PADRECC NATIONAL VANTS AUDIO CONFERENCE Deep Brain Stimulation Frances M. Weaver, M.D. March 12, 2009 Good afternoon everyone. Welcome to the PADRECC EES series of audio conferences for FY09. My name is Lynn Klancher and I am the Associate Director of Education for the Southeast PADRECC in Richmond and I will be your Moderator for today. This is the third of a series of conferences on movement disorders and I would just like to remind the audience to please mute your phones so that we can avoid any background noise and distractions during the presentation. Hopefully, you have all been to the VA catalog link and downloaded the handouts, the PowerPoint slides for today and we will be following along with those. There is a link in the brochure part of the handout and there you will find a PDF document, which is the evaluation, please fill that out and submit it online. It goes electronically and you have two weeks to fill that out. Evals must be done by March 26th to get your continuing education credits. Today’s presentation is Best Medical Therapy versus Deep Brain Stimulation for Parkinson’s Disease. Six months results from a multi-Site Randomized Trial. Our presenter today is Dr. Frances Weaver, Ph.D. She is the director for the Center for Management of Complex Chronic Care at the Hines VA Hospital. She is a Research Associate Professor at the Department of Neurology and Institute for Healthcare Studies at Northwestern University. She is the study Co-Chair person for CSP 468 Study Group. I will go ahead and turn it over to Dr. Weaver. Good afternoon and thanks to everyone for joining me this afternoon. Because this is not a live meeting, you will be following along with the handouts. I will try and remember to say next slide when I am moving on. I know I don’t have to give this group a whole lot of background on Parkinson’s Disease. We know it’s a progressive neurologic disease and it’s based primarily on symptoms, that’s how we diagnose it. The tremor, bradykinesia, rigidity and postural instability. We also know that the gold standard treatment for Parkinson’s is levodopa. Next slide. However, we also know that over time that levodopa becomes less effective in our patients. While they may have had good response in the past, over time they often have longer periods when they are not having a good response, they may have dyskinesia and they may have more motor fluctuations, more periods of time when they are on and off or have end of dose wearing off. At that point, patients and providers get very frustrated with the fact that they have less control over the symptoms of Parkinson’s. So, at that point, surgery may be a consideration. Individuals who would be considered for surgery need to have good psychological status and otherwise need to be a good candidate for surgery. Next slide. So, we know that deep brain stimulation is an accepted surgical intervention for Parkinson’s patients who have motor complications with medication. However, there are a number of questions that still remain about deep brain stimulation, including, when should deep brain stimulation be offered? Traditionally, it’s been offered to individuals in more advanced stages, but would it be beneficial to offer it earlier? That’s a question that has yet to be answered. Who are the best candidates for deep brain stimulation? We know it doesn’t work for everyone. We have some sense of who might be good candidates for undergoing surgery, but we still don’t have a real good sense of who responds well and who may not respond as well. Then for the purposes of our study, we had two questions that we were interested in. One is what side of the brain is deep brain stimulation for Parkinson’s more effective? That’s phase two of our study and phase one of our study was the question about how deep brain stimulation compares to best medical therapy. When we started developing this project over ten years ago, there had been no studies done that did a head-to-head comparison of medicine versus surgery for Parkinson’s. So, we felt that was an important question to try and answer. Many of the papers that have been published over the last ten years on deep brain stimulation, most of them had been focused on surgery in a single site. The subthalamic nucleus. These designs are pre-post designs. They often lack a comparison group or the comparison group is not equivalent and we often lack standardized reporting on outcomes such as adverse events and lacking standardized outcomes on issues such as adverse events in neuropsychological functioning. Most of these studies are only looking at outcomes very short term over approximately six months to a year. Next slide. In a study recently published in the New England Journal of Medicine in 2006, Deuschl Colleagues used the matched pairs designs comparing best medical therapy to deep brain stimulation and found that deep brain stimulation patients improved significantly on motor function and on quality of life, but about a 1/3 of the patients did not improve significantly over their matched medically treated controls on motor functioning. Today, I am going to present the six months results of a large randomized control trial, comparing deep brain stimulation to best medical therapy that included a significant number of older patients. Next slide. So, the primary objectives of the phase one of our study were to compare patient motor functioning based on self reported motor diaries at six months, following either receipt of deep brain stimulation or best medical therapy in patients with Parkinson’s Disease. Patients were asked to complete motor diaries over a two-day period indicating at thirty-minute intervals, how they were functioning. So, were they functioning well with good movement? Were they having difficulty controlling their movements, such as dyskinesias? Were they off functioning in the sense that they were unable to move or had great difficulty moving or were they asleep? And so, we averaged that information over two days to see what the predominant functioning was for that individual. We also wanted to look at objective motor functioning. So, we used the unified Parkinson’s Disease rating scale, the UPDRS for patients with Parkinson’s Disease, who had undergone the bilateral deep brain stimulation or best medical therapy, again, looking at six months following intervention. Next slide. In phase two, which I am not going to report on today, our deep brain stimulation patients were randomized to where in the brain the surgery was provided. Half of the patients were randomized to receive stimulation in the subthalamic nucleus and the other half were randomized to stimulation of the globus pallidus interna. Best medical therapy patients continued onto surgery after six months of treatment and they too were then randomized to surgery either the STN or the GPI. And in phase two, our primary objective was to compare motor function, using again, the UPDRS motor function sub-scale at two years, comparing STN to GPI. We were fortunate to have a sub group of patients where we were able to follow them for three years. So, we do have three years worth of follow-up for a smaller cohort of patients, and we plan to look at outcomes at 3 years for this group by treatment. Next page. Patient eligibility criteria for enrollment in the study, included patients having a Hoehn & Yahr stage of two or greater when off medication. Individuals had to have idiopathic Parkinson’s Disease. That is, they had to be responsive to levodopa. They had to experience either off time and/or on time with troubling dyskinesias for at least three hours a day and that was based on the motor diary. No contraindications to surgery or having had prior Parkinson’s surgery. No cognitive impairment or dementia and to had to have been on a stable dose of Parkinson’s medication for at least one month prior to enrollment. Next slide. Our patients were then stratified by our study site, in which we had 12 and I will describe those in a moment and by patient age. We broke our patients into two groups by age. Those less than 70 and those 70 and older. We do this to ensure that we would have equal numbers of younger and older patients in both the best medical therapy and the deep brain stimulation arms. Okay, next slide. Our six-month data included a repeat of the patient self-report motor diaries and an assessment of the motor functioning using the UPDRS motor sub-scale, using both unblinded and blinded assessments, quality of life, using the Parkinson’s Disease Questionnaire 39. We also utilized the other subscales of the UPDRS, the ADL and the mentation motor behavior and the dyskinesia subscales. We carefully monitored adverse events and complications. We tracked the amount of Parkinson’s medication individuals were taking, converting that to levodopa equivalent and we tracked a number of neuropsychological outcomes. In fact, our neuropsychological battery took about two hours to complete. That was conducted at baseline and again at six months. Next slide. We thought it was very important that we have a blinded assessor. Someone who was not part of the study to conduct independent evaluations of patient motor functioning, using the UPDRS Part III. We did this because it is possible that our study neurologists, who are not blinded to treatment, may in some way, have a bias when they evaluate patients, particularly since they knew how patients were at baseline, they may have had some bias in their rating of functioning. In this way, we would have individuals who did not know what treatment the patient received, independently evaluating these individuals. We had our patients wear caps and gowns to cover any possible surgical scars. We did ask our blinded assessors at the end of the study how frequently they thought they knew the patient’s treatment or had actually discovered which treatment group the patient had received. Our blinded assessors told us that less than 2% of the time were they able to discern or did they think they knew which group the patient was in. Next slide. So, what was best medical therapy? We standarized best medical therapy to some extent, but we know that treatment of Parkinson’s is very individualistic. So, best medical therapy included individuals who are actively managed by movement disorder specialists, either at the PADRECC or at the University clinics. Some of our patients refer to the study, had not necessarily been managed by a movement disorder specialist before they were enrolled. Our neurologists were able to adjust Parkinson’s medications as needed, in terms of dose, frequency and timing. They were able to utilize therapies, including physical, occupational and speech therapy as needed and the goal was to achieve best symptom control while optimizing functioning. Next slide. So, this is a picture of the actual deep brain stimulation system. Thank you to the National Institute of Neurological Diseases and Strokes for sharing this diagram with us. This is a one sided view. We know that Parkinson’s is a bilateral disease and so electrodes are implanted on both the left and the right side and connected to the battery pack. Next slide. So, here is the actual procedure that we followed and we did standardize the procedure so that this could be replicable if someone wanted to try this in another study or in general practice. All of our patients had lead implantation, using stereotactic frames with MRI and/or CT guidance to direct where the electrodes would be implanted. We used intraoperative microelectrode recording and test stimulation to optimize target location. We, whenever possible, did the bilateral implantation on the same day. So, both electrodes would be implanted at the same time and if the patient was able to tolerate, also undergoing the implant of the post generator, the Kinetra system, provided Medtronic on the same day, whenever possible. In some cases, we did have to do the implantation of the electrodes and the generator on separate days. The stimulator was turned on within a week in the majority of cases. There were a few stragglers, but the majority were able to have their stimulators on within a week of surgery. Patients were provided with hand-held controllers for minor stimulator adjustments. So, for the major adjustments, obviously, the patients would come into the clinic and adjustments would be made until function was optimized. But, patients had the ability to make minor adjustments at home and some of our patients did that frequently and some patients never did that. Next page. So our participating sites were the VA PADRECC Centers and thank you to all of you for participating in that and our university sites were the university partners to the PADRECC’s to the VA’s. I believe in all cases the neurosurgeon was operating on our patients, both on the VA and the university side of the house. Next page. This is a diagram of the process of enrollment in randomization and what happened during that process. So, for phase one, the medical therapy versus the surgery, we screened 278 patients for eligibility. 23 patients were excluded at that point. The most common reasons for exclusion included 11 patients not willing to be involved in all of the follow-up that was required for study participation and 7 patients were excluded because upon further neuropsychological testing, they were determined to have some psychological issues that would exclude them from the study. That left us with 255 eligible patients who were randomized to receive best medical therapy or deep brain stimulation. 131 received best medical therapy, 121 received surgery. The deep brain stimulation patients were then randomized to globus pallidus stem, there were 61 patients that received that and 60 patients to subthalamic nucleus stem. We did an abbreviated assessment at three months and a more complete assessment at six months of patients. We lost some patients along the way. Patients withdrew consent for medical or psychological problems or they no longer with to participate. We did have two patients who specifically withdrew from the study when they learned they were randomized to best medical therapy, because they did not want to wait six months to receive the surgery, so they withdrew and presumably went and obtained their surgery outside of the study. As part of the cooperative trial, we have a Data Safety Monitoring Board. They meet every six months to evaluate the outcomes data and look particularly for whether there is any significant adverse events or other reasons that we might want to stop the study early. What they determined was that we had significant power to stop the study enrollment to phase one sooner than we had anticipated. We had originally targeted 316 patients to be enrolled in the study, however, during interim analysis, they deemed that we had significant power already to determine the significant difference between the outcomes and we were able to stop the phase one enrollment at that point. So, there were six patients who had been enrolled into best medical therapy who were then offered the opportunity to go directly to surgery. So, that is why they were withdrawn from the best medical therapy group and went immediately into the surgerical group. We did a true intent to treat analysis, so we included all 255 patients in the analyses. We did do a sensitivity analyses on the individuals in which we had complete data, that was 230 patients. The outcomes were very comparable and so, I report the intent to treat findings in this presentation today. Next slide. These are the baseline characteristics of our two groups. The medical therapy and the surgical group. You can see that they are very comparable on almost all characteristics. Our average age was about 62, although over 25% of our sample were age 70 and older. I believe the range of ages, our youngest patient was 37 and our oldest patient was 83, so we had a significant age. The vast majority of our patients were male. 60% of our patients were veterans, coming from the VA hospitals. The one significant difference was on number of years on Parkinson’s medications before participating in the trial. It was somewhat longer in our medical therapy than our deep brain stimulation group. The large majority of our population was white. We had very few minorities. We had a great deal of difficulty recruiting minorities. The majority of our patients were married, lived with family and slightly less than half had personal caregiver help in the home. In terms of impairment, although our criteria was a score of two or higher on the Hoehn-Yahr to enroll in the study, our patients were significantly more impaired than that. At baseline, they were averaging about 3.3 on the 5-point Hoehn-Yahr scale. Next slide. Additional baseline characteristics, these are the other subscales of the UPDRS. The motor diary information at baseline and some of the quality of life measures, some of the subscales and as you can see, they are very, very comparable in all cases. There’s no significant differences. Next slide. We also, as I mentioned, did an extensive neuro psych battery. And these are just some of the tests that were included in that battery. As you can see at baseline, our groups are once again, very comparable. So, randomization works. These groups are comparable in all of these areas at baseline. Next page. This was our primary outcome. Patient motor diaries at six months. I want to direct you to the first two columns, which are the best medical therapy group at baseline and six months. The light blue indicates the amount of time with good functioning. This was the number of hours on average. They had good functioning without any troublesome dyskinesia. Our best medical therapy patients did not change. They averaged seven hours at baseline and at six months, they averaged 7.1 hours. So, essentially no change in on time. Really, no change in any of the different states. If you look at the next columns, these are the surgical patients. At baseline, our surgical patients were averaging 6.4 hours in a 24-hour period, with good functioning. Following surgery, that increased to 10.9 hours. So, on average, they were gaining 4.6 hours of good functioning time per day, following surgery. Not only did they have better, more time with good functioning, they had less time that they had troublesome dyskinesia and less time when they were off in the off state. The only thing that didn’t change was the amount of time that they slept. As a sub-analysis, we were interested in looking at how these outcomes might have differed by how old the patient was. So, if you see in the footnote at the bottom of that slide, our younger surgery patients, those less than age 70, their on time improved by an average of 5.2 hours per day, while our older patients, those individuals who were 70 ad older, their on time improved by 3.8 hours, so a little bit less. But, the bottom line is they both showed significant improvement in their on time following surgery. Next slide. This table presents some of the other motor function outcomes comparing baseline to six months. Medical therapy versus surgery and then looking at the difference. I have highlighted a couple. One is the UPDRS ADL subscale. You can see the best medical therapy arm showed absolutely no change in their average ADL score, where our surgical patient group showed significant improvement going from 19.1 to 14.5 on that subscale, which was statistically significant. The other outcome with our secondary outcome, the motor functioning using the UPDRS III for the objective motor functioning. This was assessed when the patients were off medication, but on stim. Obviously, for the medical patients, it was off medication. Again, we see very little change in the best medical therapy group, but significant improvement. So, change from 43 to 30.7 on that subscale at six months, which was statistically significant. We also saw a significant drop in the amount of milligrams of levodopa equivalent that our surgical patients required at six months compared to our medical therapy patients, which essentially showed no change. So, most of these outcomes were significantly better improved in our surgical patients at six months. Next slide. This next slide is the quality of life assessment. These are the eight subscales, plus the overall quality of life assessment on the PDQ-39 and not to go through each one of these, you can see that with the exception of social support, all of the quality of life indicators improved significantly in our surgical group, compared to the medical therapy group, which showed very little change over time. We think that the social support variable did not change because these individuals had significant social support to begin with. Their scores were much better on social support than on the other quality of life indicators and we know that the majority of these patients were married, lived with family and had caregiver support. Next slide. Now, it’s a little bit different when we look at the neuropsychological outcomes, comparing baseline to six months between our medical therapy and our deep brain stimulation group. I have highlighted in sort of a pink, fuchsia color, the tests where we found a statistically significant difference. What we see here is that our medical therapy patients at six months were actually showing some very slight improvement on aspects, including working memory, processing speed and phonemic fluency. Whereas, our deep brain stimulation patients were actually seeing a slight decrement. So, those differences were statistically significant. It’s quite possible that our medical therapy patients were experiencing a bit of a learning affect and so that might account for the slight improvement, but that is countered to what we are seeing in our surgical patients. That even if they had a learning affect, they still had a decrement. So, it appears that deep brain stimulation was having a slight negative effect on some aspects of neurocognitive functioning following surgery. Next slide. These are additional neuropsychological outcomes. As you can see, we have also the delayed recall assessment that show the exact same pattern as the other statistically significant neuro psych outcomes that there was a slight decrement in our surgical population and a slight improvement in our medical therapy population. Next slide. One thing that the cooperative study did was to very, very carefully monitor all adverse events that patients experienced during the course of the study. Whether they were related to the procedure or the treatment or not. So, we included events that may have occurred that had nothing to do with Parkinson’s Disease and as you can see, we found a lot of adverse events. Over 500 in our medical therapy group and over 1,460 in our surgery group. The good news is that most of them were mild, but that there were a lot of them. In particular, we looked at the serious adverse events and broke those out. Those are also included above, but these are the ones that we were required to report to FDA because we were under an investigative device requirement when we started this study. These are events that would result in hospitalization, would prolong an existing hospitalization or resulted in death. We had 19 serious adverse events in our medical therapy group and 82 in our deep brain stimulation group. Next slide. We were interested in looking at some of the more frequent moderate and severe adverse events, not only in their frequency, but in their timing. So, we broke up when these events occurred into two time periods, from baseline to three months. So, early events and then from four to six months, so the later events, with the idea that some of these adverse events may be related to the surgery or the need to make adjustments to the stimulation or the medication. In the fuchsia again, you see that there were a couple of adverse events that were much more frequent in deep brain stimulation than in medical therapy early on. These included headaches, bradykinesia and patients experiencing some confusion. In all of these cases, these were resolved due to just recovery from the surgery, from adjustment to the stimulation and/or some adjustment to medication. The only adverse event that was more frequent at six months than it was at three months for the surgical patients was dystonia. The one thing that was interesting to us was the number of falls. We saw significantly more falls, both early after surgery and closer to six months in our surgical population than in our best medical therapy group and that was statistically significant. Next slide. Then we looked more carefully at the serious adverse events. We had 49 surgical patients who experienced a total of 82 serious adverse events, while only 15 best medical therapy patients experienced 19 serious adverse events. So, the overall incident risk of experiencing a serious adverse event, was 3.8 times higher in our surgical than our medical therapy patients. Next slide. We then broke out the serious adverse events by treatment group, more specifically in our surgical population, as you would expect, there might be some device or particular related problems that would not be applicable in our medical therapy group. These included 16 cases where we had an infection at the implant site, either where the electrodes entered the body or where the post generator or the battery was inserted. Ultimately, either the electrodes, the pulse generator or both were explanted in these patients, they were treated with antibiotics and in most cases, they were reimplanted with new devices later on. We also had some other complications including migration of the lead wires. We had one or two patients where the lead wires broke and had to be replaced. We did have one case where a patient experienced a subdural hematoma after the electrodes were implanted. The electrodes were then explanted, however, the patient slipped into a coma and died several days later. The other death that we experienced, so there were two deaths in the first month of the trial, the other death was attributed to cancer and was not related to either of the treatments. We saw a larger number of nervous systems disorders in our deep brain stimulation group, including dyskinesia, akinesia, balance problems, other kinds of nervous system disorders. Again, many of those were resolved when the stimulation was adjusted. We also saw more psychiatric complications, adverse events in our surgical group than our best medical therapy group, including mental status changes, confusion, hallucination, depression, anxiety. Again, many of these were addressed by altering stimulations and/or PD medications. We had four cases of cancer, interestingly enough, they were all in the surgical group. Can’t really explain that. Then, we had a number of other conditions or diseases, including cardiac, GI and other types of infections that were probably not related to the procedures. Next slide. So, in conclusion, deep brain stimulation was superior to best medical therapy in improving motor function in a large cohort of persons with Parkinson’s Disease. The on time gain of 4.6 hours on average, was significantly larger than the gains that we have seen in studies of adjunctive medications reported in other studies, which average one to two hours. So, this is a significantly greater improvement in on time than we see with medication. And, quality of life improved significantly for our surgical patients with very little change in our medical therapy group. Next slide. There were a large number of serious adverse events experienced by the surgical group, in fact, 10% were infections. However, these were resolved within six months and a large number of adverse events, in general, were related disease progression and other chronic conditions and not related to the procedures themselves. Our older patients did almost as well as our younger patients, following deep brain stimulation on both motor function and quality of life. What I didn’t mention when we looked at the serious adverse events is that we did not find a difference in the rate or the type of serious adverse events between our older and our younger patients. So, that was quite interesting. So, when people ask me what I would say is the take home message from this, I say that physicians and patients should carefully weigh the potential short term and long term risks versus the benefit of deep brain stimulation when making decisions about surgical interventions for Parkinson’s. We know an awful lot more now about what the risks are, what the possible adverse events are. We also know what the benefits can be and so we have more information to make a more informed choice about treatment. Next slide. I wanted to acknowledge our funding sources. This study was funded by the Department of Veteran Affairs, Cooperative Study Program and by the National Institute of Neurologic Diseases and Stroke. We received additional support from Medtronic for some additional monitoring and allowed us the ability to collect data for a subset of patients for three years. Next slide. There are many acknowledgements to make on this study. The Cooperative Studies Coordinating Centers here at Hines in Albuquerque, which manage the devices and in Boston, which manage the electronic data collection. The PADRECC’s and our University affiliates in terms of participating. Our study teams, including our Movement Disorder Neurologists, Neurosurgeons, Neuropsychologists, Study Nurses and I am sure many others and of course, our patients, our veterans and our other patients with Parkinson’s Disease, who agree to participate to benefit perhaps themselves, but definitely to benefit others in the future. A major thank you to my colleagues, Drs. Ken Follet and Matt Stern, who are probably the biggest brains behind this operation. So, I am going to stop now and take any questions that you may have. Thank you. Thank you Dr. Weaver. Are there any questions out there? Again, someone has an open mic on, so unless you are asking a question, please mute the phone. This is Susan Heath from San Francisco and I am wondering when we might be able to see a breakdown of the infection rate by site? By study site, Susan? Yes. We have that information. Shoot me an email and I will get that to you. That would be great. There’s no difference, by the way. They are very low. There’s only 16 infections total and we have 13 sites. I guess it said 10% was the SAE’s? The 10% was the infection rate for the surgical group. Not bad. Well, people still think it’s high. Yeah, they do. They want it half that. I know. One question, my name is Barry Cusak, I am calling from Boise, Idaho. You mentioned that there was a reduction in the dose of levodopa in the surgical treated group compared to the best medical therapy group. That’s correct. But, I didn’t hear what the numbers were, just to get a sense of what the average numbers might be. Okay, I am going to that right now. So, at baseline, our surgical patients were averaging 1,281 milligrams. At six months, it dropped to 985 milligrams. Now, keep in mind that STN in the GPI patients were combined in the surgical arm, because our question for phase one was medicine versus surgery. Okay, so it was reduced by maybe about 1/3 or something like that. Not quite, but yeah, around there. Thank you. This is Susan Heath again, another question. Do you have an estimation of when we will learn about the results for the phase two? Well, I can tell you we are working furiously to put together a paper for New England Journal of Medicine and as soon as we have a draft, we will share it with our site investigators. So, as soon as we can write it. Great. You can’t give us the skinny on that at the present time, no? No, I don’t want to effect the ?? of getting this published in the New England Journal. Fran, this is Penny Hoger. Hi Penny. How are you? Good. Just a question about, are there any plans to do or enough power to do a sub-group analysis for the older patients in the study? Because that was one of the points in the paper that our study didn’t exclude people over the age of 70, so it seems like that might be an important sub-group. I think we had a fair number, but I don’t know whether you think we have enough power to do a sub-group analysis. Well, we did report on a couple of findings by age, actually in the JAMA paper. So, we looked at on time and we looked at UPDRS. We didn’t go beyond that at this point. We certainly, by the time we finish phase two, could do more of that. I think the power is a little on the weak side, but I still think it’s worth taking a look at it. Well, should we wrap this up if there’s no further questions? Anybody out there? Annie from San Juan, I am sorry, I came in late because there’s was a patient last minute. I have been waiting, I will get it next time I suppose. Did you have a question? Not right now. I have a patient that has dyskinesia and he is going to be seen by one of the centers in the state of Virginia on the study first. I saw him the other day and they hadn’t reduced, so I think that I will refer him, so I don’t know what is going to happen the day that we have the appointment. . .it’s a good day or a bad day. Are you Annie from San Juan? Yes. Are we seeing him in person or tele-medicine? Tele-medicine. They are going to give me a class on how to use it because I have never done tele-medicine. It would be the first time, so I have to get training or something like that. We will make sure you hook up with your tele-medicine coordinator at your site. Oh yes. It’s just that he keeps postponing me. I guess he also has a big list of things to do. So, we have a date scheduled? Yes, it’s the 31st of this month. Excellent. I was wondering. I have another patient that actually is looking worse than him and I don’t know if I could bring them both in or is that not kosher? Well, you know, it might work because it took so hard to make this one work. So, I think we would be amenable to that and that’s the day our neurosurgeon is here. Oh, okay. Then, I am going to call him and ask them if they can come. I will just tell them that if there is time, maybe both can be seen on the same day and such. So that they know what to expect. I will talk with our clerk and we will get together on that. This is Susan again about the study, a question on the study if I might. On the SAE’s again, Fran. You know, I know that one of the SAE’s was one of our patients who fell off a roof because he was so physical able to, in his mind, that he could go up there and he fell. So, are you going to try and sort out or can we sort out the SAE’s in terms of exactly what they were? Then, we had another patient, who, against our recommendation, drove and was in a car accident. You know what I mean? So, there are those kind of serious. . . We do have a lot of information on our serious adverse events and that we know, for example, the falls resulted in the DBS group, there were lots of fractures. You know, they broke an elbow, they broke a leg, they dislocated their shoulder. One of our patients was riding his motorcycle, you know. It’s kind of a good, bad kind of thing. They have all this new found independence, but then they are subject to trauma. Right and so, Susan, as you know, about mid-way through the study, when we saw that falls were really kind of creeping up there, we told everyone to remind patients that falls are still an issue because gait and balance isn’t affected in the same way as tremor. Right, exactly. I think they probably good quality of life up to that point. They did as your study survey shows on the quality of life, which is great. The other thing is what I am wondering is that and you may not be able to answer this because I am just going to throw this out ahead of time. In the medication reduction, there may be a difference between the STN and the GPI, but if and also in the DBS settings and how the different centers program, I don’t know if they really differed or not. I got the feeling, the sense just from talking with other people that we are using much higher settings maybe than most. Whether that is good or bad, I have no idea. If we can sort of look at medication reduction and outcomes versus program settings. Well, we have all that data, Susan, so if you are interested in writing a paper that focuses on that. Let me know. Sounds good. As you can see, we have more data than we know what to do with. Right, exactly and not enough hands to write all the papers. All right. Well, that sounds great. Thank you for presenting this. We are going to have a little DBS reunion and we are going to, with your permission, maybe extrapolate or use your sites to share with our patients. Oh, absolutely. You know, I was telling Lynn earlier and I don’t know if other folks are interested or not, I have been asked to present this study to Research Week in Washington, DC. It is actually going to be at the Capital. So, I am doing a presentation and trying to make it applicable for the lay population. If you are interested in that slide set after I have finished it, I am happy to share that. Ours is at the end of the April, when is yours? End of March. Perfect. Yes, I would be interested, if you would be willing. Sure. That would be great. Like I said, I know the ADOE would be interested too. Yes. Sure. Okay, then. Anybody else? Last chance for questions. Well, this was excellent Dr. Weaver. I am so impressed with how the groups were matched so well. That just amazes me to see this data laid out so nicely. I want to thank you again and thanks for everyone who called in. Let me remind to get your continuing education, please complete an evaluation. You will find that link online, on the handout that says “Brochure”, it’s also been on some of the flyers. You can fill that out electronically and submit it electronically. They are due by March 26th. They will email you the Certificate. Please tune in for our next PADRECC EES Presentation, it will be May 14th on A Typical Parkinsonian Disorders. Thank you very much and have a great day. END OF CONFERENCE. PADRECC National Vants Audio Conference Deep Brain Stimulation Frances M. Weaver, M.D. March 12, 2009 Page 1