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Nerve vagus stimulation experience from USA
european journal of paediatric neurology 12, suppl. 1 (2008) S20–S25
Official Journal of the European Paediatric Neurology Society
17th May 2008 (Saturday) 08.15−9.45 Non-pharmacological treatment of epilepsy INV47 Expanding indications for epilepsy surgery in childhood I. Tuxhorn, P. Kotagal. Pediatric Epilepsy Center in the Neurologic Institute, Cleveland, USA The incidence of epilepsy peaks in childhood and a number of well defined syndromes are amenable to surgical management. Early seizure onset, a high seizure frequency and intractability are significant risk factors for developmental and social outcome. Therefore children with surgically remediable epilepsies should be selected early for operation. Presurgical evaluation should be considered as a multi-step approach to assure that the individually available resources for pre-surgical evaluation and surgical therapy are well and timely utilized by the treating network of physicians. The first diagnostic steps should include a good characterization of the seizure semiology by history, parental documentation by home video if possible, a good quality surface inter-ictal EEG and structural imaging with MRI. Unifocal epilepsy due to a well demarcated lesion (tumor, malformation of cortical development, other acquired vascular, ischemic or inflammatory pathologies) carries the best seizure outcome prognosis. Referral to an experienced and well versed epilepsy center where a standardized presurgical evaluation with surface interictal and ictal EEG, structural and functional imaging, language, memory and cognitvie testing is performed, should be considered early in such cases. Even intractable epilepsies due to multicentric or extensive bilateral disease such as tuberous sclerosis, Sturge Weber Syndrome or remote epilepsies due to strokes may be surgically remedial in terms of either cure or palliation. The presurgical evaluation in these cases may require invasive video EEG monitoring with intracranial electrodes, functional interictal and ictal imaging with SPECT, PET, fMRI to localize the epileptogenic zone and delineate it from eloquent cortex that may not be sacrificed. Although congruence of diagnostic findings is the goldstandard for presurgical selection, it is becoming increasingly clearer that generalized epileptiform discharges in the constellation of other localizing features (e.g. pathologic substrate, seizure semiology) may not be a contraindication to surgery. This may particularly apply to the static structural epileptic encephalopathies in infants which may be particularly challenging to demarcate from progressive metabolic disorders. Epilepsy surgery should be considered early in the treatment paradigm of any intractable epilepsy of childhood along
with the newer antiepiletics, ketogenic diet and vagal nerve stimulation. OP10 Bone marrow transplantation for Rasmussen Syndrome A. Nishimura1 , M. Morimoto1 , A. Morimoto1 , M. Koyama2 , K. Kawa2 . 1 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan, 2 Department of Hematology/Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan Purpose: Rasmussen Syndrome is a rare but severely and slowly progressive disease of chronic inflammation in the CNS, leading to unilateral hemispheric atrophy, associated progressive neurological deficit and intractable partial motor seizures. Based on recent data on the pathogenesis of the disease, some autoimmune mechanisms have been postulated. Immunomodulatory therapies have been applied, and several case reports have been reported with controversial results. Rasmussen Syndrome might be responsive to suppression or modulation of the immune system with such as bone marrow transplantation (BMT). Case: We report a 10-year-old male with Rasmussen Syndrome whose symptoms began at the age of 7 years. Various therapies including antiepileptic drugs, steroids, cyclosporins, immunoglobulin, were applied, but the effects were not satisfied. The patient’s family has decided to treat the patient with BMT at the age of 10 years, under the permission of Ethical Committee of our university. Frequency and intensity of epileptic seizures were reduced significantly, but a good outcome regarding progression rate of brain atrophy on MRI was not decided because of his death at 149th day after the BMT. The cause of his death was bronchiolitis obliterans organizing pneumonia (BOOP) associated with chronic GVHD. Conclusion: BMT might be possible therapeutic choice for Rasmussen Syndrome. However, a greater number of patients and a longer observation period are needed before definitive conclusions can be drawn. INV48 Nerve vagus stimulation
experience from USA
E. Thiele. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA The Vagus Nerve Stimulator (VNS; Cyberonics, Inc) was approved by the US Food and Drug Administration in 1997 as adjunctive therapy for intractable partial epilepsy in patients 12 years of age and older. To date, 40,338 patients have had the VNS implanted in the USA for the treatment of epilepsy or depression; 47,787 patients have had the VNS implanted worldwide. The VNS has two modes of operation: continuous intermittent stimulation and magnet activated stimulation. Magnet activation is used at onset of aura or
1090-3798/ $ – see front matter © 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
17th May 2008 (Saturday), Oral presentations 08.15−09.45
S21
seizure onset, and can cause the seizure to be aborted, less severe, and can lessen the postictal period. Multiple clinical studies have shown that the VNS is both effective with regard to improving seizure control as well as overall very well tolerated. Commonly reported side effects include voice alteration during stimulation, cough, hoarseness and throat parasthesias, but the cognitive side effects known to occur occasionally with anticonvulsant medications have not been seen. Although the exact mechanism of action of the VNS is unknown, several hypotheses haven been proposed, including modifying the activity of the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. A recent retrospective study at the Carol and James Herscot Center for Tuberous Sclerosis Complex identified 16 patients with TSC who underwent VNS implantation due to intractable epilepsy. Three of the 16 (19%) had a >80% reduction in seizure frequency, five (31%) had a 50−79% reduction, two (13%) had a <50% reduction, one had benefit from magnet activation only, and five (31%) had no improvement in seizure frequency. Intermittent magnet use effectively aborted seizures in eight (50%) of the patients. Five of the 16 patients reported improved cognition and/or behavior after VNS implantation.
outcome in order to avoid ineffective VNS implantation surgery.
OP11 Transcranial direct current stimulation (tDCS) for the prediction of VNS therapy outcome in pediatric patients I. Orosz1 , G. Kerling2 , J. Hoffmann3 , T. Polster4 , M. Hoppe4 , I.R. Konig5 , J. Sperner1 . 1 Children’s Hospital, University of Lubeck, Germany, 2 Epilepsy Center, Department of Neurology, University of Erlangen, Germany, 3 Department of Epileptology, Medical Center University of Bonn, Germany, 4 Epilepsy Center Bethel, Bielefeld, Germany, 5 Institute of Medical Biometry and Statistics, University of Lubeck, Germany Objective: To test the hypothesis of similar effects of vagus nerve stimulation (VNS) and tDCS on seizure reduction and its use as a predictive tool for VNS efficacy for refractory epilepsy in children and adolescents. Scientific background: VNS is effective in 30−40% of patients with pharmacoresistant epilepsy. However, no prediction is possible for VNS therapy outcome. tDCS is a recently developed method to stimulate the cortex non-invasively and painless and is used for treatment of epilepsy and depression. The cathodal stimulation induces a local hyperpolarization of the cortex and leads to an increase of the seizure treshold, which explains anticonvulsive effects. Methods: VNS non-responders were treated with a CEcertified tDCS device (Neuroconn, Germany) and seizure frequency together with epileptic discharges were compared before and after tDCS. VNS candidates were treated with tDCS one to four weeks before implantation. Changes in seizure frequency and EEG were correlated to VNS-outcome in terms of seizure reduction six months after implantation. tDCS was performed with two flat electrodes (area 35 cm2 ) using 1 mA direct current for 15 minutes. The cathode was placed over the epileptic focus and the anodal electrode to the contralateral hemisphere. EEG results were drawn immediately before and after stimulation. All participants were aged <18 years. Results: In 9/9 VNS-nonresponders no effects have been observed after tDCS, neither on EEG nor on seizure frequency. However, in 3/12 (25%) VNS-candidates tDCS resulted in short term reduction of seizure frequency and epileptic discharges. Conclusion: According to our preliminary results, short tDCS effects seem to be correlated with VNS outcome. A German multicenter study has started (Lubeck, Bethel, Erlangen and ¨ Bonn) to proof the predictive power of tDCS for VNS therapy
OP12 Long-term results of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of pharmacoresistant epilepsy in children and adolescents under 18 years of age P. Zwolinski, M. Roszkowski. Dept of Neurosurgery, The Children’s Memorial Health Institute, Warsaw, Poland Objective: To evaluate long term seizure reduction and ondemand magnet use in children and adolescents under 18 years of age with pharmacoresistant epilepsy who were treated with adjunctive vagus nerve stimulation (VNS) therapy. Material and Methods: 57 children and adolescents (32 M, 25 F; 59.6% 12 years). Mean age at implantation: 11.4±3.85 years; mean duration of epilepsy: 9.2±4.14 years. Seven patients underwent prior epilepsy surgery; 64.9% were mentally retarded and 38.6% had neurological deficits. MRI was abnormal in 57.9%. Simple partial seizures: 38.6% of the patients; complex partial: 96.5%; secondarily generalized tonic-clonic: 56.1%; myoclonic: 8.8%. Seizure reduction was evaluated after 6, 12, 24, 36 and 48 months of VNS Therapy in 56, 56, 54, 35 and 18 patients, respectively. Magnet effect (cessation of seizures, partial effect or no effect) was evaluated within the first week after implantation (‘early magnet effect’ EME) and after 6, 12, 24, 36 and 48 months of treatment (‘stable magnet effect’ SME). Results: There was a significant mean seizure reduction of 48.2%, 52.4%, 57.1%, 53.4% and 53.1% and seizure reductions 50% were observed in 46.4%, 50.0%, 55.6%, 51.4% and 50.0% of the patients after 6, 12, 24, 36 and 48 months of treatment, respectively. The percentage of seizure-free patients was 1.8%, 8.9%, 9.3%, 11.4% and 16.7% after 6, 12, 24, 36 and 48 months, respectively. EME: cessation of seizures, 16.1%; partial effect, 73.2%; no effect: 10.7%. SME: cessation of seizures, 8.9%, 8.9%, 9.3%, 8.6% and 5.6%; partial effect, 69.6%, 69.6%, 68.5%, 57.1% and 55.6%; no effect, 21.4%, 21.4%, 22.2%, 34.3% and 38.9% after 6, 12, 24, 36 and 48 months of treatment, respectively. A subanalysis of children 12 years (N = 34) showed similar results after 36 months of follow-up. Conclusion: These data indicate that VNS therapy is an effective adjunctive treatment for children and adolescents of all ages with pharmacoresistant epilepsy. Considering partial effect and cessation of seizures together, the magnet was beneficial in more than 60% of the patients.
08.15−09.45 Progress in neurophysiology and neuroimaging INV49 Neurophysiology in neuromuscular disorders in children K. Edebol Eeg-Olofsson. Section of Clinical Neurophysiology, Department of Neuroscience, University Hospital, Uppsala, Sweden Although we live in the era of DNA analyses, clinical neurophysiology has a lot to offer in diagnosis of neuromuscular disorders in children. The disorders of the motor unit can all be investigated by neurophysiological methods; from anterior horn cells (SMA, poliomyelitis) to peripheral nerve (polyneuropathy, mononeuropathy), to endplate (congenital myasthenic syndromes, autoimmune myasthenia gravis etc.), to muscle fibres (myopathy, muscle dystrophy). The neurophysiological findings may suggest further investigations with muscle biopsy or genetic testing. The main methods for evaluation of neuromuscular disorders are nerve conduction studies (NCS; incl. repetitive nerve
Official Journal of the European Paediatric Neurology Society
17th May 2008 (Saturday) 08.15−9.45 Non-pharmacological treatment of epilepsy INV47 Expanding indications for epilepsy surgery in childhood I. Tuxhorn, P. Kotagal. Pediatric Epilepsy Center in the Neurologic Institute, Cleveland, USA The incidence of epilepsy peaks in childhood and a number of well defined syndromes are amenable to surgical management. Early seizure onset, a high seizure frequency and intractability are significant risk factors for developmental and social outcome. Therefore children with surgically remediable epilepsies should be selected early for operation. Presurgical evaluation should be considered as a multi-step approach to assure that the individually available resources for pre-surgical evaluation and surgical therapy are well and timely utilized by the treating network of physicians. The first diagnostic steps should include a good characterization of the seizure semiology by history, parental documentation by home video if possible, a good quality surface inter-ictal EEG and structural imaging with MRI. Unifocal epilepsy due to a well demarcated lesion (tumor, malformation of cortical development, other acquired vascular, ischemic or inflammatory pathologies) carries the best seizure outcome prognosis. Referral to an experienced and well versed epilepsy center where a standardized presurgical evaluation with surface interictal and ictal EEG, structural and functional imaging, language, memory and cognitvie testing is performed, should be considered early in such cases. Even intractable epilepsies due to multicentric or extensive bilateral disease such as tuberous sclerosis, Sturge Weber Syndrome or remote epilepsies due to strokes may be surgically remedial in terms of either cure or palliation. The presurgical evaluation in these cases may require invasive video EEG monitoring with intracranial electrodes, functional interictal and ictal imaging with SPECT, PET, fMRI to localize the epileptogenic zone and delineate it from eloquent cortex that may not be sacrificed. Although congruence of diagnostic findings is the goldstandard for presurgical selection, it is becoming increasingly clearer that generalized epileptiform discharges in the constellation of other localizing features (e.g. pathologic substrate, seizure semiology) may not be a contraindication to surgery. This may particularly apply to the static structural epileptic encephalopathies in infants which may be particularly challenging to demarcate from progressive metabolic disorders. Epilepsy surgery should be considered early in the treatment paradigm of any intractable epilepsy of childhood along
with the newer antiepiletics, ketogenic diet and vagal nerve stimulation. OP10 Bone marrow transplantation for Rasmussen Syndrome A. Nishimura1 , M. Morimoto1 , A. Morimoto1 , M. Koyama2 , K. Kawa2 . 1 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan, 2 Department of Hematology/Oncology, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan Purpose: Rasmussen Syndrome is a rare but severely and slowly progressive disease of chronic inflammation in the CNS, leading to unilateral hemispheric atrophy, associated progressive neurological deficit and intractable partial motor seizures. Based on recent data on the pathogenesis of the disease, some autoimmune mechanisms have been postulated. Immunomodulatory therapies have been applied, and several case reports have been reported with controversial results. Rasmussen Syndrome might be responsive to suppression or modulation of the immune system with such as bone marrow transplantation (BMT). Case: We report a 10-year-old male with Rasmussen Syndrome whose symptoms began at the age of 7 years. Various therapies including antiepileptic drugs, steroids, cyclosporins, immunoglobulin, were applied, but the effects were not satisfied. The patient’s family has decided to treat the patient with BMT at the age of 10 years, under the permission of Ethical Committee of our university. Frequency and intensity of epileptic seizures were reduced significantly, but a good outcome regarding progression rate of brain atrophy on MRI was not decided because of his death at 149th day after the BMT. The cause of his death was bronchiolitis obliterans organizing pneumonia (BOOP) associated with chronic GVHD. Conclusion: BMT might be possible therapeutic choice for Rasmussen Syndrome. However, a greater number of patients and a longer observation period are needed before definitive conclusions can be drawn. INV48 Nerve vagus stimulation
experience from USA
E. Thiele. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA The Vagus Nerve Stimulator (VNS; Cyberonics, Inc) was approved by the US Food and Drug Administration in 1997 as adjunctive therapy for intractable partial epilepsy in patients 12 years of age and older. To date, 40,338 patients have had the VNS implanted in the USA for the treatment of epilepsy or depression; 47,787 patients have had the VNS implanted worldwide. The VNS has two modes of operation: continuous intermittent stimulation and magnet activated stimulation. Magnet activation is used at onset of aura or
1090-3798/ $ – see front matter © 2008 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
17th May 2008 (Saturday), Oral presentations 08.15−09.45
S21
seizure onset, and can cause the seizure to be aborted, less severe, and can lessen the postictal period. Multiple clinical studies have shown that the VNS is both effective with regard to improving seizure control as well as overall very well tolerated. Commonly reported side effects include voice alteration during stimulation, cough, hoarseness and throat parasthesias, but the cognitive side effects known to occur occasionally with anticonvulsant medications have not been seen. Although the exact mechanism of action of the VNS is unknown, several hypotheses haven been proposed, including modifying the activity of the reticular activating system, the central autonomic network, the limbic system, and the diffuse noradrenergic projection system. A recent retrospective study at the Carol and James Herscot Center for Tuberous Sclerosis Complex identified 16 patients with TSC who underwent VNS implantation due to intractable epilepsy. Three of the 16 (19%) had a >80% reduction in seizure frequency, five (31%) had a 50−79% reduction, two (13%) had a <50% reduction, one had benefit from magnet activation only, and five (31%) had no improvement in seizure frequency. Intermittent magnet use effectively aborted seizures in eight (50%) of the patients. Five of the 16 patients reported improved cognition and/or behavior after VNS implantation.
outcome in order to avoid ineffective VNS implantation surgery.
OP11 Transcranial direct current stimulation (tDCS) for the prediction of VNS therapy outcome in pediatric patients I. Orosz1 , G. Kerling2 , J. Hoffmann3 , T. Polster4 , M. Hoppe4 , I.R. Konig5 , J. Sperner1 . 1 Children’s Hospital, University of Lubeck, Germany, 2 Epilepsy Center, Department of Neurology, University of Erlangen, Germany, 3 Department of Epileptology, Medical Center University of Bonn, Germany, 4 Epilepsy Center Bethel, Bielefeld, Germany, 5 Institute of Medical Biometry and Statistics, University of Lubeck, Germany Objective: To test the hypothesis of similar effects of vagus nerve stimulation (VNS) and tDCS on seizure reduction and its use as a predictive tool for VNS efficacy for refractory epilepsy in children and adolescents. Scientific background: VNS is effective in 30−40% of patients with pharmacoresistant epilepsy. However, no prediction is possible for VNS therapy outcome. tDCS is a recently developed method to stimulate the cortex non-invasively and painless and is used for treatment of epilepsy and depression. The cathodal stimulation induces a local hyperpolarization of the cortex and leads to an increase of the seizure treshold, which explains anticonvulsive effects. Methods: VNS non-responders were treated with a CEcertified tDCS device (Neuroconn, Germany) and seizure frequency together with epileptic discharges were compared before and after tDCS. VNS candidates were treated with tDCS one to four weeks before implantation. Changes in seizure frequency and EEG were correlated to VNS-outcome in terms of seizure reduction six months after implantation. tDCS was performed with two flat electrodes (area 35 cm2 ) using 1 mA direct current for 15 minutes. The cathode was placed over the epileptic focus and the anodal electrode to the contralateral hemisphere. EEG results were drawn immediately before and after stimulation. All participants were aged <18 years. Results: In 9/9 VNS-nonresponders no effects have been observed after tDCS, neither on EEG nor on seizure frequency. However, in 3/12 (25%) VNS-candidates tDCS resulted in short term reduction of seizure frequency and epileptic discharges. Conclusion: According to our preliminary results, short tDCS effects seem to be correlated with VNS outcome. A German multicenter study has started (Lubeck, Bethel, Erlangen and ¨ Bonn) to proof the predictive power of tDCS for VNS therapy
OP12 Long-term results of adjunctive vagus nerve stimulation (VNS) therapy for the treatment of pharmacoresistant epilepsy in children and adolescents under 18 years of age P. Zwolinski, M. Roszkowski. Dept of Neurosurgery, The Children’s Memorial Health Institute, Warsaw, Poland Objective: To evaluate long term seizure reduction and ondemand magnet use in children and adolescents under 18 years of age with pharmacoresistant epilepsy who were treated with adjunctive vagus nerve stimulation (VNS) therapy. Material and Methods: 57 children and adolescents (32 M, 25 F; 59.6% 12 years). Mean age at implantation: 11.4±3.85 years; mean duration of epilepsy: 9.2±4.14 years. Seven patients underwent prior epilepsy surgery; 64.9% were mentally retarded and 38.6% had neurological deficits. MRI was abnormal in 57.9%. Simple partial seizures: 38.6% of the patients; complex partial: 96.5%; secondarily generalized tonic-clonic: 56.1%; myoclonic: 8.8%. Seizure reduction was evaluated after 6, 12, 24, 36 and 48 months of VNS Therapy in 56, 56, 54, 35 and 18 patients, respectively. Magnet effect (cessation of seizures, partial effect or no effect) was evaluated within the first week after implantation (‘early magnet effect’ EME) and after 6, 12, 24, 36 and 48 months of treatment (‘stable magnet effect’ SME). Results: There was a significant mean seizure reduction of 48.2%, 52.4%, 57.1%, 53.4% and 53.1% and seizure reductions 50% were observed in 46.4%, 50.0%, 55.6%, 51.4% and 50.0% of the patients after 6, 12, 24, 36 and 48 months of treatment, respectively. The percentage of seizure-free patients was 1.8%, 8.9%, 9.3%, 11.4% and 16.7% after 6, 12, 24, 36 and 48 months, respectively. EME: cessation of seizures, 16.1%; partial effect, 73.2%; no effect: 10.7%. SME: cessation of seizures, 8.9%, 8.9%, 9.3%, 8.6% and 5.6%; partial effect, 69.6%, 69.6%, 68.5%, 57.1% and 55.6%; no effect, 21.4%, 21.4%, 22.2%, 34.3% and 38.9% after 6, 12, 24, 36 and 48 months of treatment, respectively. A subanalysis of children 12 years (N = 34) showed similar results after 36 months of follow-up. Conclusion: These data indicate that VNS therapy is an effective adjunctive treatment for children and adolescents of all ages with pharmacoresistant epilepsy. Considering partial effect and cessation of seizures together, the magnet was beneficial in more than 60% of the patients.
08.15−09.45 Progress in neurophysiology and neuroimaging INV49 Neurophysiology in neuromuscular disorders in children K. Edebol Eeg-Olofsson. Section of Clinical Neurophysiology, Department of Neuroscience, University Hospital, Uppsala, Sweden Although we live in the era of DNA analyses, clinical neurophysiology has a lot to offer in diagnosis of neuromuscular disorders in children. The disorders of the motor unit can all be investigated by neurophysiological methods; from anterior horn cells (SMA, poliomyelitis) to peripheral nerve (polyneuropathy, mononeuropathy), to endplate (congenital myasthenic syndromes, autoimmune myasthenia gravis etc.), to muscle fibres (myopathy, muscle dystrophy). The neurophysiological findings may suggest further investigations with muscle biopsy or genetic testing. The main methods for evaluation of neuromuscular disorders are nerve conduction studies (NCS; incl. repetitive nerve