Drug-Resistant Epilepsy and Surgery.

BACKGROUND: Epilepsy is a chronic brain disease that is caused by various factors and characterized by recurrent, episodic and temporary central nervous system dysfunction which results due to excessive discharge of brain neurons. In the past decades, despite the continuous development of antiepileptic drugs, there are still many patients with epilepsy progressing to drugresistant epilepsy. Currently, surgical treatment is one of important way to cure drug-resistant epilepsy.
METHODS: Data were collected from Web of Science, Medline, Pubmed, through searching of these keywords: "surgery" and "drug-resistant epilepsy".
RESULTS: An increasing number of studies have shown that surgery plays an important role in the treatment of drug-resistant epilepsy. Moreover, the comprehensive treatment mainly based on surgery can achieve the remission and even cure of drug-resistant epilepsy.
CONCLUSION: In this review, we discuss the pathogenesis of drug-resistant epilepsy and the comprehensive treatment mainly based on surgery; this review may provide a reference for the clinical treatment of drug-resistant epilepsy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Introduction

Epilepsy is a chronic brain disease that is caused by various factors and characterized by recurrent, episodic and temporary central nervous system dysfunction which results from excessive discharge of brain neurons [1]. As a serious health problem worldwide, epilepsy accounts for 1% of the world's diseases [2]. In the past few decades, despite the continuous development of antiepileptic drugs, there are still more than 30% patients with epilepsy progressing to drug-resistant epilepsy [3], which leads to a significant increase in the morbidity and mortality of epilepsy. Drug-resistant epilepsy may be defined by International League Against Epilepsy (ILAE)as failure of adequate trials of two tolerated and appropriately chosen and used AED schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [4]. Currently, surgical treatment may be the only possible way to cure drug-resistant epilepsy. However, due to the complicated etiology and unclear pathogenesis of drug-resistant epilepsy, surgical treatment alone is always difficult to achieve a radical effect, and antiepileptic comprehensive treatment mainly based on surgery needs tobe combined with other treatment methods. The present paper mainly reviews the pathogenesis of drug-resistant epilepsy and the comprehensive treatment mainly based on surgery, which provides a reference and guidance for the clinical treatment of drug-resistant epilepsy.

Pathogenesis of drug-resistant epilepsy

The pathogenesis of epilepsy is complex and, at present, commonly acknowledged to be caused by the excitatory and inhibitory imbalance of the central nervous system. So far, the hypotheses regarding the pathogenesis of drug-resistant epilepsy mainly include transporter hypothesis, target hypothesis, etc.

Transporter Hypothesis

Most antiepileptic drugs play the antiepileptic role in the brain via the blood-brain barrier [5]. Moreover, the overexpression of multidrug transporters that have a role in the efflux from the capillary endothelial cells which form the blood-brain barrier may lead to increased intracellular drug efflux or isolated vesicles, resulting in decreased intracellular drug concentration or changed drug distribution; consequently, antiepileptic drugs in epileptogenic zone and surrounding tissues cannot achieve the effective drug concentration, which leads to drug resistance [6]. At present, multidrug transporters that are frequently studied include P-glycoprotein (P-gp), multidrug resistance protein (MRP), breast cancer resistance protein (BCRP) [7]. Some common drugs, such as carbamazepine, felbamate, gabapentin, lamotrigine, phenobarbital, phenytoin and topiramate, are all substrates of P-glycoprotein; meanwhile, phenytoin is substrates of multidrug resistance protein-2 (MRP2) [8, 9]. Kerstin Römermann et al. found that lamotrigine is a substrate of BCRP, which is evidenced in this hypothesis [10].

Target Hypothesis

Target hypothesis proposes that antiepileptic drugs cannot inhibit the excessive discharge of neurons through binding the predetermined target when the structure or function of the target of antiepileptic drugs changes, resulting in uncontrollable epilepsy attack, which is mainly reflected by abnormal ion channel function [11]. Currently, it has been confirmed that the voltage-gated sodium channel (VGSC) is mainly expressed in excitatory cells, and is the main target of the traditional first-line AEDs [12]. Research has proved that SCN1A gene (coding for the sodium channel, neuronal type I, alpha subunit) mutation is the main pathogenic gene of severe myoclonic epilepsy in infancy [13]. In addition, the model experiment of gene knockout mice for simulating human channel diseases has verified that SCN1A mutation causes reduced expression level of sodium channel subtype Nav1.1, leading to decreased excitatory of inhibitory neurons, functional decline in inhibitory loop and increased neuronal excitability, which are necessary for the onset of epileptic seizures [14]. Sodium channel gene mutations cause the loss of partial functional targets of the AEDs, decreased amplitude and duration of inhibitory sodium current, increased excitability of the whole neural network, and action potential spreading to the whole or partial brain, and thereby forming epileptic discharge. Also, Escayg A et al. compared 226 patients with drug-resistant epilepsy and 185 controls, revealing that the proportion of SCN1A mutations in the patients with drug-resistant epilepsy was significantly higher than that in the control group [15].

Surgical treatment of drug-resistant epilepsy

Although there were multiples of new-type antiepileptic drugs that have been continued to be approved for application, there still exist more than 30 percent of patients with epilepsy developed into drug-resistant epilepsy [3]. Wiebe S et al. conducted an RCT research and proved that the one year cure rate of patients with temporal lobe epilepsy by surgical treatment was significantly higher than that by drugs treatment (58% vs. 8%), which proved that surgical operation might be workable for the control of the incidence of temporal lobe epilepsy [16]. In addition, Fiest KM et al. found that patients at 6 months after surgery in the surgical group achieved positive minimum clinically important change (MCID) on the Quality of Life in Epilepsy (QOLIE)-89, compared with those in the medical group (56.0% vs. 11.0%,p < 0.001), meanwhile 62.0% of the surgical group achieved positive MCID on the QOLIE-31 (p < 0.001) compared with 17.0% of the medical group [17]. With the continuous development of related science and technology, a variety of different surgical treatment methods emerged in response to the proper time and conditions, and now surgical treatment has become a very important therapeutic tool for drug-resistant epilepsy treatment. The goal of surgery is to reduce the seizures, to avoid the adverse reaction after surgery, and to a certain extent, to improve the quality of life. In general, we need to adjust the preoperative state of patients to meet the criteria of surgery. At present, surgical treatment methods for epilepsy are divided into resective surgery, palliative surgery, neurostimulation and other surgical interventions.

Resective Surgery

Temporal lobe epilepsy is the most common type of drug-resistant epilepsy, which is usually treated by surgical operation [18]. Resective surgeries are gradually recognized to be the major treatment choice for drug-resistant epilepsy based on a large numbers of clinical experiments, and the early mesial temporal lobe epilepsy is particularly recommended to be treated by surgical operation [19, 20].

Mesial Temporal Lobe Epilepsy Resection

Surgical treatment methods for mesial temporal lobe epilepsy include anterior temporal lobectomy and selective amygdalohippocampectomy. In a long-term research which involved 615 cases of epilepsy patients, there were approximately 52% (95%CI, 48 to 56) patients who had no recurrence of seizures even after five years of surgery, and about 47% (95%CI, 42 to 51) patients did not indicate any signs of epilepsy attacks ten years postoperatively [21]. The study of RCT, Jerome Engel Jr, MD PhD et al. indicated that antiepileptic integrated therapy mainly based on surgical treatment showed a significantly greater efficacy in epilepsy patients escaping from relapse after treatment for two years than those received continues drugs treatment (OR = ∞; 95% CI, 11.8 to ∞; P <0.001). The Quality of Life (QOL) overall T-score of patients in the surgical group was significantly higher than that in the medical group (12.8 points vs. 2.8 points; treatment effect =9.9; 95% CI, 2.2 to 17.7; P =0.01) [19].

Anterior temporal lobectomy is applicable for cases with epileptogenic zones on one side of the temporal lobe [22]. As almost all of epilepsy lesions of the mesial temporal lobe are from amygdala, hippocampus and parahippocampal gyrus, resection of the above structures can contribute in controlling the attack of epilepsy. With respect to the above, anterior temporal lobe unrelated to the occurrence of mesial temporal lobe epilepsy should be resected in anterior temporal lobectomy, as well as most of the hippocampus, amygdala and the parahippocampal structure. Anterior temporal lobectomy has become the standard surgical procedure for the treatment of intractable mesial temporal lobe epilepsy [16], and there were previous reports of about 66% seizure freedom rates [23].

Selective amygdalohippocampectomy is applicable for mesial temporal lobe epilepsy patients accompanied with hippocampal sclerosis [24], and major surgical operation methods include transsylvian [25], transmiddle temporal gyrus [26], subtemporal [27] approach, etc. Based on the results of systematic review and Meta-analysis of patients who received two different surgical treatments postoperatively, Josephson CB et al. found that patients who were managed by anterior temporal lobectomy were more likely to achieve Engel Class I as compared to patients managed by selective amygdalohippocampectomy (RR= 1.32, 95% CI, 1.12 to 1.57; P < 0.01) [28]. However, there has no distinct conclusion regarding the strengths and weaknesses of anterior temporal lobectomy and selective amygdalohippocampectom in the treatment of epilepsy [28, 29], which should further be verified by multi-center clinical research.

Extratemporal Lobe Epilepsy Resection

Surgical management of extratemporal lobe epilepsy is mainly applicable for patients who had drug-resistant epilepsy induced by cortical dysplasias, accompanied with tumor, ischemic change, and vascular malformation, etc. [30]. The incidence of extratemporal lobe epilepsy is mainly from the lateral temporal cortex [31]. A previous retrospective study conducted by Theys T et al. has identified the efficacy and safety of surgical treatment for epilepsy in the lateral temporal lobe [32]. The surgical management of extratemporal lobe epilepsy is more common in children due to the prevalence of progressive cortical dysplasia associated with diffuse epileptogenic zones [30, 33]. Epileptogenic zones are often distributed in the cortex, but vary from person to person, and sometimes may reside in the deep structure of the brain. So, an accurate positioning of the epileptogenic zones is a major challenge for the successful implementation of lateral temporal lobe epilepsy surgery [34]. In general, in the premise of ensuring the injury of non-functional areas in the brain, the more thorough the resection of the lesion, the smaller the possibility of recurrence of patients.

Hemispherectomy

Hemispherectomy is predominantly applicable for hemiconvulsions hemiplegia epilepsy syndrome, perinatal injury, unilateral hemispheric cerebral malformations, diffuse cortical dysplasia (such as hemisphere megalencephaly), Rasmussen syndrome and Sturge-Weber syndrome, etc. [35]. Major surgical operation methods include anatomical hemispherectomy, functional hemispherectomy, and hemidecortication, etc. [36]. Through the study of 83 children with drug-resistant epilepsy, Delalande O et al. discovered that about 77% patients achieved the goal of non-relapse of epilepsy(Engel Class I) under the circumstance of non-continuous antiepileptic drugs treatment after hemispherectomy, and 12% of children rarely occurred epilepsy attacks (Engel Class II), and 14% of children indicated a continuous occurrence of epilepsy(Engel Class III or IV) [37], suggesting the efficacy of hemispherectomy in the treatment of drug-resistant epilepsy. Through an average 4.5-years follow-up study, Carlo Efisio Marras et al. found 8 of 13 pediatric patients (62%) were seizure free (Engel Class I) after hemispherotomy, and one was classified as Engel Class II, four were Engel Class III or IV [38].

Major complications during the process of excision operation is neurological deficits occurring after surgical resection, including cranial nerve palsy, conscious of visual field defects (hemianopsia) which is not easily perceived by patients, etc., but most of the symptoms are temporary [39, 40]. In addition, postoperative complications are more common for surgical resection with a wide range of surgery fields, such as cerebral hemisphere resection. Serious complications may also appear after surgery, including hemiplegia, intracranial infection and intracranial hematoma, brain abscess [41, 42].

Palliative Surgery

Palliative surgery is a conservative treatment for the treatment of drug-resistant epilepsy, mainly through surgical operation to block the epilepsy discharge diffusion pathway, suitable for epilepsy drug-resistant patients who failed in surgical treatment or patients who are not considered suitable for surgical treatment. Surgical operation methods mainly include corpus callosotomy, multiple subpial transection etc. Palliative surgery can reduce or relieve epilepsy seizures to a certain extent.

Corpus Callosotomy

Corpus callosotomy is applicable for patient with multiple epilepsy types, including secondary generalized epilepsy, Lennox–Gastaut syndrome, or Lennox-like syndrome, West syndrome and refractory idiopathic generalized epilepsy, etc. [43]. As the largest white matter structure in the human brain, callosum corpus connects the cortex of the two cerebral hemispheres, and callosum corpus fibers play an important role in seizure spread [43, 44]. Callosum corpus is partial or completely dissected in corpus callosotomy, thereby destroying the fiber connections between the two cerebral hemispheres, preventing the focal seizures or the tonic and atonic seizures spread to the opposite side. Seizures in the form of tonic, atonic or mixed epilepsy can cause severe falls (so-called drop seizures). There were previous studies which proved that corpus callosotomy also has a very good therapeutic effect in decreasing seizures [45]. However, the rate of complications after the operation is relatively high, the most classic complications is the disconnection syndrome, and other complications include temporary or permanent motor dysfunctioning, memory and language dysfunctioning [46]. A systematic study on the use of classification Engel by Graham et al. observed that total corpus callosotomy had a better curative effect in reducing epilepsy attack as compared to anterior corpus callosotomy (88.2% vs. 58.6%, P < 0.05) at least 1 year after surgery, the occurrence of disconnection syndrome was significantly higher following total corpus callosotomy than that following anterior corpus callosotomy (12.5% vs. 0%; P < 0.05) [47].

Multiple Subpial Transection

Multiple subpial transection, originally invented by Morrell in 1989 [48], and continuous improvement was achieved to increase the therapeutic effect, is now mainly used in the following epilepsy types where the epileptogenic zones are observed to be located in language, vision, original motion and sensory function areas, such as Landau Kleffner syndrome (LKS), etc. [49, 50]. Epileptic discharge spread is mainly accomplished through the horizontal direction of fibers in the cortical neurons; besides, via cutting short fiber in horizontal direction within the cerebral cortex, multiple subpial transection can protect vertical column, which can contribute to the reservation of the function of functional areas, and can also block the epilepsy discharge pathway, so as to control epilepsy seizures [51]. Through the follow-up of at least 2 years after modified MST operation, Ntsambi-Eba G, et al. found that about 79% patients (single MST treatment group, 75%) showed at least 50% decrease of epilepsy attack rate, and 42% patients revealed no epilepsy attack (single MST treatment group, 33%) [52].

Neurostimulation

Neurostimulation includes vagus nerve stimulation, deep brain stimulation, responsive neurostimulation etc.

Vagus Nerve Stimulation

Vagus nerve stimulation was proposed by Zabara in 1985, and in 1988 for the first time, it was applied to the human body [53], which is applicable for drug-resistant epilepsy patients who were unable to remove the lesion and for drug-resistant epilepsy patients with a previous history of surgical treatment failure. The method is to implant the produced electric pulse stimulator in the left chest, and the electrode is connected with the left vagus nerve through the subcutaneous channel to the neck, so as to stimulate the vagus nerve to control epilepsy attack [54], vagus nerve stimulation has been approved by the U.S. FDA in 1997, as an adjuvant therapy for drug-resistant epilepsy [55]. The antiepileptic mechanism of Vagus Nerve Stimulation is still not understood sufficiently, and some studies have speculated that it may be associated with brainstem nuclei [56]. Nucleus of the solitary tract (NTS), which is the main terminal point, has direct or indirect projections to the raphe nuclei, locus coeruleus, reticular formation, and other brainstem nuclei. These nuclei have been confirmed to affect the cerebral seizure susceptibility, thereby, vagal modulation of these nuclei could represent the mechanism for seizure-attenuating [57]. Krahl et al. demonstrated that the locus coeruleus plays a crucial role in suppressing epilepsy of VNS in rat models [58]. In addition, GABAA receptor density, the immunomodulatory function of the vagus nerve, noradrenaline and serotonin could contribute to the seizure attenuating effects of VNS [59-61]. The earliest trial of the vagus nerve stimulation is reported to be applied for refractory epilepsy patients in the early 1990s [62]. Englot DJ et al. found through Meta analysis that following vagus nerve stimulation, the frequency of epilepsy seizures reduced to over 50% (OR = 1.83 95%CI 1.80-1.86) [63]. By a 5-year follow-up study of drug-resistant epilepsy patients who are managed by vagus nerve stimulation, Pakdaman H et al. found that overall mean frequency of monthly seizures decreased by 57.8-67%, which confirmed the safety and effectiveness [64]. Vagus nerve stimulation has fewer side effects, and the incidence rate is about 2%, mainly including hoarse voice and cough, postoperative hematoma, and infection, etc. [65]. But the vagus nerve stimulation is currently only used as an adjuvant therapy for drug-resistant epilepsy, rarely able to completely prevent the onset of epilepsy. At the same time, the current vagus nerve stimulation is an invasive treatment, and requires a second surgery per 5-10 years to complete the replacement of the battery, which is likely to cause the emergence of complications again. Furthermore,vagus nerve stimulator can not get effective imaging observation by MRI, which is a challenge for the wide application in clinic in future. At present, transcutaneous vagus nerve stimulation (tVNS) is gradually rised and has been proved to be safe and effective in the treatment of epilepsy. Through a double blind randomized controlled trial, Bauer S found that transcutaneous auricular vagus nerve stimulation (ta-VNS), as a non-invasive technique, has a high treatment compliance and tolerability, and compared with the control group, patients in the 25 Hz treatment group indicated a significant decrease regarding the frequency of epilepsy seizures (20 weeks; n = 26, 34.2%, P = 0.034) [66]. Rong P et al. found in their research that in comparison of ta-VNS treated patients and the controls, the frequency of epilepsy seizures reduction in the former group was significantly higher than the latter group after 8 weeks of treatment (42.6% vs. 11.5%, P < 0.05) [67]. Although, ta-VNS has been proven to be effective in the treatment of drug-resistant epilepsy, more basic and clinical studies are needed to provide further supports and guidance for the clinical application of the technology.

Deep Brain Stimulation

Deep brain stimulation has been involved in the therapeutic test for the treatment of drug-resistant epilepsy since 1950s, and targets for the deep brain stimulation in the treatment of epilepsy include centromedian nucleus of the thalamus, anterior nucleus of the thalamus, subthalamic nucleus, hippocampus, locus coeruleus, etc., yet the antiepileptic mechanism of deep brain stimulation still remains unclear. A multi-center double blind RCT regarding anterior thalamic nucleus stimulation suggested that a 56% median percent reduction in seizure frequency and 54% of patients had a seizure reduction of at least 50% [68]. Thalamic deep brain stimulation has been approved in the European Union, Canada and other countries as an adjunctive therapy for drug-resistant epilepsy and secondary generalized seizures, but still not approved by U.S. FDA [69]. Most common complications include bleeding, infection, mechanical complications, neuropsychiatric changes, but death and serious complications are rare [70]. Although deep brain stimulation in the treatment of anterior nucleus of the thalamus and hippocampus has been demonstrated through a large number of RCTs, however, further research is needed to confirm therapeutic effects of other targets.

Responsive Neurostimulation

Responsive neurostimulation is applicable for the treatment of refractory focal epilepsy patients who have failed in a variety of treatment modalities [71]. Responsive neurostimulation is a new technology that can discover epilepsy seizure activities in the brain through monitoring electrocorticographic activity, and to give a direct focal electrical stimulation, so as to reduce epilepsy seizure through the targeted way [72]. Responsive neurostimulation can precisely suppress the γ band (35-100 Hz) phase locking to suppress the epileptiform activity, and separate the stimulation region from the downstream target [73]. Through target area electrode placement in the brain, it is connected with the analysis device placed subcutaneously, which can achieve continuous recording neural physiological signals in the target area of the brain, and can support data analysis with the self-taking program, to give appropriate stimulus processing. Hence the advantage of this device is the effective combination of seizure activities monitoring and electrical stimulation,. Morrell MJ et al. have found that 12 weeks after implantation, frequency of seizures were significantly deceased in the treatment (-37.9% n =97) compared to the sham group (-17.3% n =94; p =0.012) and there was no significant difference found between two groups regarding the adverse events, which approved the effectiveness of responsive neurostimulation in the treatment of epilepsy [71]. However, to date, the method is limited [74], and more RCT researches are needed to make the method widely used in clinical applications.

Other Surgical Interventions

Stereotactic Radiosurgery

In the recent years, the non-invasive radiation therapy has been applied for the control of epilepsy. By focusing on the ionizing radiation targeted to the deep lesions, this method can avoid the damage to the surrounding tissue. The photon accelerator is the most widely used in ionizing radiation, such as cyber knife, gamma knife etc. Mainly through the neuromodulation mechanism, stereotactic radiosurgery can contribute to the reduction of both excitatory neurotransmitter and inhibitory neurotransmitter, or through ischemic necrosis of epileptic tissue to isolate and destruct connection between the middle neuron and to block the conduction of the epileptic attack, to achieve the purpose of reducing the occurrence of seizures or changing the form of seizures and protecting the brain function [75]. The main advantage of stereotactic radiosurgery lies in the non-invasive treatment, without the need for craniotomy and other surgical procedures to complete the treatment of deep lesions and multiple lesions, so as to avoid the inherent brain tissue traction or injury, but require higher precise positioning. The disadvantage is that the curative effect of stereotactic radiosurgery is delayed to decrease the frequency of epilepsy attack, Chang EF et al. have shown in their study that an epilepsy remission occurred later in patients treated by stereotactic radiosurgery [76]. And during this period, epilepsy attacks still occur, and the risk associated with the incidence of epilepsy and mortality remains. In addition, there is a secondary injury and delayed malignancy that is secondary to radiation. Stereotactic radiosurgery is an open surgical operation for the treatment of drug-resistant epilepsy, the antiepileptic mechanism still remains unclear. It was first discovered that its antiepileptic effect was in the treatment of the tumor, such as tumors, Arteriovenous Malformations (AVMs), cavernous malformations (CMs) and hypothalamic hamartoma (HHs), etc., which is the most obvious especially in the treatment of arteriovenous malformations associated with epilepsy. During the median 65.6-months follow-up period, Przybylowski CJ et al. found that a sum up of 65 cases of patients (89%) achieved seizure remission in altogether 73 cases of epilepsy patients before SAR, and there were 21 cases of patients (33%) who reduced the usage of antiepileptic drugs in the 63 cases of patients before surgery (P = 0.05) [77], suggesting that stereotactic radiosurgery may be effective for the control of long-term arteriovenous malformations associated epilepsy seizures.

Stereotactic Laser Ablation (SLA)

When the epileptogenic zone is located in the deep brain or the important structure of the brain, which is not suitable to do the surgery, the stereotactic laser ablation may be a good choice [78]. The stereotactic laser ablation procedure can be performed with a small scalp incision and miniature burr hole, with a laser probe which is placed using a stereotactic frame or interventional MRI technique [79]. By locating and destroying the epileptogenic zone, SLA can inhibit the abnormal electrical activity of neurons in the epilepsy, and destroying the conduction pathway of epilepsy activity, blocking the spread of epileptic discharge to the surrounding cortex, thereby controlling the epilepsy attack. Lewis EC et al. conducted their study by involving 17 cases of postoperative patients managed by nuclear magnetic guided laser interstitial thermal therapy and found that seven patients (41%) achieved Engel class I outcome, and one of the seventeen patients (6%) achieved Engel class II outcome, Engel class III in three of 17 the patients (18%), and Engel class IV in six (35%) [80]. By observing the epilepsy attack in 20 cases of patients following laser interstitial thermal therapy, Kang JY et al. found that 8 of 15 patients (53%, 95% CI 30.1-75.2%) were free of seizures after 6 months postoperative, 4 of 11 patients (36.4%, 95% CI 14.9-64.8%) were free of seizures after 1 year, and 3 of 5 patients (60%, 95% CI 22.9-88.4%) were free of seizures at 2-year follow-up [81]. These studies have demonstrated the efficacy and safety of SLA in the treatment of drug-resistant epilepsy, but more basic and clinical studies are needed to be carried out in future.

The time for surgery is especially crucial due to complexity and progressivity of epilepsy. For children with drug-resistant epilepsy, early surgery may obtain a better outcome because children have greater plasticity and ability to reorganize functions in the developing brain compared to a more mature brain. A large scale of researches has confirmed. Chugani HT et al. reviewed from 65 (33 male) patients with epileptic spasms who underwent surgery and found that in 34 patients operated <3 years after seizure onset, 30 (88%) achieved class I outcome that is higher than average success rates (71%), which indirectly demonstrate curative epilepsy surgery in epileptic spasms patients, with or without history of infantile spasms, is best accomplished at an early age [82]. Anita Althausen et al. divided 61 patients into three groups (early:<7 years/intermediate: 7–16 years/late: >16 years) and found that best seizure outcome was obtained for early surgery patients (90% seizure free) through a long-term outcome followed-up hemispheric surgery, [83]. For adults with drug-resistant epilepsy, who are suitable for surgery, it seems that performing a surgery as soon as possible is beneficial. However, a correlation between outcome after surgery and time for surgery is moderate. And the best time for surgery remains to be explored.

Adjuvant Therapy with Antiepileptic Drugs in the Perioperative Period

Seizure freedom and without further needs of continuous application of antiepileptic drugs are surely the most desirable outcome in patients with drug-resistant epilepsy postoperatively. But in most cases, simple surgery does not completely control the onset of epilepsy. Perioperative drug therapy is also critical, and is currently the most important part of the comprehensive therapy targeting drug-resistant epilepsy. The cure of epilepsy after operation is not only related to the completion degree of surgical resection, but also related to perioperative medication strategy. Usually, antiepileptic drugs should be used for one to two years in patients with epilepsy postoperatively, or even indefinite [84].

Levetiracetam (LEV) is a new type of antiepileptic drugs, by inhibiting the N type calcium current in the CA1 region of the hippocampus [85], reducing zinc ion and β-carbolines mediated GABA- and glycine-gated current, affecting the function of GABA receptor, thereby exerting antiepileptic roles [86]. Currently, the drug is mainly applied for first-line treatment of generalized tonic clonic seizures, myoclonic seizures and focal seizures. Jehi et al. found in their study showing that in the perioperative period of temporal lobectomy, patients of the LEV administration group revealed a relatively lower frequency of epilepsy seizure postoperatively (RR=0.62, 95% CI 0.43-0.89, RR = 0.57, 95% CI 0.39-0.83) [87], suggesting that there existed possibility of LEV in the postoperative antiepileptic treatment. However, a retrospective analysis of clinical data of 106 cases of epilepsy patients receiving resection surgery was made, Ramsekhar Menon et al. attempted AED withdrawal in 94 cases of patients (88.7%). Following withdrawal, it was found that there were 44 cases of patients (41.5%) who showed another relapse of epilepsy due to the decreased administration of antiepileptic drugs, among which seizure-free did not occur subsequently in about 14 cases of patients (31.8%), besides, the one-third recurrence patients failed to control the occurrence of seizures upon AEDs reintroduction [88]. By performing the withdrawal of antiepileptic drugs in 223 cases of postoperative patients, Park et al. conducted antiepileptic drugs reduction processing in 147 cases of patients (65.9%) and found that a total of 78 cases of patients (53.1%) indicated a relapse of epilepsy after initial reduction. The phenomenon of antiepileptic drug termination was detected in a sum up of 73 cases of patients (32.7%), among which 59 cases of patients (80.8%) were seizure free even once until final assessment [89].

Although antiepileptic drugs are of great significance in postoperative consolidation therapy and reducing the recurrence of epilepsy, there are no clear standards for the perioperative treatment of drug-resistant epilepsy. How to use and terminate, and when to terminate drugs and other issues still exist along with great controversy in patients with drug-resistant epilepsy in the perioperative period when using antiepileptic drugs [84], which needs to be further explored on the basis of further basic and clinical researches.

Expectation

As for drug-resistant epilepsy, accurate surgical resection has more important significance for the complete or incomplete free of seizure, accurate preoperative localization can not only contribute to the reduction of the risk of surgery, but also help to develop a perfect operation strategy, which can also have a significant impact on the reduction of postoperative complications and improvement of prognostic outcomes. Therefore, it is very important to accurately locate the epileptogenic zone and the functional areas of the brain.

While preoperative assessment of new technologies is emerging, the role of EEG in clinical trials is still irreplaceable because it can describe the onset and progression of a specific description of epilepsy in time domain. Since the promotion of stereolectroencephalography (SEEG) by Bancaud and Talairach in 1970s, it has been used for the preoperative location and evaluation of epilepsy, and achieved great success [90]. Magnetic resonance imaging of epilepsy provides an intuitive and clear anatomical image for the etiological diagnosis of epilepsy. It has been widely used in the preoperative localization of epilepsy. At present, structural MRI is still the main neuro imaging technology for localization of epileptogenic zone. However, 15 - 30% patients with drug-resistant epilepsy lesions did not have an obvious lesion on the MRI (for example, they were MRI negative) [91, 92], which greatly limits the effective application of MRI technology. Recently, the emerging of functional MRI and magnetic resonance spectroscopy provides new development for the application of magnetic resonance technology. Functional MRI is based on the application of blood oxygen level dependent technique to detect the changes of cerebral blood flow dynamics, and it could be used to locate the epileptogenic zones or the functional areas related to language, motor function, memory and so on [93]. On the other hand, relied on the combination techniques of magneto encephalography (MEG) and MRI data, magnetic resonance spectroscopy can lead to a relative quantitative analysis for in vivo brain biochemical substances concentrations, which may contribute to the direct reflection of changes in the metabolism of nerve cells, which thus leads to the indirect confirmation pathological changes of lesions, which is especially sensitive in temporal lobe epilepsy localization [94]. At the same time, along with the development of nuclear medicine technology, 18F-FDG (18F-fluorodeoxyglucose) PET and ictal SPECT has also been used in the evaluation of epilepsy surgery. The main advantages of clinical PET imaging are not only reflecting the progress of the blood flow of the tracer in the body including perfusion and metabolism, but also quantitatively reflecting the distribution of radioactive markers. And in the epileptogenic region of ictal SPECT, there was an area of hypoperfusion, which might be caused by blood flow shifting to the epileptogenic zone or might represent an inhibitory zone that limits the spread of seizure, thereby resulting in locating lesion of the epilepsy [95]. M. Goodfellow et al. used mathematical models to simulate recurrent pathological dynamics and quantify global (whole brain) and local (brain regions) ictogenicity based on preoperative ECoG data of epilepsy patients, which provide a promising prospect for preoperative assessment and postoperative prediction of drug-resistant epilepsy [96]. At the same time, several techniques have been developed to map the source of interictal epileptiform discharges (IEDs), including electroencephalography-functional (EEG-fMRI), electroencephalography source imaging (ESI), and magnetic source imaging (MSI), and has made great progress [97, 98].

With the continuous development of science and technology, preoperative evaluation and location method of epilepsy will be perfected to continue to improve the accuracy of lesion localization, also contribute to a wild application perspective for comprehensive treatment mainly based on surgery.

As an important portion of adjuvant therapy for drug-resistant epilepsy, drug therapy plays an irreplaceable role in the treatment of epilepsy. Recently, some promising drugs targets have been emerging gradually, which provides some novel possibilities and potential biochemical indicators for clinical evaluation in the management of epilepsy in future. Glutamate neurotransmitters and Ca2+ channels are known to play an important role in the etiology of epilepsy [99-101]. TRPV1 is a non-selective channel with high Ca2+ permeability, and synaptic terminals whose activation typically facilitates glutamate release through increased excitability of neurons [102]. There are two main TRPV1 channel blockers, namely capsazepine (CPZ) and resiniferatoxin, which have been reported on anticonvulsant roles [103]. Thus, targeting the TRPV1 channel activity may provide a feasible strategy for treatment of drug-resistant epilepsy. Na+ K+ 2Cl- co-transporter (NKCC) belongs to cation-dependent chloride co-transporter family and induces transport of Na+, K+ and Cl- ions into the cell [104]. Activation of NKCC allows the entry of Na+, K+ and 2Cl- inside the cell, and that roles of the NKCC1 blocker (bumetanide) about decreased the Cl- accumulation, suppressed epileptiform activity in neonatal rats have been proved [105]. Sen et al. also confirmed the increased expression of NKCC1 in medically resistant refractory human epilepsy with hippocampal sclerosis and focal cortical dysplasia [106]. Although some reports have demonstrated potential of NKCC1 blocker for drug-resistant epilepsy treatment, more studies are still required to explore. Enhanced gap junctional communication between neurons may be an underlying factor related to the generation of epilepsy [107]. Some chemical compounds, such as Carbenoxolone, mefloquine, quinine, quinidine et al. characterized as gap junction blockers have been evaluated on animal seizure models, which can be an underlying possibility for development of antiepileptic drug [108]. There is an experimental evidence indicating that oxidative stress may be involved in the epileptogenesis of epilepsy [109], providing possibility for Selenium as a potential drug to treat epilepsy due to its inoxidizability [110]. Savaskan NE et al. have shown that Selenium deficiency may lead to increased susceptibility to glutamate-induced excitotoxicity. Undoubtedly, a mass of clinical studies needs to be continued. Recent advances in studies on interacting proteins of neurotransmitter receptor systems suggest that agonists or antagonists of mGluRs, especially group I mGluR antagonists are promising candidate drugs to control seizures and subsequent neurodegeneration. And different receptor systems may share the common signal transduction pathways or interacting proteins, which may provide therapeutic targets for pharmaceutical treatment of epilepsy [111].

In addition to drug therapy, the ketogenic diet, Chinese medicine therapy and immunotherapy are also effective adjuvant therapy for drug-resistant epilepsy. Ketogenic diet is a high fat, low carbohydrate and appropriate protein diet therapy, applicable for all age groups of children with drug-resistant epilepsy [112]. This therapy may inhibit the onset of epilepsy by interrupting the glutaminergic synaptic transmission, inhibiting the activation of the ATP sensitive potassium channel and the GABAB receptor and enhancing the GABA mediated inhibition [113]. Through the study of 1-18 years old children and adolescents with drug-resistant epilepsy, Lambrechts et al. observed that the frequency of epilepsy seizure in ketogenic diet treatment group was significantly lower than that in the care as in usual group, providing class I evidence that ketogenic diet may be effective therapeutic method for the treatment of drug-resistant epilepsy in children and adolescents [114].

Drug-resistant epilepsy is referred to as refractory epilepsy in the traditional Chinese medicine, the disease course is long accompanied with progressive deterioration. In the past few thousand years, plant extracts and herbs are often used in the treatment of individuals with epilepsy seizures, and in many cases are considered to be safe [115, 116]. A large number of clinical and experimental studies have confirmed antiepileptic effects of compound prescriptions, such as saiko-ka-ryukotsu-borei-to and Epilepsy tablets [117, 118]. Immunotherapy is also a new adjuvant therapy for drug-resistant epilepsy. Currently available options for the treatment of epilepsy include steroids (corticosteroids, glucocorticoids), plasmapheresis, intravenous immunoglobulin, steroid-sparing drugs such as azathioprine and so on [119]. Immunotherapy can effectively avoid side effects of antiepileptic drugs, and also prevent traumatic brain injury, stroke, intracranial infection through the addressing of inflammation in patients at high risk for epilepsy seizure. However, the relevant mechanism of immunotherapy is not completely clear, and the cost of treatment is high, above which are the problems that need to be solved in a wide range of applications.

With the development of genomic and genetic research, cell transplantation and gene therapy have been gradually acknowledged by people as potential antiepileptic therapies. Gene therapy has been shown to inhibit the local neocortical epilepsy seizure in a rodent model [120], and breakthrough progress has been made in animal experiments [121]. Targets of gene research include galanin (GAL) and neuropeptide Y (NPY), etc. Relevant study indicated that NPY was widely expressed in the brain and can reduce chronic spontaneous seizures in temporal lobe epilepsy mice models [122]. Overexpression of recombinant adeno-associated viral (rAAV) vector mediated endogenous polypeptide in the hippocampus can exert long-term effect of decreasing epilepsy seizure in a variety of animal models [122-124]. However, the treatment efficacy of gene therapy and cell transplantation needs to be verified in a large number of animals and clinical trials.

Above mentioned therapies are the adjuvant therapies of drug-resistant epilepsy, we look forward to see more clinical studies combining these methods with the standard surgical treatment, further promoting new exploration of antiepileptic comprehensive treatment mainly based on surgery, so as to achieve the remission and even cure of drug-resistant epilepsy with the development of the epileptogenic zone localization and imaging technology, as well as the deepening of drug-resistant epilepsy mechanism researches, comprehensive treatment mainly based on surgery will continue to be improved and popularized, and finally bring a new dawn for drug-resistant epilepsy patients.

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