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Male Speaker: We mentioned the important role of neuropathy as one of the leading risk factors for lower extremity problems in diabetes. So Iâm very happy to have Dr. Stephanie Wu talk to us about neuropathy, the common denominator for all these problems. Dr. Wu is an Associate Dean of Research at the Scholl College. Am I â is the city â Iâm still allowed to call it the Scholl College? And is the director now of the CLEAR Institute for Lower Extremity Ambulatory Research. Sheâs travelled a lot. Sheâs done a lot of speaking. And sheâs published some very important publications. So Iâm very happy that weâre able to get Dr. Wu to come and speak to us all today. So letâs welcome Dr. Wu.
Stephanie Wu: Thank you, Dr. [Freiburg] [0:01:01]. Itâs great to be here. I see a lot of familiar faces. So today, weâre going to talk about neuropathy. Before I start, I like to first state that I have nothing to disclose. And the learning objective. So at the end of the talk, I hope that youâll have a better understanding of the ideology of the diabetic foot ulcers and have a better â be able to explain the pedal effects of motor, autonomic as well sensory neuropathy in patients with diabetes as well some of the risk factors for diabetic ulcer development.
So when we first think about the cause of diabetes foot ulcer, what are some of the more common things that kind of pops in our head? Certainly, the loss of protective sensation from diabetic neuropathy. Of course, thereâs the deformity thatâs often there in patients who have diabetes and of course we canât really ignore pressure that these feet are susceptive to when they start walking.
Now, this actually really isnât exclusive just to the diabetic patients. I have here a picture one of the diabetic mice that weâre working with and as you can see here. You can see here that the diabetic mice actually developed a diabetic tummy ulcer. So what happened with the diabetic mice was it got so fat that it was literally dragging its belly on the bottom of the cage. And in a very short period of time, the diabetic mice actually had these diabetic wounds on the abdominal area.
Now, in some cases we were able to heal it with some of the advance wound healing products that we were trying on the mice, but you can see from the previous picture very similar to that of a diabetic foot ulcer. These diabetic mice tummy ulcers also go extremely deep. So in the previous picture, Iâll go back to it again. Unfortunately, the poor mice, the wound went deep into the abdominal cavity and we had to euthanize the mice.
But when we take a look at these risk factors, be it loss of protective sensation, deformity, pressure. Now if we think about it, each risk factor or each component in and of itself doesnât quite cause the diabetic foot ulcer. So if you think of a patient with the worst diabetic neuropathy in the world, doesnât feel anything whatsoever and has the worst deformity, if we are able to suspend this patient in the middle of the air and their feet never touches the ground, they can have the worst neuropathy and deformity and youâre not going to get develop the ulcer. Why? Because the ground reactive forces are not there.
Conversely, we have many patients since some of us ourselves have painful calluses on the bottom of our feet. These calluses develop in reaction to the abnormal pressures that weâre walking to because of our deformity. So why is that some people donât â the people without diabetes donât tend to get the ulcers and the ones that do because people with diabetes have loss of protective sensation.
So when we look at these components, really in order for the diabetic foot ulcer to occur, you really have to have some component of the deformity, loss of protective sensation as well as the abnormal pressure thatâs imposed on to the foot when the patient is walking. However, if we look and separate it at each component and look at them individually so deformity, loss of protective sensation as well as pressure and if we examine each of this component, itâs pretty obvious that neuropathy really has a hand in the development of each of these component is hence the common denominator in the development of diabetic ulcers.
So diabetic neuropathy, now thereâs a saying out there that anyone who has diabetes got diabetic neuropathy. Why is it that people say that? Well, itâs because about 75% of the patients with diabetic neuropathy do not experience any symptoms. So if you think about your clinical experience, most of the diabetic patients that come in, you know, youâve got the small portion about 25% that complains of the tingling, the burning, the numbness, most of the people especially with the diabetic foot ulcers, they actually do not complain about their neuropathy at all.
However, if weâre diligent in the way we examine the patient in terms of vibratory testing in terms of protective sensation via the Semmes-Weinstein, via reflexes, most of the patients that weâre going to see are going to have some of the signs, so itâs important that weâre diligent with our examination and itâs also important that we perform periodic evaluations of the patients.
Why is that? Well, if we examine the natural history of neuropathy, here on the left-hand side, we got the baseline of the patients. Hereâs the group with diabetes. Hereâs the controls. And as you can see here, the Y-axis represent percentage with neuropathy. So here you can see that when the patients first get diagnosed with diabetes, only about 4% of them have polyneuropathy. Thereâs an additional four that may have probable neuropathy for the control. As we expected, youâre looking at about 1% for each.
However, 10 years later it grew. It expanded to at least fourfold. So now youâre looking at about 22% of the patients with definite polyneuropathy, another 22% with probable neuropathy whereas the controls havenât grown quite a bit. So we know that with the natural evolution of diabetes that neuropathy is going to progress. Thatâs why itâs extremely important that these patients maintain good glycemic control and also that we just donât check them the one time. We need to check these patients periodically.
So what causes a neuropathy? Well, we know that diabetes is really hyperglycemia. You got too much sugar in the blood and thatâs through all these different proposed pathways, the polyol pathway, the sugar autooxidation pathway. With all these pathways thatâs out there, what ultimately happens is it actually ends up adding oxidative stress to the endothelial cells, so you get endothelial dysfunction. And that eventually leads to nerve dysfunction.
So as more simply put, you can see here on the left-hand side, weâve got a cartoon of a healthy nerve. Youâve got the vasa nervorum that is feeding oxygen, nutrients to the nerve and here you got the myelinated and unmyelinated nerves. And then what happens with the oxidative stress, the endothelial injury is the vasa nervorum eventually become occluded. And then youâve got hypoxia to the nerve so eventually they become damaged.
So when it comes to the damaged nerves, I bet youâd think, âOh my gosh, I never want to see, you know, this peripheral nervous system again.â But when we think about this nerve damage, remember it doesnât pick and go, âOh, let me damage this nerve. Let me damage that nerve.â Every bit of the nerve in the peripheral nervous system is going to be damaged.
Kind of going back and this is a very simplified view. Well, you recall that the motor nerves are the thicker nerves, the myelinated A alpha fibers and they control â they do the motor control. And then sensory, remember how youâve got a broader spectrum of the myelinated to thin unmyelinated fibers, the A alpha/beta and then the thinly myelinated to the unmyelinated A delta C fibers that controls everything from vibratory sensation to position sense, to touch, hot, cold and as well as the autonomic nerves, which are the thinly myelinated to the unmyelinated or mainly the A delta fibers.
So each of these fibers are going to be effected secondary to diabetes. So letâs first talk about motor neuropathy and Iâm sure youâve all been through this before. You hear about instability of the intrinsic foot muscles that ultimately leads to destabilization of the digits that ends up with claw toe deformity which in turn causes anterior displacement of the fat pad as well increased plantar prominence on the metatarsal heads.
Now, how does these all occur? Well, before we even talk about that, next time when we talk about this intrinsic muscle wasting, next time when you see a patient come in especially one with a diabetic ulcer, check their hands. We are so busy to check their feet that we never really look at their hands. You may shake their hands a little bit but never look at it. Next time they come in, half of them actually try to flatten out their hand as much as they can.
You will notice something very similar to the picture that Iâm showing you here. The patient is unable to straighten out their hand. Why? Because the intrinsic muscle, always think that happens in the feet happens to the hand as well. So you can see here the contractor of the digits, the anterior placement of whatever little fat pad that you see on the hand. So you end up with a very like almost a claw hand kind of deformity, claw finger deformity very similar to that of the foot.
So this actually occurs both in the hands and the feet but unfortunately going back to our Venn diagram, remember, you have to have the pressure and thatâs why you tend not to see diabetic ulcers of the hand, we tend to see it off the feet.
So when it comes to intrinsic muscle atrophy, Sicco Bus and his team out of the Netherlands took eight patients with diabetes as well as for neuropathy as well as eight age and gender controls and they took MRIs so on the frontal plane and they were able to see that all the patients that had diabetes and neuropathy had remarkable atrophy in all the intrinsic muscles for all the subjects.
And they further looked at 13 patients with diabetes and neuropathy that had the claw or hammer toe deformity, age and gender matched controls as well as age and gender matched patients with diabetes neuropathy but no claw toe deformity. And what they did was they actually looked at the fat pad. They measured the fat pad thatâs underneath the metatarsal head as well as that at the base of the toes. And what they found was if you look at underneath metatarsal heads, those with the hammer toe and the claw toe deformity and a mean of about 2.5 whereas for those with no deformity, it was about six. So itâs reduced by more than half.
Underneath the toes, the subphalangeal fat pads, well, because of the anterior displacement of it underneath thigh, you got a mean of 9.1 versus of 7.6. This is great but now the fat pad is sitting where it really has no use. And then because of the anterior displacement of the fat pad, if you look at the peak plantar pressure underneath the metatarsal head for those with the hammer toe of claw toe deformity, itâs only at 626 whereas for those with no deformity itâs nearly half.
So we know that, âHey, this is something that we can show on the MRI. We can measure in patients. And because of this deformity, we know that the patients are more prone to developing ulcers in those areas.â
And furthermore, in addition to the clawing of the digits, we also have contractor of the tendons as well as thickening of the joint capsule secondary to the non-enzymatic glycosylation process for patients with diabetes. Ultimately, these patients end up with whatâs called an intrinsic minus foot structure where youâve got the equinus deformity thatâs going to limit the joint, ankle joint range of motion along with the digital contractures and the fat pad being displaced anteriorly and all this is really going to increase the peak plantar pressure when the patient weight bearing.
This is why when we walk, if you think about the way we walk as being bipedal, the first thing that hits the ground is our heel, right, followed by the forefoot, followed by toe. This is why if you look at our patients, most of the wounds are actually going to be in the forefoot area or in the heel area because of that.
However, when we look at a pressure, is there really a critical pressure? What is it thatâs going to cause these ulcers to form? Well, Dr. Armstrong actually looked at it back in 1989 and you can see here by the dotted line, this is the plantar pressure of patients that do not have ulceration and by the solid black line this is the plantar pressure of the patients who ended up within ulcer.
Whatâs the first thing that you notice when you look at this graph? Thereâs actually a lot of overlap, isnât there? Itâs not as clear a separation as you would think it is. Well, when they separated out the plantar pressures for those actually that had no ulcer versus those that ended up developing an ulcer, they came up with this number which is 70 newtons per centimeter squared. However, the 70 newtons only have a specificity of 70% and itâs not very high. Sorry, a sensitivity of 70% in a specificity of 65%. Itâs not very good at all, is it? And thatâs why they conclude and said, âYou know, yeah, we came up with the 70 but you canât really tell and you need to really look at everything else including loss of protective sensation and deformity and everything else because there really isnât a cutoff point thatâs going to say one pressure is going â we know that with that pressure the patient is going to develop the ulcer.â
Stephanie Wu: So, we know that, yes, is pressure important? Of course, it is, but it cannot be the only factor. Thereâs got to be other things thatâs going on. So the other thing that we consider is really a time dimension so that when a patient is walking with a diabetes, theyâve got the abnormal pressure, but you notice how slow the diabetic patients are walking. So, the pressure time integral or in other words the amount of time that the diabetic patient spends on his or her feet along with the higher pressure, that pressure may not be as high as we think, but the length of time that they spend on it actually is going to be another component to them developing the ulcer.
Their contributory factors include footwear. Itâs been found that among almost 700 patients with a foot ulcer, only 21% of them actually got it from rubbing from footwear. Most of the time, the patient donât even inspect it to ensure fit. Why? Theyâve got neuropathy. Everything feels great. Theyâre a size 12. Theyâre going to squeeze themselves into a size 10 shoe and they donât â âHey, itâs great.â So, itâs really up to us to have the due diligence to make sure that we not only check their feet, but also check to ensure that they have good fit of their ulcers.
Their contributory factors include cutaneous manifestations. These patients often come in with dried fissured skin. Patients with diabetes are prone to developing onychomycosis as well as developing calloused tissue and itâs important to debride that down to make sure that thereâs no ulcer kind of hidden underneath the calloused tissue.
So, this actually makes a perfect segue to the next component which is the autonomic neuropathy. So, we know that with people â patients with diabetes, autonomic neuropathy can result in heart rate abnormalities, orthostatic hypotension, silent ischemia. Impotence is actually one of the highest complications in this patient population. And of course, for our purpose, itâs a sudomotor dysfunction. Why? Because these patients have denervations of sweat glands, denervation of their hair follicles.
So, here, we have histopathology slides. On number eight here on the top left corner, you see that dark lines that surround this. So, this is actually a sweat gland. These are sweat glands and the dark lines that you see are actually stains. So, itâs stained on purpose for the nerves that innervate the sweat glands. Well, what happens after long-term diabetes is you see how the lines all disappear. So, they end up being denervated because of the autonomic neuropathy.
Same thing with the hair follicles, so, this is the hair follicle right here on slide â the top right corner. All these little dots that you see or these little lines are the innervations to the hair follicles. As you can see, as time progresses, you donât really see it anymore. And this is why when we examine our patients, youâll see that their skin texture is abnormal. They often do not have any digital hair growth and their skin tends to be thicker and more rigid because of the increased non-enzymatic glycosylation of the cross linking of the collagen. So, what this ultimately results is you get reduced sweating. You get dry, cracked skin.
So, in addition to them not feeling anything, abnormal pressures, more time spent on the feet with these abnormal pressures, theyâve got dry, cracked skin that is more prone to developing the ulceration.
So, finally, letâs take a look at sensory neuropathy. This is the one that you and I are probably the most familiar with. Common signs for sensory neuropathy often include absent or reduced sensation to pain, to touch, to hot, cold, to vibration and we often see it in the stocking and glove distribution.
And studies have found that when it comes to the sensory neuropathy, oftentimes, itâs whatâs called a small fiber disease. So, this is an electromyograph of the cutaneous nerve. So, this is actually the edge of the skin and you can see the cutaneous nerves that goes to the end. This is what allows you and I to feel the light touch when you and I run our fingers on the top of our hand. Well, letâs take a look at what happens in the patient with diabetes. So, in the patient, weâre getting this histopathology slide from the back. So, you can see this is it on a skin and you can see here you got normal density of the epidermal nerves in the back. And then, as we go down lower to the proximal thigh area, so you can see this is the top of the skin, you donât really see that normal distribution as much, do you? In fact, you actually see â I donât know if you can see here â these little globs really. Theyâre abnormal nerve fiber swellings that you can see in the abnormal [thigh] [0:19:48]. However, as we go more distally to the calf, you end up with this complete clearance of the nerve fibers in the calf. And then, as you can imagine in the feet, oftentimes, they do not feel anything.
And this is where it becomes dangerous because these are the patients who because they donât feel, they walk around barefoot. They end up stepping on rusted screws, bottle caps. And sometimes, youâll notice that, you know, in their shoes, they may have â in fact, one of my patients, he had a used insulin needle that was stuck in his shoe. And so, itâs extremely important that when these patients come by that we not only examine their feet, but examine their shoe as well.
So, when we talk about the etiology of diabetic foot ulceration, we know that theyâve got diabetes and with neuropathy and it can be motor, sensory, and as well as autonomic. With motor neuropathy, theyâve got small muscle atrophy. As well as with the non-enzymatic glycosylation, youâve got the limited joint mobility. Thatâs going to result in high foot pressures. Thatâs going to result in foot ulcer. Theyâve got the sensory neuropathy and that leads to them having reduced pain as well as proprioception, making them more susceptible to developing the foot ulcer. Theyâve got autonomic dysfunction. Thatâs going to result in dried, calloused skin and pericapillary flow. Thatâs going to result in foot ulceration. So, really, if we think about it, all these risk factors that these patients have really neuropathy is the common denominator.
And I really just like to end with a quote by Lindsay, âFor one mistake made for not knowing, 10 are made for not looking.â A lot of our diabetic patients really rely on us to be their advocate to go and do their exams properly. Itâs important not only to examine them in terms of their neuropathy and do it periodically, but itâs also important to examine their shoes as well to make sure thereâs nothing in the shoe, to make sure that the orthotics are not worn out and also that theyâve had proper shoe wear and itâs got a proper fit. Thank you very much.
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