Diseases information. Disorders. Treatment.

Now the first point to make, the pallidal surgeries, as I said before – what’s old is new. This pallidotomy stuff was way back when, in 1952. Early. Irving Cooper. You know the story. You know the whole story about this? I’ve got to tell the story. So Cooper has got this guy with an anterior choroidal aneurysm and he is going to go in and do an aneurysm clip. And he’s Irving Cooper, he’s a neurosurgeon. So he goes in there and the patient is parkinsonian. It’s a left anterior choroidal artery aneurysm. So he goes in there with his clip. He clips the aneurysm and the artery. So he says, “Oh, my. Oh darn. This is going to be a rather large subcortical basal ganglionic infarction because I have just clipped off the anterior choroidal artery. Oh, cest la vie” and closes him up. The next morning he goes into the patient’s room and the patient says, “Dr. Cooper. It’s amazing. You are absolutely amazing.” And Cooper, standing at the bedside, says “Thank you very much. We try our best.” And walks out of the room. True story. He leaves the room and he spends the next 25 years trying to figure out what he did. Honest to God, that’s a true story. A completely serendipitous observation that lesions in the pallidum can be associated with improvement in parkinsonism in the contralateral side. Absolutely serendipitous. So what is old is new.

The over-activity of certain subcortical structures, specifically subthalamic nucleus and globus pallidus pars intern, key to the understanding of how these surgeries might work. The primary indication for pallidotomy and pallidal stem, levodopa-induced dyskinesia. There is no controversy about it. People say, “Oh, it clearly improves the major cardinal features of the disease. It clearly treats rigidity, it clearly treats bradykinesia, it clearly treats this and that..” the major thing that we see in study after study after study, consensus conference after consensus conference, for pallidotomy; it works for levodopa-induced dyskinesia. Now Anthony Lang and his group in Toronto have also made the observation that if you are asking the question, who is best for this surgery, ask the question, who is responding to levodopa. Because they think that the people who respond best to pallidotomy are the people who respond to levodopa still. Long term efficacy is still debated. Now Laury Lightman from Sweden, now in someplace else – in semi-retirement – had a huge experience. He gets up, Laury Lightman – a very nice man – he gets up publicly and describes his experience based on his work and the work of his mentors before him. He’s got hundreds of patients and he is absolutely crucified because he does not have long term follow-up in a systematic way. Laury Lightman, incredibly thick skinned, lets it wash off his back. He doesn’t even worry, but the Americans and the Canadians are all over him for lack of follow-up. The reason why Lang’s paper was published just two years ago, because it is systematic follow-up for two years and that’s the longest study we’ve got, interestingly enough. After some 50 years of experience with pallidotomies. Systematic follow-up, two years is the longest study. It’s longer now if you read the abstracts. But the upshot seems to be that the long term efficacy of pallidotomy is still debated but it seems to be effective for at least two years, based on the literature that we have. Levodopa is still required after surgery. There may be an allowance for some decrease in dose initially, and then because there is less likelihood of levodopa-induced dyskinesia in the appropriate contralateral hemibody, yeah, you can probably increase levodopa dosage over time. But they still need some levodopa. It ain’t no cure. The difference though is the subthalamic nucleus, the lesions of subthalamic nucleus with the stimulation of subthalamic nucleus, seems to be associated with a virtual lack of need for levodopa in the post-operative course, and that’s pretty striking.

Ophthalmotomy was a major treatment back then. It was with the advent of levodopa that we saw the waning of surgical treatments for Parkinson’s disease, and in 1992 we saw a renaissance of the surgical treatments. These surgical treatments have gone mad, as have other treatments that have been explored. Let’s review them, shall we? Now this was also there in 1992, maybe a little bit after. Amantadine is an agonist, Symmetrel, that was originally designed as an antiviral. It has mild dopamine agonist activity. It’s a marvelous drug. Little pearl on the side; I like to use amantadine in early disease or even in late disease, for whatever reason they get like two or three months of, you know, you don’t want to increase the levodopa because they get dyskinesias or they get confused or psychotic. You don’t want to add an agonist for the same reasons. Oh, what to do? So I give them a little bit of amantadine. It helps, it energizes them. Just like in MS. I don’t know why. Maybe it’s the antiviral thing. Maybe Parkinson’s is a viral disease, I don’t know. Who knows. Vitamin E, sure why not? Two thousand units, can’t hurt. Levodopa both the controlled release and regular format. Is the controlled release all that advantageous? Well, because it smoothes out the response, it smoothes out the levodopa concentrations. There’s this one woman, a practicing parkinsonologist, this same woman comes from DuPont every single week to tell me, “Did you realize that the controlled release preparation of Sinemet really smoothes out levodopa level during the course of the day? And that’s because of its controlled release, enteric preparation.” “Joanne, I know.” Next week, “Did you know …” it’s some kind of a plan, it’s a plot.
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Various dopamine agonists that I’ve reviewed for you, the CO and T inhibitors, the two major ones right now, tolcapone which does cross the blood-brain barrier, entacapone which does not. Growth factors coming out. I don’t want to spend a lot of time on that. If you want to read about it, my appendix in 9 font will tell you all about it. Thalamotomy, pallidotomy; now we are going to talk a little bit about this. To understand these surgeries one has to understand this model for basal ganglionic function. Remember now where we have come in surgical ablation treatments in Parkinson’s disease. The story goes back to the 1930’s. Neurosurgeon, ” I see a person with parkinsonism, a right hemibody parkinsonism with tremor and stiffness. My solution to this is very simple. I will completely ablate the left motor cortex. This should fix everything. That is what I think because I am a very powerful neurosurgeon. I think that if I take out the entire motor cortex on the left side this will certainly help his parkinsonism.” And they did this, in point of fact. Brilliant, absolutely brilliant. Complete paralysis but no more parkinsonism. It was about at that level of sophistication. With the advent of that amazing story of MPTP and the availability of MPTP in a monkey model, in which you can stick probes in there and try and figure out what’s going on in different centers in the brain, now we can start to forge a new model for an understanding as to why putting holes in certain parts of the brain could conceivably relieve the cardinal aspects of idiopathic Parkinson’s disease. And that was the major advance between 1968 and 2006, or 2006, in terms of understanding how it is that pallidotomy, for example, for subthalamic lesions can work. That’s the first point. The second point is, curiously enough – I don’t understand it – but electrical stimulation of a site at high frequency can accomplish the same end as a larger lesion in the same locale. I don’t understand why. I like to watch people get up and try to explain. These are formidable people. Big. Mark Halleck. Did you see Mark Halleck’s platform two years ago? He understands dystonia now. Amazing. Mark Halleck is not to be trifled with. You get Mark Halleck on your tail in a conference, you are not in good shape. So Mark Halleck gets up there and he starts explaining this stuff and he thinks we understand. We don’t, of course, but we are coming closer it seems to me, and it’s a function really of understanding some of these connections, which I now want to draw for you. Cheap generic pills

Let’s go back a little bit; 1989, the New England Journal of Medicine, the big selegiline thing. So what they did was they had three arms to this study. They have a bunch of parkinsonians, they didn’t start them with levodopa. They started them on one of three options: either placebo or vitamin E, 2,000 units a day, or selegiline, Eldepryl, 5 mg b.i.d. They stopped the study early because they saw that the two groups, vitamin E and placebo on one side and selegiline on the other were clearly diverging. The argument was – New England Journal 1989 – that selegiline is neuro-protective. Then all the articles came out, “How do you know that it’s neuro-protective? Maybe it has some inherent dopamine-sparing activity. How do you know it’s not an antidepressant effect from the MAO inhibitor? How can you prove ….” The controversy continued until 2006. If you are really interested in neurologic kind of Peyton Place-ism, read that story. It’s absolutely fascinating. Add to that the most recent little twist on it, which is that in the United Kingdom they reported an increase in mortality associated with long term use of selegiline when compared to a population who didn’t receive long term use of selegiline. And the Brits said, “We don’t want to use it anymore.” So the Americans went gaga. There were all kinds of phone calls, “Retrieve all your data from the study from seven years ago, today!” So we go scrambling around trying to find that stuff and they come up with a report that “We in America find absolutely no increase in mortality. We will continue to use selegiline with wild abandon.” So back and forth, and in the meantime people are saying, “Well we will become even more sophisticated in our capacity to provide dopamine-sparing strategies. We will come up with other kinds of inhibitors of other aspects of the catecholamine pathway, including catechol _ transferase inhibitors.” Tolcapone in particular. And then Britain starts to report, “Oh no, major liver damage and two fatalities associated with tolcapone.” Letters go out to all clinicians everywhere, “Watch out now. We have to start checking liver function studies every six hours for the rest of their lives.” Really astonishing. I mean, I have to deal … I have 750 parkinsonians, 750 letters have to go out. I don’t know who’s on tolcapone, I forget. I don’t have a database like that, I’m just a clinician. So anyway, very strange, amazing story. And it doesn’t stop. You have the tolcapone, that’s out, Tasmar. Entacapone, FDA approved. It’s coming out. The difference is entacapone does not cross the blood-brain barrier, tolcapone does. Then of course there is the next generation, Al Capone is coming out! It’s going on forever and ever. If you want to know about the pathways this diagram is in your handout. I don’t know how significant this is.

Selegiline, a summary. The uncontroversial summary, just the facts. We are aware of the 1989 data. The argument for neuro-protection has fallen on difficult times. We do use it in early disease. The dosage is not clear because some people have advocated 5 mg per day rather than 10. It is a useful adjunct in the movement disorders world. We are aware of course of the recent report of about a year-and-a-half ago that selegiline, one arm, vitamin E 2,000 units per day, second arm, are both relatively helpful in Alzheimer’s disease. Oh no, could it be neuro-protective? I don’t know. Can you imagine the arguments that would come up now? You remember that. Also in the New England Journal of Medicine, thank you very much. So I think that’s, as of 2006, that’s where we stand. Selegiline is still being very much used and the question of it’s neuro-protection, although unclear, it does have a role.

So if you take a look at treatment options in, say, 1968. Some of use weren’t even born in 1968. Great year though. Treatment options in 1968; back in those days psychotherapy was still a treatment. “You realize of course that parkinsonism is unbridled rage, not expressed, hence it is tied up in a bound up body.” There’s some fascinating literature too. Anticholinergics were a big part. You remember, and I think some of us still remember in medical school what they taught us, “Not enough dopamine, dopamine loss.” “Uh, oh, too much cholinergics so we will give anticholinergics to restore the balance.” Remember that? Then we hear all this other stuff come up. You don’t hear about the cholinergic nervous system. Who’s talking about it? It’s something else. But back in those days anticholinergics were very much the treatment of choice. Levodopa in 1968 was experimental. The neurologists started it and said, “Ah, I’m a neurologist. I’m an expert in the brain. I do not think levodopa has any role in the treatment of idiopathic Parkinson’s disease.” It’s true and George Cotheous, in internist, says, “Ah, these neurologists are sort of weird. I think they are wrong.” And he’s the one who really started the use of levodopa. So that’s why the George Cotheuous lecture and all that kind of stuff. He was an internist. Very humbling for the neurologists.
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One of the things that has been coming up in the recent literature that I think people should know about is this whole argument that okay you give somebody levodopa. They are going to make dopamine. In the synthesis of dopamine there is the liberation of hydroxyl radicals and other free radicals. These free radicals contribute to neuro-degeneration by oxidative mechanisms. Perhaps they are vulnerable. It’s a vulnerable substrate because their capacity to deal with these kinds of free radicals and other moieties is lowered perhaps. So if we give levodopa to these people they are at greater risk for the continuing degeneration that we are trying to treat in the first place. Corroborated by in vitro data. Oh no, we shouldn’t use levodopa then! But the problem is, levodopa remains our best treatment for idiopathic Parkinson’s disease. Simple. And in the clinical experience that story of greater neuro-degeneration as a result of the use of levodopa has not been corroborated to the degree that we see in in vitro study. So it’s a very controversial area. But the point, the reason I want to bring this up is because it’s the whole issue of oxidative stress, or oxidative neuro-degeneration as a mechanism for this selective cell loss that we see in this disorder. There is the story that the longer people are on levodopa the more likely dyskinesias will happen. For all those reasons they are advocating that the dopamine agonists are the first line of therapy for early disease. In clinical settings this is not what you will necessarily hear. It depends. If it is a 70-year-old who is presenting for the first time, retired and otherwise enjoying his life and wants to maximize the next 5-7 years, yes you use Sinemet. It depends. It depends on many different things.

When we start talking about stroke, for example, when we get into that really dicey area of tissue plasminogen activator for example, know what is not controversial in the literature. Don’t worry about the controversies in the literature. That’s not what the Boards are trying to determine. That you’re aware of a controversy … oh, and by the way, that is especially true in the orals. If you are standing in front of a person whose kids are going to private schools because of dopamine agonists, you don’t want to sit there and say, “Well, I personally think the use of levodopa is very important in the early treatment of disease. I use it all the time. I think this argument on the other side of dopamine agonists are really sponsored by people whose kids are being sent to private schools by …” you don’t want to do that. Say, “I realize that there is a controversy. The Keystone conferences have put up this kind of consensus idea of how we should treat early disease, but it seems to me that it would depend on ….” Now you are vomiting up sort of a stock response. But the point is, there is a difference between… the orals are a different kind of mind set. You don’t want to walk into controversy in the orals. All you want to do is to say, “I acknowledge that there are controversies out there.” There is one guy, M.S. Maven – a real lab rat- said, “Um, there is no differential diagnosis in this case. It must be multiple sclerosis.” He was shot down. He was right but that’s not the time to do that. It’s the time to sort of generate large differential diagnoses. If they don’t like that then you have to rearrange real quick and start talking about something else. It requires a flexibility on your part. It’s very different from what you do sometimes in clinical settings. Which makes the point, all we are doing is preparing for a test. We are not preparing for clinical practice. Clinical practice is something different.
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The dopamine transporter is a transporter thing that allow for the concentration of dopamine and/or metabolites, taken up from the synaptic cleft, taken into the presynaptic cleft. So far so good, right? You know about that re-uptake mechanism. Makes sense there would be a transporter. Except that it also seems to pick up on toxins that may be selectively neurotoxic for those cells. Therefore, the presence of this dopamine transporter may be a marker for those cells vulnerable to selective neuro-degeneration in Parkinson’s disease. It’s either you have more dopamine transporter activity, or DAT activity in certain pathologic preparations, or a decrease in that thing which sequesters either dopamine or toxin in the presynaptic cleft, this entity of the vesicular monoamine transport, or VMAT. Here’s the point: either more of that or less of that transporter will be associated with increases in putative toxin or increases in dopamine in the presynaptic cleft, greater likelihood of neuro-degeneration. That’s the thought behind this whole enthusiasm about dopamine transporter activity. In the next few years you are going to see spec studies trying to quantify amounts of dopamine transporter in nigra etc. So you are going to be hearing this stuff I think in the next few years. There’s a little scientific factoid that I think they might pick up on.

What follows then is a review of our current … sort of a quick review of where we stand in the treatment of  Parkinson’s disease, and I’ll run through these points. I’m sure all of you are familiar with these. The first point having just been made, that the effects of levodopa treatment relate in some way to extra-nigral changes in the disease process. Characteristically, in the first five years the so-called honeymoon period, we see this lovely continuous nice robust response to levodopa at relatively low doses. And to summarize the natural history of the treatment of this disease from five years say to 10 after the so-called honeymoon period, this is the way I would describe it: it’s not as if we don’t get a response to levodopa, we do, but the response changes. What happens is it’s much more likely that I will develop some kind of dyskinetic manifestation. I get less on, I get a greater likelihood of dyskinesia, and the impression is that my therapeutic window is narrowing. In that period of time I have to deal with other kinds of complications related, I think, to the pharmacokinetics and pharmacodynamics of levodopa in the body, and that is a phenomenon of wearing off. The feeling that the patient has towards the end of a dose – even a controlled release dose – that the medication is not working. So, these two major aspects – the evolution of dyskinesia and the perception of a narrowing therapeutic window, and the development of dose response fluctuations – characteristic after that honeymoon period. The honeymoon period, by the way, can last anywhere from two years to seven years. The important point to make, in terms of testing, is that the exception to that rule seems to be the poor young onset parkinsonian. The poor young onset parkinsonian is the one, onset below the age of 40. You exclude all the usuals, you exclude that this is Wilson’s disease and you find that these are the people who have a response to levodopa but soon thereafter you find a quick evolution to dyskinesia. Or should we say a quick proclivity or tendency or diathesis to dyskinesia. Which can be difficult to manage. Very difficult in that population. Those are the people who end up getting their pallidotomies relatively early. But the overall natural history, some people have argued, the overall course of that disease can be rather kind despite a rocky early course.
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We have seen in the last three years the advent of a whole family of dopamine agonists, so I thought I’d review some of that here for you. There are fundamental differences of course between the use of levodopa and the use of the dopamine agonists. Levodopa of course is a precursor as opposed to the agonists which act directly on postsynaptic receptor sites. Levodopa itself results in phasic restoration of intra-synaptic dopamine, associated with an increase in dopamine turnover – because it is being synthesized. The agonists, however, act directly on postsynaptic sites and are associated with a decrease in dopamine turnover, the fundamental difference between the two agents. Never mind their mechanism of action. The agonists, unlike levodopa, do not compete with amino acid transport systems across the gut. So the agonists don’t work by those amino acid transport mechanisms either across the gut or across the blood-brain barrier. Levodopa does use those transport mechanisms. The agonists – at least, so the agonist people tell us – may allow for reduction in levodopa dose. I think that’s general consensus. I think we agree that does happen. But what is striking and interesting, I think, is that the agonists, the early use of the agonists, are not associated with the evolution in the long run of dyskinesias the way that levodopa is. Pretty straightforward observations about the differences between levodopa precursor therapy and the agonists.

Here’s a list of them, a list of the agonists. The important thing I think to gather from this list is that the new agents, pramipexole or Mirapex, ropinirole or Requip, are selective for the D2 population. These two are qualitatively different from those that came before; pergolide with slight D1 agonism. Bromocriptine was actually a D1 antagonist of mild degree. Apomorphine also a mixed agonist. All these agents with some certain anergic activity as well. Standard dose ranges here, some comments about what the people from the drug companies are saying about this. I don’t know what the significance of the D3 affinity might be. People are talking about it but I don’t think we know. The point to take home from this list of five representative agents – of course none of us use apomorphine very much although it is used in Britain a great deal – the major difference I think is the difference in the receptor affinities; mixed for the older agents, very selective for the new agents. The implication being that these two D2 receptors have particular activity on the indirect system and the significance of the indirect system I’ll review with you momentarily.

I am going to be spending more time talking about differential diagnosis in a little bit, but there have been a number of articles in our literature, in the movement disorders literature, in recent years talking about the thing we tend to confuse most readily with idiopathic disease, and that’s multiple system atrophy. Now multiple system atrophy comprises three different entities. The three different entities are OPCA, Shy-Drager, striatonigral degeneration. So the three are olivopontocerebellar atrophy, striatonigral degeneration and Shy-Drager. Now why are these three together? Well, because they have been identifying some highly clinically heterogeneous but what seems to draw them together is the presence of these argyrophilic cytoplasmic inclusion bodies, typically in oligodendrocytes. This list from Quinn is really to point out to you some of those things that are heralds of multiple system atrophy in the same way that we can think of the kinds of heralds for idiopathic disease. So, say for example, if I see somebody with disproportionate antecholis. Not just the sort of flexed posture, but actually that neck tucked down forward, I’m beginning to think of something else. If I’m hearing the story of wife complaining violently because husband with this disproportionate antecholis spends the entire night keeping her up with outrageous stridorous snoring, suggesting abductor vocal paresis – another characteristic feature of multiple system atrophy – in association with sleep apnea. I love this one. The involuntary sign, which actually to be perfectly honest is entirely non-specific in my clinic. Other things, other kinds of autonomic features, Raynaud’s phenomenon and of course the story of early urinary or bowel difficulties that you certainly would not expect in idiopathic disease in its early course, say within its first 5-7 years. I also find in this population that they are exquisitely sensitive – for whatever reason – to levodopa. These are the people who get very nauseous on it, or very orthostatic on it and at very low doses.
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So now some comments from Quinn’s list about some characteristic clinical features of this entity, multiple system atrophy, and three diagnostic entities that he thinks are most commonly confused with idiopathic disease. Ole Hornikowitz who was responsible for really describing in the greatest detail, in the late 50’s and early 60’s, the specific apparently specific cell loss to the pars compacta of the nigra, has made some arguments recently that it is striking to him how much – if you take a look at quantitative dopamine in the brain of parkinsonian’s – that the area that seems to be hardest hit is the putamen. Now a little bit later we are going to go through that horrendous wiring diagram that for some reason is so … everybody talks about it. For those people who go to the movement disorder section, I don’t know of any talk that doesn’t go over that ridiculous wiring diagram. So just in case they hit you with it – you know, movement disorders is not all of clinical neurology – but just in case I’m going to walk you through that diagram a little bit later on and why, in that diagram, the putamen might be of significance. But the point here is that the putamen seems to be hit relatively hard. This is a graph showing the relative dopamine ratio from caudate to putamen in, for example, three different related parkinsonian disorders. Or differential diagnosis of parkinsonism. He goes on to say that if you start talking about comparing dopamine in putamen versus the place where we think the lesion is in Parkinson’s disease, we find surprisingly that the putamen seems more hit than the nigra. Which seems strange. Except to say that that’s the projection pathway, so maybe that’s the reason why. But Hornikowitz is making the point that just when you think that you know what’s going on in Parkinson’s disease, the pathology is restricted to the nigra – well, of course it’s not. Extra-nigral involvement is one of the key features of this disease and that the extent of that extra-nigral involvement is going to play an important part in levodopa response, for example. And that’s basically the argument that Hernikowitz is making.