Stimulating topics in epilepsy treatment
Jeez I crack myself up. In this follow up segment to last week’s episode on minimally invasive strategies for drug-resistant epilepsy, Dr. Becker and I discuss the various modes of neurostimulation in patients with intractable seizures.
In the late nineteenth century, a leading theory as to why seizures occurred had to do with blood flow to the brain. Too much was not a good thing. So efforts were taken to reduce cerebral perfusion, including carotid compression, and eventually electrical vagus nerve stimulation, with
the hope of slowing the heart rate. At the time, neuroscientists like the American James Leonard Corning in the late 1800s believed that seizures were precipitated by increases in cerebral blood flow. The English physician Caleb Parry just a century prior had observed facial flushing and bounding carotid pulses in patients with seizures, and he proposed direct carotid massage in order to abort the seizures by reducing blood flow to the brain. This became a standard of practice at many institutions throughout the nineteenth century. The development of a carotid truss, which would apply pressure to the carotid arteries in seizure patients, looks more like a torture instrument than a therapeutic tool (right). Electrical stimulation of the carotid and nearby vagus nerve was also attempted (see featured image to this blog, from Yuan & Silberstein, 2016), with the thought that vagus nerve stimulation would slow the heart rate and reduce blood flow to the brain. As it turns out, vagus nerve stimulation increases cerebral blood flow. More than 100 years later, we still don’t really know how VNS works.
Still, tens of thousands of patients are treated with a VNS in the United States. The basic concept is that the device sends repetitive, intermittent electrical impulses up to the nucleus of the solitary tract in the brainstem, and this reduces synchronication of brainwaves which could ultimately transform into seizures. To give patients a little extra push, when they need more seizure control (if they were to feel an aura coming on), the patients can trigger an additional electrical impulse by waving a magnet over the subcutaneous device.
When epileptologists think about the VNS and its efficacy, two major clinical trials come to mind: EO3 and EO5. In EO3, an international clinical trial, 113 patients were implanted with the VNS and randomized to two groups: high stimulation and low stimulation. The high stimulation arm experienced a median 24.5% reduction in seizures compared to 6.1% in the low stimulation arm. In EO5, the US multicenter trial, 199 patients were also randomized to high or low stim. Similar results were observed with higher stimulation being more effective at seizure control than lower vagal nerve stimulation. The results from these and other trials were even more impressive at long-term follow-up, with fewer side effects reported over time. For example, using the outcome of seizure reduction by at least 50%, 23% of patients with VNS achieved this favorable outcome within 3 months of implantation. By 12 months, this proportion of patients reached 37%. And at 24 months, 43%, where it appeared to plateau. So nearly half of patients with refractory epilepsy can achieve a seizure reduction by over half with this device, if they are appropriately selected for implantation. Side effects of VNS include:
- Vocal changes (60% early on, drops to 20% after several years)
- Shortness of breath with exertion
VNS has an approved indication for seizures in children, for LGS-associated seizures, and for improving mood in adults with epilepsy according to the 2013 AAN guidelines. Largely it is indicated for primary generalized epilepsy syndromes. But VNS is not all that’s out there. The second device we’re going to talk about is deep brain stimulation, or DBS, which is kind of like an intracranial version of VNS. Several locations for DBS have historically been attempted, and many just in small case series, with very few in controlled clinical trials. Perhaps the most widely targeted region for neurostimulation is the anterior nucleus of the thalamus. This is best supported by evidence from a randomized controlled crossover trial published in 2010 in which 110 patients underwent bilateral anterior thalamic implantation of a stimulation device and were randomized to 4 months of stimulation or no stimulation. After 4 months of monitoring, the stimulated group had a statistically significant absolute risk reduction of seizures of 29% versus the control group. At this point, the arms were unblinded and everyone’s stimulation was turned on. The survival curves for treatment responsiveness then merged and there were significant falls in seizure recurrence in both groups. By 2 years, 54% of patients had a reduction in seizure events by 50% or more—which you will recall is perhaps slightly more than the response rate observed in prior trials of VNS where 43% of patients responded to stimulation. But we are comparing apples to oranges here, so it’s not really appropriate to compare these numbers between trials when the patient population and methods were so different.
The third device under review this week is the Responsive Neurostimulation System. While VNS and DBS are like the pacemaker for the brain, the RNS is like a debrillator—shocking the system back into normal function whenever things go awry. Unlike DBS, RNS only delivers an electrical impulse when a seizure is detected. In the first landmark trial of RNS, published in 2011, investigators demonstrated a reduction in rate of seizures by 39% at 1 year and 51% at 2 years in a cohort of 191 patients with drug-resistant epilepsy. Important to note here is that, like VNS and DBS, the effect seems to improve over the first several years of treatment. But unlike the typical plateau that’s often seen with VNS at 2 years, for example, RNS continues to increase in efficacy. At follow up 7 years later, this climbs to 70%. With a quarter of patients having a reduction in frequency of seizures by 90% or more.
Remember the patients who were included in these original trials were patients who had drug-resistant epilepsy. They continued to have clinical seizures despite being on at least 2 therapeutic anti-epileptic drugs for a substantial amount of time, and now we know they’ve had countless more subclinical seizures because of this device. Now all of the sudden, their average seizure counts are dropping precipitously and a substantial number of patients are going on to seizure freedom. Then there is also the mortality benefit. SUDEP rates fall with these interventions from 9 per 100,000 person-years to 2 per 100,000 stimulation-years.
There is another benefit to monitoring for seizures using the RNS, and that is the fact that RNS allows for real-world event monitoring. Like Dr. Becker said, we typically rely on patients to recount for us their history of clinical events—are they happening more frequently, less frequently in recent weeks—and if we can’t be sure if the interventions we are using are helpful to these patients, or we want to better characterize their events, we will bring these patients into an epilepsy monitoring unit. Now this is a very unnatural setting. The beds are uncomfortable, alarms are going off—we are trying to stress them, mind you. But we’re also taking them out of their typical day to day life. We wean off their anti-epileptic medications, we sleep deprive them, we stress their bodies with photic stimulation and hyperventilation in many cases, and these may precipitate seizure events that aren’t typical for the patient. And if we find a string of seizures in this unnatural setting that originate from a single area of the brain, we might pat ourselves on the back and say, “we figured it out.” But in some cases, there may be more than one epileptogenic foci, and these can take 40 or 50 days of monitoring to identify.
As we continue to utilize these devices more an more, and appropriate candidates are referred for these devices, we are optimistic that seizure frequency, quality of life, and not to mention our understanding of this disease process, all will improve with time.
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