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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. Often, if you have a movement disorders practice and you get a basal ganglionic with pain, run the other way. I’ll tell you a case. Here’s what they do. I can’t go to a movement disorders conference anymore because they are just too long. You get these movement disorders guys and they bring their video tapes in, like half an hour video tapes. And they say, “I want to present a case of cortical basal ganglionic degeneration with pain.” Groan. Why? Because the pain is this deafferentation pain. So terrible pain, cortical deafferentation pain. So the guy - completely neurologic, completely straight-faced, completely like it’s no problem whatsoever - says, “Well the pain was intractable to the usual interventions, including 25 mg of Elavil and a variety of analgesic preparations and several other antidepressant trials, and therefore we opted to amputate the hand.” Oh, that’s good. So there’s this hush from the crowd. Because we all know how these central pain things can be and you try everything on the face of the earth, and so they amputate the hand and now the pain continues. Now it’s here in the stump. So what do they do? They amputate there. It’s like a Monty Python thing. So it’s just amazing and they guy is still telling us, so what are you going to do? A hemi-body-ectomy? But it’s true. Cortical basal ganglionic is a strange disorder and it’s associated with temporal parietal perfusion deficits on Spectra-PET. It’s widespread involvement on that side, characteristic presence of the achromatic neural inclusions in a variety of places in the involved hemisphere. And it has pathology that overlaps with Pick’s. With Pick’s disease. That’s at the level of PATH now, not at the level of frontal atrophy-sparing superior temporal varix. Not at that level, at the level of what it looks like under a microscope. Cheap Canadian Pharmacy

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. There’s a beautiful picture in the New England Journal about two years ago. You know, those images in clinical medicine. Yeah, Kayser-Fleischer ring. It actually looks like oculus senilis almost, but only on one side. Sort of a cloudy haze between the iris and the sclera on one side. Weird looking. It even had little flecks of copper in it. It was like copper deposition in there. There’s a little bit of white cloud to it too, almost like a cataract with a little bit of copper flakes in it. So have a mental image. You see neuronal loss all over the place, not only in the substantia nigra but also in other places. The putamen, the globus pallidus. Most have reduced ceruloplasmin. Now most will also have Kayser-Fleischer rings. By the time they have neurologic involvement, it has been said, 100% of patients will have Kayser-Fleischer rings, so they say. So why not just stop your workup by looking for Kayser-Fleischer rings? Well, because we are imperfect. Because most of the time when I refer to the ophthalmologist they say, “Oh God, another referral from Milwaukee.” Just means he doesn’t have it because he never does. Sort of like getting the echo in embolic work-up.
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The hepatic involvement in Wilson’s disease can be of many different types. As simple as hepatosplenomegaly. It can be a hepatitis, it can be portal hypertension. It can be a chronic active picture. It could be one of those “I don’t know what the cause of that person’s liver demise is, but I don’t know.” And the standard workup is, if the ceruloplasmin is low, it’s a very… if it’s low then you’ve got to chase it. Then you get your 24 hour urine. If that’s high, then you go to liver biopsy. That’s the workup of Wilson’s disease. Why? You want to be sure because you are committing them to a long course of chelation therapy if that is the case, but the reason to go through all this trouble is because it is one of the few reversible movement disorders that we have. Association again, chromosome 13 associated with young-onset parkinsonism, some familiality.

Supranuclear gaze palsy. We are talking about PSP. Supranuclear gaze palsy. Some associations. If the supranuclear gaze palsy happens, what is a supranuclear gaze palsy? Look at my hand, follow my hand down. Follow my hand up. So it is a palsy but why is it supranuclear? Because if I roll the head … up and down. Implication? The lesion must be above the level of the nucleus. It is not a probable paresis. That’s why it is supranuclear. Now we’ve defined that term so; the supranuclear gaze palsy happens in a kid, six-year-old. There is no differential diagnosis. Well, there always is but there’s one entity that leaps to mind with a little bit of parkinsonism. Niemann-Pick type C. Next case. Middle age, about 40, Wilson’s. Next case. Look for some facial myokymia. In old age, PSP. Next case. Quick, quick associations. Niemann-Pick, major pathologic finding; sea-blue histiocytes. Get a picture of it, look at it. That kind of thing. Quick, associations. I don’t know everything about Niemann-Pick. I just know that about supranuclear gaze palsy. For movement disorders, that’s almost enough. But especially for testing, I think you need to have associations. Neurofibromatosis type II, major association; it’s chromosome 22, it’s both acoustics, it’s optic nerve, that’s two. All those kinds of things you want to keep in your head and click off. Because you are sitting there thinking neurofibromatosis. That has something to do with the café-au-lait spots, doesn’t it? How big a café-au-lait spot? I don’t remember. I’ve been there. Wilson’s disease; autosomal recessive. When in doubt, they are always autosomal recessive, right? Associated with chromosome 13. Other little lists to generate, chromosomal associations, they kill us with this. Have some in your kit bag. You don’t have to know all of them, but you need to know some of them. Why? Because they show up in matching questions. That’s where they show up. Of course you all know about the enzymes and the kiddie stuff. Make sure you generate a list on that. Not only the enzymes, but what’s deficient because of the enzyme deficiency. Don’t get confused. You have to have two columns in your list.

Just a couple of very fatuous concluding observations. There are a number of therapeutic options in Parkinson’s disease and the fact that there are so many of them that we are talking about means that we haven’t found a cure. No surprise. We haven’t found the gene, we haven’t found the cure, but we are making some headway, I think. So that was my Parkinson’s talk. I’d love to get going on the movement disorder stuff.

The question is, why is it that people with parkinsonism, many different types, seem to improve with ECT? An awful good question. My rejoinder question is, why is it that ECT, what is the pathophysiology of ECT, helping depression? I don’t know nor do I understand why but it certainly is true. In fact, I’ve used ECT for the treatment of very recalcitrant Parkinson’s disease, but the real thing is that we don’t see it anymore. The epidemic of encephalitis lethargica, what, 1920, thereabouts. The last reported case of post-encephalitic parkinsonism in the 50’s? Something like that. Levodopa-responsive but weird. There were weird things in that post-encephalitic parkinsonism like - read those early descriptions -oculogyric crises with arrhythmo- mania. Think about that one for a second. So their eyes are off to one side, they are gyrating to beat the band like it’s an acute dystonic reaction. It’s most bizarre and that’s what post-encephalitic parkinsonism is all about. Very strange manifestations, is what I’m getting at. The path on these things … again, what are some of the other weird features? Tics, these oculogyric crises that I mentioned, sleep reversal, startle myoclonus, early dementia, all these kinds of things. The path on these things have Lewy bodies that you would expect but you see gliosis in midbrain nuclei. Perhaps associated with all the weird kinds of eye movement abnormalities that you see in that disorder. So I would underline sort of midbrain path in that. Also written about by the Oliver Sachs, at great length.
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The parkinsonism, dementia, ALS complex of Guam, which also goes by the much more poetical name of Lydego-Bodeg (?). I think the Lydego refers to the parkinsonism and the Bodeg refers to the ALS features of this disorder. Some people present early with motor neuron features, some people present early with parkinsonian features, but they all look like hell later on in life. Now, there has been some talk about putative neurotoxins associated with this disorder. I stress the word putative. Because there was much enthusiasm about these but it didn’t bear fruit. Two of them. What they did, of course, is they were looking at a plant, the cycad nut because they use it for flour to bake their bread and all that. So they looked at the cycad nut and thought they had found the neurotoxin in the cycad nut. They thought it was BMAA. This beta n-methylamine-L alanine. Then they also thought about cycasin, this methanol beta glucoside. So you will see those names or those terms associated with the disorder, although there is some controversy surrounding that so I’m not sure that would be a fair question. In that disorder, the pathology resembles Alzheimer’s disease much more so than Parkinson’s disease. So you see gliosis, you see tangles, you see plaques widespread throughout those specimens. Hard to distinguish, in other words, from Alzheimer’s disease. It would be very unfair of them to show you a picture of that and say, “Could this be ALS complex of Guam?”

This is the approach; know the disease, know a little bit about it, move on. Please do not feel that you have to have encyclopedic knowledge of all these things because you’ve got too much. You’ve already had your kiddie neurology stuff so you know how much you have to do. And please go through the process, especially for you guys who are starting your preparation early, generate your lists. Become familiar with lists and associations. That’s the way to go. You don’t have to know everything there is to know about Crabbe’s. You don’t have to know everything there is to know about Niemann-Pick. I tried, brief mental hospitalization, fine now. Please just go with associations, in my opinion. My feeling is that generate lists and associations.

Now as a result of this diagram, now you can become quite confused because in the direct system you have two inhibitions back-to-back. Two negatives, as it were, equaling a positive. Oh, how complicated. Let me try to make it simple for you. The net effect of the direct pathway is to dis-inhibit the thalamus. It must be dis-inhibited because dis-inhibit begins with a D. Dis-inhibits the thalamus, specifically. By that argument then, if I’m talking about the indirect pathway, the net effect of the indirect pathway, since it begins with an I, must be to inhibit the thalamus. Specifically the thalamus. That’s the way I remember it. The net effect of the direct pathway, D, is to dis-inhibit the thalamus. The net effect of the indirect pathway is to inhibit the thalamus. Now the gentleman in the third row says, “Well, what about dopamine?” all in due time. Because we have to add a couple of neurotransmitters in here. We have glutamate, we have inhibitory neurotransmitters. I asked this question to the residents, “The major inhibitory neurotransmitter in the central nervous system is … ?” who said glycine? I’ve got this incredible encyclopedic dissertation about glycine as an inhibitory neurotransmitter. Fair enough, it’s important, but it’s GABA. It’s GABA. I mean glycine is very interesting, fascinating. So is nitrous oxide, but … so GABA, they are all GABA-ergic. Now there are some co-transmitters in here too - I might screw this up because I always do - I think it’s substance P and dinorphine in the direct pathway and substance P an encephalon in the indirect pathway. I won’t write those down because it’s in my notes and I always screw those up. I apologize ahead of time. But there are some co-transmitters.
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So now the question becomes, “What about dopamine and dopamine’s projections to the striatum?” Because, after all, it is the nigra striatal projection so we might as well talk about it. Dopamine will project from the substantia nigra pars compacta to the striatum. But it’s getting too complicated, so I’m going to make it a little simpler. So now we are going to talk about the striatum here and we are going to talk about the substantia nigra pars compacta. This arrow will represent the direct pathway and this arrow will represent the indirect pathway. Dopamine projections onto both pathways mediated by different receptor populations. The direct pathway mediated by D1 receptors, which tend to be excitatory, dopamine projection to the indirect pathway at the level of striatum on D2 receptors, which tend to be inhibitory. Thus, in the normal state there is a general tendency to give some juice to the direct pathway and to put the brakes a little bit on the indirect pathway in the normal … (break in tape) In the inhibition of the indirect pathway what net result do we see? Relatively less direct, much more indirect by the model. So what are the bottom line consequences of that? Now we can go to the slides. The net effect of dopamine denervation over the course of time, as I mentioned before, less stimulation of the D1 mediated direct system, less inhibition of the D2 mediated indirect system, and two hot centers. Two hot places; the subthalamic nucleus of Lewy’s and globus pallidus pars interna. So in the early 90’s you see these reports in monkeys, MPTP monkeys. We put a hole in the subthalamic nucleus of an MPTP monkey associated with contralateral hemibody parkinsonism, and lo and behold we improved his parkinsonism. We actually put a hole in there. We also noticed that there was incredible firing rates in the GPI and perhaps this may have theoretical significance. You know when a scientist is writing like that, he is onto something. Sort of like Crick, Francis Crick, and Watson. At the very last paragraph of their page and a half contribution on DNA, “We think this finding may have theoretical and practical implications.” Now they are playing with GPI. Putting holes in GPI. People have been putting holes in GPI for many years, they just didn’t understand what they were doing. Now they think they understand it a little bit better because they see that they can measure the hot activity of motor-related GPI. They put a hole in that area, they see improvement in the cardinal aspect of Parkinson’s disease. How it explains why the dyskinesia’s go away, you’ve got me. How it improves tremor in certain cases, you’ve got me. But this is the operative model of many smart people in the MA group.

So how do we understand these phenomena that we see? Now we can go to a review of the pathways. I actually like to draw it out, so I’m going to go to the overhead momentarily. But it begins with this concept. And that is, the connection between cortex and subcortical structures. It’s been known since the turn of the century. Kahal was writing about it, a lot of people writing about it. The cortex is associated or linked to other aspects of other subcortical structures in a rather paradigmatic way that we’ve known about for a long time. So by cortex here, I’ll refer to specific cortical areas, let’s say the motor strip and the supplementary motor area, going to the structures of the striatum. If you don’t know now, then let me tell you, that the striatum, the corpus striatum is comprised by four major structures that arise from the same embryologic restive tissue then migrate to different anatomic locales during development. These four locales are: the caudate, the putamen, and the structures of the ventral stratum, which include the nucleus secumbans (?) and the olfactory tubicle. All part of the striatum. The striatum sends its projections - that’s the major receiving port, if you will, for the basal ganglia - sends its projections to the globus pallidus and its homologous areas. Meaning, the globus pallidus pars interna is functionally homologous to - basically does the same thing as - the pars reticulata of the nigra. Not the compacta but the reticulata of the nigra. So when I say globus pallidus there, I’m talking about the globus pallidus and its homologous areas specifically. The globus pallidus sends its projections to specific nuclei of the thalamus in the motor system, particularly VA and VL. And the thalamus sends its projections back up to cortex in loops. Many different loops. Five different loops that have been identified to date. Now that’s the simple diagram. Let’s make it a little more complicated. I want to show you where I am going to go with this. This is the wiring diagram that you all see in the movement disorders things, but rather than just show it to you I want to draw it out for you to give it a little more sense. We are going to run through the list a little more quickly, so I am going to go over it.
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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. From GPI to, and specifically, VA and VL nuclei in the thalamus motor system. Direct because there are only two arrows involved. Now the indirect pathway, so-called, makes a way-station stop at globus pallidus pars externa, externa to sub-thalamic nucleus of Lewy’s, subthalamic nucleus of Lewy’s to globus pallidus pars interna. From thence to thalamus. Thalamus completes its loop back upstairs. So the basic loop that I described to you before is still there, but now we’ve elaborated on it a little bit. The organizing principle behind this pathway is actually very simple. There are a lot of negatives in all of this. A lot of inhibition going on. In fact, most all of the arrows within subcortical structures are inhibitory and therefore GABA-ergic, with one exception which is the subthalamic nucleus projection to globus pallidus pars interna. The neurotransmitter therefore must be glutamate because it’s excitatory. Everything else is inhibitory within the structure because this projection pathway from thalamus going up to cortex also is excitatory and glutamate-ergic.