- Email: [email protected]
Vagus Nerve Stimulation
CHAPTER 15
Vagus Nerve Stimulation COLIN ROBERTS, MD • CARLI BULLIS, MD
INTRODUCTION Vagus nerve stimulation (VNS) is a palliative treatment modality for refractory epilepsy. It involves the placement of electrodes coiled around the cervical vagus nerve. The electrodes are connected to a generator that sits on the chest wall and gives off chronic intermittent stimulation. The history of vagus nerve stimulation and its relation to seizures dates back at least a century. Stimulation of the vagus nerve and its effects on cerebral activity were first documented in 1938 by Bailey and Bremmer. This was followed in 1951 by Dell and Olson, who discovered that stimulating the vagus nerve causes an evoked response at the ventroposterior complex and intralaminar regions of the thalamus.1 In 1952, Zanchetti et al. used a chemically induced seizure model in cats and found that stimulation of the vagus nerve stopped the seizures. The first human implantation of a vagus nerve stimulator was done in 1988 by William Bell. The patient was a 25-yearold man with medically refractory epilepsy.2 It was not until 1997 that vagus nerve stimulation was approved by the US FDA as an adjunctive therapy for patients above 12 years with partial-onset and medically refractory epilepsy.3 Difficult-to-treat partial epilepsy affects between 150,000 and 300,000 people in the United States. As an effective treatment modality for these patients, VNS has become a very common procedure.4 As of January 2016, there had been 133,000 vagus nerve stimulator implantations in a total of 85,000 patients. This chapter will highlight the proposed mechanisms of vagus nerve stimulation and give a brief overview of the implantation process and the indications (both on- and off-label) and outcomes of implantation.
MECHANISM The mechanism of vagus nerve stimulation is not fully understood. There have been a number of hypotheses of its mechanism. We do know that the vagus nerve communicates with the nucleus tractus solitarius (NTS). The NTS then has numerous projections, including the locus ceruleus and raphe magnus.2 Stimulation to these areas
via the vagus nerve suggests that modulation of norepinephrine and serotonin release may play a role. Multiple studies have shown that stimulation of the vagus nerve increases blood flow to bilateral thalami. Krahl et al. found that lesioning of the locus ceruleus in rats decreased the efficacy of VNS, another suggestion that the locus ceruleus is involved in the mechanism. Cukiert et al. noted that there is typically not a significant effect on electroencephalography (EEG) postimplantation. This would suggest that the action of VNS is likely modulatory rather than affecting the seizure generation itself.5 In terms of the VNS system (Fig. 15.1), the stimulator functions by a programmable pulse generator delivering a chronic intermittent electric stimulation to the vagus nerve. This can be set to different intensities and rates. A very common therapeutic setting is 30 s of stimulation, followed by 5 min of off time. If there is a suspected aura or seizure occurring, a magnet can be swiped over the generator, which causes it to deliver an extra dose of stimulation, hopefully aborting the seizure in the process. The FDA-approved VNS implantation is for patients aged >12 years who have refractory partial epilepsy with no option for resective surgery. Focal disorders, such as mass lesions or mesial temporal sclerosis should be surgically treated with resection or ablation. Lesions that are unresectable, such as in eloquent areas, can be treated with VNS. Patients who have failed prior epilepsy surgery, such as resection of seizure focus or corpus callosotomy, may also be candidates for VNS. They may or may not meet FDA criteria based on their age or seizure type, but studies do show an improvement in seizure frequency for many of these patients with refractory epilepsy. There are also a number of off-label indications that are frequently associated with VNS placement. Many children aged <12 years undergo placement. In fact, it has been suggested in some literature that implanting children at a younger age may be a greater benefit than waiting until they are older.1 Uncontrolled seizures can lead to a cognitive decline over time. It is likely that children implanted at an earlier age have a lesser period of time 109
110
Functional Neurosurgery and Neuromodulation
FIG. 15.1 VNS therapy, as depicted in photo Model 10 6 (https://us.livanova.cyberonics.com).
of inadequately controlled seizures, and therefore do not experience as much cognitive decline. This theory could explain the trend of improved cognition in children implanted at a younger age. Patients with generalized seizures, such as in Lennox-Gastaut syndrome (LGS), are also being treated with VNS with a relative amount of success. Treatment for refractory depression has now also become an FDA-approved indication for VNS placement. The latest versions of the VNS device are capable of delivering automatic stimulation in response to detection of acceleration of heart rate that precedes seizure activity while delivering the chronic duty cycle chronic stimulation.
PROCEDURE The patient is placed under general endotracheal anesthesia. Preoperative antibiotics are given. They are positioned in the supine position on a standard table. A shoulder roll is placed beneath the scapula, and the head is rotated about 15 degrees to the right to expose the left side of the neck. Approximately halfway between the sternal notch and mandible, a transverse incision is drawn from the sternocleidomastoid to approximately the midline. Local anesthetic is infiltrated. The incision is sharply incised. The platysma is undermined and overmined with scissors and then opened transversely with monopolar electrocautery. Blunt dissection is used to dissect down to the carotid sheath. The carotid sheath is opened sharply. The vagus nerve is encountered deep and lateral to the carotid artery and deep and medial to the jugular vein at approximately the level of the thyroid cartilage. Vessel loops are placed around the vagus
nerve to help isolate and elevate it. At this point, we then perform the pocket incision. An approximately 5-cm transverse incision is made 1 cm below the clavicle. Monopolar electrocautery is used to dissect down to the pectoralis fascia. The pocket is made inferiorly in a suprafascial plane. The test generator can be used to help for sizing. Once the pocket is made, a tunneling device is then used to tunnel from the neck incision to the pocket. The leads are then passed through the tunnel. The helical electrodes are then opened by the strings at their ends and wrapped around the vagus nerve. The generator end of the leads is then connected to the generator. Excess lead length is coiled behind the generator, and the generator is placed in the pocket. The device is then interrogated. Upon successful interrogation, the incisions are then irrigated, a small amount of vancomycin powder (<1 g) is placed within them, and they are closed in the usual fashion with absorbable sutures. The patient is woken from general anesthesia and is ultimately taken to the ward where he or she recovers overnight.
OUTCOMES VNS has demonstrated a reduction in seizures in both adults and children across a number of studies. Greater than 50% reduction of seizures has been considered a positive outcome, with patients known as “responders,” in most studies.5,6 How meaningful this is to the individual patient, however, can vary, depending on their seizure severity and type. For instance, drop seizures can pose a danger to those patients secondary to trauma. Any reduction in the amount of these seizures will decrease the risk of trauma. Unless a person is completely seizure free, however, a reduction in seizures will still leave them with an impaired quality of life, unable to drive, perform certain jobs and activities, and leave the possibility for mild seizure-related cognitive impairment. Although only about 5% of patients will be completely seizure free after VNS placement, many will have a significant reduction in their number and severity of seizures, which, depending on the seizure type, may have a profound impact on their quality of life. In studying the effects of VNS, and seizure treatments in general, it is very meaningful to study not just the number of seizures a patient has but their improvement in quality of life after treatment.5 Sirven et al. published a study in 2000, which analyzed 45 patients above 50 years. Twenty of these patients were in randomized controlled trials. Twentyfive of them received the device open label after FDA approval. Sixty-seven percent of the patients had at least 50% reduction in their seizures with the device on high stimulation (35 mA for 30 s every 5 min). This study
CHAPTER 15 also showed a significant increase in the seizure reduction rate over time. Twenty-seven percent of people had greater than 50% seizure reduction at 3 months. Sixty-seven percent of people had greater than 50% reduction at 1 year.7 In that particular study, they used low stimulation as a control group. High stimulation has been shown in some studies, such as Handforth et al. in 1998, to have a significantly increased seizure frequency reduction over low stimulation.4 GarcíaNavarrete et al. performed a prospective trial of 43 patients, followed them for 18 months, and found that 62% of the patients had >50% reduction in number of seizures. There was no significant correlation with age of onset, duration of onset, stimulation intensity, previous surgery, or seizure type.8 Benifla et al. also studied 41 children, aged 3e19 years, and found that 38% had a seizure reduction of >90%. Forty-one percent had >50% seizure reduction. The same number had no response to VNS. They also found no correlation with age of onset, duration, prior surgeries, or seizure type.9 A 2015 Cochran Review analyzed the results of five randomized controlled trials of patients with different VNS frequencies and found that patients with high frequency were 1.73 times more likely to be responders than those on low frequency (which in many studies is considered a placebo setting).6 Degiorgio et al. performed a randomized prospective trial of 64 patients, placing all the patients in three different high-frequency groups, and found that there was no difference between these groups. These results have been echoed in other studies, finding no significant difference in the responder rate between different highfrequency settings.10 In addition to helping seizure frequency, studies have also shown a significant improvement with mood in adults treated with VNS. Elger et al. in 2000 published a randomized, double-blinded study, which analyzed mood in adults with medically refractory seizures treated with VNS. They found a significant improvement in mood within the first 3 months after implantation. This benefit was unrelated to any decrease or change in seizure frequency. This benefit was maintained at 6 months postimplantation, and it did not seem to be dose-dependent.11 The FDA has now approved the use of VNS as an adjunctive treatment for refractory depression in patients above 18 years who have not responded to at least four other treatment options. Although not originally indicated for treatment in the pediatric population, VNS has become very widely used in this setting. In 1999, the Pediatric VNS Study Group published a landmark study that showed an improvement in seizure frequency in children. Sixty-
Vagus Nerve Stimulation
111
six children, aged 3e18 years, with medically refractory epilepsy underwent VNS placement under a compassionate protocol. At 1 year, 46% of the children had a 42% reduction in seizure frequency.1 In a literature review, Morris et al. found that out of the 470 children with VNS placed, 55% of them saw at least a 50% reduction in seizures.3 There have not, however, been randomized controlled trials to study its impact on children. As noted in other studies, they also found that the effectiveness of VNS increased over time, 7% in years 1e5 after implantation.1,12 Healy et al. did retrospective review of 16 patients below 12 years and found that 56% had >50% reduction in seizures. They also found a significant decrease in the use of AEDs after VNS implantation.13 LGS has become another increasing off-label use for VNS in both children and adults. LGS consists of multiple seizure types in affected patients. It is refractory to multiple medications and is not amenable to any respective surgery. Often, imaging for these patients will appear normal or be associated with diffuse gliosis, but there is generally no discrete lesion.5 Morris et al. studied 113 patients with LGS and found that 55% of these patients had at least a 50% decrease in the number of their seizures.3 Cukiert et al. prospectively studied 24 patients with LGS or LGS-like syndrome and found that there was >50% reduction in 35 seizure types. Seventeen of the seizure types were stopped entirely with VNS. They found that the seizure types with the highest rates of success with VNS were atypical absence, generalized tonic-clonic, and myoclonic seizures. They found VNS less affective at treating atonic, or drop, seizures, although other studies have shown differing results.5 Benifla et al. found in a retrospective review that 4 of their 10 patients with LGS had >50% decrease in seizure frequency.
COMPLICATIONS VNS implantation is generally an uncomplicated surgery. Aside from the standard risks in surgery of infection and bleeding, there are the risks of minimal or no seizure improvement, hoarse voice, headache, cough, and dysphagia.6,14 Infection is a very significant risk in these surgeries because a surgical site infection often necessitates the removal of the entire system and treatment with long-term antibiotics. The risk of infection is typically quoted to be 3%e5%, although this varies between institutions and patient populations.1 Some have reported rates as high as 11%.15 Headaches, cough, and hoarseness or voice alteration are common and generally transient side effects caused by decreased
112
Functional Neurosurgery and Neuromodulation
adduction of the left vocal fold via the left recurrent and left superior laryngeal nerves.16 Those side effects will generally diminish between the first and third years after implantation.17 For the same reason, patients can also have worsening of obstructive sleep apnea and dysphagia.9 In general, VNS is very well tolerated by the majority of patients, and hoarseness of voice is the most common postoperative complaint.
REFERENCES 1. Hauptman J, Mathern G. Vagal nerve stimulation for pharmacoresistant epilepsy in children. Surg Neurol Int. 2012; 3(5):269. https://doi.org/10.4103/2152-7806.103017. 2. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. Neurosurg Focus. 2009;27(3):E5. https:// doi.org/10.3171/2009.6.FOCUS09126. 3. Morris GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy. Epilepsy Curr. 2013;13(6):297e303. https://doi.org/10.5698/1535-759713.6.297. 4. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1998;51(1):48e55. https://doi.org/10.1212/WNL.51.1.48. 5. Cukiert A, Cukiert CM, Burattini JA, et al. A prospective long-term study on the outcome after vagus nerve stimulation at maximally tolerated current intensity in a cohort of children with refractory secondary generalized epilepsy. Neuromodulation. 2013;16(6):551e555. https://doi.org/ 10.1111/j.1525-1403.2012.00522.x. 6. Panebianco M, Rigby A, Weston J, Ag M. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015;(4). https://doi.org/10.1002/14651858.CD002896. www.cochranelibrary.com. 7. Sirven J, Sperling M, Naritoku D, Schachter S. Vagus nerve stimulation therapy for epilepsy in older adults. Neurology. 2000:1179e1182. http://www.neurology.org/content/54/ 5/1179.short.
8. García-Navarrete E, Torres CV, Gallego I, Navas M, Pastor J, Sola RG. Long-term results of vagal nerve stimulation for adults with medication-resistant epilepsy who have been on unchanged antiepileptic medication. Seizure. 2013; 22(1):9e13. https://doi.org/10.1016/j.seizure.2012.09.008. 9. Benifla M, Rutka JT, Logan W, Donner EJ. Vagal nerve stimulation for refractory epilepsy in children: indications and experience at The Hospital for Sick Children. Childs Nerv Syst. 2006;22(8):1018e1026. https://doi.org/10.1007/ s00381-006-0123-6. 10. Degiorgio C, Heck C, Bunch S, et al. Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms. Neurology. 2005;65(2):317e319. 11. Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000;42(2e3):203e210. https:// doi.org/10.1016/S0920-1211(00)00181-9. 12. Dodrill CB, Morris GL. Effects of vagal nerve stimulation on cognition and quality of life in epilepsy. Epilepsy Behav. 2001;2:46e53. https://doi.org/10.1006/ebeh.2000.0148. 13. Healy S, Lang J, Te Water Naude J, Gibbon F, Leach P. Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy. Childs Nerv Syst. 2013;29(11): 2095e2099. https://doi.org/10.1007/s00381-013-2143-3. 14. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45: 224e230. https://doi.org/10.1212/WNL.45.2.224. 15. Rossignol E, Lortie A, Thomas T, et al. Vagus nerve stimulation in pediatric epileptic syndromes. Seizure. 2009;18(1): 34e37. https://doi.org/10.1016/j.seizure.2008.06.010. 16. Klinkenberg S, Aalbers MW, Vles JSH, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med Child Neurol. 2012;54(9):855e861. https://doi.org/10.1111/j.14698749.2012.04305.x. 17. Morris GL, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology. 1999;53(8):1731. https://doi.org/10.1212/WNL. 53.8.1731.
Vagus Nerve Stimulation COLIN ROBERTS, MD • CARLI BULLIS, MD
INTRODUCTION Vagus nerve stimulation (VNS) is a palliative treatment modality for refractory epilepsy. It involves the placement of electrodes coiled around the cervical vagus nerve. The electrodes are connected to a generator that sits on the chest wall and gives off chronic intermittent stimulation. The history of vagus nerve stimulation and its relation to seizures dates back at least a century. Stimulation of the vagus nerve and its effects on cerebral activity were first documented in 1938 by Bailey and Bremmer. This was followed in 1951 by Dell and Olson, who discovered that stimulating the vagus nerve causes an evoked response at the ventroposterior complex and intralaminar regions of the thalamus.1 In 1952, Zanchetti et al. used a chemically induced seizure model in cats and found that stimulation of the vagus nerve stopped the seizures. The first human implantation of a vagus nerve stimulator was done in 1988 by William Bell. The patient was a 25-yearold man with medically refractory epilepsy.2 It was not until 1997 that vagus nerve stimulation was approved by the US FDA as an adjunctive therapy for patients above 12 years with partial-onset and medically refractory epilepsy.3 Difficult-to-treat partial epilepsy affects between 150,000 and 300,000 people in the United States. As an effective treatment modality for these patients, VNS has become a very common procedure.4 As of January 2016, there had been 133,000 vagus nerve stimulator implantations in a total of 85,000 patients. This chapter will highlight the proposed mechanisms of vagus nerve stimulation and give a brief overview of the implantation process and the indications (both on- and off-label) and outcomes of implantation.
MECHANISM The mechanism of vagus nerve stimulation is not fully understood. There have been a number of hypotheses of its mechanism. We do know that the vagus nerve communicates with the nucleus tractus solitarius (NTS). The NTS then has numerous projections, including the locus ceruleus and raphe magnus.2 Stimulation to these areas
via the vagus nerve suggests that modulation of norepinephrine and serotonin release may play a role. Multiple studies have shown that stimulation of the vagus nerve increases blood flow to bilateral thalami. Krahl et al. found that lesioning of the locus ceruleus in rats decreased the efficacy of VNS, another suggestion that the locus ceruleus is involved in the mechanism. Cukiert et al. noted that there is typically not a significant effect on electroencephalography (EEG) postimplantation. This would suggest that the action of VNS is likely modulatory rather than affecting the seizure generation itself.5 In terms of the VNS system (Fig. 15.1), the stimulator functions by a programmable pulse generator delivering a chronic intermittent electric stimulation to the vagus nerve. This can be set to different intensities and rates. A very common therapeutic setting is 30 s of stimulation, followed by 5 min of off time. If there is a suspected aura or seizure occurring, a magnet can be swiped over the generator, which causes it to deliver an extra dose of stimulation, hopefully aborting the seizure in the process. The FDA-approved VNS implantation is for patients aged >12 years who have refractory partial epilepsy with no option for resective surgery. Focal disorders, such as mass lesions or mesial temporal sclerosis should be surgically treated with resection or ablation. Lesions that are unresectable, such as in eloquent areas, can be treated with VNS. Patients who have failed prior epilepsy surgery, such as resection of seizure focus or corpus callosotomy, may also be candidates for VNS. They may or may not meet FDA criteria based on their age or seizure type, but studies do show an improvement in seizure frequency for many of these patients with refractory epilepsy. There are also a number of off-label indications that are frequently associated with VNS placement. Many children aged <12 years undergo placement. In fact, it has been suggested in some literature that implanting children at a younger age may be a greater benefit than waiting until they are older.1 Uncontrolled seizures can lead to a cognitive decline over time. It is likely that children implanted at an earlier age have a lesser period of time 109
110
Functional Neurosurgery and Neuromodulation
FIG. 15.1 VNS therapy, as depicted in photo Model 10 6 (https://us.livanova.cyberonics.com).
of inadequately controlled seizures, and therefore do not experience as much cognitive decline. This theory could explain the trend of improved cognition in children implanted at a younger age. Patients with generalized seizures, such as in Lennox-Gastaut syndrome (LGS), are also being treated with VNS with a relative amount of success. Treatment for refractory depression has now also become an FDA-approved indication for VNS placement. The latest versions of the VNS device are capable of delivering automatic stimulation in response to detection of acceleration of heart rate that precedes seizure activity while delivering the chronic duty cycle chronic stimulation.
PROCEDURE The patient is placed under general endotracheal anesthesia. Preoperative antibiotics are given. They are positioned in the supine position on a standard table. A shoulder roll is placed beneath the scapula, and the head is rotated about 15 degrees to the right to expose the left side of the neck. Approximately halfway between the sternal notch and mandible, a transverse incision is drawn from the sternocleidomastoid to approximately the midline. Local anesthetic is infiltrated. The incision is sharply incised. The platysma is undermined and overmined with scissors and then opened transversely with monopolar electrocautery. Blunt dissection is used to dissect down to the carotid sheath. The carotid sheath is opened sharply. The vagus nerve is encountered deep and lateral to the carotid artery and deep and medial to the jugular vein at approximately the level of the thyroid cartilage. Vessel loops are placed around the vagus
nerve to help isolate and elevate it. At this point, we then perform the pocket incision. An approximately 5-cm transverse incision is made 1 cm below the clavicle. Monopolar electrocautery is used to dissect down to the pectoralis fascia. The pocket is made inferiorly in a suprafascial plane. The test generator can be used to help for sizing. Once the pocket is made, a tunneling device is then used to tunnel from the neck incision to the pocket. The leads are then passed through the tunnel. The helical electrodes are then opened by the strings at their ends and wrapped around the vagus nerve. The generator end of the leads is then connected to the generator. Excess lead length is coiled behind the generator, and the generator is placed in the pocket. The device is then interrogated. Upon successful interrogation, the incisions are then irrigated, a small amount of vancomycin powder (<1 g) is placed within them, and they are closed in the usual fashion with absorbable sutures. The patient is woken from general anesthesia and is ultimately taken to the ward where he or she recovers overnight.
OUTCOMES VNS has demonstrated a reduction in seizures in both adults and children across a number of studies. Greater than 50% reduction of seizures has been considered a positive outcome, with patients known as “responders,” in most studies.5,6 How meaningful this is to the individual patient, however, can vary, depending on their seizure severity and type. For instance, drop seizures can pose a danger to those patients secondary to trauma. Any reduction in the amount of these seizures will decrease the risk of trauma. Unless a person is completely seizure free, however, a reduction in seizures will still leave them with an impaired quality of life, unable to drive, perform certain jobs and activities, and leave the possibility for mild seizure-related cognitive impairment. Although only about 5% of patients will be completely seizure free after VNS placement, many will have a significant reduction in their number and severity of seizures, which, depending on the seizure type, may have a profound impact on their quality of life. In studying the effects of VNS, and seizure treatments in general, it is very meaningful to study not just the number of seizures a patient has but their improvement in quality of life after treatment.5 Sirven et al. published a study in 2000, which analyzed 45 patients above 50 years. Twenty of these patients were in randomized controlled trials. Twentyfive of them received the device open label after FDA approval. Sixty-seven percent of the patients had at least 50% reduction in their seizures with the device on high stimulation (35 mA for 30 s every 5 min). This study
CHAPTER 15 also showed a significant increase in the seizure reduction rate over time. Twenty-seven percent of people had greater than 50% seizure reduction at 3 months. Sixty-seven percent of people had greater than 50% reduction at 1 year.7 In that particular study, they used low stimulation as a control group. High stimulation has been shown in some studies, such as Handforth et al. in 1998, to have a significantly increased seizure frequency reduction over low stimulation.4 GarcíaNavarrete et al. performed a prospective trial of 43 patients, followed them for 18 months, and found that 62% of the patients had >50% reduction in number of seizures. There was no significant correlation with age of onset, duration of onset, stimulation intensity, previous surgery, or seizure type.8 Benifla et al. also studied 41 children, aged 3e19 years, and found that 38% had a seizure reduction of >90%. Forty-one percent had >50% seizure reduction. The same number had no response to VNS. They also found no correlation with age of onset, duration, prior surgeries, or seizure type.9 A 2015 Cochran Review analyzed the results of five randomized controlled trials of patients with different VNS frequencies and found that patients with high frequency were 1.73 times more likely to be responders than those on low frequency (which in many studies is considered a placebo setting).6 Degiorgio et al. performed a randomized prospective trial of 64 patients, placing all the patients in three different high-frequency groups, and found that there was no difference between these groups. These results have been echoed in other studies, finding no significant difference in the responder rate between different highfrequency settings.10 In addition to helping seizure frequency, studies have also shown a significant improvement with mood in adults treated with VNS. Elger et al. in 2000 published a randomized, double-blinded study, which analyzed mood in adults with medically refractory seizures treated with VNS. They found a significant improvement in mood within the first 3 months after implantation. This benefit was unrelated to any decrease or change in seizure frequency. This benefit was maintained at 6 months postimplantation, and it did not seem to be dose-dependent.11 The FDA has now approved the use of VNS as an adjunctive treatment for refractory depression in patients above 18 years who have not responded to at least four other treatment options. Although not originally indicated for treatment in the pediatric population, VNS has become very widely used in this setting. In 1999, the Pediatric VNS Study Group published a landmark study that showed an improvement in seizure frequency in children. Sixty-
Vagus Nerve Stimulation
111
six children, aged 3e18 years, with medically refractory epilepsy underwent VNS placement under a compassionate protocol. At 1 year, 46% of the children had a 42% reduction in seizure frequency.1 In a literature review, Morris et al. found that out of the 470 children with VNS placed, 55% of them saw at least a 50% reduction in seizures.3 There have not, however, been randomized controlled trials to study its impact on children. As noted in other studies, they also found that the effectiveness of VNS increased over time, 7% in years 1e5 after implantation.1,12 Healy et al. did retrospective review of 16 patients below 12 years and found that 56% had >50% reduction in seizures. They also found a significant decrease in the use of AEDs after VNS implantation.13 LGS has become another increasing off-label use for VNS in both children and adults. LGS consists of multiple seizure types in affected patients. It is refractory to multiple medications and is not amenable to any respective surgery. Often, imaging for these patients will appear normal or be associated with diffuse gliosis, but there is generally no discrete lesion.5 Morris et al. studied 113 patients with LGS and found that 55% of these patients had at least a 50% decrease in the number of their seizures.3 Cukiert et al. prospectively studied 24 patients with LGS or LGS-like syndrome and found that there was >50% reduction in 35 seizure types. Seventeen of the seizure types were stopped entirely with VNS. They found that the seizure types with the highest rates of success with VNS were atypical absence, generalized tonic-clonic, and myoclonic seizures. They found VNS less affective at treating atonic, or drop, seizures, although other studies have shown differing results.5 Benifla et al. found in a retrospective review that 4 of their 10 patients with LGS had >50% decrease in seizure frequency.
COMPLICATIONS VNS implantation is generally an uncomplicated surgery. Aside from the standard risks in surgery of infection and bleeding, there are the risks of minimal or no seizure improvement, hoarse voice, headache, cough, and dysphagia.6,14 Infection is a very significant risk in these surgeries because a surgical site infection often necessitates the removal of the entire system and treatment with long-term antibiotics. The risk of infection is typically quoted to be 3%e5%, although this varies between institutions and patient populations.1 Some have reported rates as high as 11%.15 Headaches, cough, and hoarseness or voice alteration are common and generally transient side effects caused by decreased
112
Functional Neurosurgery and Neuromodulation
adduction of the left vocal fold via the left recurrent and left superior laryngeal nerves.16 Those side effects will generally diminish between the first and third years after implantation.17 For the same reason, patients can also have worsening of obstructive sleep apnea and dysphagia.9 In general, VNS is very well tolerated by the majority of patients, and hoarseness of voice is the most common postoperative complaint.
REFERENCES 1. Hauptman J, Mathern G. Vagal nerve stimulation for pharmacoresistant epilepsy in children. Surg Neurol Int. 2012; 3(5):269. https://doi.org/10.4103/2152-7806.103017. 2. Lulic D, Ahmadian A, Baaj AA, Benbadis SR, Vale FL. Vagus nerve stimulation. Neurosurg Focus. 2009;27(3):E5. https:// doi.org/10.3171/2009.6.FOCUS09126. 3. Morris GL, Gloss D, Buchhalter J, Mack KJ, Nickels K, Harden C. Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy. Epilepsy Curr. 2013;13(6):297e303. https://doi.org/10.5698/1535-759713.6.297. 4. Handforth A, DeGiorgio CM, Schachter SC, et al. Vagus nerve stimulation therapy for partial-onset seizures: a randomized active-control trial. Neurology. 1998;51(1):48e55. https://doi.org/10.1212/WNL.51.1.48. 5. Cukiert A, Cukiert CM, Burattini JA, et al. A prospective long-term study on the outcome after vagus nerve stimulation at maximally tolerated current intensity in a cohort of children with refractory secondary generalized epilepsy. Neuromodulation. 2013;16(6):551e555. https://doi.org/ 10.1111/j.1525-1403.2012.00522.x. 6. Panebianco M, Rigby A, Weston J, Ag M. Vagus nerve stimulation for partial seizures. Cochrane Database Syst Rev. 2015;(4). https://doi.org/10.1002/14651858.CD002896. www.cochranelibrary.com. 7. Sirven J, Sperling M, Naritoku D, Schachter S. Vagus nerve stimulation therapy for epilepsy in older adults. Neurology. 2000:1179e1182. http://www.neurology.org/content/54/ 5/1179.short.
8. García-Navarrete E, Torres CV, Gallego I, Navas M, Pastor J, Sola RG. Long-term results of vagal nerve stimulation for adults with medication-resistant epilepsy who have been on unchanged antiepileptic medication. Seizure. 2013; 22(1):9e13. https://doi.org/10.1016/j.seizure.2012.09.008. 9. Benifla M, Rutka JT, Logan W, Donner EJ. Vagal nerve stimulation for refractory epilepsy in children: indications and experience at The Hospital for Sick Children. Childs Nerv Syst. 2006;22(8):1018e1026. https://doi.org/10.1007/ s00381-006-0123-6. 10. Degiorgio C, Heck C, Bunch S, et al. Vagus nerve stimulation for epilepsy: randomized comparison of three stimulation paradigms. Neurology. 2005;65(2):317e319. 11. Elger G, Hoppe C, Falkai P, Rush AJ, Elger CE. Vagus nerve stimulation is associated with mood improvements in epilepsy patients. Epilepsy Res. 2000;42(2e3):203e210. https:// doi.org/10.1016/S0920-1211(00)00181-9. 12. Dodrill CB, Morris GL. Effects of vagal nerve stimulation on cognition and quality of life in epilepsy. Epilepsy Behav. 2001;2:46e53. https://doi.org/10.1006/ebeh.2000.0148. 13. Healy S, Lang J, Te Water Naude J, Gibbon F, Leach P. Vagal nerve stimulation in children under 12 years old with medically intractable epilepsy. Childs Nerv Syst. 2013;29(11): 2095e2099. https://doi.org/10.1007/s00381-013-2143-3. 14. The Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology. 1995;45: 224e230. https://doi.org/10.1212/WNL.45.2.224. 15. Rossignol E, Lortie A, Thomas T, et al. Vagus nerve stimulation in pediatric epileptic syndromes. Seizure. 2009;18(1): 34e37. https://doi.org/10.1016/j.seizure.2008.06.010. 16. Klinkenberg S, Aalbers MW, Vles JSH, et al. Vagus nerve stimulation in children with intractable epilepsy: a randomized controlled trial. Dev Med Child Neurol. 2012;54(9):855e861. https://doi.org/10.1111/j.14698749.2012.04305.x. 17. Morris GL, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. Neurology. 1999;53(8):1731. https://doi.org/10.1212/WNL. 53.8.1731.