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Long-term outcome of vagus nerve stimulation therapy in patients with refractory epilepsy
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Journal of Clinical Neuroscience 15 (2008) 127–129 www.elsevier.com/locate/jocn
Clinical Study
Long-term outcome of vagus nerve stimulation therapy in patients with refractory epilepsy Abuhuziefa Abubakr *, Ilse Wambacq
1
Seton Hall University for Graduate Medical Education, New Jersey Neuroscience Institute, JFK Hospital, Edison, New Jersey 08818, USA Received 30 May 2007; accepted 24 July 2007
Abstract We retrospectively assessed the long-term efficacy of vagus nerve stimulation (VNS) therapy in 31 patients with refractory partial and generalized seizures who were not candidates for resective epilepsy surgery. Following implantation of VNS there was significant improvement in seizure frequency at 6 months. Sixteen patients continued to have sustained response to VNS therapy 4 years later. Adverse effects of VNS therapy were transient and tolerable. The majority of the patients did not gain body weight and some of them had significant weight loss. Therefore VNS is safe and effective therapy and has a long-term sustained effect in refractory epilepsy. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: VNS; Refractory epilepsy; Responder; Weight loss
1. Introduction Epilepsy is well controlled in most patients with seizures due to recent advances in antiepileptic drug (AED) therapy, which provides several options for physicians who treat patients with seizures. However about one-third of patients have pharmacoresistant seizures or unacceptable side effects from AEDs. In this group of patients with refractory epilepsy, generally accepted non- medical therapies are limited to ketogenic diet, epilepsy surgery, and vagus nerve stimulation (VNS). The ketogenic diet may not be effective in adults, and a considerable proportion of patients with pharmacoresistant partial-onset seizures are not candidates for, or are opposed to intracranial surgery. For such patients, VNS therapy may be a therapeutic option.1,2 The US Federal Drug Administration (FDA) has approved VNS since 1997 for use as an adjunctive therapy in reducing the frequency of seizures in adults and adoles-
*
Corresponding author. Tel.: +1 732 321 7950. E-mail addresses: [email protected] (A. Abubakr), [email protected] (I. Wambacq). 1 Current address: Montclair State University, Montclair, New Jersey 07043, USA. 0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.07.083
cents over 12 years of age with partial onset seizures, who are refractory to antiepileptic medications. The long-term outcome of VNS therapy has been reported in several studies with varied success. Therefore we retrospectively evaluated the long-term outcome of VNS therapy in patients with intractable epilepsy treated in the comprehensive epilepsy center of the New Jersey Neuroscience Institute. 2. Methods The medical records of patients implanted with VNS between 1998 and 2001 were reviewed. All patients with chronic refractory partial and secondarily generalized seizures were admitted to the epilepsy-monitoring unit at the comprehensive epilepsy center of the New Jersey Neuroscience Institute for phase 1 presurgical evaluation. The evaluation consisted of history and physical examination, interictal electroencephalogram (EEG), video EEG for ictal recordings and clinical semiology, MRI of the brain and neuropsychological tests. All patients were being treated with maximum tolerable doses of two to four AEDs. Patients were offered VNS therapy if their surgical evaluation indicated that they would not benefit from resective surgery. The VNS (Neurocyberonic Prosthesis system
128
A. Abubakr, I. Wambacq / Journal of Clinical Neuroscience 15 (2008) 127–129
[NCP]; Cyberonics Inc., Houston, TX, USA) was implanted according to routine methodology.3 The records review collected patients’ data regarding seizure frequency before and at 6 months and 4 years following VNS therapy. All patients or their caregivers provided seizure diaries, which were collected during regular clinic visits approximately every 4 months. Patients were identified as responders by having > 50% reduction in seizure frequency from the baseline before the VNS implant. Similarly, adverse effects of VNS therapy were assessed. The collected data were also reviewed for changes of body weight over time at the baseline and after VNS therapy at 6 months and 4 years. Patients who were involved in diet restrictions were excluded from the assessment. 3. Results Thirty-one patients including, three adolescents aged 14, 16 and 17 years, were implanted with VNS. There were 15 males and 16 females. The age range was 14–62 years. The duration of epilepsy was 26.7 years (range 8–54 years). Eighteen patients had mean seizure frequencies of 8.8/ month (range 4–35/month) and 13 patients had mean seizure frequencies of 33.3/day (range 3–100/day). Before implant there were 11 patients on four AEDs, 12 on three AEDs and eight on two AED combinations. At 6 months and 4 years following VNS therapy, seven patients had their AED combinations switched but the overall range of AEDs used did not change among patients (2 to 4 drugs) since none of the patients were rendered seizure-free. Out of the 31 patients, one patient died of an unrelated cause, and four (13.4%) asked their device to be removed, one due to lack of efficacy and three due to adverse effects such as hoarseness of voice, cough and vomiting. Therefore, 26 patients provided long-term data. Twenty-two patients (73%) showed considerable improvement in terms of feeling better, being more alert and having fewer seizures; they were considered to be responders to VNS therapy. Among those who initially responded to VNS, 20 patients (66%) demonstrated >50% reduction in seizure frequency at 6 months (good responders) and 16 of them (53.3%) continued to have sustained improvement (>50% reduction in seizure frequency) 4 years later. None of the patients attained seizure freedom during the follow-up period. Six patients (23%) developed transient side effects that were tolerable; two patients had hoarseness of voice, two patients developed cough, one had pain at the generator site and another had transient dysphagia. However, in four patients (13.3%) seizures increased in frequency and severity and they were considered poor responders to VNS therapy. The analysis of weight change over time was based on 22 patients because records were incomplete in eight patients, and one died. In 15 out of 22 patients (68%) the body weight remained stable throughout the evaluation period and four patients (18%) had significant weight loss ranging
between 11.4–28.5%. There were only four patients who gained weight in the range of 8–15.5%. 4. Discussion This retrospective uncontrolled study illustrates continued seizure reduction after long-term adjunctive VNS therapy in patients with intractable partial-onset epilepsy. Improving seizure control in the long-term supports the possibility of a sustained VNS effect on seizure reduction over time. However, none of our patients attained seizure freedom; this may be due to selection of the most refractory epilepsy patients in our cohort. Similar to our evaluation, a retrospective review of the safety, tolerability, and efficacy of VNS in 48 patients with intractable partial epilepsy was performed by Uthman et al.4 They found that there were few side effects, which were mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment, which is in support of cumulative effects of VNS therapy. However, our patients were assessed for 4 years only following VNS therapy, but based on the above findings we may predict that they will continue to respond to VNS long-term. In a multi-center study of long-term VNS treatment, VNS was not associated with development of tolerance over time and the responders to VNS maintained significant reductions in their seizures in the long-term.5 In their study the patients habituated to VNS-induced adverse effects over time, yet this tolerance to adverse effects was lost when VNS was interrupted for 3 weeks or longer. This is similar to the findings reported by Spanaski and colleagues6 on the long-term efficacy of VNS, and to our finding that VNS therapy was not associated with tolerance, although we did not interrupt VNS therapy in any of our patients so we could not reach any conclusion with regard to the findings reported by DeGoirgio.5 With more than 32 000 patients implanted with VNS worldwide (Cyberonics Inc., Houston, TX, USA), VNS therapy has assumed an increasingly important role in the treatment of medically refractory seizures since its approval in 1997 in the USA. Anatomic-physiologic studies, experimental epilepsy studies, and human imaging, EEG, and cerebrospinal fluid studies suggest that multiple mechanisms underlie the antiseizure effects of VNS and that alterations of vagal parasympathetic efferent activities do not underlie these antiseizure effects. Putative antiseizure mechanisms are mediated by altered vagal afferent activities, and probably include altered activities in the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. Anatomicphysiologic studies fully account for the common and rare adverse effects of VNS.7 All but four patients in our study either did not gain body weight or lost weight. This is in contrast to most experience with AEDs, which are associated with significant gain in body weight.8 However, in our series we did
A. Abubakr, I. Wambacq / Journal of Clinical Neuroscience 15 (2008) 127–129
not assess the caloric intake of our patients but relied on their personal report of any major change in dietary habits; obviously this is a crude way to evaluate changes in body weight. However, we believe it gave us a reasonable idea about weight changes and we suggest that VNS is weight-neutral. Our findings are similar to Holmes and Koren’s study, in which they conducted a retrospective study of weight changes in 21 patients who received VNS therapy for refractory epilepsy. They did not find any significant body weight changes over time and they concluded that the stimulation parameters used in patients with epilepsy were not associated with any significant weight changes.9 The mechanisms underlying body weight changes in VNS are not very clear. The vagus nerve provides innervations to the proximal stomach, the pylorus, and the duodenum. In regards to changes in eating behavior, surgical vagotomies appear to attenuate the effects on cholecystokinin, a hormone that mediates gastric distension after eating.10 There is also evidence of an increment in the vagus nerve activity with gastric distension and food intake. Animal experiments have shown that stimulation of the vagus nerve effectively reduces eating, with a corresponding weight loss.11 Bruneo et al.12 reviewed their VNS series and they concluded that weight loss appeared to be related to some of the mechanisms mentioned above. They also looked at the possibility of a weight correlation with changes in seizure rate, but only one patient in their cohort achieved optimal seizure control, and they noted that a clear tendency toward weight loss was present when the output current of the stimulator was increased. They finally concluded that although weight loss may be multifactorial, its occurrence in their patients appeared to be causally related to VNS implantation. Weight loss may be due to decreased appetite, resulting in changes in eating
129
behavior, or to gastrointestinal side effects, such as dyspepsia, previously reported as a side effect of VNS.13 Even though our study is not controlled, it appears that VNS with parameters used in treating epilepsy patients is not associated with significant changes in body weight. We suggest that in order to determine precisely the effect of VNS treatment on body weight changes, a well-controlled prospective study is warranted. References 1. Schachter SC. VNS stimulation therapy. Neurology 2002;59:S15–29. 2. Ben-Menachem E. Vagus nerve stimulation for treatment of seizures. Arch Neurol 1998;55:231–2. 3. Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. VNS for treatment of partial seizures: A controlled study effect on seizures. Epilepsia 1994;35:616–26. 4. Uthman BM, Reichl AM, Dean JC, et al. Effectiveness of vagus nerve stimulation in epilepsy patients. Neurology 2004;63:1124–6. 5. DeGiorgio C, Schachter S, Handforth A, et al. Prospective long-term study of Vagus Nerve Stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–200. 6. Spanaki MV, Allen LS, Mueller WM, et al. VNS stimulation therapy: 5-yrs or greater outcome at university-based epilepsy center. Seizure 2004;13:587–90. 7. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002;59:S3–S14. 8. Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63:S24–9. 9. Korean MS, Holmes MD. VNS does not lead to significant changes in body weight in patients with epilepsy. Epilepsy Behav 2006;8:246–9. 10. Smith GP, Jerome C, Cushing BJ, et al. Abdominal vagotomy blocks the satiety effect of cholecystokinin in rats. Science 1981;213:1036–7. 11. Roslin M, Kurian M. The use of electrical stimulation of the vagus nerve to treat morbid obesity. Epilepsy Behav 2001;2 (Suppl. 11):1–6. 12. Burneo JG, Faught E, Knowlton R, et al. Weight loss associated with vagus nerve stimulation. Neurology 2002;59:463–4. 13. Ramsay RE, Uthman BM, Augustinsson LE, et al. VNS for treatment of partial seizures. Epilepsia 1994;35:627–36.
Journal of Clinical Neuroscience 15 (2008) 127–129 www.elsevier.com/locate/jocn
Clinical Study
Long-term outcome of vagus nerve stimulation therapy in patients with refractory epilepsy Abuhuziefa Abubakr *, Ilse Wambacq
1
Seton Hall University for Graduate Medical Education, New Jersey Neuroscience Institute, JFK Hospital, Edison, New Jersey 08818, USA Received 30 May 2007; accepted 24 July 2007
Abstract We retrospectively assessed the long-term efficacy of vagus nerve stimulation (VNS) therapy in 31 patients with refractory partial and generalized seizures who were not candidates for resective epilepsy surgery. Following implantation of VNS there was significant improvement in seizure frequency at 6 months. Sixteen patients continued to have sustained response to VNS therapy 4 years later. Adverse effects of VNS therapy were transient and tolerable. The majority of the patients did not gain body weight and some of them had significant weight loss. Therefore VNS is safe and effective therapy and has a long-term sustained effect in refractory epilepsy. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: VNS; Refractory epilepsy; Responder; Weight loss
1. Introduction Epilepsy is well controlled in most patients with seizures due to recent advances in antiepileptic drug (AED) therapy, which provides several options for physicians who treat patients with seizures. However about one-third of patients have pharmacoresistant seizures or unacceptable side effects from AEDs. In this group of patients with refractory epilepsy, generally accepted non- medical therapies are limited to ketogenic diet, epilepsy surgery, and vagus nerve stimulation (VNS). The ketogenic diet may not be effective in adults, and a considerable proportion of patients with pharmacoresistant partial-onset seizures are not candidates for, or are opposed to intracranial surgery. For such patients, VNS therapy may be a therapeutic option.1,2 The US Federal Drug Administration (FDA) has approved VNS since 1997 for use as an adjunctive therapy in reducing the frequency of seizures in adults and adoles-
*
Corresponding author. Tel.: +1 732 321 7950. E-mail addresses: [email protected] (A. Abubakr), [email protected] (I. Wambacq). 1 Current address: Montclair State University, Montclair, New Jersey 07043, USA. 0967-5868/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jocn.2007.07.083
cents over 12 years of age with partial onset seizures, who are refractory to antiepileptic medications. The long-term outcome of VNS therapy has been reported in several studies with varied success. Therefore we retrospectively evaluated the long-term outcome of VNS therapy in patients with intractable epilepsy treated in the comprehensive epilepsy center of the New Jersey Neuroscience Institute. 2. Methods The medical records of patients implanted with VNS between 1998 and 2001 were reviewed. All patients with chronic refractory partial and secondarily generalized seizures were admitted to the epilepsy-monitoring unit at the comprehensive epilepsy center of the New Jersey Neuroscience Institute for phase 1 presurgical evaluation. The evaluation consisted of history and physical examination, interictal electroencephalogram (EEG), video EEG for ictal recordings and clinical semiology, MRI of the brain and neuropsychological tests. All patients were being treated with maximum tolerable doses of two to four AEDs. Patients were offered VNS therapy if their surgical evaluation indicated that they would not benefit from resective surgery. The VNS (Neurocyberonic Prosthesis system
128
A. Abubakr, I. Wambacq / Journal of Clinical Neuroscience 15 (2008) 127–129
[NCP]; Cyberonics Inc., Houston, TX, USA) was implanted according to routine methodology.3 The records review collected patients’ data regarding seizure frequency before and at 6 months and 4 years following VNS therapy. All patients or their caregivers provided seizure diaries, which were collected during regular clinic visits approximately every 4 months. Patients were identified as responders by having > 50% reduction in seizure frequency from the baseline before the VNS implant. Similarly, adverse effects of VNS therapy were assessed. The collected data were also reviewed for changes of body weight over time at the baseline and after VNS therapy at 6 months and 4 years. Patients who were involved in diet restrictions were excluded from the assessment. 3. Results Thirty-one patients including, three adolescents aged 14, 16 and 17 years, were implanted with VNS. There were 15 males and 16 females. The age range was 14–62 years. The duration of epilepsy was 26.7 years (range 8–54 years). Eighteen patients had mean seizure frequencies of 8.8/ month (range 4–35/month) and 13 patients had mean seizure frequencies of 33.3/day (range 3–100/day). Before implant there were 11 patients on four AEDs, 12 on three AEDs and eight on two AED combinations. At 6 months and 4 years following VNS therapy, seven patients had their AED combinations switched but the overall range of AEDs used did not change among patients (2 to 4 drugs) since none of the patients were rendered seizure-free. Out of the 31 patients, one patient died of an unrelated cause, and four (13.4%) asked their device to be removed, one due to lack of efficacy and three due to adverse effects such as hoarseness of voice, cough and vomiting. Therefore, 26 patients provided long-term data. Twenty-two patients (73%) showed considerable improvement in terms of feeling better, being more alert and having fewer seizures; they were considered to be responders to VNS therapy. Among those who initially responded to VNS, 20 patients (66%) demonstrated >50% reduction in seizure frequency at 6 months (good responders) and 16 of them (53.3%) continued to have sustained improvement (>50% reduction in seizure frequency) 4 years later. None of the patients attained seizure freedom during the follow-up period. Six patients (23%) developed transient side effects that were tolerable; two patients had hoarseness of voice, two patients developed cough, one had pain at the generator site and another had transient dysphagia. However, in four patients (13.3%) seizures increased in frequency and severity and they were considered poor responders to VNS therapy. The analysis of weight change over time was based on 22 patients because records were incomplete in eight patients, and one died. In 15 out of 22 patients (68%) the body weight remained stable throughout the evaluation period and four patients (18%) had significant weight loss ranging
between 11.4–28.5%. There were only four patients who gained weight in the range of 8–15.5%. 4. Discussion This retrospective uncontrolled study illustrates continued seizure reduction after long-term adjunctive VNS therapy in patients with intractable partial-onset epilepsy. Improving seizure control in the long-term supports the possibility of a sustained VNS effect on seizure reduction over time. However, none of our patients attained seizure freedom; this may be due to selection of the most refractory epilepsy patients in our cohort. Similar to our evaluation, a retrospective review of the safety, tolerability, and efficacy of VNS in 48 patients with intractable partial epilepsy was performed by Uthman et al.4 They found that there were few side effects, which were mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment, which is in support of cumulative effects of VNS therapy. However, our patients were assessed for 4 years only following VNS therapy, but based on the above findings we may predict that they will continue to respond to VNS long-term. In a multi-center study of long-term VNS treatment, VNS was not associated with development of tolerance over time and the responders to VNS maintained significant reductions in their seizures in the long-term.5 In their study the patients habituated to VNS-induced adverse effects over time, yet this tolerance to adverse effects was lost when VNS was interrupted for 3 weeks or longer. This is similar to the findings reported by Spanaski and colleagues6 on the long-term efficacy of VNS, and to our finding that VNS therapy was not associated with tolerance, although we did not interrupt VNS therapy in any of our patients so we could not reach any conclusion with regard to the findings reported by DeGoirgio.5 With more than 32 000 patients implanted with VNS worldwide (Cyberonics Inc., Houston, TX, USA), VNS therapy has assumed an increasingly important role in the treatment of medically refractory seizures since its approval in 1997 in the USA. Anatomic-physiologic studies, experimental epilepsy studies, and human imaging, EEG, and cerebrospinal fluid studies suggest that multiple mechanisms underlie the antiseizure effects of VNS and that alterations of vagal parasympathetic efferent activities do not underlie these antiseizure effects. Putative antiseizure mechanisms are mediated by altered vagal afferent activities, and probably include altered activities in the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. Anatomicphysiologic studies fully account for the common and rare adverse effects of VNS.7 All but four patients in our study either did not gain body weight or lost weight. This is in contrast to most experience with AEDs, which are associated with significant gain in body weight.8 However, in our series we did
A. Abubakr, I. Wambacq / Journal of Clinical Neuroscience 15 (2008) 127–129
not assess the caloric intake of our patients but relied on their personal report of any major change in dietary habits; obviously this is a crude way to evaluate changes in body weight. However, we believe it gave us a reasonable idea about weight changes and we suggest that VNS is weight-neutral. Our findings are similar to Holmes and Koren’s study, in which they conducted a retrospective study of weight changes in 21 patients who received VNS therapy for refractory epilepsy. They did not find any significant body weight changes over time and they concluded that the stimulation parameters used in patients with epilepsy were not associated with any significant weight changes.9 The mechanisms underlying body weight changes in VNS are not very clear. The vagus nerve provides innervations to the proximal stomach, the pylorus, and the duodenum. In regards to changes in eating behavior, surgical vagotomies appear to attenuate the effects on cholecystokinin, a hormone that mediates gastric distension after eating.10 There is also evidence of an increment in the vagus nerve activity with gastric distension and food intake. Animal experiments have shown that stimulation of the vagus nerve effectively reduces eating, with a corresponding weight loss.11 Bruneo et al.12 reviewed their VNS series and they concluded that weight loss appeared to be related to some of the mechanisms mentioned above. They also looked at the possibility of a weight correlation with changes in seizure rate, but only one patient in their cohort achieved optimal seizure control, and they noted that a clear tendency toward weight loss was present when the output current of the stimulator was increased. They finally concluded that although weight loss may be multifactorial, its occurrence in their patients appeared to be causally related to VNS implantation. Weight loss may be due to decreased appetite, resulting in changes in eating
129
behavior, or to gastrointestinal side effects, such as dyspepsia, previously reported as a side effect of VNS.13 Even though our study is not controlled, it appears that VNS with parameters used in treating epilepsy patients is not associated with significant changes in body weight. We suggest that in order to determine precisely the effect of VNS treatment on body weight changes, a well-controlled prospective study is warranted. References 1. Schachter SC. VNS stimulation therapy. Neurology 2002;59:S15–29. 2. Ben-Menachem E. Vagus nerve stimulation for treatment of seizures. Arch Neurol 1998;55:231–2. 3. Ben-Menachem E, Manon-Espaillat R, Ristanovic R, et al. VNS for treatment of partial seizures: A controlled study effect on seizures. Epilepsia 1994;35:616–26. 4. Uthman BM, Reichl AM, Dean JC, et al. Effectiveness of vagus nerve stimulation in epilepsy patients. Neurology 2004;63:1124–6. 5. DeGiorgio C, Schachter S, Handforth A, et al. Prospective long-term study of Vagus Nerve Stimulation for the treatment of refractory seizures. Epilepsia 2000;41:1195–200. 6. Spanaki MV, Allen LS, Mueller WM, et al. VNS stimulation therapy: 5-yrs or greater outcome at university-based epilepsy center. Seizure 2004;13:587–90. 7. Henry TR. Therapeutic mechanisms of vagus nerve stimulation. Neurology 2002;59:S3–S14. 8. Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004;63:S24–9. 9. Korean MS, Holmes MD. VNS does not lead to significant changes in body weight in patients with epilepsy. Epilepsy Behav 2006;8:246–9. 10. Smith GP, Jerome C, Cushing BJ, et al. Abdominal vagotomy blocks the satiety effect of cholecystokinin in rats. Science 1981;213:1036–7. 11. Roslin M, Kurian M. The use of electrical stimulation of the vagus nerve to treat morbid obesity. Epilepsy Behav 2001;2 (Suppl. 11):1–6. 12. Burneo JG, Faught E, Knowlton R, et al. Weight loss associated with vagus nerve stimulation. Neurology 2002;59:463–4. 13. Ramsay RE, Uthman BM, Augustinsson LE, et al. VNS for treatment of partial seizures. Epilepsia 1994;35:627–36.