Robin (00:01):

Hello, and welcome to today's installment of Diagnostics in Practice, where we discuss new and innovative diagnostic offerings from Mayo Clinic Laboratories. I'm Robin Huiras, a senior marketing specialist with Mayo Clinic Labs, and strong proponent of advanced laboratory testing to improve patients' lives. Today, I'm joined by Dr. Andrew McKeon, a Mayo Clinic neurologist and co-director of the Neuroimmunology Laboratory at Mayo Clinic, to discuss dysautonomia testing. Thanks for joining us today, Dr. McKeon.

Dr. McKeon (00:32):

Oh, thank you very much, Robin, for the invitation to discuss autoimmune autonomic testing.

Robin (00:38):

Now, before we dig into our discussion topic, I'm hoping you can share with our listeners a little bit about your background at Mayo Clinic and specifically about your experience with autoimmune dysautonomia testing.

Dr. McKeon (00:51):

Sure. I'm a neurologist by way of background. I trained in general neurology residency in Ireland, and then did subspecialty fellowships in movement disorders and autoimmune neurology at Mayo Clinic. And I've been a staff neurologist at Mayo since 2009, and I have a joint appointment in Lab Medicine, where I co-direct the Neuroimmunology Lab. So autoimmune neurology really encapsulates all of the specialty work relating to different neurology subspecialties and how they interface with the immune system. And so that could be everything from autoimmune encephalitis to autoimmune ataxias, movement disorders, and what we're discussing today, autoimmune dysautonomia. So, we have a very strong autonomic neurology group here at Mayo Clinic, also, who characterized a lot of the autonomic disorders, including a collaboration dating back some years ago between Dr. Low and Dr. Lennon, where they described autoimmune autonomic ganglionopathy.

Robin (01:51):

Thanks so much for providing those details, Dr. McKeon. Your experience in this space really highlights the expertise that supports test development at Mayo Clinic. Now, to set the stage for our conversation, I'm hoping you can provide an overview of dysautonomia. What is it and how does it manifest in patients?

Dr. McKeon (02:09):

Well, the autonomic nervous system, when I'm counseling patients, sometimes I tell them so that they can try to remember the word better, is it's like the automatic nervous system. So, this is that primitive part of the nervous system that innervates some basic bodily functions like blood pressure, heart rate, gut motility, bladder function, sweating, heat regulation. So, dysautonomia means that there's dysfunction in those modalities of function. And so that can manifest with one or more manifestations, including feeling faint, blacking out, having an overdistended bladder that's hard to empty, heat stroke, difficulty with regulating heat and sweating, and then gastrointestinal dysmotility, which can manifest in many different ways. So it could be that people get full very easily when they start to eat a meal, what we call early satiety, and leads to vomiting, or could be what's called pseudo-obstruction, which means that somebody may present to an emergency room with what seems like to be a bowel obstruction, but there's actually no mechanical obstruction at all.

It's just that the nerves are not innervating the gut the way that they should be and causing that motility or that contraction of the gut smooth muscle to move food along. And then finally, some patients can develop very severe constipation or what we call obstipation, and then also sexual dysfunction, so erectile dysfunction.

Robin (03:38):

Got it. Thanks for providing us with those details, Dr. McKeon. And what are some of the causes of dysautonomia?

Dr. McKeon (03:46):

So dysautonomia really can intersect with a lot of different types of neurologic disorders. So, one could take the degenerative disorders. So, when we talk about neurodegenerative disorders, a famous one that's well known would be Alzheimer's disease, but there are forms of neurodegenerative disorders where dysautonomia is a very prominent manifestation. So, the key one there is multiple system atrophy. Then there are a whole host of metabolic disorders, vitamin deficiency states that can result in autonomic problems. And then there are autoimmune disorders, which we will discuss today. And then there are some genetic phenomena as well. So, some patients could have a hereditary neuropathy that includes autonomic failure. There are some very elderly people who develop primary autonomic failure where there really doesn't seem to be any other associated features. So, they don't have multiple system atrophy, they literally just have the autonomic failure piece. And then I suppose one other disorder that's very common is diabetes mellitus.

So that's probably the most common form of autonomic failure. Rather than just the peripheral nerves in the feet being involved, leading to numbness or weakness in walking, there are some people who develop dysautonomia, or loss of autonomic function, often after decades of diabetes or who have had diabetes that's poorly controlled.

Robin (05:09):

Got it. Thanks for breaking down all of those causes of dysautonomia, Dr. McKeon. Since you specialize in autoimmune disorders, I'd like to talk more specifically about autoimmune dysautonomia. And I'm wondering if you can share if there's a specific patient profile for this type of cause.

Dr. McKeon (05:29):

This would typically arise in patients who are anywhere from the 20s up to the 70s who are presenting with lightheadedness and fainting that's unexplained or gastrointestinal motility problems, so that they often have been to a cardiologist or to a gastroenterologist in the first instance. Sometimes there's a lot of fatigue that kind of goes along with that as well. There may be autoimmune disorders in the background as well, so the patient may have a clue to some autoimmunity. The other group of patients we have to think about are patients who have cancer or have had cancer in the recent past. And so, their autoimmune dysautonomia may be paraneoplastic or an aberrant immune response to a cancer that is then unleashed on the nervous system and manifesting as dysautonomia. That group of patients we usually have to think a little bit about because there could be other factors leading to autonomic failure, such as chemotherapy.

Robin (06:30):

I see. Some of the symptoms you're describing, Dr. McKeon, sounded to me like a common condition called POTS. Can you explain how POTS and dysautonomia might be confused?

Dr. McKeon (06:44):

Yes, they can present in very similar fashions. In fact, we are often asked to evaluate patients where autoimmune is being considered, but POTS turns out to be the cause. Postural orthostatic tachycardia syndrome can manifest with orthostatic intolerance, meaning that the person has lightheadedness or feeling faint or feeling fatigued or feeling like they're losing function when they stand up and when they walk around. When it comes down to it, in the assessment of those patients with the type of detailed autonomic electrophysiology testing we do at Mayo, it becomes apparent that the person has really restricted orthostatic tachycardia, just as the name suggests, and does not have other features of autonomic failure. So, the autonomic testing, electrophysiology testing, can be very helpful in that situation and then can be complemented by autoantibody testing as well.

Robin (07:36):

Thanks for talking a little bit about those differences. It sounds like sorting through the possible causes to get to the correct diagnosis for autoimmune dysautonomia can be a little bit of a diagnostic odyssey. So, I was hoping we could shift gears just a little bit and talk about diagnosis. Can you walk me through this process?

Dr. McKeon (07:55):

Sure, absolutely. So, the key to the evaluation here in the first instance is really getting a very good history and exam. And a key feature with this disorder is, often it can be either subacute or insidious, which is a little different to a lot of autoimmune neurologic diseases. So, with autoimmune neurologic diseases of the brain, for instance, things occur usually over days to weeks, and people develop disability quite quickly. Whereas with autoimmune autonomic ganglionopathy or other forms of autoimmune dysautonomia, it can be a little more insidious. And that might be because of the types of symptoms people have, where they're manifesting with gastrointestinal symptoms to begin with and they're probably going to their primary care doctor and then maybe a gastroenterologist. And then as they're going through that process, then maybe other features start to become apparent, like lightheadedness and fainting. So, the other key things then are really excluding other components, because as mentioned, the differential diagnosis includes this disorder called multiple system atrophy where people have literally involvement of multiple systems within the body, not just the autonomic nervous system.

So, really being careful to exclude things like cerebellar ataxia occurring alongside the dysautonomia or Parkinsonism or indeed dementia, because there are some patients with a disease called Lewy body disease where dysautonomia occurs also. And then really on the history and exam side, listening for those features that might make one think of POTS in that particular age group as well. So, that's kind of the starting point. And then after that, then it's some neurophysiology testing that is done, and that could be the autonomic reflex screen that I mentioned or another test we do here called a thermoregulatory sweat test. Sometimes MRI imaging might be important to look for features of multiple system atrophy or cerebellar degeneration. And then EMG testing is sometimes helpful as well, because as mentioned, there are some autonomic disorders that manifest with the somatic peripheral nerves that affect the hands and feet predominantly as well as the autonomic.

And that wouldn't be typical for autoimmune autonomic ganglionopathy one might find in a hereditary disorder. And then finally, autoantibody testing. And so, once the phenotype has been established, so this is what the person has, they have a pure autonomic problem, it looks like an autoimmune autonomic ganglionopathy or other autoimmune autonomic disorder that's in the differential diagnosis, then autoantibody testing comes into play.

Robin (10:17):

Thanks for walking us through that diagnostic process, Dr. McKeon. I'd like to shift gears now and talk about how Mayo Clinic tests for autoimmune dysautonomia. Is this a new test offering from Mayo Clinic Labs?

Dr. McKeon (10:29):

No, it's been around for a few years, and so I think we've had a formal evaluation for this. Boy, I'm thinking probably seven or eight years. Prior to that, the autoantibody was offered in other evaluations, so it was kind of mixed in with other disease states, but we didn't specifically have an autoimmune autonomic evaluation. The antibodies have been around for a few years. So, for instance, the alpha-3 ganglionic acetylcholine receptor antibody was discovered in the 1990s.

Robin (10:59):

Thanks for giving us a little bit of the history of how this test has evolved through the years. It sounds like it has a really great origin story with our researchers discovering this alpha-3 antibody, and it continues to evolve to provide meaningful results to patients. Is there anything specific about the way that our test is done, the method that's used, that sets it apart from tests offered by other laboratories?

Dr. McKeon (11:25):

Sure. As mentioned, the test was developed here at Mayo Clinic and described here. Two observations that have given us pause as far as, should we continue to offer the test in the fashion that we do, is number one, the assay is a radioimmune precipitation assay, which means that there are radioactive reagents associated with that, which is not ideal for our lab staff. And then secondly, while the assay is very sensitive for picking up autoimmune autonomic ganglionopathy, it also generates some false positives, particularly in the low-positive end of the range. So, we've been very clear with people over time that it's better really to only to test for this antibody where there's a high pretest probability that the patient has an autoimmune autonomic disorder. But we have been able to offset both of those risks by development of a live flow cytometry cell-based assay that doesn't involve radioactive reagents.

And when we've done a case-control study, we haven't picked up any false positives, and maintained our sensitivity as well. So, we're very excited about this. We have a paper that's under review at the moment, and we look forward to this test going live in our practice.

Robin (12:29):

Yeah, that's very exciting to hear. Thanks for providing those insights, Dr. McKeon. In your opinion, which medical specialists would be most likely to want to order this test for their patients?

Dr. McKeon (12:43):

I think there are a number of different groups. So, within neurology, I would think general neurologists. So, oftentimes in the hospital setting where there's somebody with problems with low blood pressure, what we call orthostatic hypotension, which means blood pressure dropping on standing up, neurology are asked to come by and evaluate those patients. Then in gastroenterology practice, I think this will be important, particularly in the subspecialty of motility clinics within gastroenterology. And then in cardiology, I think it also comes up, this possibility of an autonomic disorder, because frequently when patients are presenting with syncope, lightheadedness, fainting, and so on, the initial thought is, well, perhaps this person has heart failure or some other cardiovascular cause for those presenting symptoms.

Robin (13:31):

Got it. Thanks for providing your insight on that, Dr. McKeon. I just want to swing back a little bit to the advantages that this test offers. You mentioned the live-cell flow cytometry method. Are there other aspects of our tests that are advantageous?

Dr. McKeon (13:53):

Sure. I think that the overall design of the evaluation I think is advantageous because from our own knowledge from clinical practice and review of the literature, we know which autoantibodies are pertinent to autoimmune dysautonomia. So, there are some antibodies that are relevant to that disease state, but then there are many other antibodies that just aren't relevant. So, for example, ANNA1, so known as anti-H- U or anti-Hu, is relevant to autoimmune autonomic neuropathy in the setting of lung cancer. And then there is other autoantibodies like adapter protein 3B2, which is relevant in patients who present with maybe ataxia and dysautonomia or a myelopathy and dysautonomia. And then there's a disorder known as DPPX autoimmunity, where patients actually present with too much autonomic activity. So, patients frequently present with diarrhea and weight loss before they develop other kind of more clearly neurological phenomena. We really design our neurological evaluations around the phenotype about how patients present so that when a provider has a potential autoimmune autonomic patient in front of them, they're not trying to pick individual tests or have that kind of level of knowledge that a laboratory expert would have and can just order the test.

Robin (15:13):

Nice. Thanks for calling out that differentiator, Dr. McKeon. I think that is so important that the relevant antibodies are included in this test. And kind of as a segue to the next question, for patients who do have positive antibody results and are identified definitively as having autoimmune dysautonomia, what is the next step for them?

Dr. McKeon (15:37):

It depends on the autoantibody identified. So, in the setting of maybe ANNA1 neurological autoimmunity, the first thing to do would be to search for a small cell carcinoma either in the lung or extrapulmonary because there's approximately 70 to 80% positive predictive value for cancer found in those patients. And then if that's negative, then the patient would require surveillance scanning for every three to six months for a couple of years. Then there are other autoantibodies where maybe it's a benign neoplasm association, but at a much lower frequency, such as CASPR2 autoimmunity, we'd be thinking about thymoma and looking for thymoma. But if we don't find thymoma, we're not going back and looking for that again. And then there are some disorders where we really very rarely encounter cancer at all, such as the alpha-3 ganglionic acetylcholine receptor antibodies. So, in that situation, we might screen generally for cancer one time and then not do any further testing beyond that other than what would be appropriate for age and sex.

So then thinking beyond cancer testing, then we'd be thinking about immunotherapy. So, we're trying to bring about reversal of the autoimmune autonomic problems. And so, corticosteroids, intravenous immunoglobulin, or IVIG plasma exchange would be pretty standard first-line treatments. For patients with paraneoplastic disorders that have very severe problems that don't respond to those treatments, sometimes cyclophosphamide will be considered. For patients with an antibody-mediated disease such as CASPR2 autoimmunity, we would typically consider rituximab as a further treatment and also as a maintenance therapy. And then there's also just treating the disorder symptomatically. And so, for patients with orthostatic hypotension or low blood pressure standing up, we typically recommend fludrocortisone to enable retention of salt and water, midodrine to try and boost the adrenergic system to drive blood pressure up, and sometimes fluid and salt replenishment, and then compression garments in the legs or around the abdomen to try and just increase venous return.

And then there are some medicines that we use to try and promote GI motility as well, such as pyridostigmine, that's usually a treatment for myasthenia gravis, but can also stimulate the gut. And then we measure all of this, because a lot of the time patients will have been sick for quite some time, they may not feel the immediate benefits of the treatment, but autonomic neurological testing, this autonomic reflex screen or thermoregulatory sweat test, we can follow these over time to see objective improvements of treatment.

Robin (18:09):

Thanks for detailing all of those treatments, Dr. McKeon. It sounds like there's a lot of hope for patients who have this diagnosis in terms of getting better and curing their illness. I'd like to take a step back, if you don't mind, and talk a little bit about the interplay between electrophysiology testing and antibody testing, because you've mentioned the electrophysiological testing a couple of times. So, I'm curious, what are your thoughts on the advantages of having access to both types of testing for patients with suspected cases of autoimmune dysautonomia?

Dr. McKeon (18:42):

I think having this type of testing is key. Measuring the autonomic nervous system clinically is quite difficult to do. So, it would be quite different to maybe an encephalopathy or a spinal cord disorder where a clinical exam can give us a lot of information. That's more difficult with autonomic disorders. We can essentially kind of measure the pupil and what responds to light, and we can measure the blood pressure lying, sitting, and standing. So, it's a little rudimentary. So having this kind of advanced autonomic testing really helps us. And so, when we establish then, kind of the phenotype using this testing along with our clinical history and exam, we can then define, OK, what does this fall into? Does this fall into an isolated autonomic nervous system disorder with involvement of cardiovagal adrenergic and sweat function, or is this kind of a very isolated disorder like POTS?

And then once we've kind of established, yeah, this looks like kind of quite a severe dysautonomia, then I think autoantibody testing becomes really pertinent. And so that particular test then, as mentioned, really is quite tailored for patients with these kind of autonomic problems.

Robin (19:54):

Thanks so much for sharing your insights on how autoimmune testing fits into the overall diagnostic picture, but more importantly, bringing up the collaborative model of testing at Mayo Clinic and how all of these tests can be used in conjunction to really drive the right answer for patients. As we wind down our conversation today, Dr. McKeon, I'm wondering, do you have any closing thoughts on the benefits of this antibody test for these sorts of patients?

Dr. McKeon (20:23):

Sure. I think autoimmune dysautonomia testing is useful for patients whereby an autoimmune cause is suspected for orthostatic hypotension leading to presyncope or syncope patients with altered GI motility where there's not an obvious common cause for that problem, and where there are progressive symptoms leading to early satiety, weight loss, severe constipation, or indeed for patients who have unexplained bladder dysfunction, unexplained heat intolerance, and where we've been able to objectively document that there is an autonomic disorder. I think this type of autoantibody testing is reasonable. It will give insight into potentially an autoimmune diagnosis, but also give information as to possibilities for associated occult undiagnosed cancer, and then also would give information regarding potential for response to treatment and prognosis.

Robin (21:23):

Nice. Thanks so much for sharing those final thoughts, Dr. McKeon. I think it's so important to highlight the different strategies that can be taken to really get the right answer for patients. I want to thank you so much for sharing your time with us today. I really learned a lot, and I sure hope our listeners have as well. And to our listeners, thanks for joining us. We hope you'll tune in again for our next installment of Diagnostics in Practice.