ReviewNeurostimulation in the treatment of epilepsy
Introduction
Patients with partial seizures (simple and complex) comprise over 50% of patients with epilepsy (Hauser et al., 1996). In contrast to patients with primary generalized epilepsy where > 80% of patients achieve seizure control, only about half of patients with partial epilepsy have their seizures controlled (Sillanpää et al., 1998). Despite the introduction in the United States of 14 new antiepileptic drugs (AEDs) since 1993, there still is a very large unmet need for patients with drug-resistant epilepsy. The major benefit of the new (since 1993) AEDs has been better tolerability and side effect profiles and more desirable pharmacokinetics, especially fewer drug interactions. Unfortunately few patients with drug resistant partial epilepsy become seizure free with the new AEDs after failing previous trials of 2 or 3 or more drugs (Kwan and Brodie, 2000). Seizure surgery can produce seizure freedom in a significant number of patients with drug-resistant partial seizures and surgery remains underutilized. Many patients, however, are not candidates for resective surgery. The lack of a major impact of the new AEDs on seizure freedom, despite many new and novel compounds with new mechanisms of action, has led to increased interest in alternative therapies such as dietary management (Kossoff and Hartman, 2012), immunotherapy (Bien and Scheffer, 2011) and newer methods of neurostimulation.
The concept of neurostimulation for the treatment of epilepsy is not new. Unsuccessful trials of stimulation of the cerebellum and the median thalamic nucleus have been performed. While both sites showed promise in unblinded studies (Cooper, 1978, Cooper et al., 1976, Davis and Emmonds, 1992), subsequent controlled trials failed to demonstrate significant efficacy (Wright et al., 1984). Vagus nerve stimulation (VNS) was the first approved therapy utilizing chronic stimulation, gaining FDA approval in 1997. Recently two pivotal trials of neurostimulation in humans with drug-resistant epilepsy, one employing chronic programmed bilateral stimulation of the anterior thalamus and another utilizing closed-loop responsive stimulation of intracranial structures have been completed and published (Fisher et al., 2010, Morrell and RNS System in Epilepsy Study Group, 2011). Anterior thalamic stimulation has not received FDA approval but was recently approved in Europe. The responsive neurostimulation device (RNS) was recommended for approval by a scientific advisory panel in early 2013; FDA approval is pending. In addition there are early reports of potential benefits of stimulating other extracranial sites (e.g. trigeminal nerve) (DeGeorgio et al., 2009, DeGiorgio et al., 2013, Pop et al., 2011). It is therefore timely to examine the current status of neurostimulation in the treatment of epilepsy. While some historical context will be provided, the purpose of this review is to discuss the current modalities of neurostimulation being utilized or studied as potential therapies with an emphasis on those that have completed pivotal blinded trials and involve implanted devices. The potential benefits of neurostimulation, regardless of the treatment modality, are several. Neurostimulation does not have the side effects, CNS or systemic, that AEDs have. Although not formally assessed, it is reasonable to assume that there is no teratogenicity associated with neurostimulation. The mechanisms of action of neurostimulation, although not established, are probably distinct from those of AEDs. Neurostimulation also occurs automatically, whether programmed or open loop and while patients with VNS can employ magnet activation, this is a supplemental therapy; benefit was demonstrated without patient activation. When one considers that trials of additional AEDs add to the medication burden with attendant potential additive side effects, the attraction of neurostimulation in patients who are not good resective surgery candidates is obvious (Table 1).
Section snippets
Neurostimulation: types and theoretical considerations
Neurostimulation can be classified in two ways, the location of the stimulation target (intracranial or extracranial) and the method of stimulation (chronic programmed or responsive, closed loop). The theories behind the mechanisms of action of each type of therapy are different. The concept of any type of neurostimulation for control of epilepsy might at first consideration appear counterintuitive. Epileptic seizures, after all, are reflections of increased neuronal network excitation and
Extracranial programmed stimulation: vagus nerve stimulation
VNS therapy is the first FDA approved neurostimulation therapy for epilepsy. The early studies of VNS were done in cats (Bailey and Bremer, 1938, Chase et al., 1967, Zanchetti et al., 1952). Studies by Chase et al. (1967) reported that stimulation of the vagus nerve desynchronized the EEG in cats, but this has not been demonstrated in humans (Salinsky and Burchiel, 1993). Later Fernández-Guardiola et al. (1999) demonstrated that kindling of the amygdala, also in cats, could be reduced with VNS.
Extracranial programmed stimulation: other
With the success of VNS therapy, it is not surprising that other sites for external chronic programmed neurostimulation are being investigated. Currently stimulation of the trigeminal nerve is being most actively pursued. The trigeminal nerve projects to brainstem structures distinct from those activated by VNS, but like the VNS, then has supratentorial influences. Stimulation of the trigeminal nerve, while perceived by the patient, does not produce the hoarseness or cough that may result from
Central programmed stimulation — early studies
With the modest, but significant benefits of stimulation of the vagus nerve, it is reasonable to postulate that stimulation of intracranial structures might demonstrate improved efficacy. Central stimulation, while requiring surgery to implant the electrodes, does have the benefit of being transparent; the patient does not feel the stimulation since the brain is pain insensitive, in contrast to VNS stimulation which is perceived to some degree by the patient. This lack of central sensation also
Central programmed stimulation — anterior thalamic
Early reports of anterior thalamic stimulation in humans with drug resistant epilepsy suggested efficacy (Kerrigan et al., 2004). Recently the results of a well designed multicentral trial of anterior thalamic stimulation were reported (Fisher et al., 2010). A total of 110 patients at 17 sites were entered into this blinded trial. These were highly refractory patients, 54% had previous epilepsy surgery or VNS therapy. Patients were required to have focal or partial seizures, but could have
Central stimulation — closed loop responsive
The concept of closed loop responsive stimulation is an attractive one. Instead of preventing seizures, closed loop therapy would respond shortly after seizure onset to provide therapy that would lead to early seizure termination before the seizure evolves to a disabling seizure (e.g. with altered consciousness). The underlying principle is that seizures are intrinsically self-limited events and that early intervention can result in reduced seizure duration. While any therapy (e.g. cooling,
Central stimulation — other
Drawing on the experience of stimulation of the subthalamic nucleus for movement disorders, limited trials have been employed in patients with epilepsy. The subthalamic nucleus is thought to activate the nigral control system (Deransart et al., 1998) and may act to prevent secondary generalization. Small studies in humans suggest efficacy (Chabardès et al., 2002, Wille et al., 2011) of stimulation of the subthalamic nucleus in humans but no large controlled trials are ongoing.
The hippocampus
Stimulus parameters
There is a suggestion from some animal studies that higher frequency stimulation (e.g. 130 Hz) is more effective than lower frequency (e.g. 5 Hz) stimulation (Wyckhuys et al., 2010). Studies in the anterior thalamus have suggested that low frequency stimulation may be detrimental (Mirski et al., 1997). In animal models of temporal lobe epilepsy, however, some have found low frequency beneficial (Rashid et al., 2012). Stimulus frequency does appear to be an important stimulation parameter (Rajdev
Trial design and assessment of efficacy
As is the case with antiepileptic drug trials, reduction in absolute seizure numbers and responder rate (percentage of patients who experience a > 50% reduction in seizures) during the blinded period are the outcome variables. In AED trials assessment of true efficacy can be compromised by a number of variables. If the doses of the trial agent are too low, efficacy may be underestimated. If AED doses are too high, or titration is too rapid, patients may withdraw from the trials due to side
Current status of neurostimulation for the treatment of epilepsy
Vagus nerve stimulation, anterior thalamic stimulation, and closed-loop responsive stimulation all have demonstrated significant efficacy in well-designed controlled trials. Interestingly the recent results for anterior thalamic stimulation and responsive neurostimulation are remarkably similar in comparable patient populations with highly drug resistant partial seizures. Although one or the other might have hypothetical advantages, at present there is no evidence to recommend one modality over
Acknowledgments
GKB serves as site PI for the NeuroPace responsive neurostimulation trial but receives no support from NeuroPace.
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