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A new therapy for refractory partial epilepsy: Current shunt
Medical Hypotheses 81 (2013) 763–765
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A new therapy for refractory partial epilepsy: Current shunt q Limin Zhang a,b,1, Shuli Liang b,⇑, Guojun Zhang a, Xixiong Kang a a b
Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China Capital Epilepsy Therapy Center, Department of Neurosurgery, First Affiliated Hospital of Chinese People’s Liberation Army General Hospital, Beijing 100048, China
a r t i c l e
i n f o
Article history: Received 5 March 2013 Accepted 22 July 2013
a b s t r a c t A large number of epileptic patients suffer from refractory epilepsy, despite optimal treatment; thus these patients require new therapeutic approaches. Focal seizure activity is typically initiated in a fixed and localized region, which subsequently spreads to neighboring regions or more distant areas. At the initial onset of a seizure, the epileptic discharge will generate a relatively high voltage in seizure focus, and the discharge subsequently spreads to other relatively low-voltage regions. However, it is unknown whether seizure can be controlled through current shunt using a conduction microelectrode to conduct the epileptic discharge with a relatively high voltage in the seizure focus outside the brain. The current therapies for epilepsy, including drugs, resective surgery and neuromodulation, focus on inhibiting abnormal excessive or synchronous neuronal activity to control seizures; thus, the basic mechanism underlying these therapies is ‘‘inhibition’’. In contrast, we proposed a ‘‘conduction’’ mechanism, whereby a current shunt with conduction electrode is used to control seizures. To our knowledge, this therapeutic strategy has not been previously reported, and we propose that this approach might be an alternative choice for the treatment of refractory partial epilepsy in the future. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Epilepsy is one of the most common neurological disorders worldwide due to abnormal excessive or synchronous neuron discharge in the brain. Epilepsy affects at least 50 million people [1], and more than 30% of these individuals remain inadequately controlled, despite optimal antiepileptic drug therapy [2,3]. Epileptic surgery and neuromodulation therapy have been rapidly developed in recent years, which might provide additional benefits in combination with medical treatment to control seizures. Based on the pathogenesis, the current therapies have focused on inhibiting abnormal excessive or synchronous neuronal activity to control seizures; thus, the basic mechanism underlying these therapies is ‘‘inhibition’’. However, every therapy has limits, and 20% of patients experience repeated seizures, reflecting the lack of effective treatment; thus, novel therapeutic strategies are required to treat these patients.
q This work is attributed to: Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University. No. 6, Tian Tan Xi Li, Beijing 100050, China.Capital Epilepsy Therapy Center, Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China. ⇑ Corresponding author. Tel.: +86 10 66848352. E-mail addresses: [email protected] (L. Zhang), [email protected] (S. Liang). 1 Offprints should be sent to: Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University, No. 6, Tian Tan Xi Li, Beijing 100050, China. Tel.: +86 10 67096875; fax: +86 10 67096877.
0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.046
Deep brain stimulation might be a promising therapy. An array of sites has recently been explored, including the cerebellum and the anterior nuclei of the thalamus, hippocampus, subthalamic nucleus, brainstem, and corpus callosum; the direct stimulation of the cortex has also been explored. Studies [4–7] on the anterior nuclei of the thalamus of patients with focal epilepsy have shown a 46–67% reduction of seizures. Stimulation on cranial nerves has also been studied and shown to be effective. Clinical trials on vagus nerve stimulation have demonstrated that 20–40% of patients achieve greater than 50% reduction in seizure frequency in the first year of use [8]. Taken together, these results suggest that external factors influence the intrinsic excitability of neurons. During a seizure, the epileptic discharge in seizure focus generates a relatively high voltage (about 2000–3000 lV) in intracranial electrode EEG, with a wave amplitude of approximately 30 times that in scalp EEG (about 50–100 lV). As current transmits from regions with relatively high voltage toward regions with low voltage, it is not known whether seizures can be controlled through current shunt using a customized conduction microelectrode with low resistance to conduct the epileptic discharge in seizure focus outside the brain. In contrast to electrical stimulation, current shunt involves an electrical current output, not an afferent input. In contrast with traditional therapies, the basic idea of this mechanism is ‘‘conduction’’ rather than ‘‘inhibition’’.
764
L. Zhang et al. / Medical Hypotheses 81 (2013) 763–765
Hypothesis We hypothesized that seizures can be controlled through a current shunt, using a customized conduction microelectrode to conduct epileptic discharge in seizure focus outside the brain. To our knowledge, this therapeutic strategy has not been previously reported; however, this approach is feasible and deserves further examination. The characteristics of epileptic discharge Seizure results from a shift in the normal balance of excitation and inhibition within the central nervous system. Indeed, seizure is a paroxysmal event reflecting abnormal excessive or synchronous neuronal activity in the brain. The hyperexcitability of neurons leads to epileptic discharge or seizure. Studies [9–12] on scalp EEG and intracranial electrode EEG have shown that focal seizure activity is typically initiated in a fixed and localized region of the cortex, which subsequently spreads to neighboring regions or more distant areas. At the initial onset of a seizure, the epileptic discharge will generate a relatively high voltage (2000–3000 lV) in intracranial electrode EEG, with a wave amplitude approximately 30 times that of the scalp EEG (about 50– 100 lV). In previous experiments, we have also observed this intracranial electrode EEG recoding phenomenon. In addition, the propagation of bursting activity in patients with focal epilepsy, from the seizure focus to the early spread of ictal discharge, typically exhibits a relatively fixed spreading pathway, and seizure propagation requires one to several seconds, which is much longer than the spreading time of normal nervous electrical activity. Since the pioneering work of Benabid and colleagues [13,14] the late 1980s, researchers have attempted to interfere with the electrical activity through the application of electrical stimulation. To date, multiple sites have been explored, and the preliminary results are encouraging. In addition, Trevelyan [15] showed that seizure propagation could be opposed through feedforward inhibition. These data suggest that external factors influence the intrinsic excitability of neurons. The feasibility analysis of current shunt Biocurrent can be transmitted outside the brain. We observed the electrical activity of neurons using an EEG recording system, as the biocurrent of the neurons forms a circuit loop between the recording machine and the ground-wire. Because of the high resistance of the machine, the current is weak, and the recording does not affect the electrical activity of neurons. Electrical stimulation influences the excitability of neurons and controls seizures. The nature of brain stimulation is the transmission of a current impulse from the high-voltage stimulator to the low-voltage brain. Due to the properties of current, we can also transmit the epileptic discharge to regions with a voltage lower than that of the seizure focus using a conduction microelectrode with low resistance. During seizure, the relatively high-voltage epileptic discharge is limited to the fixed onset zone for several seconds during the intracranial EEG recording in patients with focal epilepsy; thus, if we connect the seizure focus and the scalp using a special conduction electrode, a current will form and transmit along the electrode. As for the conduction electrode, we will design a customized microelectrode using a nanometer material with low resistance, and if possible, a superconductive material will be used under special conditions. Silver might be the optimal material, as this substance has the lowest resistance among all metals. The head end of the conductor will be needle-shaped to minimize the
mechanical injury during the implantation. The head end can be inserted into the seizure focus through a guide cannula, and the tail end, with a silver patch, can be embedded under the parietal scalp. Discussion We will first perform studies using rat models, as no related studies have been reported. At the initial onset of a seizure, part of the abnormal discharge transmits along the conduction microelectrode, thus the intensity of the discharge will be attenuated, and the seizure would be controlled or degraded. We can compare the average number and duration of seizures through EEG, and the behavioral seizure frequency before and after electrode implantation can be used to evaluate the validity of the treatment. Indeed, seizure can lead to brain damage, mediated though the apoptosis pathway [16,17]; therefore apoptosis can also be measured to determine whether the shunt plays a neuronprotective role in epileptic rats. This hypothesis suggests an alternative approach to treat refractory partial epilepsy. This strategy is a promising new approach with microinvasion, and if the results are encouraging, this technique will enhance the quality of life and show a significant value on social and economic benefit for epilepsy patients. Conflict of interest statement No significant conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Acknowledgements This work was supported by National Natural Science Foundation of China (Grant No. 81000555) and Beijing Science & Technology New-star Training Program (Grant No. 2010B084) to S.L. The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or preparation of the manuscript. References [1] Dua T, de Boer HM, Prilipko LL, Saxena S. Epilepsy care in the world: results of an ILAE/IBE/WHO global campaign against epilepsy survey. Epilepsia 2006;47(7):1225–31. [2] Sander JW. Some aspects of prognosis in the epilepsies: a review. Epilepsia 1993;34:1007–16. [3] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. [4] Lim SN, Lee ST, Tsai YT, et al. Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia 2007;48:342–7. [5] Fisher R, Salanova V, Witt T, et al. SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908. [6] Boon P, Vonck K, De Herdt V, et al. Deep brain stimulation in patients with refractory temporal lobe epilepsy. Epilepsia 2007;48:1551–60. [7] Hodaie M, Wennberg RA, Dostrovsky JO. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:603–8. [8] Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45:224–30. [9] Jan MM, Sadler M, Rahey SR. Electroencephalographic features of temporal lobe epilepsy. Can J Neurol Sci 2010;37:439–48. [10] Javidan M. Electroencephalography in mesial temporal lobe epilepsy: a review. Epilepsy Res Treat 2012;2012:637430. http://dx.doi.org/10.1155/2012/ 637430 [Epub 2012 January 17]. [11] Raghavendra S, Nooraine J, Mirsattari SM. Role of electroencephalography in presurgical evaluation of temporal lobe epilepsy. Epilepsy Res Treat 2012;2012:204693. http://dx.doi.org/10.1155/2012/204693 [Epub 2012 October 31]. [12] Sakamoto AC. Current role of EEG in the presurgical evaluation of temporal lobe epilepsy patients. Suppl Clin Neurophysiol 2004;57:383–91.
L. Zhang et al. / Medical Hypotheses 81 (2013) 763–765 [13] Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987;50:344–6. [14] Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–6. [15] Trevelyan AJ, Sussillo D, Yuste R. Feedforward inhibition contributes to the control of epileptiform propagation speed. J Neurosci 2007;27:3383–7.
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[16] Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. J Neurochem 2000;74:1215–23. [17] Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005;25:1557–72.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
A new therapy for refractory partial epilepsy: Current shunt q Limin Zhang a,b,1, Shuli Liang b,⇑, Guojun Zhang a, Xixiong Kang a a b
Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China Capital Epilepsy Therapy Center, Department of Neurosurgery, First Affiliated Hospital of Chinese People’s Liberation Army General Hospital, Beijing 100048, China
a r t i c l e
i n f o
Article history: Received 5 March 2013 Accepted 22 July 2013
a b s t r a c t A large number of epileptic patients suffer from refractory epilepsy, despite optimal treatment; thus these patients require new therapeutic approaches. Focal seizure activity is typically initiated in a fixed and localized region, which subsequently spreads to neighboring regions or more distant areas. At the initial onset of a seizure, the epileptic discharge will generate a relatively high voltage in seizure focus, and the discharge subsequently spreads to other relatively low-voltage regions. However, it is unknown whether seizure can be controlled through current shunt using a conduction microelectrode to conduct the epileptic discharge with a relatively high voltage in the seizure focus outside the brain. The current therapies for epilepsy, including drugs, resective surgery and neuromodulation, focus on inhibiting abnormal excessive or synchronous neuronal activity to control seizures; thus, the basic mechanism underlying these therapies is ‘‘inhibition’’. In contrast, we proposed a ‘‘conduction’’ mechanism, whereby a current shunt with conduction electrode is used to control seizures. To our knowledge, this therapeutic strategy has not been previously reported, and we propose that this approach might be an alternative choice for the treatment of refractory partial epilepsy in the future. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Epilepsy is one of the most common neurological disorders worldwide due to abnormal excessive or synchronous neuron discharge in the brain. Epilepsy affects at least 50 million people [1], and more than 30% of these individuals remain inadequately controlled, despite optimal antiepileptic drug therapy [2,3]. Epileptic surgery and neuromodulation therapy have been rapidly developed in recent years, which might provide additional benefits in combination with medical treatment to control seizures. Based on the pathogenesis, the current therapies have focused on inhibiting abnormal excessive or synchronous neuronal activity to control seizures; thus, the basic mechanism underlying these therapies is ‘‘inhibition’’. However, every therapy has limits, and 20% of patients experience repeated seizures, reflecting the lack of effective treatment; thus, novel therapeutic strategies are required to treat these patients.
q This work is attributed to: Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University. No. 6, Tian Tan Xi Li, Beijing 100050, China.Capital Epilepsy Therapy Center, Department of Neurosurgery, First Affiliated Hospital of Chinese PLA General Hospital, Beijing 100048, China. ⇑ Corresponding author. Tel.: +86 10 66848352. E-mail addresses: [email protected] (L. Zhang), [email protected] (S. Liang). 1 Offprints should be sent to: Laboratory Diagnosis Center, Beijing Tiantan Hospital, Capital Medical University, No. 6, Tian Tan Xi Li, Beijing 100050, China. Tel.: +86 10 67096875; fax: +86 10 67096877.
0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.07.046
Deep brain stimulation might be a promising therapy. An array of sites has recently been explored, including the cerebellum and the anterior nuclei of the thalamus, hippocampus, subthalamic nucleus, brainstem, and corpus callosum; the direct stimulation of the cortex has also been explored. Studies [4–7] on the anterior nuclei of the thalamus of patients with focal epilepsy have shown a 46–67% reduction of seizures. Stimulation on cranial nerves has also been studied and shown to be effective. Clinical trials on vagus nerve stimulation have demonstrated that 20–40% of patients achieve greater than 50% reduction in seizure frequency in the first year of use [8]. Taken together, these results suggest that external factors influence the intrinsic excitability of neurons. During a seizure, the epileptic discharge in seizure focus generates a relatively high voltage (about 2000–3000 lV) in intracranial electrode EEG, with a wave amplitude of approximately 30 times that in scalp EEG (about 50–100 lV). As current transmits from regions with relatively high voltage toward regions with low voltage, it is not known whether seizures can be controlled through current shunt using a customized conduction microelectrode with low resistance to conduct the epileptic discharge in seizure focus outside the brain. In contrast to electrical stimulation, current shunt involves an electrical current output, not an afferent input. In contrast with traditional therapies, the basic idea of this mechanism is ‘‘conduction’’ rather than ‘‘inhibition’’.
764
L. Zhang et al. / Medical Hypotheses 81 (2013) 763–765
Hypothesis We hypothesized that seizures can be controlled through a current shunt, using a customized conduction microelectrode to conduct epileptic discharge in seizure focus outside the brain. To our knowledge, this therapeutic strategy has not been previously reported; however, this approach is feasible and deserves further examination. The characteristics of epileptic discharge Seizure results from a shift in the normal balance of excitation and inhibition within the central nervous system. Indeed, seizure is a paroxysmal event reflecting abnormal excessive or synchronous neuronal activity in the brain. The hyperexcitability of neurons leads to epileptic discharge or seizure. Studies [9–12] on scalp EEG and intracranial electrode EEG have shown that focal seizure activity is typically initiated in a fixed and localized region of the cortex, which subsequently spreads to neighboring regions or more distant areas. At the initial onset of a seizure, the epileptic discharge will generate a relatively high voltage (2000–3000 lV) in intracranial electrode EEG, with a wave amplitude approximately 30 times that of the scalp EEG (about 50– 100 lV). In previous experiments, we have also observed this intracranial electrode EEG recoding phenomenon. In addition, the propagation of bursting activity in patients with focal epilepsy, from the seizure focus to the early spread of ictal discharge, typically exhibits a relatively fixed spreading pathway, and seizure propagation requires one to several seconds, which is much longer than the spreading time of normal nervous electrical activity. Since the pioneering work of Benabid and colleagues [13,14] the late 1980s, researchers have attempted to interfere with the electrical activity through the application of electrical stimulation. To date, multiple sites have been explored, and the preliminary results are encouraging. In addition, Trevelyan [15] showed that seizure propagation could be opposed through feedforward inhibition. These data suggest that external factors influence the intrinsic excitability of neurons. The feasibility analysis of current shunt Biocurrent can be transmitted outside the brain. We observed the electrical activity of neurons using an EEG recording system, as the biocurrent of the neurons forms a circuit loop between the recording machine and the ground-wire. Because of the high resistance of the machine, the current is weak, and the recording does not affect the electrical activity of neurons. Electrical stimulation influences the excitability of neurons and controls seizures. The nature of brain stimulation is the transmission of a current impulse from the high-voltage stimulator to the low-voltage brain. Due to the properties of current, we can also transmit the epileptic discharge to regions with a voltage lower than that of the seizure focus using a conduction microelectrode with low resistance. During seizure, the relatively high-voltage epileptic discharge is limited to the fixed onset zone for several seconds during the intracranial EEG recording in patients with focal epilepsy; thus, if we connect the seizure focus and the scalp using a special conduction electrode, a current will form and transmit along the electrode. As for the conduction electrode, we will design a customized microelectrode using a nanometer material with low resistance, and if possible, a superconductive material will be used under special conditions. Silver might be the optimal material, as this substance has the lowest resistance among all metals. The head end of the conductor will be needle-shaped to minimize the
mechanical injury during the implantation. The head end can be inserted into the seizure focus through a guide cannula, and the tail end, with a silver patch, can be embedded under the parietal scalp. Discussion We will first perform studies using rat models, as no related studies have been reported. At the initial onset of a seizure, part of the abnormal discharge transmits along the conduction microelectrode, thus the intensity of the discharge will be attenuated, and the seizure would be controlled or degraded. We can compare the average number and duration of seizures through EEG, and the behavioral seizure frequency before and after electrode implantation can be used to evaluate the validity of the treatment. Indeed, seizure can lead to brain damage, mediated though the apoptosis pathway [16,17]; therefore apoptosis can also be measured to determine whether the shunt plays a neuronprotective role in epileptic rats. This hypothesis suggests an alternative approach to treat refractory partial epilepsy. This strategy is a promising new approach with microinvasion, and if the results are encouraging, this technique will enhance the quality of life and show a significant value on social and economic benefit for epilepsy patients. Conflict of interest statement No significant conflicts of interest exist with any companies/ organizations whose products or services may be discussed in this article. Acknowledgements This work was supported by National Natural Science Foundation of China (Grant No. 81000555) and Beijing Science & Technology New-star Training Program (Grant No. 2010B084) to S.L. The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or preparation of the manuscript. References [1] Dua T, de Boer HM, Prilipko LL, Saxena S. Epilepsy care in the world: results of an ILAE/IBE/WHO global campaign against epilepsy survey. Epilepsia 2006;47(7):1225–31. [2] Sander JW. Some aspects of prognosis in the epilepsies: a review. Epilepsia 1993;34:1007–16. [3] Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000;342:314–9. [4] Lim SN, Lee ST, Tsai YT, et al. Electrical stimulation of the anterior nucleus of the thalamus for intractable epilepsy: a long-term follow-up study. Epilepsia 2007;48:342–7. [5] Fisher R, Salanova V, Witt T, et al. SANTE Study Group. Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia 2010;51:899–908. [6] Boon P, Vonck K, De Herdt V, et al. Deep brain stimulation in patients with refractory temporal lobe epilepsy. Epilepsia 2007;48:1551–60. [7] Hodaie M, Wennberg RA, Dostrovsky JO. Chronic anterior thalamus stimulation for intractable epilepsy. Epilepsia 2002;43:603–8. [8] Vagus Nerve Stimulation Study Group. A randomized controlled trial of chronic vagus nerve stimulation for treatment of medically intractable seizures. Neurology 1995;45:224–30. [9] Jan MM, Sadler M, Rahey SR. Electroencephalographic features of temporal lobe epilepsy. Can J Neurol Sci 2010;37:439–48. [10] Javidan M. Electroencephalography in mesial temporal lobe epilepsy: a review. Epilepsy Res Treat 2012;2012:637430. http://dx.doi.org/10.1155/2012/ 637430 [Epub 2012 January 17]. [11] Raghavendra S, Nooraine J, Mirsattari SM. Role of electroencephalography in presurgical evaluation of temporal lobe epilepsy. Epilepsy Res Treat 2012;2012:204693. http://dx.doi.org/10.1155/2012/204693 [Epub 2012 October 31]. [12] Sakamoto AC. Current role of EEG in the presurgical evaluation of temporal lobe epilepsy patients. Suppl Clin Neurophysiol 2004;57:383–91.
L. Zhang et al. / Medical Hypotheses 81 (2013) 763–765 [13] Benabid AL, Pollak P, Louveau A, Henry S, de Rougemont J. Combined (thalamotomy and stimulation) stereotactic surgery of the VIM thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 1987;50:344–6. [14] Benabid AL, Pollak P, Gervason C, et al. Long-term suppression of tremor by chronic stimulation of the ventral intermediate thalamic nucleus. Lancet 1991;337:403–6. [15] Trevelyan AJ, Sussillo D, Yuste R. Feedforward inhibition contributes to the control of epileptiform propagation speed. J Neurosci 2007;27:3383–7.
765
[16] Henshall DC, Chen J, Simon RP. Involvement of caspase-3-like protease in the mechanism of cell death following focally evoked limbic seizures. J Neurochem 2000;74:1215–23. [17] Henshall DC, Simon RP. Epilepsy and apoptosis pathways. J Cereb Blood Flow Metab 2005;25:1557–72.