Christopher Bromley, DPM discusses the autonomic nervous system, the role of neuropathy in wound healing, as well as the impact of autonomic neuropathy in the evaluation and treatment of the diabetic foot.
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TAPE STARTS – [00:00]
Our next speaker is Christopher Bromley. Dr. Bromley serves as the Department Chair of Foot and Ankle Surgery at Vassar medical Center. Dr. Bromley is the Managing Partner of a large multi-specialty group in Upstate, New York. He completed his surgical residency training in 1992 in Baltimore, Maryland. His training included work at the University of Maryland in Johns Hopkins. He's going to talk this evening about the latest autonomic neuropathy trends and evaluations.
Dr. Christopher Bromley: Awesome. So thank you to the last talk to get done early because this is – they really only give me a 30 minutes but this is an hour and a half talk, kidding. Alright, I wanted to thank present for my invitation also for providing all the sugar and caffeinated beverages at the last break, which will hopefully keep you awake during this thrilling talk about autonomic neuropathy.
To Bob's comment on the total contact cast versus fixed ankle device, I had a comment, which was that I found that the newer flexible TCC I had a significant improvement and if we could do a study on that together that would be great. So I think the flexible TCC I give it one or two talks on that. It does a really good job at pumping that leg, which is much better and a lot less complications than the fixed TCC.
So moving forward, as advertised, we’re going to talk a little bit about autonomic neuropathy. How many people in here treat autonomic neuropathy by a show of hands in their practice? Couple, maybe a third. I will admit to you, even though I consider myself to be a pretty great guy, I do a lot of teaching. I really didn't until the last few years really have an appreciation for the role of autonomic neuropathy, and I'm spent many years almost 10 years lecturing about biologics and amnion and chorion and wound healing and really if you don't treat the underlying PAD, the chronic venous insufficiency that we talked about this morning and evaluate for an autonomic neuropathy, you are wasting that biologic.
So I think we have all these great wound treatments and great products out there, but we still have to never, ever, ever forget the basics. No conflicts to disclose. Goals today is to obviously review and have a better understanding of the role of the autonomic nervous system, particularly when it comes to wound healing, because that's really going to be an important take away from today's talk, understand what testing options you have in your practice for autonomic nervous system, evaluation and again realize the role of autonomic neuropathy in our patient care and the different wounds that we treat.
So what is autonomic neuropathy, we will abbreviate AN just to make it quick. Basically, there is a damage that occurs to the autonomic nervous system. This disrupts the signaling and the balance between the sympathetic and parasympathetic systems. As you remember from your training, the autonomic nervous system is made up of sympathetic and parasympathetic. They need to be in balance all the time. If you have a scary event, somebody runs in here, yells fire, everybody jumps up that's sympathetic response, your heart rate increases, you get very excited and you're able to have super human strength to run out here. At the same time, your parasympathetic system is trying to balance that out. The parasympathetic will always try to balance and the two of them when they’re in balance work very efficiently and affect every single cell in your body. I remember when I was in Boston doing one of my training, I think it was with Bob when you’re still in Boston. I remember sitting in a lecture, you may or may not have been there and I remember having this epiphany that diabetes isn’t just a foot disease that it's an entire body disease. I was a pretty good student, but I remember sitting there having that epiphany. Well, I want you to have an epiphany that although sensory neuropathy is really important and we talk about it all the time in podiatry, autonomic neuropathy is far more important in a far bigger problem, so if you take away that epiphany today that would be great.
So when you have your sympathetic and parasympathetic systems in flux, it’s going to affect your blood pressure, your heart rate, obviously perspiration, it’s going to affect every cell, your whole, what's going on with your digestive system, what's going on with wound healing. If there's an imbalance, it's going to affect everything. We know this because one of the dreaded conditions in podiatry is chronic regional pain or RSDS. If we have imbalance, we have a problem, but the imbalance is happening on a moment-by-moment basis in everybody that's in this room. So what are the causes of autonomic neuropathy? Obviously, factors such as an injury to the nerves that could be from alcoholism, diabetes is obviously an epidemic in a big part of our patients, chronic illnesses such as HIV and Parkinson's, medications that patients take. We all know that Metformin number one prescribed drug in the world for diabetes interferes with B12 absorption, that's not good for your nervous system. Other things such as trauma, injuries, a burn to a patient, a cut or injury, unusual buildup of proteins, autoimmune disorders, lupus, degenerative things. There are numerous diseases that affects the autonomic nervous system on a moment-by-moment basis.
So what are the risk factors obviously, age, patients who’ve had elevated and uncontrolled hypertension, patients who have elevated cholesterol or patients who might be overweight I think that describes probably 70% of the US population. Most patients are overweight, they’ve got issues with uncontrolled lipids, obviously diabetes is a huge risk factor as we said all the other things that are listed there.
So what is the clinical presentation -- do you ever seen that when they have a commercial on TV and they describe what the side effects of the drugs are headache, stomach upset. Basically the clinical presentation of autonomic neuropathy is pretty much what almost everybody in this room has experienced. Dry mouth, lightheadedness, dry eyes, hopefully not a big problem with impotence, but if so we have medications, lots of sweating, nocturnal diarrhea, small fiber neuropathy also is a part of it. We know that diabetic neuropathy as we talk about all the time is usually a small fiber disease, obviously the C fibers go first, large fibers are spared.
The neuropathy that affects the biggest nerve in our body is autonomic neuropathy. The vagus nerve is the longest nerve you have, it's obviously very, very involved in the whole sympathetic and parasympathetic balance. The vagus nerve is a parasympathetic nerve. So what are the common symptoms, obviously these are things that we all experience. Obviously, how many people in here has heartburn, nobody okay you guys are okay, you stay with me. So obviously there these are issues patients have constipation, diarrhea, reproductive issues, erectile dysfunction, difficulty with dryness or climax, heart and circulatory issues, fainting and dizziness, rapid heart rate, patients who have difficulty, I know at 54 years old I don't see as well in the dark as I used to when I'm driving home. Obviously for us in podiatry, dry skin, reduced sweat gland function, and impaired healing because it's a cellular, which will spend a lot of time as we dive in in the second hour of this talk.
So if you look at the autonomic nervous system, if you look at the diagram here, you can see basically we have parasympathetic over here, we have sympathetic function over here and every single thing in your body is a balance of these two systems, so if you have an issue and you get a lot of stimulation on this side, you’re basically going to have the parasympathetic that’s trying to balance it out.
So autonomic balance, there's a number of factors when we look at -- this is a particular study, that came out of the Clinical Journals of Endocrinology in 2015. If a patient has an autonomic nervous system issue, what is the predictor of mortality and morbidity. So if they look at this particular study they went back and they did a secondary analysis from the Framingham study. You remember the Framingham study it’s very long study, and they basically looked at patients who are 18 or older, and they looked at variable factors. What they did is they measured heart rate variability, they measured blood pressure, fasting glucose, triglycerides, high-density lipoprotein, cholesterol and BMI. And they filed them out and what they found is that autonomic imbalance predicts cardiovascular, diabetes, MI and all causes of morbidity and mortality. So it’s a huge risk factor.
In fact, I think we should be looking at autonomic neuropathy as one of the things that's part of our physical exam, is looking at and we talked earlier this morning about adding chronic venous insufficiency evaluation to our PAD on our vascular evaluation. I think when you look at your neurologic evaluation in your podiatry documentation, you should be also adding a section about are there any autonomic changes because that's really important I mean it’s great that they have a deep tendon reflex, which is what we are taught in school, but that has nothing to do with whether or not they have the ability to heal from any of the things that we want to do that. So I think this is when we look at the data and we look at the exam, when we make that physical exam, part of our documentation that would be really important. So what is a dysautonomia. Basically, this refers to an disorder of the autonomic nervous system where we have the imbalance.
One of the prime examples of that would be chronic regional pain or RSDS, someone has a trauma. What I do I explain to patient just like in your house, you have a fuse panel and you have all this injury or all this trauma, basically it's like an excess of vultures, the body throws the breaker once the sympathetic system gets stuck and the parasympathetic can no longer balance it, it get stuck in that first phase of the RSDS or chronic regional pain and eventually it flips over and goes to be a limb that has no sympathetic function.
So obviously some of these acute changes if you get to them early enough are reversible, if they're not and they become chronic, they are very, very progressive. Common causes we talked a little bit about this obviously, patients who are diabetic or have alcoholism in their background are more at risk. The hallmarks of that include the things that we talked about before, difficulty with orthostatic hypotension, excessive sympathetic activity such as hypertension, heart rate, in man obviously there's an issue with impotence. So the factors, obviously we talked about these, we kind of moved through these already the diabetes we know about. Some of the ones I left the slide amyloidosis purpura, hypothyroid is an issue, in patients who have had cancer, and some of the long-term chemotherapy drugs obviously have a big factor. You’ll see patients I think in your practice as well – they’ve been under chemotherapy for breast cancer or other forms of cancer you come in, you can see if you look at the tips of their fingers, tips of their toes, all the autonomic changes that occur because of the chemotherapy drugs.
So diabetic neuropathy, we talk about in podiatry in all the time and obviously it is a polyneuropathy. It's going to damage the motor, the sensory and the autonomic changes will occur. Obviously, the motor changes we’re familiar with, patients will have the orthopedic deformities, they could develop foot drop, obviously the Charcot is a combination of sensory and motor. The autonomic changes are really important because once you start to see that the sweat glands and the dry skin and we start to see the changes, these are the early warning symptoms of autonomic neuropathy and that's going to show you that this is a patient who is not going to heal, they’re going to have trouble at a cellular level to heal because there's an imbalance.
Autonomic neuropathy, as we said this is a study from the clinics in microcirculation 2016. They looked at how does the sympathetic nervous system affect angiogenesis. As we know from all the wound care that we do, if there's no angiogenesis, there's no healing. They particularly looked at this in a soft tissue, pan-end [phonetic] at all, looked at the angiogenesis in healing, they basically found that the sympathetic nervous system participates with the angiogenesis and obviously affecting endothelial cells and the pericytes for new capillaries. Without that and if they have impairment, obviously we’re not going to have the proper healing.
This is obviously a discussion we look at the balance between the two. The sympathetic nervous system mediates that increased fight or flight, basically there are number of neurotransmitters involved, epinephrine, norepinephrine and dopamine. These neurotransmitters are going to stimulate the cellular response interacting with G-protein coupled with adrenergic receptors, dopamine [phonetic] receptors, and that's going to start that whole healing process. At the same time, you have to have parasympathetic balance because if you don't have parasympathetic balance that sympathetic changes will go unchecked and they will get out of hand. So this particular system is going to balance, it’s going to slow down the response, it's going to use the neurotransmitters acetylcholine, which interacts with the G-protein again and that's going to reduce the acetylcholine receptors M1 and M5, are going to reduce the channels and get that whole process to slow down. Again, as we talked about in the middle that's all about balance.
So we look at here we see the way the autonomic system starts and basically working down through the adrenal glands, you got glucocorticoids, and this is going to obviously stimulate down to a macrophage level and obviously there's this balance between the whole system and what we want to remember is that the autonomic neuropathy if it's out of balance will affect the body's ability to heal at a cellular level. So when we talk about inflammation, we've talked about inflammation on a wound care side all the time. So we say that the wound that won't heal is stuck in the inflammatory cycle. Why is it stuck in the inflammatory cycle, well it’s stuck in the inflammatory cycle because the autonomic nervous system is stuck. It’s stuck when the sympathetic, so if we look at inflammation and we know that inflammation, when it occurs as a process of the damage, it occurs and it’s stuck because of the diabetes and the comorbidities, we have micro and macrovascular changes. We know that the inflammatory system, there is an afferent arc and the afferent arc is what it causes the body to respond to an injury whether you’ve been cut or you have a chronic injury or a chronic inflammation, the afferent arc is really important.
And then you'll see that inflammatory reflex that inflammatory reflex is what causes the response to the pathogen or the infectious changes and this is stimulating the receptors through the vagus nerve and the glomus cells to respond. At the same time, there's an afferent potential, which is going to go back stimulate through the nervous system and the central spinal system to decrease the cytokines and decrease the inflammation. So that balance of afferent and efferent response is very important to work. So that said, how do you test to see whether or not your autonomic nervous system is working. So I want you guys, this is the end of the day, everybody here know how to take a pulse, right so I want you to take your pulse right, now I want you to stand up when you stand up, go ahead stand up you can do it, keep taking your pulse I want you to feel your pulse, if you feel it from hand do you feel the difference?
Right, so what happened is when you stood up, you can sit down, when you stood up your body went from sitting to standing. If you didn't have the ability of your autonomic nervous system you would pass out, so your autonomic nervous system is the communication between every cell in your body, your brain and your heart. So your heart knew that when you stood up, it had to increase its heart rate in order to balance the change and flow. So when we look at all the different types of testing, we just did the easiest nervous system testing in the world, but there are number of autonomic tests out there. So there is a breathing test where you do deep breathing and you're trying to stimulate the vagus nerve that's called the breathing test. They also did it for many years what's called the tilt table response where you tilt the patient and you tilt them up and you monitor the response and the heart rate variability. Dr. Vinick [phonetic] did a great paper and I don't know if I have it in this particular talk. It is the gold standard as we talked about in the last talk. The gold standard for autonomic nervous system is heart rate variability and we’ll talk about that as we move forward.
Other tests include gastrointestinal tests, which I have no experience with. Quantitative tests, I do have some experience, anybody here remember the pseudoscan when it came out a number of years ago. There is a very interesting system. It’s a French company, they basically had galvanic plates, you put your both hands and both feet without socks on these plates and what it does is it created a current and that current would stimulate the small cells in the hands and feet, the sweat glands, and then they would measure the response between the galvanic plates. So it was a really nice, really nice idea, but it was a $35,000 machine that has zero reimbursement. So although it was a good idea it didn't really catch on.
Thermal regulatory sweat tests are done, but not that common. A number of years ago, I was lecturing at a meeting I forgot where and I went by and there was this little booth, you know we have all these booths out there with colored brochures and I went by this booth and the booth had like no sign. It was a black tablecloth and one little guy sitting behind the table and I thought this is kind of weird. I stopped just because I didn’t know what he was doing and he was this Russian scientist, and he had come to the meeting from Cornell, and he had this exact set up on his table and I thought to myself, “what the hell is this guy doing here.” So I stopped and his name was Dr. Alexander Riftine and he was trained in Russia and he had come to United States. And he had spent his whole life figuring out how to test for autonomic neuropathy and it was probably eight or nine years ago that I met him. He was the guy that convinced me to take a look at autonomic neuropathy because I really admitted to myself at the time, I had no idea. I mean, I knew what is sympathetic and parasympathetic were, but I had no idea what the role was or whether or not you could test it. So he had developed this system, basically you have a printer here, but you have a four-lead EKG, a blood pressure cuff, and a computer. And he'd come up with this brilliant program where he could have the patient lay down, they were connected to the lead with the blood pressure cuff and then they would start reading and this is a different reading, but it works the same way. And then he would have the patient stand up and he would record through the ECG leads, he would record the heart rate variability that's what's going on here. And then he would score you based on the X-Y axis. If you’re over here you are good, over here less good, down here bad. And then he had a number of other measurements and then he would make a determination based on the first part of the test and then the second part of the test whether or not a patient had an autonomic nervous system imbalance.
So the second part of the test was the same, but it would stimulate. So when you stood up before I showed you the sympathetic response, which is your heart rate increasing to the flow. The sympathetic response was basically stimulating the vagus nerve. So the patient will be sitting, they would be doing deep breathing, which is making the diaphragm go up and down again via the vagus nerve, and then they would do a Valsalva maneuver where you take a deep breath and push down, hold your breath push down with your diaphragm and try not to have an accident. And what he would do is he would have the same reading here and then there would be a number of findings and they’ll put all this together and they’ll have a conclusion, which I thought was brilliant. So the first thing I did was ask him if he could test me, and he did and I didn't do too bad. And then we determined that we could quantify and start to measure, this system is called an IntelleWave system. I still have one in my office and it's pretty interesting. So where you can actually find neuropathy because the autonomic nervous system changes that we talked about today occur in diabetics before they have their sensory loss. So we've been able to use this and we’ve collecting data for a few years now on our patients to see and then track them.
And the other thing we did was we got a baseline on autonomic neuropathy and then we started treating them. Some we treated with Metanx [phonetic], some we treated with alpha lipoic acids, some we treated with both, some we treated with Neurontin, amitriptyline, Lyrica. And then we’ve been following two or three years out to see what kind of results that we have. So that's how we tested, that's one of the systems that out there. So what are the treatment options. If you determine that patients have autonomic neuropathy, the biggest ones that we see in our practice are obviously diabetics are those patients who have comorbid conditions that we talk about. The other big group of autonomic neuropathy patients in my practice is patients who have Raynaud’s, obviously that's huge, particularly for women.
And then the third group that we typically worry about are those patients who present with chronic regional pain or RSDS, either after our surgery or after trauma. So we have these three groups of patients, so what do you do. Obviously the first thing you do is if you have a patient who is a diabetic and alcoholic and a smoker, you try to get them to control their blood sugar, stop drinking and stop smoking, obviously very important. Medical food options I still use Metanx on a regular basis. We start Metanx a lot earlier in our diabetic patients, we do a lot of the screening, we do the IntelleWave screening as an opportunity to reverse the nitric oxide stress that's really how it works and get some improvement in neuropathy. Alpha lipoic acid it still has a role. We do use in the office, we don't use as much tense, we’re doing a trial right now with Bemer, which comes out of Germany. It's an electromagnetic stimulation of blood flow that's been pretty interesting. We still have great success and we do have a cohort of patients that we've been using low-level laser on for a few years. Those are typically the patients who have that burning painful diabetic neuropathy, again it will influence the improvement.
Obviously, there all the pharmacologic stuff that big pharma likes us to use, I'm not a big fan, but patients do have some relief. So those are the treatment options. Obviously, the biggest thing with our diabetics is to get into the preventative to make sure we manage that and obviously identify just it like I mentioned earlier if you have an opportunity to set up in your EMR, your neurologic exam, get in the habit of documenting the autonomic changes and look for them. When you start looking for them, you'll see them and talk to the patients about it, not waiting for them to have sensory loss, getting out in front of and understanding the role of autonomic nervous system in wound healing is really important because as I said at the top of the lecture we have some really great biologics to use, we have really great things to use for wound healing.
But we got to remember to go back and take care of the basics good offloading like in the last lecture, good surgical debridement, removing the bio-burden and using the things at our disposal as opposed to only relying on the 3,000 hour biologic graph.
So thank you for your attention, you’ve been great. I appreciate your staying to the very end and if you have questions you can ask now or I'll be outside available for questions. Thank you very much.
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