Epilepsy & Behavior 31 (2014) 329–333
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Vagus nerve stimulation in pediatric patients: Is it really worthwhile? Vera C. Terra a,⁎, Luciano L. Furlanetti b, Altacílio Aparecido Nunes c, Ursula Thomé a, Meire Akico Nisyiama a, Américo C. Sakamoto a, Helio R. Machado a a b c
Centro de Cirurgia de Epilepsia (CIREP), Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, SP, Brazil Division of Stereotactic and Functional Neurosurgery, University Hospital Freiburg, Freiburg im Breisgau, Germany Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, SP, Brazil
a r t i c l e
i n f o
Article history: Received 12 September 2013 Revised 6 October 2013 Accepted 10 October 2013 Available online 5 November 2013 Keywords: Epilepsy Vagal nerve stimulation Pediatric neurosurgery
a b s t r a c t Vagus nerve stimulation (VNS) seems to be effective in the management of selected cases of pharmacoresistant epilepsy in children. This was a case–control prospective study of children with refractory epilepsy submitted to vagal nerve stimulator implantation and a control group with epilepsy treated with antiepileptic drugs. Patients under 18 years of age who underwent clinical or surgical treatment because of pharmacoresistant epilepsy from January 2009 to January 2012 were followed and compared with an age-matched control group at ﬁnal evaluation. Statistically signiﬁcant differences were observed considering age at epilepsy onset (VNS group — 1.33 ± 1.45 years; controls — 3.23 ± 3.11; p = 0.0001), abnormal ﬁndings in neurological examination (p = 0.01), history of previous ineffective epilepsy surgery (p = 0.03), and baseline seizure frequency (p=0.0001). At long-term follow-up, 55.4% of the patients in the VNS group had at least 50% reduction of seizure frequency, with 11.1% of the patients presenting 95% reduction on seizure frequency. Also, a decrease in traumas and hospitalization due to seizures and a subjective improvement in mood and alertness were observed. The control group did not show a signiﬁcant modiﬁcation in seizure frequency during the study. In this series, VNS patients evolved with a statistically signiﬁcant reduction of the number of seizures, a decreased morbidity of the seizures, and the number of days in inpatient care. In accordance with the current literature, VNS has been proven to be an effective alternative in the treatment of pediatric patients with drug-resistant epilepsy. © 2013 Elsevier Inc. All rights reserved.
1. Introduction Epilepsy is probably the most prevalent neurological disease that requires ongoing treatment in all age groups and can have signiﬁcant and even devastating consequences for the patient and his or her family. In infants and young children, epilepsy is even more frequent compared with adults and may be associated with developmental stagnation or regression. If not properly treated, the affected child's outcome for cognitive achievement remains restrained . Despite recent advances in the comprehension of the neuropathology of epilepsy and concerning its clinical management, satisfactory seizure control remains elusive in 30–40% of patients . Although surgical treatment may be appropriate if the epilepsy is severe, medically refractory, and/or caused by a focal epileptogenic lesion, only 10–30% of these patients are appropriate candidates for temporal lobectomy, focal cortical resection, callosotomy, hemispherectomy, subpial transection, or other surgical procedures . Clinical experience with vagal nerve stimulation (VNS) was initiated around twenty years ago with the ﬁrst human implantation. The Food and Drug Administration (FDA) approved the Cyberonics stimulator in ⁎ Corresponding author at: Centro de Cirurgia de Epilepsia, Departamento de Neurologia, Psiquiatria e Psicologia Médica, Ribeirão Preto CEP 14048-900, Brazil. Fax: + 55 16 3633 0760. E-mail address: [email protected]
(V.C. Terra). 1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.yebeh.2013.10.011
1997 as an adjunctive therapy for the treatment of pharmacoresistant epilepsy in patients over 12 years of age , and since then, most of the studies that aimed to evaluate clinical efﬁcacy were conducted with adults [4–6]. However, recent reports regarding its application in children and adolescents have shown an encouraging experience that supports the application of this tool in young patients [4,6–12]. In the present study, we performed a matched case–control study to explore the outcome of epilepsy in patients submitted to vagal nerve stimulator implantation in a consecutive and prospective study group of 36 children with epilepsy operated on in the same institution. 2. Materials and methods We reviewed all medical records of patients younger than 18 years of age that underwent clinical or surgical treatment due to pharmacoresistant epilepsy, in our university hospital, from January 2009 to January 2012. Data of a subgroup of patients submitted to implantation of a vagal nerve stimulator were analyzed concerning epilepsy classiﬁcation, previous medical or surgical therapies, adverse events due to VNS, and ﬁnal outcomes and were compared to an age-matched control group with epilepsy not implanted with a vagal nerve stimulator. Approval of the ethical committee was given to conduct this analysis. All patients were ﬁrst evaluated in outpatient clinical care and then submitted to
V.C. Terra et al. / Epilepsy & Behavior 31 (2014) 329–333
long-term video-electroencephalographic monitoring and highresolution 3-T Siemens Vision magnetic resonance imaging (MRI). The VNS group consisted of patients in whom resective surgery was not possible or surgery was ineffective to seizure control. The control group consisted of patients matched by age with one of the following conditions: patients waiting for epilepsy surgery (26 cases), patients with incomplete investigation that needs PET scan or subdural grids (24 cases), patients with vagal nerve stimulator implantation indicated in which surgery could not be done because of insufﬁcient local resources (16 cases) or families that refused surgery (2 cases), and one patient with severe thrombocytopenia. Selection for vagal nerve stimulator implantation was done considering order of evaluation. Follow-up ranged from 12 months to four years. A simple questionnaire which considered the main data observed in the literature was developed to evaluate the effects of epilepsy in patients' life. In this questionnaire, we evaluated seizure intensity, presence of different seizure types, occurrence of hospitalizations, and history of traumas secondary to seizures. Also, incidence of side effects related to vagal nerve stimulator implantation was evaluated by direct questions. The questionnaire was answered by parents. Hospitalizations were calculated based on all visits to the hospital per year lasting more than 12 h. We considered as traumas all traumatic events that led the patient to hospital care per year. Surgical procedure consisted of left-sided lead and generator implantation, according to the surgical technique already described . Patients had the generator activated 24 h after surgery and were discharged from the hospital at the third postoperative day. Current was increased until 1.25 mA except in patients that complain of discomfort and present persistent coughing or autonomic changes. Other parameters were maintained stable at this moment (signal frequency: 30 Hz; time on: 30 s, time off: 5 min, and pulse width: 500 μs). Routine postoperative outpatient follow-up appointments were scheduled within one week and then one month, three months, and every six months. Patients in the control group were evaluated every three months. Data collected included age at onset of seizures, etiology and classiﬁcation of epilepsy, seizure types, patient's age at surgery, history of previous surgical treatment, antiepileptic drugs (AEDs) in use, and average monthly frequency of seizures before and after VNS, as well as surgical complications or side effects. 2.1. Statistical analysis A chi-squared test was used to compare categorical variables between controls and patients implanted with a vagal nerve stimulator. Differences between numerical data were assessed using unpaired Student's t-tests. Analyses were implemented by the software PASW Statistics 18 (release 18.0.0, July 30, 2009). 3. Results We analyzed all 36 patients within the age range of up to 18 years old, with medically intractable epilepsy, who were submitted to vagal nerve stimulator implantation in our service. Patients were implanted from February 2009 to January 2012 and were compared to 72 agematched controls with refractory epilepsy not submitted to vagal nerve stimulator implantation who were selected in the same period.
Table 1 Epilepsy onset and mean seizure frequency.
Age at epilepsy onset Age at last evaluation Baseline seizure frequency (month) Last evaluation seizure frequency (month)
1.33 ± 1.45 9.93 ± 4.89 346.64 ± 134.11 152.62 ± 135.48
3.23 ± 3.11 10.15 ± 4.91 83.63 ± 41.43 104.46 ± 65.89
0.0001 0.82 0.0001 0.22
Table 2 Demographic data comparing patients in the VNS and control groups. VNS Control p group (%) group (%) Sex Male Female IPI Yes No Number of different seizure types 1 2 3 Epilepsy syndrome Focal Generalized Indetermined Physical examination Normal Abnormal Neurological examination Normal or mild MR Moderate or accentuated MR Number of AEDs 1/2 3/4 Previous epilepsy surgery Yes No
16 (44.4) 20 (55.6)
27 (37.5) 45 (62.5)
11 (30.6) 25 (69.4)
20 (27.8) 52 (72.2)
17 (47.2) 18 (50.0) 1 (2.8)
48 (66.7) 22 (30.6) 2 (2.7)
19 (52.8) 12 (33.3) 5 (13.9)
56 (77.8) 16 (22.2)
32 (88.9) 4 (11.1)
55 (76.4) 17 (23.6)
10 (27.8) 26 (72.2)
39 (54.2) 33 (45.8)
7 (30.6) 25 (69.4)
26 (36.1) 46 (63.9)
9 (25) 27 (75)
6 (8.3) 66 (91.7)
OD: odds ratio; CI: conﬁdence interval; IPI: initial precipitating event; MR: mental retardation; AEDs: antiepileptic drugs. a Considering one and two seizure types.
The descriptive data are presented in Tables 1 to 3. Males represented 55.6% of the VNS group and 62.5% of the control group (OR: 1.33). Age at epilepsy onset was statistically signiﬁcantly earlier for the VNS group (1.33 ± 1.45 years) when compared to the control group (3.23 ± 3.11; p = 0.0001), but patients were last evaluated at approximately the same age (VNS: 9.93 ± 4.89 and control: 10.15 ± 4.91; p = 0.82). Considering other demographic data, no differences were observed between the VNS group and the control group (Table 2), including the incidence of initial precipitating injury, number of different seizures types, epilepsy syndrome, physical examination, and number of antiepileptic drugs in use at the time of evaluation. Focal epilepsy was observed in 52.8% of the patients in the VNS group and 77.8% of the patients in the control group, demonstrating a prevalence of this form of epilepsy in our patients. However, patients in the VNS group had signiﬁcantly more abnormal ﬁndings on neurological examination (p = 0.01) and history of previous ineffective epilepsy surgery (p = 0.03). Baseline seizure frequencies per month were 346.64 ± 134.11 episodes for the VNS group and 83.63 ± 41.43 episodes for the control group (Table 1). This result showed a statistically signiﬁcant difference (p = 0.0001). Considering patients with focal or generalized epilepsies,
Table 3 MRI ﬁndings in the VNS and control groups.
Brain atrophy MCD Gliosis Tuberous sclerosis Mesial temporal sclerosis Othersa Normal Total
VNS group (%)
Control group (%)
12 (33.3) 10 (27.8) 5 (13.9) 1 (2.8) 0 2 (5.5) 6 (16.7) 36
16 (22.2) 19 (26.4) 12 (16.7) 4 (5.6) 4 (5.6) 3 (5.4) 13 (18.1) 71
28 29 17 5 4 5 19 107
MCD: malformation of cortical development. a Ischemic vascular accident, Sturge–Weber syndrome, arteriovenous malformation, hypothalamic hamartoma, mesial temporal sclerosis + MCD.
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we could not observe a signiﬁcantly different response in respect to seizure control when comparing both groups. At long-term follow-up, monthly seizure frequency for the VNS group decreased to 152.62 ± 135.48 episodes, and in the control group, seizure frequency was 104.46 ± 65.89 episodes (p = 0.22). This result demonstrated that the VNS group had more seizures at baseline than the control group, suggesting that the VNS group may have more severe epilepsies. However, long-term follow-up demonstrated that both groups had similar seizure frequencies. Comparing pre- and postseizure frequency in the VNS group, we observed that seizure reduction was statistically signiﬁcant (p = 0.0001), showing that VNS was effective. Also, 55.4% of patients had a reduction of at least 50% in seizure frequency, and from these patients, 4 or 11.1% of all patients in the VNS group had at least 95% reduction of seizure frequency, and one patient was seizurefree for 8 months in the last follow-up. However, two patients (5.6%) had worsening of seizure frequency (one with a focal cortical dysplasia in the motor strip and the other with bilateral asymmetric posterior cortex gliosis), and three patients (8.4%) had less than 25% reduction in seizure frequency. In respect to the control group, we observed that seizure frequency at baseline was 83.63 ± 41.43 episodes, and at last follow-up, seizure frequency was 104.46 ± 65.89 episodes (p N 0.0001). This may suggest an aggravation of epilepsy or may correspond to seasonality of seizures. Antiepileptic drug medications were modiﬁed equally in both the control and VNS groups during the study according to the needs of the patient considering seizure frequency and adverse events. Considering MRI ﬁndings (Table 3), the majority of patients presented with brain atrophy, followed by malformation of cortical development, gliosis, and tuberous sclerosis. In the control group, mesial temporal sclerosis was found in four patients, and surgery was not indicated in these cases because of inadequate lateralization. Normal MRI ﬁndings were observed in six patients of the VNS group and 13 control patients. A simple questionnaire was given to all patients at the time of implantation and then after long-term follow-up (Table 4). Before vagal nerve stimulator implantation, the VNS group had signiﬁcantly more hospitalizations (p = 0.0001) and traumas related to epilepsy (p=0.02) than the control group. At long-term follow-up, this difference did not become signiﬁcant (p = 1.00 for hospitalization and for history of traumas). The seizures of patients whose seizure frequency was maintained had similar aspects to those observed before implantation, and only six patients in the VNS group considered their seizures as becoming more severe or more prolonged than those observed before vagal nerve stimulator implantation. However, 76.4% of the patients in the control group considered their seizures as more severe.
Table 4 Negative seizure effects in the VNS and control groups. VNS group Control group Seizure intensity Weaker Similar Stronger Different seizures Yes No Hospitalizations (pre) Yes No Hospitalizations (post) Yes No History of traumas (pre) Yes No History of traumas (post) Yes No
10 (27.8) 20 (55.6) 6 (16.6)
0 17 (23.6) 55 (76.4)
1 (2.8) 35 (97.2)
1 (1.4) 71 (98.6)
19 (52.8) 17 (47.2)
6 (8.3) 66 (91.7)
0.0001 12.29 4.25–35.55
3 (8.3) 33 (91.7)
6 (8.3) 66 (91.7)
16 (44.4) 20 (55.6)
16 (22.2) 56 (77.8)
8 (22.2) 28 (77.8)
16 (22.2) 56 (77.8)
Negative side effects were observed in some patients and were reported as hoarseness (36.1%), cough (30.6%), hiccup (16.7%), breathlessness (8.3%), and somnolence (8.3%). These symptoms were aggravated by an increase in stimulus intensity but were tolerated in all except one patient who needed a decrease in VNS parameters. Positive side effects were also observed and were reported by the parents as improvement in attention (72.2%), mood (52.8%), language (19.4%), and memory (19.4%), and 44.4% of the parents reported that their children were happier. Considering the control group, the number of hospitalizations and traumas due to seizures did not have any changes. Neither patient group identiﬁes modiﬁcations in attention, mood, language, memory, and humor. Two patients died during follow-up: one patient with Lennox– Gastaut syndrome who died from aspiration pneumonia and one patient who had worsening of seizure frequency after vagal nerve stimulator implantation. This last patient had already been submitted to an ineffective epilepsy surgery in the posterior cortex, did not tolerate an increase in VNS parameters, and died in immediate postoperation of a callosotomy performed in another hospital. Three patients developed an infection that could not be treated with antibiotics, and the device had to be removed, and one patient experienced lead fracture 16months after vagal nerve stimulator implantation. No other signiﬁcant complications were observed. 3.1. Device programming None of the patients needed device substitution. The device was activated on the next day of surgery, and, the current was increased up to 1.5 mA in the next two days, with maintenance of the following parameters: time on: 30 s, time off: 5 min, pulse width: 500 μs, and frequency: 30 Hz. Parameters remained stable for at least three months, and these were then changed according to seizure frequency and/or the presence of side effects. Details of the parameters used are shown in Table 5. 4. Discussion Here, we describe a case–control prospective study comparing pediatric patients with refractory epilepsy submitted or not to vagal nerve stimulator implantation. Analyzing the data presented, we can observe that patients submitted to vagal nerve stimulator implantation had early epilepsy onset and signiﬁcantly more seizures than the control group, suggesting that this group contains patients with more severe forms of epilepsy. Nevertheless, long-term follow-up demonstrated that these patients had an overall signiﬁcant reduction in seizure frequency, with 55.4% of the patients presenting at least 50% reduction in seizure frequency, and 11.1% of patients presenting an excellent outcome, with 95% seizure reduction. Only two patients evolved with worsening of seizures, and in these cases, the vagal nerve stimulator was turned off. These results are in concordance with those reported in the literature by almost all authors [14–19]. In a meta-analysis study, Englot et al.  demonstrated an average reduction in seizure frequency of 45%, with 51% reduction in patients followed for more than one year of therapy. Table 5 VNS parameters. Output current
1.00 1.25 1.50 1.75 2.00 2.25 2.75
2 8 8 11 4 2 1
21 30 60
1 34 1
1.80 3.00 5.00
4 6 26
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Almost 25% of the patients with refractory epilepsy fall in the pediatric age group . Only 10–20% of the children with epilepsy, who remain with active epilepsy in adulthood, will have spontaneous seizure remission, suggesting that early attempts to control the epilepsy should be pursued [22–24]. In this way, epilepsy surgery should be considered a treatment option early in life, and vagal nerve stimulator implantation should be considered if resective surgery is not possible or if signiﬁcant deﬁcits have to be avoided. This is the ﬁrst prospective study in the literature concerning vagal nerve stimulator implantation in children with refractory epilepsy compared with a cohort of clinically similar children with difﬁcult-to-control epilepsy. Although this study does not represent a very long-term follow-up, we observed in our control group that epilepsy severity remained stable with time, showing persistence of seizures. Also, a number of hospitalizations and traumas were stable, and positive factors related to humor and learning were not observed. It should be considered that patients did not have a signiﬁcant worsening of these conditions but considering that this is a pediatric group of patients, the maintenance of high seizure frequency may contribute to the development of future social and cognitive sequelae related to epilepsy . In this study, the VNS group also showed a signiﬁcant reduction in traumas associated with seizures and in the number of hospitalizations. This has been widely discussed by Helmers et al.  and other authors [16,20]. Also, many positive effects such as improvement of mood and alertness, irrespective of a reduction in seizure frequency, have been demonstrated, suggesting that VNS may act beyond seizure control [18,26]. Vagal nerve stimulation is considered as an adjunctive treatment for adult patients with pharmacoresistant epilepsy, and only recently,it has been indicated for children. However, most published studies, until now, suggest that VNS therapy in children has a similar proﬁle of efﬁcacy for seizure control to that in adults, with low mortality and morbidity [13,18]. Pediatric patients should also be considered as a special group since in this age, effects of antiepileptic drugs and seizures on neurodevelopment may be long-lasting. In this way, VNS has additional beneﬁcial effects in children as opposed to antiepileptic drugs, and there are no negative effects on cognition . An important question that still remains is how to identify the patients who will best beneﬁt from VNS treatment, especially in countries with limited resources that may need to deﬁne a more restrictive policy of VNS indication. However, most of the reports in the literature had an insufﬁcient number of patients with speciﬁc epilepsy syndromes. In this way, Englot et al.  observed that patients with generalized epilepsies, posttraumatic epilepsies, and tuberous sclerosis had a positive predictor of a favorable outcome. Zamponi et al.  and, more recently, Morris et al.  reported that VNS led to a greater reduction in drop attacks and absence status epilepticus in patients with Lenox–Gastaut syndrome. Abd-El-Barr et al.  also suggested that atonic head nods were more amenable than tonic drop attacks, and patients with focal or lateralized epileptiform abnormalities responded better compared to those with more diffuse or poorly localized ictal and interictal abnormalities. In our study, almost half of the patients had focal epilepsy, but we could not demonstrate a different response in seizure control when comparing both groups. Overall, our results suggest that VNS treatment is well tolerated in pediatric patients, with a reasonable effect on seizure control, reduction of hospitalizations and traumas due to epilepsy, and improvement of mood and alertness. These results are in accordance with those reported by the American Academy of Neurology , and this is especially important considering that these patients usually have dozens of seizures per day that were unresponsive to other therapy. However, one should always bear in mind that VNS is an adjunctive palliative treatment, and approximately 25 to 30% of the patients may not reap beneﬁts from therapy.
5. Conclusion Neuromodulation has vastly expanded the treatment options for patients with epilepsy during the last decade; however, at least in developing countries, the initial investment still represents a barrier for its implementation. Yet in long-term follow-up, our results in pediatric patients are similar to those of previous studies showing that VNS may be more cost-effective in comparison with the best medical antiepileptic therapy [2,4–6,11,12,30,31]. The equipment is not covered by insurance even if treatment with conventional AEDs is proven to have failed. This may explain why VNS therapy was just lately introduced in our armamentarium, and only few patients were treated in 3 years of follow-up. In accordance with the current literature, in our series, VNS has been proven to be an effective alternative in the treatment of pediatric patients with drug-resistant epilepsy.
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