Devices in the treatment of epilepsy

Devices in the treatment of epilepsy

Nitin K Sethi, MD

A number of neurostimulation devices are now available for the treatment of medically refractory epilepsy. Medically refractory epilepsy is currently defined as the failure of the patient’s epilepsy to respond to the use of at least 2 frontline and appropriate anti-epileptic drugs (AEDs)) (some physicians use up to 3 drugs) used in a successive fashion.

Types of devices for the treatment of medically refractory epilepsy:

1. Vagus Nerve Stimulator (VNS)
2. Responsive Neurostimulator (RNS)
3. Deep brain stimulator (DBS)

Neurostimulation not a replacement for resective surgical options.

Vagus Nerve Stimulator (VNS): fundamental concepts

1. pacemaker like device to stimulate the Vagus (CN X) nerve.
2. manufactured by Cyberonics Inc, Houston, Tx
3. gained FDA approval in 1997 for the adjunctive treatment of patients over 12 years of age with medically intractable partial onset seizure disorder.
4. Approved in Europe in 1994.
5. simple device consisting of 2 electrodes, an externally programmable pulse generator and a battery pack.
6. the stimulating electrode is implanted around the midcervical portion of the left vagus nerve (composed of 80% afferent fibers) while the impulse generator along with the battery pack is implanted in a subcutaneous pocket in the left infraclavicular region.
7. left vagus nerve is the preferred site of stimulation due to the higher risks of cardiac arrhythmias with right vagus nerve stimulation as it innervates the sinoatrial node and thus influences heart rate and rhythm.
8. the pulse generator is programmed externally through the skin via a magnetic currently hand held wand.
9. different parameters of stimulation can be programmed such as current strength, pulse width, pulse train frequency, current on and off times as well as magnet current strength.
10. a magnet usually worn on the patient’s arm can provide on-demand stimulation.

Mechanism of action of VNS:

1. Not fully elucidated.
2. Vagus nerve has afferent inputs to multiple areas which may be involved in the generation or propagation of ictal activity: reticular formation, thalamus, cerebral cortex.
3. Electrical impulses via the left vagus nerve travel to the nucleus of tractus solitaries (NTS). From the NTS are outflow tracts to reticular formation and locus ceruleus (LC) increasing the release of norepinephrine and serotonin. VNS may thus increase the release of gamma amino butyric acid or inhibit the release of glutamate. Rats in which the LC is destroyed, VNS is no longer effective in controlling seizures.
4. Widespread cortical de-synchronization by the afferent volley of impulses leading to inhibition of recruitment of epileptic discharges may be another mechanism.
5. Alteration of cerebral blood flow (CBF) in specific areas of the brain-not widely accepted.
6. Peripheral stimulation of CN X may modify the epileptic network circuit in the brain by synaptic modulation.
7. Effects on the amygdala likely mediate the antidepressant effects and mood elevating effects of VNS.

Stimulation parameters which can be adjusted:

1. Output current (usual settings are between 1.5 and 2.25 mA)
2. Pulse width (usually between 250-500microsecs)
3. Frequency (usually between 20 to 30 Hz)
4. Time on (usually on for 30 secs)
5. Time off (usually off for 3 to 5 mins)
6. Magnet current (usually set at 0.25 mA above output current)
7. Fast cycling 7 secs on and 14 secs off.
8. Battery life depends upon stimulation settings

Generator models currently available:

1. 102 Pulse
2. 102 Pulse Duo
3. 103 Demipulse
4. 104 Demipulse Duo
5. 105 Aspire HC
6. 106 Aspire SR

Clinical efficacy of VNS:

1. Multiple studies establish the efficacy of VNS in patients with partial onset (focal) epilepsy both in children and adults.
2. Currently FDA approved for adjunctive therapy in reducing the frequency of seizures in adults and adolescents over 12 years of age with partial onset seizures that are refractory to antiepileptic medications.
3. Currently FDA approved for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.
4. Used at times for generalized epilepsy but efficacy not established-lack of good quality studies.
5. Case reports showing efficacy in Lennox-Gastaut syndrome (LGS).

Side-effects/ complications of VNS therapy:

1. infection at the generator implantation site.
2. dyspnea, coughing bouts, laryngeal spasms and choking as current is increased.
3. dysphagia, odynophagia as current is increased
4. hoarseness or change in voice
5. thermal injury to the Vagus nerve can occur but is not commonly reported
6. use with caution in patients with COPD and asthma.
7. VNS may worsen pre-existing obstructive sleep apnea (OSA) due to central and peripheral mechanisms by altering the tone of the upper airways mucles.
8. Recommendation is to turn off VNS prior to CPAP titration.

Contraindications of VNS therapy:

1. MRI is not an absolute contraindication.
2. MRI can be carried out-but recommendation is to turn the device off first.
3. Interrogate device both before and after MRI scan.
4. Avoid use of short-wave diathermy, microwave diathermy and devices which generate strong electric or magnetic fields in the vicinity of the VNS.

Responsive Neurostimulation Device (RNS): fundamental concepts

1. Pacemaker like device to stimulate the epileptogenic focus or foci in the brain.
2. manufactured by NeuroPace, Mountain View, California.
3. generator is implanted in a pocket drilled into the skull bone by the neurosurgeon.
4. cortical strip leads and NeuroPace depth leads are implanted onto or into the epileptogenic focus or foci determined by
5. remote monitor and wand used by patient to interrogate device, collect data and upload to the Internet for the physician.
6. programmer and wand used by physician to collect data and program the neurostimulator.
7. a magnet can be swiped over the device to trigger storage of ECoG and also to temporarily stop stimulation.
8. FDA approved as adjunctive therapy in individuals 18 years of age or older with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures and/or secondarily generalized seizures).
9. Unlike VNS which is an open-loop device, RNS is semi-closed. The device continuously records electrocorticogram (ECoG) and then based on an algorithm can be programmed to deliver brief pulses of electrical stimulation when it detects activity that could lead to a seizure.

Mechanism of action of RNS:

1. rationale for RNS is responsive stimulation of an epileptic focus/ foci in the brain
2. if stimulated in time and with current of appropriate intensity, evolving seizure shall get aborted
3. involves real time electrographic analysis and responsive and automatic delivery of stimulation

Stimulation parameters for RNS:

1. two different epileptogenic foci can be stimulated individually
2. wide range of stimulation settings/parameters that can be adjusted-from 40 to 1000 microseconds, 1 to 333 Hz, 0.5 to 12 mA

Clinical efficacy of RNS:

1. Results similar to other stimulation devices
2. At the end of 2 years, the median seizure reduction was 56%.

Side-effects/ complications of RNS therapy

1. Surgical complications during implantation of device-risk of hemorrhage, infection
2. Lead breakdown/disconnection
3. Replacement of generator requires another craniotomy
4. Patient needs close follow up for stimulation parameters adjustment hence not ideal for patients who live in rural areas or cannot come for regular follow ups.

Deep Brain Stimulator (DBS): fundamental concepts

1. Stimulation of the anterior nucleus of thalamus (ANT)
2. Electrodes implanted bilaterally in the ANT.
3. Stimulator and battery implanted under left clavicle.

Stimulation parameters for DBS:

1. high-frequency stimulation
2. 5 V, 145 pulses per sec, 90 microseconds, cycle time 1 minute on and 5 minutes off

Mechanism of action of DBS:

1. thalamus is a major relay station and thalamocortical networks are widely believed to be involved in seizure propogation by synchronization of ictal activity.
2. stimulation of ANT may cause desynchronization and thus inhibit seizure propogation.
3. in animal experiments low-frequency stimulation leads to EEG synchronization and high-frequency causes EEG desynchronization.

Clinical efficacy of DBS:

1. SANTE (stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy) study-results similar to other stimulation devices.
2. Fourteen patients were seizure-free for 6 months.

Side-effects/ complications of DBS therapy

1. Surgical complications during implantation of device-risk of hemorrhage, infection
2. Lead breakdown/disconnection
3. Replacement of generator requires another craniotomy
4. Patient needs close follow up for stimulation parameters adjustment hence not ideal for patients who live in rural areas or cannot come for regular follow ups.


References

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