Medical Hypotheses 81 (2013) 426–428
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Electroacupuncture at acupoints could predict the outcome of anterior nucleus thalamus high-frequency electrical stimulation in medically refractory epilepsy Na Yan a, Ning Chen b, Jiapeng Lu a, Youxin Wang a, Wei Wang a,c,⇑ a b c
Beijing Municipal Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing 100050, China Department of Neurosurgery, Beijing Sanbo Brain Hospital, Capital Medical University, Beijing 100050, China Systems and Intervention Research Center for Health, School of Medical Sciences, Edith Cowan University, Perth, WA 6027, Australia
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Article history: Received 22 February 2013 Accepted 1 June 2013
a b s t r a c t Preliminary reports have demonstrated that anterior nucleus thalamus high-frequency electrical stimulation (ANT-HFS) is an effective treatment for patients who suffer from medically refractory epilepsy. However, its extensive application has been hampered by the high cost and the unpredictable outcome before the operation. Just like ANT-HFS in the brain, electroacupuncture (EA) at acupoints with electrical stimulation is also efficient in treating medically refractory epilepsy. Although the therapeutic mechanisms involve different activated positions, the neurotransmitters generated by the electrical stimulation are similar. It has been demonstrated that both ANT-HFS and EA at acupoints are related to an imbalance between the excitatory [glutamate (Glu), aspartate (Asp)] and inhibitory [GABA, glycine (Gly) and taurine (Tau)] neuronal transmitters. We, therefore, hypothesize that outcome of EA at acupoints can predict the therapeutic effect of ANT-HFS. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction Epilepsy is a family of neurological disorders that result in seizure activity. According to the World Health Organization’s report, the number of people with epilepsy is estimated to be more than 50 million worldwide [1]. Some of these patients may be candidates for resection operation, but some are not. Currently, deep brain stimulation (DBS) is approved in the United States and Europe for the treatment of Parkinson’s disease (PD), tremor, dystopia, obsessive compulsive disorder (OCD) and epilepsy [2]. For patients who suffer from pharmaco-resistant epilepsy and who are not candidates for resection surgery, anterior nucleus thalamus high frequency stimulation (ANT-HFS) is a valuable treatment option with success reported in both human clinical trials and animal experiments [3]. Although the therapeutic effect has been confirmed, its more extensive application has been hampered due to its high cost and the unpredictable outcome before the operation. It has been reported that the therapeutic mechanisms of ANT-HFS may be related to the metabolic imbalance of amino acids in animal studies [4]. Meanwhile, the acupunctural antiepileptic effect has also been demonstrated in both experimental and clinical evidences. The therapeutic effect of electroacupuncture (EA) at acu⇑ Corresponding author at: Systems and Intervention Research Center for Health, School of Medical Sciences, Edith Cowan University, Perth, WA 6027, Australia. Tel.: +61 8 6304 3717. E-mail address:
[email protected] (W. Wang). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.06.001
points in medically refractory epilepsy is also related to the amino acid [5–7]. And it has been reported that EA at acupoints could predict the efficacy of hippocampal high-frequency electrical stimulation in pharmacoresistant temporal lobe epilepsy patients because both hippocampal HFS and EA at acupoints are related to the metabolism of amino acids [8]. Accordingly, we hypothesize the followings. The hypothesis We hypothesize that EA at acupoints can predict the outcome of ANT-HFS in treating medically refractory epilepsy patients because both ANT-HFS and EA at acupoints are effective in treating medically refractory epilepsy involving the metabolism of amino acids in spite of their differing activation positions. Evaluation of the hypothesis Electrical stimulation of the ANT is effective but is difficult to predict the outcome before the operation Data provided from animal experiments as well as clinical trials support the idea that the ANT-HFS is an effective target for treating medically refractory epilepsy in both animals and human beings [4]. In kainic acid (KA) rat epilepsy model, continuous ANT-HFS at 130 Hz can significantly reduce the number of spontaneous sei-
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zures [9]. In humans, ANT-HFS is a valuable treatment option for patients who suffer from drug-resistant epilepsy and who are not candidate for resection surgery [10]. The efficacy of long-term ANT-HFS in patients with medically refractory epilepsy has been demonstrated in a multicenter trial and it provides a non-resection method that improves seizure outcome without significant adverse effects [10,11]. In 2010, Fisher et al. reported a multicenter, doubled-blind, randomized trial of stimulation of the anterior nuclei of the thalamus for epilepsy (SANTE) in 157 patients with treatment-resistant epilepsy. Of these, 110 patients underwent bilateral implantation of DBS electrodes in the ANT. At the end of the 3month treatment, the median percent reduction in seizure frequency was approximately three times greater for the active stimulation group (40.4%) than for the control group (14.5%) (P = 0.0017). After two years, there was a 56% median percent reduction in seizure frequency and 54% of the patients had a seizure reduction of at least 50%, and fourteen patients were seizure-free for at least 6 months and 8 patients were seizure free for a year or more [11]. However, the effective rate of ANT-HFS is varied greatly. Some authors found that ANT-HFS only produced a median reduction in seizure frequency of 20%, although the results did not reach significance (P > 0.05) [12]. The therapeutic mechanism of ANT-HFS is related to the imbalance between the excitatory and inhibitory neuronal transmitters It is reported that epileptic seizures is related to an imbalance between the excitatory [glutamate (Glu), aspartate (Asp)] and inhibitory [GABA, glycine (Gly) and taurine (Tau)] neuronal transmitters [13]. The therapeutic mechanism of ANT-HFS may be related to the regulation of equilibrium between excitatory amino acid and inhibitory amino acid, and therapeutic efficacy may be achieved when the metabolisms of amino acid are functionally balanced. ANT-HFS at 130 Hz has been proposed as a therapeutic strategy to control neurological disorders such as medically refractory epilepsy and micro-dialysis experiment has revealed that ANT-DBS has therapeutic effects in medically refractory epilepsy patients by inhibiting the hyper-activation of the excitatory process and promoting the inhibitory process [4]. Stimulation of the ANT-HFS causes decreases in concentrations of Glu and Asp, however, an increase in the concentration of GABA [4]. The therapeutic mechanism of EA at acupoints in medically refractory epilepsy is also related to the imbalance of metabolic amino acids Previous studies have demonstrated that EA at acupoints, such as DU26 ‘‘RenZhong’’, K ‘‘YongQuan’’, HT8 ‘‘SoBu’’, St36 ‘‘ZuSanLi’’, can inhibit epileptiform activities [5–7,14]. It has been verified that the biological basis underlying EA anti-convulsion is related to the imbalance of metabolic amino acids [6,7]. It is reported that EA at acupoints may inhibit epilepsy via up-regulating the concentration of Tau transporter to increase the release of Tau, which may play an inhibitory role against epilepsy as an inhibitory amino acid in the central nervous system, in the hippocampus of epilepsy rats models [6,15]. In addition, EA at acupoints can significantly reduce the times of spontaneous recurrent seizure and elevate the expression of GAD67 mRNA in DG granule cell layer, which can be translated into protein GAD67, i.e., a sign of activity of GABAergic neurons for releasing GABA in the mouse model of KA-induced epilepsy [5,16]. In recent years, it has been realized that stimulation therapies, including localized brain and acupuncture, appear to activate ‘‘therapeutic’’ neuronal networks [17]. It has been presumed that ANT-HFS may treat epilepsy by activating the neuronal networks. ANT stimulation has therapeutic effects in intractable epilepsy by suppressing the cortical-thalamic circuit and then leading to less
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cortical input to the hippocampus and hence inhibiting the release of excitatory amino acid and increasing the release of inhibitory amino acid [4,18,9]. And EA-mediated stimulation of other parts of the body, even those are not applied within the brain, such as some acupoints, can also activate ‘‘therapeutic’’ neuronal networks. It has been demonstrated that stimulation of acupuncture points on the extremities results in antiepileptic effect through the nucleus of solitary tract via vagus nerve stimulation [19]. Although the activated position is different, the stimulation-generated neurotransmitters are similar, which means that the effect and efficacy of electrical stimulation in the brain could be predicted by EA at acupoints. Consequences of the hypothesis and discussion Although no clinical practice has been carried out to verify whether electroacupuncture at acupoints could predict the outcome of anterior nucleus thalamus high-frequency electrical stimulation in medically refractory epilepsy, the validated animal model of intractable epilepsy should be testified to see whether there would be therapeutic effect of ANT-HFS of EA at acupoints. ANT-HFS operations are carried out on the epileptic patients who are medically refractory or poorly controlled by the surgical procedure, but no guidelines have formulated out definite indications for these patients. Doctors may just predict the prognosis of the ANTHFS and could not tell the exact outcome of the operation. In addition, the price of the implanted medical consumables is very expensive. However, if we apply EA at acupoints for these patients, which is inexpensive and mini-invasive, we could predict better prognosis of ANT-HFS operation by reference to the responses from the patients to EA at acupoints, because the therapeutic mechanism of ANT-DBS and EA at acupoints are both related to an imbalance between the excitatory [glutamate (Glu), aspartate (Asp)] and inhibitory [GABA, glycine (Gly) and taurine (Tau)] neuronal transmitters. If patients have responded positively to EA at acupoints, then they could be the best candidates for the operation of ANTHFS treatment. Conflict of interest None declared. Acknowledgements The study was financially supported by the Commonwealth of Australia (ACSRF06444), National ‘‘12th Five-Year’’ Plan for Science and Technology Support, China (2012BAI37B03), the National Natural Science Foundation of China (31070727), and the National Science Technology, China (2010ZX09401). Prof Wei Wang was supported by the Importation and Development of High-Calibre Talents Project of Beijing Municipal Institutions. References [1] Perucca E, Tomson T. Epilepsy: seizures, syndromes, and survival. Lancet Neurol 2009;8:10–2. [2] Sankar T, Tierney TS, Hamani C. Novel applications of deep brain stimulation. Surg Neurol Int 2012;3:S26–33. [3] Zhong XL, Yu JT, Zhang Q, Wang ND, Tan L. Deep brain stimulation for epilepsy in clinical practice and in animal models. Brain Res Bull 2011;85:81–8. [4] Liu HG, Yang AC, Meng DW, Chen N, Zhang JG. Stimulation of the anterior nucleus of the thalamus induces changes in amino acids in the hippocampi of epileptic rats. Brain Res 2012;1477:37–44. [5] Guo J, Liu J, Fu W, et al. Effect of electroacupuncture stimulation of hindlimb on seizure incidence and supragranular mossy fiber sprouting in a rat model of epilepsy. J Physiol Sci 2008;58:309–15. [6] Jin HB, Li B, Gu J, Cheng JS, Yang R. Electro-acupuncture improves epileptic seizures induced by kainic acid in taurine-depletion rats. Acupunct Electrother Res 2005;30:207–17.
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