- Email: [email protected]
Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures
Epilepsy & Behavior 29 (2013) 416–419
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures Elinor Ben-Menachem b,⁎, Bertil Rydenhag a, Hans Silander a a b
Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
a r t i c l e
i n f o
Article history: Received 29 May 2013 Revised 9 August 2013 Accepted 12 August 2013 Available online 24 September 2013 Keywords: Vagus nerve stimulation Refractory epilepsy Treatment
a b s t r a c t Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of drug-resistant epilepsy. A new VNS system (“FitNeS”; manufactured by BioControl Medical (B.C.M.) Ltd., Yehud, Israel) was implanted in 5 patients with refractory focal epilepsy. The system is composed of a programmable pulse generator and a cuff electrode that is able to provide unidirectional stimulation, both of which are implanted in the left chest and in the neck, respectively. FitNeS is based on the CardioFit vagus nerve stimulation system, which is intended for the treatment of heart failure and which is currently in a randomized controlled phase III clinical trial. Long-term stimulation in the 5 patients resulted in a 50% seizure reduction in 2 patients, 25% in 2 patients, and no effect in one patient, with few reports concerning side effects. There were no complaints of hoarseness at levels of stimulation below 2 mA nor were there any reports of dysphagia or cough. The lack of perceived stimulation effects might finally allow for the design of a truly blinded randomized controlled study to evaluate the efficacy of VNS compared to placebo. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Vagus nerve stimulation (VNS) is a well-established option for the treatment of drug-resistant epilepsy. One VNS system is also approved in Europe and the USA for the treatment of depression [1], and studies are ongoing for the treatment of refractory heart failure with the CardioFit system [2]. Until recently, there has only been one VNS system available, which has shown considerable success in treating patients with drug-refractory epilepsy [3–5]. However, current VNS treatment has some disadvantages that are related to its design, especially the limitation on the increase of current amplitude due to side effects such as dyspnea, cough, hoarseness, and pain [6,7]. The FitNeS™ vagus nerve stimulation system is constructed with the aim of reducing the leakage of current to external tissue and obtaining a unidirectional stimulation of the vagus nerve. A cuff electrode, in combination with a stimulus paradigm where the signal is a trapezoid wave instead of a square wave signal, is designed for this purpose. The clinical goal is to diminish some of the known side effects seen during VNS stimulation by a decrease in the leakage of currents to external tissue. Safety of the cuff electrode has been demonstrated by histopathological and nerve function preclinical studies comparing nerve structure and conductance between baseline and 6-month postimplant in both activated and nonactivated animals. Those studies did not show any adverse effect of the cuff electrode or the activation regimen used on the nerve ⁎ Corresponding author. Fax: +46 31211552. E-mail address: [email protected] (E. Ben-Menachem). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.08.014
[8]. In addition, the asymmetric arrangement of the contacts in the cuff enables predominately unidirectional stimulation of nerve fibers [9]. The same cuff electrode, set to preferentially stimulate efferently, had been used in a pilot study of 32 patients aimed at demonstrating the safety and performance of the CardioFit® vagus nerve stimulation for the treatment of heart failure, which showed promising results [10]. That system is currently undergoing a multinational, phase-III, randomized controlled trial [increase of vagal tone in heart failure — INOVATE-HF; registered in clinicaltrials.gov under NCT01303718]. While the features of the lead had been demonstrated in subjects with heart failure by enabling average current amplitudes of 4.1 mA (frequency: 1–2 Hz) without major side effects [10], its application in epilepsy is still not tested or evaluated clinically, even though the device is CE-certified for the treatment of epilepsy. We now report on the first 5 patients with refractory focal onset epilepsy who have been implanted with the FitNeS system for VNS therapy and followed for up to 15 months. 2. Materials and methods 2.1. Patients The five patients (3 females and 2 males; age range: 29–53 years; median: 41.5 years; Table 1) were implanted with the FitNeS system after being treated for epilepsy for 21–47 years (median: 31.5 years). During the course of their treatment, they had tried 6–10 different antiepileptic drugs (AEDs) and other treatments, such as right temporal lobe resection in one case. The other 4 patients were judged not to be
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
417
Table 1 Patients' baseline data. Patient
DoB
Gender
Diagnosed since
Monthly seizure frequency
Previous AEDs; other treatments
Seizure focus
Current AEDs
1
1983
M
1995
4
5 drugs
Intractable focal (complex partial) seizures with generalization (GTCS) due to resection of craniopharyngioma and bilateral frontal foci Intractable focal (complex partial) epilepsy with generalization (GTCS) due to bilateral temporal lobe foci Intractable focal (complex partial epilepsy) with generalization due to right temporal–occipital focus Intractable focal (complex partial epilepsy) with generalization due to left temporal lobe focus Focal (complex partial seizures) due to left temporal lobe focus
CBZ, PHT
2
1960
F
1966
26
3
1977
F
1992
15
4
1959
F
1970
7
9 drugs
5
1971
M
1977
6
10 drugs
9 drugs; right temporal lobe resection 8 drugs
CBZ, VPA, LTG OXC LCM, CBZ CBZ/CLB
Carbamazepine (CBZ). Phenytoin (PHT). Valproic acid (VPA). Lamotrigine (LTG). Oxcarbazepine (OXC). Lacosamide (LCM). Clobazam (CLB).
candidates for resective surgery after undergoing epilepsy surgery evaluation. Based on that experience and their apparent drug-resistant condition, implantation of the FitNeS vagus nerve stimulation system (BioControl Medical, Yehud, Israel; see Fig. 1) was judged to be suitable. All patients gave their informed consent to have FitNeS implanted, and data were recorded and reported. They were given the opportunity to choose between the 2 available VNS products. All patients kept a seizure diary for at least one year before and throughout the observation period. The baseline seizure frequency was the 3-month retrospective average of the monthly seizure frequency. Prospective seizure calendars were maintained by the patient and relatives. The seizure frequency was the monthly seizure rate. Seizure severity was estimated at each visit using a visual analog scale from 1 to 10, with 10 representing their subjective state of severity at the start of the study. In other words, patients were normalized to a baseline severity of 10 on the visual analog scale. If there was an increase in seizure severity, then the severity number could be more than 10. All patients were followed by EBM before being implanted with the VNS and throughout the whole study period. The decision for implantation was made by EBM together with the individual patient after verbal and written information concerning VNS treatment. Before implantation, all patients had a new MRI scan since new MRI scans would not be possible afterwards as FitNeS is not yet approved for use with MRI.
Fig. 1. The FitNeS™ vagus nerve stimulation system (BioControl Medical, Yehud, Israel) with the cuff magnified in Fig. 2.
2.2. The FitNeS™ vagus nerve stimulation system The FitNeS™ system is an implantable device consisting of an implantable pulse generator (IPG) weighing 35 g with the dimensions of 75 × 47 × 11 mm, a vagus nerve stimulation lead with a cuff electrode, and a noninvasive clinician programmer. The battery life depends on the parameters used and will last for about 5 years. The system is implanted by a surgeon who places the electrode around the left cervical vagus (see Fig. 1). 2.3. The FitNeS™ system cuff stimulation lead The FitNeS™ cuff stimulation lead (CSL; see Figs. 1 and 2) is a cufftype electrode designed to stimulate the vagal axons while limiting the current escaping into the surrounding tissue. This has the effect of minimizing the inappropriate activation of efferent axon and cervical structures, thus reducing the side effects that occur with other devices and methods [9]. The CSL has several additional features: – Designed geometry enabling afferently directed stimulation at lower currents; – Nerve–electrode interface that enables direct contact only between the nerve and a soft silicone layer;
Fig. 2. Picture of the CSL with emphasis on the cuff. The cuff is made of silicone, which is the only material contacting the nerve. The anode and cathodes are recessed. The two flanking contacts are used to trap current from the anode or cathodes. An empty recess is used to decrease pressure on the nerve. The silicone-made “belt and buckle” closure mechanism is shown in the front.
418
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
– Closed structure, resulting in a reduced leakage of current causing potentially fewer undesirable leakage-based side effects; – A “belt and buckle” closure mechanism that is designed for positioning and removal on the nerve (see Fig. 2 below).
The left vagus was exposed via a transverse incision at a at midcervical level. Cuff electrode size was estimated using the supplied Nerve Diameter Gauge (NDG; see Fig. 3). After verifying appropriate contact with the nerve, the lead was tunneled and connected to the stimulator. The stimulator was then placed over the left pectoralis major muscle, wounds were closed, and the procedure was ended. Implant duration was 110 min for the first two procedures and 90 min for the last three. 2.5. Statistics Since this is a small case series and only 5 patients were included, the results did not lend themselves to statistical analysis. The power would have been so small that the statistics would not be meaningful. This is a descriptive study only. 3. Results
10
Subjective Scale
2.4. Implant procedure and activation
Seizure Severity 12
Patient 1
8
Patient 2 6
Patient 3 Patient 4
4
Patient 5 2 0 Baseline
3-m
6-m
12-m
15-m
Fig. 4. Subjective seizure severity of patients implanted with the FitNeS system and followed for up to 15 months. Baseline severity is normalized to 10.
has been markedly reduced, and seizure frequency has been variable, with two patients experiencing 50% reduction (Patients 3 and 5) and two others with 25% reduction (see Figs. 4 and 5, respectively). One patient has not responded to VNS by reduction of either seizure severity or frequency. At one point, seizure severity and seizure frequency actually increased (Patient 4).
3.1. Adverse events 4. Discussion Following a month of weekly clinic visits, the current amplitude was increased by successive steps of 0.25 mA based on patient sensations and clinical outcomes, and 12–15 months after implanting the system, all 5 patients were on amplitudes of 1.5–2.0 mA with a frequency of 20 Hz and a duty cycle of 30-s on/1.8- to 3-min off (14.3–20.3%) with a pulse width of 0.3 ms and a quasitrapezoidal pulse shape. Because at this site, 2 mA is considered a high or maximum chronic current used in our center, evaluation of higher currents was not undertaken during this 15-month follow-up. This evaluation at levels above 2.0 mA is now ongoing. The patients did not report side effects, such as cough or hoarseness, until a stimulation current of 2.0 mA was reached. At this level, all patients opted to reduce the level back to 1.75 mA except for one. All have subsequently increased stimulation to 2.0 mA without experiencing hoarseness or discomfort. Since there is some initial hoarseness at levels of 2 mA or above, a test of nerve fiber activation was possible.
The use of vagus nerve stimulation in the treatment of drug-refractory epilepsy is an important part of the treatment arsenal; nevertheless, there are several limitations to its use, including the implantation procedure and possible removal as well as the limited ability to increase the current in order to achieve better efficacy without undue side effects. Not all of these aspects were evaluated in our small population. However, the preliminary results seem encouraging, and only a double-blind placebocontrolled study will be able to truly address these problems. The implantation according to BR and HS was relatively easy to do. Although the operation time was the same as for other similar devices, they subjectively felt that the operation time could be reduced with practice. Since no removal of the device was attempted, it is an aspect that was not investigated in this study. However, the arguments that support this hypothesis, which were not investigated in the study, are as follows:
3.2. Efficacy At this time, 4 patients have had VNS for over 15 months and one patient for 12 months. In 4 patients, the subjective seizure severity
1. The cuff electrode fits onto the nerve and does not press on it; 2. The FitNeS cuff electrode is relatively rigid; 3. The contact area between the nerve and the cuff is minimal;
Fig. 3. The FitNeS system Nerve Diameter Gauge (NDG) for assistance in cuff size estimation.
Fig. 5. Seizure frequency (no. of seizures per month) in patients implanted with the FitNeS system and followed for up to 15 months. Baseline monthly seizure frequency was based on a 3-month retrospective estimation based on seizure calendars kept by each patient.
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
4. Together with the silicone isolator and recessed conductors (which do not touch the nerve), the cuff–nerve interface does not promote adhesions, which should theoretically reduce the burden of removing the electrode from the nerve. Although the current was not adjusted above 2 mA, we are now attempting to evaluate stimulation at higher currents, but no information is available yet. Because the conventional device causes unwanted discomfort at 2 mA, most of the patients in our clinical population, some of whom we have followed for 23 years, have not been able to achieve that level of stimulation. All 5 patients had severe refractory focal onset epilepsy. The number of AEDs tested in the past ranged from 6 to 10. The most interesting result in this small cohort has been the significant decrease in seizure severity reflected, for example, by Patient 1's reduction in recovery time from 6 h down to 30 min. Patients 3 and 5 had an average seizure reduction N50% with the elimination of GTCSs and a reduction of seizure severity of 80%. One patient (No. 4) did not respond at all to VNS, which is to be expected in such a patient population with refractory epilepsy. In other words, our results are similar to those seen with the conventional VNS, while it appears that the patients had fewer complaints about hoarseness, pain, and voice changes. It is unknown if higher stimulations would improve efficacy. This has not been our clinical experience in our patient population numbering over 400 using the conventional device. While the reported sample size is small, there are some pertinent observations. For example: the smaller cuff size seems easier to implant according to BR and HS although the operation time was the same, and the patients did not report any side effects, such as increased cough and hoarseness, which have previously been reported by at least 38 (60%) users of other VNS systems during the first 3 months of use and, thereafter, 8 (28%) with long term use [5]. In addition, we were able to increase the current to a high therapeutic level without any side effects, and clinical benefit was observed in current amplitudes as low as 1 mA. That the electrode has been implanted on the right side (when used for the treatment of heart failure under a study protocol) also demonstrates that this device can be safely implanted on both the right and left sides [10]. These features of the FitNeS cuff electrode are noteworthy because they might finally allow for the design of a truly blinded randomized controlled study, the lack of which has been a point of criticism for the claims of efficacy from the earlier VNS trials [11]. Only with this type of study can VNS be truly assessed. Disclosures We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is con-
419
sistent with those guidelines. Dr. Ben-Menachem serves as chief editor for Acta Neurologica Scandinavica; is involved in sponsored research for which she served as the primary investigator for Bial, UCB, and Eisai; received research support from Bial, UCB, and Eisai; and received institutional support from the Västra Götaland for research in neuromodulation. Dr. Ben-Menachem has been a consultant for Janssen-Cilag, UCB, Eisai, Lundbeck, and BioCont. Dr. Rydenhag reports no disclosures. Dr. Hans Silander reports no disclosures.
Acknowledgments We would like to thank BioControl Medical VNS systems, especially Rami Biran, Itzik Sinai, and Shai Ayal for their advice, for providing the devices, for teaching us how to use the FitNeS VNS stimulator, and especially for the information concerning the structure and development of the leads.
References [1] Martin JLR, Martin-Sachez E. Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry 2012;27:147–55. [2] Hauptman PJ, Schwartz PJ, Gold MR, Borggrefe M, Van Veldhuisen DJ, Starling RC, et al. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J 2012;163:954–62. [3] Ben-Menachem E, Mañon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia 1994;35:616–26. [4] Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation for partial-onset seizures: a randomized activecontrol trial. Neurology 1998;51:48–55. [5] Morris III GL, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01–E05. Neurology 1999;53:1731–5. [6] Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol 2002;1(8):477–82. [7] Ching S Khan, White P, et al. Long-term effectiveness and tolerability of vagal nerve stimulation in adults with intractable epilepsy: a retrospective analysis of 100 patients. Br J Neurosurg 2012:1–7 [Early Online]. [8] Cohen ML, Georgievskaya Z. Histopathology of the stimulated vagus nerve: primum non nocere. Heart Fail Rev 2011;16(2):137–45. [9] Ahilea-Anholt T, Ayal S, Goldberg JA. Recruitment and blocking properties of the CardioFit stimulation lead. J Neural Eng 2011;8:034004. [10] De Ferrari GM, Crijns HJGM, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847–55. [11] Hoppe C, Wagner L, Hoffmann JM, von Lehe M, Elger CE. Comprehensive longterm outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: a retrospective matched pairs case–control study. Seizure 2013;2:109–15.
Contents lists available at ScienceDirect
Epilepsy & Behavior journal homepage: www.elsevier.com/locate/yebeh
Brief Communication
Preliminary experience with a new system for vagus nerve stimulation for the treatment of refractory focal onset seizures Elinor Ben-Menachem b,⁎, Bertil Rydenhag a, Hans Silander a a b
Department of Neurosurgery, Sahlgrenska University Hospital, Gothenburg, Sweden Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
a r t i c l e
i n f o
Article history: Received 29 May 2013 Revised 9 August 2013 Accepted 12 August 2013 Available online 24 September 2013 Keywords: Vagus nerve stimulation Refractory epilepsy Treatment
a b s t r a c t Vagus nerve stimulation (VNS) is an accepted therapy for the treatment of drug-resistant epilepsy. A new VNS system (“FitNeS”; manufactured by BioControl Medical (B.C.M.) Ltd., Yehud, Israel) was implanted in 5 patients with refractory focal epilepsy. The system is composed of a programmable pulse generator and a cuff electrode that is able to provide unidirectional stimulation, both of which are implanted in the left chest and in the neck, respectively. FitNeS is based on the CardioFit vagus nerve stimulation system, which is intended for the treatment of heart failure and which is currently in a randomized controlled phase III clinical trial. Long-term stimulation in the 5 patients resulted in a 50% seizure reduction in 2 patients, 25% in 2 patients, and no effect in one patient, with few reports concerning side effects. There were no complaints of hoarseness at levels of stimulation below 2 mA nor were there any reports of dysphagia or cough. The lack of perceived stimulation effects might finally allow for the design of a truly blinded randomized controlled study to evaluate the efficacy of VNS compared to placebo. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Vagus nerve stimulation (VNS) is a well-established option for the treatment of drug-resistant epilepsy. One VNS system is also approved in Europe and the USA for the treatment of depression [1], and studies are ongoing for the treatment of refractory heart failure with the CardioFit system [2]. Until recently, there has only been one VNS system available, which has shown considerable success in treating patients with drug-refractory epilepsy [3–5]. However, current VNS treatment has some disadvantages that are related to its design, especially the limitation on the increase of current amplitude due to side effects such as dyspnea, cough, hoarseness, and pain [6,7]. The FitNeS™ vagus nerve stimulation system is constructed with the aim of reducing the leakage of current to external tissue and obtaining a unidirectional stimulation of the vagus nerve. A cuff electrode, in combination with a stimulus paradigm where the signal is a trapezoid wave instead of a square wave signal, is designed for this purpose. The clinical goal is to diminish some of the known side effects seen during VNS stimulation by a decrease in the leakage of currents to external tissue. Safety of the cuff electrode has been demonstrated by histopathological and nerve function preclinical studies comparing nerve structure and conductance between baseline and 6-month postimplant in both activated and nonactivated animals. Those studies did not show any adverse effect of the cuff electrode or the activation regimen used on the nerve ⁎ Corresponding author. Fax: +46 31211552. E-mail address: [email protected] (E. Ben-Menachem). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.08.014
[8]. In addition, the asymmetric arrangement of the contacts in the cuff enables predominately unidirectional stimulation of nerve fibers [9]. The same cuff electrode, set to preferentially stimulate efferently, had been used in a pilot study of 32 patients aimed at demonstrating the safety and performance of the CardioFit® vagus nerve stimulation for the treatment of heart failure, which showed promising results [10]. That system is currently undergoing a multinational, phase-III, randomized controlled trial [increase of vagal tone in heart failure — INOVATE-HF; registered in clinicaltrials.gov under NCT01303718]. While the features of the lead had been demonstrated in subjects with heart failure by enabling average current amplitudes of 4.1 mA (frequency: 1–2 Hz) without major side effects [10], its application in epilepsy is still not tested or evaluated clinically, even though the device is CE-certified for the treatment of epilepsy. We now report on the first 5 patients with refractory focal onset epilepsy who have been implanted with the FitNeS system for VNS therapy and followed for up to 15 months. 2. Materials and methods 2.1. Patients The five patients (3 females and 2 males; age range: 29–53 years; median: 41.5 years; Table 1) were implanted with the FitNeS system after being treated for epilepsy for 21–47 years (median: 31.5 years). During the course of their treatment, they had tried 6–10 different antiepileptic drugs (AEDs) and other treatments, such as right temporal lobe resection in one case. The other 4 patients were judged not to be
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
417
Table 1 Patients' baseline data. Patient
DoB
Gender
Diagnosed since
Monthly seizure frequency
Previous AEDs; other treatments
Seizure focus
Current AEDs
1
1983
M
1995
4
5 drugs
Intractable focal (complex partial) seizures with generalization (GTCS) due to resection of craniopharyngioma and bilateral frontal foci Intractable focal (complex partial) epilepsy with generalization (GTCS) due to bilateral temporal lobe foci Intractable focal (complex partial epilepsy) with generalization due to right temporal–occipital focus Intractable focal (complex partial epilepsy) with generalization due to left temporal lobe focus Focal (complex partial seizures) due to left temporal lobe focus
CBZ, PHT
2
1960
F
1966
26
3
1977
F
1992
15
4
1959
F
1970
7
9 drugs
5
1971
M
1977
6
10 drugs
9 drugs; right temporal lobe resection 8 drugs
CBZ, VPA, LTG OXC LCM, CBZ CBZ/CLB
Carbamazepine (CBZ). Phenytoin (PHT). Valproic acid (VPA). Lamotrigine (LTG). Oxcarbazepine (OXC). Lacosamide (LCM). Clobazam (CLB).
candidates for resective surgery after undergoing epilepsy surgery evaluation. Based on that experience and their apparent drug-resistant condition, implantation of the FitNeS vagus nerve stimulation system (BioControl Medical, Yehud, Israel; see Fig. 1) was judged to be suitable. All patients gave their informed consent to have FitNeS implanted, and data were recorded and reported. They were given the opportunity to choose between the 2 available VNS products. All patients kept a seizure diary for at least one year before and throughout the observation period. The baseline seizure frequency was the 3-month retrospective average of the monthly seizure frequency. Prospective seizure calendars were maintained by the patient and relatives. The seizure frequency was the monthly seizure rate. Seizure severity was estimated at each visit using a visual analog scale from 1 to 10, with 10 representing their subjective state of severity at the start of the study. In other words, patients were normalized to a baseline severity of 10 on the visual analog scale. If there was an increase in seizure severity, then the severity number could be more than 10. All patients were followed by EBM before being implanted with the VNS and throughout the whole study period. The decision for implantation was made by EBM together with the individual patient after verbal and written information concerning VNS treatment. Before implantation, all patients had a new MRI scan since new MRI scans would not be possible afterwards as FitNeS is not yet approved for use with MRI.
Fig. 1. The FitNeS™ vagus nerve stimulation system (BioControl Medical, Yehud, Israel) with the cuff magnified in Fig. 2.
2.2. The FitNeS™ vagus nerve stimulation system The FitNeS™ system is an implantable device consisting of an implantable pulse generator (IPG) weighing 35 g with the dimensions of 75 × 47 × 11 mm, a vagus nerve stimulation lead with a cuff electrode, and a noninvasive clinician programmer. The battery life depends on the parameters used and will last for about 5 years. The system is implanted by a surgeon who places the electrode around the left cervical vagus (see Fig. 1). 2.3. The FitNeS™ system cuff stimulation lead The FitNeS™ cuff stimulation lead (CSL; see Figs. 1 and 2) is a cufftype electrode designed to stimulate the vagal axons while limiting the current escaping into the surrounding tissue. This has the effect of minimizing the inappropriate activation of efferent axon and cervical structures, thus reducing the side effects that occur with other devices and methods [9]. The CSL has several additional features: – Designed geometry enabling afferently directed stimulation at lower currents; – Nerve–electrode interface that enables direct contact only between the nerve and a soft silicone layer;
Fig. 2. Picture of the CSL with emphasis on the cuff. The cuff is made of silicone, which is the only material contacting the nerve. The anode and cathodes are recessed. The two flanking contacts are used to trap current from the anode or cathodes. An empty recess is used to decrease pressure on the nerve. The silicone-made “belt and buckle” closure mechanism is shown in the front.
418
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
– Closed structure, resulting in a reduced leakage of current causing potentially fewer undesirable leakage-based side effects; – A “belt and buckle” closure mechanism that is designed for positioning and removal on the nerve (see Fig. 2 below).
The left vagus was exposed via a transverse incision at a at midcervical level. Cuff electrode size was estimated using the supplied Nerve Diameter Gauge (NDG; see Fig. 3). After verifying appropriate contact with the nerve, the lead was tunneled and connected to the stimulator. The stimulator was then placed over the left pectoralis major muscle, wounds were closed, and the procedure was ended. Implant duration was 110 min for the first two procedures and 90 min for the last three. 2.5. Statistics Since this is a small case series and only 5 patients were included, the results did not lend themselves to statistical analysis. The power would have been so small that the statistics would not be meaningful. This is a descriptive study only. 3. Results
10
Subjective Scale
2.4. Implant procedure and activation
Seizure Severity 12
Patient 1
8
Patient 2 6
Patient 3 Patient 4
4
Patient 5 2 0 Baseline
3-m
6-m
12-m
15-m
Fig. 4. Subjective seizure severity of patients implanted with the FitNeS system and followed for up to 15 months. Baseline severity is normalized to 10.
has been markedly reduced, and seizure frequency has been variable, with two patients experiencing 50% reduction (Patients 3 and 5) and two others with 25% reduction (see Figs. 4 and 5, respectively). One patient has not responded to VNS by reduction of either seizure severity or frequency. At one point, seizure severity and seizure frequency actually increased (Patient 4).
3.1. Adverse events 4. Discussion Following a month of weekly clinic visits, the current amplitude was increased by successive steps of 0.25 mA based on patient sensations and clinical outcomes, and 12–15 months after implanting the system, all 5 patients were on amplitudes of 1.5–2.0 mA with a frequency of 20 Hz and a duty cycle of 30-s on/1.8- to 3-min off (14.3–20.3%) with a pulse width of 0.3 ms and a quasitrapezoidal pulse shape. Because at this site, 2 mA is considered a high or maximum chronic current used in our center, evaluation of higher currents was not undertaken during this 15-month follow-up. This evaluation at levels above 2.0 mA is now ongoing. The patients did not report side effects, such as cough or hoarseness, until a stimulation current of 2.0 mA was reached. At this level, all patients opted to reduce the level back to 1.75 mA except for one. All have subsequently increased stimulation to 2.0 mA without experiencing hoarseness or discomfort. Since there is some initial hoarseness at levels of 2 mA or above, a test of nerve fiber activation was possible.
The use of vagus nerve stimulation in the treatment of drug-refractory epilepsy is an important part of the treatment arsenal; nevertheless, there are several limitations to its use, including the implantation procedure and possible removal as well as the limited ability to increase the current in order to achieve better efficacy without undue side effects. Not all of these aspects were evaluated in our small population. However, the preliminary results seem encouraging, and only a double-blind placebocontrolled study will be able to truly address these problems. The implantation according to BR and HS was relatively easy to do. Although the operation time was the same as for other similar devices, they subjectively felt that the operation time could be reduced with practice. Since no removal of the device was attempted, it is an aspect that was not investigated in this study. However, the arguments that support this hypothesis, which were not investigated in the study, are as follows:
3.2. Efficacy At this time, 4 patients have had VNS for over 15 months and one patient for 12 months. In 4 patients, the subjective seizure severity
1. The cuff electrode fits onto the nerve and does not press on it; 2. The FitNeS cuff electrode is relatively rigid; 3. The contact area between the nerve and the cuff is minimal;
Fig. 3. The FitNeS system Nerve Diameter Gauge (NDG) for assistance in cuff size estimation.
Fig. 5. Seizure frequency (no. of seizures per month) in patients implanted with the FitNeS system and followed for up to 15 months. Baseline monthly seizure frequency was based on a 3-month retrospective estimation based on seizure calendars kept by each patient.
E. Ben-Menachem et al. / Epilepsy & Behavior 29 (2013) 416–419
4. Together with the silicone isolator and recessed conductors (which do not touch the nerve), the cuff–nerve interface does not promote adhesions, which should theoretically reduce the burden of removing the electrode from the nerve. Although the current was not adjusted above 2 mA, we are now attempting to evaluate stimulation at higher currents, but no information is available yet. Because the conventional device causes unwanted discomfort at 2 mA, most of the patients in our clinical population, some of whom we have followed for 23 years, have not been able to achieve that level of stimulation. All 5 patients had severe refractory focal onset epilepsy. The number of AEDs tested in the past ranged from 6 to 10. The most interesting result in this small cohort has been the significant decrease in seizure severity reflected, for example, by Patient 1's reduction in recovery time from 6 h down to 30 min. Patients 3 and 5 had an average seizure reduction N50% with the elimination of GTCSs and a reduction of seizure severity of 80%. One patient (No. 4) did not respond at all to VNS, which is to be expected in such a patient population with refractory epilepsy. In other words, our results are similar to those seen with the conventional VNS, while it appears that the patients had fewer complaints about hoarseness, pain, and voice changes. It is unknown if higher stimulations would improve efficacy. This has not been our clinical experience in our patient population numbering over 400 using the conventional device. While the reported sample size is small, there are some pertinent observations. For example: the smaller cuff size seems easier to implant according to BR and HS although the operation time was the same, and the patients did not report any side effects, such as increased cough and hoarseness, which have previously been reported by at least 38 (60%) users of other VNS systems during the first 3 months of use and, thereafter, 8 (28%) with long term use [5]. In addition, we were able to increase the current to a high therapeutic level without any side effects, and clinical benefit was observed in current amplitudes as low as 1 mA. That the electrode has been implanted on the right side (when used for the treatment of heart failure under a study protocol) also demonstrates that this device can be safely implanted on both the right and left sides [10]. These features of the FitNeS cuff electrode are noteworthy because they might finally allow for the design of a truly blinded randomized controlled study, the lack of which has been a point of criticism for the claims of efficacy from the earlier VNS trials [11]. Only with this type of study can VNS be truly assessed. Disclosures We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is con-
419
sistent with those guidelines. Dr. Ben-Menachem serves as chief editor for Acta Neurologica Scandinavica; is involved in sponsored research for which she served as the primary investigator for Bial, UCB, and Eisai; received research support from Bial, UCB, and Eisai; and received institutional support from the Västra Götaland for research in neuromodulation. Dr. Ben-Menachem has been a consultant for Janssen-Cilag, UCB, Eisai, Lundbeck, and BioCont. Dr. Rydenhag reports no disclosures. Dr. Hans Silander reports no disclosures.
Acknowledgments We would like to thank BioControl Medical VNS systems, especially Rami Biran, Itzik Sinai, and Shai Ayal for their advice, for providing the devices, for teaching us how to use the FitNeS VNS stimulator, and especially for the information concerning the structure and development of the leads.
References [1] Martin JLR, Martin-Sachez E. Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs. Eur Psychiatry 2012;27:147–55. [2] Hauptman PJ, Schwartz PJ, Gold MR, Borggrefe M, Van Veldhuisen DJ, Starling RC, et al. Rationale and study design of the increase of vagal tone in heart failure study: INOVATE-HF. Am Heart J 2012;163:954–62. [3] Ben-Menachem E, Mañon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H, Mirza W, et al. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled study of effect on seizures. Epilepsia 1994;35:616–26. [4] Handforth A, DeGiorgio CM, Schachter SC, Uthman BM, Naritoku DK, Tecoma ES, et al. Vagus nerve stimulation for partial-onset seizures: a randomized activecontrol trial. Neurology 1998;51:48–55. [5] Morris III GL, Mueller WM. Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. The Vagus Nerve Stimulation Study Group E01–E05. Neurology 1999;53:1731–5. [6] Ben-Menachem E. Vagus-nerve stimulation for the treatment of epilepsy. Lancet Neurol 2002;1(8):477–82. [7] Ching S Khan, White P, et al. Long-term effectiveness and tolerability of vagal nerve stimulation in adults with intractable epilepsy: a retrospective analysis of 100 patients. Br J Neurosurg 2012:1–7 [Early Online]. [8] Cohen ML, Georgievskaya Z. Histopathology of the stimulated vagus nerve: primum non nocere. Heart Fail Rev 2011;16(2):137–45. [9] Ahilea-Anholt T, Ayal S, Goldberg JA. Recruitment and blocking properties of the CardioFit stimulation lead. J Neural Eng 2011;8:034004. [10] De Ferrari GM, Crijns HJGM, Borggrefe M, Milasinovic G, Smid J, Zabel M, et al. Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure. Eur Heart J 2011;32:847–55. [11] Hoppe C, Wagner L, Hoffmann JM, von Lehe M, Elger CE. Comprehensive longterm outcome of best drug treatment with or without add-on vagus nerve stimulation for epilepsy: a retrospective matched pairs case–control study. Seizure 2013;2:109–15.