Click here to view next page of this article New Treatments for Parkinson's Disease and Movement DisordersParkinson’s disease. Cardinal features of Parkinson’s disease are rigidity, slowness of movement and tremor, postural instability being another cardinal sign. Blepharospasm, weird kinds of dystonia’s, weird kinds of striatal toes and odd things that happen when they swallow. But the point is that the early presentation, as you know, is an asymmetric presentation. 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. 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. 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. 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. 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. 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. 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? 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. 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. 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. Like I said, then … so we were talking about the cortex, right? And here I’m specifically talking about primary motor area and supplementary motor cortex, supplementary motor area. Sends its projections to stratum. Now there are two pathways from the stratum. The first one is the so-called direct pathway. The direct pathway is direct because it goes from the stratum, particularly the caudate and putamen and its homologous structures, substantia nigra pars reticulatum. Wilson’s disease is in the differential diagnosis of parkinsonism that presents early. It has certain characteristic features, including this really weird wind- beating tremor, this odd sort of spastic gait. It has a mix of parkinsonian and long-tract spastic signs. The Kayser-Fleischer rings. There has been a picture of that. You can see it. It’s a gross examination. You don’t have to see it on slit-lamp exactly. Cortical basal ganglionic degeneration is a very weird disorder, very weird disorder. It is the only movement disorder in which it behooves you to do a sensory examination and a cortical sensory examination. It has been associated with these weird, sort of alien limb things, cortical sensory deficits. Very weird movements of the arm. So you ask them to do some kind of apraxia test and they will sort of do some kind of weird thing. "I’m trying, Doc, I’m trying." Virtually no cortical sensation in this hand. Strictly unilateral. Hallervorden-Spatz disease. Now why you should be inclined, if you are not a movement disorders person, ever to worry yourselves about Hallervorden-Spatz disease I’ll never know. But it is associated with a very characteristic MR. It literally looks like there are tiger’s eyes looking right back at you. Multiple system atrophy. I mentioned to you before. A constellation of three entities; Shy-Drager, which in the older nomenclature was going by the term idiopathic orthostatic hypertension, or pure anatomic failure. Olivopontocerebellar atrophy, or PCA, striatal nigral degeneration. The clinical picture of these things varies of course. There’s all kinds of issues. Like an OPCA can start off with a little bit of appendicular dysmetria, truncal ataxia. Progressive supranuclear palsy, the major features of that disorder there. To organize your trivia, I just gave you that little vignette a little while ago. You know what I mean by supranuclear gaze palsy, you know that there is a difference in the disease processes at different ages; Niemann-Pick in youth, Whipple’s in middle age and PSP in older ages. Men tend to be involved, and there is a picture associated with progressive supranuclear palsy. Machado-Joseph’s disease. I mention it because there is a lot of interest in the spinal cerebral ataxia’s. Seven types have been identified. I’ve seen seven and they are all CAG, Triplet repeat diseases. Basically there are now chromosomal associations for at least five of the seven types. But the concept here is that all these ataxias, they think, are associated with Triplet repeat disease. You’ve got to know a little bit about the Triplet repeat diseases. The paradigmatic Triplet diseases: Huntington’s disease. Neuroid-acanthocytosis. Autosomal recessive. I like this disorder because it embraces a lot of different things. It embraces a little bit of a picture. These are the things, the acanthocytes, on a saline preparation in the blood. Just a smear with a little saline, they have acanthocyte formation. They have a little elaboration of CK but no myopathy to speak of. Weird movement disorders. In the differential diagnosis of a hyperkinetic movement disorder, early onset, no explanation. Paroxysmal kinesigenic choreoathetosis and the paroxysmal non-kinesigenic choreoathetosis because when I was reviewing the tests over recent years, I saw it on a matching thing and I said, "Those bastards. Why would they take a general neurologist and ask him about PKC?" The difference is, PKC is weird. It begins with this kind of strange, funny feeling and then they begin a movement and there is something weird. I’m going to pass over the hypnagogic dyskinesia. That’s the sleep disorder stuff. Sleep disorder people like to talk about that. The things that happen as you are drifting off to sleep. Isaacs’ syndrome - Isaac was a man, by the way, a real man - Isaacs’ is a variant of stiff-person syndrome. It’s not an axial disturbance, it’s an appendicular disturbance. Much more distal but it’s a variant on the theme of stiff-person syndrome. I don’t want to talk about progressive encephalomyelitis with rigidity, I just don’t. Hereditary dystonia, I do want to talk about that. Now when you see a dystonia, what’s weird about it is that it can be easily confused with spasticity and it can be easily confused with a kind of astasia abasia of complete ludicrous-ness that wastes your time. In a young person, in an Ashkenazi Jew for example, although it has also been described in the Philippines - it is a well-recognized disorder with an associated chromosomal abnormality. Touretteism. Look, Touretteism is a symptom. A symptom of many different things. What I’ve done for you is provided the TSSG criteria for Tourette’s disease, just so that you have seen them. The Tourette’s Syndrome Study Group criteria. I think people who have seen Tourette’s know the story. The criteria say onset before age 21. It’s always much younger. Don’t you find? I always find the onset of this, at least in some way, shape or form, before the age of like 10. Sandifer’s syndrome. I mention it because it’s in the differential diagnosis of pediatric neurologic cases, and you will get them. Remember, in your orals you will spend at least one part with vignettes, pediatric vignettes. And the pediatric vignettes can hurt you. So have in your mind, because all of you will pass the written part, this is something that we will assume. Now, myoclonus. Two types of myoclonus. If I had my hands like this and I had a needle in the extensor compartment of the arm and I hold it like this so it must be firing, because I’m extending my hands at the wrist. I would see continuous firing and then a transient drop, firing, now it’s firing again and transient drop and firing. This is the so-called negative myoclonus. So it can be a drop out and firing, or alternatively firing. Unverricht-Lundborg disease. Here’s the list. In that list is this family of MERF diseases, myoclonic epilepsy and regular end fibers. The significance of MERF and to a certain degree - as well, is that we have now seen. I want to get to two other points on this list and the first is palatal myoclonus. Now palatal myoclonus is a weird thing and it is associated with a little anatomic factoid that people like to ask about so I’ll review it for you. Here is the phenomenon. This is some kind of, I don’t know, 76-year-old hypertensive, diabetic, alcoholic, multi-system renal failure. Just to end the case, there’s this weird syndrome of painful legs and moving toes and is just what it is called. What the presentation is, is typically in someone who has had a failed back or some kind of radiculopathy this is what happens. |