Implatable Devices for the management of refractory epilepsy

Author: Alberto Loris De Donno
Date: 09/03/2015


De Donno Alberto, Bonaventura Matteo


Epilepsy is a group of neurological disorders characterized by epileptic seizures, it’s a common disease affecting approximately 50 million people worldwide and is associated with considerable morbidity and mortality. Epilepsy is defined as a predisposition to experience seizures as a result of abnormal neuronal activity in the brain. There are two types of seizures: partial (focal) or generalized, depending on the extent to which they affect the brain. The majority of epilepsy cases are ascribable to idiopathic causes, whereas the remaining are genetic or structural (tumor, stroke, head injury, infection).


Antiepileptic drugs ( AEDs ) are the mainstay of treatment for epilepsy. Seizure freedom is achieved in around 50% of patients with the first trial of pharmacotherapy, and this is increased with add-on medications. Unfortunately AEDs can have suboptimal tolerability profiles, especially with regard to behavioral and cognitive aspects. When a patient fails to respond to adequate trials of two AEDs because of poor efficacy and/or tolerability, a diagnosis of “treatment resistant” or “refractory” epilepsy is formulated. This occurs in up to one-third of patients with epilepsy. In such cases other treatments are available, including novel AEDs, ketogenic diet, epilepsy surgery, and more recently, implantable neurostimulation devices.

Clinical utility of implantable neurostimulation devices as adjunctive treatment of uncontrolled seizures - 2014


Three types of implantable neurostimulation devices have been introduced and approved for the management of refractory epilepsy: vagus nerve stimulation ( VNS ), deep brain stimulation ( DBS ), and responsive neurostimulation systems ( RNSs ).

VNS is an invasive extracranial neurostimulation technique involving implantation of a device at the level of the subclavian region. Two or three leads are woven around the left vagus nerve and connected to a generator producing electrical impulses that modulate the signals conducted by its afferent fibers. The exact mechanism by which VNS reduces seizure activity is unknown, although several models have been proposed. In particular it has been suggested that VNS works by increasing cerebral blood flow and by activating neuronal networks in the thalamus and other deep brain structures. A potential role of norepinephrine has also been postulated.

The vagus nerve stimulator provides scheduled ( open-loop ) stimulation to a peripheral nerve and reduced partial seizure frequency by 24.5%–28% during the blinded period of randomized controlled trials and demonstrated median seizure reductions in a prospective open-label study of 35% at 1 year and 43% at 3 years.

Long-term treatment with vagus nerve stimulation in patients with refractory epilepsy. - 1999
Evidence-based guideline update: vagus nerve stimulation for the treatment of epilepsy: report of the Guideline Development Subcommittee of the American Academy of Neurology. - 2013
Implantable Devices Could Detect and Halt Epileptic Seizures - 2012

DBS involves the placement of one or more electrode leads into the brain parenchyma; these are connected to a battery-powered implanted pulse generator positioned in the subclavian space and maintain an intermittent stimulation of the brain ( open-loop ). Different deep brain structures are targeted depending on the condition to be treated. The DBS can be used to treat patients whose seizures appear to engulf the entire brain, or large portions of it, at once. Stimulation of basal ganglia structures has been widely used in the management of treatment refractory movement disorders such as Parkinson’s disease, dystonia and tremor. DBS has also been used in the treatment of neuropsychiatric conditions such as depression, obsessive-compulsive disorder, chronic pain, cluster headache, and Tourette syndrome. The exact mechanism of action of DBS in reducing seizure frequency is unknown and a number of theories have been proposed. It is unclear whether the stimulation from the implanted electrodes results in excitation or inhibition of the local neurons or whether its effects are due to disruption of neuronal transmission.
A randomized controlled trial of scheduled deep brain stimulation (DBS) of the anterior nucleus of the thalamus showed reductions in partial seizures of 41% at 13 months and 56% at 26 months

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. - 2010

The RNS Systems are a new method of neurostimulation which provides responsive ( closed-loop ) stimulation directly to 1 or 2 seizure foci when abnormal electrocorticographic (ECoG) activity is detected, typically epileptiform activity that has been observed at the onset of electrographic seizures. A cranially implanted programmable neurostimulator is connected to the depth or subdural cortical strip leads that are surgically placed at 1 or 2 previously identified seizure foci. Each lead contains 4 electrode contacts. Although as many as 4 leads could be implanted in the clinical trials (no more than 2 depth leads), only 2 leads can be connected to the neurostimulator at a time. The neurostimulator continually senses ECoG activity through the electrodes and is programmed by the physician to detect specific ECoG patterns and deliver brief stimulus pulses in response to detections. The physician adjusts detection and stimulation parameters for each patient as needed for seizure reduction.

The reduction in seizures in participants treated with responsive neurostimulation increased progressively over the first 2 years of treatment and remained stable over years of follow-up. During the randomized blinded period of the pivotal study (months 3 through 5 after implant), the overall seizure reduction in the participants receiving active responsive stimulation (37.9%) was greater than in the participants receiving sham stimulation (17.3%) relative to baseline (p = 0.012). In the first month of the blinded period, seizure reduction in the treatment group was 34.2%, increasing to 38.1% in the second month and reaching 41.5% in the final month.

Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: Final results of the RNS System Pivotal trial - 2014
Long-term treatment with responsive brain stimulation in adults with refractory partial seizures - 2015


Implantable neurostimulation devices, including VNS, DBS, and RNS, offer promising avenues for reduction in seizure frequency in patients with refractory epilepsy a group of patients that presents high morbidity, mortality, and reduced quality of life. Seizure freedom appears to be a less realistic expectation according to published data, possibly reflecting selection bias. Further research should be carried out to explore other potential benefits of implantable neurostimulation devices; for example, reducing seizure severity. This may include prevention of spread of epileptic discharge or the occurrence of loss of consciousness across both partial-onset and generalized seizures. A further aspect to make this therapeutic option appealing is the relatively low prevalence of serious adverse effects, a factor contributing to significant improvement in health-related quality of life.

Clinical utility of implantable neurostimulation devices as adjunctive treatment of uncontrolled seizures - 2014

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