Dr. Wolfgang Singer: Alright. Well, we’ve come to the last portion of this and I thought at first we can simply do sort of a question/answer, I could show some interesting cases tell a little bit more about pitfalls, things to watch out for, but I think we have a live patient here, who would actually show us a Valsalva maneuver and how it can look different from Jade’s and I think Dr. Goldstein may introduce the patient a little bit and tell us about her history.
Dr. David Goldstein: Thank you (all clapping).
Dr. Goldstein: I’m Dave Goldstein from NIH and this is Ashleigh Pike. And Ashleigh very generously agreed to demonstrate what Valsalva looks like in a patient with a quite rare form of autonomic failure, called auto-immunity associated autonomic failure with sympathetic denervation. Ashleigh has been studied in a variety of institutions including ours. And we reported her case because she had neurogenic orthostatic hypotension that was quite severe, but it was associated with dramatically low plasma levels of catechols, all catechols, to the extent that we thought maybe she had a genetic cause of tyrosine hydroxylase deficiency, which she did not. Her fluorodopamine PET scanning showed also a very dramatic absence of fluorodopamine derived radioactivity in the heart meaning substantial sympathetic noradrenergic deficiency and finally a skin biopsy, which was analyzed at a follow-up by Risa Isonaka who is sitting over there, revealed hardly any tyrosine hydroxylase in arrector pili muscle, indicating sympathetic denervation. So, this is, this is not autoimmune autonomic ganglionopathy. This is a different form of autoimmunity associated autonomic failure.
She has a pretty dramatic unilateral Horner syndrome, meaning that there is ptosis, that’s a droopy eyelid, miosis – which I think since I’ve seen her last has gotten better – that means a constricted pupil, also enophthalmos, which sort of means the eyeball is kind of sunken in there, and although she won’t demonstrate it, decreased sweating on that side – anhidrosis. Also, as part of Horner syndrome, because of the nasopharyngeal mucosa having so much sympathetic noradrenergically innervated blood vessels, when patients with Horner syndrome get a cold, they, whatever side has Horner syndrome, the congestion is worse on that side. So, Ashleigh has the Horner syndrome but that’s not why she’s here. She’s here to demonstrate the Valsalva maneuver, we’re not going to do 40 mmHg, it’s excessive in this case, and the duration of the maneuver will be 12 seconds. I’m going to pretend that she’s never had this done, and I’m going to instruct her as I would a patient. The way we do it, we record and show the delivered pressure and then if the patient doesn’t rapidly get pressure up to where we wanted, we can say you know you have to get it up a little quicker, and so forth and so on. Different systems have different characteristics.
Dr. Singer: David, the expiratory pressure is actually displayed on the bottom panel.
Dr. Goldstein: Great, okay, so we want it to go to 30. Ashleigh we’re going to be doing this test, it’s a blowing test, all you have to do is breathe and you’ve been breathing for several years so I’m pretty confident you’ll be able to do this test but to be scientific about it, we’re going to have you blow into some device.
Mr. David Sletten: We’re not ready yet. We’re getting there.
Dr. Goldstein: It could be tubing that’s connected to a regular blood pressure meter so that the patient can see the needle and have a target, or it could be through a bugle kind of device, you have to have positive pressure in order to get that air through – different ways of doing this. And then the sequence is for 30 mmHg that’s a moderate amount of effort but I’m sure you’d be able to do it. So, the sequence will be as follows, don’t do anything yet, just listen. I’m going to say, “Take a slow deep breath, when I say deep breath that’s what I want you to do, I want you to let the air in and I want to see your chest actually rise, like an opera singer”. Then I’m going to say, “Blow”, that’s when you blow into the gizmo, whatever it is, and I’m going to use a stopwatch, that’s going to be for exactly 12 seconds. At the end of the 12 seconds I’m going to say, “And relax, don’t talk or move”, and when I say, “Relax”, that’s what you’re going to do, just let the air out, I don’t care what happens to the gizmo, it can pop out into the space, that’s okay. The pressure that you’re delivering is then going to down to 0, which is fine. Don’t talk or move unless it’s an emergency. Because we’re going to be measuring your blood pressure and every heartbeat both while you’re blowing and also when you relax, got it?
Mr. Sletten: So, we’re were waiting for a calibration here – we had a cuff issue. So, you were seeing there was a fault indicator that was coming up on the screen here and that told us that the cuff was bad so we had to run, go grab one really quick, so just give us about 2 minutes.
Dr. Goldstein: Okay.
Anonymous: Does the patient have anemia?
Dr. Goldstein: You have an anemia, right, you have an anemia, as I recall. You know, this is something that, we see that in people with chronic autonomic failure there. And you can have all the workup you want but in addition when I say autoimmunity associated, she has serum markers for lupus as an example, and there can also be an anemia associated with that. I don’t think it’s from vasoconstriction. Maybe while we’re waiting, I just want to talk about her, the clinical course, she, see if I remember right. You came up to the DC area to attend a Beyoncé concert and there’s a Merriweather Post Pavilion, I think, and you stayed with a friend I think in northern Virginia and it’s not clear whether you got sick before, or you we’re on the way to getting sick before, but after it anyway you got real sick; and was admitted for an encephalitis, I believe, and had inappropriate ADH secretion I think. So, this is quite serious and very rapidly she developed a pandysautonomia, pandysautonomia, for instance you had to be fed through a feeding tube, right? And I think you had urinary retention, but I’m not positive about that, and no sweating, no sweating at all. Sweating remember, is a sympathetic cholinergic system function. She had extreme orthostatic hypotension that’s a sympathetic noradrenergic function and she had a constant heart rate, that’s parasympathetic cholinergic function, so she had a pandysautonomia. She didn’t have adrenaline levels measured until she was at the NIH. Over the course of time, gradually the GI problem, the urinary problem, kind of receded but she still had severe orthostatic hypotension and lack of sweating. For those of you who took the Introduction to Autonomic Medicine course, you can begin to understand what parts of the autonomic nervous system were involved and why. Because the sympathetic postganglionic neurons are non-myelinated, they’re wispy, slow conducting and very long. The postganglionic parasympathetic fibers are short because most of the, most of the vagus nerve for instance is myelinated rapidly conducting and the postganglionic fibers are in, the ganglia, are in or near the target organ. So, because of this rapid recovery of the parasympathetic and continuing sympathetic problems, it seemed like there was an axonopathy, if you will. Because the sympathetic neurons are long, it’s going to take a long time for them to recover. The parasympathetic postganglionic fibers are short maybe they’ll recover quickly, at least that’s what I was thinking. Subsequently, over the course of a long period of time, she started to develop a little bit of sweating and it’s been about a year since I saw her, and she has a little bit more sweating but still way, way less than it’s supposed to be. And her fluorodopamine scan, when she was seen last, did show some fluorodopamine derived radioactivity so, there is evidence for recovery of the sympathetic noradrenergic terminals in the nerves that supply the heart. She’s due to come back for follow-up testing in March. And okay, so now we’re ready here, you can see her, you can see her blood pressure signal that’s in red there and it looks kind of weird because there’s a sudden, there’s that plateau that shouldn’t be there, should be a dicrotic wave and you can’t control the sweep speed, right.
Mr. Sletten: No.
Dr. Goldstein: But we can review up on the top, the record of the blood pressure as soon as she is done?
Mr. Sletten: Yes.
Dr. Singer: Now David, one thing to point out, you saw the recording of Jade’s before and you saw what the spontaneous blood pressure, how it varied. Look at this blood pressure, there’s not much variation going on, there’s not much variability, it’s a pretty steady pressure. If you do frequency analysis on this, we would have a very low power spectrum and that is already a sign of autonomic failure in itself so, even without doing anything.
Dr. Goldstein: Okay I think we can, you remember the instructions? That’s good, okay. So, put that in your mouth, just at first just breathe around it, breathe through your nose, don’t do anything yet. Okay are you going to be able to mark when I say, and mark when I stop?
Mr. Sletten: It’s going to do it automatically for us.
Dr. Goldstein: Alright, you ready? Take a slow deep breath, that’s good and go, and relax, don’t talk or move.
Dr. Goldstein: Okay we’ll do, we’ll do one more. Nobody gets this right the first time, it always has to be repeated and we repeat it until we get just the signals that we’re looking for. Okay so we’re going to give it another shot, so you can go ahead and put that in her mouth. At first just breathe normally, don’t blow into the thing. Alright, take a slow deep breath, that’s good and go, and relax, don’t talk or move. That’s pretty good recovery.
Mr. Sletten: How long do you want to wait?
Dr. Goldstein: Okay, that’s enough, I think. Now if you can display this pressure signals that would be helpful. Alright, well, it’s close enough for government work. What you’re going to see is that in phase 2, the blood pressure just sort of goes down, phase 3 this is the normal drop in blood pressure and then phase 4, you want to see a rapid return of the blood pressure and kind of an overshoot and then it sort of settles down.
Dr. Goldstein: Well what you want to get out is, this is her baseline pressure. So, it looks like she’s rapidly returning to baseline but in fact it’s taking a long time, there we go, okay now you can spread them out a little bit. There we go, okay. Let’s see what we got here. See the dicrotic wave moves down it’s even separated; this is a valid recording. See there’s a dicrotic wave there and then it goes down, it’s really important to be able to see the pressure signal itself, I think. And then here is the return towards baseline, here’s baseline, so you can see she actually hasn’t returned to baseline in all this time. That’s grossly abnormal. The way we quantify this is we look at the baseline pressure, which goes below baseline, the pressure goes below baseline here and then we just simply integrate this area right there, is the lowest pressure. We integrate that area using a trapezoid rule and then when the person finishes, we integrate the area under the baseline pressure, which in this case is going to be a huge area and we take the log of that because it’s very difficult to figure out when you’re exactly back to baseline, so this is kind of equivocal. I don’t see the progressive fall, but the return to baseline is very abnormal. There’s no overshoot at all. Can you display her heart rate?
Mr. Sletten: The green on top is the heart rate.
Dr. Goldstein: The green on top is the heart rate.
Mr. Sletten: This is the heart rate.
Dr. Goldstein: From 0-250 is, pretty drastic. How about going from let’s say from 50-150. Okay, now you can see that when her blood pressure’s going down, her heart rate clearly is going up. That’s a baroreflex cardiovagal response that involves integrity of the parasympathetic cholinergic system. So, what we’re seeing here is a discrepancy between the sympathetic noradrenergic response which is screwed up and the parasympathetically mediated cardiovagal response. I have to find out what the numbers are, but I can certainly see an increase in heart rate is, there’s going to be some baroreflex cardiovagal function, whether it’s normal or not, I don’t know. You see anything else there Ashleigh? Good (laughing). I’m supposed to be the expert. So, thank you very much there. I hope this is sticky that somebody who has baroreflex sympathoneural failure as a cause of orthostatic hypotension, that person has a prolonged phase for pressure recovery time and no rapid overshoot in pressure. Okay, thanks a lot.
Dr. Singer: And I’d like to correct Dr. Goldstein, it was not grossly abnormal; it was just abnormal (laughing).
Mr. Sletten: I’ll let you guys are worry about it (laughing).
Dr. Singer: Thank you for doing this.
Wolfgang Singer, MD
Associate Professor of Neurology
Mayo Clinic Rochester, MN