How does DBS differ from other methods of neuromodulation? This question and more in this Q&A with Dr Robert Gross, a neurosurgical primary investigator in an important trial.
Following the footsteps of the approval of a deep brain stimulation (DBS) device for medically refractory epilepsy, Emory University recently announced the successful implantation in its first patient.1 About one third of all patients with epilepsy do not respond to traditional pharmacological options. This device offers a new option for clinicians-and new hope for patients.
Robert E. Gross, MD, PhD, the MBNA Bowman chair and professor at Emory University’s department of neurosurgery, and the neurosurgical primary investigator for the Stimulation of the Anterior Nucleus of the Thalamus in Epilepsy (SANTE) trial,2 chatted with Neurology Times about DBS, the breakthrough, and what this means for neurology.
Neurology Times: How does DBS works in patients with epilepsy?
Dr Gross:How DBS works is not entirely certain in general, much less in epilepsy. In DBS for epilepsy as FDA approved, we put the DBS leads into a structure called the anterior nucleus of the thalamus, thus Stimulation of the Anterior Nucleus of Thalamus for Epilepsy. (SANTÃ also means “health” in French!) This is one way-station in the limbic circuitry in the brain that plays a role in mood and memory. Many patients have seizures that hijack that circuitry. It was proposed many years ago that electrically stimulating that area with a DBS electrode might impair the flow of seizures through the limbic network and, indeed, both the early and late pilot studies and the SANTE trial validate that idea.
As to how the stimulation actually blocks the seizures is not completely understood. Our best guess at this time is that stimulation decreases the hyperexcitability of the neurons in the anterior nucleus and other connected limbic structures, such as the hippocampus, and thus essentially dampens down the circuit sufficiently enough that the seizure never takes off.
NT: How does DBS differ from other methods of neuromodulation?
Dr Gross:Other approved modalities of neuromodulation are vagus nerve stimulation (VNS) and responsive neurostimulation. In VNS, the vagus nerve in the neck is electrically stimulated on its way up to the brain. The vagus nerve has various influences on the brain, including on autonomic activity. Once again, the mechanism is not well understood, but likely involves desynchronization through influences, via the brainstem, on the limbic system as well as other brain networks. That influence is not as direct as the ANT pathway, which could factor into possible differences in results.
Responsive neurostimulation (RNS) uses electrodes (some like the DBS electrodes; others specific for surface recording/stimulation) coupled to a device that records electrocorticographic activity, which is similar to EEG but that comes directly from the surface of or within the cortex, and responds to detection of a seizure by electrically stimulating that region.
In contrast to ANT DBS, RNS ostensibly stimulates the epileptic focus of activity directly. That may have theoretical advantages in some circumstances and disadvantages in others (eg, you need to identify the location of that focus or foci [up to 2] to stimulate it). It is interesting, however, that the results from separate clinical trials with ANT DBS and RNS are virtually identical with respect to their effectiveness.
NT: What were the results from the SANTE clinical trial?
Dr Gross:The SANTE study enrolled 110 subjects with medically refractory (or drug resistant) focal epilepsy with impaired awareness (the present nomenclature for complex partial seizures). All subjects received bilateral ANT DBS; half were randomly assigned to have the stimulation activated for 3 months while the other half had sham stimulation. This was a double-blind study, in that neither the patients nor the evaluators knew the treatment group for each participant.
After three months, there was a statistically significant difference between the groups: the stimulated group experienced a 40% reduction in seizures whereas the non-stimulated patients experienced only a 15% improvement. After the three months’ time, all patients had their devices activated.
Two years after randomization, there was a 56% median reduction in seizures in the whole group. Subsequent long-term follow-up of the patients has shown a progressive decrease in seizures with time; after seven years the group experienced a 75% reduction of seizures, with associated significant improvements in quality of life measures. Finally, the stimulation has been very well tolerated as far as adverse effects.
NT: How did you first get involved in studying DBS for this patient population?
Dr Gross:I have been interested in DBS since my residency in the mid-90s, with the advent of DBS for movement disorders such as tremor and Parkinson. Since I was also interested in epilepsy, I was very curious as to how we could apply the same principles to that disorder.
I used DBS for epilepsy for the first time when I was a fellow in 1996, as part of one of the pilot study cases that set the stage for the SANTE trial. I was involved in the planning of this trial from the outset, was the primary neurosurgeon investigator on the trial, and with my neurology colleagues at Emory contributed the second highest number of patients (12) to that trial.
Pros and cons of DBS>
NT: What are the pros and cons of DBS in this patient population?
Dr Gross: The pro is that this gives patients an option. This group of patients have persistent disabling seizures despite taking multiple medications (at least three and, in many instances, quite a few more) and they are not candidates for any sort of resective or ablative surgery (ie, surgical treatment of their epilepsy); many of them have failed VNS therapy. These patients, therefore, have no other treatment options. Yet with ANT DBS, most of the patients have experienced a substantial decrease in their seizure burden. And it is well tolerated.
The con is that it is in fact surgery, albeit a minimally invasive one that only requires a one-day hospital admission. Side effects included surgical complications such as bleeding, but fortunately there were no symptomatic or clinically significant bleeding events during the SANTE trial. There were no brain infections, and all superficial infections were treated with antibiotics, although 8% needed to have their stimulators removed (they could be replaced again at a later time).
Other side effects included complaints of depression and memory loss, but many of these patients had these problems from their seizures prior to surgery. These complaints occurred more frequently in the stimulated as compared to the non-stimulated patients, but 50% of the depression complaints and all of the memory complaints resolved in time. And there was no demonstrable difference in memory function between the stimulated and non-stimulated group on standardized neuropsychological measures.
NT: What are you most excited about regarding this approval?
Dr Gross:Those of us treating patients with epilepsy encounter many (30%) patients whose seizures are not stopped by medical treatment alone. Oftentimes we have had no options for these patients. While some patients may be candidates for surgical resection or ablation of their epilepsy focus, if they have several foci, or they cannot be identified, we have no other options, especially when VNS has not worked (as it often does not). ANT DBS gives us another very good tool to help these patients have a better life. I never like to tell a patient with epilepsy that I have nothing to offer them; now I don’t have to!
NT: Do you have future studies planned?
Dr Gross: ANT DBS is very good, as is RNS, and even VNS . . . but at their best, even when the majority of patients have stopped the majority of their seizures, there are still few patients who become totally free of disabling seizures on these therapies. Our goal in the treatment of epilepsy is NO seizures and NO side effects. Therefore, we have to continue to work to make these electrical stimulation therapies better or come up with other therapies.
My research group is working on an approach to make electrical stimulation even better by being more nuanced in how we apply the stimulation, taking into account the mechanism of action and using so-called closed-loop feedback to help optimize the therapy. Our research on this new approach to electrical neuromodulation, which is supported by the NIH BRAIN Initiative, hopes to have a first-in-human pilot study launched in the next 3 years-with just a little bit of luck! We also are beginning to consider how we can extend DBS for epilepsy to other epilepsy patient populations, such as those with generalized epilepsy that are not covered by the present ANT DBS approach.
NT: What advice can you give clinicians considering DBS for their patients with refractory epilepsy?What do you think the future holds for treating these patients?
Dr Gross: We have a number of tools in our armamentarium to treat intractable epilepsy that we never had before, including DBS and RNS and other approaches such as stereotactic laser ablation. I would advise other clinicians to consider what might be the best tool to use in any individual patient. These approaches need to be personally tailored to each patient, after careful and complete diagnostic work, and realistic consideration of the risks and benefits of each tool.
The good news is that we have something to offer now, be it resection or DBS or RNS or laser ablation, to the large majority of the patients we see who have failed medical management. So we are in a good place now . . . and I think the future is even brighter, when one considers the bold new technologies that are being developed-many under the auspices of the BRAIN initiative-to treat brain disorders including epilepsy.
1. Emory first in U.S. to treat epilepsy with deep brain stimulation since commercial approval. Emory University. February 19, 2019. https://news.emory.edu/stories/2019/02/jjm_epilepsy_deep_brain_stimulation/index.html. Accessed March 7, 2019.
2. Salanova V, Witt T, Worth R, et al. Long-term efficacy and safety of thalamic stimulation for drug-resistant partial epilepsy. Neurology. 2015;84:1017-1025.