VNS and other neuromodulation in epilepsy Flashcards
History of VNS in epilepsy
Approved indications for VNS
The VNS has been approved by the food and drug administration (FDA) for:
1. Adjunctive therapy in patients >= 12 years with refractory (drug-resistant) partial onset epilepsy, and
2. Adjunctive therapy in patients >= 18 years with chronic or recurrent major depressive episodes refractory to adequate response to
>= adequate antidepressants.
Clinical indication for VNS (in epilepsy)
Patients with documented refractory partial epi- lepsy who are not eligible for brain surgery, e.g., having multifocal epilepsy, unclear seizure focus, overlapping eloquent cortex, or those who are opposed to are considered potential candidates for the VNS Therapy. VNS may have a limited role in patients with previous unsuccessful resective epilepsy surgery. In a recent series, 18.75% of such patients had 50% reduction in seizure frequency with one case of worsening seizures, but it may be an option given its potential antipsychotic and mood-stabilizing effects [5].
Refractory Epilepsy—Definition
More than 50% of patients with epilepsy have partial epilepsy. The AED success rate in patients with partial epilepsy is about 50% compared to more than 80% rate in primary generalized epilepsy [1–3].
The current definition of refractory epilepsy requires failure of adequate trials of two appropriate and tolerated AEDs at maximum possible doses, whether as monotherapy or in combination, for enough time (a follow-up period 3 times the longest interseizure interval or 1 year, whichever longer) [4]. However, only about 20% of these patients will be eligible for resective brain surgery. Therefore, in these patients, VNS Therapy is a viable palliative treatment option.
VNS anatomy and lead placement
The lead electrodes must be placed below where the superior and inferior cervical cardiac branches separate from the vagus nerve. Stimulation of either of these two branches during the system diagnostics (lead test) may cause bradycardia and/or asystole. In most patients, the main vagus nerve is the largest of the three nerves (Figure 24.1).
VNS electrode polarity and pulse stimulation
A bipolar lead transmits stimulation from the generator to the left vagus nerve. The lead consists of a pin that connects to the generator on one end, and the helices that contain the stimulation electrodes and anchor tether on the other end.
VNS initial clinical trials
Adjunctive use of left VNS Therapy in patients with refractory epilepsy was tried in five acute-phase landmark clinical studies in 45 cen- ters (40 US, 1 Canada, 4 EU). A total of 454 patients were implanted with VNS with a total patient exposure of 901 device-years. Individual mean patient exposure was 24 months (8 days– 7.4 years).
Eligible patients were implanted (baseline period 12 weeks) and the generator was activated 2 weeks later. In the two randomized, blinded, active control trials (E03 and E05), patients were randomized to: (1) HIGH group (higher fre- quency, pulse width, higher duty cycle) and 2) LOW group (active control) and were fol- lowed for a 14-week treatment period (E05: [6]).
VNS clinical trials - efficacy and safety
The HIGH group showed significant seizure frequency reduction compared with the baseline and the LOW group (24.5% vs. 6.1%, p = 0.01). In the HIGH group, 31% experienced >= 50% seizure reduction as opposed to 13% in the LOW group (p = 0.02). The most common adverse events were voice alteration and dyspnea. The treatment was well tolerated and 97% patients (306 of 314) continued into the long-term follow-up phase of the study (Fig. 24.2).
VNS parameters, safety, and initial settings
Parameters: output current, signal frequency, pulse width, and ON/OFF time.
Therefore, each parameter can be pro- grammed in a variety of combinations to achieve optimal stimulation setting. However, based on animal studies stimulation at high frequency (>= 50 Hz) + ON time >= OFF time may result in degenerative nerve damage. The ON time OFF time can be induced by continuous or very frequent magnet activation (> 8 h) and therefore should be avoided.
The VNS is activated >= 2 weeks after implan- tation and when the healing process is com- pleted. The initial recommended parameters are as follows:
Output current of 0.25 mA,
ON time 30 s/OFF time 5 min, Signal frequencies of 20–30 Hz, and Pulse width 250–500 μs.
Adverse effects of VNS
The most common side effects associated with VNS Therapy include:
– Hoarseness: up to 60% and may indicate device malfunction, nerve constriction (ap- parent within a few days), nerve fatigue with intense stimulation parameters (turn off for several days until hoarseness subsides), and persistent hoarseness not associated with stimulation suggests nerve irritation (requires immediate investigation).
– Dysphagia and aspiration: there is higher risk with preexisting swallowing difficulties.
– Dyspnea: higher risk with underlying COPD or asthma.
– Obstructive sleep apnea (OSA): higher risk of apneic events during the stimulation with OSA (lower stimulus frequency of 2 Hz or longer “OFF” time recommended). Since new onset cases of OSA have been reported, prior evaluation in high-risk patients should be considered.
– Nerve damage with device malfunction: may cause painful stimulation (tape magnet over the generator to stop stimulation if suspect a malfunction; evaluate for possible surgical intervention).
– Laryngeal irritation: more common in smokers.
– Lead break: may prevent patients from receiving efficient therapy. If diagnostics suggest a fracture, turn the pulse to 0 mA output current (to prevent possible dissolution of the conductor material hence pain, inflammation, and vocal cord dysfunction).
– Trauma to the vagus nerve: can occur during surgery and can result in permanent vagal nerve dysfunction.
– Sudden unexplained death in epilepsy (SUDEP): through August 1996, 10 (definite/probable and possible) cases were recorded among 1000 VNS patients (2017 patient-years of exposure) indicating an inci- dence rate of 5/1000 patient-years. However, estimates for non-VNS epilepsy patients range from 1.3 to 3.5 in the epilepsy popu- lation and 9.3 in surgical candidate population. Therefore, the recorded rates of SUDEP did not seem to have been increased significantly by VNS Therapy.
– Manipulation of pulse generator and lead by patients through the skin (Twiddler’s syn- drome): may damage or disconnect the lead from the generator (Cyberonics.com, Physi- cian’s manual).
VNS precautions
Cardiac evaluation: in case of family history, past medical history, or EKG indications of dysfunctional cardiac conduction systems (reen- try pathway).
Serum electrolytes: Mg2+, Ca2+ levels to be checked before implantation.
Postoperative bradycardia: can occur in patients with cardiac arrhythmias; consider postimplant EKG and Holter monitoring.
Bradycardia (<40 bpm) and/or asystole: may occur during intraoperative system diag- nostics (lead test). In such patients cardiac monitoring at the time of device activation is recommended.
Optimizing Parameters
and Alleviating Side Effects
Optimizing Results
This can be achieved by increasing output cur- rent and/or modifying ON/OFF times (duty cycle).
Managing Side Effects
The following steps may be taken as needed to alleviate side effects: decreasing signal frequency (from 30 to 20 Hz) or decreasing output current (by 0.25 mA). If decreasing the output current does not achieve tolerability, lowering the pulse width (from 500 to 250 ls) may be considered.
VNS warning with MRI
The VNS is MRI compatible including 1.5T and 3T scanners. Head and extremity scans are allowed using a transmit and receive type of RF coil. Before patient enters into the MR system room, both output current and magnet current should be set to 0 mA since MRI-induced mag- netic field may cause magnet-mode activation and stimulation. After the MRI is done, reprogram- ming is needed to restore the setting parameters.
MRI should not be performed on patients with lead breaks, see product labeling for all condi- tions. Diathermy (shortwave, microwave, thera- peutic—not diagnostic—ultrasound) should not be used on VNS Therapy patients.
VNS MOA
The precise mechanism of action of VNS remains unknown. In animal models (maximum electroshock, PTZ, alumina gel, strychnine, kin- dling), VNS prevented seizures or seizure spread (except for the alumina gel model). A series of facts have been considered to play a role in its function, e.g., VNS affects heart and respiratory rates, vagus-initiated activity in the brain has been localized through use of fos1 immunoreac- tivity, regional brain glucose metabolism (in animals), and via PET imaging in human. The newest version of VNS labeled Aspire adds the advantage of cardiac rhythm detection of seizures.
Investigational Neurostimulators
In recent years, two pivotal trials of neurostim- ulation in humans with drug-resistant epilepsy have been conducted: deep brain stimulation (DBS) via chronic programmed bilateral stimu- lation of anterior thalamus (SANTE trial) [7] and closed-loop responsive neurostimulation (RNS) of intracranial structures [8]. The DBS (thalamic stimulation) has not yet been approved by the FDA, but it has been recently approved in Europe [3]. The RNS system (NeuroPace device) has been FDA approved in late 2014. There are also early reports of potential benefits of stimu- lating other extracranial sites (e.g., trigeminal nerve) ([9–11]).
Electrical Stimulation of the Anterior Nucleus of the Thalamus (SANTE Trial)
A multicenter, double-blind, randomized clinical trial including 110 patients with partial epilepsy (baseline seizure frequency 19.5/month) was conducted. After a 3-month blinded phase half of the patients received stimulation and the other half received no stimulation. Then, all patients received unblinded stimulation. In the last month of the blinded phase, the stimulated group had a 29% greater seizure reduction compared with the control group (p = 0.002) [7] (Fig. 24.3).
