Acta Neurol Scand 2015: 131: 1–8 DOI: 10.1111/ane.12288
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Review Article
Vagus nerve stimulation magnet activation for seizures: a critical review Fisher RS, Eggleston KS, Wright CW. Vagus nerve stimulation magnet activation for seizures: a critical review. Acta Neurol Scand 2015: 131: 1–8. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0–89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15–67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.
Introduction
Pivotal clinical trials (1, 2) documenting the efficacy of VNS Therapyâ in patients with epilepsy utilized stimulation cycling at 30 s ON and 5 min OFF. Intermittent stimulation has several advantages over continuous stimulation, including reduced side effects that affect the voice or throat, preserved battery life, and possibly decreased potential for injury or irritation to the vagus nerve (3). In addition to cycling (normal mode) stimulation, the VNS Therapy system also is equipped with a magnet that patients or
R. S. Fisher1, K. S. Eggleston2, C. W. Wright2 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; 2Cyberonics, Inc., Houston, TX, USA
Key words: Vagus nerve stimulation; VNS; magnet; epilepsy; seizures; neurostimulation R. S. Fisher, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room A343, Stanford, CA 94305 5235, USA Tel.: +650-498-3056 Fax: +650 498 3056 e-mail: [email protected] Accepted for publication July 14, 2014
caregivers can pass over the implanted generator to activate stimulation on-demand (magnet mode) during a seizure (4). Patients using on-demand stimulation via the magnet mode have reported the following effects: termination of a seizure, reduction in seizure duration, reduction in seizure severity, reduction in post-ictal recovery, or no effect (5). A next-generation stimulator for VNS Therapy has a programmable ability to automatically activate stimulation upon detecting a predetermined pattern and magnitude of heart rate increase (responsive stimulation). A recent review has 1
Fisher et al. summarized the literature pertaining to the prevalence of ictal tachycardia (6). This automatic mode (referred to as AutoStim) activates stimulation much the same way that the current magnet mode feature triggers stimulation when the patient or caregiver passes a magnet over the device, except that the stimulation is initiated automatically rather than manually. The stimulator with the AutoStim feature received CE Mark approval in the EU and clinical trials are ongoing in the United States (clinicaltrials.gov identifiers: NCT01325623, NCT01846741). This study reviews what is known about the use, effectiveness, and safety of magnet mode stimulation of VNS Therapy. Methods
To determine the effect of VNS Therapy magnet mode stimulation in patients with epilepsy, a review of the literature was performed. Only full original research (no meeting abstracts or review articles) related to the safety or effectiveness of magnet mode were included. All articles were in English. The reference lists of key relevant articles were also searched and additional articles were identified. Known references that were not found in the literature search were also included for completeness. The literature search for this topic was conducted in January 2014 (Fig. 1) using PubMed, and it resulted in 16 primary citations. Search terms used in the database were ‘VNS’ OR ‘Vagal Nerve Stimulation’ OR ‘Vagus Nerve Stimulation’ AND ‘Magnet’. Three publications were review articles on VNS Therapy (one specific to magnet use), and three were not related to the effectiveness of the VNS Therapy magnet. One additional publication (7) was excluded as it reported on the same database as one of the primary articles selected (8). For the primary search, nine studies met the inclusion criteria and were reviewed (5, 8–15). Eleven additional clinical articles were included as secondary references: two (16, 17) were found after reviewing the reference lists of those articles obtained during the primary search, and nine articles were known to the authors (6, 18– 25). As the evaluation of magnet mode was not the primary outcome of the articles, these were not found during the initial search. Five preclinical articles (26–30) that addressed the acute effects of VNS Therapy were identified during review of the primary clinical articles and are also included as secondary references. Articles were included if they reported outcomes for magnet mode activation. In total, 20 clinical and 2
January 2014 PubMed Literature Search Vagus Nerve S mula on and Magnet
16 Cita ons
Abstract Review
Review Ar cles -3 Ar cles
Not Related to the Effec veness of VNS Therapy Magnet Mode -3 Ar cles
Reported Results from the Same Database -1 Ar cle
Primary Ar cles (n=9) +11 Addi onal Ar cles from Review of Primary Ar cles +5 Known PreClinical Ar cles
20 Clinical and 5 Pre-Clinical Ar cles Reviewed and Summarized
Figure 1. Flow Chart of literature review of VNS therapy magnet mode.
5 preclinical articles met the inclusion criteria and were reviewed. The literature was assessed for several key outcomes of magnet mode stimulation: termination of a seizure, reduction in seizure duration, reduction in seizure severity, reduction in post-ictal recovery, or no effect. Articles were also reviewed for potential safety concerns of magnet mode including any adverse events reported by patients associated with on-demand stimulation. Results Preclinical models
Five papers reviewed and summarized in Table 1 report on preclinical research with chemically
VNS magnet activation for seizures induced seizures in the laboratory (26–30). Although the VNS Therapy magnet was not used to initiate stimulation, these studies are related to the on-demand delivery of stimulation and are thus included in this review. All articles showed that acute delivery of VNS immediately before or after the onset of experimentally induced seizures could attenuate or abort seizures. However, in one article (27), when VNS was administered more than 3 s after seizure onset, the seizure was not altered. Clinical studies
Table 2 summarizes the results of peer-reviewed literature pertaining to magnet activation in patients with epilepsy receiving VNS Therapy. A total of 20 studies comprise magnet stimulation outcome information for 829 patients, including male and female adults and children as young as 2 years of age. Five studies reported exclusively on pediatric populations (10–12, 16, 20). Most studies included patients with partial or generalized seizures, although two reported results for patients with exclusively partial onset seizures (8, 22). Some degree of intellectual disability was noted for patients in several studies (6, 9–12, 15, 16, 25). None of the studies reviewed were designed to provide level I evidence of efficacy of manual use of the magnet. The study designs utilized by the articles reviewed were primarily prospective or retrospective case series of data based on patient and caregiver report. Effectiveness – No controlled study has prospectively evaluated the isolated effect of magnet
mode stimulation at the time of the onset of a seizure. The E-03 study (1) was the first large, randomized trial of Cyberonics’ VNS Therapy. This trial used an active control group with low intensity, infrequent stimulation. Table 3 compares outcome of magnet mode stimulation in the active treatment and the active control groups (5). The percent of seizures aborted by magnetactivated stimulation was 21.3% (n = 50) in the active treatment group and 11.9% (n = 42) in the control group. This difference did not reach statistical significance. A significant difference, however, was observed by combining seizures aborted or decreased compared with the group made by combining those whose seizures were unchanged or worse (Fisher’s Exact test, P = 0.048). Figure 2 illustrates a case of termination of a seizure by magnet mode stimulation of the vagus nerve (18). Another study that emphasized EEG changes found that stimulation at the onset of seizures consistently terminated behavioral and EEG seizure activity in one patient over three recorded seizures (17). Among the studies in Table 2, benefit was reported in a weighted average of 45% of patients (range 0–89%), with seizure cessation claimed in a weighted average of 28% of patients (range 15–67%). In addition to seizure termination, some patients reported that magnet-induced stimulation decreased the intensity or duration of seizures, or of the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (9). Magnet mode stimulation may interrupt individual seizures even in some individuals who do not benefit overall from VNS Therapy. In the study by McHugh and colleagues (14), three
Table 1 PreClinical studies of acute vagus nerve stimulation First author/Year
Demographics
Diagnosis
Effect of magnet
Woodbury 1990 (28) Woodbury 1991 (29)
Sprague–Dawley rats, sample size was not reported Sprague–Dawley rats, sample size was not reported
Chemically induced seizures
Zabara 1992 (30) McLachlan 1993 (27)
20 dogs of mixed breeds (10 M/10 F)
Chemically induced seizures
15 M Wistar rats
Chemically induced seizures
Dedeurwaerdere 2006 (26)
17 rapidly kindled rats. Animals were implanted with electrodes in both amygdala and around the left vagus nerve
After discharges and Stage 5 seizures
Initiation of VNS shortens but does not eliminate chemically induced seizures VNS abolishes the extensor component of the maximal electroshock seizure and shortened or prevented tonic chemically induced seizures when applied 10–30 s before electroshock and continuing for 10–30 s after Seizures were either interrupted or terminated by vagal stimulation; VNS terminated seizures within 0.5–5 s Acute VNS started within 3 s of seizure onset reduced mean seizure duration from 30.2 15.7 s without stimulation to 5.0 1.8 s. Stimulation >3 s after onset failed to alter the seizures VNS showed anticonvulsant effects (P < 0.01) in rats when applied immediately after a kindling stimulus; 2 of 6 rats showed complete suppression of stage 5 seizures
Chemically induced seizures
3
Fisher et al. Table 2 Effectiveness of VNS Therapy Magnet Mode Activation. In all studies, outcomes were indicated by patient or caregiver reports First author/Year
Study design
Demographics
Diagnosis
Double blind RCT; magnet efficacy was a secondary outcome
E03 trial, n = 114; Magnet use in E03, n = 92; E04 trial, n = 124, Magnet use in E04, n = 86
Murphy 2003 (9)
Retrospective chart review of case series data
Refractory epilepsy
Bremer 2006 (11)
Retrospective chart review of case series data
Kang 2006 (20)
Prospective case series of patients
Ardesch 2007 (22)
Prospective case series of consecutive patients
100 pts; mean age at implantation 10.4 years, age range 2–40 years. Magnet information available for 70 pts; 79% with developmental disabilities 46 pts (21 M/25 F); age range 4–16 years; 57% had developmental delay and all had learning disabilities 16 pts (8 M/8 F); mean age at implant 9 years, age range 2–17 years 19 pts (11 M/8 F); mean age at implant 33 years, age range 17–46 years
Khurana 2007 (12)
Retrospective chart review of case series data Case series
26 pts (16M/10F); age range 3–17 years, 77% had moderate to severe mental retardation 12 pts (2 M/10 F); mean age 30.7 years, age range 11–48 years
Refractory epilepsy; 77% SGE
McHugh 2007 (14)
Retrospective chart review of case series data
48 pt (24 M/24 F); mean age at implantation 30 years
Refractory epilepsy; 78% partial epilepsy, 22% generalized epilepsy
Major 2008 (13)
Retrospective case series
Refractory epilepsy; tuberous sclerosis complex
Kuba 2009 (23)
Retrospective case series
16 pts (8 M/8 F); mean age at evaluation 15 years, age range 2–44 years 90 pts (50 M/40 F); mean age 36.3 years, age range 13–64 years
Qiabi 2009 (19)
Retrospective chart review of case series data
34 pts (14M/20F); mean age at implantation 29.9 years, age range 16–57 years
Wang, Chen 2009 (18)
Prospective case series
8 pts with VNS implant (4 M/4 F); mean age at implantation 30.5 years, age range 17–41 years rsRefractory epilepsy; ABS (n = 2); CPS (n = 1); GTCS (n = 1); CPS + SGTC (n = 4)
Morris 2003 (5)
Kostov 2007 (24)
4
E03: Refractory partial epilepsy
E04: Refractory epilepsy; 61% partial seizures, 22% generalized; 17% mixed
Effect of magnet E03 trial: Patients who used magnets were more likely to report improvement (P = 0.048) E04: seizure cessation in 22% of patients, seizure diminution in 31% of patients, and no change in 47% of patients. Of 9482 seizures, 24% were terminated, 38% diminished, 38% were not affected Cessation or reduced post-ictal lethargy in 48.6% of pts, 50% reported no benefit, worse in 1%
Refractory epilepsy; focal (30%), generalized or multifocal (70%)
61% (n = 28/46) of pts experienced a positive effect of magnet activation
Refractory epilepsy; LGS (n = 11), CPS (n = 4), Myoclonic (n = 1)
2/16 pts (13%) had a brief reduction in seizure severity by magnet >50% of pts and caregivers reported that magnet activation prevented the onset of a seizure or aborted a seizure 4 pts (15.4%) terminated seizures with the magnet
Refractory epilepsy; partial seizures
Refractory epilepsy; idiopathic generalized epilepsy
Refractory epilepsy; TLE (n = 30), FLE (n = 26), Multifocal (n = 26), Generalized (n = 4), Parietal lobe (n = 1), Operculo-insular (n = 1), unknown (n = 2) Refractory epilepsy; PS with or without SG (n = 32), refractory idiopathic generalized epilepsy (n = 2)
Six auras and 3 seizure attacks happened during EEG recordings in 3/8 pts. These attacks were terminated by magnet clinically and electrographically
5/12 pts (42%) reported the magnet was effective at aborting or reducing the intensity or duration of seizures always or most of the time. 1/12 pts reported some efficacy from the magnet 2/12 pts reported the magnet had no effect. 4/12 pts did not use the magnet 3 pts (6%) had improvement with magnet only defined as preventing progression, limiting duration or severity Aborted seizures in 8/16 pts (50%), 1/16 pts (6%) benefited from magnet only 35 pts (38.9%) reported that magnet activation led to suppression or shortening of the seizure
9/34 pts (26%) benefited from the magnet: of these 7/34 (20%) pts reported seizure termination, 2/34 (6%) pts reported the magnet shortened the ictal and post-ictal durations
VNS magnet activation for seizures Table 2 (continued) First author/Year
Study design
Demographics
Diagnosis
Effect of magnet 1 pt (11%) reported the magnet was effective in aborting or decreasing the intensity or duration of seizures; 2 pts (22%) reported the magnet had no effect 2 pts (22%) had not used the magnet No patients reported benefit by manually activating the magnet; mean seizure reduction rate was 41% at 6 months, 50% at 12 months, and 54% at 36 months Cessation in 16.1% (at 48 month 5.6%), partial effect in 73.2% (at 48 months 55.6%), no effect in 10.7% (at 48 months 38.9%) within 1 week of implantation
Franzoni 2010 (21)
Case series
9 pts (4M/5F); age range 8–28 years
Refractory epilepsy; ABS (n = 1), PAR + SG (n = 5); Drop attacks (n = 2); PAR (n = 3)
Zamponi 2011 (25)
Retrospective case series
39 pts (19 M/20 F); mean age at implantation 13 years, age range 2–51 years, all with mental retardation
Refractory epilepsy; LGS (n = 14), SE-MISF (n = 25)
MajkowskaZwolinska 2012 (10)
Prospective case series of consecutive patients
57 pts (32 M/25 F); mean age at implantation 11.4 years, age range 3–
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd ACTA NEUROLOGICA SCANDINAVICA
Review Article
Vagus nerve stimulation magnet activation for seizures: a critical review Fisher RS, Eggleston KS, Wright CW. Vagus nerve stimulation magnet activation for seizures: a critical review. Acta Neurol Scand 2015: 131: 1–8. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0–89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15–67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.
Introduction
Pivotal clinical trials (1, 2) documenting the efficacy of VNS Therapyâ in patients with epilepsy utilized stimulation cycling at 30 s ON and 5 min OFF. Intermittent stimulation has several advantages over continuous stimulation, including reduced side effects that affect the voice or throat, preserved battery life, and possibly decreased potential for injury or irritation to the vagus nerve (3). In addition to cycling (normal mode) stimulation, the VNS Therapy system also is equipped with a magnet that patients or
R. S. Fisher1, K. S. Eggleston2, C. W. Wright2 1 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA; 2Cyberonics, Inc., Houston, TX, USA
Key words: Vagus nerve stimulation; VNS; magnet; epilepsy; seizures; neurostimulation R. S. Fisher, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Room A343, Stanford, CA 94305 5235, USA Tel.: +650-498-3056 Fax: +650 498 3056 e-mail: [email protected] Accepted for publication July 14, 2014
caregivers can pass over the implanted generator to activate stimulation on-demand (magnet mode) during a seizure (4). Patients using on-demand stimulation via the magnet mode have reported the following effects: termination of a seizure, reduction in seizure duration, reduction in seizure severity, reduction in post-ictal recovery, or no effect (5). A next-generation stimulator for VNS Therapy has a programmable ability to automatically activate stimulation upon detecting a predetermined pattern and magnitude of heart rate increase (responsive stimulation). A recent review has 1
Fisher et al. summarized the literature pertaining to the prevalence of ictal tachycardia (6). This automatic mode (referred to as AutoStim) activates stimulation much the same way that the current magnet mode feature triggers stimulation when the patient or caregiver passes a magnet over the device, except that the stimulation is initiated automatically rather than manually. The stimulator with the AutoStim feature received CE Mark approval in the EU and clinical trials are ongoing in the United States (clinicaltrials.gov identifiers: NCT01325623, NCT01846741). This study reviews what is known about the use, effectiveness, and safety of magnet mode stimulation of VNS Therapy. Methods
To determine the effect of VNS Therapy magnet mode stimulation in patients with epilepsy, a review of the literature was performed. Only full original research (no meeting abstracts or review articles) related to the safety or effectiveness of magnet mode were included. All articles were in English. The reference lists of key relevant articles were also searched and additional articles were identified. Known references that were not found in the literature search were also included for completeness. The literature search for this topic was conducted in January 2014 (Fig. 1) using PubMed, and it resulted in 16 primary citations. Search terms used in the database were ‘VNS’ OR ‘Vagal Nerve Stimulation’ OR ‘Vagus Nerve Stimulation’ AND ‘Magnet’. Three publications were review articles on VNS Therapy (one specific to magnet use), and three were not related to the effectiveness of the VNS Therapy magnet. One additional publication (7) was excluded as it reported on the same database as one of the primary articles selected (8). For the primary search, nine studies met the inclusion criteria and were reviewed (5, 8–15). Eleven additional clinical articles were included as secondary references: two (16, 17) were found after reviewing the reference lists of those articles obtained during the primary search, and nine articles were known to the authors (6, 18– 25). As the evaluation of magnet mode was not the primary outcome of the articles, these were not found during the initial search. Five preclinical articles (26–30) that addressed the acute effects of VNS Therapy were identified during review of the primary clinical articles and are also included as secondary references. Articles were included if they reported outcomes for magnet mode activation. In total, 20 clinical and 2
January 2014 PubMed Literature Search Vagus Nerve S mula on and Magnet
16 Cita ons
Abstract Review
Review Ar cles -3 Ar cles
Not Related to the Effec veness of VNS Therapy Magnet Mode -3 Ar cles
Reported Results from the Same Database -1 Ar cle
Primary Ar cles (n=9) +11 Addi onal Ar cles from Review of Primary Ar cles +5 Known PreClinical Ar cles
20 Clinical and 5 Pre-Clinical Ar cles Reviewed and Summarized
Figure 1. Flow Chart of literature review of VNS therapy magnet mode.
5 preclinical articles met the inclusion criteria and were reviewed. The literature was assessed for several key outcomes of magnet mode stimulation: termination of a seizure, reduction in seizure duration, reduction in seizure severity, reduction in post-ictal recovery, or no effect. Articles were also reviewed for potential safety concerns of magnet mode including any adverse events reported by patients associated with on-demand stimulation. Results Preclinical models
Five papers reviewed and summarized in Table 1 report on preclinical research with chemically
VNS magnet activation for seizures induced seizures in the laboratory (26–30). Although the VNS Therapy magnet was not used to initiate stimulation, these studies are related to the on-demand delivery of stimulation and are thus included in this review. All articles showed that acute delivery of VNS immediately before or after the onset of experimentally induced seizures could attenuate or abort seizures. However, in one article (27), when VNS was administered more than 3 s after seizure onset, the seizure was not altered. Clinical studies
Table 2 summarizes the results of peer-reviewed literature pertaining to magnet activation in patients with epilepsy receiving VNS Therapy. A total of 20 studies comprise magnet stimulation outcome information for 829 patients, including male and female adults and children as young as 2 years of age. Five studies reported exclusively on pediatric populations (10–12, 16, 20). Most studies included patients with partial or generalized seizures, although two reported results for patients with exclusively partial onset seizures (8, 22). Some degree of intellectual disability was noted for patients in several studies (6, 9–12, 15, 16, 25). None of the studies reviewed were designed to provide level I evidence of efficacy of manual use of the magnet. The study designs utilized by the articles reviewed were primarily prospective or retrospective case series of data based on patient and caregiver report. Effectiveness – No controlled study has prospectively evaluated the isolated effect of magnet
mode stimulation at the time of the onset of a seizure. The E-03 study (1) was the first large, randomized trial of Cyberonics’ VNS Therapy. This trial used an active control group with low intensity, infrequent stimulation. Table 3 compares outcome of magnet mode stimulation in the active treatment and the active control groups (5). The percent of seizures aborted by magnetactivated stimulation was 21.3% (n = 50) in the active treatment group and 11.9% (n = 42) in the control group. This difference did not reach statistical significance. A significant difference, however, was observed by combining seizures aborted or decreased compared with the group made by combining those whose seizures were unchanged or worse (Fisher’s Exact test, P = 0.048). Figure 2 illustrates a case of termination of a seizure by magnet mode stimulation of the vagus nerve (18). Another study that emphasized EEG changes found that stimulation at the onset of seizures consistently terminated behavioral and EEG seizure activity in one patient over three recorded seizures (17). Among the studies in Table 2, benefit was reported in a weighted average of 45% of patients (range 0–89%), with seizure cessation claimed in a weighted average of 28% of patients (range 15–67%). In addition to seizure termination, some patients reported that magnet-induced stimulation decreased the intensity or duration of seizures, or of the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (9). Magnet mode stimulation may interrupt individual seizures even in some individuals who do not benefit overall from VNS Therapy. In the study by McHugh and colleagues (14), three
Table 1 PreClinical studies of acute vagus nerve stimulation First author/Year
Demographics
Diagnosis
Effect of magnet
Woodbury 1990 (28) Woodbury 1991 (29)
Sprague–Dawley rats, sample size was not reported Sprague–Dawley rats, sample size was not reported
Chemically induced seizures
Zabara 1992 (30) McLachlan 1993 (27)
20 dogs of mixed breeds (10 M/10 F)
Chemically induced seizures
15 M Wistar rats
Chemically induced seizures
Dedeurwaerdere 2006 (26)
17 rapidly kindled rats. Animals were implanted with electrodes in both amygdala and around the left vagus nerve
After discharges and Stage 5 seizures
Initiation of VNS shortens but does not eliminate chemically induced seizures VNS abolishes the extensor component of the maximal electroshock seizure and shortened or prevented tonic chemically induced seizures when applied 10–30 s before electroshock and continuing for 10–30 s after Seizures were either interrupted or terminated by vagal stimulation; VNS terminated seizures within 0.5–5 s Acute VNS started within 3 s of seizure onset reduced mean seizure duration from 30.2 15.7 s without stimulation to 5.0 1.8 s. Stimulation >3 s after onset failed to alter the seizures VNS showed anticonvulsant effects (P < 0.01) in rats when applied immediately after a kindling stimulus; 2 of 6 rats showed complete suppression of stage 5 seizures
Chemically induced seizures
3
Fisher et al. Table 2 Effectiveness of VNS Therapy Magnet Mode Activation. In all studies, outcomes were indicated by patient or caregiver reports First author/Year
Study design
Demographics
Diagnosis
Double blind RCT; magnet efficacy was a secondary outcome
E03 trial, n = 114; Magnet use in E03, n = 92; E04 trial, n = 124, Magnet use in E04, n = 86
Murphy 2003 (9)
Retrospective chart review of case series data
Refractory epilepsy
Bremer 2006 (11)
Retrospective chart review of case series data
Kang 2006 (20)
Prospective case series of patients
Ardesch 2007 (22)
Prospective case series of consecutive patients
100 pts; mean age at implantation 10.4 years, age range 2–40 years. Magnet information available for 70 pts; 79% with developmental disabilities 46 pts (21 M/25 F); age range 4–16 years; 57% had developmental delay and all had learning disabilities 16 pts (8 M/8 F); mean age at implant 9 years, age range 2–17 years 19 pts (11 M/8 F); mean age at implant 33 years, age range 17–46 years
Khurana 2007 (12)
Retrospective chart review of case series data Case series
26 pts (16M/10F); age range 3–17 years, 77% had moderate to severe mental retardation 12 pts (2 M/10 F); mean age 30.7 years, age range 11–48 years
Refractory epilepsy; 77% SGE
McHugh 2007 (14)
Retrospective chart review of case series data
48 pt (24 M/24 F); mean age at implantation 30 years
Refractory epilepsy; 78% partial epilepsy, 22% generalized epilepsy
Major 2008 (13)
Retrospective case series
Refractory epilepsy; tuberous sclerosis complex
Kuba 2009 (23)
Retrospective case series
16 pts (8 M/8 F); mean age at evaluation 15 years, age range 2–44 years 90 pts (50 M/40 F); mean age 36.3 years, age range 13–64 years
Qiabi 2009 (19)
Retrospective chart review of case series data
34 pts (14M/20F); mean age at implantation 29.9 years, age range 16–57 years
Wang, Chen 2009 (18)
Prospective case series
8 pts with VNS implant (4 M/4 F); mean age at implantation 30.5 years, age range 17–41 years rsRefractory epilepsy; ABS (n = 2); CPS (n = 1); GTCS (n = 1); CPS + SGTC (n = 4)
Morris 2003 (5)
Kostov 2007 (24)
4
E03: Refractory partial epilepsy
E04: Refractory epilepsy; 61% partial seizures, 22% generalized; 17% mixed
Effect of magnet E03 trial: Patients who used magnets were more likely to report improvement (P = 0.048) E04: seizure cessation in 22% of patients, seizure diminution in 31% of patients, and no change in 47% of patients. Of 9482 seizures, 24% were terminated, 38% diminished, 38% were not affected Cessation or reduced post-ictal lethargy in 48.6% of pts, 50% reported no benefit, worse in 1%
Refractory epilepsy; focal (30%), generalized or multifocal (70%)
61% (n = 28/46) of pts experienced a positive effect of magnet activation
Refractory epilepsy; LGS (n = 11), CPS (n = 4), Myoclonic (n = 1)
2/16 pts (13%) had a brief reduction in seizure severity by magnet >50% of pts and caregivers reported that magnet activation prevented the onset of a seizure or aborted a seizure 4 pts (15.4%) terminated seizures with the magnet
Refractory epilepsy; partial seizures
Refractory epilepsy; idiopathic generalized epilepsy
Refractory epilepsy; TLE (n = 30), FLE (n = 26), Multifocal (n = 26), Generalized (n = 4), Parietal lobe (n = 1), Operculo-insular (n = 1), unknown (n = 2) Refractory epilepsy; PS with or without SG (n = 32), refractory idiopathic generalized epilepsy (n = 2)
Six auras and 3 seizure attacks happened during EEG recordings in 3/8 pts. These attacks were terminated by magnet clinically and electrographically
5/12 pts (42%) reported the magnet was effective at aborting or reducing the intensity or duration of seizures always or most of the time. 1/12 pts reported some efficacy from the magnet 2/12 pts reported the magnet had no effect. 4/12 pts did not use the magnet 3 pts (6%) had improvement with magnet only defined as preventing progression, limiting duration or severity Aborted seizures in 8/16 pts (50%), 1/16 pts (6%) benefited from magnet only 35 pts (38.9%) reported that magnet activation led to suppression or shortening of the seizure
9/34 pts (26%) benefited from the magnet: of these 7/34 (20%) pts reported seizure termination, 2/34 (6%) pts reported the magnet shortened the ictal and post-ictal durations
VNS magnet activation for seizures Table 2 (continued) First author/Year
Study design
Demographics
Diagnosis
Effect of magnet 1 pt (11%) reported the magnet was effective in aborting or decreasing the intensity or duration of seizures; 2 pts (22%) reported the magnet had no effect 2 pts (22%) had not used the magnet No patients reported benefit by manually activating the magnet; mean seizure reduction rate was 41% at 6 months, 50% at 12 months, and 54% at 36 months Cessation in 16.1% (at 48 month 5.6%), partial effect in 73.2% (at 48 months 55.6%), no effect in 10.7% (at 48 months 38.9%) within 1 week of implantation
Franzoni 2010 (21)
Case series
9 pts (4M/5F); age range 8–28 years
Refractory epilepsy; ABS (n = 1), PAR + SG (n = 5); Drop attacks (n = 2); PAR (n = 3)
Zamponi 2011 (25)
Retrospective case series
39 pts (19 M/20 F); mean age at implantation 13 years, age range 2–51 years, all with mental retardation
Refractory epilepsy; LGS (n = 14), SE-MISF (n = 25)
MajkowskaZwolinska 2012 (10)
Prospective case series of consecutive patients
57 pts (32 M/25 F); mean age at implantation 11.4 years, age range 3–
