Dr. David Goldstein: How do we know this patient doesn’t have PAF (pure autonomic failure)?
Dr. Goldstein: She has neurogenic orthostatic hypotension. There isn’t any obvious secondary cause. She has no evidence of central nerve degeneration, parkinsonism’s, cerebellar atrophy, dementia, right?
Ms. Ashleigh Pike: I forgot (jokingly).
Dr. Goldstein: The fact that you say you’ve forgotten; means you didn’t forget (laughing). So, by some criteria, some definitions, she has pure autonomic failure. When we do our evaluation, we look for cardiac noradrenergic deficiency, part of the criteria for diagnosing pure autonomic failure. In her case, I’ll have to trust my recollection, she had remarkable loss of fluorodopamine derived activity in the heart, but a year and half later quantitatively she did have an increase in fluorodopamine compared to baseline. That never is in a patient of PAF. PAF is a progressive disease, whatever she had, is something that came on rather acutely, which is also very odd for PAF, and seems over the course of very frustratingly long time, had this partial recovery.
Dr. Wolfgang Singer: And one other important factor, age. PAF is a neurodegenerative disease and below age 30 it would be acquired. Right, (laughing)?
Anonymous: Did she have Horner syndrome from onset?
Dr. Goldstein: Did everybody get a chance to see the Horner syndrome? Anyway, that’s correct. She did have bilateral when I first saw her. And over time, the right side for some reason has in general recovered, she sweats on the right side, only. So, I don’t know why but this one is more prominent always on the right side.
Anonymous: Which antibody test?
Dr. Goldstein: Which antibody test? She was actually referred by Steve Vernino. He’s the world’s authority on autoimmune autonomic ganglionopathy. And at least at the time, she had a pandysautonomia, so it was reasonable to look for a circulating antibody to the neuronal nicotinic receptor – which mediates ganglionic transmission, which she was negative. That’s part of what the puzzle was because if she were positive, it would be easy, but she was negative and that’s how she ended up coming to the NIH.
Anonymous: How was treatment?
Dr. Goldstein: How was treatment? Imperfect. I would say I think, from the point of view here from the orthostatic hypotension you are quite responsive to droxidopa.
Ms. Pike: Yes, yes.
Dr. Goldstein: And actually, she had droxidopa today demonstrating that you don’t necessarily have to be off of your medicines in order to see an abnormal Valsalva response. Droxidopa is a norepinephrine precursor. It gets turned into norepinephrine, all sorts of cells. Does not have to be taken up in the sympathic nerves, and actually she’s a good demonstration of that because she has such severe loss of sympathetic noradrenergic innervation. The droxidopa still works because it’s the being turned into norepinephrine in non-neuronal cells that express the enzyme l-aromatic amino acid decarboxylase. This is what carbidopa locks with some of the enzymes, Sinemet. The plasma norepinephrine levels increase when a person’s on droxidopa and when the person is on droxidopa and carbidopa which prevents that conversion, then you don’t see the increase in plasma norepinephrine or the increase in blood pressure. So, it’s been taught, it’s not correct, but it’s been taught that the reason the blood pressure goes up in somebody on droxidopa is because of the increase in plasma norepinephrine. But we’ve measured the plasma norepinephrine, I think we’ve measured in your case because you were tested without and with droxidopa. And the increase in plasma norepinephrine with droxidopa is trivially small. It can’t possibly explain the increase in blood pressure that occurs in somebody on droxidopa. And Guillaume Lamotte, he was here but he stepped out, has a first authored paper based on his assessment of how droxidopa works that raises blood pressure, if it’s not by way of plasma norepinephrine. And if we gather that since the kidneys have a tremendous amount of DOPA decarboxylase, l-aromatic amino decarboxylase, and when the proximal tubular cells of the kidneys see and take up droxidopa, they think it’s DOPA, and they turn it into norepinephrine. As a result, when he measured the norepinephrine concentration in the urine, compared to the plasma, there was a humongous increase of norepinephrine in the urine. Droxidopa is a catechol, some of you know what catechol looks like, and so we can assay droxidopa and norepinephrine simultaneously, and our catechols assay, and we can show and I think your urine is an extreme example of it, that the ratio of norepinephrine to droxidopa in urine was 100 times that being plasma. Many, many fold higher. Well, if the norepinephrine and droxidopa in the urine were just coming from the plasma, that wouldn’t explain it. The finding of a tremendous amount of norepinephrine in the urine, in somebody on droxidopa, implies that there’s a lot of norepinephrine being made in the kidneys from that droxidopa. Well, norepinephrine in the kidneys has important effects on blood pressure, there’s local vasoconstriction, there’s stimulation of the Renin-Angiotensin-Aldosterone System, there’s stimulation of sodium reuptake, which can result in an increase in blood pressure as well. So, our current hypothesis is that at least one of the reasons the droxidopa raises blood pressure, is because of production and local action of norepinephrine in organs such as the kidneys and possibly in the gut.
Anonymous: With sympathetic failure and receptor sensitization, should you use low or high dose Northera?
Dr. Goldstein: That’s an interesting question. What’s being referred to here is denervation super sensitivity. If she has a dramatic loss of sympathetic noradrenergic innervation, the receptors for norepinephrine are looking for it, don’t find it so they become supersensitive. Nobody knows exactly what that means, supersensitive, but let’s just say for the sake of argument, that it’s from receptors accumulating on the membrane surface. In that situation, droxidopa which is going to generate norepinephrine, could reach these noradrenergic receptors that are supersensitive and you get a nice increase in blood pressure and I’m guessing that that’s the part of the reason that she does have a good response to droxidopa. The other reason would be the baroreflex sympathoneural failure which, we just demonstrated. If you have some stimulus that raises the blood pressure, if there is any baroreflex mediated inhibition of the sympathetic outflow, there isn’t any sympathetic outflow to inhibit. So, there are two reasons why the person could have a very nice increase in blood pressure with droxidopa.
Wolfgang Singer, MD
Associate Professor of Neurology
Mayo Clinic Rochester, MN