PADRECC NATIONAL VANTS AUDIO CONFERENCE Diagnosis and Treatment of Parkinson’s Disease Jeff Bronstein, M.D. PhD. July 9, 2009 So, if everybody will start with the slides and we will try and get through these in time, so that we have some time for questions at the end. So, if everybody turns to slide two, which is really the first content slide, it’s just a little review of the epidemiology of Parkinson’s Disease. I think many of you know that it is second to Alzheimer’s as the most common and there’s about a 1 in 50 to 100 lifetime risk for men in this county, that’s even without a family history of Parkinson’s. So, it’s common and many people are at risk of getting it. Most people get it over the age of sixty, though 10 – 20% will get it under the age of 50. So, young onset still contributes a really significant number of patients if you were to think about there’s a half a million to a million patients with Parkinson’s in the U.S. alone, that would mean that there could be 10, 000 – 20,000 people with Parkinson’s under the age of 50 or even more. So, it’s not just a disease of the elderly. Men get it almost twice as much as women for reasons that we don’t understand. Now, we don’t know the causes of Parkinson’s Disease, although you hear a lot about genetic causes. They are really helpful in trying to understand the underlying pathophysiology, but you have to remember that only about 5% of all Parkinson’s patients have a known genetic mutation that would pass it on in either a dominant or recessive manner. That means that most of them are going to be caused either by environmental influences or a mixture of genetic predisposition environmental influences. There’s lots of examples to believe that this is true. Now, within the VA population, estimates are somewhere between 40,000 – 70,000 Veterans suffer with Parkinson’s Disease now. So, it’s a significant problem for the VA population. Next slide. Now, it’s important whenever you first meet a patient in the clinic. You want to really make a diagnosis and Parkinson’s Disease is not the only thing that can cause the symptoms. So, Parkinsonism is the constellation of symptoms that we often see with Parkinson’s, but with a variety of other disorders and those are listed in the slide, which is tremor, rigidity, bradykinesia, things like slow movement, decreased facial expression, small handwriting. So, all these things that we all associate with Parkinson’s Disease, we really call Parkinsonism. Next slide. It’s a very short list, but th primary causes of Parkinsonism. Now, I like to think of them in two broad categories. Kind of primary degenerative diseases, things that we really don’t know the causes of and then secondary Parkinsonisms, things that injure the basil ganglion. It’s very important to try and distinguish what is the underlying cause of the Parkinsonism because it has implications, not only in treatment, but in prognosis. So, among the secondary causes, the most common is usually the first two vascular or neuroleptics. Vascular injures the basil ganglion through little small vessel strokes that often are insidious in onset. In other words, it’s not the sudden onset that we usually think about with strokes, but it’s a more slowly progressive course, which can imitate a primary degenerative process. There are characteristics, which I will mention in a minute that help you distinguish, but the diagnosis is usually made by MRI. Now, history of neuroleptic exposure or current neuroleptic use, including antiemetics, can imitate Parkinsonism as well. Obviously, the anti psychotics, such as Haldol and Risperdal and even some of the A Atypicals, can all cause Parkinsonism. The normal pressure hydrocephalus or the large ventricles can cause a Parkinsonism syndrome and again, imaging can help you make this diagnosis. There are clinical features that help distinguish it as well, but for time sake, I won’t go over those right now. Now, in the primary degenerative disorder shown in the top group of patients, obviously, Parkinson’s is the most common and somewhere about ten times more common than each of the other disorders. Multiple System Atrophy, which is a collection of subtypes is probably the next most common, but similar in frequency as progressive supranuclear palsy. Cortical basil ganglionic degeneration and diffuse Lewy body disease. Now these other three, often called Parkinson’s Plus because they have Parkinsonism, plus other features. If you look at the next slide, I tried to summarize at least some of the plusses to help you in broad strokes on how to separate these. Now, Multiple System Atrophy comes in three flavors. The audit dysautonomic type, what used to be called Shy-Grager, now we call it MSAA and that is early loss of autonomic function. Things like early loss of continence, urinary continence, orthostatic hypertension and things like that. Striatal nigral degeneration has a non response of Parkinsonism and often it will have some parameatal track signs and OPCA or MSAC will often, well, has to have cerebellar dysfunction. All of then will have early loss of postural instability. Progressive Super Nuclear Palsy, the plus is problems with eye movement. It is usually vertical gaze, paresis and slow saccade horizontally. Although, that doesn’t have to present with that. That can be a later feature it’s important to know. There are other features that we look for as well, such as expression of their face, axial rigidity and a few other things. Now, if somebody presents with Parkinsonism and has early cognitive problems, either preceding or within the first year of the Parkinson’s symptoms, they often have Diffused Lewy Body Disease and the plus in this would be the cognitive impairment early on. They often have early hallucinations, unrelated to medications. Finally in this list, cortical basil ganglionic degeneration, have a heavy dystonia and apraxia, which characterize that disease, though pathologically, most of those people actually have dementia and may not present in the typical fashion. But, in general, to clump all of these together to kind of separate Parkinson’s Disease from any of the Parkinson’s Plus, is the Parkinson’s Plus are usually not very Alodopa responsive and these people often have early loss of postural reflexes and in the MSA patients, 85% of pathologically proven MSA patients in any one of those three categories, will have urinary incontinence in the first two years, so that could be a clue as well. Next slide. Now, imaging can help us, more to rule out the secondary causes, things like normal pressure hydrocephalus or vascular disease, but there are some subtle signs, such as the one here that can help rule in or support the diagnosis of things like MSA for example. In this case, the arrows are pointing to either the higher, the dark signal in the striatum, thought to be iron or the high signal, the white rim around the striatum, shown in the bottom panels, E and F, and that white line is thought to refer to some overall atrophy of striatum and a little bit of gliosis. Now, these aren’t by any means diagnostic and if it’s not there, it doesn’t rule it out and if they are, it’s not 100% specific, but it can be helpful and there’s been a controversy of the utility of this in ruling in or ruling out MSA. But, they can be supportive and again, imaging is mostly to rule out structural causes. Now, if you look at the next slide, please mute if you haven’t muted your phone already, is F-dopa Pet Scan, which can look at the integrity of dopamine terminals that are in the striatum and this also can be supportive, but is not 100% diagnostic. What it will tell you is whether somebody has Parkinsonism or not and so, if you have a normal F-dopa Pet Scan, we can say you don’t have Parkinson’s Disease, but if it it’s abnormal, we can’t differentiate between the other causes, at least 100%. Now, in this slide, you can see on the right, B, that’s a typical patient with somebody with early Parkinson’s and you can see in the lower parts, the inferior parts of the butamine, especially in the left part of the figure or right brain, you can see decreased uptake, it’s less red and that is typical is that you can see the head of the caudate is actually fairly in tact, but the butamine is decreased and the right brain has less uptake than the right. So, it’s asymmetric in both the caudate, the butamine access, as well as left to right and that’s classic for idiopathic Parkinson’s. It’s much more symmetrical in most of the other Parkinson’s Plus disorders, but there’s enough overlap to make this not very diagnostic between the Parkinson’s Plus disorders. But, in some cases, it can be very useful in differentiating some subtle signs of Parkinsonism from Parkinson’s Disease. There are spec scans where the isotope binds to the dopamine transporter and that has very similar utilities as F-Dopa Pet, but that’s not FDA approved at this time. To summarize, if you look at the next slide, how I think of the easy algorithm to try to think about who actually has Parkinson’s Disease and who likely has something else. So, if they have the classic features of asymmetric onset, they are L-dopa responsive and they have a rest tremor and they don’t have any of the plusses that I talked about, things like cerebellar signs, dementia, early dysautonomia, then it is very likely, over a 90% chance, that they are going to have pathologically proven Parkinson’s Disease. If somebody presents with early falls, it’s almost never Parkinson’s. So, early falls is actually a red flag for this. Now, regarding treatment, there are a number of considerations, which I have outlined on the next slide. Next slide. Now, the first and probably the most important is the age of the patient. Young patients are invariably are going to have issues with motor fluctuations. We will be talking a little bit more in the future slides, but mainly we are referring to excessive, involuntarily movements or dyskinesia, after they take their medicines or a loss of effect over time of the medication. When I say over time, over hours and not over years of the disease. It is called wearing off. Young patients also are going to have the disease a long time, so if you have any medications that may be modifying disease course, we think a little bit long and hard about it in the younger patient, because a small effect, over 20 years is going to have a significant on their quality of life later on. Now, older patients have much higher incidents of cognitive problems and comorbidities and so some of the medications have a higher incidence of side effects and we may want to stay aware from them in the older patients because they are going to be more sensitive to this. Now, the level of disability is going to help determine what we are going to treat people with because you don’t necessarily have to treat non-disabling symptoms. In some cases, cause can be prohibitive and will help us decide which medications are needed, just because they just can’t afford it. Next slide. Now, this slide shows the American Academy of Neurology guidelines that was updated a few years ago. On the right side are the non-pharmacologic treatments and I think every patient with Parkinson’s should be educated on the prognosis and things to watch for with important stress on two things in my opinion. One is that the prognosis can still be very good and it’s not a terrible death sentence if they get the diagnosis and that just because you picture like the Pope of being very disabled, most people with Parkinson’s are actually doing quite well and can be very productive and have a high quality of life. So, just try to have a more positive attitude and realistic attitude is very important. Then, the value of exercise is really important and there’s multiple studies have shown that people who exercise do better and we actually think it may alter progression of the disease. So, those are very, very important. Now, when it comes to pharmacologic therapy, there’s a lot of controversy of whether you have the need to treat somebody, but I think there’s evidence gaining that it’s a good think to initiate therapy early. There’s some evidence that starting a MAO-B inhibitor and possibly other agents and we will go over this a little bit, do modify the disease course, but none of them have really been proven to be neuroprotective. The real decision is going to be of the main symptomatic therapies or whether we start with a dopamine agonist or whether we start with levodopa therapy. Next slide. The first drug that most of us consider when initiating therapy, when we have just diagnosed, is a MOA-B inhibitor. Selegiline and Rasagiline are the two that are available. Now, both of them have very small, but detectable symptomatic benefits. In other words, the patient may feel that the symptoms are a little bit better after taking them, but many patients won’t notice a difference. There is some evidence for both of them that it may have disease modification. Now Selegiline has been around for over 15 years and there’s a lot of data supporting that it may modify disease, but none of it has been definitive because of this confound of the symptomatic benefit. Now, it’s not a big fact for either Selegiline or Rasagiline, but there does appear to be a disease modifying effect. With Rasagiline, it’s a newer agent and they have better study design and that has been supportive of disease modification. Though, again, it’s not proof and we are not even sure it’s specific to a MAO-B inhibitor. It may be, starting anything is better than starting nothing and I will review some of that as well. Now, in addition to the use early on, we also can use a MAO-B for motor fluctuations, especially Rasagiline has been useful for wearing off, which I will mention a little bit later. Next slide. This is the results of the first delayed start study with Rasagiline called the Temp Trial and what it shows is that people that were started on Rasagiline did better than if they were started on placebo. So, the way this study worked was half of the patients were started in a double blinded manner on placebo and half on Rasagiline and then after six months, everybody was then put on Rasagiline and then people were evaluated in one year and the idea here is that if it’s all due to symptomatic benefit, then the people after a year, should all be the same since they are all on the symptomatic therapy for the past six months. If it’s disease modifying, the people that have been on Rasagiline for a whole year would do better because they had an extra six months of disease modification. In fact, that’s what the data suggested that people that have been on one or two milligrams a year were better off than the people that were only on the Rasagiline for six months and there was a much bigger study called Adagio, which ended recently and it hasn’t been published, but the results have been released showing very, very similar effects, especially with one milligram, which is now the current recommended dose. So, there’s some evidence that starting Rasagiline and probably Selegiline is people do better if you start that versus nothing. To move on to our most effective therapy, which is Levodopa, we know a lot about this. It’s been around for over 30 years now. It by far, help the Parkinson’s symptoms the most and better than any other therapy and actually, has very few side effects. The most important side effect is the long-term risk of motor fluctuations or the dyskinesias. They cycling that Michael J. Fox has, it’s a great example of that. And again, the younger patients are at higher risk. Now many of us believe that motor fluctuations come from, it’s very potent effect and it’s short half-life and it doesn’t stay in the blood stream very long, only about 90 minutes is the half-life, but the actions can be a little bit longer. There’s also an effect of protein on it’s absorption since Levodopa is a neutral amino acid, it’s dependent on the neutral amino acid transporter to help the absorption and therefore, if you eat protein at the same time you take the medication, it actually significantly reduces absorption. Next slide. This is the results of a study published in the New England Journal that was done by the Parkinson’s Study Group headed by Stan Fawn, which was called the L-Dopa Trial. Early versus late Levodopa and the idea of this trial was to determine whether starting Levodopa made the disease progress faster. So, people were randomized to one of four treatments, placebo, low, medium or higher dose Levodopa. They were followed for 40 weeks and then the drug was washed out for two weeks to get all of the effects. So, if Levodopa were to make the disease progress faster, the people that were on the 600-milligram, the high dose group, you would think would be much worse off than the placebo group. In fact, they found the exact opposite. After the washout, people on the 600 were still better off than placebo and you can see from this slide that the 300 and 150 groups were intermediate. So, there was a dose response. Some of the patients were actually washed out longer and this effect held up. So, we can definitely say it didn’t make the disease progress faster, but whether it’s truly disease modification is still unclear. And that’s especially in light of the fact that PET Scans actually seem to be a little worse with the Levodopa group, but this is very difficult to really resolve because of some likely effects of the Levodopa on the scanning parameters themselves. Now, the 600 milligram group did start developing motor fluctuations and so, it did confirm what we already know is that Levodopa therapy, especially when you use higher doses can cause motor fluctuations, which is clearly the main negative of Levodopa. Now, in the next slide, you can see what is the protein effect and this is an old slide, but really demonstrates this fact really well. This is from a patient and if you give an oral dose of 125 milligrams of Levodopa with a glass of water, you get a nice peak of serum Levodopa after about a half hour and that is shown in the black lines there in circles. Now, if you give the same amount of Levodopa, but with some milk, you can see that very little gets absorbed and if it does, it’s over a very prolonged period of time. This protein effect can be very important for more brittle patients later on, but it can explain loss of effect or dose failures that we see in patients quite often. So, the medicine just doesn’t get absorbed. So, most of us can get around this by just having patients take their Levodopa 45 minutes to an hour before meals. Occasionally, later on, we will have people that are really sensitive to this effect, minimize protein during the day to minimize this effect. But, early on in the disease you rarely have to resort to that. Now, in the next slide it summarizes dopamine agonists and these include Pramipexole and Ropinirole , which are the two most commonly used. They are not quite as efficacious as Levodopa, but are clearly more efficacious than the MAO-B inhibitors in relieving the symptoms. They do have long half lives and starting with an agonist, clearly delays the onset of dyskinesias an motor fluctuations and I will review some of the data in a minute. Absorption doesn’t depend on the transporter, so food doesn’t affect it. We can actually use them in different ways in alternate routes. We have an injectable agonist called apomorphine and we also have a transdermal Rotigotine, which was temporarily removed from the market, but should be coming back shortly. Now the side effects are the real problem with the dopamine agonists, including, I think most people know about the most common, which is sedation, but the one that I stress the most and I think is the most damaging are the impulse control disorders and these are the compulsive gambling, sexual compulsions, eating, shopping, internet. There’s a number of them that appear to be a much higher risk in dopamine agonists and have been estimated to be 15% of everybody on agonist or even more and these can be really insidious in onset. People can be on these drugs for five years and start having these problems. You need to counsel patients when you initiate them, you need to counsel their spouses and you need to question them over and over and over again for these. Now, the other side effects include hallucinations, nausea, apedalademia. So, those are the pros and cons. If you look at the next slide, this is from the study with Pramipexole, called CALM PD and you can see that patients that are on Pramipexole tend not to be treated as the effect is not as pronounced as with Levodopa, even though they have the ability to add additional Levodopa and this is true with Ropinirole as well. If you look at the next slide, this is a similar study with Ropinirole, where people were started and initiated with Ropinirole versus Levodopa. If you look at the top right corner, you can see by the red line, those are the Ropinirole people and almost nobody had motor fluctuations. About half of the patients who started on Levodopa had them at five years. Now, even the people that needed additional Levodopa on top of the Ropinirole, there motor fluctuations at five years were markedly lower. That’s in the bottom right corner. Only about 20% of the people at five years had fluctuations. So, there’s no doubt that starting with a dopamine agonist as compared to Levodopa dramatically reduces motor fluctuations. On the left, it’s a very similar study that was done in non-human primates and monkeys and so these results were actually predicted perfectly by these non-human primate studies. So, the main advantage of the dopamine agonist is that it lowers the risk of motor fluctuations. And for this reason, we tend to start younger patients, who are at the highest risk, we tend to start younger patients on dopamine agonists. If you look at the next slide, it kind of summarizes how I approach initiating. If people are not disabled at the right, I always educate them, get them to exercise if possible and will often start a MAO-B inhibitor. Either Rasagiline or Selegiline and I think you can make an argument for either one. Now, if they are disabled from their symptoms and despite being on a MAO-B, the young people I tend to start on an agonist and the older people I usually start on Levodopa therapy and older can be anywhere from 65 and above and I think given the side effect profile that’s emerging with the agonists that we are even moving a little bit younger with starting with Levodopa and many people will start with Levodopa even in the younger people now because of the problems with the agonist. I just watch for the side effects very carefully and so I don’t like to withhold therapy that may really help a young person delay fluctuations, just because there’s a 30% chance of them having a side effect. That means you are withholding them from 70%. It just means it is going to be a little more work for you and you need to be more vigilant. Now, I tend to like controlled release to start or the extended release of Levodopa formulations. There’s arguments for and against that, versus immediate release, though the studies using Stalevo or Entacapone suggest that it’s not advantageous to start with Stalevo. So, either immediate release or controlled release and if they don’t respond well, definitely try immediate release, which is absorbed a little bit better than in the controlled release and then we might even question the diagnosis because they may not be dopa responsive. That’s important to remember that tremor doesn’t always respond to Levodopa or dopamine agonist and so if tremor is the only symptom and doesn’t respond, it doesn’t mean that they don’t have Parkinson’s, it just means they have a resistant tremor and those patients if they are young especially, may try anticholinergic drug. Now, in more advanced patients, we have a lot of problems that can emerge. Next slide. We have both problems with motor fluctuations and then we have problems that are either, I wrote, non-motor problems, but I should say non-dopa responsive problems because some of these problems, such as postural instability are actually motor, but they are non-responsive to therapy and those tend to be later in the disease, although things like depression can be earlier as well. Now, the motor fluctuations are usually a bigger problem with the young and again, they include wearing off dyskinesias and going from the medicines working well, the on state to medicines turning off suddenly, called the off state. That’s the on/off phenomenon. Medication induced psychosis, along with cognitive decline are common in the older patients that have had the disease for a while, but also loss of postural reflexes or postural instability can be common after people have had the disease for a number of years and are older. Same thing with urinary frequency urgency and incontinence and problems with sleep. If you look at the next slide, I summarized the different approaches that we all use to try to minimize the motor fluctuations and the concepts basically are to use smaller, more frequent dosing, not necessarily lower doses, but at least more frequent. If you are on CR alone and adding regular, reducing the controlled release formulation can help because the controlled release formulation by itself is actually very difficult to use when people are fluctuating. Sometimes, being just on immediate release is helpful, but I find sometimes a combination of the two will minimize wearing off and not cause too many dyskinesias. Clearing, adding a COMPT inhibitor, such as entacapone or tolcapone can really help with the wearing off, as can adding Rasagiline. I haven’t been very impressed with the sub-lingual Selegiline for wearing off and I personally prefer Rasagiline as an MAO-B inhibitor. Studies have shown that it’s about equivalent to the COMPT inhibitor, such as entacapone and it’s ability to wearing off. Now, sometimes, those things will induce dyskinesias and you can try lowering the Levodopa dose, but sometimes, especially with Rasagiline, you will have to get rid of that if you can’t control the dyskinesias. We can tend to use amantadine to help control the dyskinesias and that’s the only drug by itself that actually will reduce dyskinesias without worsening on time. It helps in a little more than half of the patients. Finally, we also use dopamine agonists, especially for wearing off and that can be useful and as you add it on, remember that you may have to reduce Levodopa doses to reduce dyskinesias. Now, deep brain stimulation is very effective for motor fluctuation, if all else fails, and in fact, that’s what surgery treats are motor fluctuations and nothing more, except for tremor, that can be resistant to therapy. So, that’s all I am going to talk about deep brain therapy today, deep brain stimulation, because of time. Now, if you look at the next slide, it just reviews the biochemistry of the caracal methylase trans phrase inhibitors or the COMPT inhibitors, such as entacapone and tolcapone, but they primarily work by altering Levodopa kinetics in the serum. Now, tolcapone can act centrally as well. Most people don’t use it. So, if you look at the next slide, you could see what it does, is it doesn’t increase the peak of Levodopa concentrations in the serum, but it does increase the half life, which is shown in blue and in fact, will double the half life to about 190 minutes from 90 minutes. Next slide. I have reviewed the next problem that we will summarize, which can be hallucinations and these are really a spectrum of paranoia, nightmares, visual hallucinations, which can be either with insight or without insight. It’s really, really important to address these and ask those questions and treat them immediately, because they can be quite disastrous. If not at the present time because they have insight, eventually, within two years, almost everybody will have severe problems. It’s important to know that hallucinations usually occur in the more cognitively impaired people or as cognitive impairment starts. So, drugs that normally didn’t cause hallucinations for years, may start causing them as somebody has cognitive problems. So, the first thing o do is try to get rid of any drug that is not really helping the Parkinson’s that much and may be contributing. Those include things like Selegiline, anticholinergics and Amantadine . Next, we lower the dopaminergic agents, especially the dopamine agonists and then finally, if you can’t lower the Levodopa anymore without causing severe motor problems, then we add an atypical neuroleptic and the only two that I will use are Quetiapine or Clozapine. Clozapine is the best and the best data supports it, but because of the need for frequent blood draws, we tend to start with Quetiapine first with a nightly dose. Cholinesterase inhibitors can sometimes help with hallucinations as well. The ones that have been best studies have been the Exelon, especially the patch, which is actually tolerated better, but Aricept likely works as well. Falls are a real problem and the real cause, in addition to cognitive problems and hallucinations, falls and injuries from falls are one of the leading things that lead to nursing home placement and mortality and morbidity. So, it’s really important to first try to identify why people fall. Now, some people because the medicines wear off and they freeze. Their feet get stuck and those people tend to fall forward. If they bruises on their face, it’s often from freezing. And, that can be improved, by improving their off time by optimizing their dopaminergic medications. Now, some people fall because they get orthostatic. Their blood pressure drops, they get lightheaded and they fall down and that’s usually determined by history and also by checking their blood pressure, both sitting and standing. If that’s the case, obviously, you want to treat the orthostatic hypotension and that will usually solve the problem. Unfortunately, some people will be falling because they lose their postural reflexes, no matter if the meds are working, if they are on or if they are off, you give them a little tug from behind and they tip over. Those people tend to fall backwards and the best way to treat them is by having physical therapy and rehab services work with them and using a walker and usually a four-wheeled walker is the most useful, often with a seat, so that they don’t have to try and carry things around. It makes it a lot easier for them. It’s hard to get people to use them, but it does actually help with independence. So, it’s important to emphasize this. We always screen for falls on every visit, as well as hallucinations. Next slide. Now, depression can be really common, not only in later disease, but actually early in the disease, it can be the presenting symptom. So, it’s really important to screen for depression as well. Anxiety is a very common part of this syndrome, a high anxiety type of depression and it’s thought to be due to not only loss of dopaminergic neurons, but serotonergic neurons and other monoamine neurons are also affected in Parkinson’s Disease. Now, there’s no great data to support one versus the other. In fact, the most recent study supported the use of tricyclic antidepressants, that was nortriptyline versus Paxil CR. Although, I think most of us still find that the SSRI’s tend to be tolerated better and work quite well for the anxiety and the depression, without worsening the Parkinsonism in most patients, so rarely will it worsen tremor, but usually it doesn’t. Some of the mixed uptake inhibitors like Effexor or Cymbalta are useful and in people that don’t have a lot of anxiety, Wellbutrin can be a good drug, because it doesn’t have the sexual side effects that the SSRI’s have. There may be a use for Tricyclics and some people still might even promote them as a first line. I am not quite there yet. I do continue to try, but I haven’t had as much luck with them as in the one recent published study. Now, cognitive decline is really important to identify and screen for as well. The first thing to do is not just assume it’s due to the Parkinson’s Disease because people can get B12 deficiency, they can get strokes, they can have other causes. So, I think people, I think it’s important to rule out metabolic and other treatable forms of the problems that may be causing cognitive decline. Now, once you have done that or treated them and they still have cognitive problems, we tend to reduce medications in general. Especially, things like the anticholinergics, some of the obvious things. All of the ones that I mentioned for hallucinations are really appropriate here as well. Most people with hallucinations start getting some cognitive problems and it’s the combination of the medication and the cognitive decline that seem to cause hallucinations. Now, once you have done that, there is evidence that cholinesterase inhibitors can help cognitive problems in Parkinson’s Disease and the best study has been again, the Exelon patch and whether the other cholinesterase inhibitors work as well or not is not certain, but that at least has been studied and shown some benefit. Though, it’s not always apparent clinically. There’s less data on memantine or Namenda, but there’s a few smaller studies that have suggested that in some patients that this can be useful as well. In my experience, it can be useful, especially in kind of apathetic sort of patients, but you have to be careful, some people get agitated, it’s worsened hallucinations in a few people, so you do need to be careful, but it’s worth trying in some people. Finally, sleep problems, which are in the next slide or insomnia in particular. First thing is to screen for sleep hygiene. People have terrible sleep habits and then if they are taking long naps during the day or they are drinking a lot of caffeine late at night or a lot of liquids, that definitely can interfere with people’s ability to sleep. So, it’s important to review sleep hygiene. Now, some people have problems falling asleep at night or waking up at night because they are stiff and rigid and they can’t turn over or they get a restless leg sort of feeling and that can be often relatively easily treated with a nighttime dose of Levodopa, often in the controlled release formulation. So, optimizing dopamine therapy in the evening can often help. Now, some patients are depressed and that’s why they can’t sleep, so you need to treat depression. Some people have sleep apnea, which causes them to wake up or REM sleep behavior and those need to be evaluated. So, you may want to send them for a sleep study if they snore or have pauses or have a lot of activity at night in sleep and those should be treated appropriately. Now, when you do all those things and you have them exercise, optimize everything and they are still having problems sleeping, it’s important to determine whether it’s a problem with falling asleep or staying asleep. Falling asleep is relatively easy using a short action, selective benzodiazepines such as Ambien or Sonata or the melatonin agent, Rozerem. They can be helpful in people falling asleep and don’t interfere with sleep architecture significantly. So, they are pretty good for that. For people who have problems staying asleep, some of the longer acting ones like Lunesta or Ambien CR are actually quite good in helping with sleep maintenance without causing a marked, disorganization of sleep architecture. Trazodone or nortriptyline, the tricyclic antidepressants can be helpful for sleep maintenance and sometimes the antidepressant Remeron and occasionally Benadryl, although many geriatricians, don’t like using Benadryl, but occasionally and cognitively intact people it can be useful. The fact that it’s non-prescription, people seem to like that. The last slide kind of summarizes all that we can do. Motor fluctuations are really quite treatable, you just need to work with the patient and get good histories and have them keep diaries, but they are really quite treatable, both medically and if all else fails, surgically. People don’t screen for non-motor problems, but they are actually very, very important and lead to most of the long-term disability. So, screening for depression, screening for falls, screening for psychosis, things like that are extremely important to do that. Then, if you have problems, we have a National Parkinson’s Disease Consortium, a National VA Consortium, which is a group of Movement Disorder Specialists or Neurologists that have an interest in Parkinson’s patients and they can help you manage the difficult patients and ultimately, if you can’t get the answers by phone or by email, you can make a referral and obviously, we would be happy to see them. I put the website up there on the slide and if you look at the next slide, it’s the map of where we are right now and if anybody wants to help join the Consortium, you can contact me or Becky Martinez at the University of Pennsylvania, the Philadelphia VA and we can help you get on board. At this point, I think we have a few minutes for questions. Is that true Virginia? Yes, thank you for a very helpful presentation. If you have questions, please introduce yourself and tell us where you are from. I actually have a question. I am not a neurologist. I’m an RESPONDENT IS UNINTELLIGBLE medicine physician. I was wondering at your facility do you have a team you use after you use PET to differentiate Parkinson’s Disease versus atypical RESPONDENT IS UNINTELLIGBLE. So, it’s F-Dopa PET, not FDG. FDG is normal in Parkinson’s or there’s some subtle things. So, at the VA, we don’t have routine F-Dopa PET’s right now. At UCLA, we do use it on occasion, but it really doesn’t help you differentiate between atypical Parkinsonism and Parkinson’s Disease. There are differences, but there’s enough overlap. It’s by symmetry and caudate and so in normal, in Parkinson’s, you tend to spare the caudate relative to the butamin and that’s not true, say in MSA. There also seems to be asymmetry from left to right that’s more prominent in Parkinson’s than MSA or PSP, but it’s not enough to help differentiate. If you are struggling clinically to differentiate them, you are going to struggle with the scan. Now, where it can be helpful is somebody that presents, say with a mixed tremor and has a big of a postural tremor and maybe a slight rest component and so that can be helpful in differentiating if it is abnormal F-Dopa, then it’s going to be Parkinson’s Disease in probably a tremor dominate form. Some people have a slight amount of rigidity or a tiny bit of tremor and you can’t determine whether it’s Parkinson’s or not or even psychogenic in some cases and an abnormal F-Dopa PET scan will tell you that there’s definitely Parkinsonism and done at the right center, a normal PET scan, in my opinion, means you don’t have Parkinson’s Disease. You mean a normal PET scan with FDG or with F-Dopa? F-Dopa. Now, the FDG can be helpful for things like cortical basil ganglionic degeneration, where you can see some cortical problems. In MSA, you don’t have cortical problems, so it’s normal in those and I can tell you, most people notoriously bad at measuring metabolism in the sub-cortical region. So, it can be done in research centers, but the average scan doesn’t help you. Then, PSP can have some frontal abnormalities that can be helpful. The FDG kind of helps you more rule in some of these other things, but the diagnostic accuracy is not a whole lot better as a group than clinical. They can be adjunct, but they are usually not that helpful. What about dopamine transporter scans? So, the dopamine transporter scans done by SPEC are not FDA approved, so they are not routinely available, but they are just, you can pretty much, everything I said about F-Dopa is pretty much true with the things like beta Sid scanning. There’s subtle differences. It seems like there’s less up regulation of the dopamine transporter early on, so in the early, when somebody is just diagnosed, there’s about a 30% decrease in butaminal uptake in Parkinson’s at the earliest uptake onset, where there’s about 50% of DAT. Now, with time, they equal out, so there seems to be more compensation with the transporter and MODERATOR IS UNINTELLIGBLE and neuros for DAT, but overall, the diagnostic accuracy, the patterns are all almost identical between DAT SPEC and F-Dopa PET. The resolution is better for PET, but that’s about it. Thank you. Any other questions? Hi, this is Lynn ?? from Richmond. Just a comment. Thank you so much, Jeff, for this wonderful talk. I think it was put together so nicely. I want to apologize for the group this afternoon and all of the noise and open mike. There’s just some kinks that have to be worked, VANTS and EES can’t seem to help us with this. I don’t know what the answer is, but I want to apologize and thank you for your patience and the great talk. Thanks for inviting me. It is, it’s very disrupting for everybody and so, if anybody is still listening, if you can try to remember to mute your phones and not put on hold, because it does really disrupt these calls. We have this on all our VANTS calls, so it’s MODERATOR IS UNINTELLIGBLE. Yes, people try to multi-task. Yes. That’s why God gave us mute buttons. We are running out of time, so thank you again Dr. Bronstein and thank you everyone for joining us today and for your interest in movement disorders. So, join us for the next session, Caregiving and Psychosocial Issues in Parkinson’s Disease on September 10, same time, same station and do complete the registration and valuation forms by July 23rd to get credit. There are two Scantron forms to complete, registration form and faculty evaluation and then send them to your satellite coordinator or the EES Center in Birmingham. Thank you again for joining us today and we will see you next time. Thanks Virginia. Bye bye. END OF CONFERENCE. PADRECC National Vants Audio Conference Diagnosis and Treatment of Parkinson’s Disease Jeff Bronstein, M.D. July 9, 2009 Page 14