the nerve. Each helix has
3 coils and the middle turn is a platinum ribbon coil, which
is welded to the lead wire. This shape ensures optimum
contact with the nerve. This open helical design prevents
damage to the nerve. Although snugly fitting around the
nerve, the electrode is meant to move with the nerve thus
minimizing shear on the nerve. Model 102 is the generator
currently available. It is powered by a lithium cadmium
battery and is hermetically sealed in a titanium module.
It has a projected battery life of 6 years. The actual life is
dependent upon the stimulus intensity and frequency.
The pulse generator is placed in a subcutaneous
pocket in the left infraclavicular region. The leads are
placed on the midcervical portion of the left vagus nerve
and the leads are tunneled to the generator pocket. There
is an interrogating device for checking the device before
implantation and after it is implanted. The output
current, frequency, pulse width, and signal on and off
time have to be set on the generator. Activation is
initiated with 0.25 mA current and increased gradually to
1.25 to 2 mA over several weeks. The other settings are
pulse width of 250 to 500 ms, 20 to 30 Hz frequency, and
signal on for 30 seconds and off for 3 to 5 minutes.
Settings are altered as per the patient’s requirement. The
baseline signal output from the generator is continuously
on. Each patient is given a hand held magnet. When the
magnet is run briefly over the generator it manually
triggers a train of stimuli superimposed on the baseline
activation. If a patient has an aura then manual triggering
can be initiated to abort or minimize a seizure activity.
Alternatively if a patient wants to stop the device (in case
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of malfunction) placing the magnet on the generator
continuously, terminates the baseline activation. The
magnet is also used for testing the device. Patients are
advised to check the device periodically by manually
inducing activation. Patients perceive the activation as a
mild tingling in the throat.
Clinical Efficacy (http://www.vnstherapy.com/
epilepsy/hcp)29
On the basis of a randomized control trial, in 1999 the
Therapeutics and Technology Assessment Subcommittee of
the American Academy of Neurology noted that ‘‘sufficient
evidence exists to rank VNS for epilepsy as effective
and safe on the basis of a preponderance of class I
evidence.’’30,31 More than 32,000 VNS devices have been
implanted worldwide with 94,000 patient years of followup. The efficacy of the device is measured in terms of the
median (50%) reduction in seizure frequency.32 In a
multicenter trial, 113 patients were studied to determine
the optimum stimulation parameters. All patients satisfied
the criteria for medically refractory seizures and were
implanted the device. Half the patients were stimulated
every 5 minutes for 30 seconds and the other half every 90
minutes for 30 seconds. The rest of the stimulation parameters were the same—30 Hz frequency, 3.5 mA current,
and pulse width of 500 ms. At 3 months, 31% in the high
stimulation group had a 50% reduction in seizure frequency compared with 13% in the low stimulation group.26
Studies reveal that 50% reduction in seizure frequency (a bench mark for assessing the efficacy of the VNS
therapy) is achieved in 37% of the subjects in the first year
and 43% in the second and third year.32 A 12-year followup was reported by Uthman et al33 in 48 patients. With
longer follow-up the efficacy of the VNS tends to improve.
Twenty-nine out of the forty-eight patients (60%) had a
50% reduction in seizure frequency over 12 years whereas
42% of the subjects had a 75% reduction in seizure
frequency.33 Three patients were seizure free. In addition to
the decrease in seizure frequency patients also reported a
significant improvement in quality of life. They were more
alert, daytime sleeping was less, they were less depressed,
and memory also improved.34,35 Patients on VNS are less
likely to discontinue this therapy compared with those on
medical therapy.
Side Effects/Complications
Side effects/complications with the VNS placement
could be acute or chronic. Acute side effects reported are
wound infection, left vocal cord palsy, lower facial palsy,
and very rarely severe bradycardia/asystole.26 The incidence
of wound infection reported is in the range of 3% to 6%
and in one of the studies infection led to removal of the
device in 3 out of 198 cases. Left vocal cord palsy was
reported in 2 out of 198 cases in the EO5 study.32 It
resolved spontaneously. Left facial nerve palsy was related
to surgical incision placement—with change in surgical
technique it is no longer observed. Severe bradycardia
leading to asystole (reversible) was related to the immediate
testing of the device on implantation. Reported incidence
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was 0.1%. The current practice is not to test the device
immediately after implantation. The device is activated
2 weeks after the implantation. With this approach patients
have been able to use the device without any risk of
bradycardia. It is advisable to have continuous electrocardiogram monitoring and resuscitation equipment when
the device is activated for the first time.
Both the sensory and the motor innervations of the
pharynx and the larynx are supplied by the vagus nerve.
Hence most of the chronic side effects of the VNS therapy
are related to the activation of the pharynx and the
larynx. Hoarseness of voice (37.2%), hypophonia
(37.2%), and coughing (45%) have been reported—
because of the activation of the recurrent laryngeal nerve
and the superior laryngeal nerve.26 Many patients report
a constriction in throat and change in voice—which may
persist for a long time. Laryngo-pharyngeal dysfunction
because of the vocal cord palsy leading to aspiration of
pharyngeal secretions has been reported in some subjects.
Vocal cord palsy and evidence of aspiration was seen on
doing an endoscopic evaluation during the stimulation
interval.36 This implies that patients on chronic VNS
therapy may be at risk of aspiration and standard
aspiration precautions may be required in these cases.
Occasionally pain in the jaw, headache, and pain in the
abdomen has been reported. There is a case report of
chronic diarrhea with VNS therapy.37 In a follow-up it
was observed that most of the side effects resolve within
the first year. Some of the side effects (like throat pain,
cough, and dyspnea) subside with alteration in the
stimulation parameters. It may reappear with generator
change (if the stimulation gap is more than 3 wk).
In the neck, vagus nerve lies between the carotid
artery and the internal jugular vein, within the carotid
sheath.5 Hypoglossal nerve is proximal to the midcervical
part of vagus whereas the phrenic nerve lies beneath the
carotid sheath. High current output can infrequently
cause hemiparalysis of the diaphragm and weakness of
one-half of the tongue. The sympathetic trunk is deep and
posterior to the vagus nerve. Horner syndrome has also
been reported after VNS therapy.
Implications for Anesthesiologist38
As anesthesiologist, we should be cognizant of the
fact that as the mechanism of the VNS device is
understood and cumulative data regarding its efficacy
comes up, more and more of these devices are likely to be
implanted. Even more so now, with the expansion of its
indications for major depressive disorders. As of now
there is no report of any electrical interference with the
VNS device. Anesthetic management may be required in
the following situations:
(1) Seizure patients coming for VNS implantation.
(2) Patients coming for generator change.
(3) Patients with VNS coming for incidental surgery.
The VNS implantation procedure is usually done
under general anesthesia. During surgery the head is
turned to the right, as the middle segment of the left
side vagus nerve has to be exposed. Hence general
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endotracheal anesthesia is preferred. Generator change
can be carried out under local anesthesia. The important
anesthetic implications in a patient coming for VNS
implantation are
(1) Optimum seizure control in the perioperative period:
antiepileptic medication should be continued till the
morning of surgery and resumed as soon as possible
in the postoperative period. Plasma level of the
antiepileptic medication should be checked to ensure
that the level is therapeutic.
(2) Augmented metabolism of drugs: Because the patients
with refractory seizures are likely to be on multiple
antiepileptic medications as a side effect there is an
augmented hepatic metabolism of drugs resulting in
enhanced requirement for muscle relaxants, narcotics,
and benzodiazepines. This is observed only with
phenytoin and carbamazepine. It is not seen with
newer antiepileptic medications. Intermediate acting
neuromuscular blockers vecuronium and rocuronium
are predominantly metabolized in the liver and their
requirement is likely to be higher. Cisatracurium
has a nonorgan-dependent metabolism and its dosage
requirement may not be influenced by chronic antiepileptic medication. Up-regulation of acetylcholine
receptors would also contribute to the altered dose
requirement of muscle relaxants.38
(3) Proconvulsant drugs to be avoided: Because of the
propensity for seizures, anesthetic agents and
adjuvant drugs, which potentially cause seizures or
decrease seizure threshold are preferably avoided.
Induction dose of sevoflurane has been shown to
cause epileptic EEG activity in children and adults.39
This has also been demonstrated to occur at surgical level of anesthesia in epileptic and nonepileptic
subjects.40 This is because of the structural similarity
between sevoflurane and enflurane (enflurane can
cause seizures at normocapnea and hypocapnea). So
it would be prudent to avoid sevoflurane and
enflurane in these cases.
High doses of opioids can also cause epileptic EEG
activity. This has been demonstrated in laboratory
models and in humans. In humans, fentanyl dose of
25 to 100 mg/kg and sufentanil dose of 2.5 to 10 mg/kg
was shown to cause epileptic EEG activity in patients
without history of seizure undergoing cardiac surgery.41 In clinical practice for a 1 to 2-hour surgical
procedure it is highly unlikely that such a high dose of
opioids will be required. However, because of the
enhanced metabolism, opioid dose requirement could
be higher than normal.
(4) Physiologic factors that can decrease seizure threshold
should be avoided. This would include hypoxia,
hypotension, hypocarbia, and hyponatremia.
When a patient with a VNS comes for an incidental
surgery issues related to anesthesia/anesthetic management are:
(1) We have to ensure that the VNS device is working
effectively and seizures are being managed as effectively
as is medically feasible. VNS patients are generally
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(2)
(3)
(4)
(5)
(6)
(7)
under the medical supervision of a neurologist. Hence
it is advisable to contact the concerned neurologist to
ensure that the device is interrogated before and after
the surgical procedure, carry out the appropriate device
adjustment if required and optimize the medical
management of seizure.
Anesthesiologist must be cognizant of the side effects
associated with a VNS, such as hoarseness of voice,
mild throat constriction, and hypophonia. At all
times we have to be aware that any medication/
biochemical alteration (hyponatremia, acidosis, and
hypoxia) which decreases the seizure threshold can
make a patient more prone to get seizure.
As discussed above, some patients may be at a higher
risk for aspiration because of laryngo-pharyngeal
dysfunction. Standard aspiration precautions should
be followed if there is an evidence of aspiration risk.
Use of electrocautery, external defibrillator: these
devices could potentially damage the VNS generator
and/or the electrodes. As of now there are no reports
in literature about electrical interference with a VNS
device. However, it would be prudent to avoid the use
of electrocautery and external defibrillator within the
vicinity of the device and the electrodes. If electrocautery is required a bipolar cautery is preferable.
As followed for a permanent pacemaker, monopolar
cautery grounding pad should be placed away from
the VNS generator and closer to the operative site.
The defibrillator paddles also should be placed away
from the VNS generator. As far as possible lower
current energy level should be used. Current vector in
both the electrocautery and defibrillator should be
perpendicular to the direction of the VNS leads.
Airway obstruction: in patients with obstructive sleep
apnea during VNS activation airway obstruction has
been reported and confirmed by polysomnography
studies. The incidence of obstructive sleep apnea in
medically refractory seizure patients is somewhere in
the range of E33%. Considering this, combined effects
of the residual effects of anesthesia, opioids, and VNS
stimulation could increase the chances of postoperative
airway obstruction in patients with obstructive sleep
apnea.42 Institution of constant positive alveolar
pressure can relieve the obstruction. VNS stimulation
may have to be turned down or turned off temporarily.
Placement of a central intravenous access on the side of
the VNS placement should be avoided. The neck should
be in neutral position to avoid any stretching or
displacement of the electrodes implanted on the vagus
nerve.
Though the VNS device is magnetic resonance
imaging compatible, radiofrequency current can
generate heat in the vicinity of the vagus nerve,
which could potentially damage the nerve. Settings of
the device could be altered by the magnetic resonance
imaging magnet. As a general rule after any possible
potential electrical interference with the VNS device,
the device should be interrogated and reset if
required.
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Ramani
Nonepileptic Indications for VNS
In addition to epilepsy other potential indications
for the VNS therapy are depression and anxiety disorders
(eg, panic disorder, irritable bowel syndrome).21 In July
2005, FDA approved the VNS therapy for patients over
18 years of age with major recurrent depressive disorder,
with inadequate response to 4 or more antidepressant
medications. This implies that in the future we are likely
to see more patients with the VNS device.
CONCLUSIONS
The VNS therapy is a promising nonpharmacologic
alternative for decreasing the seizure frequency in partial
onset medically refractory seizures. There is class I
evidence to justify its use in epilepsy. Device is well
tolerated by most subjects. In addition to seizure control
it also improves the quality of life.
ACKNOWLEDGMENTS
The author thanks Dr Kenneth Vives, Assistant
Professor of Neurosurgery and Dr Keith Ruskin, Professor
of Anesthesia and Neurosurgery at the Yale University
School of Medicine, New Haven, Connecticut for reviewing
this manuscript and for their valuable comments and
suggestions.
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