ReviewDeep brain stimulation for epilepsy in clinical practice and in animal models
Highlights
► Clinicians have begun to open up to the possible use of DBS for refractory Epilepsy. ► DBS of various neural targets has been investigated in clinical studies and animal studies. ► ANT is a promising and preferable target in seizure control for intractable epilepsy. ► We review mainly the animal studies and clinical studies of ANT DBS for epilepsy.
Introduction
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures [5]. About 50 million people worldwide have epilepsy, with almost 90% of these people being in developing countries [105]. If seizures cannot be controlled, the patient may experience major disruptions in family, social, educational, and vocational activities that can have profound impacts on the quality of life [31].
Despite chronic medication therapy, which is based on the modulation of cortical inhibition/excitation balance to prevent seizures, up to 30% of patients with epilepsy will suffer from persistent seizures [77], [84]. A subset of these patients will be candidates for anterior temporal lobectomy, which in reported series has resulted in 80–90% seizure freedom [94]. In addition, stereotactic radiosurgery (RS) is currently under evaluation as an alternative to open surgery for mesial temporal lobe epilepsy (MTLE) [10]. However, both open surgery and stereotactic radiosurgery can be limited by anticipated functional deficits such as memory loss or cognitive impairment [41]. Moreover, patients who have seizures arising from eloquent cortex, or which are multiple focal, bilateral, or generalized, are not candidates for resective surgery [45]. Such intractable epilepsy, both resistant to drug treatment and unsuitable for surgery, is a significant public health problem so that other alternative therapeutic approaches are needed.
For these patients, neurostimulation has a potential for benefit. Different approaches exist for treatment, depending on the brain region that is targeted and the way the stimulation is applied [27], [41], [65], [76], [86]. The aim is to reduce the probability of seizure occurrence and/or propagation, either by manipulating remote control systems (vagus nerve stimulation, deep brain stimulation) or by interfering with the epileptogenic zone itself (direct cortex stimulation).
Vagal nerve stimulation has already been a success in intractable epilepsy and suggests that neuronal excitability can be significantly altered by electrical currents [6]. Nevertheless, most of these patients will not be seizure-free. Thus, due to the remarkable success of deep brain stimulation (DBS) for movement disorders [34], [48], combined with its advantages of programmability, reversibility, and low risk of complications [19], [81], there has been an explosion of research into implantable deep brain devices for treating refractory epilepsy [54], [55]. DBS of various neural targets has been investigated in clinical studies and animal studies, including the anterior nucleus of thalamus (ANT), cerebellum, hippocampus, subthalamic nucleus (STN), Centromedian nucleus of the thalamus (CMT), caudate nucleus (CN) (Table 1, Table 2). Recently, a multicenter and randomized trial (SANTE) of 110 patients was conducted to demonstrate the effectiveness of bilateral stimulation of ANT and had already provided encouraging data, added with its close connection to the mesial temporal structures via the fornix, mamilllothalamic tracts, and thalamocortico radiations, making ANT the most well-established target for DBS in the treatment of epilepsy to date.
Section snippets
Deep brain stimulation of ANT
Relevant circuits and advantages of targeting ANT: There is a concept that disorders of treated with DBS are fundamentally disorders of a specific brain network, as opposed to a specific neuron type, ion channel, or molecule [18], [56], which appears to hold true with epilepsy. Radiologic imaging and animal studies have confirmed the enhancement of metabolic activity in structures of neuroanatomic circuits described later, which supports the hypothesis that the neuroanatomic circuits may be
Hippocampus
Stimulation of the seizure onset zone is another attempt to control seizures by brain stimulation. Velasco et al. pioneered stimulation in the hippocampus with continuous stimulation, and reported exceedingly good outcomes in nine patients [101]. Boon implanted ten patients in the hippocampus and reported a good outcome in seven of the ten patients [7]. Another study with five patients reported less successful outcomes [90]. Stimulation of hippocampus could potentially avoid memory loss
Mechanisms of action of DBS
The mechanisms of action of DBS in reducing seizures remain unclear. Studies showed that both stimulation parameters and relevant modulators work together to take part in the potential mechanisms of DBS to influence stimulation outcomes [1] (Fig. 1). Some authors support the hypothesis that actual stimulation is not necessary to achieve efficacy and claim that efficacy is based on the lesion provoked by the insertion of the electrode (the so-called microthalamotomy effect) in animal and in
Optimizing stimulation to avoid DBS failures
Optimizing stimulation parameters: Most protocols that have evaluated DBS for epilepsy have used stimulation parameters derived from the literature on DBS for movement disorders. In DBS for movement disorders, continuous stimulation during therapy is standard [4], [42]. Recent experimental data suggest that continuous stimulation may fail to control the occurrence of seizures for a refractory period of about 60 s exists during which any stimulation is ineffective [24], [78]. Continuous
Conclusion
The momentum for DBS in the treatment of epilepsy is quickly building with the recent SANTE trial and the FDA's review of potential approval, making ANT a promising and preferable target in seizure control for intractable epilepsy. However, SANTE trial excluded the seizure types such as Lenox-Gastaut or generalized onset epilepsy in patient selection. In addition, only the patients with seizures of temporal lobe origin had a significant decrease in seizure frequency with ANT stimulation and
Conflict of interest
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (30870884) and the Shandong Provincial Outstanding Medical Academic Professional Program.
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These two authors contributed equally to this work.