In this video Dr. Goldstein discusses geriatric dysautonomias including an introduction to autonomic synucleionpathies, Lewy body disease, Pure Autonomic Failure and Multiple System Atrophy.
Geriatric dysautonomias, this is where I do most of my research, especially in Parkinson’s disease, in pure autonomic failure, and in multiple system atrophy. All of these diseases are synucleinopathies, that means they all involve deposition of the protein alpha synuclein. In the case of Parkinson’s and PAF dementia with Lewy bodies, there are neurons in the case of multiple system atrophy the synuclein deposition is in glial cells – these are non-neural helper cells, which actually are the most prominent cell types in the brain. When I am dealing with a patient who is referred for orthostatic hypotension, I think of four steps. The first is orthostatic hypotension is a persistent consistent thing, if it’s part of the disease, persistent consistent thing. Often, I would say most of the time there’s an identifiable cause, such as a drug. There can also be a secondary cause like diabetes would be a very common one. Then I ask whether the orthostatic hypotension is neurogenic. And one way to tell if it’s neurogenic, remember, is from the Valsalva maneuver remember the progressive fall in blood pressure in phase two, the slow recovery of blood pressure in phase four. The fourth step, which is a little bit more research-y but I think is important clinically is, is the orthostatic hypotension that’s neurogenic associated with sympathetic denervation. In Parkinson’s disease with orthostatic hypotension, this is a blood flow scan, you can see where the heart is, but you do not see the heart at all on the sympathetic imaging scan, very dramatic noradrenergic deficiency.
In multiple system atrophy, in most cases the innervation is normal. In pure autonomic failure, you don’t see the heart, it looks very much like in Parkinson’s with orthostatic hypotension. Why is this important? It’s important because if a patient has denervation, then there’s a phenomenon called denervation supersensitivity. Basically, the receptors for norepinephrine are there in the heart blood vessel walls, they’re looking for norepinephrine, they don’t see it. So, they become supersensitive – nobody knows exactly what that means in the molecular terms. But as a result, if they see anything that looks like norepinephrine, they are going to respond. Denervation supersensitivity, actually referred to originally by Walter Cannon, if not Claude Bernard of 19th Century. It’s been known for long time. The mechanism is completely unknown, I’m sure there is a Nobel Prize for anybody who finds out what the mechanism of denervation supersensitivity is. But you can exploit it in terms of treatment, so if you give an alpha adrenal receptor agonist such as midodrine or norepinephrine precursors such as droxidopa, marketed it as Northera, those receptors – they are going to love it. They see a lot of norepinephrine and they are going to respond, plus these patients have baroreflex failure, so any increase in blood pressure is going to be buffered. So, in somebody who has a denervation, sympathetic noradrenergic denervation, the first line treatment would be a norepinephrine receptor agonist; either a direct agonist or a norepinephrine precursor. Somebody who has multiple system atrophy, let’s say, there probably would be some increase in blood pressure because they have baroreflex failure, but not as much as in PAF or in Parkinson’s with orthostatic hypotension. This is what a Lewy body actually looks like. In Parkinson’s disease, the main damage is in the Putamen. This thing that looks like a slug is the Striatum and it has two parts Caudate and Putamen. I think of a sad clown’s eyes and the eyes themselves are the head of the Caudate and then the eyeliner is the Putamen. And in Parkinson’s disease the main damage is at the level of the Putamen.
So, with that background now we can look at the patient. You can see here, this is what his Striatum looked like originally, and it was normal. Two years later, there were two phenomena. First, this is what his Putamen looked like and it looked a little bit chewed up compared to baseline, still within a normal range. But a second thing that happened was clinically, for the first time, he complained of visual hallucinations. Very strong finding that would fit with incipient dementia with Lewy bodies. By two years later, now you can see his Putamen is really messed up – more on one side than the other, which is what happens in Parkinson’s disease. So, I’m sure if I were to show this to an expert in Parkinson’s disease, this would be called Parkinson’s disease. PAF, pure autonomic failure, can evolve into either Parkinson’s with orthostatic hypotension or dementia with Lewy bodies. PAF is a rare disease, Parkinson’s with orthostatic hypotension is not rare. Dementia with Lewy bodies I think it’s underestimated how common it is, but certainly it’s second to Alzheimer’s disease in terms of geriatric dementia. And you can see here that PAF evolved into dementia with Lewy bodies the patient already had a loss of sympathetic nerves in the heart. The fluorodopa PET scanning was normal, but you can see that over the course of time it became abnormal, and this is a kind of pattern you see in Parkinson’s disease. This patient died and did have evolution from PAF into Parkinson’s with orthostatic hypotension. This is a normal sympathetic ganglion provided by Risa Isonaka. You see the tyrosine hydroxylase there in red and cell nuclei in blue and this is what we’ve seen in sympathetic ganglion from that patient who evolved from PAF into dementia with Lewy bodies and orthostatic hypotension. And you see that there’s hardly any sympathetic nerves anymore, instead there’s been a replacement by alpha synuclein, alpha synuclein is that major protein in Lewy bodies so this provided I think of pathologic proof that the patient did have evolution from PAF into DLB. What about people with Parkinson’s who don’t have orthostatic hypotension? Well, you can get evolution there as well and most, about half of people Parkinson’s who don’t have orthostatic hypotension, already have a loss of sympathetic nerves in the heart and a substantial minority have like a partial loss. On occasion, especially in young patients with Parkinson’s, they can have normal innervation. This shows the progressive loss over time. These are what glial cytoplasmic inclusions look like, very different from Lewy bodies and it’s kind of ugly looking, there are spots of alpha synuclein in glial cells. Now that you know the organization of the autonomic nervous system, just think back about what you would see clinically in a patient with autoimmune autonomic ganglionopathy. That’s from a circulating inhibitor of the neuronal nicotinic receptor and you can see that the neuronal nicotinic receptor is involved in every part, even the adrenal medulla. So, autoimmune autonomic ganglionopathy is one of the very rare situations that you can truly say is a cause of autonomic failure, the entire autonomic nervous system is shot.
David S. Goldstein, M.D., Ph.D
Chief, Autonomic Medicine Section
NINDS, National Institutes of Health