Pediatric Epilepsy Diagnosis and Therapy - part 10 pdf

63 • OUTCOME OF EPILEPSY SURGERY IN CHILDHOOD
805
recovery of memory deficits in children than in adults
undergoing temporal lobectomy. Their data suggest an
increased neuronal plasticity in childhood, with a pro-
posal of a strong argument in favor of early surgery.
Literature review shows a dearth of information on
other lobar resections. There are very few studies on post-
surgical series in children with frontal lobe and posterior
epilepsies (100). Preoperative groups with frontal lobe
epilepsy have deficits in the domain of executive func-
tioning and motor coordination. Lendt et al (111, 112)
compared the one-year postsurgical cognitive profiles in
groups of 12 children, one group with temporal and the
other with frontal lobe epilepsy. Both groups showed
important gains in attention, processing speed, memory,
and bimanual coordination. Surgery did not lead to any
additional impairment. The neuropsychologic profile in
frontal lobe epilepsy (113) is akin to that of adults with
frontal lobe lesions. Surgical outcome has no bearing
on the postoperative neuropsychologic profile in chil-
dren with frontal lobe epilepsy in both good- and poor-
seizure-outcome groups. Some gains, albeit insignificant,
are made in the domain of motor coordination. Data
from other studies lend weight to offering surgery to suit-
able candidates, as the benefits from epilepsy surgery
far outweigh the risks of inflicting minor deficits in the
form of working memory and visual constructional skills
(114, 115).
The posterior epilepsies are relatively rare in chil-
dren. In terms of cognition, the posterior cortex plays an

important role in attention and visuoconstructional abili-
ties (116, 117). In general the group of patients with pos-
terior epilepsies (100) has a low IQ compared to groups of
temporal or frontal lobe epilepsy. The deficit is especially
in the domain of visuoconstruction performance; also of
note is the fact that the effects are even more disabling in
children with early-onset damage to the posterior cortex.
Sinclair et al (77) studied a group of children undergo-
ing extratemporal resections, and within this group the
children with frontal lobe epilepsy were relatively better
preserved, with a mean full-scale IQ nine points higher
than in the children with posterior epilepsies, and the
postsurgical outcome mirrored the preoperative assess-
ment. Postoperatively, except for an improvement in the
sphere of verbal learning, there was no change in the intel-
lectual functioning and memory. Similar results of a stable
postoperative cognitive profile were seen in a group of
26 children (118). Even though the group is quite small,
the data show no impairment or adverse effects of sur-
gery on the intelligence or memory. Mabbott and Smith
(119) assessed memory in a series of 44 children and
adolescents undergoing temporal or extratemporal resec-
tion and found no significant decline in memory in either
group of children. Children have variable performance on
the tasks used for assessment. Within the surgical groups,
some children perform poorly within tasks, while others
perform well on the same tasks. The observed variability
may be dependent on several factors, probably including
age, duration of epilepsy, nature of material used to test
memory, and number of medications. Also of note is the

effect of age at onset; children with older age of seizure
onset performed better on tasks of verbal memory and
face recognition.
Hemispherectomy
Many children coming to this procedure have devel-
opmental malformations as their underlying respon-
sible pathology, such as hemimegalencephaly (120) or
widespread hemispheric cortical dysplasia. The remain-
ing patients have other etiologies such as Rasmussen
encephalitis or vascular pathology. Both the groups tend
to have a low IQ/DQ preoperatively; but the deficit is
most marked in the group with developmental malforma-
tions (121–23). This is particularly relevant, considering
the data suggest that age of onset of epilepsy is likely
to have a major impact on ultimate developmental out-
come, and the onset tends to be earlier in the group with
developmental malformations (124, 125). Most studies
do not show any significant longitudinal change with
regards to developmental and cognitive outcome follow-
ing hemispherectomy. There are a few studies that do
report some gain (98, 120–122), whereas others have
reported loss of skills postoperatively, predominantly
in those with acquired pathology (124). In a group
of 71 children (124), 11 children showed a decline of
more than 15 points in the IQ at follow-up, but eight of
the 11 children had Rasmussen syndrome, and the decline
may have been a result of the progressive nature of the
disease. Even in this study almost 80% of the children
had a postoperative neuropsychologic profile similar to
or slightly better than the preoperative score.

The majority of children who come to hemispher-
ectomy are developmentally delayed, as verified by data
from the literature. This has not been a criterion to exclude
them from a surgical program. Evidence to date suggests
that, although we aim to optimize neurodevelopment,
we are more likely to prevent possible further cognitive
damage from ongoing epilepsy. Data to date suggest the
final outcome to be usually comparable to the preopera-
tive level of functioning, suggesting a maintenance of the
developmental trajectory. Children who are well main-
tained preoperatively tend to do better than those with
poor developmental skills (126). A recent meta-analysis
(127) showed a better outcome in children than in adults,
and the short-term cognitive outcomes were maintained
in the longer term. Overall, children undergoing left hemi-
spherectomy (128) with early-onset epilepsy and devel-
opmental malformations have a poor cognitive profile as
compared to children with right hemispheric lesions, and
this translates to a similar postoperative profile.
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
806
FUNCTIONAL OUTCOME
When deciding on whether resective surgery should be
offered, the likelihood of inflicting a possible neurologic
deficit should be carefully considered. The presurgical
evaluation is undertaken with meticulous care to reduce
the chance of causing this deficit, by outlining the elo-
quent cortices and, if necessary, using invasive monitoring
with subdural grids and functional stimulation. Recently,
with the advent of functional imaging to complement the

presurgical evaluation and mapping of the motor and
language cortex, the need for invasive monitoring for
delineation of eloquent cortex has been reduced. In each
individual case the risk-benefit ratio needs to be carefully
considered.
Reorganization (129–132) of the eloquent cortices
has a bearing on the eventual area of resection. Early-onset
epilepsy may be presumed to lead to a greater chance of
relocalization of function, but studies have shown that
language and motor function (129–132) may be local-
ized within dysplastic cortex. In such cases the risk of
postoperative functional deficit is very high. The majority
of children with congenital hemiplegia (associated with
a structural brain pathology) and early-onset epilepsy
can expect little change between pre- and postoperative
functional status, although a visual field defect is inevi-
table if not present preoperatively. Surgery for right-sided
lesions (128) in the acquired pathology group tends to
have a better outcome; overall, however, the outcome is
poor in the developmental pathologies as compared to the
acquired pathologies. Curtiss et al (133) showed a better
outcome for right-sided hemispherectomies with under-
lying acquired pathologies, but even the left hemispher-
ectomies may have better postoperative performance on
the subdomains of language function, suggesting that the
right hemisphere can support language reorganization,
with better receptive language than expressive (134). Also
in the study by Curtiss et al (133), postoperative seizure
outcome had a positive impact on language development
in children with developmental pathologies.

Frank aphasia and major language dysfunction are
usually not seen after standard temporal lobe resection.
The only deficit seen in patients with dominant temporal
lobe resection is in naming and, probably, verbal learning
(135). This too usually resolves within 6–12 months of
surgery. Verbal fluency is unaffected in both dominant
and nondominant resection.
Hemiparesis is an expected effect of hemispherec-
tomy, but focal motor deficits may be seen in focal, lobar,
or multilobar resections encroaching upon eloquent cor-
tex. The degree of motor deficit will vary with time, and
many deficits improve, suggesting that the cause is revers-
ible, such as edema or ischemia, or that in the longer term
some reorganization can take place. In a group (136)
of 15 children posthemispherectomy, etiology-specific
differences in reorganization of the remaining cortex were
shown. Ambulation is important for independence, and
in those undergoing hemispherectomy (137), children
who are ambulant prior to surgery continue to remain so
after surgery irrespective of developmental and acquired
pathologies. In terms of other musculature, they do show
slight deterioration in their function within the first few
months after surgery, but they usually recover to near the
presurgical level of functioning except for finger dexterity
and power in the distal upper limb musculature.
Formal discussion with the parents and the child
regarding the expected motor, visual, or language defi-
cit will eventually decide the optimum time for surgery.
The risk-benefit assessment should be discussed at length
before offering surgery. This is particularly true for chil-

dren with progressive conditions such as Rasmussen
encephalitis and Sturge-Weber syndrome.
BEHAVIORAL AND PSYCHIATRIC OUTCOME
The prevalence of behavioral problems in intractable
childhood epilepsy is high (138), and a proportion of
these children will enter a surgical program for evalu-
ation. Psychiatric disorder (34) is reported in 29% of
children with idiopathic generalized seizures and in 58%
of children with seizures and structural brain abnormal-
ity. Davies et al (139) showed that the presence of psy-
chiatric disorder and behavioral problems adds to the
already significant disability in these children. At times,
behavior can be the most challenging aspect of epilepsy
management.
Surgery for epilepsy has a variable impact on the
psychiatric and behavioral outcome postoperatively. Few
of the patients improve, few worsen, and few remain the
same, while (140) a further proportion develop new symp-
toms following surgery for epilepsy (34, 141). Although
new symptoms may evolve in previously normal children,
it is generally seen that absence of psychiatric disorder
preoperatively predicts a good postoperative psychiatric
outcome. Thus, epilepsy surgery has a predominantly
positive effect on the behavioral outcome in children with
intractable epilepsy beginning early in life. Psychiatric
and behavioral outcomes in slightly older children are
unclear, with variable results, as mentioned previously.
Following surgery there appears to be a risk of precipi-
tating new psychiatric disorders with a Diagnostic and
Statistical Manual (DSM) IV diagnosis in a proportion

of these children.
When hemispherectomy was first described by
MacKenzie in 1938 and subsequently by Krynau in the
1950s, it was noted that significant improvement in
behavior could be achieved. In one study (142) 36 of
50 children had severe behavioral problems that resolved
in 54% of the children postsurgery and improved in a
63 • OUTCOME OF EPILEPSY SURGERY IN CHILDHOOD
807
further 40%. White (143), looking at 144 surgeries for
infantile hemiplegia and epilepsy, saw behavior improve
in 80% of the 108 patients with behavioral dysfunction.
Later studies show behavioral difficulty in 33% of chil-
dren preoperatively, with improvement in all but one
child and new symptoms emerging in five children. In
the study by Pulsifer et al (124), there was no difference
in the pre- and postoperative scores as measured by the
Child Behavior Check List (CBCL).
The rate of behavioral disorders in children com-
ing to temporal lobe resection is high (34), with 83%
demonstrating a DSM IV diagnosis at any point pre-
and postoperatively. Though poor postoperative seizure
control heralds a poor outcome in psychiatric symptoms
in adults, studies in children fail to confirm this obser-
vation, although in the group of McLellan et al (34),
24% of seizure-free children lost the DSM IV diagno-
sis, whereas only 4% from the poor-seizure-outcome
group lost their diagnosis. Szabo et al (141), in their
small series of five patients, did not find any signifi-
cant change between the pre- and postoperative behav-

ior in children with pervasive developmental disorder
undergoing temporal lobectomy for the treatment of
epilepsy. Whether the natural history of the disorder
may be influenced by early surgery and seizure control
remains under debate (144). Lendt et al (145) looked at
a cohort of 56 children, with a study group and a control
group of 28 children each. The 28 children underwent
surgery, and the control group was managed medically.
On review of the CBCL scores, there was normalization
of behavior in the study group; at the same time, the
control group had new emergent behavioral issues. This
study highlights the likelihood of impact of surgery on
behavioral outcome as opposed to the natural history
of the condition.
CONCLUSIONS
Surgery for epilepsy in childhood can confer consider-
able benefits, not only with regard to seizure control but
also with regard to neurodevelopmental and behavioral
outcome. The degree to which the latter can be achieved,
however, is difficult to assess in each individual case. Such
needs to be considered carefully, and the likely outcome,
however uncertain, in all domains should be outlined to
the family prior to any final decision. Further prospec-
tive data collection is required to enable more accurate
preoperative counseling.
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811
Vagus Nerve Stimulation
Therapy in Pediatric
Patients: Use and
Effectiveness
hildhood epilepsies are often char-
acterized by a wide range of seizure
types and accompanying comor-
bidities such as mental retardation
or developmental delay (MR/DD), autism, and language
disorders, often making treatment difficult. However,
advances in our understanding of the underlying mecha-
nisms that result in seizures and epilepsy syndromes have
also led to advances in epilepsy treatments. Traditionally,
the two primary treatment modalities used to control
seizures have been mono- and polytherapy with antiepi-
leptic drugs (AEDs) and epilepsy surgery. Among pedi-
atric patients, the ketogenic diet is used among a small
number of children.
In 1997, however, the United States (U.S.) Food
and Drug Administration (FDA) approved a new, non-
pharmacologic treatment—vagus nerve stimulation
(VNS) therapy—for adjunctive use among patients aged
12 years and older with partial-onset seizures refractory
to standard therapies. Although VNS therapy is not cur-
rently approved in the United States for children younger

than age 12 years, studies indicate that success with VNS
therapy can be achieved independent of patient age and
seizure type or syndrome. Reports indicate that VNS ther-
apy may have unique benefits for pediatric patients (aged
less than 18 years), including improvements in quality of
life resulting from the lack of pharmacologic interactions
James W. Wheless
known to impair development, and success at reduc-
ing seizure frequency and severity among patients with
age-related and difficult-to-control syndromes such as
Lennox-Gastaut syndrome (LGS). This chapter outlines
both the safety and effectiveness of VNS therapy among
pediatric patients with epilepsy, as discerned from current
treatment practices and reports in the literature.
THE VAGUS NERVE STIMULATION
THERAPY SYSTEM
Vagus nerve stimulation (VNS) was the first nonphar-
macologic therapy approved by the FDA for the treat-
ment of seizures. The treatment, which attenuates seizure
frequency, severity, and duration by chronic intermittent
stimulation of the vagus nerve, is intended for use as an
adjunctive treatment with AED therapies. As of March
2006, more than 35,000 patients with epilepsy have been
implanted with the VNS therapy system worldwide, with
approximately 30% of those patients being younger than
age 18 at the time of their first implant. Approximately
one-third of patients receiving VNS therapy experience
at least a 50% reduction in seizure frequency with no
adverse cognitive or systemic effects (1, 2). Moreover,
clinical findings indicate that the effectiveness of VNS

therapy continues to improve over time (2–8), independent
C
64
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
812
of changes in AEDs or stimulation parameters (9). Also
notable is the fact that tolerance, which is often accom-
panied by a reduction in efficacy for many treatments,
does not appear to be a factor with VNS therapy, even
after extended (Ͼ10 years) periods of time (2). Response
to VNS therapy may be delayed for some patients (8, 10).
As a result, the long-term safety and effectiveness seen
with this treatment have made VNS therapy a mainstream
treatment option for a broad range of epilepsy patients,
including children and adolescents. VNS therapy is sec-
ond only to AED therapy as a treatment category for
childhood epilepsy in the United States.
The VNS therapy system consists of the implant-
able pulse generator and bipolar VNS therapy lead, a
programming wand with software, a tunneling tool, and
a hand-held magnet. The original systems consisted of
the Model 100 and Model 101. However, in June 2002,
Cyberonics, Inc. (Houston, Texas), introduced a new gen-
erator model, the Model 102 system, which is thinner
(6.9 mm), lighter (25 g), and has less volume (52.2 mm
in diameter) than the previous models (11). The smaller
size of the Model 102 offers children an improved cos-
metic appearance and increased comfort. In addition,
the Model 102 has a single- rather than a dual-pin lead,
making it easier and faster to implant than the previous

models. Both the Model 101 and Model 102 are currently
being implanted. The average battery life for the genera-
tor (Model 101 or 102) is approximately 7 to 10 years
with normal use (11). Increases in stimulation intensities
or frequency will decrease battery life.
The magnet provided to patients as part of the VNS
therapy system allows for on-demand stimulation, which
has the potential to abort seizures, either consistently or
occasionally, among some patients or caregivers who are
able to anticipate the onset of their seizures (12–14). The
additional stimulus train that results when the magnet
is held over the generator is typically stronger than the
programmed stimulus parameters. This added ability of
on-demand stimulation provides a greater sense of con-
trol for patients and their caregivers over their disorder,
which can help improve how they perceive their quality
of life. The magnet also allows temporary interruption of
stimulation if needed, particularly when singing or play-
ing wind instruments or during speaking engagements.
However, stopping the stimulus should be done sparingly
and with care, as doing so creates the potential risk of
breakthrough seizures.
Implantation Procedure
The implant surgery is most often performed under gen-
eral anesthesia and typically lasts about 1 hour (4). The
pacemaker-like generator device is generally implanted in
the subcutaneous tissues of the upper left pectoral region,
with a lead then run from the generator device to the
left vagus nerve in the neck, where it is attached by a
coiled electrode (Figures 64-1, 64-2) (15, 16). Two inci-

sions are made during the procedure: one in the chest to
create the generator pocket, and the other along a fold
in the neck to expose the vagus nerve for placement of
the electrode (Figures 64-3, 64-4). A loop of lead wire is
coiled beside the generator to allow for strain relief and
patient growth.
FIGURE 64-2
Lead wire starting to be placed on the left vagus nerve.
FIGURE 64-1
VNS lead wire prior to placement on the left vagus nerve.
Cathode electrode (green suture) placed proximal (right side
of picture), then anode electrode (white suture), then anchor
tether (green suture; caudal; left side of picture).
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
813
The procedure is well tolerated in both children and
adults (17, 18) and is usually performed as outpatient
surgery; however, in some cases, patients may be kept
in the hospital overnight for observation. The device is
often turned on in the operating room or in the office
immediately after surgery, generally with a low initial
setting of 0.25 mA (Figure 64-5) (19). The programming
wand (Figure 64-6) is used at follow-up visits to check
and fine-tune the stimulation settings according to patient
comfort and level of seizure control. Instructions concern-
ing care of the incision sites, magnet use, and necessary
follow-up visits are given to patients and their families
before the patient leaves the hospital.
The length of battery life for the VNS generator is
dependent on the device model implanted and the stimu-

lation parameters used (20). Often an increase in seizure
frequency or intensity suggests clinical end of service (20).
Other indications of battery failure include a sudden stop
in sensing stimulation or unexpected changes in stimula-
tion. Once a generator reaches end of service, another
surgery is required to replace the generator. The entire
generator is replaced rather than just the battery so as to
prevent opening the hermetically sealed titanium case of
the generator, which could lead to a rejection reaction (21).
The generator-replacement surgery typically lasts approx-
imately 10 to 15 minutes and is performed on an outpa-
tient basis. Because the leads remain untouched during
a generator replacement, only one incision is needed.
Generator replacement is recommended and preferred
by patients before the battery is completely depleted so
as to prevent an interruption in treatment (20). A 12-year
follow-up study showed that multiple device replacement
surgeries are well tolerated (2). Often, however, tolerated
device currents are lower after reimplantation but are not
equated with a reduction in benefit from VNS therapy,
which suggests improved battery strength in the newer
models of VNS generators; parameter settings other
than current are generally the same as with the initial
device (20). For patients not obtaining a substantial level
of benefit from VNS, it has been suggested that stimula-
tion parameters be tapered down over an extended period
of time before end of service to allow for explantation of
FIGURE 64-3
Implantation of the Model 102.
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION

814
the device before clinical signs of generator dysfunction
become evident (20).
Potential Complications. Although the implant sur-
gery is a relatively simple procedure that is safe and well
tolerated by the vast majority of VNS therapy patients,
complications can arise. One possible risk resulting from
the implant surgery is an infection at the implant site.
This risk may be increased in the pediatric population
because young children or patients with neurocognitive
disorders may tamper with the wound before the incision
has had time to heal properly (22–24). Such infections can
be treated with antibiotics but typically lead to explanta-
tion of the device if antibiotic treatment is not effective
or if tampering continues (25, 26). Stimulator pocket
infections among the pediatric population have been rela-
tively uncommon, however (25, 27). No infections were
observed in a recent study of 36 children aged younger
than 18 years who were followed up for an average of
30 months (27).
The routine lead test performed during surgery also
has resulted in reports of bradycardia and asystole in a
small number of patients (ϳ0.1%) (28–31). Neither of
these cardiac events, however, has occurred after surgery
during day-to-day treatment with VNS therapy or in chil-
dren; these events are usually transient and self-limiting
and are rarely of clinical significance (28–31). Vocal cord
paresis, although rare, can be caused by manipulation of
the vagus nerve during the implant procedure, but such
paresis is most often transient (32). On the whole, the sur-

gery required with VNS therapy is much less invasive and
generally better tolerated than other traditional epilepsy
surgeries. Although side effects associated with the sur-
gery cannot be avoided completely, they can be minimized
with a correct technical procedure (27). In addition, the
implant surgery is not associated with any performance
or cognitive impairments and can be reversed if the treat-
ment is not effective.
Alternative Generator Placements. Depending on the
circumstances of the patient, alternative generator place-
ments have been reported with successful results. Le
et al (22) successfully used an interscapular placement
of the generator to reduce the risk of wound tamper-
FIGURE 64-4
Neck incision (right) after final closure with Durabond; chest incision after final closure (bottom left).
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
815
ing among pediatric patients with cognitive delay who
may be prone to tampering with the wound. Of the
nine patients with an interscapular generator placement,
none required explant; no discomfort or changes in daily
routine (e.g., sleeping positions) were reported; and the
effects of VNS therapy on seizure reduction and qual-
ity of life were consistent with the results seen with
the traditional generator placement. An infraclavicu-
lar placement also has been used for developmentally
delayed children, as well as for young women and chil-
dren with small muscular mass (33, 34). Three children
have had a device reimplanted on the right side rather
than the left after undergoing explantation of a VNS

device owing to infection (35). All three patients had
been deriving benefit from the left-sided implant, but
reimplantation of another device on the left side was
not pursued because of the potential of inflicting nerve
damage. The right-sided implantations were effective
in once again reducing seizure frequencies, but a differ-
ence was noted in the level of seizure control achieved
between the right- and left-sided implants. Although
right-sided implantations are not recommended by the
device manufacturer because of possible cardiac side
effects, no cardiac events presented among these three
children; however, two of the three children did experi-
ence transient respiratory events.
Stimulation Parameters
VNS therapy “dosing” is defined by five interrelated
stimulation parameters (Figure 64-7): output current
(measured in mA), signal frequency (Hz), pulse width
(µs), signal On time (s), and signal Off time (s/min).
The output current, signal frequency, and pulse width
define how much energy is delivered to the patient, with
the combination of settings for these three parameters
being analogous to the size or dose of a pill. The signal
On and Off times constitute the duty cycle (i.e., how often
the energy is delivered) and are analogous to the dos-
ing schedule for drug therapy. An optimal dose-response
relationship for VNS therapy, however, is elusive, in part
because of the interindividual variability between patients
and in part because of the number of parameters involved
in regulating the dose.
FIGURE 64-5

Intraoperative use of the handheld computer and programming wand to initiate stimulation.
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
816
FIGURE 64-6
A programming wand is held by the patient over the device while a physician checks and/or adjusts stimulation parameters
using a handheld computer.
FIGURE 64-7
Stimulation parameters (all duty cycles except low output [р10 Hz]).
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
817
of VNS therapy, typically every 2 to 4 weeks for the first
2 to 8 weeks following generator implantation. Once a
patient responds to a tolerated dose, further parameter
adjustments are performed only as clinically necessary.
However, routine assessment of lead-wire integrity and
generator function should be performed.
Response to VNS therapy has been shown to be
age dependent and therefore VNS stimulus parameters
may need to be adjusted differently for the pediat-
TABLE 64-1
Stimulation Parameter Setting Ranges
MEDIAN SETTINGS
PEDIATRIC (n ϭ 743) ADULT (n ϭ 1,486)
P
ARAMETER TYPICAL RANGE 3 MONTHS 12 MONTHS 3 MONTHS 12 MONTHS
Output current 0.25–3.5 mA 1.25 mA 1.75 mA 1.00 mA 1.50 mA
Signal frequency 20–30 Hz 30 Hz 30 Hz 30 Hz 30 Hz
Pulse width 250–500 µs 500 ␮s 500 ␮s 500 ␮s 250 ␮s
Signal on time 7–270 s 30 s 30 s 30 s 30 s
Signal off time 12 s–180 min 5 min 3 min 5 min 3 min

*No standard settings have been defined on the basis of patient age or seizure type. The median settings shown here are taken from
the VNS therapy patient outcome registry (Cyberonics, Inc; Houston, Texas).
FIGURE 64-8
Safety ranges for VNS therapy stimulation parameters.
Standard parameter settings, as determined from
the clinical trials and outlined by Heck et al (36), range
from 20 to 30 Hz at a pulse width of 250 to 500 ms and
an output current of 0.25 to 3.5 mA for 30 s On time
and 5 min Off time (Table 64-1). Initial stimulation is set
at the low end of these ranges and slowly adjusted over
time and within the safety limits (Figure 64-8) on the
basis of patient tolerance and response. Patients should
be closely monitored during the dose adjustment phase
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
818
ric patient (37). Several studies indicate that pediatric
patients may require higher output currents (Table 64-1)
than those used in adult patients to reach a therapeutic
dose (2.0 to 2.5 mA compared with 1.0 to 1.75 mA,
respectively), particularly when lower (р250 µs) pulse
durations are used (33, 36, 38). Additional reports indi-
cate clinically significant responses with low stimulation
intensities (1.25 to 1.50 mA) (2, 5, 17). A multicenter,
randomized trial looking at device parameter efficacy
showed that various duty cycles were equally effec-
tive (39). Some reports among children with severe epi-
leptic syndromes showed an increase in seizure frequency
and severity at higher output currents (10, 40). Func-
tional magnetic resonance imaging (fMRI) in humans
also suggests that pulse width is an important variable in

producing brain effects (41). Optimal parameter settings
for specific ages and seizure types or syndromes, if they
exist, have yet to be defined.
Mechanisms of Action
The mechanisms of action of VNS therapy are not fully
understood, but they are believed to be manifold, owing
to the diffuse distribution of vagal afferents throughout
the central nervous system, and are distinct from those
of traditional AED therapy (42, 43). Studies suggest that
altered vagal afferent (not efferent) activities resulting from
VNS are responsible for mediating seizures (43, 44). Such
altered activities have been recorded in both cerebral hemi-
spheres. Rat studies indicate that VNS activation of the
locus coeruleus may be a significant factor for the attenu-
ation of seizures (45–47). Human imaging studies also
implicate the thalamus in having an important role in regu-
lating seizure activity (48, 49). The exact antiseizure role
of the thalamus is likely to be complex, however, because
of the diffuse connections of the thalamus throughout the
brain (48). Additionally, the reticular activating system,
central autonomic network, limbic system, and noradren-
ergic projection system all may play a role in the antiseizure
mechanisms of VNS therapy (43, 50–53).
Positron emission tomography (PET) imaging stud-
ies in humans show that the VNS-induced changes in
cerebral blood flow (CBF) and synaptic activity vary
over time (53). Widespread alterations in CBF activa-
tion during acute VNS was much more restricted after
prolonged VNS, indicating that those sites of persisting
VNS-induced changes may reflect the antiseizure actions

of VNS therapy (53). During chronic VNS, no new sites
of CBF alterations that were not also affected acutely
were observed (53). Additional human imaging studies
using various methods, including functional magnetic
resonance imaging (fMRI) and single-photon emis-
sion computed tomographic (SPECT) techniques, have
produced similar findings in both acute and chronic
studies (53). These imaging findings, coupled with the
clinical findings that the effectiveness of VNS therapy
continues to improve over time, seem to indicate that
rapidly occurring subcortical effects rather than rapidly
occurring cortical effects may be more important in the
VNS antiseizure mechanism (53). It is believed that rap-
idly altered intrathalamic synaptic activities as well as
other mechanisms likely occurring independently of tha-
lamic activation constitute the therapeutic mechanisms of
VNS (53). Electroencephalogram (EEG) observations also
suggest that unilateral rather than bilateral abnormali-
ties may show more benefit from VNS (2). Other human
studies show that some antiepileptic mechanisms affected
by VNS are either modulated by or are the reflection of
EEG changes, although the effect of VNS on the EEG
background remains uncertain (54). Finally, gamma-ami-
nobutyric acid (GABA) receptor (GABA
A
) plasticity may
contribute to the ability of VNS to modulate the cortical
excitability of brain areas associated with epileptogen-
esis (55). Like medications, many different actions prob-
ably contribute to the efficacy of VNS therapy; therefore,

determining whether there is a single mechanism that is
most important may not be possible.
Animal Trials
VNS therapy was developed on the basis of early findings
of neuroinhibition in the regulation of emesis, and changes
in EEG activity resulting from vagal stimulation (56–58).
Studies among animals showed that VNS therapy worked
both acutely to abort seizures and chronically to control
seizures (59, 60). In addition, VNS was effective beyond
the period of active stimulation and across a wide range of
seizure types and severities, thereby indicating the potential
for long-term, phase-dependent seizure control. Tests of
VNS therapy in the traditional animal models used to test
AED efficacy, including rat, canine, and monkey models
(60–64), further indicated that VNS therapy, like AEDs,
may be effective for multiple seizure types. The clinical trials
that followed proved the safety and efficacy of VNS therapy
for controlling seizures, with few and mild side effects that
were generally related to stimulation intensities.
A more recent PET imaging study in rats revealed
differences between acute and chronic changes in glucose
metabolism during VNS, which may reflect cerebral adap-
tation to VNS (65). These findings are in line with clinical
findings and other animal and human studies that show
improvements in seizure control and changes in CBF over
time (3–5, 65, 66). Other animal studies also have shown
that VNS may facilitate the recovery of function following
brain damage, both in the rate of recovery and in the final
level of performance reached postinjury, as well as enhance
memory storage processes (67, 68). This enhancement of

neural plasticity is believed to occur by the ability of VNS
to enhance norepinephrine release throughout the neuraxis,
but further studies are needed to explore the mechanisms
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
819
behind these effects more fully (68, 69). Improvements in
behavior among rats with induced brain damage also are
suggestive of a neuroprotective effect of VNS, which may
also help to reduce the behavioral deficits associated with
seizures among humans receiving VNS therapy as part of
their antiepileptic treatment (67).
SEIZURE EFFICACY
Clinical Trials
A series of acute-phase studies with long-term follow-
up data proved the safety and efficacy of VNS therapy
for the treatment of refractory epilepsy and thereby led
to its approval by the FDA in 1997. Results from two
randomized, placebo-controlled, double-blind trials (E03
and E05) were pivotal in demonstrating the antiseizure
effect of VNS therapy. Patients in the 14-week acute E03
study (n ϭ 113) who received therapeutic doses of stimu-
lation (high; 30 Hz, 500 µs, up to 3.5 mA for 30 s every
5 min) showed a significantly higher median decrease in
seizure frequency of 24.5% compared with only a 6.1%
median decrease among patients receiving nontherapeutic
levels of stimulation (low; 1 Hz, 130 ␮s, р3.5 mA for
30 s every 90 min; p ϭ 0.01) (70).
Seizure frequency reductions of at least 50% were
reported for 31% of patients in the high-stimulation group
and for 13% in the low-stimulation group (p ϭ 0.02).

In the acute E05 study, the median reduction in seizure
frequency was 27.9% for the 94 patients in the high-
stimulation group and 15.2% for the 102 patients in the
low-stimulation group at 3 months (p ϭ 0.04) (71).
Long-term follow-up of patients in the acute E03
and E05 studies showed that the effectiveness of VNS
therapy was cumulative. After the acute phase of these
studies, patients receiving low stimulation had their stimu-
lation levels titrated to therapeutic (high) settings, and all
patients were then followed for an additional 12 months
of treatment. For the 100 patients in the E03 open-label
extension study treated for the additional 12 months, the
median reduction in seizure frequency increased to 32%
at 12 months from only 20% at 3 months (5). For the
196 patients with evaluable seizure data in the E05 trial,
the median reduction in seizure frequency was 45% after
an additional 12 months of treatment in the prospective,
long-term extension study (4). At this same time point,
35% of patients had at least a 50% reduction in seizure
frequency, and 20% had at least a 75% reduction. These
seizure frequency reductions were sustained over time.
Pediatric Outcomes
Although the controlled clinical trials did not focus specifi-
cally on the pediatric patient, the children and adolescents
included in one of the five clinical studies (E04) responded
at least as favorably as the adults (14, 72). Of the 60 pedi-
atric patients included in the E04 open, prospective study,
16 were younger than age 12 (mean age, 13.5 years).
At 3 months, the median reduction in seizure frequency
was 23% (n ϭ 60); for the 46 patients with follow-up

data available at 18 months, the median reduction was
42%. The results, although in a much smaller group,
were similar for the patients aged 11 years and younger,
indicating that age does not seem to be a factor in the
effectiveness of VNS therapy to control seizures. More-
over, data from other pediatric study experiences with
VNS therapy indicate that younger patients may have a
higher tolerance and more effective response than adult
patients (14, 17, 72–75).
The largest study to date to evaluate the effective-
ness, tolerability, and safety of VNS therapy among
pediatric patients was a six-center, retrospective study
of 125 patients aged 18 years or younger (41 patients
aged less than 12 years) (19). This study showed greater
reductions in seizure frequency than those found in the
pediatric subgroup of the E04 clinical trial, with a median
reduction in seizure frequency at 3 months of 51.5%
(range, Ϫ100% to ϩ312%; n ϭ 95) and 51.0% at 6
months (range, Ϫ99.9% to ϩ100.0%; n ϭ 56). A simi-
lar response was reported at 6 months for children aged
less than 12 years (median seizure frequency reduction of
51%; n ϭ 20). These reductions did not differ between
patients with different seizure types.
Special Patient Populations
Although few prospective or controlled trials have been
performed among pediatric epilepsy patients, the num-
ber of young patients receiving VNS therapy across the
United States and Europe is growing. Observations of
pediatric patients with age-related or specialized syn-
dromes receiving VNS therapy indicate that this treat-

ment is safe and effective across a broad range of seizure
types and syndromes, independent of age. Table 64-2
(2–5, 7–9, 14, 16, 18, 19, 24, 38, 70–74, 76–85) shows
the epilepsy syndromes, seizure types, and associated
conditions in which VNS therapy may be helpful. Addi-
tionally, VNS therapy also seems to be a palliative treat-
ment option for patients who have failed cranial surgery
(Figure 64-9) (83, 86).
Lennox-Gastaut Syndrome, Infantile Spasms,
and Ring Chromosome 20 Syndrome
Lennox-Gastaut syndrome (LGS) and infantile spasms are
rare but difficult-to-treat epileptic disorders. These condi-
tions are also accompanied by neurologic comorbidities
that can be exacerbated by the cognitive adverse side
effects typically associated with drug therapy. Although
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
820
TABLE 64-2
Epilepsy Syndromes, Seizure Types, and Associated Conditions in which
VNS Therapy May Be Helpful
EPILEPSY SYNDROME, SEIZURE TYPE,
AND/OR ASSOCIATED CONDITION REFERENCES
Simple partial seizures Simple partial seizures (2–5, 7–9, 14, 16, 18, 70–72, 74)
progressing to complex partial seizures
or secondary generalization
Complex partial seizures with or without
secondary generalization
Symptomatic generalized tonic-clonic seizures (14, 19, 24, 72, 74, 76)
Drop attacks in Lennox-Gastaut syndrome (19, 38, 73, 77)
Primary generalized epilepsy (JME) (76, 78–80)

Tuberous sclerosis complex with complex partial (81)
or generalized tonic-clonic seizures
Autism with symptomatic epilepsy (82)
Status epilepticus (83–85)
FIGURE 64-9
Suggested treatment sequence flowchart for patients with epilepsy.
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
821
limited data are available for children receiving VNS ther-
apy for the treatment of infantile spasms (87), recent ret-
rospective studies of the efficacy of VNS therapy among
patients with LGS have shown some success in reducing
seizure frequency without adverse side effects (10, 34,
38, 73, 779).
The largest retrospective study of LGS patients
receiving VNS therapy was done by Frost et al (73) on
50 patients from six centers (median age at implant was
13 years; range, 5 to 27 years). This study showed that
median reductions in seizure frequency at 1, 3, and 6
months of VNS therapy were 42%, 58.2%, and 57.9%,
respectively (n ϭ 46 who had complete seizure data avail-
able). Seizure reductions at 6 months by type showed an
88% decrease in drop attacks and an 81% decrease in
atypical absence seizures. At 3 months, a 23% decrease
was seen in complex partial seizures. In addition, improve-
ments in quality of life with minimal and tolerable side
effects from both the surgery and therapy were reported
for this patient population. The most notable change in
quality of life was an increase in alertness reported for
more than half of the patients. Previous corpus calloso-

tomy was not a contraindication for VNS therapy among
this patient population, with the five patients who had
undergone such surgery showing a 69% reduction in sei-
zure frequency at 6 months. However, the one patient
with a previous lobectomy surgery did not show a change
in seizure frequency with VNS therapy. Age also was not
a contraindication, because those patients aged less than
12 years showed similar response rates to the group as
a whole.
A smaller, longer-term study on the behavior of 19
patients with LGS receiving VNS therapy showed no
deterioration from baseline in either quality of life or
cognitive measures after 24 months of treatment (88).
In addition, a positive increase in cognitive measures
indicated a gain in mental age of 4.2 months at follow-
up. These findings were independent of seizure response
to VNS therapy, indicating a potential additional treat-
ment benefit from VNS therapy to patients with LGS.
Two-year follow up of 19 children (aged 7 to 18 years)
with LGS or Lennox-like types of epilepsy, mental retar-
dation, and multiple seizure types, along with a high
seizure frequency, showed that four patients had a sei-
zure frequency reduction of at least 50% (34). One
patient remained seizure free 2 years postimplantation.
Atypical absence seizures responded better to VNS than
other seizure types; moreover, higher baseline seizure
frequency, the lowest quantity of interictal epileptic
activity, and the highest baseline mental level seemed
to predict a higher response rate. A mild improvement
in mental age, though modest, and a positive effect on

behavior that was independent of seizure control were
seen over time. However, unlike some studies that show
increased effectiveness over time with VNS therapy,
the duration of treatment in this small study did not
appear to increase VNS efficacy among this group of
patients.
A case study by Buoni et al (10), however, indi-
cated that the ability of VNS to reduce seizure frequency
among patients with LGS may require extended periods
of treatment before positive outcomes are observed. A 22-
year-old man with LGS reported no reductions in seizure
frequency for 1 year of VNS therapy, although improve-
ments in alertness and appetite were achieved. But by
3 years, the patient’s seizures abruptly disappeared, and
his EEG was borderline normal without any changes in
drug therapies or stimulation parameters.
Three separate cases of the use of VNS therapy
among patients with ring chromosome 20 have been
reported in the literature (40, 89, 90). In 2002, the first
report of a girl aged 6 years indicated that VNS may be
successfully used to treat the medically refractory gen-
eralized clonic epilepsy characteristic of this disorder,
which also is marked by developmental delay (90). After
receiving VNS therapy, the child became free of seizures
and remained seizure free 9 months postimplantation.
Moreover, the child was reported to have an increased
level of alertness and less lethargy, and, after 4 months of
VNS treatment, spontaneous vocalization was reported.
The achievement of new developmental milestones after
the initiation of VNS therapy was encouraging. A sec-

ond report of a male implanted with a VNS device at
the age of 8 years also showed a good response to VNS
therapy (40). Seizures began at the age of 5 years, and
the patient was experiencing numerous absence and
nocturnal tonic-clonic seizures as well as nonconvul-
sive status epilepticus at the time of VNS implantation.
Following initiation of VNS, seizure frequencies were
eventually reduced to only occasional nocturnal epi-
sodes and some previously lost skills were reacquired,
including ambulation, eye contact, social smiling, and
improved mood. The third report was a 14-year-old
male with ring chromosome 20 syndrome who was
also diagnosed with LGS and experiencing a range of
seizure types and severe impairment of cognitive func-
tions. However, he did not show similar results to those
reported previously (90). Following implantation of the
VNS device at the age of 11 years, the child experi-
enced a 50% reduction in seizure frequency. However,
tonic seizures during sleep and secondary generalized
seizures continued at a rate of 1 to 3 seizures per day.
At age 13 years, a corpus callosotomy was performed
with no additional benefit in terms of seizure frequency
reduction, but some reduction in seizure severity was
achieved. An increase in behavioral problems, fear
attacks, and visual hallucinations began after calloso-
tomy. These case reports suggest, therefore, that earlier
use of VNS therapy among patients with ring chromo-
some 20 syndrome may be more beneficial.
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
822

Mental Retardation/Developmental Delay
Mental retardation or developmental delay (MR/DD)
often co-occur among patients with epilepsy, and the
causal relationship between these disorders is com-
plex (91). Both the seizures caused by the epilepsy and
the AEDs used to treat the epilepsy are, however, known
to potentially exacerbate delays in development, which
can complicate treatment among this patient population.
The likelihood of additional behavioral and psychiat-
ric disorders, which are estimated to be about sevenfold
higher among this population, also further complicates
the treatment regimen (91). Moreover, the increased use
of polytherapy among this population is indicative of
the large number of patients with MR/DD experienc-
ing refractory seizures (92, 93). Therefore, VNS therapy
may be an attractive treatment option among patients
with developmental and behavioral comorbidities in
addition to epilepsy, because VNS therapy may reduce
the frequency of seizures without the pharmacologic side
effects or interactions of additional drug therapy. Another
potential benefit is the fact that VNS therapy is delivered
automatically, meaning that compliance and caregiver
reliance for treatment are minimized, which is particu-
larly attractive for this patient population because many
are unable to care for themselves.
Studies of the effects of VNS therapy among patients
with MR/DD show success with VNS therapy (24, 93, 94).
A retrospective study by Andriola and Vitale (24) of 21
mildly to severely affected MR/DD patients (age range,
3 to 56 years; 5 patients Ͻ16 years) with a range of

seizure types and etiologies showed VNS therapy to be
both effective and well tolerated. Seventy-one percent
(15 of 21) saw some degree of change for the better in
seizure frequency or severity. Of the 16 patients who had
known pre- and postoperative seizure data available, all
of them had some degree of seizure reduction reported,
with 11 (68%) having at least a 50% reduction. One
patient with secondary generalized seizures became sei-
zure free and remained that way at 3 years postimplant.
Improvements also were reported by caregivers for many
areas of the patients’ functional status, including alert-
ness, mood, and daily task participation. In addition, such
improvements were not always associated with decreases
in either seizures or AEDs.
Similar findings were found by Gates et al (94) in
a retrospective study comparing outcomes of patients
receiving VNS therapy living in residential treatment
facilities (RTFs) with those not living in RTFs. Despite
numerous statistical differences in the demographics and
medical histories found between the 86 RTF (age range,
7 to 59 years) and 690 non-RTF (age range, 2 to 79)
patients, the 12-month responder rates (у50% reduction
in seizure frequency) for the two groups were similar at
55% and 56%, respectively. Patients in both groups were
reported to have some degree of improvement in alertness,
verbal communication, memory, achievement at school
or work, mood, postictal period, and seizure clustering,
with more improvements reported at 12 months than
at 3 months, thereby indicating a cumulative effect of
VNS therapy.

A more recent, prospective study among 40 patients
institutionalized with MR/DD and followed for
2 years of VNS therapy confirmed that VNS was an
effective treatment option for this population (93).
Most patients (34 of 40) had some reduction in seizure
frequency. More notable, however, is the fact that this
group experienced fewer epilepsy-related hospitaliza-
tions after receiving VNS therapy, and postictal recov-
ery periods were reduced among 75% of the patients.
Furthermore, the quality of life for these patients was
improved by significant improvements at both 1 and
2 years in attention span, word usage, clarity of speech,
standing balance, ability to wash dishes, and ability to
perform household chores. Other areas of improvement
included an increase in their ability to dress themselves,
interact with their peers, express themselves nonver-
bally, and perceive auditory and visual stimuli.
All of these studies to date indicate that VNS therapy
was well tolerated and did not introduce the central ner-
vous system or cognitive side effects that commonly occur
when a new AED is added to a treatment regimen (24, 93,
94). Reported side effects were minimal and manageable
with changes in stimulus parameters. In addition, the
surgery was less invasive and thereby more tolerable than
other epilepsy surgeries. However, wound tampering can
be a potential problem with this patient population. One
patient in the Andriola et al (24) study was explanted
as a consequence of self-inflicted wound infection. This
patient was reimplanted and extra measures (extensive
bandages over the implant site and additional barriers)

were taken to prevent wound tampering until after the
implant incisions had healed. As discussed earlier, a sec-
ond option to prevent wound tampering would be an
interscapular placement of the generator (22).
Tuberous Sclerosis Complex, Autism, and
Landau-Kleffner Syndrome
A retrospective, multicenter, open-label study of
10 patients (mean age of 13 years) with tuberous sclerosis
complex (TSC) receiving at least 6 months of VNS ther-
apy (with a mean of 22 months) found a high response
rate to VNS therapy, with 9 out of 10 patients experienc-
ing at least a 50% reduction in seizure frequency (81).
More notably, 5 of the 10 patients experienced a more
than 90% reduction in seizure frequency. In addition,
three patients were reported to be more alert by their
parents and teachers, two were reported to have briefer
seizures, and one was reported to have less-intense sei-
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
823
zures in addition to the reduction in seizure frequency. A
patient diagnosed with an autism spectrum disorder in
addition to TSC also was reported to have an 80% reduc-
tion in injurious behavior after the start of VNS therapy.
These results were not countered by any major complica-
tions or side effects. In addition, the high response rate of
patients with TSC receiving VNS therapy, compared with
patients of similar age and seizure frequencies who were
also receiving VNS therapy but did not have TSC, indi-
cated that this patient population may be more responsive
to VNS therapy. However, the small number of patients

involved in this study was not enough to determine any
statistical significance between responses among the TSC
and non-TSC groups.
Preliminary data also suggest that VNS therapy may
be effective among patients with epilepsy and either autism
or Landau-Kleffner syndrome (LKS), which are both
childhood disorders known to co-occur with epilepsy (82).
Among 6 patients with LKS, 3 experienced a reduction
in seizure frequency of at least 50% at 6 months of VNS
therapy. Of 59 patients with autism, 58% experienced at
least a 50% reduction in seizure frequency at 12 months.
More notable, however, were the reported improvements
in quality of life, particularly in the area of alertness; 4 of
6 children with LKS and 76% of the children with autism
were reported more alert at 6 and 12 months, respectively.
Therefore, the benefit of VNS therapy for patients with
such disorders may extend beyond or be independent from
seizure frequency reductions.
Hypothalamic Hamartomas
A small study of six pediatric patients (Յ16 years) with
hypothalamic hamartomas and refractory epilepsy indi-
cates that VNS therapy may have the ability to inde-
pendently improve behavior and, to a lesser extent,
decrease seizure frequency or severity in this patient
population (95). Three of the six patients experienced
some degree of seizure control. However, the immediate
and notable improvements in behavior among four of the
patients characterized as having severe behavioral prob-
lems are of particular interest. Such behavioral improve-
ments were seen independent of seizure control and were

dependent on ongoing stimulation. One patient who had
the generator turned off for a 2-week period for stereo-
tactic surgery had the injurious and antisocial behavior
return in the absence of VNS therapy. Those behaviors
once again subsided when stimulation was restarted.
Status Epilepticus
Four pediatric patients (83, 84) and one adult patient
(85) have seen a complete cessation of status epilepticus
upon initiation of VNS therapy. As reported in a case
report by Winston et al (83), a 13-year-old boy was
implanted with the vagus nerve stimulator 15 days
after being admitted to the hospital for pharmacoresis-
tant generalized convulsive status epilepticus. While he
was hospitalized, his condition continued to deterio-
rate despite numerous pharmacologic treatments. The
patient also had previously undergone a 90% anterior
corpus callosotomy, which had been followed by the
return of seizures up to 80% of the preoperative fre-
quency. Immediately following the initiation of stimula-
tion in the operating room, the child’s refractory status
epilepticus ceased. Over the next year and half, the sta-
tus epilepticus never reappeared, the rate and sever-
ity of seizures significantly decreased with little or no
postictal phase, and the patient’s neurologic condition,
nutritional state, and quality of life all improved.
Another case series presented by Malik et al (94)
reports on three children (aged 14 months to 10 years)
who also presented with pharmacoresistant status epilep-
ticus and who were emergently implanted with the VNS
device. All three children experienced complete resolu-

tion of the status epilepticus and continued to have a
marked reduction in seizure frequency at their 8-week
follow-up visit. The seizure types varied for each of these
three patients, with one experiencing atonic, hypomotor,
and partial seizures; another atonic, general tonic-clonic,
and myoclonic seizures; and the third, multifocal-onset
seizures. A 30-year-old man who presented with pharma-
coresistant status epilepticus and was placed in a pento-
barbital coma also experienced a cessation of seizures and
remained seizure free 19 days postimplantation. These
preliminary case reports suggest that VNS therapy should
be considered as a nonpharmacologic treatment option
among children with pharmacoresistant status epilepticus
independently of seizure type.
SAFETY
Adverse Events
Adverse events reported with VNS therapy are generally
transient and mild, and are often related to the duration
and intensity of stimulation. Serious adverse events have
not been reported with standard therapy, and no patients
have died or had a higher mortality risk as a result of
VNS therapy (96). The most common adverse events
reported during the clinical trials were mild hoarseness
or voice alterations, coughing, and paresthesia (primarily
at the implant site and decreasing over time) and were
not considered clinically significant (4, 18, 70, 71). Other
adverse events reported less frequently during these stud-
ies include dyspnea, pain, headache, pharyngitis, dyspep-
sia, nausea, vomiting, fever, infection, depression, and
accidental injury (4, 70, 71). Not all of these events were

related to VNS therapy. Outside of the clinical trials,
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
824
occasional reports of additional adverse events such as
shortness of breath (3) and vocal cord paresis (97) have
been reported, but did not result in discontinuation of
therapy. Many of the side effects initially reported with
VNS therapy, such as lower facial weakness and lead
breaks, have been resolved. Adverse events associated
with the implant surgery are discussed earlier in the chap-
ter in the description of the implantation procedure.
Generally, the side effects associated with VNS
therapy are well tolerated and not prohibitive to patients
receiving this adjunctive treatment (28). Moreover, many
of the side effects tend to diminish or disappear altogether,
as patients adjust to the stimulation therapy. If side effects
persist or are bothersome to the patient, reductions in stim-
ulation intensity or frequency oftentimes alleviate the side
effects, most of which occur only during active stimulation
(98). Overall, the mechanisms of action of VNS therapy
are different from those of traditional AED therapy and,
therefore, produce a unique side effect profile that does not
cause the cognitive, sedative, visual, affective, or coordina-
tion side effects typically associated with AEDs.
Pediatric Safety
Pediatric patients seem to have a higher tolerance for the
treatment. Technical complications (99) and pain at the
implant site (17) have been reported among some pedi-
atric patients. However, the smaller and lighter design
of the current Model 102 generator has reduced some

of these types of complications. Increased salivation
(19, 73, 100) and increased hyperactivity (19) have been
reported for pediatric patients. Zamponi et al (17) also
reported increased salivation and asthenia in one pediat-
ric patient who was switched to rapid-cycling stimulation
parameters; these events ceased once standard cycling was
resumed. Lundgren et al (100) reported swallowing dif-
ficulties among two severely impaired pediatric patients
with a history of swallowing difficulties. However, a study
of eight patients without a history of swallowing diffi-
culties by Schallert et al (101) showed that VNS therapy
did not put patients at an increased risk of aspiration.
Overall, the side effects reported for pediatric patients
are often mild and transient, and not a contraindication
to VNS therapy for this patient population.
Device Safety
Safety features are built into the VNS therapy system to
protect patients from stimulation-related nerve injury.
The primary safety feature is the “off switch” effect of
the magnet. If a patient begins to experience continuous
stimulation or uncomfortable side effects as a result of
VNS therapy, the magnet can be held or taped over the
generator to stop stimulation until the patient can visit
the physician. A watchdog timer also is programmed into
the device to monitor the number of pulses a patient
receives. If a certain number of pulses is delivered without
an Off time, the device will turn itself off to prevent excess
stimulation from potentially causing nerve injury.
Procedures such as diathermy and full-body MRI
scans, which have the potential to heat the device leads

around the vagus nerve and thereby result in either tem-
porary or permanent tissue and nerve damage, are contra-
indicated among patients receiving VNS therapy. Patients
requiring an MRI should have the procedure performed
with a head coil, which has been done successfully in VNS
therapy patients (102). Of 27 MRI scans performed among
25 patients across 12 centers, 24 scans were performed
with the VNS device turned off as recommended by the
manufacturer. No stimulation was induced either during
these scans or during the three scans performed with the
device remaining in the on position. One child (age 11)
reported chest pain while experiencing severe claustropho-
bia during the scan, and one patient had a mild objective
voice change lasting several minutes (102). A successful
body-coil MRI with the use of an ice pack over the area of
the device leads was reported for three patients receiving
VNS therapy, but is not recommended by the manufacturer
(103). As recommended by the FDA, any instructions for
MRI imaging that may be in the labeling for the implant
should be followed exactly, and information on the types
and/or strengths of MRI equipment that may have been
previously tested for interaction with the implanted device
should be noted (104). And because leads or portions of
leads are sometimes left in the body among patients who
have had the pulse generator explanted, it is important to
get information regarding previously implanted devices,
as the remaining leads could possibly become heated and
damage the surrounding tissue (104). A bench study also
supported anecdotal evidence that the VNS therapy mag-
net may inadvertently adjust the settings of programmable

shunt valves commonly used to treat hydrocephalus (105).
Therefore, physicians should be aware of the possibility of
potential device interactions as the development and use of
other implantable devices continues to evolve (105).
CANDIDATE SELECTION
Because the mechanisms of action are not well defined,
the selection of patients for VNS therapy does not follow
a clear set of guidelines. In addition, the clinical trials
for VNS therapy could not distinguish any correlation
between patient response and seizure type or etiology, age,
sex, frequency of seizures, or frequency of interictal spikes
on EEG (106) from which to generate any obvious can-
didate selection criteria. The number of coadministered
AEDs or seizure types (78–80) or the type of coadminis-
tered AEDs (107) are not predictors of response, either.
Therefore, as with AED therapy, there are currently no
64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS
825
markers to predict the success of VNS therapy on a case-
by-case basis. The safety and effectiveness of this treat-
ment, achieved without the common adverse side effects
associated with traditional AED therapy, and the fact that
VNS therapy is reversible if a patient does not respond,
make VNS therapy an attractive adjunctive treatment
option for patients with refractory epilepsy who are not
surgical candidates. VNS therapy is particularly attrac-
tive for the pediatric population, given the added benefit
of the freedom from compliance issues associated with
this therapy (108). Figure 64-9 shows a suggested treat-
ment sequence flowchart that can be helpful in determin-

ing which palliative surgical procedures to chose when
patients are experiencing refractory seizures.
Patients of any age should be considered for VNS
therapy if they experience seizures refractory to other
therapies, including AEDs, the ketogenic diet, and epilepsy
surgery. Preliminary data suggest that patients treated with
VNS therapy earlier in the course of their epilepsy (i.e.,
when seizures fail to respond to treatment with two or
three AEDs within 2 years of epilepsy onset) may have
a higher response rate to treatment (109). Early use of
VNS therapy in treatment-resistant children would fur-
ther allow physicians to decrease the negative side effects
associated with AED therapy, which are compounded
after long-term use and known to hinder development in
this population (89, 110). Earlier use may also improve
response to VNS therapy among the pediatric population
because of a higher degree of neuronal plasticity at an early
age that has the potential for permanent damage from
long-term epilepsy (78). Earlier use of VNS therapy during
the course of pharmacoresistant epilepsy (Ͻ6 years) also
has been shown to be twice as likely to eliminate seizures
than when VNS was initiated among patients who had
been experiencing for 6 or more years, which reinforces
the view that lesser cumulative seizure loads may improve
patients’ chances for recovery (111).
Precautions should be taken with patients predis-
posed to cardiac dysfunction and obstructive sleep apnea
(OSA), because stimulation may increase apneic events,
and chronic obstructive pulmonary disease may increase
the risk of dyspnea (112, 113). A study by Nagarajan et

al showed that seven of eight children (aged 4 to 16 years)
receiving VNS therapy had respiratory pattern changes
during sleep, but these changes were not associated with
significant hypoxia or hypercapnia (114). Also, no apnea
or hypopnea indexes were in the abnormal range. Although
the changes in respiratory patterns during sleep appear to
be mild, care should be taken when using VNS therapy
among those with sleep apnea syndromes or compromised
respiratory function, because vagal afferents influence
respiratory control centers (113, 114). Lowering the stimu-
lus frequency or increasing the Off time may prevent exac-
erbation (112, 114). It is not known whether the effects of
VNS on sleep-related breathing diminish over time (113).
The daytime effects of the altered nighttime breathing pat-
terns also are not clear, because VNS has been shown both
to facilitate and to inhibit REM sleep (115). A case report
by Holmes et al (116) showed that an adult patient began
experiencing sleep apneas and arousals associated with
the intermittent VNS stimulation patterns, which led to
the development of excessive daytime sleepiness. However,
reports by Rizzo et al (115, 117) on a broader sample of
10 patients show that sleep modifications induced by VNS
therapy among patients with refractory epilepsy actually
enhance sleep EEG power, reduce rapid eye movement
sleep, and improve daytime alertness. A study by Malow
et al (112) among 16 patients receiving VNS therapy also
showed an improvement in daytime sleepiness independent
of seizure frequency control.
Patients who have undergone a bilateral or left cervi-
cal vagotomy are not considered candidates for VNS ther-

apy (11). Evaluation by a cardiologist is recommended
for patients with a personal or family history of cardiac
dysfunction. If clinically indicated, Holter monitoring and
electrocardiograms also should be done before implant.
COST EFFECTIVENESS
Previous cost analyses for VNS therapy indicate that
the initial costs of VNS are offset over time by reductions
in health care costs and hospital admissions following
implantation (118–121). The reductions in economic bur-
den for both patients and society were seen even among
patients with less than a 25% reduction in seizures, indi-
cating that even those without a substantial benefit in
terms of seizure frequency reductions receive some ben-
efit from the device (118). Although the efficacy of VNS
therapy has been shown to increase over time, a cost
analysis study calculated from 18 months before to 18
months after VNS device implantation showed that inten-
sive care unit and ward admissions decreased from the
very start of treatment with VNS (118). From a financial
standpoint, the economic argument against VNS therapy
is weak, particularly considering the potential for mean-
ingful reductions in seizure frequency among patients
with refractory epilepsy and the fact that efficacy remains
and possibly increases over the long-term (119, 121).
Therefore, the decision as to whether to proceed with
VNS therapy for a patient population with few options
should be made on the basis of clinical judgment rather
than short-term costs (119).
CONCLUSION
VNS is emerging at the forefront of epilepsy treatments

as a well-tolerated adjunctive therapy. With its minimal
adverse side effects, lack of pharmacokinetic interactions
VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION
826
with drug therapies, negligible compliance issues, resid-
ual improvement in quality of life, and improved efficacy
over time, VNS therapy may be particularly effective
among special patient populations, including pediatric
patients and patients with comorbid conditions. Use of
VNS therapy, however, must be balanced against the
necessity of surgery, although VNS therapy surgery is
well tolerated. As our understanding of what character-
izes refractory epilepsy continues to evolve, adjunctive
treatments such as VNS therapy will play an increas-
ingly larger role in improving the lives of patients with
epilepsy.
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PSYCHOSOCIAL ASPECTS
VII