NIH CLINICAL CENTER GRAND ROUNDS
Episode 2009-024
Time: 57:11
Recorded December 9, 2009
Contemporary Clinical Medicine: Great Teachers
Treatment of Parkinson's Disease Joseph Jankovic, MD Professor of Neurology and Distinguished Chair in Movement Disorders Director, Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology Baylor College of Medicine
ANNOUNCER: Discussing Outstanding Science of the Past, Present and Future – this is NIH Clinical Center Grand Rounds.
(Music establishes, goes under VO)
ANNOUNCER: Greetings and welcome to NIH Clinical Center Grand Rounds. We have a special "Contemporary Clinical Medicine, Great Teachers" lecture for today's podcast, recorded December 9th, 2009. The topic, "Treatment of Parkinson's Disease". Our speaker is Dr. Joseph Jankovic, Professor of Neurology and Distinguished Chair in Movement Disorders, Director, Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine.
We take you to the Lippsett Ampitheater for today's presentation.
JANKOVIC: Thank you, Jeff for the generous introduction. I'm delighted to be here. Education always has been one of my primary missions to be recognized as a great teacher is a great honor for me. I appreciate the invitation. Thank you very much.
The topic that I was asked to cover is treatment of Parkinson's disease and we could spend days or weeks on this topic so I'm going to paint broad brush strokes just to sort of bring you up to date as to where we are with respect to treatment of Parkinson's disease. I'll start with clinical observations and talk more about the clinical trials and then conclude with hopefully helpful guidelines to the clinicians in the audience when -- they can use as they approach patients with Parkinson's disease. In way of disclosure, I'm a consultant for some companies, and organizations and foundations. The only drug that I may mention and which I potentially could have a confident interest is TAXOL and IPX o 66 I consult for those companies. I may mention (indiscernible) toxin and also I probably will say something about acetylene which has received attention recently. This is my disclosure. If any of you would like to make a contribution to my center and would like to be listed here I'll be or than happy to list you here.
So these are the objectives to describe clinical features and progression of Parkinson's disease. I would review some of the clinical trials that are relevant to the treatment of Parkinson's disease in terms of medical and surgical approaches and want to then conclude with guidelines that I find useful when I approach patients with Parkinson's disease.
I always start with a slide which is a slide I'm very proud of that is one of my photography colleagues that I think illustrates very nicely the typical features of Parkinson's. The shuffling gate, those are features that James Parkinson first described on his essay in 1817. There are virtually hundreds of symptoms and signs of Parkinson's disease that are not obviously illustrated here but a cardinal sign of Parkinson can be grouped under just the acronym trap, tremor, rest tremor, frequency tremor, rigidity, increased muscle tone, akinesia, bradykinesia and postural instability because of the disease, and causes difficulty with mobility and falls.
The brunt of the pathology in Parkinson's disease is mainly in the brain stem, especially in the substantia nigra. In the left you see the normal nigra with a highly pigmented area of the mid brain and Parkinson disease is a result of these dopaminergic neurons, there's a pigmentation of the substantia nigra. So it provides input to the striatum and as a result of this degeneration there's a denervation of the striatum. And as a result there's a denervation illustrated by decreased terminals in the striatum. Histologically one can see Lewy bodies the histological hallmark of Parkinson's disease which is a cytoplasm inclusion body that stains with HME ubiquitin and variety of other antibodies.
Now, until quite recently what I just told you was often a typical clinical and pathological substrate for Parkinson disease. Over the last few years it has been increasingly recognized that also non-motor symptoms of Parkinson which in many ways can be more disabling than the classic symptoms. These include cognitive and behavioral changes, olfactory deficit, pain, I submit to you one of the earliest symptoms of Parkinson's disease is shoulder pain. We don't exactly understand why shoulder pain is the presenting symptom in so many patients of Parkinson but one of the sensory phenomena that is seen. Sleep disorders may precede motor symptoms by several years or decades particularly around behavioral disorder where patients act out their dreams during sleep. Autonomic dysfunction, hypotension, constipation, erectile dysfunction and other symptoms that are typically associated with Parkinson disease. Olfactory deficit, RDD depression anxiety and insomnia and erectile dysfunction are some features not only associated with it but may precede onset of motor symptoms by several years.
Now, we could spend a great deal of time discussing the current hypothesis about pathogenesis of Parkinson disease but I will summarize a huge body of scientific knowledge in this slide. I apologize to the basic scientists in the audience for being short on the basic science of Parkinson disease but focus of my talk is on treatment so I wanted to summarize it very quickly.
There are basically two theories, one is that Parkinson disease results from mutation of certain genes that code for certain proteins that are important in the development and maintenance of the nigra striatal system and there are environmental hypotheses that are also important. Among the genes that have identified cause of Parkinson's disease in alpha synuclein, parkin, DJ pink 1 ECHL 1. These are genes in which mutations are clearly associated with Parkinson's disease. I can tell you that only about 10% of all patients with Parkinson's disease have an identifiable genetic mutation. Now, that is not true for the young Parkinson for young onset Parkinson in which the symptoms start before the age of 40, about 40 to 50% of those patients have a Parkinson mutation. So that is the most common cause of young onset Parkinson. Then there are susceptibility genes such as (…) which is a gene important also identified as a susceptibility gene in patients with Parkinson's disease. And we're very interested in a gene called NER-1 gene which codes for tropic factor that is important in the development and maintenance of the dopaminergic system. I'll come back to that later.
There are a number of environmental factors that we feel are playing an important role including rural living well water pesticide, exposure to pesticides and things associated with Parkinson in humans and animals. There's a number of other toxins that have been identified as potential cause of Parkinsonism in humans and animals the most commonly used toxin is MPTP first identified in San Francisco Bay Area among heroin addicts as cause of Parkinsonism in these young drug addicts. These various factors result in a number of changes that occur in the brain including excite toxicity, mitochondrial dysfunction, increased oxidative stress, there is a growing evidence that in Parkinson's disease there's protosomal dysfunction. As a result of these changes there's protein abrogation which results in cell death and eventually apoptosis that involves not only the substantia nigra and other neurons but other nuclei. What I did is a great deal of injustice to a larger body of knowledge but hopefully will summarize where our thinking is about the pathogenesis of Parkinson disease.
One of the questions frequently asked, when does Parkinson really start? A number of clinical imaging studies and pathological studies have suggested neuronal degeneration of substantia nigra starts 6 to 7 years prior to on sets of symptoms. This may or may not be true actually. There's growing evidence that Parkinson's disease may start even before the individual is born. And this illustrates hypothesis that we proposed just last year where we suggested there might be a new beginning for Parkinson's disease. There are a number of various factors involved in the development and maintenance of dope my dopaminergic system including NER-1 and PITX-3 and we partially -- postulated that alteration in these genes may result in abnormality of the protein product that may result in mild development of the dopaminergic system so there are some individuals that may start with fewer than 100% dopaminergic neurons and if they start with 80% of dopaminergic neurons as a result of age-related attrition they may reach the threshold of 60% loss of dopaminergic neurons where Parkinson's develops. This is a hypothesis we're currently pursuing in our lab.
With respect to the environmental factors, as I said, a number of toxins that have been identified, this is from a paper just published where we studied 419 cases and 411 controls. And did extremely detailed analysis of their exposure to a variety of toxins and occupations. And found that there's a threefold increase in the risk of the disease among people who have been exposed to certain toxins including 24D, it is of interest that PERQUAD has an almost identical to MTPT that I mentioned earlier. On the other hand there are some factors that appear to be protective against Parkinson's disease including tobacco and caffeine, demonstrated by a number of other studies as well. Clearly smoking and caffeine appear to be protective for Parkinson. I'm not suggesting to you that you should start smoking or drinking more coffee. But that is just based on various epidemiological studies. Another potential neuroprotective factor is exercise. And of all the different studies that have been done I think exercise provides the most robust protection against Parkinson's disease epidemiological studies and recent studies in animal models suggesting it may enhance neural plasticity in the basal ganglia.
One question being asked by researchers is how we identify population that is at risk for developing Parkinson disease? What are some of the biomarkers that will help us identify those individuals because those individuals will potentially be targeted for neuroprotective therapy if we develop neuroprotective therapy. I'll talk about that in a moment. We talk about gene mutations and susceptibility genes, I actually happen to believe that essential tremor might be a risk factor for Parkinson disease and we have evidence to suggestion that people with essential tremor, much higher risk for developing Parkinson disease later in life than individual whose done have essential tremor. We talk about the various non-motor features that precede onset of Parkinson and serve as biomarker for onset of Parkinson. There's a recent paper that show that people with red and blonde hair have increased risk for Parkinson. That's good news to me. Slow reaction time is potential risk. There's evidence that people with low uric acid have increased risk for Parkinson disease, there's studies underway seeing increasing acid might protect patients from Parkinson disease. Low LDL, we talked about the NER-1 gene and found this is -- this gene is not expressed as well in the peripheral lymphocytes in patients with Parkinson's disease as normal controls. There are many, many studies trying to identify certain proteins that may increase the risk for Parkinson, maybe associated with increased risk for Parkinson. There are many imaging studies that suggest that there are some markers of -- in the brain that suggestion for example some early atrophy of the substantia nigra, other functional imaging studies that may indicate that sort of individuals might be at risk for Parkinson disease.
So again, I want to focus on therapies. So I just wanted very quickly review the natural history of the disease because it's important to understand the natural history in order to understand the therapy of the disease. We talked about genetic environmental interaction, certain individuals to the loss of neurons in the substantia nigra as well as outside including cortical brain stem and olfactory neurons. The patient developed symptoms usually in the form of tremor. They are often treated with dopamine replacement such as levodopa and they experience a honeymoon period during which the symptoms may be completely controlled. That period may last from 3 to 20 years but eventually most patients begin to experience problems just like any honeymoon, sometimes things develop. In the Parkinson patients the things that develop usually are motor complications from levodopa therapy. In our Parkinson clinic we don't treat Parkinson disease we deal with complications such as motor complications and dyskinesia. I will spend most of the presentation how to prevent and deal with these complications. Eventually many patients develop non-dopaminergic symptoms that do not respond to the therapy and they become more disabling symptoms and advanced stages of disease and eventually succumb to death. Eventually we have to recognize Parkinson disease is not a single entity but different entities and that there's a great deal of interest among Parkinsonologists about identifying different subtypes of Parkinson's disease. This briefly summarizes our thinking about it. Within Parkinson disease already like 25 years ago we identified at least two major subtypes, the main subtype is a tremor dominant form of Parkinson which obviously the main symptom is tremor, the most disabling symptom. There's evidence there's overlap between the tremor from Parkinson disease and essential tremor. Another subtype of Parkinson disease is the partial instability gait difficulty PIGD form of Parkinson from the major problem is with -- the patients tend to develop gait and balance difficulties early and fall early. They are the ones who tend to progress more rapidly and more likely to develop dementia in a more advanced stage of the disease. These are just two major subtypes within Parkinson's disease but in addition to Parkinson disease there are many, many parkinsonian disorders that I won't have time to talk about that neurologist needs to think about when they are faced with a patient who has Parkinson symptoms one has to think about certain drugs including dopamine ventor blocking drugs the antipsychotics and a variety of other causes that we done have time to discuss including vascular problems. Multi-infarct is probably one of the biggest causes of Parkinson other than Parkinson disease. There's a group of diseases called multiple system degeneration such as multiple atrophy, progressive cerebral palsy where patients have trouble looking up and degeneration manifested by ataxia and Parkinsonian disorders that don't fulfill the criteria for Parkinson disease. So one of the best studies looking at long term progression of Parkinson is a study from Sidney where 136 individuals were enrolled and followed up -- enrolled and followed up to 22 years. They found after this long term follow-up almost all patients had some difficulties with levodopa, dyskinesia, falls, dementia, freezing, hallucinations, dysautonomia and other symptoms those are the problems Parkinson patients face at the end of the cause of the disease. And unfortunately those are the kind of symptoms that usually do not respond to levodopa.
Let me start with the goals are and the patients of Parkinson disease. We want to develop neuroprotective or disease modifying therapy and eel say a few words about that. We would like to improve the treatment of motor neuron motor symptoms of course. We would like to prevent and treat levodopa complications. We would like to develop safe and effective surgical treatments, reverse the pathology of Parkinson, that is the reason for many studies looking at tropic factors cell grafts, stem cells, those are strategies that are being investigated in that regard. We would like to find a cause of Parkinson disease to design pathogenesis targeted therapy and cure and prevent the disease all together. We are not there yet. But I'm hopeful that we'll be there sometime maybe in -- during our lifetime.
Whatever I'm going say I should emphasize really a general outline about the therapeutic approach to Parkinson disease, there are many exceptions to whatever I'm going say and therapy always has to be individualized depending on needs of individual patients let's start with pharmacology, pharmacologic approach to Parkinson disease. As you know we cannot get dopamine though that's the definition neurotransmitter of Parkinson brain because it does not cross the blood brain barrier. We use L-dopa to cross the blood brain barrier. It's metabolized by carbidopa (…), by methyl transfer ration and we can block the peripheral metabolism of levodopa by using enzymes such as carbidopa, these are the two CMD inhibitors that are currently being used. Centrally dopamine's metabolized into HVA by (…) or by methyl transferase. There are drugs that block central metabolism of dopamine including inhibitors such as rasagiline and (indiscernible) is the main CMD inhibitor that acts peripherally and centrally. We can bypass the dopamine synthesizing step all together by using dopamine agonists which stimulate the post synaptic dopamine receptors directly.
I'm going start with drugs that we tend to use in the early stages of the disease and as the disease progresses I'm going to introduce the drugs that we use at different stages of the disease. In very early stage of disease before the patient becomes incapacitated or troubled by symptoms we tend to monomean oxidase inhibitors for two reasons one there's some evidence that inhibitors might possibly slow down progression of disease, the other is MAOB inhibitors are systematically effective particularly when symptoms are relatively mild. So I want to first -- one of the first inhibitors was SELEGILINE, it was shown in a study by the Parkinson study group that showed that early introduction of SELEGILINE delays the need for L-DOPA by nine months. It was a robust effect because we had a lot of patients, 800 patienst and there's dispute about this finding. There is some discussion about interpretation of this finding did SILEGILINE provide benefit or was it neuroprotective. I won't go into the discussion now though I'll be happy to address it in Q&A.
When SELEGILINE is introduced early and is compared to L-DOPA early those patients initially treated with SELEGILINE had less disable at the end of the 7 year follow-up shown by the Scandinavian study by the Parkinson rating scale, the motor scale is lower and the ADL scores are also lower. Clearly SELEGELINE introduced early does appear to delay progression of disable associated with Parkinson disease. In addition patients treated early require lower dose of L-DOPA after follow-up period and the side effects of L-DOPA appear to be less in those treated with SELEGILINE early. That clearly shows MAOB inhibitors such as SELEGILINE might have benefit when introduced early in the cause of Parkinson disease.
The next MAOB inhibitor was RESEDULINE it's irreversible MAOB inhibitor approved by the FDA in 2006 as initial mono therapy and therapy in patients already treated with LEVODOPA. It prolongs the effects of LEVADOPA by increased off time, the time when patients are not functioning well by almost two hours. There are some side effects that one has to be concerned about when introducing RASAGILINE including the fact that it may increase dyskinesia in patients taking LEVODOPA overall it's one of the best tolerated medications. Because it's MAO inhibitor, there are some potential risks including the cheese effect, cheese reaction, I must say I have never seen in any patients or even reported the warnings that you need to be aware of. When you prescribe RASAGALINE you should provide patients information about it. Certain restrictions of food intake that are rich in THAMINE, pickle herring, beer and red wine. Red wine is probably and beer especially is a major obstacle to using RASAGILENE. There are certain contraindications including certain drugs such as MEPERDENE that may interact with RASAGILINE infrequent but something one need to be aware of.
Before I describe the study, the most important study done with RASAGILENE, a consultant that sponsored this study. In this study we asked the question would early introduction of RASAGILINE delay progression of Parkinson disease, that's the question we wanted the address. We designed a study in a novel design called delay star design and will be basically did is randomized patients in very early stages of Parkinson disease and it was large number of patients randomized in 1,166 patients that had symptoms for less than 5 months. Randomized 1 milligram of RASAGILINE and two of that and placebo and they were followed and after 36 weeks those patients that were initially randomized to placebo was switched to RASAGILENE. We predicted that initially there maybe some symptomatic benefit but the patients will then continue to progress when they are treated with RASAGILINE and the benefit should be less with placebo and progression should be more rapid in the placebo treated group. When the placebo treated group was switched with RASAGILENE one things to see dramatic benefit. The RASAGILENE treated patients would progress in apparent fashion so at the end of 72 weeks what we would expect is those individuals initially treated with RASAGILENE have a lower DPER score than those patients treated with placebo. To our surprise, this is exactly what happens. So we reported this in the New England Journal of Medicine about two months ago. Those patients treated with one million gram had some initial improvement in progression but at the end of the follow-up they had less disability at the end of 72 weeks than those patients treated with placebo. We could not demonstrate this affect with 2-milligram dose and we don't have a good explanation for it but it's something we are analyzing currently. So we concluded that in these 1,176 untreated Parkinson patients when RASIGILENE is introduced early those patients had slow progression of the disease which could be consistent with possible disease modifying effect. We could not demonstrate with 2-milligrams but we felt this was an encouraging result that needs to be further pursued. This is in de novo Parkinson patients never exposed to LEVADOPA. What about patients treated with LEVADOPA? Two studies that showed patients with L-DOPA conducted by the Parkinson study group and this study group we have patients treated with RASIGILENE had significantly increased off time than those randomized to a placebo. In another study conducted in Europe RASIGILENE was compared to a (indiscernible) inhibitor and we showed that in compare comparison to placebo patients with RASIGILENE had significant reduction in off time compared to those treated and reduction was similar to reduction that was noted in patients treated with the inhibitor of (indiscernible).
Another question being frequently asked is does LEVADOPA hasten the disease? People thought for long time because it increases oxidative stress that potentially it could accelerate the progression of the disease. The answer to that is probably not. And the reason why I say that is because of the study, again, we conducted with the Parkinson study group, we randomized patients in early stage of Parkinson never treated with LEVODOPA to four groups. Placebo 450-milligrams 300-milligrams and 600-milligrams per day of LEVODOPA, patients were followed for a period and we showed that there was a dose response in terms of reduction of PDRS and those patients treated with LEVODOPA so those treated with higher dose had robust improvement with PDRS, when we withdrew LEVODOPA we showed deterioration one would expect over a two week period. None of these patients reached the disable that was severe enough that was seen in patients who were right beginning treated with placebo. That suggested that LEVODOPA was not neurotoxic because if it were we would expect that the level of LEVODOPA treated patients would have more disability at the end of the follow-up period than those patients treated with placebo.
The next question to ask, of the patients treated with LEVODOPA, what do we do to prevent complications mainly motor fact, treatment of the benefit from LEVODOPA shortening, patients developing wearing off effect or involuntary movements referred to as dyskinesia which is in the form of monoclonal Dystonia. So what we see when patients are treated with LEVADOPA they have benefit, the duration of benefit gradually slowed from 3 to 5 hours and they develop peak dose dyskinesia. After prolonged period the duration maybe shortened to one hour or less and patients are either on and when they are on they are dyskinetic or off and have severe bradykinesia and a variety of other symptoms. Let me show you an example of a patient who has dyskinesia. This is a classic example of a patient with a type dyskinesia occurring at peak dose. And I think everyone has seen patients like this. Michael J. fox is probably one of most famous patients that demonstrate these dyskinesias.
Let me show another patient and illustrate a certain point. This patient called me one week after I increased her LEVODOPA stating my tremor got worse. That didn't make much sense to me because we know that LEVODOPA doesn't increase tremor so I said come on in let me take a look at you. This is the movement she had when I saw her. Now, to the novices in the audience, this may actually indeed look like increased tremor. But actually what it is, it's a form of dyskinesia which we refer to as (indiscernible). I don't expect everybody in the audience the make that distinction but the point I'm making is that one -- sometimes has to be skilled and actually recognizing some of these symptoms of Parkinson and LEVADOPA complications in order to make appropriate adjustments. The actual examination of the patient is sometimes more important than what the patient tells you. So to actually what she had was LEVODOPA related seropothy, not increased tremor.
What are some of the risk factors for development of dyskinesia, young onset Parkinson patient like the Parkinson patients mentioned earlier are the highest risk for developing LEVODOPA complications or wearing off effect as well as dyskinesia. So age of onset is probably the most important risk factor. Genetic predisposition, patients with certain genetic forms of Parkinson such as the Parkinson mutation or the log 2 mutation that I mentioned earlier, can also be increased risk. Certainly duration of treatment, dosage, but the half life of the dopaminergic agent is probably the most pharmacologic reason why they develop fluctuations because the short half life results in striatum receptors and results in a variety of effects and I'm not going to go through this in any detail but there's a cascade of events that occurs as a result of the stimulation which results in induction of immediate early genes altered neuronal firing and increased motor fluctuation of dyskinesia. That's the reason many Parkinsonologists propose as a therapeutic strategy continues dopaminergic stimulation. Instead of having short stimulation of the dopamine receptors having more stimulation might prevent development of these complications.
What are some of the strategies that are we are currently using in order to provide a more prolonged stimulation of the dopamine receptors? One strategy is to develop LEVODOPA formulations that have longer duration of action. And we are currently studying a formulation called IPX 066 where we show that this formulation of slow release LEVODOPA one can prolong on time quite significantly or release the off time with IPX 066 relative to LEVODOPA CARBIDOPA relief. We are recruiting an advertisement if you have a patient that you would like to refer for these motor fluctuations let us know. Another strategy would be to add transferase inhibitors and you can see patients treated with LEVOPOPA have more fluctuations. We can smooth out these fluctuations so instead of having the peaks and valleys when we add the peaks and valleys can be largely eliminated because of prolongation of the the on time. Many studies show that in addition to the inhibitor improves daily on time when added to LEVODOPA. There is a formulation of LEVODOPA, CARBIDOPA which makes it easier for patients to take so they don't have to take all these tablets and it's a combination drug. When this drug was first introduced we thought well, wouldn't that be interesting if early introduction of ENTACAPONE might delay progression of LEVODOPA related complications and just to summarize those two studies they are negative, we couldn't show that early introduction of ENTACAPONE delays onset of LEVODOPA related complications.
I read a lot of scientific journals including star. In this journal it described a miracle cure for Michael fox. Being interested I said wow I need to learn more about it. What do you think was the miracle cure that cured Michael J. fox? AMENTADINE. That's been around 30 years. Probably longer actually, 50 years. And it's in the a new drug. But this drugs does have benefit in LEVODOPA related. Michael J. Fox suffers from that so the miracle drug was AMANTADINE to provide symptomatic benefit, enhances dopamine release and causes reuptake inhibition. The main reason it's anti-dyskinetic drug because of its antagonist effect. It has some side effects including swelling (inaudible) and it clearly LEVODOPA dyskinesia, the best we have to control dyskinesia, though it's not a miracle drug, it tease best we have currently. There's some evidence that it may prolong survival of patients with Parkinson disease. Here is a patient of ours treated with AMANTADINE with one of the side effects of -- doesn't mean they have to discontinue the drug but something to let them know about other side effects common with AMANTADINE ankle swelling and possible congestive heart failure.
Another way one can respond to LEVODOPA is to introduce agonists. The question, whether early introduction of dopamine agonist may delay onset of LEVODOPA complications. I won't go into detail, just a summary of these studies looking at (inaudible) and PERGOLI all which showed when patients are treated with these dopamine agonists early they are less likely to develop LEVODOPA complications than if they are treated with LEVODOPA alone, the early dopaminergic therapy. So again as part of the Parkinson study group we followed patients treated with PEXOL or LEVODOPA early. We found patients treated with PEXOL had a less wearing off effect on dyskinesias, the common LEVODOPA complications than those initially treated with LEVODOPA. On the other side of the coin is the increased risk of side effects such as EDEMA and sleepiness. So one has to always take into account the pros and cons but generally what most Parkinsonologists in patient whose are relatively young and who are then sentenced to a long life of dopaminergic therapy those patients we use dopamine agonists early and try to delay introduction of LEVODOPA therapy as long as possible.
Another way to improve this is by using dopamine agonist that have more prolonged effects and AROPINOL XL was introduced. We show that with XL there's a significant reduction in the off time compared to the short acting ROPINIROLE and on time without troublesome dyskinesia the most desirable time for Parkinson patient is increased with ROPINIROLE XL compared to palace to summarize the side effects of the various dopamine agonists, low blood pressure is one of the side effects headaches insomnia, dyskinesia is one side effect so patients who are already have a mild dyskinesia, exacerbation can occur with introduction of a dopamine agonist. There are a number of other side effects including vasoconstriction, retro poietin pulmonary fibrosis. Almost always due to the ERGOT dopamine agonist we no longer use. By ERGOT, dopamine agonists, really ever used those dopamine agonists. We use as the main agonist. Edema is another side effect. A variety of psychiatric side effects occur with dopamine agonists including pathological gambling. This is a main concern we have with -- when we introduce dopamine agonists. I have to tell you that I have a lot of patient whose have lost their life savings because of dopamine agonists causing gambling. There's a group of disorders we contribute to dopamine agonists though relatively also seen with LEVODOPA called impulsive disorders, dopamine disregulation syndrome, homeostatic disregulation, a number of names and that includes pathological gambling, hypersexuality craving binge eating all kinds of compulsive features. Many patients crave more LEVODOPA when they take the dopamine agonist and become addicted to LEVODOPA. They have a variety of mood disorders and may experience to responding which is intense fascination with arranging of objects. I can show an example one of my patients, this is a letter I got from his wife. He said he has growing fascination with collecting objects, behavior that seems to have blossomed since he began the medications. Examples include axes oil cans canes, wooden boxes and and other item he is collects and basically has taken over his whole house. Cravings are another side effect of dopamine agonists particularly for sweets, I have never taken it but I have constant craving for sweets but certainly patients who do take dopamine agonist have a much higher incidence of craving for sweets and chocolate.
Let's talk about surgery. Just wanted to introduce the topic of deep brain stimulation. Where we implant an electrode into the target area, usually to the subthalamic nucleus. We can select which of these four electrodes we can stimulate with the supposed generator which is implanted under the skin. And the upper chest area. All this is under the skin, you cannot see it and it's very effective treatment for a variety of Parkinson-related problems in LEVODOPA related complications. Let me show you an example, this is a patient with young onset Parkinson who has very severe LEVADOPA dyskinesia. He has two choices. Be in this constantly being dyskinetic or being off. When he's off he's essentially bedridden unable to move because of severe bradykinesia and rigidity. Many patient whose have dyskinesia they refer being dyskinetic than off but obviously in this case the dyskinesia is disabling and you can imagine how difficult it is to function if he stayed this way all time. So at that time we tried to manage him the best we could with various adjustments of his med medications but he ended up having surgery. In those days we were doing -- instead of stimulating the global striatum we ablated the POLYDOME. Later on he did extremely well but later on he progressed and we then did bilateral STN DBS, we planted electrodes into the nucleus. Even though he previously had PALLIDOTOMY. This is 15 years after the initial video and you can see he's doing very well, he continues to function well and he's in this condition that I'm showing here most of the time. And I just wanted to demonstrate the robustness of surgery in terms of improving motor fluctuations dyskinesias due to chronic LEVODOPA therapy. So that's one of the main therapeutic strategies in patient whose have LEVODOPA complications in whom we cannot control complications with pharmacologic adjustment. In this first study in the New England Journal of Medicine we showed that those patients receiving subthalamic stimulation had significant increase in on time with dyskinesia from 27% to 74% at six months. When we targeted GPI, increase was from 28% to 64%. This was one of the first studies to clearly demonstrate the benefits of deep brain stimulation in patients due to fluctuation. This is probably the most recent study, this was a study conducted in 6 VA centers including a house at Baylor and there were two questions that were being asked from the study. One, would DBS be better than optimal medical therapy in patients with motor fluctuations. Second question, what are the best targets for DBS, STN or GPI? Basically what this study showed the second question is not publicly answered so I won't discuss it with you so I'll discuss the first question. Basically what we showed is those patients randomized to DBS versus medical therapy did better so 71% of DBS patients an best medical therapy patients experienced clinically meaningful motor function. Some improvement in quality of life measures and a variety of other measures. Those patients who received DBS had higher frequency of adverse effects compared to those patients with best medical therapy. One has to always optimize the therapy and individualize it according to the needs of a particular patient. So this is the summary of that study, patients treated with DBS has increase in their on time dyskinesia 6 hours to 11.4 hours compared to patients treated with best medical therapy when there was no change in their on time.
How did we select patients for DBS? Obviously all patients should have Parkinson disease, we found patients with multiple system atrophy cerebral palsy or other forms of Parkinsonism do not respond well. We would like to optimize treatment with medical therapy and they should be responsive to LEVODOPA, so the patients don't respond to LEVODOPA chances are they are not going to respond to DBS. They should have troublesome side effects including dyskinesia despite optimal medical therapy. We occasionally operate on patients who have very severe high tremor because that tremor may not be ad adequately treated with medical therapy. We rarely operate on patients who cannot tolerate dopamine therapy and surgery might be a better option. They should be carefully screened, normal MRI and not have dementia or depression. Probably the most important aspect of selecting patients for DBS is make sure they and their family have realistic expectations as to what we can achieve.
So this is almost my summary slide. I'm going to show a couple more slides after this but I wanted to sort of summarize how we approach patients with Parkinson disease. The first question when we see patients with symptoms and signs, first question we ask is does this patient have Parkinson disease or some other parkinsonian disorders? 75% of all patients that come to us with Parkinson symptoms turn out to have Parkinson disease at autopsy. 25% have other causes for their Parkinsonism, so we want to exclude the other causes. We would like to initiate neuroprotective therapy in those patients with early stages of the disease. But unfortunately we don't have neuroprotective therapy yet. But I mention to you that SALADILINE do appear to delay the progression of the disease whether it's because there are neuroprotective drugs or because they delay the need for LEVODOPA and delay LEVADOPA related complications is not clear.
The next question we want to ask, is this patient functionally impaired? The answer to that is no, then we (…) these patients under these MAOB inhibitors. If they are functionally impaired then the question we ask, is this patient old and old cognitively impaired and depending on the age you can answer whichever up. But the patient is usually 65, 70 years old, instead of going through a dopamine agonist that we tend to use in young patients we probably would start initially on LEVODOPA with or without entacapone. In the patients are young and cognitively impact we start a dopamine agonist, may use anti-colonic drugs in parables with tremor but almost all patients end up on LEVODOPA. We occasionally use aPoe morphine, a motor soluble dopamine agonist we can injection and within 5 to 10 minutes the patient goes from being off with severe bradykinesia to being on. If someone is an opera and they turn off, they can inject themselves through the clothes, the pants, and within 35 or ten minutes they can turn on that, tease way most Parkinson patients tend to use it as a rescue therapy from the wearing off. But the vast majority of why Parkinson patients on combination of therapy and we tried to manage these patients the best we can with the lowest possible dosage and try to make sure they have the best quality of life. If we can not succeed with medical therapy obviously those patients would be considered candidates for surgery.
Now, I have not talked about the management of the non-motor symptoms of Parkinson that's a topic for a totally difference discussion. So I'm not going to cover that but I wanted to emphasize that there are many treatments available for the cognitive impairment, depression apathy, sensory symptoms next week I was asked to give a talk at the (inaudible) of virology on dysautonomia. Sleep disorders can be also treated with the variety of medications. BOTULINUM toxin is playing a role in variety of movement disorders particularly dystonia and cervical dystonia. But also in a variety of symptoms associated with Parkinson disease. Such as drooling, injectioning it into the salivary glands can significantly reduce drooling. Dysphagia is improved by injecting the toxin into the -- overactive bladder, constipation, all these symptoms can be potentially treated with BOTULINUM toxin injection.
Finally a few words about therapeutics of Parkinson disease. This is a whole different topic that I don't want to get into but just wanted to emphasize that even though the pipeline is not as healthy as we would like it to be there are a number of important developments in the therapy of Parkinson ease disease. We talked about level of operations. We talked about MAO inhibitors and some -- there maybe some inhibitors dopamine agonists. There are new dopamine agonists being tested. Reuptake blockers drugs for motor fluctuations. There are a variety of drugs for the non-dopaminergic systems being currently investigated. There are tropic agents being investigated. We are particularly interested in GDNF and SERUB 120 which is a way of delivering a tropic factor called nurTURIN a gene therapy type delivery into the striatum and that's something we are very interested in. And a variety of potentially disease modifying drugs that are currently being investigated and surgery -- a number of surgical treatments they are also being investigated, possibly magnetic stimulation. S that study we are currently conducting with the support of NIH. So I want to mention that. This is a way of potentially modifying the progression of disease using creatinine, and we hope this five year study will eventually show that creatinine will modify favorably to progression of the disease. Of court NIH plays an important role in many of the clinical trials, in Parkinson disease and will probably play an important role in stem cell therapy and all of you are familiar with this announcement by Dr. Collins just a couple of days ago ab releasing 13 embryonic stem cell lines for treatment of a variety of diseases including Parkinson's disease. Hopefully availability of these stem cells will prevent what is referred to as stem cell tourism. This is a common problem. All of you probably have seen patients who travel to China, Russia, Germany, Mexico. Whatever countries in order to get stem cells for whatever disease they might have. And unfortunately this often results in terrible tragedies as I will traited in this ABC news article.
Finally I wanted to say couple of things about what you can do, those who done have Parkinson but are concerned you might be, this is an interesting development all of you probably know SERGE GRENO, at least know of him, but he's one of the wealthiest people in the world, co-founder of Google, whose mother was diagnosed with Parkinson and was found to have log-2 mutation. Being married to a woman who is a co-founder of the largest genetics company in the world, he of course tested himself for the mutation and was found to be positive. Now he has at least 30% risk of developing Parkinson disease. So what can he do, he's one of the richest people in the world, all the resources available to him. Based on his extensive research he concluded the best thing that he can do is to increase his exercise. Exercise is certainly one all of us can do to prevent a number of disease including Parkinson's disease. It's an important component of therapy. I want to show you one of my patients who took me seriously. This is a patient who I told him he needs to exercise. This is the exercise he chose. He does it several times a day, he gets on top of the skyscrapers and he skate boards down and he believes this is the best Keefe exercise. He's also an entrepreneur and actually started a company that makes these dopamine long boards. I have no vested interest, this is not an advertisement but those who are a promoter of his company the dopamine long board maybe the thing for you. It is tough to make predictions especially about the future as YOGI BERRA said, I think the future is bright for Parkinson patients and I hope these recent developments in our understanding of the pathogenesis of cell death will translate into better therapies and improved quality of life for patients with Parkinson. I'm going to stop here.
If you want to learn more about Parkinson, this is -- you are all invited to our annual course in Aspen, this is going to be our 20th anniversary so if you want to learn more about Parkinson and other movement disorders, I hope to see you there. Thank you very much.
[Applause]
>> We have time for one or two questions.
QUESTION: I have two questions that relate to neuroprotection. The first one is very practical question. I'm wondering if with the results of -- if we have enough information to offer (indiscernible) to all the patients at least the ones early in the disease an do you do that with your patients? The second has to do with the findings of the L-DOPA study. I was wondering if you could comment on that and give us your comments on that.
JANKOVIC: Before I answer the question, I'm a consultant -- I strongly believe in the data that we published, I think that those patients treated early with RASIGILENE have done better in the 72 week period supported by the long term SELEGILENE study from Scandinavia, so I do prescribe RASAGILENE in patients that have early symptoms of Parkinson but not yet troubled by the symptoms. Once troubled we have to go to something strong every. So RASIGILENE may have a mild symptomatic benefit but I think in long run may even have a potentially disease modifying benefit that would like to take advantage of. As far as the L-DOPA study, what you're referring to is something I didn't talk about. There's another component to the study, again, to remind you the L-DOPA was the study where I talked about where patients with Parkinson were randomized to receive REVODOPA in different dosages of placebo and followed and at the end of 40 weeks we discontinued LEVODOPA and you saw deterioration but not severe enough seen in patients initially treated with placebo. There was another component to the study where we did imaging CET speck scan to image the dopamine transports, unfortunately that result wept in the wrong direction. Not completely in the wrong direction but somewhat in the wrong direction. I didn't want to spend a lot of time discussing the difference and the imaging effect. That study hopefully will be supported by NIH and the study was supported by NIH and we are hoping to redesign the study and use different imaging techniques and maybe have the -- we go longer than two weeks. There are a lot of things we can do to implement the study but it demonstrated LEVODOPA is not neurotoxic.
(off mic)
JANKOVIC: Right. So the question is what is the long term event of deep brain stimulation. DBS was introduced about 15 years ago or a little bit longer. We have a 15 year follow-up on the patients testimony majority of patients continue to do well. DBS does not slow down progression of the disease. So it is particularly useful in improving the motor fluctuations in dyskinesia, the LEVADOPA related complications but doesn't slow down progression of disease. I must say that there is growing concern especially over the last few years about some of the behavioral side effects of DBS including increased suicide rate, depression, cognitive decline. You'll hear more about it and we submitted papers specifically looking at the neural behavioral connective deficit that is seen in patients chronically treated with DBS compared to LEVODOPA. Maybe the pendulum will start swinging a little bit back toward medical therapy but this study was published in JAMA, suggested that even the best medical therapy DBS patients don't do better. It's a short term study so your question is very relevant what are the long term effects. I think many of us are increasingly concerned about the neural behavioral psychiatric side of things.
>> Thank you very much.
[Applause]
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ANNOUNCER: We were pleased to bring you a special "Contemporary Clinical Medicine, Great Teachers" lecture, recorded on December 9, 2009. The topic was "Treatment of Parkinson's Disease". Our speaker was Dr. Joseph Jankovic, Professor of Neurology and Distinguished Chair in Movement Disorders, Director, Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine.
You can see a closed-captioned videocast of this lecture by logging onto http://videocast.nih.gov -- click the "Past Events" link, or by clicking the "View Videocast" link for today's podcast at the Grand Rounds podcast page at www.cc.nih.gov/podcast/grandroundpodcasts.html. The NIH CLINICAL CENTER GRAND ROUNDS podcast is a presentation of the NIH Clinical Center, Office of Communications, Patient Recruitment and Public Liaison. For more information about clinical research going on every day at the NIH Clinical Center, log on to http://clinicalcenter.nih.gov. From America's Clinical Research Hospital, this has been NIH CLINICAL CENTER GRAND ROUNDS. In Bethesda, Maryland, I'm Bill Schmalfeldt at the National Institutes of Health, an agency of the United States Department of Health and Human Services.
