Novel Approaches for Treatment of Epilepsy

Epilepsy is a serious neurological disorder on the juncture of psychiatry and neurology. It is characterized by recurrent and episodic seizures which are due to excessive discharge by the brain neurons. The therapeutic response failure of more than one or two antiepileptic drugs (AEDs) is the benchmark of refractory or intractable epilepsy. The aim of the study was to determine new approaches which lead towards the treatment of epilepsy. In order to treat focal mesial temporal lobe epilepsy or neocortical epilepsy in adults and any malformation of cortical development such as focal dysplasia surgical resection remains the gold standard treatment. Disconnection procedures such as corpus callosotomy and multiple subpial transections are the best alternative treatment for that patient whose seizure origin is in eloquent cortex or having generalized epilepsy syndromes. Palliative neuromodulation procedures such as Vagus nerve stimulation (VNS), Responsive neurostimulation (RNS) and Deep brain stimulation (DBS) are best approach to treat intractable epileptic patients who are not suitable candidates of surgery.  As the search of better management of epilepsy continues gene therapy and optogenetics gain a momentum in neuroscience.

intrinsic severity hypothesis. The normal human brain is protected by P glycoprotein(P-gp), multi drug resistance gene 1(MDR1), which is found only in the vicinity of blood vessels on endothelial cell membrane that constitute BBB and multi drug resistance associate's protein 1 (MRP1), which is found only in the choroid plexus epithelium. Normally, P-glycoprotein(P-gp) export the drug out of cell in order to protect the cells against in ux of xenobiotics. P-gp transport few AEDs, several AEDs have similar chemical structure to P-gp substrate [4,5]. Hence it can be concluded that the inhibition of P-glycoprotein may contribute towards the treatment of patients suffering from antiepileptic drug resistant epilepsy [6]. Hence, researchers are of the view that the genetic variation of the Treatment of Epilepsy

I N T R O D U C T I O N
Epilepsy is a serious neurological disorder on the juncture of psychiatry and neurology. It is characterized by recurrent and episodic seizures which are due to excessive discharge by the brain neurons. The therapeutic response failure of more than one or two antiepileptic drugs (AEDs) is the benchmark of refractory or intractable epilepsy. The aim of the study is to determine new approaches which lead towards the treatment of epilepsy. In order to treat focal mesial temporal lobe epilepsy or neocortical epilepsy in adults and any malformation of cortical development such as focal dysplasia surgical resection remains the gold standard treatment. Disconnection procedures such as corpus callostomy and multiple subpial transections are the best alternative treatment for that patient whose seizure origin is in eloquent cortex or having generalized epilepsy syndromes. Palliative neuromodulation procedures such as Vagus nerve stimulation (VNS), Responsive neurostimulation (RNS) and Deep brain stimulation (DBS) are best approach to treat intractable epileptic patients who are not suitable candidates of surgery. As the search of better management of epilepsy continues gene therapy and optogenetics gain a momentum in neuroscience. genes encoding enzymes that are responsible for metabolism of antiepileptic drugs, drug receptors and ion channels may be responsible for the resistance faced by some individuals in case of antiepileptic drug therapy [7,8]. As shown in Figure 1, there are various novel treatment approaches for treating epilepsy. This study provides an extensive review of various novel treatment approaches ( Figure 1) that have been used for the treatment of the epilepsy.

SURGERY
Current AEDs which mainly targets ion channels and transmitter receptors are only effective in 60-70% of individuals idiopathic generalized epilepsy can be easily controlled by medication than the focal epilepsies and symptomatic generalized epilepsies [9,10]. Epilepsy surgery can be divided into two categories, resective and disconnective procedures. The former includes lesionectomy, corticectomy, and lobectomy. The latter comprises MST (multiple subpial transections), corpus callosotomy, and hemispherotomy [11]. Surgical intervention need not be considered only as a last resort [12]. HEMISPHRECTOMY The best candidates for hemisphrectomy are patients having progressive (Rasmussen's encephalitis and Sturge-Weber syndrome), acquired (e.g.; intracranial hemorrhage, hemiconvulsion-hemiplegia-epilepsy syndrome, and other sequelae of brain trauma and infection) developmental (e.g., cortical dysplasia, hemimegalencephaly) etiologies [13,14]. Depending upon etiology and extension of anatomic abnormality there are three different surgical techniques.

Anatomic hemispherectomy
In anatomic hemisphrectomy lobes such as temporal, frontal, parietal and occipital lobes are removed with the preservation of the basal ganglia, insular cortex and thalamus.

Functional hemispherectomy
In functional hemispherectomy the procedures which are performed are (a) temporal lobectomy which extend to the trigone including hippocampus amygdala, (b) central excision in which lateral ventricle is exposed, (c) disconnection of corpus callosum from the ventricle to the course of anterior cerebral artery and pericallosal to the basal frontal region, and (d) posteriorly, corpus callosum is followed by subpial disconnection through temporal l o b e c t o m y t o p e r fo r m m e s i a l p a r i e t o o c c i p i t a l disconnection.

Modi ed anatomic hemispherectomy
Modi ed anatomic hemispherectomy is similar to anatomic hemispherectomy but in modi ed anatomic hemispherectomy the disconnection of frontal or occipital lobes or both are preserved depending upon the etiology, anatomic abnormality and the location of epileptogenic zone. This progression began with the development of hemidecortication and functional hemisphrectomy in the 1970's and 1980's. further in 1990s several different approaches such as hemispherotomy was introduced [15-17].

Corpus Callostomy
Corpus Callostomy is a palliative surgical procedure which is performed in those patients who suffer from idiopathic generalized epilepsy (IGE) and are not the best suitable candidates of focal resection [18]. Seizures in IGE occur due to the absence of structural lesions or are inherited in nature [19]. Approximately in 40% to >70% of patient's seizure frequency and severity may reduce [20,21]. In corpus callostomy complete section corpus callosum, anterior two third or three-fourth callostomy or anterior and posterior callostomy is performed. At present the most common procedure is two-third callostomy because of the less complications as compared to complete callostomy.

Multiple Subpial Transections (MST)
MST is one of the most novel approaches which are extensively used in those patients in which epileptogenic zone cannot be resected because it lies in eloquent cortex. In this method the horizontal connections which lies between the cortical neurons and are responsible for the propagation of the epileptic discharges is sectioned in this procedure [22]. MST can be performed alone or in combination with resective surgery such as a lesionectomy or large disconnections to treat epileptogenic foci present in eloquent cortex. MST not only treat unifocal epilepsy but also effective to treat Landau-Klefener Syndrome (LKS) in children and multifocal epilepsy in adults [23]. Hence, it was concluded that MST proved to be an alternative treatment for RSE [24]. NEUROMODULATION Neuromodulation has become a major eld of innovation in epilepsy therapy. Neuromodulation are palliative procedures which are minimal invasive and nonrespective. In neuromodulation electrical pulses are directly administered to nervous tissue to stimulate a pathologic substrate in order to achieve a therapeutic effect (Figure 2

VNS
Vagus nerve stimulation (VNS) as shown in Figure 2, is a neuromodulatory technique that stimulates the left vagus nerve [26]. Other than epilepsy, VNS is also use for mood improvements and for the treatment of drug resistant depression [27] hence VNS become a feasible treatment option in both neurology and psychiatry [28]. In worldwide more than 100,000 VNS devices were implanted in more than 75000 patients in August, 2014 [29]. In VNS batterypowered device which looks similar to cardiac pacemaker is implanted in the upper chest and electrodes with 2 connecting wires are placed subcutaneously to the left vagus nerve. The generator is connected by a wand and is attached with a laptop for monitoring. VNS is a broadspectrum treatment and is very effective in refractory focal onset seizure patients. It can be used in those patients who already had surgical treatment.
increased seizure threshold or reduction in the frequency of seizures or both [33][34][35]. RNS RNS is a closed loop stimulation which have an ability to stimulate the seizure focus automatically after the spontaneous detection of seizures. In this technique depth and subdural electrodes along with the neurostimulator is implanted in the cranium where seizure focus is located. According to a study performed by a group of researchers in 2011 concluded that there was a seizure reduction in intractable partial epileptic patients by receiving RNS [36]. RNS received FDA approval for the treatment of partial onset epilepsy in adults, in 2013 [25].

GENE THERAPY
In the past two decades advancement in technology and genetics led the researchers towards the discovery of almost 1000 genes solely associated with epilepsy [37]. Therefore, gene therapy ( Figure 3) techniques can be used as an alternative to respective surgeries in case of patients suffering from intractable focal epilepsies. The main idea behind the gene therapy approaches is the transfer of therapeutic genes into the ictogenic areas of the brain. These therapeutic genes are involved in the expression of neuromodulatory molecules having special anticonvulsive and antiepileptic properties [38,39].

Deep brain stimulation (DBS) is one of the open loop
systems. In DBS the target sites for stimulation are anterior nucleus of thalamus, centromedian thalamus, thalamus and seizure focus [30,31]. Anterior nucleus deep brain stimulation (AN-DBS) was reported by copper and Upton for the rst time. AN-DBS was introduced by these researchers for the treatment of complex partial seizures. The main idea behind this approach was the data collected over the year about the involvement of AN in the occurrence of generalized seizures [32]. Furthermore, it was concluded after research on animal-based models that high-frequency stimulation of AH may result in the Neuropeptide System in Gene Therapy Galanin in Gene Therapy A12 neuropeptide system known as galanin system is most abundantly expressed in the temporal lobe of the brain. This system releases galanin which is a neuro peptide. Galanin acts by suppressing the excitatory glutamatergic neuronal transmissions which are involved in seizures [40].
Researchers developed viral vectors which act by exogenously releasing galanin in order to suppress the seizures. This approach was one of the rst therapeutic approaches which are used to suppress seizures by the help of gene therapy [41].

NPY Gene Therapy
Neuropeptide Y (NPY) system is another neuropeptide system that is widely expressed in the brain. NPY naturally released in the brain by NPY system plays a vital role in controlling seizures [42]. Hence NPY is considered as a target candidate in case of antiepileptic gene therapy approach. Researchers are developing NPY gene therapy which will soon be entering the clinical trials for speci cally treating temporal lobe epilepsy. This approach would prevent the surgical removal of ictogenic tissues [43].

OPTOGENETICS
Optogenetics is an evolution in the treatment of neurological disorders. It's a new advanced technique for the treatment of intractable epilepsy. Optogenetics is a combination of optical technology and gene targeting of neurons or proteins. If patients are not suitable candidates for surgery, then they are subjected to neuro stimulation such as VNS for the reduction of the seizure frequency. But if patients are suffering from post-surgical relapse, remission [44] or bilateral temporal lobe epilepsy or having seizure focus in eloquent cortex then they can get bene t from such an advanced and fascinating molecular-genetic tool which is known as Optogenetics. In this technique light sensitive proteins which are known as opsins are used [45,46] which manipulate the brain activity. This fascinating approach can be used to treat epilepsy [47].

OTHER TREATMENTS OF EPILEPSY
Some other previous treatments used for treating epilepsy are mentioned in Table 1.

Interventions Used References
Decrease nerve impulses that are responsible for causing seizures.
Used as a rst-line drug for generalized and focal seizures.
Used for generalized and focal seizures.
Used for generalized and focal seizures.
Restructuring of maladaptive thought patterns.
Tense a group of muscles while breathing in and relaxes them while breathing out. Release tension in key joints through combination of body postures.
Found to be involved in potentiation of GABAergic activity in brain.
Neurotransmitter modulation in brain by ketone bodies.
Increase Ca2+ uptake and decrease neuronal excitability. [48] [49] [48] [48] [50] [51] [52] [53] [54] [55] There are many approaches to treat epilepsy. Among all approaches surgical treatment remain the gold standard to treat temporal lobe epilepsy, any malformation in cortical development or to treat any lesion. Alternative treatments for those patients who are not suitable candidates for resective surgery is neuromodulation. There are three types of neuro modulation and all of them are safe and effective in terms of reducing frequency of seizures. The best candidates for RNS and DBS are those patients whose seizure origin is in eloquent cortex. Optogenetics proved to be very effective in animal models to reduce the frequency of seizure. However, still some research such as optimization of light delivery, opsin introduction is required to be done before its application in humans. S o u r c e o f F u n d i n g The authors received no nancial support for the research, authorship and/or publication of this article.