In this video Dr. Goldstein presents several helpful autonomic function tests including the tilt table test, the heart rate variability test, the Quantitative Sudomotor Axon Reflex Test (QSART) and other helpful tests.
Tilt table testing. You probably have come across this a lot and what good is tilt table testing? Well I think the main purpose is to identify and study the mechanisms of orthostatic hypotension. So, for instance, when a person is tilted and the blood pressure goes down, as you can see in that blue arrow, and heart rate doesn’t change at all, that points to a baroreflex problem, right? Heart rate is supposed to go up, it’s not. So, this suggests a neurogenic cause of orthostatic hypotension.
Another test that’s done is heart rate variability. Heart rate variability in the time domain just means, how much does your heart rate change over time. A constant heart rate is bad. You don’t want a constant heart rate. You want a heart rate that goes up a little bit when you take a slow deep breath in and goes down when you breathe slowly out. That’s called respiratory sinus arrhythmia, it’s not an abnormality at all, it’s normal. In somebody who has a kind of a metronomic heart rate, it doesn’t change at all, that’s bad, that’s abnormal. And this is what you find about heart rate variability in the time domain in somebody with Multiple System Atrophy.
What about in the frequency domain? This is a much more difficult to kind of convey but imagine how much power there is for your heart rate variability. This is your heart rate, and each time you’re taking your breath in it’s going up, but then it sort of looks like this. In other words, there’s also a slower wave for that heart rate variability. So, you have power at the respiratory frequency, respiratory sinus arrhythmia that’s normal, but there’s a low frequency power and researchers have argued for years and years about what that low frequency power represents. And, in a nutshell I think that the low frequency power has something to do with the ability to modulate autonomic outflow to the heart by baroreflexes. It’s not a measure of autonomic tone, it’s a measure of the ability to modulate that tone. With the thermostatic analogy it’s not like you’re measuring the activity of the furnace, you’re measuring the ability to modulate activity of the furnace by way of the thermostat. Gastric emptying. We talked about how catecholamines slow gastric emptying. There of course are many other reasons why you can have slow gastric emptying, but that’s a common feature in patients who have functional types of dysautonomia. They’re adults, the apparatus is there, it’s not being regulated right.
A QSART – this is a test of the sympathetic cholinergic system, remember that’s the major system involved with sweating. The way it works is, acetylcholine, which is as you know the chemical messenger that mediates that sweating response, is delivered to the skin by electricity by iontophoresis. And then by way of an axon reflex, the person’s own sympathetic cholinergic nerves release the person’s own acetylcholine nearby, so there’s sweating nearby. And that’s the basis of the QSART. If you don’t have sympathetic cholinergic nerves, because it’s a problem, then you’re not going to have a normal QSART. You could have intact sympathetic cholinergic nerves, still have a problem with temperature regulation, like happens in Multiple System Atrophy, and if the person is put into a heat chamber, the person doesn’t sweat like the person is supposed to. Well, why would that be? And what’s taught is that in Multiple System Atrophy, because the sympathetic cholinergic fibers are there, it’s a brain problem regulating temperature, but the sympathetic cholinergic nerves are there. In that situation the QSART is normal, even though the thermo regulatory sweat test, where you’re put in this hot chamber, is abnormal. There are other reasons for doing the QSART. To look for what’s called, small fiber neuropathy. Remember the sympathetic cholinergic fibers are, well I ask you, are they myelinated or unmyelinated? Unmyelinated, they’re postganglionic fibers. So, if you have a small fiber neuropathy, the QSART could be abnormal because of the problem with the postganglionic fibers.
Nowadays there’s a way to see sympathetic innervation, at least in the heart, by a special type of scanning, and there are two types of sympathetic imaging agents that are used. One is a catecholamine. The catecholamines are substrates for the cell membrane norepinephrine transporter, they get into the sympathetic nerves and then inside they get translocated into the vesicles. Non-catecholamine imaging agent like MIBG also gets into the nerves, but you can see there’s a difference. MIBG gets taken up in the vesicles, the catecholamine, like fluorodopamine, can be metabolized and the radioactivity comes out. From a scientific point of view, this is really important. From a clinical point of view, it doesn’t really make a hell of a lot of difference. If you don’t have sympathetic nerves in the heart, then you’re not going to have this norepinephrine transporter and you’re not going to see the radioactivity from either type of imaging agent. This is what MIBG looks like. It’s often referred to in the literature as a norepinephrine analogue. Now is MIBG is a catechol? It’s not a catechol. Where are the two adjacent hydroxyl groups on the benzene ring? It’s not a norepinephrine analogue, it’s not even close. It’s an analogue of a different type of sympatholytic drug called Guanethidine. But it is a substrate for the cell membrane norepinephrine transporter and so it does radiolabel the sympathetic nerves in the heart.
This I think is something for the future. You can see sympathetic nerves under a microscope. If you look in a skin biopsy sample and underneath the epidermis in the dermis here, there are three structures that receive sympathetic noradrenergic nerves. There is arrector pili muscles, these are the little muscle that cause your hair to stand up when you come out of a Jacuzzi and go into a cold locker room let’s say. Every hair you’ve got has a little muscle called an arrector pili muscle, it receives pure sympathetic noradrenergic innervation, so it’s very handy. You’ve got blood vessels that have sympathetic noradrenergic nerves, that’s why the Valsalva maneuver for instance works in terms of blood pressure responses. And although I’ve taught that sweat glands receive sympathetic cholinergic innervation, they also receive sympathetic noradrenergic innervation, and you can see that here – this red is tyrosine hydroxylase. It’s the rate-limiting enzyme in norepinephrine synthesis. So, although it’s taught that the sweat glands receive sympathetic cholinergic innervation, it’s true, but they also have sympathetic noradrenergic innervation. And by technique called immunofluorescence microscopy, you can see the tyrosine hydroxylase containing fibers and arrector pili muscles around blood vessels and around the sweat glands. This is the work of Risa Isonaka.
David S. Goldstein, M.D., Ph.D
Chief, Autonomic Medicine Section
NINDS, National Institutes of Health