Emerging Innovations in Parkinson Disease Treatment: Q&A With Dr Matthew Brodsky

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Neurology Advisor spoke with Dr Brodsky about his research and about other changes and innovation in Parkinson’s treatments.
Neurology Advisor spoke with Dr Brodsky about his research and about other changes and innovation in Parkinson’s treatments.

Surgical interventions for Parkinson disease (PD) are experiencing a swell in innovation, thanks in part to the entry of two additional medical device companies into a field previously dominated by one company. Most innovation has focused on improvements in equipment in deep brain stimulation (DBS), but changes to current DBS procedures may also be on the horizon as new evidence suggests approaches with better outcomes.

Matthew A. Brodsky, MD, an associate professor of neurology and medical director of the DBS program at Oregon Health & Science University in Portland, recently led a study on one of the new approaches. In research published in Neurology in November 2017, his team compared the use of intraoperative imaging guidance to confirm electrode placement in asleep patients undergoing DBS with the use of microelectrode recording to confirm placement in awake patients, the current standard practice.

When they compared 6-month outcomes in the 69 patients, they found greater improvements in cognition, communication, speech, and dyskinesia during on time in the asleep patients, although both groups showed improvement in quality of life (QoL).

Neurology Advisor spoke with Dr Brodsky about his research and other changes and innovation in PD treatment.

Neurology Advisor: What role did evidence-based medicine play in your motivation to conduct your study?

Dr Brodsky: There are some side effects from DBS that were overlooked for many years but came to light after enough evidence was collected. For example, people can have difficulties with speech fluency and other adverse events thought to be related only to the low-current stimulation from these devices, but that's not the whole story. Probably, multiple passes in the brain and possibly even prolonged surgeries themselves might be at play.

We had a lot of skeptics who asked, ‘”Well, how do you know you're in the right spot if you don't do the microelectrode recording or if you don't wake up the patient in the OR [operating room] and do the test stimulation?” But it turns out that the patients in our study did at least as well as patients who were asleep with regard to improvement in tremor, slowed movement, and muscle rigidity, and in some respects patients actually had better outcomes, for example, in speech fluency.  Getting people to adapt to a different method can take time, but I think we will eventually see procedures change, and that is going to provide a QoL for patients.  

Neurology Advisor: What are the most important surgical advances in PD treatment that have occurred in recent years?

Dr Brodsky: DBS was, of course, a significant advance and improves QoL in a lot of people. Innovations in the first generation of equipment were quite slow to emerge until just recently. We're seeing the emergence of new technology within the world of DBS with implanted leads and how we deliver current through those leads.

Traditionally, we used concentric leads that covered a gross area within very, very small structures in the brain, delivering electrical current in a spherical or conical shape. But we didn't really have the ability to steer that current. Now we can direct a current fairly well in the medial-lateral and anterior-posterior axes, which helps us minimize potential stimulation-related side effects. Frankly, that innovation was driven by the entry of two device manufacturers — Abbott (St. Jude Medical) and Boston Scientific — into the field of movement disorders, which previously only included Medtronic.

Another advance is segmented leads that allow activation of tissue with greater directionality. If an electrode is placed more than a few millimeters off-target it makes a big difference in terms of the usability of that implanted lead. Now, we can direct that current away from parts of the brain in which stimulation would cause adverse events and in a direction that will enable more effective therapy. In addition, other more advanced technology, such as delivering different amounts of current through different leads, is only now becoming available in the United States. A lot of research is going on into providing an evidence base for these new methods of delivering current with both greater directionality and independent control.

Another technique several groups are working on is the closed-loop system. Right now, a patient has the DBS leads implanted and then we see them in clinic for a couple of hours on their first visit and then every month or so at the next few visits. We can only do so much when we see them in the clinic setting — running them through the exam and testing for side effects. When they go about their lives back at home, the leads are generally set to where you left them. People can select different groups of leads and change settings within those groups, but it's not a system that is constantly changing and adapting based on demand.

Closed-loop systems can change settings moment-by-moment based on demand. There have been a lot of barriers to this type of innovation, such as the need for a system that can record and then deliver stimulation based just on input from brain signals. Other researchers are exploring the possibility of using peripheral devices. We're starting to see publications now on how to approach a closed-loop system, so that's going to be an emerging innovation in the world of DBS.

Neurology Advisor: What types of therapies are researchers currently exploring beyond surgical interventions for PD?

Dr Brodsky: The hottest area at the moment, which is already in phase 2 trials, is immunotherapy for PD, as well as more personalized medication approaches based on etiology. With immunotherapy, the strategy so far is to deliver antibodies that will help clear alpha-synuclein, the protein that in PD is misfolded and clumped up in nerve cells in the body, including in the brain. We're still a couple years out from that, so we'll see.

With the more personalized medicine approach, we're now recognizing that PD is not really a single disease. If you put 100 people who have PD in a room, you would likely have at least 50 different causes. It's a lot more complex than we thought it might be. That, of course, makes it much more complicated when you are enrolling, say, 500 people in an interventional study and they all have PD as defined by current diagnostic criteria but not based on etiology.

We're now embarking on a study that will only enroll people with PD who carry one of the known gene variants for the Gaucher gene (roughly 5% of all patients). All the genetic discoveries in PD have been important to try to understand what's going on inside of neurons, but now they're also leading to potential targeted therapies.

There isn't a clinical trial yet targeting people with the LRRK2 gene mutation, but for the Gaucher gene, there's one that's just getting up and running that blocks the production of a protein that abnormally accumulates when this enzyme stops functioning normally. This is the first study of its kind in PD targeting just a small percentage of people with PD based on a factor that's thought to be a cause of their disease.  

Neurology Advisor: Aside from reducing specific symptoms, what other outcomes are researchers now including in their research?

Dr Brodsky: In PD studies having a validated QoL assessment is key. You might improve someone's bradykinesia or balance, but if you're not ultimately improving their quality of life, is it really worth it, especially if there's risk involved? It's really important that a QoL index is part of the trial design, especially if it's a larger phase 3 trial. We now have a number of good validated measures for assessing QoL in PD, so I think it's really important to not overlook this factor.

Disclosure: The study led by Dr Brodsky was funded by Medtronic. Dr Brodsky does not have any disclosures.

Reference

Brodsky MA, Anderson S, Murchison C, Seier M, et al. Clinical outcomes of asleep vs awake deep brain stimulation for Parkinson disease. Neurology. 201;7;89(19):1944-1950.

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