Discontinuing for lack of efficacy (LOE)/adverse events (AE) at one year, excluding deaths.

*Within group broad analyses:* \* P ≤ 0.05, by Wilcoxon sign rank.

† P < 0.0001, by anova. ‡ P ≤ 0.05, by Student's *t-test. Between group broad analyses:*

*Safety information:*

¶ SAEs = serious adverse events.

**Longitudinal Parallel**

low

low

low

23% high†/ 21%

28% high†/ 15%

23% high/ 16%

low† -

low† -

low -

**Study E01 E02 E04 E03 E05 Total**

seizure.

142 Epilepsy Topics

patient visit.

More than 70 countries have approved vagus nerve stimulation (VNS) for refractory epilepsy. Table 3 lists several countries and regions. Caregivers should be familiar with the regulatory approval status in their own countries when reading this chapter. Reimbursement levels also vary by country.

The VNS therapy was also approved for depression, but is not being commercially marketed for this indication because of lack of reimbursement.


**Table 3.** VNS Regulatory Approval Dates

#### **3.1. Approved stimulation parameters**

Parameter ranges currently available are provided in Table 4. The originally approved parameters included frequencies up to 143 HZ and output currents up to 12 mA, but these were later revised to those in Table 4 [13] (Cyberonics, 2013).


\*The acute phase results include seizure frequencies of the E03 Study LOW stimulation group, which included one-half the E03 patients, N=57.

Patients were permitted to change their AEDs during these long-term follow-up studies, and these changes may have contributed to the change in seizure frequency.

**Table 4.** Stimulation Parameter Ranges [13]

#### **4. American academy of neurology--vagus nerve stimulation guideline**

In another study of 48 patients with intractable partial epilepsy, Uthman [18] (Uthman BM R.A., 2004) discussed a seizure reduction after 1 year of 26% with increases to 30% at 5 years

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Among children with epilepsy, is using adjunctive VNS to reduce seizure frequency better

After reviewing 16 studies, the AAN RGDS [14] concluded VNS is possibly effective to achieve ≥50% seizure frequency reduction (responder rate) among children. A study of 481 children found a responder rate of 55% (95% confidence interval [CI] 51%–59%), but the data were considered heterogeneous. Of the 16 studies, 2 were not included owing to a lack of responder rate or else had too many (>20%) adults. Calculations placed the pooled seizure freedom rate

In patients with LGS, is using adjunctive VNS to reduce seizures better than not using it?

showed a 55% responder rate (113 patients; 95% CI 46%–64%).

rily generalized seizures, and Rett Syndrome have been published.

The AAN RGDS [14] included 4 Class III studies about LGS patients that focused on younger patients. They stated that VNS is possibly effective among patients with LGS. A pooled analysis

In addition to the AAN RGDS publication, reviews of VNS for generalized seizures, seconda‐

Cyberonics conducted an E04 study of 114 patients to provide additional data on vagus nerve stimulation for the treatment of medically resistant seizures, including generalized seizures

Data were available for 25 patients with generalized seizures. Median decrease in seizure frequency during stimulation was 46.6% (p<0.01), 44% of patients had at least a 50% reduction in seizure frequency compared with baseline. Half of these patients were aged <18 years. However, no correlation was found between response and age. The treatment response in this group was largely driven by effects on generalized tonic clonic seizures [19]. (Salinsky, 1997)

Helmers [20] (Helmers SL D. M., 2011) reported grand mal status events decreased post-VNS compared with pre-VNS (adjusted IRR=0.79, P<0.001) in an analysis of 1655 patients in a multistate Medicaid database (January 1997-June 2009). The generalized seizure rate was

**4.3. Experience with young children and with other types of seizures**

and 52% at 12 years.

than not using adjunctive VNS?

at 7% (95% CI 5%–10%).

*4.3.3. Beyond AAN RGDS*

*4.3.4. Generalized seizures*

and children older than 2 years.

reduced by about 67% after 3 years.

*4.3.2. Lennox-Gastaut syndrome*

*4.3.1. Children*

A Report of the Guideline Development Subcommittee of the American Academy of Neurol‐ ogy (AAN RGDS), Evidence-based guideline update, Vagus nerve stimulation for the treat‐ ment of epilepsy, was approved by the AAN Board of Directors in June 2013 and published ahead of print in August 2013 [14] (Morris 2013). This proposed guideline is referenced in several places of this chapter and is based on Class III studies. Class III studies are typically controlled trials in which outcomes are independently assessed by objective outcome meas‐ ures, whereas Class I and II studies are typically prospective randomized controlled blinded trials.

Some questions from AAN Evidence Based Guideline for Vagus Nerve Stimulation are discussed here.

#### **4.1. Does efficacy improve over time?**

The AAN RGDS [14] analyzed 2 Class III studies [15-16], (Morris GL III, 1999) (Kuba R, 2009), that outlined VNS efficacy after stimulation for more than 6 months up to 12 years. Both reports discussed mostly adult refractory seizures patients. With time, the number of responders (subjects who had ≥50% seizure decrease) increased slightly. No controls were made for change in medications, so independent assessment of the VNS effect was impossible. A study [15] of 440 adult clinical trial patients with partial epilepsy reported the >50% seizure frequency reduction grew from 36.8% of patients at 1 year, to 43.2% at 2 years, and 42.7% at 3 years. From baseline, median seizure reductions after 1 year were 35%, after 2 years were 44.3, and after 3 years were 44%. The Kuba study evaluated 90 patients with multiple seizure types and ages 13-64 years. The responder rate (≥50% reduction in seizures) increased from 41% after 1 year, to 53.2% of 87 patients after 2 years, and to 48.9% of 85 patients after 5 years. These reductions applied to partial and generalized seizures, with reduction rates of 70% among patients with generalized tonic-clonic seizures.

The AAN RGDS concluded, based on data from these 2 Class III studies, that VNS is possibly associated with an increase in the number of patients achieving a ≥50% reduction in seizures.

#### **4.2. Efficacy at 10 and 12 years**

In addition to the AAN RDGS publication, two papers reviewed long term efficacy. Elliott [17] (Elliott RE, 2011) reported on a group of 65 consecutive patients with 10.4 years average followup. At last follow-up, average seizure frequency decrease was 76.3%. Seizure reduction increased from 35.7% after 6 months, to 65.7% after 6 years and 75.5% after 10 years of VNS, a significant reduction from baseline at each measured interval (P<0.0001). Toward the end of the follow-up, the data indicated a trend of increased AED burden. Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P<0.001). Data showed a trend toward increased AED burden in the latter years of the follow-up period.

In another study of 48 patients with intractable partial epilepsy, Uthman [18] (Uthman BM R.A., 2004) discussed a seizure reduction after 1 year of 26% with increases to 30% at 5 years and 52% at 12 years.

#### **4.3. Experience with young children and with other types of seizures**

#### *4.3.1. Children*

**4. American academy of neurology--vagus nerve stimulation guideline**

trials.

144 Epilepsy Topics

discussed here.

**4.1. Does efficacy improve over time?**

generalized tonic-clonic seizures.

**4.2. Efficacy at 10 and 12 years**

A Report of the Guideline Development Subcommittee of the American Academy of Neurol‐ ogy (AAN RGDS), Evidence-based guideline update, Vagus nerve stimulation for the treat‐ ment of epilepsy, was approved by the AAN Board of Directors in June 2013 and published ahead of print in August 2013 [14] (Morris 2013). This proposed guideline is referenced in several places of this chapter and is based on Class III studies. Class III studies are typically controlled trials in which outcomes are independently assessed by objective outcome meas‐ ures, whereas Class I and II studies are typically prospective randomized controlled blinded

Some questions from AAN Evidence Based Guideline for Vagus Nerve Stimulation are

The AAN RGDS [14] analyzed 2 Class III studies [15-16], (Morris GL III, 1999) (Kuba R, 2009), that outlined VNS efficacy after stimulation for more than 6 months up to 12 years. Both reports discussed mostly adult refractory seizures patients. With time, the number of responders (subjects who had ≥50% seizure decrease) increased slightly. No controls were made for change in medications, so independent assessment of the VNS effect was impossible. A study [15] of 440 adult clinical trial patients with partial epilepsy reported the >50% seizure frequency reduction grew from 36.8% of patients at 1 year, to 43.2% at 2 years, and 42.7% at 3 years. From baseline, median seizure reductions after 1 year were 35%, after 2 years were 44.3, and after 3 years were 44%. The Kuba study evaluated 90 patients with multiple seizure types and ages 13-64 years. The responder rate (≥50% reduction in seizures) increased from 41% after 1 year, to 53.2% of 87 patients after 2 years, and to 48.9% of 85 patients after 5 years. These reductions applied to partial and generalized seizures, with reduction rates of 70% among patients with

The AAN RGDS concluded, based on data from these 2 Class III studies, that VNS is possibly associated with an increase in the number of patients achieving a ≥50% reduction in seizures.

In addition to the AAN RDGS publication, two papers reviewed long term efficacy. Elliott [17] (Elliott RE, 2011) reported on a group of 65 consecutive patients with 10.4 years average followup. At last follow-up, average seizure frequency decrease was 76.3%. Seizure reduction increased from 35.7% after 6 months, to 65.7% after 6 years and 75.5% after 10 years of VNS, a significant reduction from baseline at each measured interval (P<0.0001). Toward the end of the follow-up, the data indicated a trend of increased AED burden. Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P<0.001). Data showed

a trend toward increased AED burden in the latter years of the follow-up period.

Among children with epilepsy, is using adjunctive VNS to reduce seizure frequency better than not using adjunctive VNS?

After reviewing 16 studies, the AAN RGDS [14] concluded VNS is possibly effective to achieve ≥50% seizure frequency reduction (responder rate) among children. A study of 481 children found a responder rate of 55% (95% confidence interval [CI] 51%–59%), but the data were considered heterogeneous. Of the 16 studies, 2 were not included owing to a lack of responder rate or else had too many (>20%) adults. Calculations placed the pooled seizure freedom rate at 7% (95% CI 5%–10%).

#### *4.3.2. Lennox-Gastaut syndrome*

In patients with LGS, is using adjunctive VNS to reduce seizures better than not using it?

The AAN RGDS [14] included 4 Class III studies about LGS patients that focused on younger patients. They stated that VNS is possibly effective among patients with LGS. A pooled analysis showed a 55% responder rate (113 patients; 95% CI 46%–64%).

#### *4.3.3. Beyond AAN RGDS*

In addition to the AAN RGDS publication, reviews of VNS for generalized seizures, seconda‐ rily generalized seizures, and Rett Syndrome have been published.

#### *4.3.4. Generalized seizures*

Cyberonics conducted an E04 study of 114 patients to provide additional data on vagus nerve stimulation for the treatment of medically resistant seizures, including generalized seizures and children older than 2 years.

Data were available for 25 patients with generalized seizures. Median decrease in seizure frequency during stimulation was 46.6% (p<0.01), 44% of patients had at least a 50% reduction in seizure frequency compared with baseline. Half of these patients were aged <18 years. However, no correlation was found between response and age. The treatment response in this group was largely driven by effects on generalized tonic clonic seizures [19]. (Salinsky, 1997)

Helmers [20] (Helmers SL D. M., 2011) reported grand mal status events decreased post-VNS compared with pre-VNS (adjusted IRR=0.79, P<0.001) in an analysis of 1655 patients in a multistate Medicaid database (January 1997-June 2009). The generalized seizure rate was reduced by about 67% after 3 years.

#### *4.3.5. Secondary generalized seizures with Lennox Gastaut or Lennox Gastaut-like seizures*

Cukiert [21] (Cukiert A, 2013) reported on 47 seizure types among 24 children. After VNS, seizure frequency reduction ≥50% was noted in 35 seizure types and 17 seizure types disap‐ peared after VNS. Atypical absence, myoclonic, and generalized tonic-clonic seizures were significantly reduced by VNS; tonic and atonic seizures did not improve. Transient seizure frequency worsening was noted in 10 of the 24 children, at a mean output current of 3.1 mA.

**5. Patient acceptance**

Model 100 generators.

**7. Cost effectiveness**

after initial costs have been recouped.

decreased from \$4,826 to \$2496 per year.

of the study.

**6. Battery life**

Initiating VNS requires a surgical procedure to implant the generator and leads to begin the therapy. When the battery is depleted, surgery is required to replace the generator and replace the batteries. The leads are not usually disturbed during this procedure, but reattached to the new generator. Patient-perceived benefit has been hallmarked by the willingness of recipients to undergo surgical generator replacement across the history of the treatment. Morris [15] (Morris GL III, 1999) reported a 72% 3-year continuation rate among early users, and the November 11, 2013 Cyberonics Investor Conference Call placed it at 75% for the fully depleted

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The estimated battery life decreases as pulse width, frequency, output current, duty cycle, or lead impedance increases. For example, the Cyberonics Model 103 Manual [13] estimates battery life at more than 10 years for a stimulation frequency of 20 HZ, 1.5 mA output, 3 kohm impedance and 10% duty cycle for pulse widths ranging from 130 sec to 500 sec. Under the same conditions and a 50% duty cycle, the time to near end of battery life is 7.1 years, 6.2 years,

The net cost of VNS determines medical cost reimbursement. Battery life drives cost savings

Ben-Menachem [24-25] (Ben-Menachem E H. K., 2002) (Ben-Menachem E F. J., 2005) reports that implantation cost, when calculated over 8 years (battery life), is actually less than the cost of using a new AED over a similar time period. Real savings in hospital costs owing to seizures can also be expected. Average annual cost savings were approximately \$3,000 per patient. This cost savings applied to all patients, whether or not they responded to VNS. These direct savings

In the Boon [26] (Boon P D. M., 2002) VNS group, mean seizure frequency decreased from 21 to 7 per month. Epilepsy-related direct medical costs (ERDMCs) in the VNS subgroup

Bernstein [27] (Bernstein AL, 2007) compared average quarterly utilization rates of 138 patients for 12 months before device implantation with quarterly rates during 48 months of follow-up. Results during the 4th quarter of Year 4 revealed impressive decreases in utilization of all 4 measured aspects: a 91% decrease in outpatient visits, a 99% decrease in emergency depart‐ ment visits, a 67% decrease in hospital lengths of stay, and a 70% decrease in number of hospital admissions. Notably, no visits to the emergency department occurred during the final quarter

maintained over the battery life can equal or exceed the purchase price of the device.

and 3.7 years for pulse widths of 130 µsec, 250 µsec, and 500 µsec.

#### *4.3.6. Rett syndrome*

Wilfong [22] (Wilfong AA, 2006) reported on a series of 7 patients with Rett syndrome. At 12 months, 6 of the 7 female patients had more than 50% reduction in seizures.

#### **4.4. Does VNS improve mood in epilepsy patients?**

Does VNS have a beneficial mood side effect in the treatment of epilepsy? Because VNS was approved for treatment-resistant depression by the FDA in 2005 and had already obtained a CE Mark for this indication in 2001, it could have beneficial effects on the mood of epilepsy patients.

AAN RGDS [14] cites 2 Class III studies showing significant improvements in standard patientreported mood assessment scales in adult patients with epilepsy. Test results before implan‐ tation were compared with those afterward. One study [23] (Elger G, 2000)] evaluated 11 subjects 1, 3, and 6 months after implantation. Before VNS, 7 of the 11 patients met criteria for "sub depressive mood" by the Montgomery-Åsberg Depression Rating Scale, and group mean was within the subdepressive mood range; after implantation, group mean was in the nondepressed range. Likewise, 8 of the 11 met criteria for "mild negative symptoms" by the Scale for the Assessment of Negative Symptoms before VNS. Scale and subscale scores improved at the study's 3-month follow-up (p <0.05). Mood improvements were sustained at the 6-month follow-up (9 of 11 subjects).

The second study [15] (Morris GL III, 1999) evaluated 20 subjects 3 months after VNS implan‐ tation. Results for change in subject-rated scales by t tests showed improvements in the clinician-administered Cornell Dysthymia Rating Scale (p=0.001) and the patient self-report Beck Depression Inventory (BDI) (p=0.045); results on the clinician-administered Hamilton Depression Index (investigator rated) also significantly improved. The group's mean BDI score pre–VNS treatment was 12.0 ("mild mood disturbance"); this decreased to 9.4 ("non de‐ pressed") after VNS. Further, BDI scores decreased relative to those for an epilepsy control group (no therapy) studied over the same period (by repeated measures analysis of variance, p=0.07). This benefit was not correlated with reduced seizure frequency or with stimulation frequency or intensity.

The AAN RGDS [14] concluded VNS is possibly effective for mood improvement among adults with epilepsy.

#### **5. Patient acceptance**

*4.3.5. Secondary generalized seizures with Lennox Gastaut or Lennox Gastaut-like seizures*

*4.3.6. Rett syndrome*

146 Epilepsy Topics

patients.

Cukiert [21] (Cukiert A, 2013) reported on 47 seizure types among 24 children. After VNS, seizure frequency reduction ≥50% was noted in 35 seizure types and 17 seizure types disap‐ peared after VNS. Atypical absence, myoclonic, and generalized tonic-clonic seizures were significantly reduced by VNS; tonic and atonic seizures did not improve. Transient seizure frequency worsening was noted in 10 of the 24 children, at a mean output current of 3.1 mA.

Wilfong [22] (Wilfong AA, 2006) reported on a series of 7 patients with Rett syndrome. At 12

Does VNS have a beneficial mood side effect in the treatment of epilepsy? Because VNS was approved for treatment-resistant depression by the FDA in 2005 and had already obtained a CE Mark for this indication in 2001, it could have beneficial effects on the mood of epilepsy

AAN RGDS [14] cites 2 Class III studies showing significant improvements in standard patientreported mood assessment scales in adult patients with epilepsy. Test results before implan‐ tation were compared with those afterward. One study [23] (Elger G, 2000)] evaluated 11 subjects 1, 3, and 6 months after implantation. Before VNS, 7 of the 11 patients met criteria for "sub depressive mood" by the Montgomery-Åsberg Depression Rating Scale, and group mean was within the subdepressive mood range; after implantation, group mean was in the nondepressed range. Likewise, 8 of the 11 met criteria for "mild negative symptoms" by the Scale for the Assessment of Negative Symptoms before VNS. Scale and subscale scores improved at the study's 3-month follow-up (p <0.05). Mood improvements were sustained at

The second study [15] (Morris GL III, 1999) evaluated 20 subjects 3 months after VNS implan‐ tation. Results for change in subject-rated scales by t tests showed improvements in the clinician-administered Cornell Dysthymia Rating Scale (p=0.001) and the patient self-report Beck Depression Inventory (BDI) (p=0.045); results on the clinician-administered Hamilton Depression Index (investigator rated) also significantly improved. The group's mean BDI score pre–VNS treatment was 12.0 ("mild mood disturbance"); this decreased to 9.4 ("non de‐ pressed") after VNS. Further, BDI scores decreased relative to those for an epilepsy control group (no therapy) studied over the same period (by repeated measures analysis of variance, p=0.07). This benefit was not correlated with reduced seizure frequency or with stimulation

The AAN RGDS [14] concluded VNS is possibly effective for mood improvement among adults

months, 6 of the 7 female patients had more than 50% reduction in seizures.

**4.4. Does VNS improve mood in epilepsy patients?**

the 6-month follow-up (9 of 11 subjects).

frequency or intensity.

with epilepsy.

Initiating VNS requires a surgical procedure to implant the generator and leads to begin the therapy. When the battery is depleted, surgery is required to replace the generator and replace the batteries. The leads are not usually disturbed during this procedure, but reattached to the new generator. Patient-perceived benefit has been hallmarked by the willingness of recipients to undergo surgical generator replacement across the history of the treatment. Morris [15] (Morris GL III, 1999) reported a 72% 3-year continuation rate among early users, and the November 11, 2013 Cyberonics Investor Conference Call placed it at 75% for the fully depleted Model 100 generators.

#### **6. Battery life**

The estimated battery life decreases as pulse width, frequency, output current, duty cycle, or lead impedance increases. For example, the Cyberonics Model 103 Manual [13] estimates battery life at more than 10 years for a stimulation frequency of 20 HZ, 1.5 mA output, 3 kohm impedance and 10% duty cycle for pulse widths ranging from 130 sec to 500 sec. Under the same conditions and a 50% duty cycle, the time to near end of battery life is 7.1 years, 6.2 years, and 3.7 years for pulse widths of 130 µsec, 250 µsec, and 500 µsec.

#### **7. Cost effectiveness**

The net cost of VNS determines medical cost reimbursement. Battery life drives cost savings after initial costs have been recouped.

Ben-Menachem [24-25] (Ben-Menachem E H. K., 2002) (Ben-Menachem E F. J., 2005) reports that implantation cost, when calculated over 8 years (battery life), is actually less than the cost of using a new AED over a similar time period. Real savings in hospital costs owing to seizures can also be expected. Average annual cost savings were approximately \$3,000 per patient. This cost savings applied to all patients, whether or not they responded to VNS. These direct savings maintained over the battery life can equal or exceed the purchase price of the device.

In the Boon [26] (Boon P D. M., 2002) VNS group, mean seizure frequency decreased from 21 to 7 per month. Epilepsy-related direct medical costs (ERDMCs) in the VNS subgroup decreased from \$4,826 to \$2496 per year.

Bernstein [27] (Bernstein AL, 2007) compared average quarterly utilization rates of 138 patients for 12 months before device implantation with quarterly rates during 48 months of follow-up. Results during the 4th quarter of Year 4 revealed impressive decreases in utilization of all 4 measured aspects: a 91% decrease in outpatient visits, a 99% decrease in emergency depart‐ ment visits, a 67% decrease in hospital lengths of stay, and a 70% decrease in number of hospital admissions. Notably, no visits to the emergency department occurred during the final quarter of the study.

Helmers [20] (Helmers SL D. M., 2011) reported on 1655 patients in a pre-post analysis using multistate Medicaid data (January 1997-June 2009). After 1.5 years, she found VNS was associated with decreased resource utilization and epilepsy-related clinical events. The reduction in costs related to these hospital resources were equal to the initial costs related to the cost of purchasing and implanting the VNS System. Three years after the implant proce‐ dures the health care system had a net savings of \$50,000 related to reduced hospitalizations and ER visits. Outpatient visits exceeded 50% of the total health care costs during the study. Table 5 gives the approximate net costs from Figure 2 in the Helmers paper. Using the trend line, net savings are projected for the remaining years of battery life.

The vagus nerve consists of larger myelinated A and B fibers and smaller unmyelinated C fibers. The C fibers make up about 80% of the 100,000 fibers in the vagus nerve. Of the nerves going into the brain, about 80% are afferent. The ratios of A, B, and C are assumed to be the

The approximate currents required to stimulate the A, B, and C fibers in the Woodbury paper are given in Table 6. [11]. The diameter of the rat vagus nerve is about 0.4 mm vs 2.0 mm

**Stimulation duration A fiber B fiber C fiber**

125 µseconds 10 µA 50 µA 325 µA

250 µseconds 5 µA 25 µA 200 µA

500 µseconds 5 µA 10 µA 125 µA

Smith [28] (Smith CD, 2001) discussed right and left cervical vagus nerve measurements of a 4-canine study using the Cyberonics 300 Series Bipolar Vagus Nerve Electrodes (Figure 1). Smith reported the average A fiber chronaxie values were 75.4 ± 24.5 µs and were 82.3 ± 23.3 µs for B fibers. The A fiber rheobase values were 0.63 ± 0.18 mA and 0.66 ± 0.22 mA for B fibers. The A fiber propagation velocities were 59.0 ± 9.6 m/s and 43.4 ± 8.0 m/s for B fibers. An effective

Understanding how stimulation parameters affect seizure control started with the Woodbury [11] (Woodbury DM, 1990) rat models of current, pulse width, stimulation frequency, and time delay necessary to inhibit a seizure. Rat vagus nerves are much smaller than human vagus nerves, rendering it difficult to translate the current used in the rat studies to human vagus nerve stimulation. The stimulation threshold, a function of current density, is determined by ratio of the cross sectional areas of the nerves, which is the ratio of the square of the diameters. (0.4 mm vs 2 mm). Therefore, equivalent stimulation current in humans should be approxi‐ mately 25 times that of rat vagus stimulation. Activation of B fibers in the rats at 250 µsec was 25 µA, which would correspond to a 0.625 mA activation in humans using the 25 multiplication factor. This is very close to the range of that clinically being used. In 2012, Helmers [29] (Helmers SL, 2012) developed a computational model of the activation of the human vagus nerve. She tied the computational model to clinical experience in Table 7, which shows the approximate vagus nerve stimulation threshold strength–duration curve. Nonetheless, 25 years of clinical vagus nerve stimulation experience has yielded little direct measurement of

and 12.9 mA/cm2

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for A and

**Table 6.** Stimulation Current vs Pulse Duration in Rat Vagus Nerve Model [11].

electrode area of 5 mm2 yields current densities of ±13.0 mA/cm2

same for afferent and efferent fibers.

diameter for the human vagus nerve.

B fibers, respectively.

vagus action potential.


**Table 5.** Cumulative adjusted Net Healthcare Costs from Baseline

These papers indicate marked savings to health care systems throughout the world, even though seizures are controlled in only 10-15% of patients. Primary cost saving drivers are reduced ER visits, reduced hospital admissions, and reduced hospital days.

#### **8. Stimulation parameter selection**

Selection of the output parameters consists of 2 steps. The first is full activation so that signals are sent to the brain. The second is selection of ON time, OFF time, and stimulation frequency to obtain optimum efficacy.

The vagus nerve consists of larger myelinated A and B fibers and smaller unmyelinated C fibers. The C fibers make up about 80% of the 100,000 fibers in the vagus nerve. Of the nerves going into the brain, about 80% are afferent. The ratios of A, B, and C are assumed to be the same for afferent and efferent fibers.

The approximate currents required to stimulate the A, B, and C fibers in the Woodbury paper are given in Table 6. [11]. The diameter of the rat vagus nerve is about 0.4 mm vs 2.0 mm diameter for the human vagus nerve.


**Table 6.** Stimulation Current vs Pulse Duration in Rat Vagus Nerve Model [11].

Helmers [20] (Helmers SL D. M., 2011) reported on 1655 patients in a pre-post analysis using multistate Medicaid data (January 1997-June 2009). After 1.5 years, she found VNS was associated with decreased resource utilization and epilepsy-related clinical events. The reduction in costs related to these hospital resources were equal to the initial costs related to the cost of purchasing and implanting the VNS System. Three years after the implant proce‐ dures the health care system had a net savings of \$50,000 related to reduced hospitalizations and ER visits. Outpatient visits exceeded 50% of the total health care costs during the study. Table 5 gives the approximate net costs from Figure 2 in the Helmers paper. Using the trend

> -\$19,000 cost -\$17,000 cost -\$12,000 cost -\$7,000 cost -\$1,000 cost +\$4,000 savings +\$12,000 savings +\$19,000 savings +\$27,000 savings +\$34,000 savings +\$42,000 savings +\$50,000 savings

> 5 +\$100,000 savings 7 +\$150,000 savings 9 +\$200,000 savings

These papers indicate marked savings to health care systems throughout the world, even though seizures are controlled in only 10-15% of patients. Primary cost saving drivers are

Selection of the output parameters consists of 2 steps. The first is full activation so that signals are sent to the brain. The second is selection of ON time, OFF time, and stimulation frequency

reduced ER visits, reduced hospital admissions, and reduced hospital days.

line, net savings are projected for the remaining years of battery life.

Projected Savings Year

148 Epilepsy Topics

**Table 5.** Cumulative adjusted Net Healthcare Costs from Baseline

**8. Stimulation parameter selection**

to obtain optimum efficacy.

**Quarter Cumulative Investment Return**

Smith [28] (Smith CD, 2001) discussed right and left cervical vagus nerve measurements of a 4-canine study using the Cyberonics 300 Series Bipolar Vagus Nerve Electrodes (Figure 1). Smith reported the average A fiber chronaxie values were 75.4 ± 24.5 µs and were 82.3 ± 23.3 µs for B fibers. The A fiber rheobase values were 0.63 ± 0.18 mA and 0.66 ± 0.22 mA for B fibers. The A fiber propagation velocities were 59.0 ± 9.6 m/s and 43.4 ± 8.0 m/s for B fibers. An effective electrode area of 5 mm2 yields current densities of ±13.0 mA/cm2 and 12.9 mA/cm2 for A and B fibers, respectively.

Understanding how stimulation parameters affect seizure control started with the Woodbury [11] (Woodbury DM, 1990) rat models of current, pulse width, stimulation frequency, and time delay necessary to inhibit a seizure. Rat vagus nerves are much smaller than human vagus nerves, rendering it difficult to translate the current used in the rat studies to human vagus nerve stimulation. The stimulation threshold, a function of current density, is determined by ratio of the cross sectional areas of the nerves, which is the ratio of the square of the diameters. (0.4 mm vs 2 mm). Therefore, equivalent stimulation current in humans should be approxi‐ mately 25 times that of rat vagus stimulation. Activation of B fibers in the rats at 250 µsec was 25 µA, which would correspond to a 0.625 mA activation in humans using the 25 multiplication factor. This is very close to the range of that clinically being used. In 2012, Helmers [29] (Helmers SL, 2012) developed a computational model of the activation of the human vagus nerve. She tied the computational model to clinical experience in Table 7, which shows the approximate vagus nerve stimulation threshold strength–duration curve. Nonetheless, 25 years of clinical vagus nerve stimulation experience has yielded little direct measurement of vagus action potential.

**8.1. The stimulation S curve**

**Figure 2.** Fiber Activation Curve

**8.2. Stimulation frequency**

be increased.

Figure 2 shows that activation of the individual fibers in the vagus nerve follows the typical S curve as the current increases which assumes the activations threshold follows a normal distribution. For the A and B fibers, the 10% activation current (A) is believed to be about 0.25 mA and the 90% activation current (B) is believed to be about 1.5 mA. However, the curves have not been developed for individual patients and the curves are likely to vary among

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The typical stimulation frequency is 20 Hz, based on experience in the clinical studies and the Woodbury rat studies [11] (Woodbury DM, 1990). Woodbury reported that efficacy dimin‐

The E03 and E05 studies used 1 Hz for the placebo LOW group. Stimulation greater than 30 Hz may be equally or more effective, but battery life is shortened and patient discomfort may

The AAN RGDS [14] reviewed evidence on rapid stimulation cycles. Among patients receiving VNS, does rapid stimulation (usually 7 seconds "on" and 30 seconds "off") improve seizure

ished rapidly with frequency reductions of 10 Hz and lower.

**8.3. Rapid stimulation or high duty cycle stimulation**

patients and may change over time for the individual patient.

**Figure 1.** Chronixie and Propagation Velocity of Canine Vagus [28]


**Table 7.** Vagus Nerve Stimulation Threshold Strength–Duration Table [29]

The low number in the range is the 'minimum target' and represents the minimum output current pulse width needed to activate the nerve completely in the absence of tissue ingrowth. An increase in resistance because of tissue ingrowth may occur during the first several weeks after surgery. This increase may require additional stimulation per pulse for adequate recruitment of the vagal afferents. Very few patients (6.3%) responded with output current and pulse width falling below the 'minimum target' line. More than half of the responders (57.5%) had output current pulse width combinations above the 'minimum target' and below the high number or 'maximum target'; 36.2% of responders had output current pulse width combinations above the maximum target.

#### **8.1. The stimulation S curve**

Figure 2 shows that activation of the individual fibers in the vagus nerve follows the typical S curve as the current increases which assumes the activations threshold follows a normal distribution. For the A and B fibers, the 10% activation current (A) is believed to be about 0.25 mA and the 90% activation current (B) is believed to be about 1.5 mA. However, the curves have not been developed for individual patients and the curves are likely to vary among patients and may change over time for the individual patient.

**Figure 2.** Fiber Activation Curve

**Figure 1.** Chronixie and Propagation Velocity of Canine Vagus [28]

150 Epilepsy Topics

**Table 7.** Vagus Nerve Stimulation Threshold Strength–Duration Table [29]

combinations above the maximum target.

**Pulse Width 6.3% range 57.5% range 36.2% range** 130 usec 0.25-.1.0 mA 1.0-2.25 mA 2.25-3.5 mA 250 usec 0.25-0.75 mA 0.75-1.75 mA 1.75 -3.5 mA 500 usec .0.25-0.6 mA 0.6-1.5 mA 1.5-3.5 mA

The low number in the range is the 'minimum target' and represents the minimum output current pulse width needed to activate the nerve completely in the absence of tissue ingrowth. An increase in resistance because of tissue ingrowth may occur during the first several weeks after surgery. This increase may require additional stimulation per pulse for adequate recruitment of the vagal afferents. Very few patients (6.3%) responded with output current and pulse width falling below the 'minimum target' line. More than half of the responders (57.5%) had output current pulse width combinations above the 'minimum target' and below the high number or 'maximum target'; 36.2% of responders had output current pulse width

#### **8.2. Stimulation frequency**

The typical stimulation frequency is 20 Hz, based on experience in the clinical studies and the Woodbury rat studies [11] (Woodbury DM, 1990). Woodbury reported that efficacy dimin‐ ished rapidly with frequency reductions of 10 Hz and lower.

The E03 and E05 studies used 1 Hz for the placebo LOW group. Stimulation greater than 30 Hz may be equally or more effective, but battery life is shortened and patient discomfort may be increased.

#### **8.3. Rapid stimulation or high duty cycle stimulation**

The AAN RGDS [14] reviewed evidence on rapid stimulation cycles. Among patients receiving VNS, does rapid stimulation (usually 7 seconds "on" and 30 seconds "off") improve seizure frequency more often than standard stimulation settings (30 seconds "on" and 300 seconds "off")? In all the reviewed studies, beginning parameters were output current 0.25 mA, signal frequency 30 Hz, pulse width 250–500 ms, stimulation "on" time 30 seconds, and stimulation "off" time 300 seconds, and output current usually increased to 2–3 mA per tolerance. Schermann and collegues [30] (Scherrmann J, 2001) discussed rapid as opposed to standard stimulation settings, assessing results of 73 adult epilepsy patients with adjusted settings of standard (30 seconds "on" and 300 seconds "off", n=41) or rapid (7 seconds "on" and 30 seconds "off", n=32). After 2 years of follow-up, the standard stimulation group had greater overall seizure frequency reduction than the rapid stimulation group. In this article, the authors said a group receiving VNS at either standard or rapid stimulation did not demonstrate different response rates. For several patients, a changing to rapid stimulation several years after implantation improved outcome.

effective and may explain why Lockard [7] was not successful in terminating seizures in the

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153

Several papers have suggested the possibility of using heart rate changes to detect seizures, including Leutmezer [34] (Leutmezer F, 2003) and [35] (Schernthaner C, 1999). Luetmezer reported that 86.9% of all seizures were accompanied by ictal-onset tachycardia and 1.4% of seizures were accompanied by bradycardia. Patients with mesial temporal lobe epilepsy (TLE) were significantly more likely to have ictal HR increase than those with non-lesional TLE or extratemporal epilepsy. Ictal-onset tachycardia was also more likely with right hemispheric seizures. Interestingly, the increased ictal HR preceded the EEG onset by a statistically significant difference (p=0.047); average of 13.7 s among TLE patients and 8.2 s among

Cyberonics developed the Aspire SR to provide seizure detection based on heart rate changes. Boon et al [36] (Boon P, 2013) had conducted the E36 prospective multicenter clinical study in Europe to evaluate seizure detection ability of the Aspire SR. Boon [36] had presented data on 31 patients at the 2013 American Epilepsy Meeting. The study met its primary endpoint of detecting more than 80% of seizures accompanied by ictal tachycardia and false rates were low. The detections occurred close to, and in some cases, before seizure onset. The AspireSR Generator can help patients for whom are not able to apply rapid and consistent hand-held magnet activation. For example, patients whom experience seizures while sleeping would

benefit from this feature. The CE Mark for the AspireSR was issued in February 2014.

Neuropace has evaluated EEG detection for deep brain stimulation therapy. The study [37] (Morrell, 2011) found a statistically significant reduction in seizures with treatment group vs control group, but did not report an evaluation of detection sensitivity or false detection counts.

The vagus nerve comprises approximately 80% afferent fibers. These fibers enter the nucleus tractus solitaries and branch bi-laterally into both sides of the brain. For the most part, both the right and left vagus seem to have very similar projections into neural networks. Both project equally into the right and left sides of the brain, although they probably have many small

Krahl [39] (Krahl SE C. K., 1998) reported data that indicate the LC is involved in the circuitry

Naritoku [40] (Naritoku DK, 1995) began tracing the neural networks as did Cunningham [41]

Naritoku [40] reported that specific nuclear fos immune labeling was induced by vagus nerve stimulation (VNS) in several forebrain structures, including the posterior cortical amygdaloid nucleus, cingulate, and retrosplenial cortex, ventromedial and arcuate hypothalamic nuclei.

primate study.

extratemporal epilepsy patients.

[38] (Neuropace, 2013).

differences.

(Cunningham JT, 2008).

**10. Vagus connections into neural networks**

necessary for the anticonvulsant effects of VNS.

Concerning children, 2 Class III articles reported that rapid stimulation did not provide consistently better results than standard stimulation [31] (Alexopoulos AV, 2006) [32] (Shah‐ wan A, 2009). According to the AAM RGDS, both studies lacked power to detect a difference between rapid stimulation when used either initially or after unsuccessful standard stimula‐ tion.

In contrast to the High Duty Cycle experience, very low duty cycles of 1 minute per hour have not been extensively studied, although success was observed in the E01 trial and such use would significantly extend battery life.

In summary, the physician has a range of parameter adjustments to optimize treatment for the individual patient.

#### **9. Automatic seizure detection**

Activation of VNS upon seizure detection was a long-time goal, but available technology limited such to self-activation by the patient or caregiver. A magnet, often worn on the patient's wrist, can be passed over the implanted generator to initiate stimulation. Morris [33] (Morris, 2003) conducted a retrospective analysis of magnet use during the E03 and E04 clinical trials of VNS. Magnet activation that aborted, decreased, terminated, or diminished a seizure was classified as an improvement; for purposes of evaluation, the patient was considered to have received a benefit. When patients in the E03 trial used magnets to activate stimulation, those in the active (HIGH) stimulation group reported more seizure improvement than those in the placebo (sham magnetic stimulation) group (P=0.0479, Fisher's test). In the E04 trial, 22% of the patients reported they were able to abort seizures and 31% reported the seizures were diminished.

Woodbury [11] (Woodbury DM, 1990) found that the length of the seizure was related to the length of delay between start of a PTZ-induced seizure in rats and start of stimulation. This rat study implied that stimulation should be initiated within the first 14 seconds of a PTZinduced seizure. It seems intuitive that stimulation early in the seizure cycle would be most effective and may explain why Lockard [7] was not successful in terminating seizures in the primate study.

Several papers have suggested the possibility of using heart rate changes to detect seizures, including Leutmezer [34] (Leutmezer F, 2003) and [35] (Schernthaner C, 1999). Luetmezer reported that 86.9% of all seizures were accompanied by ictal-onset tachycardia and 1.4% of seizures were accompanied by bradycardia. Patients with mesial temporal lobe epilepsy (TLE) were significantly more likely to have ictal HR increase than those with non-lesional TLE or extratemporal epilepsy. Ictal-onset tachycardia was also more likely with right hemispheric seizures. Interestingly, the increased ictal HR preceded the EEG onset by a statistically significant difference (p=0.047); average of 13.7 s among TLE patients and 8.2 s among extratemporal epilepsy patients.

Cyberonics developed the Aspire SR to provide seizure detection based on heart rate changes. Boon et al [36] (Boon P, 2013) had conducted the E36 prospective multicenter clinical study in Europe to evaluate seizure detection ability of the Aspire SR. Boon [36] had presented data on 31 patients at the 2013 American Epilepsy Meeting. The study met its primary endpoint of detecting more than 80% of seizures accompanied by ictal tachycardia and false rates were low. The detections occurred close to, and in some cases, before seizure onset. The AspireSR Generator can help patients for whom are not able to apply rapid and consistent hand-held magnet activation. For example, patients whom experience seizures while sleeping would benefit from this feature. The CE Mark for the AspireSR was issued in February 2014.

Neuropace has evaluated EEG detection for deep brain stimulation therapy. The study [37] (Morrell, 2011) found a statistically significant reduction in seizures with treatment group vs control group, but did not report an evaluation of detection sensitivity or false detection counts. [38] (Neuropace, 2013).

#### **10. Vagus connections into neural networks**

frequency more often than standard stimulation settings (30 seconds "on" and 300 seconds "off")? In all the reviewed studies, beginning parameters were output current 0.25 mA, signal frequency 30 Hz, pulse width 250–500 ms, stimulation "on" time 30 seconds, and stimulation "off" time 300 seconds, and output current usually increased to 2–3 mA per tolerance. Schermann and collegues [30] (Scherrmann J, 2001) discussed rapid as opposed to standard stimulation settings, assessing results of 73 adult epilepsy patients with adjusted settings of standard (30 seconds "on" and 300 seconds "off", n=41) or rapid (7 seconds "on" and 30 seconds "off", n=32). After 2 years of follow-up, the standard stimulation group had greater overall seizure frequency reduction than the rapid stimulation group. In this article, the authors said a group receiving VNS at either standard or rapid stimulation did not demonstrate different response rates. For several patients, a changing to rapid stimulation several years after

Concerning children, 2 Class III articles reported that rapid stimulation did not provide consistently better results than standard stimulation [31] (Alexopoulos AV, 2006) [32] (Shah‐ wan A, 2009). According to the AAM RGDS, both studies lacked power to detect a difference between rapid stimulation when used either initially or after unsuccessful standard stimula‐

In contrast to the High Duty Cycle experience, very low duty cycles of 1 minute per hour have not been extensively studied, although success was observed in the E01 trial and such use

In summary, the physician has a range of parameter adjustments to optimize treatment for the

Activation of VNS upon seizure detection was a long-time goal, but available technology limited such to self-activation by the patient or caregiver. A magnet, often worn on the patient's wrist, can be passed over the implanted generator to initiate stimulation. Morris [33] (Morris, 2003) conducted a retrospective analysis of magnet use during the E03 and E04 clinical trials of VNS. Magnet activation that aborted, decreased, terminated, or diminished a seizure was classified as an improvement; for purposes of evaluation, the patient was considered to have received a benefit. When patients in the E03 trial used magnets to activate stimulation, those in the active (HIGH) stimulation group reported more seizure improvement than those in the placebo (sham magnetic stimulation) group (P=0.0479, Fisher's test). In the E04 trial, 22% of the patients reported they were able to abort seizures and 31% reported the seizures were

Woodbury [11] (Woodbury DM, 1990) found that the length of the seizure was related to the length of delay between start of a PTZ-induced seizure in rats and start of stimulation. This rat study implied that stimulation should be initiated within the first 14 seconds of a PTZinduced seizure. It seems intuitive that stimulation early in the seizure cycle would be most

implantation improved outcome.

would significantly extend battery life.

**9. Automatic seizure detection**

tion.

152 Epilepsy Topics

individual patient.

diminished.

The vagus nerve comprises approximately 80% afferent fibers. These fibers enter the nucleus tractus solitaries and branch bi-laterally into both sides of the brain. For the most part, both the right and left vagus seem to have very similar projections into neural networks. Both project equally into the right and left sides of the brain, although they probably have many small differences.

Krahl [39] (Krahl SE C. K., 1998) reported data that indicate the LC is involved in the circuitry necessary for the anticonvulsant effects of VNS.

Naritoku [40] (Naritoku DK, 1995) began tracing the neural networks as did Cunningham [41] (Cunningham JT, 2008).

Naritoku [40] reported that specific nuclear fos immune labeling was induced by vagus nerve stimulation (VNS) in several forebrain structures, including the posterior cortical amygdaloid nucleus, cingulate, and retrosplenial cortex, ventromedial and arcuate hypothalamic nuclei. The immune labeling was also apparent in the vagus nerve nuclei of the brainstem, in the A5 and locus ceruleus noradrenergic nuclei and in the cochlear nucleus. The sham-operated, unstimulated control animals had no fos immune labeling of these structures.

(Krahl SE S. S., 2003) (rat model). Also, a positive clinical result from a pilot study of right vagus nerve stimulation for congestive heart failure has been published [47] (De Ferrari & Investigators, 2011). Although right-sided VNS may be safe, it should be used cautiously as

Vagus Nerve Stimulation Therapy for Epilepsy

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155

Would stimulation of both the right and left vagus nerve have an additive effect that might

The concept of using external stimulation has appeal because VNS requires surgical implan‐ tation, and not all patients respond. Two external vagus stimulation devices and 1 trigeminal nerve stimulator are being investigated in clinical studies. Although these devices have CE Mark approval for 1 or more indications, none have FDA approval as of February 2014.

Stefan [48] (Stefan H, 2012) described the Cerbomed NEMOS device used in a pilot study among 10 patients. Electrical stimulation was applied transcutaneously to the auricular branch of the vagus nerve (ABVN) of the left ear. Three patients left the study. Of the remaining 7

DeGeorgio [49] (DeGiorgio CM, 2013) reported a 50-patient double-blind trial of the Mon‐ arch™ eTNS Trigeminal nerve stimulation device by NeuroSigma, and Pack [50] (Pack AM, 2013) commented on the study. No significant differences were found between the active group and control group in any of the 3 predefined primary end points, but a significant within-group difference improvement was seen in the responder rate over the 18-week treatment period. The responder rate was 17.8% at 6 weeks, and it increased to 40.5% at 18 weeks, providing a significant within-group improvement (*p*=0.01). Pack [50] commented that it is unclear how the responder rates at the serial observation periods were derived and concluded that although interesting, these data do not support the effectiveness of eTNS for the treatment of refractory

Electrocore Medical makes the gammaCore battery-powered device that is held against the neck and provides a single 180-second burst of vagus nerve stimulation. A number of presen‐ tations and publications of pilot studies have reported encouraging results for migraine, cluster headaches, asthma, and bronchial COPD. Electrocore Medical has a CE Mark for epilepsy, but

Deep brain stimulation is attractive because it stimulates the specific part of the brain associ‐ ated with the seizure. Medtronic and Neuropace have conducted clinical trials with devices that provide deep brain stimulation. Both have CE Mark approval and Neuropace received

patients, 5 experienced an overall seizure reduction after 9 months of t-VNS.

no epilepsy studies have been reported as of February 2014.

improve efficacy? This approach has not been studied in animal epilepsy models.

its safety has not been established in clinical studies.

**11. External vagus stimulation**

partial seizures.

**12. Deep brain stimulation**

FDA approval in November 2013.

Cunningham studied the acute and chronic effects of VNS on brain structures using c-Fos and ΔFosB immune labeling. Acutely, VNS significantly increased c-Fos staining in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, parabrachial nucleus, central bed nucleus of the stria terminalis, and locus coeruleus, but did not increase c-Fos staining in the cingulate cortex or dorsal raphe nucleus (DRN). VNS acute stimulation did not affect ΔFosB staining in any region. Chronically, VNS significantly increased both ΔFosB and c-Fos staining bilaterally in each region affected by acute VNS as well as in the cingulate cortex and DRN.

Cunningham [41] developed the neural network schematic in Figure 3, which was presented at several conferences.

#### **10.1. Left vs right vagus stimulation**

In the clinical studies, the pulse generator was attached to the left vagus nerve for establishing safety and efficacy. Primate studies by Lockard [7] (Lockard JS, 1990) stimulated the right vagus nerve and noted no effect on heart rate nor gastric function. Several reports regarding right-sided stimulation among patients have not mentioned cardiac effects [42] (Navas M, 2010), [43] (Spuck S, 2008), [44] (Tubbs RS, 2007) (pig model), [45] (McGregor A, 2005) and [46] (Krahl SE S. S., 2003) (rat model). Also, a positive clinical result from a pilot study of right vagus nerve stimulation for congestive heart failure has been published [47] (De Ferrari & Investigators, 2011). Although right-sided VNS may be safe, it should be used cautiously as its safety has not been established in clinical studies.

Would stimulation of both the right and left vagus nerve have an additive effect that might improve efficacy? This approach has not been studied in animal epilepsy models.

#### **11. External vagus stimulation**

The immune labeling was also apparent in the vagus nerve nuclei of the brainstem, in the A5 and locus ceruleus noradrenergic nuclei and in the cochlear nucleus. The sham-operated,

Cunningham studied the acute and chronic effects of VNS on brain structures using c-Fos and ΔFosB immune labeling. Acutely, VNS significantly increased c-Fos staining in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, parabrachial nucleus, central bed nucleus of the stria terminalis, and locus coeruleus, but did not increase c-Fos staining in the cingulate cortex or dorsal raphe nucleus (DRN). VNS acute stimulation did not affect ΔFosB staining in any region. Chronically, VNS significantly increased both ΔFosB and c-Fos staining bilaterally in each region affected by acute VNS as well as in the cingulate cortex and DRN. Cunningham [41] developed the neural network schematic in Figure 3, which was presented

unstimulated control animals had no fos immune labeling of these structures.

**Figure 3.** Vagal Projections to the Brain as Developed by Cunningham [41]

In the clinical studies, the pulse generator was attached to the left vagus nerve for establishing safety and efficacy. Primate studies by Lockard [7] (Lockard JS, 1990) stimulated the right vagus nerve and noted no effect on heart rate nor gastric function. Several reports regarding right-sided stimulation among patients have not mentioned cardiac effects [42] (Navas M, 2010), [43] (Spuck S, 2008), [44] (Tubbs RS, 2007) (pig model), [45] (McGregor A, 2005) and [46]

**10.1. Left vs right vagus stimulation**

at several conferences.

154 Epilepsy Topics

The concept of using external stimulation has appeal because VNS requires surgical implan‐ tation, and not all patients respond. Two external vagus stimulation devices and 1 trigeminal nerve stimulator are being investigated in clinical studies. Although these devices have CE Mark approval for 1 or more indications, none have FDA approval as of February 2014.

Stefan [48] (Stefan H, 2012) described the Cerbomed NEMOS device used in a pilot study among 10 patients. Electrical stimulation was applied transcutaneously to the auricular branch of the vagus nerve (ABVN) of the left ear. Three patients left the study. Of the remaining 7 patients, 5 experienced an overall seizure reduction after 9 months of t-VNS.

DeGeorgio [49] (DeGiorgio CM, 2013) reported a 50-patient double-blind trial of the Mon‐ arch™ eTNS Trigeminal nerve stimulation device by NeuroSigma, and Pack [50] (Pack AM, 2013) commented on the study. No significant differences were found between the active group and control group in any of the 3 predefined primary end points, but a significant within-group difference improvement was seen in the responder rate over the 18-week treatment period. The responder rate was 17.8% at 6 weeks, and it increased to 40.5% at 18 weeks, providing a significant within-group improvement (*p*=0.01). Pack [50] commented that it is unclear how the responder rates at the serial observation periods were derived and concluded that although interesting, these data do not support the effectiveness of eTNS for the treatment of refractory partial seizures.

Electrocore Medical makes the gammaCore battery-powered device that is held against the neck and provides a single 180-second burst of vagus nerve stimulation. A number of presen‐ tations and publications of pilot studies have reported encouraging results for migraine, cluster headaches, asthma, and bronchial COPD. Electrocore Medical has a CE Mark for epilepsy, but no epilepsy studies have been reported as of February 2014.

#### **12. Deep brain stimulation**

Deep brain stimulation is attractive because it stimulates the specific part of the brain associ‐ ated with the seizure. Medtronic and Neuropace have conducted clinical trials with devices that provide deep brain stimulation. Both have CE Mark approval and Neuropace received FDA approval in November 2013.

Fisher [51] (Fisher R, 2010) reported on the 110-patient double-blind trial employing the Medtronic dual-channel Model 7428 Kinetra Neurostimulator. During the final blinded month, seizure reduction was 29% greater among the stimulated group than the controls, (GEE) model (p=0.002). At 2 years, median percent reduction in seizure frequency was 56%; 54% showed seizure reduction of at least 50%, and 14 were seizure-free 6 months or more.

**References**

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[8] Woodbury, W. (1991). PhD. (R. Terry, Interviewer)

seizures in rats. *Epilepsia.*, 31 Suppl 2:S7-19.

Nerve electrodes. *Epilepsia*, 31(Suppl 2):S27-S32.

Cyberonics, this material is subject to change.

[1] Corning, J. (1883). Considerations on pathology and therapeutics of epilepsy. *J Nerv*

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[2] Bailey, P., & Bremer, F. (1938). A sensory cortical representation of the vagus nerve (with a note on the effects of low blood pressure on the cortical electrograms. *Journal*

[3] Schweitzer A, W. S. (1937). Effects on the knee jerk of stimulation of the central end of the vagus and of various changes in the circulation and respiration. *J Physiol*,

[4] Paintal, A. S. (1973). Vagal sensory receptors and their reflex effects. *Physiol Rev*,

[5] Dell P, O. R. (1951). [Secondary mesencephalic, diencephalic and amygdalian projec‐

[6] Zabara, J. (1992). Inhibition of experimental seizures in canines by repetitive vagal stimulation. 1992 November/December, 33. *EPILEPSIA*, November/December, 33. [7] Lockard JS, C. W. (1990). Feasibility and safety of vagal stimulation in monkey mod‐

[9] Uthman BM, W. B. (1993). Treatment of epilepsy by stimulation of the vagus nerve.

[10] Penry JK, D. J. (1990). Prevention of intractable partial seizures by intermittent vagal stimulation in humans: preliminary results. *EPILEPSIA*, 31 Supplement 2:S40-43. [11] Woodbury DM, W. J. (1990). Effects of vagal stimulation on experimentally induced

[12] Agnew WF, M. D. (1990). Considerations for Safety with Chronically implanted

[13] Cyberonics. (2013, November 17). *VNS Therapy Products.* Retrieved from VNS Thera‐ py System Physicians's Manual (US): http://dynamic.cyberonics.com/manuals/ Per

[14] Morris GL 3rd, G. D. (2013). Evidence-based guideline update: Vagus nerve stimula‐ tion for the treatment of epilepsy: Report of the Guideline Development Subcommit‐

[15] Morris GL III, M. W. (1999). Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01-

tee of the American Academy of Neurology. *Neurology*, Oct 15;81(16):1453-9.

tions of vagal visceral afferences.]fr. *C\_R\_Seances\_Soc\_Biol\_Fil*, 145(13-14).

The Neuropace RNS® System detects seizures from the EEG and then initiates stimulation. Morrell [37] (Morrell, 2011) reported on the 191-patient double-blind study of the Neuropace System. Although seizures were significantly reduced during the blinded period for both the treatment and sham groups, the treatment group seizures were more significantly reduced (-37.9%, n=97) compared with the sham group (-17.3%, n=94; *p*=0.012). There was no difference in adverse events between groups during the blinded period. The treatment group sustained seizure reduction. The FDA approved the Neuropace RNS® System in November 2013.

#### **13. Conclusion**

During its first 25 years, meaningful advances have been made in VNS for epilepsy. More than 70,000 patients have been treated and more than 100,000 devices have been implanted, which includes battery replacements. Long-term clinical experience shows that efficacy continues to improve, which is different from many pharmaceutical therapies. The therapy is highly cost effective, resulting in considerable long-term savings even though most patents do not become totally seizure free. Much is still to be learned about VNS. Advances continue regarding methods of seizure detection and activation therapy. Various methods of external stimulation as well as deep brain stimulation are being developed and evaluated.

#### **Acknowledgements**

Dr. Kiffin Penry for pioneering vagus nerve therapy in the first patients, the clinical study investigators, the clinical study patients, the basic science investigators, the Cyberonics employees, the venture capital investors who funded the clinical studies, and Jacob Zabara, PhD, who conceived and patented vagus nerve therapy. The author thanks Susan Siefert, ELS, CBC, Fellow and Past President of the American Medical Writers, for her help editing this chapter.

#### **Author details**

Reese S. Terry Jr

Founder, Cyberonics Inc. (retired Houston, TX), Life Fellow, IEEE, USA

#### **References**

Fisher [51] (Fisher R, 2010) reported on the 110-patient double-blind trial employing the Medtronic dual-channel Model 7428 Kinetra Neurostimulator. During the final blinded month, seizure reduction was 29% greater among the stimulated group than the controls, (GEE) model (p=0.002). At 2 years, median percent reduction in seizure frequency was 56%; 54% showed seizure reduction of at least 50%, and 14 were seizure-free 6 months or more.

The Neuropace RNS® System detects seizures from the EEG and then initiates stimulation. Morrell [37] (Morrell, 2011) reported on the 191-patient double-blind study of the Neuropace System. Although seizures were significantly reduced during the blinded period for both the treatment and sham groups, the treatment group seizures were more significantly reduced (-37.9%, n=97) compared with the sham group (-17.3%, n=94; *p*=0.012). There was no difference in adverse events between groups during the blinded period. The treatment group sustained seizure reduction. The FDA approved the Neuropace RNS® System in November 2013.

During its first 25 years, meaningful advances have been made in VNS for epilepsy. More than 70,000 patients have been treated and more than 100,000 devices have been implanted, which includes battery replacements. Long-term clinical experience shows that efficacy continues to improve, which is different from many pharmaceutical therapies. The therapy is highly cost effective, resulting in considerable long-term savings even though most patents do not become totally seizure free. Much is still to be learned about VNS. Advances continue regarding methods of seizure detection and activation therapy. Various methods of external stimulation

Dr. Kiffin Penry for pioneering vagus nerve therapy in the first patients, the clinical study investigators, the clinical study patients, the basic science investigators, the Cyberonics employees, the venture capital investors who funded the clinical studies, and Jacob Zabara, PhD, who conceived and patented vagus nerve therapy. The author thanks Susan Siefert, ELS, CBC, Fellow and Past President of the American Medical Writers, for her help editing this

as well as deep brain stimulation are being developed and evaluated.

Founder, Cyberonics Inc. (retired Houston, TX), Life Fellow, IEEE, USA

**13. Conclusion**

156 Epilepsy Topics

**Acknowledgements**

chapter.

**Author details**

Reese S. Terry Jr


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[33] Morris, G. (2003). A retrospective analysis of the effects of magnet-activated in con‐ junction with vagus nerve stimulation therapy. *Epilepsy Behav.*, Dec;4(6):740-5.

[34] Leutmezer F, S. C. (2003). Electrocardiographic changes at the onset of epileptic seiz‐

[35] Schernthaner C, L. G. (1999). Autonomic epilepsy--the influence of epileptic dis‐ charges on heart rate and rhythm. *Wien Klin Wochenschr*, May 21;111(10):392-401. [36] Boon P, v..K.. (2013). Vagus Nerve Stimulation Triggered by Cardiac-Based Seizure detection, A Prospective Study. *American Epilepsy Society.* Washington, DC. Abst.

[37] Morrell, M. (2011). Responsive cortical stimulation for the treatment of medically in‐

[38] NEUROPACE. (2013, February 22). *RNS System for Epilepsy Neuropace, Inc.* Retrieved from FDA NEUROLOGICAL DEVICE ADVISORY PANEL: http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/ MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM340257.pdf [39] Krahl SE, C. K. (1998). Locus coeruleus lesions suppress the seizure-attenuating ef‐

[40] Naritoku DK, T. W. (1995). Regional induction of fos immunoreactivity in the brain by anticonvulsant stimulation of the vagus nerve. *Epilepsy Res.*, Sep;22(1):53-62. [41] Cunningham JT, M. S. (2008). Cunningham JT, Mifflin SW, Gould GG, Frazer A. *Neu‐*

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**Chapter 8**

**Neuromodulation Therapy: Nonmedical, Nonsurgical**

Neuromodulation therapy has been tried for patients with many neuropsychiatric disorders such as Parkinson's disease, tremor, obcessive-compulsive disorder, depression, intractable pain, or addiction etc [1]. In epilepsy, this kind of treatment has been applied to treat patients with intractable epilepsy for decades who are not controlled by antiepileptic drugs (AEDs) nor surgical candidates. Historically, the earliest report of the use of electrical brain stimulation to control seizures in humans showed that focal electrical cortical stimulation could stop both

Vagal nerve or deep brain stimulation (e.g. thalamic stimulation) is indirect neural stimulation method, which delivers high frequency electrical stimulation indirectly to the epileptic brain via vagal nerve or thalamus, regardless of seizure foci [3,4]. This kind of stimulation is called open loop system since the stimulation is delivered intermittently and regularly without external cues (e.g. seizure onset). In contrast, closed loop system has been more recently applied in which the stimulation is directly applied to the seizure focus when seizure activity actually occurs. To do this, the stimulation system is combined with early seizure detection algorithm and activated automatically to deliver the stimulation only when the seizure activity is detected [5]. Responsive neurostimulation is an example of the closed loop system, which has been tested in recent clinical trials. While these methods need surgery to implant the electrodes for stimulation, noninvasive stimulation can be tried too especially using low frequency repetitive transcranial magnetic stimulation. In this method, the stimulation has been applied directly to the seizure focus but without combining seizure detection system so far. Although the exact therapeutic mechanism is not fully understood yet, these kinds of

treatments have been reported to reduce seizures in intractable epilepsy patients.

© 2014 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**Treatment for Intractable Epilepsy**

Additional information is available at the end of the chapter

normal EEG rhythms and spontaneous epileptiform discharges [2].

Hyang Woon Lee

**1. Introduction**

http://dx.doi.org/10.5772/57441

