Hello. My name is Dr. Daniel Claassen, and I'm a professor of neurology at Vanderbilt University in Nashville, Tennessee. And it's my pleasure today to give you a short talk on pharmacotherapeutic recommendations across the disease course in Parkinson's disease. And my focus is going to be on advanced Parkinson's disease. And we'll talk a little bit about what that means, and some of the treatment issues that come up during the course of your clinical care. The three main areas that we're going to review today, we're going to review the symptoms that characterize advanced Parkinson's disease. We're going to focus on motor complications and their treatments. And then we'll talk about cognitive decline and psychosis management, which is one of the more common issues that one experiences when treating advanced Parkinson's disease patients. So, first of all, let's just orient ourselves to what happens along the continuum of a Parkinson's disease patient. So this is a general timeline of what happens in terms of the life and symptoms of Parkinson's patients. The [inaudible 00:01:15] at the time zero, is when generally speaking, patients get diagnosed. And so we talk about motor diagnosis of Parkinson's disease being the symptoms of resting tremor, slowness of movement with rigidity, cogwheel rigidity, for instance. And they're usually diagnosed by neurologists or even a primary care physician. And typically patients get put on dopamine medicines like levodopa or doping agonists, more frequently levodopa now. And the patient's motor symptoms improve. Now, if you look before that onset of diagnosis, we know that there are prodromal symptoms that help us know that a person is having these Parkinson's disease pathologies start, but they don't necessarily have Parkinson's. And one of the more common symptoms that people talk about is REM behavior disorder. And this is a parasomnia where people act out their dreams. They tend to be shouting in their sleep, seeing animals, or thinking there's an intruder in the house, and sometimes injure their bed partner. And we know that that symptom can occur 10, 20, sometimes 50 years before a patient has motor symptoms. And there are other prodromal symptoms that I've listed here, like constipation, excessive daytime sleepiness, hyposmia, lack of smell, and mood symptoms like depression. As the disease progresses, the advanced symptoms that we see are typically related to motor symptoms that become more difficult to treat. We talk about motor fluctuations, we'll talk about that in just a second, in terms of that definition. Dyskinesias, psychosis, usually visual hallucinations. Progressive instability of gait freezing, falls, dysplasia, and of progressive autonomic symptoms. And generally speaking, the way I look at advanced Parkinson's disease, is a rule of tens. So after the first 10 years, it's going to be very different from the second 10 years. And I generally view the onset of advanced Parkinson's disease coming after that first 10 years of symptoms. Of course everyone's different, and symptoms progress differently in patients. But in my clinic, that's a useful demarcation of when advanced symptoms are going to happen more often. So when we think about the cardinal symptoms of dopamine, like I'd mentioned, [inaudible 00:03:36] rigidity, resting tremor, gait instability. As these symptoms progress, they may not be dopamine responsive like before. For instance, freezing of gait is a very common symptom that occurs, and that's not always responsive to dopamine. Sometimes it is, sometimes people know they're off when they have freezing of gait, but oftentimes it can be just indicative of an advancing disease of severity in a patient. Posture instability and falls. We know through multiple different longitudinal studies that the presence of early gait instability protends earlier onset of cognitive issues, even psychosis, or even the comorbidity of REM behavior can protend that symptom. Speech problems become an issue. Palilalia or hypokinetic dysarthria are some examples of where speech becomes more dysfunctional for patients, and they require help with speech pathology. Dysphasia, difficult chewing and swallowing. And then the non-motor symptoms. Things like dementia, psychosis, that we'll talk about in a minute, progressive anxiety, autonomic symptoms, and sleep abnormalities, are also symptoms of these advanced Parkinson's disease patient [inaudible 00:04:51]. So it's worthwhile to take a step back and just remind ourselves that when when we're treating an advanced Parkinson's disease patient, or in that case, any Parkinson's disease patient, we often think about different factors that might influence our management. So the type of symptoms, the severity of symptoms, is obviously important. Is it worth using a nonpharmacologic versus a pharmacologic therapy for this symptom that a person's having. We look at their occupational status and lifestyle. For patients for instance that are working, you want to maximize employment, you may want to be more fastidious about levodopa timing, and looking at response to levodopa. The age affects management. Older patients tend to have more motor complications, tend to have more gait impairment, tend to have more cognitive impairment, and psychosis. And then the non-motor symptoms can really affect a person's management and the decisions that you make as a clinician. If a patient's having a lot of cognitive issues, it may be more or less compliant with certain complicated medication recommendations. If there are behavioral or psychiatric symptoms, it can be very challenging for a caregiver to look after. And so you really want to identify these, and help the caregiver and patient manage them. Sleep disorders of course are very important for managing symptoms, and can affect sleepiness. For instance, coexistent sleep apnea, or REM sleep behavior where the patient's having injurious behavior, can be very important as you're thinking about what management options to use for a patient. And I think one of the things that goes under asked is constipation. We tend not to ask this for patients, but it can be a big risk factor for delirium or confusion in patients, especially in the advanced patients. And of course, one of the patients other symptom, insulin resistance, diabetes, can affect things like peripheral neuropathy, gastric emptying. Things like that, that might affect the medication [inaudible 00:06:47] and gait impairment. High blood pressure, when a lot of cases, it's over-treated blood pressure. So, many times, a patient with advanced PD is going to come to us with low blood pressure, and we realize that they've had three or four antihypertensive for a long time, and no one's just bothered to stop it to see if that improves their symptoms. And then of course psychiatric symptoms. Things like depression or even demoralization, things like that which require us to intervene, to help a patient. So let's first start talking about motor fluctuations. I mentioned that these are more common as patients progress, but of course there are some patients that have these early on. They tend to be younger, early onset Parkinson's disease, but for the sake of this talk, we'll just think of it in the context of an advanced Parkinson's patient. So as I mentioned earlier, when we think about off and on-state, we're talking about off symptoms that respond to levodopa that when you take it, they go away or they dissipate, or they get better. And that's what we call, on. So you can have predictable and unpredictable off-state. So predictable ones patient says every four hours. You know? "An hour before my next dose, my tremor comes back, my gait gets a slower." Really going through those symptoms with the patient, asking them or the caregiver to jot them down when they happen, what are the factors that make it worse, what are the things that bring it on, would be very helpful in the clinical setting. There are occasions where that off symptom can be random and unpredictable. And there are several things. Like, in the morning, a person wakes up and occasionally have got terrible foot cramps, and they have off-dystonia, or there can be anxiety or fear that can bring on a sudden freezing of gait or sudden off symptom, or dyskinesia, which we'll talk about in a second. And then finally, you can have changes to how your gastric emptying occurs, or how your absorption medicine occurs. And a person might be accustomed to seeing an improvement, 30 minutes after they take their levodopa. But in the occasional times that they eat a lot of protein in their diet, they might find that they're actually delayed in terms of when they get on medication benefit. So it's important to think about these motor complications and the reasons for them and the context for them in an advanced Parkinson's patient. In the on-state, sometimes patients have dyskinesias, most commonly they're peak dose. That is, let's say, 30, 45 minutes after they take their medicine, they start developing this dance-like hyperkinetic movement. In some cases they're off. It's not very common, but sometimes you can see as the medicine wears off, that a patient gets dyskinesias. And then sometimes you can get unusual on-state motor symptoms like myoclonus. We sometimes see this especially in [inaudible 00:09:33]. So it's useful to really clarify how patients respond to therapies, to think about mood fluctuations and what symptoms are happening. And then some other more unusual or rare, so to speak, intermediate state symptoms one can have, are diphasic dyskinesias at the end or beginning of a dose, rapid fluctuations. I tend to see that more in younger folks, yo-yoing up and down in terms of how a person's doing in sudden offs. So here's a schematic to help us think through the difference between early and advanced Parkinson's disease. So you can see at the beginning of this chart here, where we have the up arrow levodopa, that's when a person takes their levodopa tablet. And you can see that early in PD, you get about 30, 45 minutes, you start seeing a clinical benefit. And when we're in that orange period where a patient's noticing a lot of benefit, they don't have a lot of dyskinesia, maybe none. They get a good response and it lasts four to five hours. As the disease progresses, we start seeing that that clinical effect narrows in terms of how long that clinical effect is, and when they have to take their levodopa. So let's say a patient takes a levodopa, they start seeing effect probably 35, 45 minutes. It works well, but it wears off sooner than it used to. And so we may have to change how often we alter the timing of levodopa in order to accommodate that. Then in advanced patients, we have an even tighter window where they take the medicine, it helps, but they also get dyskinesias. And as those dyskinesias wear off, they start getting off symptoms. It can be very frustrating for the patient to experience this kind of intermittent therapeutic benefit, which is accompanied by things like dyskinesias and off symptoms soon after. And so that's the challenge that we have with advanced Parkinson's motor symptoms. So how do we treat this? Well, we obviously want to optimize levodopa therapy. And that's usually the type of levodopa therapy that you're getting, whether or not you're using generic carbidopa levodopa, or some other medications that have longer acting components that may be better absorbed or absorbed in a different pharmacokinetic profile that helps that patient optimize their levodopa therapy. You really want to try and get continuous dopaminergic therapy without these ups and downs. And that really tends to help patients. And there's different ways to do this. You can use controlled release formulations. There are different types of those. You can add dopamine agonists, which can sometimes help, but they also have the risk of causing behavioral problems like compulsive disorder, leg swelling, low blood pressure. There's COMT inhibitors, which helps extend the duration of levodopa in the system. And there's different types of that. There's monoamine oxidase B inhibitors, and there's medicines like amantadine. So all of those can be used in combination or in a tiered approach, really based on the patient's factors. As I mentioned earlier, you really look at the patient, what are their symptoms, when are they happening, to make a educated clinical decision about what you want to try next. And there are other medicines like infusion therapies. For instance, there are some studies looking at things like apomorphine, which is a dopamine agonist that's going to be infused. There's a gel that you can give for levodopa. And there's also now studies looking at subcutaneous use of continuous levodopa. So these things are around now, they're also coming, and there are things to look for, as you think about difficult patients who are having ups and downs with their motor response. And then there's finally deep brain stimulation, which we'll talk about here in a second, in neuroablation. Deep brain stimulation has been around now for a while. And it's been a really dramatic treatment improvement for patients. We look at different targets, the globus pallidus interna or the subthalamic nucleus, occasionally use a thalamus for a tremor. But I think the key point about an advanced patient is that you want to get the right patient for this. So if you got a patient that's got a good levodopa response, but they've got wearing off dyskinesias, or even a prominent tremor, that's probably your best patient. Would say also that cognitive intact understanding of how to manage this, is very important. And that's why we often have patients go through neuropsychological assessments just to make sure they understand what they're getting into, and how they're going to respond. Clearly, one of the things, is it's not a cure. And so we often spend time managing patients expectations for these types of procedures. Now I'm going to switch a little bit to the non-motor symptoms of advanced Parkinson's disease. Of course, when we think about advanced Parkinson's disease, I think the most common thing we think of is cognitive symptoms, and psychiatric symptoms, dementia, hallucinations. But there's also things like impulse control disorder, there's compulsive reward-seeking behavior, there's mood disturbances. And then the other big one is autonomic symptoms. This really happens a lot in advanced Parkinson's patients. Classically neurogenic, orthostatic hypertension characterized by blood pressure drops in response to posture. And of course, constipation, urinary problems, sexual problems, and sweating changes. And then sleep disorders like I mentioned. I'll add a little bit of color to some of the things I didn't talk about. For instance, primary leg movements of sleep. This is that triple flexion response that often happens when a person is sleeping, is sometimes very responsive to dopamine agonists. We're making sure he clarifies, is it that, or is it restless leg syndrome. Generally, restless leg syndrome, people describe a discomfort that's relieved by movement. The primary movements of sleep, we don't necessarily see that discomfort. And then finally, there's sensory symptoms. Patients talk about lack of smell, challenges with pain, parasthesias, and that restless leg sensation. So how do we treat these? I think nonpharmacologic treatments are really useful in patients. And I think we talk a lot about exercise, but I do suggest to my patients, that exercise is a pill that you take for Parkinson's disease. To get people started, we sometimes start with physical therapy. But we know that when patients do exercise, they have better mood, they have better response to the symptom control, using levodopa. And there's some evidence that it delays progression. So it really should be part and parcel of any advanced patient's treatment. We talk about avoidance of protein when they take levodopa. This can change absorption. There also maybe changes of high fat meals that will delay absorption. And if that's an issue, you want to lengthen the duration of the benefit, especially at nighttime, you can recommend that. Sleep is imperative. We know that when you sleep, there's more dopamine in the system, so to speak, I know it's crude phrase, but it's true. Patients notice an early morning sleep benefit when they sleep well. They have better cognition, they have less confusion, there's less mood symptoms. So really making sure a patient's getting good sleep, is important. Then we talk about, for autonomic symptoms, fluid intake. That's really important. Or making sure they're not on too many antihypertensives. And then if patients are struggling with mood symptoms, getting for instance, demoralization, feeling that they have nothing left to live for, they're tired of this chronic disease. Getting therapists involved, can be very helpful. A quick review of orthostatic hypertension and how I take care of it in the clinic. I'll look at the medicines, I'll make sure that there's no medicines that I can withdraw or stop, to make sure that there's no unnecessary hypotension going on. I'll look at non-pharmacologic things like more fluid or salt in the diet. Perhaps the compression stocking or abdominal binders, strategically using exercise to help them. And then I'll think about pharmacologic measures. And the main ones we think about are things like droxidopa, which is a norepinephrine precursor, midodrine, which is a norepinephrine analog, like a doping agonist [inaudible 00:17:36] this case, to sympathetic noradrenergic receptors. You can use very low doses of fludrocortisone, but I would warn you that those can be associated with morbidity and other more specialized autonomic symptoms. Things like [inaudible 00:17:52] and things like that, but really focusing on how you're going to address the patients first with nonpharmacologic and then with pharmacologic, is very important. Psychosis is a big problem in advanced Parkinson's disease. Probably at least half or more Parkinson's patients have psychosis. And what we mean by that, is usually visual hallucinations. It's very rare to have auditory hallucinations in Parkinson's. It can, but usually it's visual hallucinations. We also know that there's a distinction between Parkinson's disease dementia, and dementia with Lewy bodies. That distinction is probably more academic than it should be, but it really has to do with when the onset of symptoms started in relation to the cognitive symptoms. But it's clear that most patients with Lewy body dementia have psychosis as well. Just remember the vulnerable regions in the brain that relate to psychosis. So what I've got here is a map. On the top is the sagittal brain, and the bottom's a medial brain, where the green is. When you have longer disease duration, you have more atrophy to those areas. And so you can see that the early atrophy that's linear, tends to be in the parietal and frontal areas. And then more non-linear in the occipital area. And that really goes to our remind us that those visual pathways, the what more than the where, I think, really gets affected in Parkinson's disease. We know that those pathways are intubated by the acetylcholine and the cholinergic system, which is what we'll talk about, some therapeutic methods you can try. But we also know that the older patients are, the more there's an interaction between the generation of those areas of the brain and age. And so it's important to remember that older patients with Parkinson's tend to have more impairments for cognition, and presence of psychosis. And this is really the key rule that people have used for a number of years, is this one year rule. You have motor symptoms a year before cognitive symptoms, we talk about Parkinson's disease, dementia. But if we have cognitive symptoms at, or before the onset of motor symptoms, we use the term, dementia with Lewy bodies. [Inaudible 00:19:56] by any other name, they tend to be a lot more similar than different. And you can see that the type of memory problems that a person has, tend to be more visuospatial, tend to be more, later, attentional [inaudible 00:20:09] issues, and then memory. And REM sleep behavior is very common, and probably a good predictor of cognitive symptoms later on. So what do these look like? Typically they could be like illusions, where patients see something running in the corner of the vision. Sometimes you can see a well formed hallucination. More commonly it's a small child or a small person. We talk about Willie Pudyen from the famous story hallucination. Sometimes they see little animals, little rats running in the corner of the vision, or running underneath their feet. And then sometimes there's a sense of presence. "There's someone next to me. I looked over and there's no one there." And then sometimes it's a frank delusion. Some of the more common delusions we deal with, are the Othello delusion, like believing that the spouse is cheating on them. And that can be a very challenging delusion for a caregiver, especially. The key concepts that we want to focus on, is that there are sometimes overlapping symptoms that really makes us ascertain what is psychosis and what is not. So for instance, if a person's having a dream of an animal chasing them or someone in the room, you might call that a psychosis event, but in fact it could just be REM dream state. And so it's important to get an assessment for when is it occurring, what's the context of that psychosis symptom happening. One of the things that I find in my practice is to ask about REM intrusions and wakefulness. This is the concept where during a wakeful part of the day, especially in the afternoon, a patient will actually go into a dream state, but be awake. And it can sometimes trick you into thinking that it's psychosis, but I try and manage the REM behavior symptom, usually with melatonin, clonazepam, at nighttime, to try and normalize the sleep cycle. The other big key that you want to ask about, is insight. And what you'll typically find is that early on, a person has insight into the hallucinations. They see a person that's not there, they know it's not real, and they're able to act on that. But as the disease progresses, as that dementia comes upon a person, that loss of insight really does affect a patient. That's where they need a lot of caregiving support. And a lot of patients with progressive psychosis, they end up in a nursing home, because it's too difficult to manage them. It's a symptom of advancing disease. Many patients with psychosis pass away, and it's largely because of the fact that the disease has progressed. Here's the medicines that I talked about, that we use. So cholinesterase inhibitors are very useful for cognitive fluctuations. They can be sometimes helpful for cognitive symptoms, and they can sometimes be helpful for visual hallucinations. We typically use medicines like donepezil, rivastigmine. There's different forms of PO versus dermal patch, or galantamine. There's a nice review of this, and it shows the evidence. But my main take home is that you have a lot of different options to try, especially if someone's having GI symptoms from donepezil. Galantamine has less GI symptoms, so if someone's having a bad response to rivastigmine, you can use the rivastigmine patch to reduce some of the GI symptoms. So there's a lot of options for you as you go through managing an advanced patient. The antipsychotics, I think, have been really emerging and evolving over the last 10 years. But really right now, the one we have is pimavanserin, which is an efficacious medication. It's a serotonin acting inverse agonist medication. It's dosed without titration and it's once a day. And it's shown to be efficacious and an acceptable risk, without specialized monitoring, as one would have with clozapine. But of course, not every patient fits nicely into a therapeutic box. And so we know that clozapine has been around for a long time. Generally, there are low doses of Clozapine that can help patients about from 6.25 to 13 milligrams per day. And there's been data that shows that giving clozapine to Parkinson's patients with psychosis can help a lot, and reduces some of the symptoms as defined in this seminal paper in 1999. Of course with clozapine, one has to use a monitoring of a pharmacopeia and such. And so it requires specialized nursing care in that process. Seroquel or quetiapine is another medicine that could be used. It's used especially at nighttime. It helps people with sleep problems. You typically dose around 25 to 50 milligrams a night. You can go to TID dosing. One of the more common issues we struggle with, is orthostatic hypotension, which is again, very common in advanced Parkinson's patients. So, be careful about this. It's generally well tolerated, easily to get to patients. And so we use that as well. I had mentioned pimavanserin, but I just want to make a little tip of the cap to some of the pivotal results from that study, which was really where they showed that in the response of pimavanserin, motor symptoms didn't get worse. And so it can potentially improve the cognitive symptoms without sacrificing the motor symptoms that we are so concerned about, especially with the dopamine medicines like olanzapine or especially haldol or risperdal. God forbid those ever get given to a Parkinson's patient, but it does happen, you've probably seen it. And I think, finally what I'll conclude with, is the concept of balance. And really, when I talk to my patients about these things, about maximizing their therapeutic benefit, and minimizing some of the troubling symptoms they have, I often use the analogy of Goldilocks and the Three Bears. We don't want it too hot, we don't want it too cold, we want it just right. And the same thing goes for cognitive and behavioral symptoms and motor symptoms. On the one hand, if you give a lot of dopamine medications, you can really cause symptoms like psychosis or hallucinations, which can be very troubling to patients. On the other hand, if you reduce their medicines and resolve those, you can have a patient that's very frustrated with off symptoms, and less on time, and worsening motor symptoms, and maybe more anxiety and apathy. So really partly what we're doing in these advanced Parkinson's patients, is a balancing act. We're trying to find balance for these motor and non-motor symptoms that are progressively troublesome, that cause clinical problems. And that's the joy of treating an advanced Parkinson's disease patient. So I thank you for your time. I hope you find that beneficial as a quick review. I'd be glad to answer any questions that you have, should you want to email me or contact me, or any of the faculty that are doing these talks. And I thank you for your time.