Neurosurg Rev DOI 10.1007/s10143-014-0555-5
ORIGINAL ARTICLE
Can we predict the response in the treatment of epilepsy with vagus nerve stimulation? A. Arcos & L. Romero & M. Gelabert & A. Prieto & J. Pardo & X. Rodriguez Osorio & M. A. Arráez
Received: 11 November 2012 / Revised: 25 February 2014 / Accepted: 13 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Despite the introduction of new antiepileptic drugs and advances in the surgical treatment of epilepsy, an important group of patients still remains uncontrolled by any of these methods. The relatively recent introduction of vagus nerve stimulation is yet another possible treatment for refractory epilepsy. This safe, simple, and adjustable technique reduces the number of seizures and multiple publications support its increasing efficacy and effectiveness, with few adverse effects. The goal of our study is to determine the efficacy of this procedure and the factors predicting a response, particularly in the presence of a temporal lobe discharge on the video electroencephalogram (video-EEG) and magnetic resonance imaging (MRI) lesions. We undertook a retrospective study of all the patients with refractory epilepsy who underwent implantation of a vagus nerve stimulator between 2003 and 2009, and with a minimum follow-up of 6 months. The statistical analysis was done with SPSS for Windows. The stimulator was implanted in 40 patients, of whom 38 had a minimum follow-up of 6 months. In one patient, the device had to be removed due to infection, so the series comprised 37 patients. These were divided into different groups, according to the epidemiologic, clinical, radiologic, and electroencephalographic data. In addition, an analysis of the response was performed.
The efficacy of the procedure was established according to the reduction in the mean seizure frequency. The baseline value of these seizures was 80.97±143.59, falling to 37±82.51 at the last revision. The response rate (reduction in seizures ≥50 %) at 6 months was 51.4 %, with 62.2 % of the patients showing this reduction at the last evaluation. Significant differences in the response were seen for the variables: baseline frequency of seizures, temporal lobe discharge on VideoEEG and MRI lesions. The mean time to response was 10 months in patients with lower rate of seizures versus 25 months of those with the higher rate (p=0.024), and the response at 6 months was higher (p=0.05). Patients with temporal lobe discharge alone or in combination with discharges over other regions had a mean time to response of 11 months versus 26 months in those without temporal discharge (p=0.037). In the analysis of the MRI, we had seen that at the last revision, 82.4 % of the patients with lesion had achieved response versus 45 % without lesion (p=0.02). Vagus nerve stimulation reduces the frequency of seizures. A temporal lobe discharge on the video-EEG is an indicator of an early response and the presence of an MRI lesion indicates a late response. Patients with fewer rates of seizures have a better prognosis. Keywords Treatment of epilepsy . Vagus nerve stimulation
A. Arcos : L. Romero : M. A. Arráez Neurosurgical Department, Carlos Haya Hospital, Málaga, Spain M. Gelabert : A. Prieto Neurosurgical Department, Clinic Hospital of Santiago de Compostela, Santiago de Compostela, Spain J. Pardo : X. R. Osorio Neurological Department, Clinic Hospital of Santiago de Compostela, Santiago de Compostela, Spain L. Romero (*) Department of Neurosurgery, HRU Carlos Haya, Málaga, Spain e-mail: [email protected]
Introduction Refractory epilepsy is a chronic incapacitating neurological disorder that affects 1 % of the general population. It is associated with a high rate of morbidity, due to the seizures and anti-epileptic drugs used, increased mortality, and reduced quality of life. The nature of the disorder leads to gradual worsening of the psychosocial, cognitive, and neuronal status [46]. Estimates by the Spanish Ministry of Health [24] suggest that 15 % of patients with refractory epilepsy are susceptible
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epilepsy surgery, though after evaluation, only 50 % of these can actually be treated with surgery, and at least 20 % continue experiencing seizures despite surgery. Patients with pharmacoresistant refractory epilepsy who are not candidates for conventional surgery, or who refuse this option or have failed to experience improvement with other surgical or medical techniques could benefit from vagus nerve stimulation (VNS) [5, 20, 26, 51]. In 1811, Parry [40] was the first to suggest that manual compression of the carotid artery could abort the epileptic seizure. Corning [20–22] then developed a carotid fork and a carotid truss, later accompanied by vagal nerve and cervical sympathetic stimulation. After performing animal experiments, Penry and Dean [42] implanted the first vagus nerve stimulator in humans in 1988. This treatment of refractory epilepsy was approved in Europe in 1994. The VNS device consists of two helicoidal electrodes (positive and negative), an anchoring cable, and a battery. It is placed by making an incision in the left lateral cervical region, exposing about 3 cm of the vagus nerve, and implanting the electrodes and the anchor around the nerve [5]. The distal end is connected to a subcutaneous bag in the anterior axilla, where the generator is placed. The risks derived from this surgery are few [6]. Complications directly related with the operation include possible systemic infections, hemorrhages, asystoles (1/1000), or acute vocal cord paralysis [7–9]. Though the exact mechanism of action of VNS remains unknown, its effect is thought to be produced by retrograde cerebral stimulation via the vagus nerve afferents, inducing increased synaptic activity in the thalamus and its projections, as well as other components of the central autonomic system. This shows a decrease in limbic system activity and an increase of some neurotransmitters such as norepinephrine and serotonin [25]. Around 80 % of the fibers of the vagus nerve, which is a mixed nerve, are afferent and proceed from the heart, lungs, aorta, and gastrointestinal tract [10]. The efferent fibers (20 %) innervate these structures and the striated musculature of the larynx and the pharynx. The activity of its afferent fibers explains the possible mechanism of action of vagal stimulation, which is projected toward the brainstem (with special importance of the solitary tract nucleus) and the encephalon, stimulating the thalamus and the amygdala (basic structures in the pathophysiology of epilepsy), and with multiple connections throughout the cerebral cortex. Its efferent fiber condition explains most of the secondary effects of stimulation and the contraindications to its implantation. The absolute contraindications for this type of surgery are left or bilateral vagotomy, right vocal cord paralysis, or severe cardiac arrhythmia. Relative complications (as stimulation might worsen the processes) include the presence of chronic obstructive pulmonary disease, obstructive sleep apnea
syndrome, severe asthma, difficulty swallowing, or the need to use the voice professionally [11, 12]. Its side effects, though relatively frequent, depend on the intensity of the stimulation and are easily controllable by adjusting the parameters of the stimulator [6]. The most common of these side effects are dysphonia, cough, cervical pain, pharyngeal problems, or even dyspnea [13]. Less common side effects include hiccups, headache, nausea, difficulty swallowing, diarrhea, urine retention, stiff neck due to sternocleidomastoid muscle spasm, phrenic involvement, or amygdala pain [14–17]. The secondary effects and complications of VNS usually diminish or disappear after correct adjustment of the stimulation parameters.
Objective The aim of this study was to assess the efficacy of VNS and determine the clinical, epidemiological and technical characteristics predicting the response.
Material and methods We undertook a descriptive, observational, retrospective study of the patients with refractory epilepsy who received a stimulator implant at the Epilepsy Unit of the Clinic Hospital of Santiago de Compostela, Spain, from 2003 to 2009. The inclusion criteria were as follows: follow-up of at least 6 months, a documented history of the seizures before implantation, and during the follow-up period, and a standardized preoperative study including at least video-EEG and MRI monitoring. The preoperative variables studied included epidemiologic data, such as the sex and age at the time of the procedure, and various clinical characteristics: the duration of the epilepsy, the baseline frequency of the seizures, risk factors, presence of mental retardation, epileptic status, and number of previous anti-epileptic drugs. The patients were divided according to the type of epilepsy into focal or generalized and the type of seizure according to the ILAE classification. The location of the epileptic discharge and the presence of a temporal lobe discharge, whether or not associated with other discharges, was established from the results of the video-EEG. The presence of MRI lesions was also evaluated. To analyze the follow-up variables, a “response” was defined with this formula: (baseline frequency of seizures—the frequency of seizures during the follow-up/the baseline frequency of seizures). We defined “responder” when the reduction in seizures was ≥50 %. These data were used to calculate the mean reduction in seizures, the percent of patients with a response, and the time to the response. Other variables studied included immediate postoperative complications, the side
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effects associated with the stimulation, and the number of anti-epileptic drugs at the last revision.
Table 2 Imaging and EEG findings
Number (%) Epilepsy discharge location Temporal Frontal Combined Generalized
Statistical analysis Univariate analysis was done to determine the influence on the response of the different variables. Quantitative variables were compared with the Student t or the Mann-Whitney test. Qualitative variables were assessed with the Chi-square test or Fisher’s exact test. To verify the hypothesis of normality of the distributions, the Kolmogorov-Smirnov test was used. Bonferroni corrections were included. Variables predicting a response were analyzed by multivariate logistic regression. The evolution of the response over time was studied by Kaplan-Meier analysis. Differences between groups were analyzed using the log-rank test. Statistical significance was set at p50 % as compared with the baseline frequency was 51.4 % at 6 months and 62.2 % at the last revision. The mean reduction in seizure frequency reported in the current literature ranges from 43 to 51 % [30, 35, 47, 54], and the response rate at the last revision reported in open studies ranges from 34 to 59 % [10, 23, 27, 37, 50, 54, 56]. These data show that patients experience a continuous and persistent improvement over time, data that coincide with earlier reports [29, 33, 45, 55]. As an indicator of the effectiveness of VNS, we also analyzed the number of drugs at the last revision as compared with baseline. It was seen that it was not possible to reduce the number of drugs. Few details have been given in the literature about changes in anti-epileptic drugs after starting VNS therapy. Salinsky et al. [45] found a significant reduction in antiepileptic drugs in the patients with VNS compared with a control group. However, Kuba et al. [30] noted that antiepileptic drugs had to be increased in 76.7 % of the patients, with a reduction in these drugs in just 10 % of the patients. Response according to epidemiologic and clinical variables In our series, no significant differences were seen in the response due to the demographic factors or clinical characteristics, apart from the baseline frequency of the seizures. This contrasts with some previous findings. The published results are discordant concerning the age at surgery. No obvious differences have been found in the response to VNS in children younger than 12 years of age as compared with adolescents, nor do clear conclusions exist concerning a greater or
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lesser response in children versus adults [2, 23, 30, 36, 41]. Our study only included three children, so no comparison can be made with the rest of the patients. Most of our patients (83.8 %) had the disease for 10 to 40 years, and only two underwent the procedure within 10 years of starting epilepsy. The data also vary greatly with respect to the possible influence of the duration of the epilepsy on the response to VNS. Some authors found no significant association between the response and the duration of the epilepsy [36, 57], though others noted that its greater duration had a significant independent effect on the efficacy of VNS [31]. In some reports about children, the age of onset of epilepsy was an independent predictive factor of intractable epilepsy [14, 58]. Concerning the risk factors for epilepsy, Vonck et al. [56] compared the results of VNS between two epilepsy centers in Europe and United States, and found that patients with a history of febrile seizures, central nervous system infection, or brain injury showed no significant differences in the reduction in seizure frequency. Mental retardation remains a controversial factor, as some series [3, 48] show that patients with mental retardation respond favorably to the therapy. Other studies [1, 32, 39] showed that the response to VNS therapy was related with the severity of the mental retardation, with more positive effects in the patients with less severe intellectual disabilities, though others failed to find any relevant differences [36]. Likewise, analysis of patients with focal epilepsy and generalized epilepsy shows contradictory results. While Rychlicki et al. [44] found that partial epilepsy predicts a better prognosis for seizure control, Montanvout et al. [34] associated a better prognosis with generalized epilepsy. Comparing patients with multifocal seizures and patients with just one type of seizure, only Rice and Valeriano [43] found a greater reduction in seizures in those patients who had just one type of seizure as opposed to patients with multifocal seizures. To study the relation between the response and the baseline frequency of seizures in our series the patients were grouped according to whether they had more or fewer than the median (20 seizures/month). The patients with fewer than 20 seizures per month achieved a response sooner, and the percentage of patients who responded by 6 months was greater than in those who had more than 20 seizures per month; this association was significant. In the literature, the prognostic influence of seizure frequency varies. Some studies found no clear relation [19, 36], others detected a better prognosis associated with more seizures [31], and yet others with a lower seizure frequency [52]. Studies have found notable improvements in seizure control in patients with daily baseline seizures, as in tuberous sclerosis [158], hypothalamic hamartomas, and LennoxGastaut syndrome [97]. Nevertheless, Tanganelli et al. [38] suggested that VNS is not advisable in patients with severe
encephalopathy and a very high seizure frequency, independently of the type of seizure.
Response according to the characteristics of the video-EEG and magnetic resonance imaging We attempted to predict the response to VNS therapy from the site of the epileptogenic focus, either in the right or left hemisphere, and in the temporal lobe or elsewhere, but no site showed a positive predictive value. This could be because the vagal nerve afferents have a wide cortical and subcortical distribution, thus making it difficult to determine any association [25]. Analysis of the discharge hemisphere in our series only showed a trend to a greater response in the patients with a bilateral discharge as compared with a unilateral discharge, though the difference was not significant. Tecoma et al. [53] found that the patients with independent epileptic foci in both hemispheres may have a lower response to VNS, though another study [28] showed that the absence of bilateral interictal epileptiform discharges on the EEG was associated with a better prognosis. Analysis of the presence of a temporal lobe discharge, with or without the participation of other regions in the origin of the seizures, showed that these patients achieved a response sooner and to a greater extent than patients with no temporal lobe discharge; and as this result was significant it can be considered an early indicator of response. Comparison of this result with other studies is difficult given that the publications considering a temporal lobe discharge associated with a better prognosis relate to series with a low number of patients. Casazza et al. [18] performed EEG recordings in 12 of 17 patients, with 5 showing participation of the temporal region. Of the 17 cases, just 4 had a reduction in seizures ≥50 %, 3 of whom had ictal temporal lobe epilepsy. Based on these results, the authors suggest a better response to VNS in patients with temporal lobe seizures than with frontal or frontocentral seizures. Another two studies have evaluated the response to VNS in bitemporal epilepsy. Alsaadi et al. [4] assessed 10 patients, 60 % of whom achieved a 50 % reduction in seizures, with the mean reduction in seizures being 50.5 %. Kuba et al. [30] studied eight patients and found a reduction of ≥50 % in the frequency of clinical pattern seizures in 62.5 % of the cases, with a mean reduction in clinical pattern seizures of 42.2 %. Advances in neuroimaging techniques have made it possible to identify structural abnormalities with a high degree of accuracy and sensitivity. The relevance of structural abnormalities has been shown by the fact that the postoperative control of seizures is significantly worse in patients with no histopathologic lesions in the resected tissue, after either temporal [16, 51] or extra-temporal surgery [49, 59].
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In our series, 17 patients (44 %) had MRI lesions, a factor that was important in the last revision as significantly more patients with MRI lesions responded than patients without MRI lesions; this, therefore, could be considered an indicator of a late response. In concordance with this finding, Montavont et al. [34], in 39 patients, found a greater response rate in the group with MRI lesions than the group with a normal MRI, though the difference was not significant. Complications and side effects The postoperative complications in our series were few (19 %) and of little importance, except for one patient in whom the device had to be explanted due to infection. Side effects associated with increasing the stimulation parameters were noted in 38 % of the patients. The most usual adverse effect was dysphonia, which was present in 76.9 % of those patients who experienced adverse effects and 27 % of all the patients. The most common adverse effects reported after VNS are dysphonia, dyspnea, increasing cough, difficulty swallowing, and nausea [33]. These generally resolve spontaneously after reducing the stimulation parameters or by gradual adaptation.
Conclusions As well as other previous studies of literature, the present confirm vagal nerve stimulation efficiently reduces the frequency of seizures in patient with refractory epilepsy. We consider as predictors of response, low seizure frequency, temporal discharge on EEG-video, and MRI lesion, which can help to define patients that apply for this surgical technique. We had found that patients with a low frequency of seizures respond in a shorter time to VNS therapy. Considering temporal region discharge, whether or not associated with other discharges on the video-EEG, was associated with a sooner response, it may be an early indicator of response. On the other side, the presence of an MRI lesion may be considered an indicator of a late response. Patients with a temporal region discharge and an MRI lesion had almost four times more likely to respond. Nevertheless, the exact characteristics that should be selecting candidates (those who would benefit most after the procedure) are not well known yet.
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Comments Felix Rosenow, Marburg, Deutschland The authors report on a total of 38 patients receiving a VNS beween 2003 and 2009 with a minimum follow-up of 6 month. One patient was excluded from the retrospective analysis because the stimulation had to be removed due to infection. So this is a retrospective per protocol (and not ITT) analysis. The following factors reportedly were of significant influence on the response: (1) baseline seizure frequency (p=0.024), (2) temporal EEG discharges in VEM (p=0.037), and (3) a lesion on MRI (p=0.02). Several other analyses were conducted. The authors report to have used a Bonferroni correction; however, it remains unclear if the p values reported are after or without Bonferroni correction applied. The response rates reported are better than average. In conclusion, considering that by now, 100,000 VNS have been implanted worldwide in 70,000 patients a very small cohort of patients is reported. The clinical analyses were done in full detail but it appears unlikely that the data on 37 patients do allow the identification of reliable and significant predictors of response. Therefore, this publication, in my eyes, does not really advance the field and should be considered as confirmatory at best of what we know already. Josef Zentner, Freiburg, Germany It is well known that vagus nerve stimulation may reduce the frequency of seizures in a significant number of patients. However, the efficacy of vagus nerve stimulation is hardly to predict for the individual patient, and only single patients become completely seizure free. Therefore, vagus nerve stimulation actually is only used as a palliative procedure in patients in whom other efficient treatment options are lacking. Reliable criterions are necessary to decide which patient will benefit from this procedure. It is the merit of the authors to address this issue. Low seizure frequency and temporal seizure origin have approved to be positive
predictions of response. Moreover, patients with a low frequency of seizures responded in a shorter time. This publication contributes to select appropriate candidates for vagus nerve stimulation. Nevertheless, further work is necessary to define more accurately the significance of vagus nerve stimulation within the epilepsy surgical program. Christian Brandt, Bielefeld, Germany Vagus nerve stimulation (VNS) is licensed for the treatment of epilepsy since 1994 in the European Union and since 1997 also in the US (Hoppe, Brandt et al. 2013). The cornerstones of epilepsy therapy are drug treatment and curative epilepsy surgery. VNS is on the third place within the ranking of epilepsy therapies and will have to compete in the future with more specific stimulation procedures like deep brain stimulation. Despite the history of more than 20 years of VNS use, there are still lots of unresolved issues: especially, prospective randomized trials concerning optimal stimulation parameters with large numbers of probands are lacking, and also data on the optimal selection of patients for VNS. The study by Arcos et al. presented in this issue of Neurosurgical Review aims to elucidate prognostic factors. Therefore, it covers an important field of interest. The authors conclude that a temporal lobe discharge on the video-EEG is an indicator of an early response, and the presence of an MRI lesion indicates a late response. The study has a couple of limitations: the retrospective nature of the study, the relatively small number of included subjects, and the more or less rough scheme of the classification of epileptiform discharges in the EEG (temporal vs. extra-temporal) and the MRI findings (lesion vs. no lesion). On the other hand, this is more than has been achieved before, and it gives at least preliminary clues for counseling of patients and also identifies issues for future research. Reference Hoppe, M., et al. (2013). Vagusnervstimulation: Epilepsie. Interventionelle Neurophysiologie. J. Claßen and A. Schnitzler. Stuttgart, Thieme: 151–158.
ORIGINAL ARTICLE
Can we predict the response in the treatment of epilepsy with vagus nerve stimulation? A. Arcos & L. Romero & M. Gelabert & A. Prieto & J. Pardo & X. Rodriguez Osorio & M. A. Arráez
Received: 11 November 2012 / Revised: 25 February 2014 / Accepted: 13 April 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Despite the introduction of new antiepileptic drugs and advances in the surgical treatment of epilepsy, an important group of patients still remains uncontrolled by any of these methods. The relatively recent introduction of vagus nerve stimulation is yet another possible treatment for refractory epilepsy. This safe, simple, and adjustable technique reduces the number of seizures and multiple publications support its increasing efficacy and effectiveness, with few adverse effects. The goal of our study is to determine the efficacy of this procedure and the factors predicting a response, particularly in the presence of a temporal lobe discharge on the video electroencephalogram (video-EEG) and magnetic resonance imaging (MRI) lesions. We undertook a retrospective study of all the patients with refractory epilepsy who underwent implantation of a vagus nerve stimulator between 2003 and 2009, and with a minimum follow-up of 6 months. The statistical analysis was done with SPSS for Windows. The stimulator was implanted in 40 patients, of whom 38 had a minimum follow-up of 6 months. In one patient, the device had to be removed due to infection, so the series comprised 37 patients. These were divided into different groups, according to the epidemiologic, clinical, radiologic, and electroencephalographic data. In addition, an analysis of the response was performed.
The efficacy of the procedure was established according to the reduction in the mean seizure frequency. The baseline value of these seizures was 80.97±143.59, falling to 37±82.51 at the last revision. The response rate (reduction in seizures ≥50 %) at 6 months was 51.4 %, with 62.2 % of the patients showing this reduction at the last evaluation. Significant differences in the response were seen for the variables: baseline frequency of seizures, temporal lobe discharge on VideoEEG and MRI lesions. The mean time to response was 10 months in patients with lower rate of seizures versus 25 months of those with the higher rate (p=0.024), and the response at 6 months was higher (p=0.05). Patients with temporal lobe discharge alone or in combination with discharges over other regions had a mean time to response of 11 months versus 26 months in those without temporal discharge (p=0.037). In the analysis of the MRI, we had seen that at the last revision, 82.4 % of the patients with lesion had achieved response versus 45 % without lesion (p=0.02). Vagus nerve stimulation reduces the frequency of seizures. A temporal lobe discharge on the video-EEG is an indicator of an early response and the presence of an MRI lesion indicates a late response. Patients with fewer rates of seizures have a better prognosis. Keywords Treatment of epilepsy . Vagus nerve stimulation
A. Arcos : L. Romero : M. A. Arráez Neurosurgical Department, Carlos Haya Hospital, Málaga, Spain M. Gelabert : A. Prieto Neurosurgical Department, Clinic Hospital of Santiago de Compostela, Santiago de Compostela, Spain J. Pardo : X. R. Osorio Neurological Department, Clinic Hospital of Santiago de Compostela, Santiago de Compostela, Spain L. Romero (*) Department of Neurosurgery, HRU Carlos Haya, Málaga, Spain e-mail: [email protected]
Introduction Refractory epilepsy is a chronic incapacitating neurological disorder that affects 1 % of the general population. It is associated with a high rate of morbidity, due to the seizures and anti-epileptic drugs used, increased mortality, and reduced quality of life. The nature of the disorder leads to gradual worsening of the psychosocial, cognitive, and neuronal status [46]. Estimates by the Spanish Ministry of Health [24] suggest that 15 % of patients with refractory epilepsy are susceptible
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epilepsy surgery, though after evaluation, only 50 % of these can actually be treated with surgery, and at least 20 % continue experiencing seizures despite surgery. Patients with pharmacoresistant refractory epilepsy who are not candidates for conventional surgery, or who refuse this option or have failed to experience improvement with other surgical or medical techniques could benefit from vagus nerve stimulation (VNS) [5, 20, 26, 51]. In 1811, Parry [40] was the first to suggest that manual compression of the carotid artery could abort the epileptic seizure. Corning [20–22] then developed a carotid fork and a carotid truss, later accompanied by vagal nerve and cervical sympathetic stimulation. After performing animal experiments, Penry and Dean [42] implanted the first vagus nerve stimulator in humans in 1988. This treatment of refractory epilepsy was approved in Europe in 1994. The VNS device consists of two helicoidal electrodes (positive and negative), an anchoring cable, and a battery. It is placed by making an incision in the left lateral cervical region, exposing about 3 cm of the vagus nerve, and implanting the electrodes and the anchor around the nerve [5]. The distal end is connected to a subcutaneous bag in the anterior axilla, where the generator is placed. The risks derived from this surgery are few [6]. Complications directly related with the operation include possible systemic infections, hemorrhages, asystoles (1/1000), or acute vocal cord paralysis [7–9]. Though the exact mechanism of action of VNS remains unknown, its effect is thought to be produced by retrograde cerebral stimulation via the vagus nerve afferents, inducing increased synaptic activity in the thalamus and its projections, as well as other components of the central autonomic system. This shows a decrease in limbic system activity and an increase of some neurotransmitters such as norepinephrine and serotonin [25]. Around 80 % of the fibers of the vagus nerve, which is a mixed nerve, are afferent and proceed from the heart, lungs, aorta, and gastrointestinal tract [10]. The efferent fibers (20 %) innervate these structures and the striated musculature of the larynx and the pharynx. The activity of its afferent fibers explains the possible mechanism of action of vagal stimulation, which is projected toward the brainstem (with special importance of the solitary tract nucleus) and the encephalon, stimulating the thalamus and the amygdala (basic structures in the pathophysiology of epilepsy), and with multiple connections throughout the cerebral cortex. Its efferent fiber condition explains most of the secondary effects of stimulation and the contraindications to its implantation. The absolute contraindications for this type of surgery are left or bilateral vagotomy, right vocal cord paralysis, or severe cardiac arrhythmia. Relative complications (as stimulation might worsen the processes) include the presence of chronic obstructive pulmonary disease, obstructive sleep apnea
syndrome, severe asthma, difficulty swallowing, or the need to use the voice professionally [11, 12]. Its side effects, though relatively frequent, depend on the intensity of the stimulation and are easily controllable by adjusting the parameters of the stimulator [6]. The most common of these side effects are dysphonia, cough, cervical pain, pharyngeal problems, or even dyspnea [13]. Less common side effects include hiccups, headache, nausea, difficulty swallowing, diarrhea, urine retention, stiff neck due to sternocleidomastoid muscle spasm, phrenic involvement, or amygdala pain [14–17]. The secondary effects and complications of VNS usually diminish or disappear after correct adjustment of the stimulation parameters.
Objective The aim of this study was to assess the efficacy of VNS and determine the clinical, epidemiological and technical characteristics predicting the response.
Material and methods We undertook a descriptive, observational, retrospective study of the patients with refractory epilepsy who received a stimulator implant at the Epilepsy Unit of the Clinic Hospital of Santiago de Compostela, Spain, from 2003 to 2009. The inclusion criteria were as follows: follow-up of at least 6 months, a documented history of the seizures before implantation, and during the follow-up period, and a standardized preoperative study including at least video-EEG and MRI monitoring. The preoperative variables studied included epidemiologic data, such as the sex and age at the time of the procedure, and various clinical characteristics: the duration of the epilepsy, the baseline frequency of the seizures, risk factors, presence of mental retardation, epileptic status, and number of previous anti-epileptic drugs. The patients were divided according to the type of epilepsy into focal or generalized and the type of seizure according to the ILAE classification. The location of the epileptic discharge and the presence of a temporal lobe discharge, whether or not associated with other discharges, was established from the results of the video-EEG. The presence of MRI lesions was also evaluated. To analyze the follow-up variables, a “response” was defined with this formula: (baseline frequency of seizures—the frequency of seizures during the follow-up/the baseline frequency of seizures). We defined “responder” when the reduction in seizures was ≥50 %. These data were used to calculate the mean reduction in seizures, the percent of patients with a response, and the time to the response. Other variables studied included immediate postoperative complications, the side
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effects associated with the stimulation, and the number of anti-epileptic drugs at the last revision.
Table 2 Imaging and EEG findings
Number (%) Epilepsy discharge location Temporal Frontal Combined Generalized
Statistical analysis Univariate analysis was done to determine the influence on the response of the different variables. Quantitative variables were compared with the Student t or the Mann-Whitney test. Qualitative variables were assessed with the Chi-square test or Fisher’s exact test. To verify the hypothesis of normality of the distributions, the Kolmogorov-Smirnov test was used. Bonferroni corrections were included. Variables predicting a response were analyzed by multivariate logistic regression. The evolution of the response over time was studied by Kaplan-Meier analysis. Differences between groups were analyzed using the log-rank test. Statistical significance was set at p50 % as compared with the baseline frequency was 51.4 % at 6 months and 62.2 % at the last revision. The mean reduction in seizure frequency reported in the current literature ranges from 43 to 51 % [30, 35, 47, 54], and the response rate at the last revision reported in open studies ranges from 34 to 59 % [10, 23, 27, 37, 50, 54, 56]. These data show that patients experience a continuous and persistent improvement over time, data that coincide with earlier reports [29, 33, 45, 55]. As an indicator of the effectiveness of VNS, we also analyzed the number of drugs at the last revision as compared with baseline. It was seen that it was not possible to reduce the number of drugs. Few details have been given in the literature about changes in anti-epileptic drugs after starting VNS therapy. Salinsky et al. [45] found a significant reduction in antiepileptic drugs in the patients with VNS compared with a control group. However, Kuba et al. [30] noted that antiepileptic drugs had to be increased in 76.7 % of the patients, with a reduction in these drugs in just 10 % of the patients. Response according to epidemiologic and clinical variables In our series, no significant differences were seen in the response due to the demographic factors or clinical characteristics, apart from the baseline frequency of the seizures. This contrasts with some previous findings. The published results are discordant concerning the age at surgery. No obvious differences have been found in the response to VNS in children younger than 12 years of age as compared with adolescents, nor do clear conclusions exist concerning a greater or
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lesser response in children versus adults [2, 23, 30, 36, 41]. Our study only included three children, so no comparison can be made with the rest of the patients. Most of our patients (83.8 %) had the disease for 10 to 40 years, and only two underwent the procedure within 10 years of starting epilepsy. The data also vary greatly with respect to the possible influence of the duration of the epilepsy on the response to VNS. Some authors found no significant association between the response and the duration of the epilepsy [36, 57], though others noted that its greater duration had a significant independent effect on the efficacy of VNS [31]. In some reports about children, the age of onset of epilepsy was an independent predictive factor of intractable epilepsy [14, 58]. Concerning the risk factors for epilepsy, Vonck et al. [56] compared the results of VNS between two epilepsy centers in Europe and United States, and found that patients with a history of febrile seizures, central nervous system infection, or brain injury showed no significant differences in the reduction in seizure frequency. Mental retardation remains a controversial factor, as some series [3, 48] show that patients with mental retardation respond favorably to the therapy. Other studies [1, 32, 39] showed that the response to VNS therapy was related with the severity of the mental retardation, with more positive effects in the patients with less severe intellectual disabilities, though others failed to find any relevant differences [36]. Likewise, analysis of patients with focal epilepsy and generalized epilepsy shows contradictory results. While Rychlicki et al. [44] found that partial epilepsy predicts a better prognosis for seizure control, Montanvout et al. [34] associated a better prognosis with generalized epilepsy. Comparing patients with multifocal seizures and patients with just one type of seizure, only Rice and Valeriano [43] found a greater reduction in seizures in those patients who had just one type of seizure as opposed to patients with multifocal seizures. To study the relation between the response and the baseline frequency of seizures in our series the patients were grouped according to whether they had more or fewer than the median (20 seizures/month). The patients with fewer than 20 seizures per month achieved a response sooner, and the percentage of patients who responded by 6 months was greater than in those who had more than 20 seizures per month; this association was significant. In the literature, the prognostic influence of seizure frequency varies. Some studies found no clear relation [19, 36], others detected a better prognosis associated with more seizures [31], and yet others with a lower seizure frequency [52]. Studies have found notable improvements in seizure control in patients with daily baseline seizures, as in tuberous sclerosis [158], hypothalamic hamartomas, and LennoxGastaut syndrome [97]. Nevertheless, Tanganelli et al. [38] suggested that VNS is not advisable in patients with severe
encephalopathy and a very high seizure frequency, independently of the type of seizure.
Response according to the characteristics of the video-EEG and magnetic resonance imaging We attempted to predict the response to VNS therapy from the site of the epileptogenic focus, either in the right or left hemisphere, and in the temporal lobe or elsewhere, but no site showed a positive predictive value. This could be because the vagal nerve afferents have a wide cortical and subcortical distribution, thus making it difficult to determine any association [25]. Analysis of the discharge hemisphere in our series only showed a trend to a greater response in the patients with a bilateral discharge as compared with a unilateral discharge, though the difference was not significant. Tecoma et al. [53] found that the patients with independent epileptic foci in both hemispheres may have a lower response to VNS, though another study [28] showed that the absence of bilateral interictal epileptiform discharges on the EEG was associated with a better prognosis. Analysis of the presence of a temporal lobe discharge, with or without the participation of other regions in the origin of the seizures, showed that these patients achieved a response sooner and to a greater extent than patients with no temporal lobe discharge; and as this result was significant it can be considered an early indicator of response. Comparison of this result with other studies is difficult given that the publications considering a temporal lobe discharge associated with a better prognosis relate to series with a low number of patients. Casazza et al. [18] performed EEG recordings in 12 of 17 patients, with 5 showing participation of the temporal region. Of the 17 cases, just 4 had a reduction in seizures ≥50 %, 3 of whom had ictal temporal lobe epilepsy. Based on these results, the authors suggest a better response to VNS in patients with temporal lobe seizures than with frontal or frontocentral seizures. Another two studies have evaluated the response to VNS in bitemporal epilepsy. Alsaadi et al. [4] assessed 10 patients, 60 % of whom achieved a 50 % reduction in seizures, with the mean reduction in seizures being 50.5 %. Kuba et al. [30] studied eight patients and found a reduction of ≥50 % in the frequency of clinical pattern seizures in 62.5 % of the cases, with a mean reduction in clinical pattern seizures of 42.2 %. Advances in neuroimaging techniques have made it possible to identify structural abnormalities with a high degree of accuracy and sensitivity. The relevance of structural abnormalities has been shown by the fact that the postoperative control of seizures is significantly worse in patients with no histopathologic lesions in the resected tissue, after either temporal [16, 51] or extra-temporal surgery [49, 59].
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In our series, 17 patients (44 %) had MRI lesions, a factor that was important in the last revision as significantly more patients with MRI lesions responded than patients without MRI lesions; this, therefore, could be considered an indicator of a late response. In concordance with this finding, Montavont et al. [34], in 39 patients, found a greater response rate in the group with MRI lesions than the group with a normal MRI, though the difference was not significant. Complications and side effects The postoperative complications in our series were few (19 %) and of little importance, except for one patient in whom the device had to be explanted due to infection. Side effects associated with increasing the stimulation parameters were noted in 38 % of the patients. The most usual adverse effect was dysphonia, which was present in 76.9 % of those patients who experienced adverse effects and 27 % of all the patients. The most common adverse effects reported after VNS are dysphonia, dyspnea, increasing cough, difficulty swallowing, and nausea [33]. These generally resolve spontaneously after reducing the stimulation parameters or by gradual adaptation.
Conclusions As well as other previous studies of literature, the present confirm vagal nerve stimulation efficiently reduces the frequency of seizures in patient with refractory epilepsy. We consider as predictors of response, low seizure frequency, temporal discharge on EEG-video, and MRI lesion, which can help to define patients that apply for this surgical technique. We had found that patients with a low frequency of seizures respond in a shorter time to VNS therapy. Considering temporal region discharge, whether or not associated with other discharges on the video-EEG, was associated with a sooner response, it may be an early indicator of response. On the other side, the presence of an MRI lesion may be considered an indicator of a late response. Patients with a temporal region discharge and an MRI lesion had almost four times more likely to respond. Nevertheless, the exact characteristics that should be selecting candidates (those who would benefit most after the procedure) are not well known yet.
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Comments Felix Rosenow, Marburg, Deutschland The authors report on a total of 38 patients receiving a VNS beween 2003 and 2009 with a minimum follow-up of 6 month. One patient was excluded from the retrospective analysis because the stimulation had to be removed due to infection. So this is a retrospective per protocol (and not ITT) analysis. The following factors reportedly were of significant influence on the response: (1) baseline seizure frequency (p=0.024), (2) temporal EEG discharges in VEM (p=0.037), and (3) a lesion on MRI (p=0.02). Several other analyses were conducted. The authors report to have used a Bonferroni correction; however, it remains unclear if the p values reported are after or without Bonferroni correction applied. The response rates reported are better than average. In conclusion, considering that by now, 100,000 VNS have been implanted worldwide in 70,000 patients a very small cohort of patients is reported. The clinical analyses were done in full detail but it appears unlikely that the data on 37 patients do allow the identification of reliable and significant predictors of response. Therefore, this publication, in my eyes, does not really advance the field and should be considered as confirmatory at best of what we know already. Josef Zentner, Freiburg, Germany It is well known that vagus nerve stimulation may reduce the frequency of seizures in a significant number of patients. However, the efficacy of vagus nerve stimulation is hardly to predict for the individual patient, and only single patients become completely seizure free. Therefore, vagus nerve stimulation actually is only used as a palliative procedure in patients in whom other efficient treatment options are lacking. Reliable criterions are necessary to decide which patient will benefit from this procedure. It is the merit of the authors to address this issue. Low seizure frequency and temporal seizure origin have approved to be positive
predictions of response. Moreover, patients with a low frequency of seizures responded in a shorter time. This publication contributes to select appropriate candidates for vagus nerve stimulation. Nevertheless, further work is necessary to define more accurately the significance of vagus nerve stimulation within the epilepsy surgical program. Christian Brandt, Bielefeld, Germany Vagus nerve stimulation (VNS) is licensed for the treatment of epilepsy since 1994 in the European Union and since 1997 also in the US (Hoppe, Brandt et al. 2013). The cornerstones of epilepsy therapy are drug treatment and curative epilepsy surgery. VNS is on the third place within the ranking of epilepsy therapies and will have to compete in the future with more specific stimulation procedures like deep brain stimulation. Despite the history of more than 20 years of VNS use, there are still lots of unresolved issues: especially, prospective randomized trials concerning optimal stimulation parameters with large numbers of probands are lacking, and also data on the optimal selection of patients for VNS. The study by Arcos et al. presented in this issue of Neurosurgical Review aims to elucidate prognostic factors. Therefore, it covers an important field of interest. The authors conclude that a temporal lobe discharge on the video-EEG is an indicator of an early response, and the presence of an MRI lesion indicates a late response. The study has a couple of limitations: the retrospective nature of the study, the relatively small number of included subjects, and the more or less rough scheme of the classification of epileptiform discharges in the EEG (temporal vs. extra-temporal) and the MRI findings (lesion vs. no lesion). On the other hand, this is more than has been achieved before, and it gives at least preliminary clues for counseling of patients and also identifies issues for future research. Reference Hoppe, M., et al. (2013). Vagusnervstimulation: Epilepsie. Interventionelle Neurophysiologie. J. Claßen and A. Schnitzler. Stuttgart, Thieme: 151–158.
