Research Paper Example: Comparing Neuromodulation Devices to Treat Drug Resistant Epilepsy

Introduction

Epilepsy is a common neurological disorder, characterized by spontaneous and recurrent seizures. The treatment for epilepsy mainly includes drug treatment, respective surgery, and neuromodulation. About 30% of epilepsy patients are classified with Drug Resistance Epilepsy (DRE) [1]. Millions of these patients cannot undergo the respective surgery, or still experience recurrent seizures despite having surgery.

Fortunately for these cases, neuromodulation can significantly reduce seizures and improve cognitive function. Vagus nerve stimulation (VNS) and anterior thalamic nucleus deep brain stimulation (DBS) are, now, the most common treatment options. Both methods have been approved by the American Food and Drug Administration (FDA) for the treatment of patients with DRE in 1997 and 2018 respectively. [1] DBS was originally approved in 1997 by the Food and Drug Administration of the United States (FDA) for treating Parkinson’s disease. The device was shown to dramatically reduce tremors, and has later been used to treat and lessen the other symptoms of the early stages of the disease [11]. It has since been approved to treat DRE. 

When looking at the more extreme side effects of these devices, the DBS treatment seems worse by comparison with the VNS treatment [3]. With such a difference in adverse events and danger connected to the treatments, it is obvious to ask the following questions; under which circumstances does the benefit surpass the risks of such invasive treatment? When is one method better than the other?

VNS and DBS                             

Both VNS and DBS are treatment techniques that involve implanting electrodes and a pacemaker-like device to activate certain areas of the cerebral cortex electrically in order to influence other areas to reduce the tendency for seizures. VNS therapy involves a small electrical device that sends impulses at regular intervals to the brain through the vagus nerve. The generator is implanted under the skin of the patient's chest and is connected to the vagus nerve by a lead. This regular stimulation can reduce the occurrence of seizures and help make them less severe. [7]  

DBS differs from VNS in that it stimulates specific areas of the brain. This is done by surgically placing a neurostimulator under the skin below the collarbone. The neurostimulator is connected to the electrodes by leads, as depicted in fig. 1. Microelectrodes are placed in specific areas of the brain where epileptic activity happens, and will continuously send out stimuli to reduce seizures. [8] These areas are mapped out in advance of the procedure. The most used target is the anterior nucleus of thalamus.

Fig 1. Both the VNS and DBS system consist of three parts. A neurostimulator, which is a small disk implanted in the clavicle. This includes battery and impulse-generation components. An extension to connect the neurostimulator to the lead. A lead which is implanted at the site of stimulation. At the left vagus nerve for VNS, and at the anterior nucleus of thalamus for DBS. In the picture above, the implanted DBS device is shown with its three parts. [4,5]

Clinical Use

DBS and VNS are treatments that are reserved for people whose epileptic symptoms can’t be controlled with medications. Before surgery, the patients are screened to make sure that the procedures are the right option for the patient. This would include medical tests, and often brain-imaging studies. The patient would need two surgeries; A chest wall surgery with an implantation of a pulse generator, and a surgery to place the electrodes. 

For the DBS treatment, a brain surgery is required to place the electrodes, which is done while the patient is awake and alert. The surgeon drills holes in the skull in order to make easy entry points for the electrodes. The leads to the simulator are tunnelled along the neck. [12, 13]

For the VNS treatment the surgery involves making a cut on the left side of the neck to expose the nerve. The surgeon then wraps the electrodes around the left vagus nerve, which is then connected to the stimulator. [14]

Two to four weeks after the surgeries the pulse generator is activated by the doctor. A special remote control is used to regulate the stimulation. It may take as long as four to six months to find the optimal setting and depends on the patient’s condition. The patient takes the remote-control home and self-regulates according to the doctor’s recommendation. 

The battery of the pulse generator needs to be replaced (about every 6 years). This is done in an outpatient procedure that only requires a small incision in the chest wall.

Discussion

The differences in the two kinds of neuromodulation are at first glance small and seemingly insignificant. A closer look into the adverse events and side effects provides a deeper look into how they might differ from each other, as the side effects for the DBS treatments are considerably worse than for VNS. For DBS these side effects include; depression, gait disturbances, cognitive disturbances, and in rare cases intracerebral haemorrhages from surgery. [3] For the VNS treatment the side effects seem milder; coughing, sore throat, difficulty swallowing and usually only when the device is activated. [6] The risks surrounding the surgery to implant the device are also considerably less.

So why use the DBS treatment when the side effects are so much worse?

The biggest reason can be found when looking at the differences in seizure reduction. According to a 1 year follow up study by Zhu. et al, comparing the efficiency between VNS and DBS therapy in DRE patients the differences in mean reduction are significant. According to the study, the mean seizure reduction in patients with DBS at 3, 6, 9 and 12 months after the operation was 57.22%, 61.61%, 63.94% and 65.28%. While patients with VNS had mean seizure reductions at 36.06%, 39.94%, 45.24% and 48.35%, respectively. [1]

DBS is also being used as treatment for patients not responding to the VNS treatment. 45% of patients previously treated with VNS, were found to benefit from DBS in the same way as patients not previously having been treated with VNS. [9] This is according to the SANTE trial. [10] The DBS treatment seems to work better for some patients, than the VNS treatment.

The differences in side effects should be considered when choosing a treatment, but there seems to be some evidence of DBS treatment working better for some patients. Hence the screening before surgery is of most importance for the choice in treatment, as the benefits can greatly outweigh the risks.