Many patients with advanced Parkinson’s disease (aPD) who are candidates for surgical or device-assisted therapies do not receive information about these therapies, despite the well-studied benefits in improving control of motor symptoms and quality of life. In this video, Joohi Jimenez-Shahed, MD, describes factors associated with aPD to assist clinicians with identifying patients in this stage of illness and introduces various therapies such as deep brain stimulation, focused ultrasound. and levodopa-carbidopa pump therapy. Timely identification and referral of potential candidates can improve outcomes for these patients.
Hi, my name is Juhi. Jena Shah and I'm a movement disorder specialist and the medical Director of Movement Disorders, neuromodulation and brain Circuit Therapeutics at the icons School of Medicine at Mount Sinai in New York City. Today, I'd like to speak to you about surgical and devices, assisted treatments of Parkinson's disease and why it's important to discuss these options with our patients. These treatments include deep brain stimulation, magnetic residence, guided focused ultrasound, also sometimes just called focused ultrasound carbo dopa, levodopa infusion pumps, and apomorphine pumps which are not yet available in the United States. First, let's consider when these therapies should be uh discussed in cases of Parkinson's disease. Generally patients are eligible, eligible when they have reached the advanced stages. However, this has not been really that easy to define. There have been several different approaches to categorization, including based on disease, phenotype disease duration, genetics and clinical characteristics, but perhaps most relevant to the eligibility for surgical and device assisted therapies are a combination of factors that relate not only to motor symptoms and non motor symptoms but also functional impacts of disease. And there have been recent efforts to try to define this better by consensus over the last 10 years or so. A Delphi panel approach was used to provide recommendations on the management of Parkinson's that was refractory to oral or transdermal therapies. There were 15 clinically important indicators that were identified by an expert panel and then evaluated in a cross sectional international observational study of over 2500 Parkinson's patients across the world. Included in these criteria are a group of motor symptoms, including presence of troublesome motor fluctuations that lead to at least two hours of the waking day with off symptoms at least one hour of the day with troublesome dyskinesias that are at least moderate in intensity dysphasia and medication doses that are taken at least five times per day. Among the non motor features were a presence of cognitive impairment, hallucinations, fluctuations in non motor symptoms and sleep disturbances. And lastly from a functional standpoint, the presence of repeated falls. The requirement for assistance with activities of daily living and impairment and mobility were all identified as clinically important indicators of advanced Parkinson's. From these clinically important indicators emerge. The manage PD tool, which is a clinician reported tool that's designed to facilitate the timely identification and management of patients with advancing Parkinson's who have suboptimal symptom control on their current treatment regimen and may require referral for devices assisted therapies. And that's a determined once the motor nonmotor and functional impact symptoms are assessed. This tool is able to classify patients into three categories including those individuals who are controlled on their current treatment regimen, those who are inadequately controlled on their current treatment regimen, but may benefit from non device assisted treatment optimization or those who are inadequately controlled on their oral treatment regimen and may benefit from a device assisted therapy. This was validated in a couple of different ways supporting the ability of the tool to differentiate individuals with advanced Parkinson's disease. The tool is really easy to use and is publicly available. The first section asks questions based on the motor clinical indicators. If none of those are present, then the patient falls into category one and may not require additional treatment optimization. However, if any one of those motor clinical features are present, then the tool moves on to ask additional questions also including the non motor clinical indicators and the functional impact indicators. Once the tool is completed, the individual patient can be identified as belonging to one of those three categories that I mentioned in order to distill this to an even shorter screening methodology. The 521 clinical criteria have been proposed which include patients who are taking five or more doses of levodopa per day or have two or more hours of off time per day or have one or more hours of troublesome dyskinesia per day. The presence of any one of these may indicate the presence of advanced Parkinson's that could benefit from medication optimization or referral for a surgical or device assisted therapy. I want to take a minute to highlight the importance of identifying patients who meet these criteria. Just as an example, we were able to investigate the impact on burden of disease with every one hour increase in good on time. In a retrospective analysis of about 800 patients with advanced Parkinson's. In this analysis, we were able to estimate that for every one hour increase in good on time, there's a 21% lower likelihood of uncontrolled motor symptoms. A 12% lower likelihood of uncontrolled non motor symptoms and a 9% reduction in the number of falls from a humanistic standpoint for every one hour increase in good on time. Patients had a 19% likelihood higher likelihood of independence to perform their activities of daily living. They had improved quality of life on both general health related quality of life indices as well as on Parkinson's disease specific quality of life measures and also had improved caregiver burden, all of which were statistically significant findings in further analysis. We were able to look at whether the 521 criteria really do identify patients with advanced Parkinson's. And this was assessed in a real world sample of patients in seven countries showing that individuals who were positive on those 521 screening criteria did have a greater disease severity as measured by the UPDRS. They had a greater number of falls and they had a lower level of independence with their activities of daily living. We were also able to show that those patients uh with uh meeting the 521 criteria, had a higher hospitalization rate, had higher numbers of physician consultations and required greater numbers of both professional and non-professional caregiver hours. Meaning that the health care resource utilization in this population of patients is definitely higher. Lastly, we also found that lower quality of life uh was present in individuals who met 521 criteria. Again, both on general health related indicators and on Parkinson's specific quality of life measures, a higher proportion of these patients were actually unsatisfied with their Parkinson's disease treatment and also had a higher degree of caregiver burden. This data really highlights the importance of identifying clinically meaningful interventions that can improve these different aspects of the patient experience with advancing Parkinson's disease. The part that's really striking in all of these investigations is that when you look specifically at those individuals who meet the criteria that we discussed about eligibility for surgical or device assisted therapies, nearly 50% report never having received information or discussions with their health care providers about surgical or devices assisted therapies. And this is really the call to action that I want to emphasize, not only do we need to identify these patients, but we also need to educate them about the surgical and device assisted therapy options that are available to them. So let's talk about those therapies, deep brain stimulation is the first one. It's an implanted hardware that delivers electrical impulses to the deep brain structures. The electrical field that is produced by deep brain stimulation induces changes in cell depolarization that alters firing patterns of those neurons within the targeted nucleus. And this leads to a regularization of neuronal firing patterns that prevent transmission of the otherwise pathologic activity that's present. This ends up leading to improved processing of sensory motor information and reduction of Parkinson's disease symptoms. The three main targets of deep brain stimulation are the dorsolateral subthalamic nucleus. The poster ventral globus, pallidus interna and ventral intermediate nucleus of the thalamus. The STN and GP I are commonly used to treat Parkinson's disease. Whereas the thalamic target can be used for treatment of tremor of multiple types. We typically talk about doing deep brain stimulation when a patient is experiencing troubling motor symptoms, which include the presence of motor fluctuations, the presence of dyskinesia or the presence of refractory tremor. We usually are considering this treatment when there is absence of significant neuropsychiatric comorbidity and certainly before refractory symptoms appear such as cognitive impairment and gate freezing. For this reason, we talk about a window of opportunity for intervening with D BS after the onset of these troublesome motor complications. But before the presence of those refract refractory indicators, the official indication for D BS at least based on one device manufacturers label are that D BS is an adjunctive therapy that's used to reduce some of the symptoms in individuals with levodopa responsive Parkinson's disease that has been present for at least four years when the motor complications have been present for at least four months and which are not adequately controlled with medications. So it's a fairly broad indication and open to individualization given a particular patient's manifestations and impairments. However, it makes it very easy to apply the 5 to 1 criteria and consider referral of patients who might benefit the data supporting deep brain stimulation are strong. There's a very important study within the va population that was published back in 2009, showing that when eligible advanced Parkinson's patients continue on best medical therapy. There really is no change in the degree of motor complications. However, when these individuals are treated with deep brain stimulation, regardless of the brain target, there is definite improvement in off time and in the dyskinesias with a corresponding improvement in good on time without troublesome dyskinesias. Additional data show that the cardinal motor symptoms of Parkinson's disease are improved, medications are reduced and there are very little in terms of neurocognitive changes. More recent investigations published in 2020 show that with bilateral STND BS. After one year, there's a 49% improvement in motor scores and a six hour increase in on time without troublesome dyskinesia experienced by patients with advancing Parkinson's disease. Additionally, there's robust evidence for improved quality of life in patients treated with D BS compared to medical therapy with the caveat that many of these investigations are done in an open label fashion, simply because randomization and blinding are difficult to maintain over the long term. Let's move next to focused ultrasound. This is also referred to as a magnetic resonance guided focused ultrasound therapy. And it's a new methodology for delivering an old therapy, namely a lesion often in the same locations as can be treated with deep brain stimulation. The treatment requires a focused ultrasound transducer that focuses beams of high intensity ultrasound waves onto the target area that is calculated by the surgeon through a series of test sonication and a calculated thermal dose. Bo ultrasound produces localized tissue destruction. This is often considered a noninvasive therapy because surgery isn't required. However, it's important to emphasize that lesions are actually being made within the brain which can certainly have its potential risks and benefits for Parkinson's disease. We have approvals in the United States for thalamotomy and pallidotomy. The thalamotomy studies show that contralateral tremor is rapidly reduced and that the effects can be maintained. However, note that there is some recurrence of tremor over time which may be more prominent than is seen in patients who are treated for essential tremor from the standpoint of pallidotomy. The targeting is a little bit more complex. However, data does support improvement in dyskinesias as well as in motor symptoms, contralateral to the lesion for some of these measures. There again is symptom recurrence over time there's actually limited long term outcomes data on focused ultrasound lesioning and Parkinson's disease. However, based on long term data from other lesioning procedures, this is not an unusual findings and patients should be counseled accordingly. Lastly, let's talk about levodopa, carbidopa intestinal gel. This is indicated for the treatment of motor fluctuations in patients with advanced Parkinson's disease. It administers carbidopa levodopa in a gel formulation. Over a 16 hour infusion. Patients are able to receive a morning dose, a continuous dose and also have access to pr n extra doses throughout the day. There's a formula for converting their existing oral levodopa regimen to the infusion rate. The apparatus itself is a little bit more cumbersome as there is a peg tube and a pump that is typically carried in a shoulder bag or vest. It's important to note that there will be newer delivery methods and newer formulations coming to market towards the end of this year. Again, data for continuous infusion of the carbidopa levodopa is robust, indicating significant reductions in off time and troublesome dyskinesia with corresponding improvements in good on time. Compared to oral levodopa regimens. Multiple systematic reviews have confirmed this efficacy demonstrating that these pumps extend the benefit of levodopa for several years. Optimization can be achieved within days and doses can remain stable for several months. The effects are also sustained over the long term other data support improvements in non motor symptoms such as sleep fatigue, gastrointestinal and urinary symptoms sexual functioning and mood and apathy. However, these benefits need to be balanced with the high rate of adverse effects that are related to the delivery mechanism. With this information and review, I wanna provide you with a few take home messages. First of all, advanced Parkinson's disease is difficult to define. But when specifically considering whether patients may be candidates for surgical or device assisted therapy, the 521 screening criteria can be a helpful first step as a reminder, a patient meets 521 screening criteria if they are taking five or more levodopa doses per day or have two or more hours of off time per day or have at least one hour of troublesome dyskinesia. Secondly, we talked about the fact that deep brain stimulation focused ultrasound and infusion therapies are able to improve symptoms and quality of life in patients with advancing Parkinson's disease. We have a window of opportunity to intervene with deep brain stimulation. Focused ultrasound thalamotomy can be used to treat contralateral tremor and pallidotomy can improve contralateral parkinsonian features and dyskinesia. However, there's limited follow up data about this therapy and potential for recurrent symptoms in the long term levodopa carbidopa intestinal gel has less restrictive candidacy requirements, but there is a higher rate of complications related to the delivery mechanisms. These may be improved with newer formulations and devices in the coming months. Thirdly and lastly, I really want to emphasize that a substantial portion of patients with advanced Parkinson's disease who may be eligible for these therapies are not receiving information and the call to action is on us as clinicians and providers to not only identify these patients but to have those informational conversations with eligible patients. Thank you for your attention.
