Vagus nerve stimulation (VNS), which attenuates seizure frequency, severity, and duration by chronic intermittent stimulation of the vagus nerve, is intended for use as an adjunctive treatment with antiepileptic drug (AED) therapies . As of January 2008, more than 45,000 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 6 Moreover, clinical findings indicate that the effectiveness of VNS therapy continues to improve over time, independent of changes in AEDs or stimulation parameters 18 Tolerance does not appear to be a factor with VNS therapy, even after extended periods of time. 26 Response to VNS therapy may be delayed for some patients 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
The VNS therapy system consists of the implantable pulse generator and bipolar VNS therapy lead, a programming wand with software, a tunneling tool, and a handheld magnet (Figure 4 . 1) . The average battery life for the generator is approximately 7 to 10 years with normal use (but depends on stimulation parameters—that is, frequency and intensity— as well as model type)
The magnet provided to patients as part of the VNS therapy system allows 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 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 control 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 playing woodwind instruments or during speaking engagements . However, stopping the stimulus should be done sparingly and with care, as doing so creates the potential risk of seizures
The implant surgery is most often performed as a day surgery under general anesthesia and typically lasts about 1 hour.7 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 (Figure 4 . 2) . Two incisions 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 (Figure 4 . 3) . 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 . The programming wand (Figure 4 .4) is used at follow-up visits to check and fine-tune the stimulation settings according to patient comfort and level of seizure control
Once a generator reaches end of service, another surgery is required to replace the generator. Often, an increase in seizure frequency or intensity suggests clinical end of service . The entire generator is replaced, rather than just the battery, so as to avoid opening the hermetically sealed titanium case of the generator, which could lead to a rejection reaction The generator-replacement surgery typically lasts approximately 10 to 15 minutes and is performed as a day surgery. Because the leads remain untouched during a generator replacement, only one incision is needed . Generator replacement is recommended before the battery is completely depleted so as to prevent an interruption in treatment
FIGuRE 4.3 Implantation of model 103 for VNS therapy. Potential Complications
One possible risk resulting from the implantation 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.8 Such infections can be treated with antibiotics, but typically lead to explantation of the device if antibiotic treatment is not effective
The routine lead test performed during surgery also has resulted in reports of bradycardia and asystole in a small number of patients (~0. 1%). 2 Neither of these cardiac events, however, has occurred after surgery during day-to-day treatment with VNS therapy, or in children; they are usually transient and self-limiting, and are rarely of clinical significance. 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
VNS therapy "dosing" is defined by five interrelated stimulation parameters (Figure 4 .5)—output current (measured in mA), signal frequency (Hz), pulse width (^s), 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 dosing schedule for drug therapy. An optimal dose-response relationship for VNS therapy, however, is elusive, owing in part to the intraindividual variability between patients and to the number of parameters involved in regulating the dose
Standard parameter settings, as determined from clinical trials,12 range from 20 to 30 Hz at a pulse width of 250 to 500 ^s and an output current of 0 .25 to 3 .5 mA
Pulse Width idth
Stimulation Time -On Time-
Pulse Width idth
FIGuRE 4.5 Stimulation parameters (all duty cycles except low output [<10 Hz]) .
stimulation parameter setting ranges
Parameter Typical range
3 Months 12 Months 3 Months 12 Months
Output current Signal frequency Pulse width
Signal on time Signal off time
Note: 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) .
for 30 s "on" time and 5 min "off" time (Table 4 . 1) . Initial stimulation is set at the low end of these ranges and slowly adjusted over time and within the safety limits on the basis of patient tolerance and response . Patients should be closely monitored during the dose-adjustment phase 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 pediatric patient. Several studies indicate that pediatric patients may require higher output currents (Table 4 . 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 (<250 |^s) pulse durations are used. However, other reports indicate that clinically significant responses may occur with low stimulation intensities (1 25 to 1 50 mA)
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. 14 Studies suggest that altered vagal afferent activities resulting from VNS are responsible for mediating seizures 15 Rat studies indicate that VNS activation of the locus coeruleus may be a significant factor for the attenuation of seizures . Human imaging studies also implicate the thalamus in having an important role in regulating seizure activity The exact antiseizure role of the thalamus is likely complex, however, owing to the diffuse connections of the thalamus throughout the brain
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 It is believed that rapidly altered intrathalamic synaptic activities as well as other mechanisms likely occurring independently of thalamic activation comprise the therapeutic mechanisms of
seizure efficacy: clinical Trials
Results from two randomized, placebo-controlled, double-blind trials (E03 and E05) were pivotal in demonstrating the antiseizure effect of VNS therapy. 11118
Although the controlled clinical trials did not focus specifically 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 Of the 60 pediatric patients included in the E04 open, prospective study, 16 were younger than age 12 (mean age, 13 .5 years) . 13 At 3 months, the median reduction in seizure frequency was 23% (n = 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
The largest study to date to evaluate the effectiveness, 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) . 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, -100% to +312%; n = 95) and 51 .0% at 6 months (range, -99 .9% to +100 . 0%; n = 56) . These reductions did not differ between patients with different seizure types
Although few prospective or controlled trials have been performed among pediatric epilepsy patients, the number of young patients receiving VNS therapy across the United States and Europe is growing Observations of pediatric patients with age-related or specialized syndromes receiving VNS therapy indicate that this treatment is safe and effective across a broad range of seizure types and syndromes, independent of age Table 4 2 shows the epilepsy syndromes, seizure types, and associated conditions where VNS therapy may be helpful Additionally, VNS therapy also seems to be a palliative treatment option for patients who have failed cranial surgery
Retrospective studies of the efficacy of VNS therapy among patients with Len-nox-Gastaut syndrome (LGS) have shown some success in reducing seizure frequency without adverse side effects 9 VNS therapy was performed 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 = 46 [who had complete seizure data available]) Seizure reductions at 6 months by type showed an 88% decrease in drop attacks and an 81% decrease in atypical absence seizures In
Epilepsy syndromes, seizure types, and associated conditions where VNS therapy may be helpful
Simple partial seizures, simple partial seizures progressing to complex partial seizures or secondary generalization, and complex partial seizures with or without secondary generalization Symptomatic generalized tonic-clonic seizures Drop attacks in Lennox-Gastaut syndrome Primary generalized epilepsy (JME)
Tuberous sclerosis complex with complex partial or generalized tonic-clonic seizures Autism with symptomatic epilepsy addition, improvements 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 callosotomy 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 seizure frequency at 6 months .
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 pharmacological 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 is minimized, which is particularly attractive for this patient population because many are unable to care for themselves Studies of the effects of VNS therapy in this patient group show success with the therapy, not just with respect to seizure frequency and severity but also improvements in many areas of the patients' functional status, including alertness, mood, and daily task participation Similar findings were obtained10 in a retrospective study comparing outcomes of patients receiving VNS therapy living in residential treatment facilities (RTFs) with those not living in RTFs, with more improvements reported at 12 months than at 3 months, consistent with a cumulative effect of VNS therapy
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 therapy (with a mean of 22 months) found a high response rate to VNS therapy, with 9 out of 10 patients experiencing at least a 50% reduction in seizure frequency. 21 More notably, 5 of the 10 patients experienced a more than 90% reduction in seizure frequency
Preliminary data also suggest that VNS therapy may be effective among patients with epilepsy and either autism or Landau-Kleffner syndrome (LKS), childhood disorders in which epilepsy is a prominent comorbid condition 22 A small study of six pediatric patients (<16 years) with hypothalamic hamartomas and refractory epilepsy indicates that VNS therapy may have the ability to independently improve behavior and, to a lesser extent, decrease seizure frequency or severity in this patient population 20
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