Elsevier

Experimental Neurology

Volume 244, June 2013, Pages 87-95
Experimental Neurology

Review
Neurostimulation in the treatment of epilepsy

https://doi.org/10.1016/j.expneurol.2013.04.004Get rights and content

Abstract

There is increased interest in neurostimulation as a treatment for drug-resistant epilepsy. Two large pivotal trials have recently been completed, one using bilateral anterior thalamic stimulation and another employing closed loop responsive therapy of the brain. These are potential additions to the therapeutic options for neurostimulation in addition to already approved vagus nerve stimulation. This review will address the principles of the various types of neurostimulation, the results of the pivotal trials and the important considerations for interpreting the results of these trials which differ from trials of antiepileptic drugs.

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.

References (78)

  • J.M. Hoogendam et al.

    Physiology of repetitive transcranial magnetic stimulation of the human brain

    Brain Stimul.

    (2010)
  • C.C. Jouny et al.

    Characterization of early partial seizure onset: frequency, complexity, entropy

    Clin. Neurophysiol.

    (2012)
  • C.C. Jouny et al.

    Improving early seizure detection

    Epilepsy Behav.

    (2011)
  • P. Kudela et al.

    Model of the propagation of synchronous firing in a reduced neuron network

    Neurocomputing

    (1999)
  • J.L. Martin et al.

    Systematic review and meta-analysis of vagus nerve stimulation in the treatment of depression: variable results based on study designs

    Eur. Psychiatry

    (2012)
  • M.A. Mirski et al.

    Anticonvulsant effect of anterior thalamic high frequency electrical stimulation in the rat

    Epilepsy Res.

    (1997)
  • Z. Nanobashvili et al.

    Suppression of limbic motor seizures by electrical stimulation in thalamic reticular nucleus

    Exp. Neurol.

    (2003)
  • J.A. Nichols et al.

    Vagus nerve stimulation modulates cortical synchrony and excitability through the activation of muscarinic receptors

    Neuroscience

    (2011)
  • M.A. Nitsche et al.

    Noninvasive brain stimulation protocols in the treatment of epilepsy: current state and perspectives

    Neurotherapeutics

    (2009)
  • J. Pop et al.

    Acute and long-term safety of external trigeminal nerve stimulation for drug-resistant epilepsy

    Epilepsy Behav.

    (2011)
  • D. Revesz et al.

    Effects of vagus nerve stimulation on rat hippocampal progenitor proliferation

    Exp. Neurol.

    (2008)
  • R.W. Roosevelt et al.

    Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat

    Brain Res.

    (2006)
  • J.A. Shetake et al.

    Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex

    Exp. Neurol.

    (2012)
  • P. Suffczynski et al.

    Dynamics of non-convulsive epileptic phenomena modeled by a bistable neuronal network

    Neuroscience

    (2004)
  • R.A. Wennberg et al.

    Intracranial volume conduction of cortical spikes and sleep potentials recorded with deep brain stimulating electrodes

    Clin. Neurophysiol.

    (2003)
  • T. Wyckhuys et al.

    Comparison of hippocampal deep brain stimulation with high (130 Hz) and low frequency (5 Hz) on afterdischarges in kindled rats

    Epilepsy Res.

    (2010)
  • A. Zanchetti et al.

    The effect of vagal afferent stimulation on the EEG pattern of the cat

    Electroencphalogr. Clin. Neurophysiol.

    (1952)
  • P. Afra et al.

    Duration of complex partial seizures: an intracranial EEG study

    Epilepsia

    (2008)
  • P. Bailey et al.

    A sensory cortical representation of the vagus nerve with a note on the effects of low pressure on the cortical electrogram

    J. Neurophysiol.

    (1938)
  • G.K. Bergey et al.

    Implementation of an external responsive neurostimulator system (eRNS) in patients with intractable epilepsy undergoing intracranial seizure monitoring

    Epilepsia

    (2002)
  • G. Bergey et al.

    Safety and preliminary efficacy of a responsive neurostimulator (RNS™) for the treatment of intractable epilepsy in adults

    Neurology

    (2006)
  • C.W. Berridge et al.

    Effects of locu coeruleus activation on electroencephalographic activity in neocortex and hippocampus

    J. Neurosci.

    (1991)
  • C.G. Bien et al.

    Autoantibodies and epilepsy

    Epilepsia

    (2011)
  • R. Boon et al.

    Deep brain stimulation in patients with refractory temporal lobe epilepsy

    Epilepsia

    (2007)
  • R. Boon et al.
  • S. Chabardès et al.

    Deep brain stimulation in epilepsy with particular reference to the subthalamic nucleu

    Epileptic Disord.

    (2002)
  • I.S. Cooper

    Cerebellar Stimulation in Man

    (1978)
  • I.S. Cooper et al.

    Chronic cerebellar stimulation in cerebral palsy

    Neurology

    (1976)
  • R. Davis et al.

    Cerebellar stimulation for seizure control: 17-year study

    Stereotact. Funct. Neurosurg.

    (1992)
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