Watch on YouTube - Watch on Rumble - Watch on Vimeo

Stephen L. Barrett, DPM, FAENS

Podiatrist and surgeon Stephen Barrett, DPM, MBA, ABPS, FAENS, brings decades of experience in foot and nerve care to US Neuropathy Centers in Marietta and Atlanta, Georgia. He is a highly-regarded expert in heel pain, pain management, peripheral nerve surgery, and diabetic peripheral neuropathy. He is proud to provide the best health care to his patients. Dr. Barrett earned his medical degree from the Dr. William M. Scholl College of Podiatric Medicine at Rosalind Franklin University in North Chicago, Illinois and completed his residency at UTMB/Danforth Hospital in Houston.

A pioneer in his field, Dr. Barrett was the first physician to invent and utilize minimally invasive endoscopic surgery to treat heel pain. He also performed the first diabetic peripheral nerve decompression in Spain, which was observed in Barcelona on closed-circuit television by 74 of Europe’s top surgeons, neurologists, and endocrinologists.

Dr. Barrett holds 5 patents; two for developing innovative endoscopic procedures — the endoscopic plantar fasciotomy (EPF) and endoscopic decompression of the intermetatarsal nerve (EDIN). He believes in preparing the next generation and has trained over 6,000 surgeons around the world to perform these procedures. The seminal textbook for orthopedic surgery, “Campbell’s Operative Orthopedics,” also includes his procedures. Dr. Barrett is also the author of two textbooks, "Diagnostic Ultrasound of the Foot and Ankle", published in 2013, and “Practical Pain Management for the Lower Extremity Surgeon,” published in 2015. In addition to his textbooks, Dr. Barrett has published more than 50 articles in peer-reviewed medical journals, chapters included in other medical textbooks, and co-authored a textbook on the interpretation of neurosensory testing. He is also a contributing editor for the Journal of the American Pediatric Medical Association and on the editorial board for Podiatry Today and Practical Pain Management.

Dr. Barrett is board-certified by the American Board of Foot and Ankle Surgery and the American Board of Podiatric Medicine. He formerly served as the president of the Association of Extremity Nerve Surgeons, where he was awarded the prestigious Jules Tinel MD Award in 2010. He now serves as the Chairman of the board of trustees for the Association of Extremity Nerve Surgeons. Dr. Barrett earned his MBA from Texas Tech University in Lubbock, Texas in 2005 with a specialization in healthcare management.

Dr. Barrett 01:07 Introduces the meeting and presents the lecture

Correction:  This lecture was given in May, 2023.

Does ozone therapy have any therapeutic future for neuropathic conditions? And the answer is, yes, it definitely does.

And I will preface everything today that I am not an ozone expert. I'm an ozone neophyte.

So now, let's look at complexity for a second, right? Everybody's heard of tarsal tunnel syndrome, right? I mean, it's pretty common, there's still, believe it or not some folks who will not recognize that it actually even exists. I don't know how that's the case. They're probably the same folks that are looking for the edge of the flat earth. But when you look at something like tarsal tunnel syndrome, you think, Wow, this is it's pretty straightforward. Well, my son's a mathematician and an engineer. And I asked him one day, I said, Listen, if I gave you all of the different factors that we look at, from a standpoint of what's causing this person's tarsal tunnel syndrome, can you calculate that out? And he said, yeah, just list everything out all the different things that you have to take into consideration. And he came back about five minutes later, and he said, 178,272, different permutations of what can be contributing to this person's tarsal Thompson. So that's something that is just very well known, but yet not appreciated for the complexity. Peripheral Neuropathy is most often start in the lower extremity. Well, why is that? Now answer is probably because of the biomechanical demands that are going on with the lower extremity versus the upper extremity. That we'll get into that a little bit more. But if you think about how much is happening from a biomechanical standpoint, in the lower extremity, it's pretty incredible. Somebody takes 10,000 steps in a day, you know, they, you know, two to four times body weights going through that extremity, step after step, you can see how easily it would be, then then if you add on to that maybe some vascular or venous insufficiency, and now they have edema. It's pretty easy to see how these nerves in the lower extremity would be affected previous to the nerves in the upper extremity. So one of the ways we can break down neuropathy is this table here? And I'm not sure these numbers are exactly right. Because you can go to many sources, and you'll see different numbers but this is relatively close. And if you look at the two big ones idiopathic, which means we're idiots and we don't know what's going on. And diabetic peripheral neuropathy, you're covering, you know, good majority of all of the cases that we see from a peripheral neuropathy standpoint, and probably the idiopathic component, if you really think about it and really workup your patient and look at them globally. That number from 23% can come down significantly with just extra you know, judicious examination and spending time listening to the patient. Now, of these, I want to emphasize that there are two types of neuropathies. Essentially this covers everything one is a compressive neuropathy and the other is a non-compressive neuropathy. So, if we know that something is compressive then we're able to actually surgically treat that component. I'm going to give you an example in just a minute or two. Now, chemo induced peripheral neuropathy is not always a compressive neuropathy, but many times it is and if we can figure out if it is compressive. And I'll explain that more than we have a definitive treatment that we can go in and do something that really benefits that patient greatly, very quickly. So, I already said this. But why is it important to figure out if there's a compressive nature to the neuropathy? And the answer is, because if you have a significant compression, you can help that patient greatly. But if they have a compressive neuropathy, and you don't address it, the likelihood of all of the other things that you do to make that patient better, are not going to really get them rid of their symptoms that they're having. So you need to be able to identify if it's compressive. So, this is a great slide that illustrates the, the difference between a systemic or metabolic effect on the nerve, and then this feedback or loop back from compressive neuropathy or focal compressions or entrapments back to leading into more systemic effects or metabolic effects. So I'll get into that a little bit. But I want you to think about that there's this feedback between diabetic or any type of systemic nature that is like diabetic peripheral neuropathy. But you have to think about, well, what is that systemic condition or metabolic condition actually doing to create this compressive nature of the neuropathy? Hopefully, that'll be less confusing. Now, there's a couple of things you know, that you don't think about as being a compressive neuropathy. And leprosy is one of them. But mainstream medicine really doesn't recognize that. There's a group of very expert peripheral nerve surgeons in our association for extremity nerve surgeons that have been going down to Peru for over 20 years now. And they're doing isolated peripheral nerve decompressions in these patients, and they reverse their symptoms, and they never, they never had any loss of fingers or toes because of insensitivity. So that's kind of an interesting compressive neuropathy, and people don't necessarily think about compression. And then the most common, and we've had a lot of genomics. And, and that topic of discussion so far. And probably true genetic aberration is a very small subset of peripheral neuropathy. But the most common is Charcot Marie Tooth disease. And one would have to ask, well, is this a compressive neuropathy, and it has a compressive nature to it. And you have to ask yourself, well, why does it preferentially select one of the two terminal branches in the lower extremity, the common fibula, or common perineal nerve versus affecting the tibial nerve. And this can be treated with nerve decompression. So we're going to talk about nerve decompression a little bit, how can basically reverse these types of conditions. Now, this was a pretty recent article. And COVID is an interesting thing, because there are a lot of things that are happening. And if you look at these, the data in this, that they had these, these people who developed peripheral nerve injuries, after they had COVID-19. And they were all in very sick patients. And my suspicion, or what I would suggest is probably going on here is that these are not necessarily induced by the by the spike protein that could be we don't know that. But they could be just from the standpoint that when that patient's lying in bed, their legs pressed up against the side of the railing of the bed, or, you know, they're positioned wrong and their brachial plexus is in a in a bad position. So, these are really more of a subsequent entrapment to somebody who has had COVID. So, it's kind of interesting. Now everybody's familiar with carpal tunnel syndrome, right? It's the most common nerve compression or nerve entrapment in the human body. In the general US population, it affects about 2% of the people. But if you look at the diabetic population, depending on what article you look at, it's anywhere between 14 and 28%. Now this is a really astounding thing because there's something going on you! With the diabetic patient who develops carpal tunnel, and the patient, or excuse me, the disease what's going on to cause all of this carpal tunnel? And this is really an important thing because if the patient has had a successful carpal tunnel decompression and their diabetic, they almost have a 100% chance of success with a lower extremity peripheral nerve decompression. Now, that's really interesting. There was a study done out of the University of Arizona there, neurosurgery department. And it's a pretty robust and good study. But I love that because when I ask a patient when they come to our office, did you ever have carpal tunnel? Oh, yeah. And did you get better after they decompressed it? Oh, yeah, it's great. Still good today? Well, that's a really great indicator that this patient will get better with other peripheral nerve decompressions in the lower extremity. So, my journey into neuropathy was really unplanned. And we talk frequently about how we want to try to plan for life. I think that we can do that to some extent, but then life ends up planning us. And I know everyone in this audience has experienced that. Like, how did I get to where I am today? Because I might not have necessarily planned that right. I had the ideation that that was what was going to be. So, when I was in a regular pediatric practice, we did everything and most of the time when a patient came in with neuropathy, Pathak symptoms, we would say, well, sorry, there's nothing that we can do for you. We'll give you a little Gabapentin or pregabalin, and be off because it's a condition you're going to have to live with, then that's it, for the rest of your life, you're going to have peripheral neuropathy. And then in early 2000, 2001, to be exact, I happened to cross paths with my mentor who is in the green circle here, Dr. Lee Dellon. He's a retired professor of plastic and neurosurgery at Johns Hopkins University. He just retired last year, you talked about a human that has a big ripple effect. This gentleman has a gigantic ripple effect. He's trained so many peripheral nerve surgeons; written textbooks. And I still don't know why he liked the little fat kid in the back. But he and I kind of clicked and he took me under his wing. Now, this story really started in about 1980 to 1983, where Lee was working in the ham clinic at Hopkins. And it was conventionally taught and it's still being taught today that once you have peripheral neuropathy and you're diabetic, that's it, you can't restore your sensation. And you're just going to have these symptoms. Well, neurologists don't have a conceptual problem with sending a patient with a carpal tunnel and diabetic peripheral neuropathy over to have the hand surgeon decompress the median nerve and treat their carpal tunnel. But what happened was that he had these patients that had tremendous carpal tunnel pain that were diabetic and had diabetic peripheral neuropathy in their feet and legs. And he would decompress that carpal tunnel, and they would come back and they would say, Wow, this is great. My pain is gone. But I have sensation in this finger, this finger and half of this finger. Now that wasn't supposed to be right, because that's not what's being taught in medical schools. And then he thought, well, what can I do for the little finger and then went up to the ulnar nerve at the cubital tunnel, decompressed that, guess what, they got sensation back in their little finger. Now this was an insensate hand and he restored it. But then they said, “Well, can you do anything for the back of my thumb?” And we went looked at one of the branches, the radial sensory nerve, and decompressed it, and lo and behold, this patient who had numbness in their hand no longer had any numbness in their hands. So, this really made him start to look at this. And the next question was, what can you do for my feet? And he's like, I have no idea. I'm a hand surgeon and plastic surgeon. I don't really go down there that much. But because he was at Hopkins, and because he was an incredible researcher. He got into the cadaver labs and figured out that there are four sites primarily that these type tunnels like the carpal tunnel, like the carpal tunnel in the hand, exist in the lower extremity. We'll talk about those in just a little bit. But He then started decompressing the nerves in the largest room To at least patients that he had done their hand surgery. And, interestingly enough, about 75% of them had restored protective sensation, which is a very big deal because you know how severe diabetic foot ulceration is, and their propensity to go from a diabetic foot ulcer to a subsequent infection and then a subsequent amputation. And once you lose a leg to amputation, your five-year mortality is really not very good. Okay. It's up there with a lot of very bad cancers. Well, because he was at Hopkins, they said, you don't have any, you don't have anything other than this clinical data, you need to prove in some type of an animal model. What can what you're doing and why there's any effect? Well, in 1978, there was a couple of publications couple of articles by a gentleman that published in diabetoliga, and his name was Jacobsen. Spelled funny like a different variation of how you would think of spelled but you can find it. And what he did, what Jacobsen did was he went and he made his rats diabetic. So, he injected them with streptozotocin, they got very high blood sugars, they were very sick. And then at six months, which is a significant portion of their life, being a rat, he would sacrifice them and then do photo micrographs of their sciatic nerve. And what he found was the cross section of the nerve showed that there was really very little demyelination. Now everybody is taught that demyelination is the cause of the symptoms and diabetic peripheral neuropathy because of the systemic effect and all of that, but Jacobson didn't find that, in fact, he found relatively good neurons that were myelinated. But they had a real high-water content. So, Jacobson was able to demonstrate that the diabetic nerve swells and it gets bigger. And I'm going to try to play this. So, this is what happens. So, glucose overloads the nerve, and it messes up the hexokinase pathway converts into another sugar called sorbitol. And for some reason sorbitol loves water, it's very hydrophilic even though it has almost the same molecular weight as glucose, it draws the water into these nerves. And that's what Jacobsen found in his early studies. So, Lee then took Jacobsen's work, and he basically did tarsal tunnel decompressions on rats. Now think about that. Rats have pretty small tarsal tunnels, but he would then take half of his rats and do tarsal tunnel decompressions in them. And the other half he left their tarsal tunnel intact. And then he made them all diabetic was streptozotocin, like Jacobson did. And each week he would run them across paper with their paw print their paws dipped in ink so that he could measure the degradation of their paw print. So, if you're neuropathic, what happens to your you lose, you know, motor strength, and, and so the paw of the rat will change. But the pod didn't change in the people that are, excuse me in the rats that and some of our patients are rats. So maybe that. But anyhow, the point was, is that he could prevent the symptoms, at least in the rat paw from a degradation standpoint, by doing a prophylactic tarsal tunnel surgery. So that's really pretty interesting. So, Hopkins said, Well, that's all nice and well, but you need to do something in primates. Okay. So, he did do that in primates. I'm going to show you one of His primate patients in just a little bit. And then he went back and did a second. Basically, the same study that he did, off of Jacobson's work did that again, and then that has been replicated from the Cleveland Clinic. Maria Siemenow. I don't know if you ever heard about the first face transplant. So, Maria was the lady who did the first complete face transplant and she's an excellent micro surgeon. But anyhow, they confirmed Lee's work some 20 years later. So, this has been known for quite a period of time, but yet it's still not recognized. And it's hard to believe, but you know, when people are in their paradigm, it's hard to sometimes get them out. So, in the lower extremity, we have four primary tunnels as we can see here, that are potential sites of entrapment. As for constriction, or entrapment, if the nerve swells the common fibula, or common peroneal nerve at the side of the knee, the superficial peroneal nerve on the anterior distal 1/3 of the lateral aspect of the leg, the, the tibial nerve at the tarsal tunnel and its branches medial lateral plantar nerve, as well as the medial calcaneal nerve, and then the deep peroneal nerve on the top of the foot. So, if you think about that, if I create a nerve compression in these four tunnels, then you're going to see that you could essentially create a complete stocking distribution of the neuropathy. And everybody talks about stocking and glove distributions. You've heard about that right? Well, the sural nerve doesn't have a known tunnel for entrapment. And a lot of times when you test these patients, they'll be totally insensate within the distributions of these four nerves. But their sural nerve is completely unaffected, which would tell you that it has to be some type of a compressive effect. And the sural not having a known tunnel aren't known site of entrapment kind of speaks volumes to that. And, in fact, the gentleman that I showed you with his wineglass empty, but we filled it with ozone Dr. Rader, he has a video of him doing a transmit a tarsal, amputation, and a diabetic patient that was completely insensate. And he didn't use any local anesthesia or general anesthesia. And as he's cutting across from medial to lateral, and this is a guy that had metatarsal 123 and four transected, with no anesthesia. And when he got to the fifth one, he said, Hey, I can feel that, you know, need to numb this up. So why would that nerve be spared? Versus the others? And the answer is, well, it swelled. But it just doesn't have a known tunnel to capture that swelling and create a focal nerve compression. So it's very interesting. Now, this is the primate from what I referred to earlier. And if you look at the photo micrographs on the left side of the screen, you can see this is tissue taken from a 31-year old primate that was a type one diabetic primate. And they named her sweetie. And she was at Hopkins, all of this time, they used her for a lot of their basically their studies because primates evidently don't have a high level of diabetes specialty type one. And it's really sad that they that we call things diabetic, type one and type two, because they're really distinct, completely different diseases. But regardless, these were sections that were taken from the ulnar nerve, the sections on the left of the ulnar nerve up in the, in this part of the arm, where there is no known site of entrapment. The same nerve, as you can see in the right side, is the cubital tunnel. Okay, and you can see, the myelin is vastly different from the left to the right. Now, if it's solely a systemic disease, how can that be? How can that be, right? Because the glucose I pretty sure the glucose level, at this part of the arm is the same as two inches south at the cubital tunnel. So, this was really very confirming evidence that it's not just this metabolic destruction, like you've been taught, but it's really, it's making the nerves swell. And then that's what's causing most of the symptoms of diabetic peripheral neuropathy. Now, this is a intraoperative photo of one of our patients, common perineal nerve, you can see the left part of your screen.

But anyhow, you can see this nerve really is constricted. And here, after we've decompressed it, you see this little vein or vase in the ballroom that appeared. Now what's really interesting is that we brought a neurologist in for 11 cases to do inter operative nerve monitoring. And there's no placebo effect with intraoperative nerve monitoring the patients asleep. And what they found was as soon as we started decompressing this, that nerves started to function. Now wait a second, people will say the nerve can't regenerate in a minute and 30 seconds? And the answer is yes, the nerve can't regenerate in 30 seconds. Because we know that nerves regenerated about a millimeter a day or an inch a month. And it takes time for nerve regeneration. So, there's a couple of processes that are happening here, and one is ischemia. Now, I don't have any slides of this. But I think it's a very compelling thing. If you have, you know, a couple of minutes to waste. You can and it's not a waste, it might be actually very beneficial for some of your folks that maybe have a drop foot that's unexplained or that type of thing. But if we're able to, with ultrasound guidance, I can put about two tenths of a cc of lidocaine on this nerve. And within about four minutes, if this is an entrapped nerve, they will have increased motor function, and you scratch your head. Well, why is that? And when I first saw this in 2017, I couldn't, it was hard for me to put my head around it. But all local anesthetics except one, does anybody know which one is not vasodilator. Cocaine. That's why the ENT’s still uses it because it causes vasoconstriction. But everything else is a vasodilator. Marcaine, is a more potent vasodilator than lidocaine. So, by putting two tenths of a CC to four tenths, five tenths sometimes is the most next to the nerve, where there's a focal compression, and about four minutes, they will get regain motor strength in their anterior and lateral compartment. So, in a patient that has a drop foot, a lot of times they're told, there's nothing that can be done for it. And the answer is, well, if you put a little bit of lidocaine in on that nerve, and you get a positive, we call it a positive Phoenix sign. So, if you go to YouTube and put in the Phoenix sign, nerve block, you'll see a three-minute video showing how we administer this block, but it's very, very diagnostic, not only from the it's sometimes very hard for clinicians, very astute clinicians to figure out what's coming from the back versus what's coming from a local focal nerve compression. And this pretty much answers it. So, then we had to, I don't want to say prove, but we had to try to strongly support that this was a vasodilatory phenomenon, and not some weird sub anesthetic phenomena. And we did a double blinded, randomized prospective study comparing lidocaine to pattern which pattern has been around for a long, long time, very well understood nasal dilator. And the same response happened with the people that we injected with a powder and and that that study has been submitted for publication and hopefully it'll be out in the very near future. That's where this band of fascia was right over that nerve. And this is what we call an hourglass deformity. So there you go. So that's kind of an interesting thing. Now, when I came across Dr. Dellon's work and met him and ended up, I actually ended up helping him teach these courses. And I was blown away. All right, I had a new hammer, and I was going to pound every one of these diabetic nails because I had the hammer, that's the surgeon mentality. And we did really well, quite frankly, we did, you know, we had a 90% reduction in pain so that 90% of the time, we didn't maybe eliminate all of their pain, but 90% of the cases, we had a dramatic and improved reduction in their pain, 75% restoration of sensation, this is a very big deal. Because if they feel they can heal, and they won't develop a diabetic ulcer, if they have protective sensation, they had improvements in balance, and what kills more people over age 65? After you take out cardiovascular and cancer, and it's probably false, right. And it's a it's a big problem, but we're able to improve a patient's balance if we can restore proprioception, and an increase their motor function. So, it's, it's pretty powerful. But like I said, as a surgeon, you give me something, and it's everything is going to be a nail. And that is just it just doesn't work. And we had a lot of patients that would come back and they would say, you know, I'm so much better. But I still have this burning, or I still have, you know, some other type of weird neuropathic symptom. And so, by default, I was forced to go from a surgeon mentality into well, I actually have to look at this patient from a global perspective, what's going on with them metabolically, what's happening, that's causing these other symptoms that I can't get better from nerve decompression. So, I love my fortune teller. I've been trying to get this on Amazon for quite a period of time. And it's on backorder unfortunately, now, here's another little subliminal thing, what send the what do we do for these patients and, and he's looking in the ball and there it is, maybe some ozone, right, maybe we can make them healthier. But peripheral neuropathy is really a very difficult thing to treat anybody that says it's easy, and you just give them some Gabapentin or Lyrica or Cymbalta. It's like you need to run away from them. Because they're really, they're not, they're not understanding it. So, we need everything we possibly can in this chess game, so to speak, to try and just deliver this patient a little bit more optimal care. So, we've kind of now broken-down neuropathies into a compressive nature and a non-compressive nature. And we're going to treat them to some extent the same way. But with it been a compressive neuropathy, we have a better obviously, from what I just told you, we have a much better success rate with that. So, what is it? What's going on in this patient that is kind of universal are common to all of these different types of peripheral neuropathy? And the answer is, well, neuro inflammation is probably the number one thing less than ideal host. Now, do you all see less than ideal hosts in your practice? I mean, I have not even seen one ideal host yet that's come in and has, you know, a non-traumatic peripheral neuropathy. They have microvascular impairment, they may have some  demyelination, oftentimes of focal neural ischemia, like we talked about. So those are common themes to what we're seeing. And its really irrelevant what name we've given it, because we're going to want to try to treat both different aspects and try to make that better. So, one of the ways that people have studied nerve compression, what happens is, you know, what's happening at a histological level and that they use what's called Bennett's model of nerve compression. And basically, what they do with this model of nerve compression, is they really put a very Small constriction, not putting a ligature around the rat sciatic nerve and tying it now, it's just a very light constriction and then they look at what happens and they are able to see a lot of interesting changes. Now, this these two slides the seeing the picture, this is a suture induced peripheral neuropathy where this surgeon had done a bunionectomy and for some reason used this ungodly huge piece of rope to close the capsule of the first metatarsal phalangeal joint. And they basically lassoed the dorsal medial proper digital branch to the hallux. And it was interesting because the patient would only have pain if they had a polar toe up. So, the nerve was running through this ligature. And when she would dorsal flex, it would just pinch right down on it, you can see that you can see the piece of suture there. So, what do we know from Bennett's model? And so what they've seen and Bennett's model is T cell inflammation, which amplifies the neuro inflammation. And TNF alpha is upregulated. Again, another contributor to peripheral nerve injury, neuropathic pain. And then what they also found with Bennett's model of nerve compression was that decompression surgery, decreased the development of the upload, or upregulation of TNF alpha and decrease the T cell recruitment. So, there is not just a benefit from improving the microvasculature by removing these sites of compression, but there is also a histological benefit. So, during his journey at Hopkins, and what they were trying to do is establish how long it took for a nerve to  demyelinate. And McKinnon and Dellon published this, like you can see 1985. So, this stuff's been around for a long period of time. But you can see in the upper left, photo micrograph. Again, myelin is pretty good, then it's six months, it's dropping out 12 months, it's negligible, how much myelin is really there, and then after they would decompress it, it would remind me, so you had read myelination, which was very important, because that was one of the criticisms about what Lee was doing with nerve decompression and diabetic neuropathy is like, well, these people are diabetic, they're not going to heal. And the answer is diabetic nerves do heal, they do regenerate, albeit slower, they have less axoplasmic flow than an ideal non diabetic nerve. But they do heal, and they do remodel. So, it's kind of interesting. So, we go back to these factors of what we see in almost every neuropathy. And we look at, well, what can affect all of those, what can positively change these? Well, ozone, and you know, we can maybe deal better with this neuroinflammation, we can make the ideal host. Or maybe we can make the less than ideal host closer to being an ideal host. And that's going to, to help them in many other ways, from a health standpoint, not just from their peripheral neuropathy. And then that can help with  demyelination. And, you know, so what's going on here? So, like I said, I'm not an expert in ozone, but I've been around it enough that I want to become more informed about it. I don't think after seeing what you all have done this this week that I could ever become an expert in ozone, but I certainly would like to try to get closer to it. And if we look at well, what is ozone potentially doing? Well, it's immune modulatory right. It has very significant and potent analgesic effects. Not all not all neuropathies are painful, you know, but some are really painful. And these people are in many cases are suicidal, it's so bad. Anti-inflammatory, obviously, all of these, these neuropathy, these have this, this component of neuro inflammation. It's anti oxidative and it up regulates nitric oxide. So that's a big thing right because all of them are nitric oxide deficient. And anytime we can increase their nitric oxide via ozone infiltration IM or rectal insufflation or even MAH that's going to help in addition to supplement. So, there's some articles that we pulled out. So, what happens with peripheral nerve injury and I don't know if this peripheral nerve injury in this particular study was Bennett's model, it could have been something much more dramatic. But basically, you get a lot of increases in activation in the cortical frontal areas, genetic changes. I was talking to Dr. Kapoor earlier today, I was really fascinated by his talk. And I thought, well, you know, maybe we need to start looking at some of these people a little bit more closely from a snip standpoint and see if there's some common theme. And we're going to try to look at that a little bit more. So, it's also anti Dima and it up regulates these antioxidants. So, everybody knows how important these all are. I don't need to really spend too much time talking about it. But the other thing that's very interesting is that nerve D, myelination increases glutamate receptor expression. So, you have somebody who has a problem. That problem then leads to more of a problem because it's up regulating the glutamate receptor, which is considered one of the big problems and what blocks the glutamate receptor ketamine, right? So, we use ketamine on every operative patient. And we treat a lot of patients with ketamine infusions, that are not surgical patients because ketamine does a really great job. It's interesting that this drug has been around so long, but they're now finding more and more physiological mechanisms of action with ketamine. So, ozone comes into play, and it helps this this glutamate receptor not be quite so active. I already mentioned this, that medical ozone increases nitric oxide. Again, anything that we can do from a nitric oxide upregulation is always a good thing has many properties, in addition to just addressing some of the hypoxic events. A couple of the other things that I found in the literature that was really interesting was that it increases were actually lowers blood viscosity. So, the big drug 20-25 years ago was Trenat, pentoxifylline. And its mechanism of action was, well, let's just make this RBC a little bit more slippery, a little bit more flexible, and maybe you can sneak through these smaller little capillary openings. And, you know, think about that's pretty cool. Ozone does the same thing that pentoxifylline does. So where, where we are now with, with chemotherapeutic induced neuropathy is not even close to where we are from a diabetic peripheral neuropathy standpoint. But this might be where we need to look and I think Dr. Shallenberger mentioned this in his talk on Thursday morning. In that is what's happening with the axon and the myelin damage, right, and ozone can induce tolerance to ischemic insult and attenuate ischemia reperfusion damage in various tissues, I won't go into this too much, but I want you to think about this, from the standpoint of the best neuropathy to get is the one that you don't get, okay. And you know, what we're going to see in a couple more slides down the line. If they're going to have some chemotherapeutic regimen for their cancer, more likely than not, they're going to have a problem with peripheral neuropathy. And depending on the agents they use, you'll see in just a minute or two, but what's the other thing that we can do with ozone, and it'll for some of these patients that have more of an isolated mono neuropathy, and there was a real interesting study here on carpal tunnel, and we've played around with subcutaneous and Peri articular infiltration of ozone. And interestingly, it almost universally reduces their pain in some patients that lasts a lot longer and other patients it's maybe 5-10 minutes and then they're saying that it hurts, you know more, but they did this study and treat treating carpal tunnel, and they found that it actually did well. They had a randomized group. The control group basically had A wrist splinting, which is really, you know, kind of one of the basic foundations of early conservative treatment for carpal tunnel syndrome. And they compared that with splinting and one ozone and infiltration. And they found that there were improvements in the electro diagnostic testing in the ozone group. So, it wasn't just somebody saying, Well, I've got a better level of pain than I had before I do you see all these studies that deal with vas. Vas is like, ridiculous. I mean, one day, they're 25 out of 10. And then, you know, they saw their kids that the day before, and they hadn't seen him for a while. And now to two out of 10. It's a very, you know, variable thing, but electrodiagnostic is a pretty objective measure. And they saw that in the ozone group, they did have an improvement in electrodiagnostic function. So, what, what we have also is this reduction of oxidative stress. And so, what's happening in chemotherapy induced peripheral neuropathy, obviously, a lot of oxidative stress. Now, we see the same thing very often. And, and that's why I said there's some chemotherapy induced peripheral neuropathy that has a compressive nature. And for some reason, in a lot of the patients that were treated for breast cancer, it seems to hit the common fibular nerve. Well, that's the same nerve that Charcot Marie Tooth disease hits. And you have to start questioning it. Well, why is it? I'm sure that oxidative stress was pretty much the same throughout this this person's entire body. But why is there this preferential nerve that seems to be more affected than then than others, when you know, it's the same level of oxidative stress that's going on? And the answer is, is that it's really hard to treat chemotherapy and drug induced peripheral neuropathy. Unless they have a very compelling clinical evaluation that shows that there is a nerve compression. And if they don't have a provocation sign, or a tunnel sign, and you decompress them, they're probably not going to get any better. But these folks are so desperate that please try again. Well, they're what my goal of having no audio-visual impairments this this lecture. So anyhow. But these folks are desperate. And if you talk to a lot of them, they'll say, yeah, if I didn't have this, this neuropathy, after the chemo, I'd be doing great, you know, but this neuropathy is just driving me crazy, or it's so painful. So, this is where I think, I don't know how to accomplish this. But it would be really great that anybody who is going to undergo chemotherapy, that they started with ozone, to really up regulate them to mitigate these effects that happen on the peripheral nerve. And, you know, certainly, it's a lot easier to prevent something. And it's kind of like a fire, if you if you have a little tiny match burn, it's pretty easy to keep that from getting out of control. But when the whole house is on fire, it's a pretty difficult thing. So, I think, you know, this should be something that when you're talking to your patients, if you know that they're going to go undergo a regimen of chemo, it's like, hey, well, what about, you know, starting them on, you know, some supportive ozone treatments before, during and after, and you're going to mitigate their symptoms. So, and this has been demonstrated in some studies, as we can see here. So, I don't know about this. I don't I'm not an expert enough to tell you that this is the right dosage. This is just some of the stuff that's in the literature. And we found of all of the ways that we have played with trying to administer ozone. I found that rectal insufflation is probably the easiest from a practice standpoint, because if the patient has the means to get an ozone generator, they can quickly implement at probably a much lower cost than coming in and having to pay per infusion. So, it's, I think, for us, that's where we're trying to steer our patients. What about anxiety and depression? About 15% of my practice is suicidal. So, when you have a nerve that is hurt, it works on the central nervous system incredibly, and they all have anxiety and depression. If you ask a patient that's had a nerve problem for a long period of time, do you have any anxiety or any depression? And they say, No. They're probably lying. You know, they're being stoic, you know, they're but it's just almost impossible to not have these effects after you have a nerve injury that has been sustained for a long period of time. So, we know that peripheral nerve cases cause anxiety and depression, I didn't realize how important this work really was, until I had a patient come back to me. And this was early 2003. And he was a petroleum engineer. This one I was practicing down in Houston. And he was mid 40s. And really successful guy. And his name was Roger, I don't know why you remember these certain things. But when something epical happens, then you kind of remember it. And he came back his first post op visit. And he said, you saved my life. And I said, well, I think I made your nerves better. But I don't know that I saved your life. He said, Oh, you don't understand. He said, I had the gun loaded, I had it in my briefcase with the note to the family. And if I didn't see any improvement within the first week, there would have not been a second post opportunities. So, this is a compelling thing to get these people out of pain, because they're suffering tremendously. So, what are we trying to do when we treat peripheral neuropathy? Well, obviously pain is the number one, okay, but there's a subset of patients where the numb This is almost as bad as the pain, it just drives them absolutely crazy. And I've had some patients that say, you know, I have this thing, it's not painful, I can do my daily functions of life pretty well. But I'm going to kill myself, if I can't get rid of this weird thing, because it's just driving me nuts. It's kind of like tinnitus, you know, it's just after a period of time, you just can't take it anymore. Loss of motor strength, we want to increase their motor strength so that we can help their balance. If we can, again, repair or get them to have some restoration of sensation, that's a really big thing, and maybe any other weird symptoms that they have. So, you have to treat both symptoms. But ideally, you need to treat the cause. And I learned this very quickly was very humbled by these patients that we had done an earth decompression time, and we got it really much better, but we just didn't get them, like ultimate. And with ozone, we're actually able to maybe treat both the cause as well as the symptoms. So, I think that's a really important thing. Already mentioned this, we we've tried these different administration methods, we've kind of made rectal insufflation, our default go to now, because it's just easier from an administration standpoint, at the clinic. I've played with the local infiltration, I've actually seen more success with intra articular injections of ozone than in, in the neuropathic situations. So, and, you know, this is kind of where we go from the standpoint of administration, and then I don't need to talk to you all about dosage because you know, all this much more than I know. In summary, neuropathy is super complex. Anybody that tells you that it's easy run from them, because they're the most disingenuous people that you could ever hang out with. And the more you go down the rabbit hole, the more you go down the rabbit hole, because you want to try to help these patients you want to try to figure out what else can I do for them, and maybe intervene and make their life better. So, the other thing, the take home message too is if you can find a component of compression, that's ideal because we can then decompress that nerve and give them a much better outcome.