William Jeffcoate, MB, BChir discusses the history, etiology and pathophysiology of Charcot, including theories and documented presentations. Dr Jeffcoate reviews statistics pertaining to the disease and relevant implications of these figures.
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William Jeffcoate, MB, BChir
Foot Ulcer Trials Unit, City Hospital
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Male Speaker: Speaker Dr. Jeffcoate wrote a paper, I think it was 2004, wasn’t it the first one, Diabetologia or something like that, where I first got hold of this whole new theory behind the demineralization and neuropeptide dysregulation occurring in acute Charcot feet. I like to give William credit for that in helping me understand after many laborious hours of trying to read the paper and understand it. I’ve asked William Jeffcoate to give us his idea of the underlying pathophysiology of Charcot foot. Welcome Dr. William Jeffcoate.
William Jeffcoate: Well, here we go again. Thank you for staying. Well, I don’t know if I can explain it simply because it’s pretty complicated. I’ll have a go. This is the first one, yeah. This is Jean-Martin Charcot. The picture actually which Lee Sanders, retired podiatrist, found himself in a specialist bookstore in Paris. He was immensely proud of because of not one of the standards ones showing Charcot there as of a typical pose and immensely proud of his [indecipherable] [01:25] which he had received. The disease which we’re concerned about best his name and it was generally accepted by us all that the involvement of the foot was first described by Charcot in Paris in 1883. Charcot himself had originally described changes in the larger joints further, more proximal lumbar spine and large joints earlier in 1868. But it’s in 1883 that he first described the involvement of the foot. But Lee Sanders just this year has written a paper. Who is first to diagnose and report neuropathic arthropathy of the foot and ankle, Jean-Martin Charcot or Herbert William Page? You can guess that it was Herbert William Page who was a London surgeon but did contrasting styles. Two years earlier in 1881, there had been a major International Medical Congress in London and Page presented a man who had tertiary syphilis with bilateral disease of the foot. At the demonstrations, he had the advantages, as the report in the BMJ, he had the advantage of Professor Charcot’s presence and of some remarks made by him, 1881. In 1883, Charcot and Fere stated that involvement of the short bones and small bones of the foot had not yet been described [indecipherable] [03:02]. We’re talking about a disease which starts with inflammation as we all know and for which many of ones which we are uncertain about the cause of the disease and you will know that you get extensive changes particularly in the tarsal bones. But it can be more distal as shown here with navicular medial cuneiform in the wrong place and all the metatarsals here going off laterally with that gap over, so being bigger and they should be. What do we know? It’s an inflammatory disorder of the foot affecting people who have neuropathy. We think neuropathy is an essential prerequisite and we also know that it gets better with time. It’s characterized by a fracture and dislocation of the bones and joints of the foot. Yeah, we know that and the standard thing is that urgent offloading is essential to protect the foot. It’s often triggered by another event like a trip or a minor event or maybe by preexisting disease of the foot. It occurs in both feet in about 20% or 25% of cases, not at the same time but maybe separated by a period of time between two, but it’s thought to be 20% to 25% get it on both sides. It doesn’t tend to recur although there are reports on the same side once it’s happened. Most people have good peripheral arterial blood flow. The pulse is reasonably palpable. It’s uncommon perhaps and this is the figure that is always quoted affecting three per thousand people with diabetes and if we accept the prevalence of neuropathies, 30% then that’s 1% of all people who have neuropathy. Mean ages, a bit earlier in diabetic foot disease but still male or female predominance of two to one. It can occasionally occur in people that are much younger, particularly young Taiwan’s women who’ve had feeding disorders in teenage.
Also people now where especially renal-pancreas combined transplant again in that young group who have got microvascular disease. There, it looks as though the incidents of Charcot is getting to be recognized to be really quite common. What causes it? Charcot of course as Herbert William Page was, was describing patients who had tabes dorsalis with loss of deep pain as well as loss of some cerebral function with loss of their perception. The loss of the deep pain when combined with sensory neuropathy and motor neuropathy, leads to abnormal forces with reduced protective behavior, perhaps some acute episode leading to micro factors and then the situation worsening and getting to more frank changes in the skeleton of the foot. That's what we all understand as the neurotraumatic course of the disease. Charcot himself though was much more instant. He understood all that although it was called the German neurotraumatic theory. He was much more instant the possibilities that the bones were abnormal in the first place. There may be changes in blood flow as a complication of neuropathy or manifestation of neuropathy were contributing to the onset of the disease. In that respect, he was a hundred years ahead of his time. We of course study it in diabetes by and large or other causes of peripheral neuropathy without coping the second most common cause that most of us see of peripheral neuropathy, although any other traumatic denervation can be associated with the disease as well as syringomyelia, etc. But it's diabetes and tabes which was the two leading causes in the 19th century and now, now. But note that the abnormalities of nerve damage are completely different. The nerve deficits in diabetes you do not have loss of deep pain, you have loss of spinothalamic pain and so you get moderate reduction of pain sensation. But deep pain sensation if you test it by squeezing across the Achilles tendon is normal. Yet the presentation of the diseases is completely the same if you look at Herbert William Page's description. It is just the same as the case that we might manage now. Chantelau has looked at this question of pain thresholds and Charcot and has really demonstrated this and really been convincing that the preservation of deep pain. The preservation that exist. We've got sensory neuropathy, we all understand that. We got motor neuropathy, you've got glycation of collagen so that could be also increasing the changes and the structure of the foot and the impairment of gait. So you get this exposure to have normal forces. There might be additional trauma. We know that it can be also triggered by other causes of inflammation. What the current theory is and I supposed this is the one that we put together in 2004, 2005 is that it’s inflammation which is the key factor. It's not necessarily just this. But on top of that, there is a problem with uncontrolled inflammation. In this respect, Charcot speculating by the abnormal blood flow were might have been very close to what we think now might be a key abnormality. If you have break a bone or if you’ve dislocated something or if you're a laboratory animal that has a bone broken for you, you will release proinflammatory cytokines. Laboratory animals they will go up for a day or two and no longer and this release of proinflammatory cytokines triggers a signaling pathway and mediated through rank L which then triggers the release of a nuclear transcription substance NF-kappaB. These then called osteoclast maturation and osteolysis. Now, the idea is that after an acute injury if you break a bone, you will splint it. You'll stop it moving. But in that acute day or two, you release these proinflammatory cytokines and this starts to break down bone as a prelude to allowing you to heal the bone thereafter. But because you splinted and don’t move it because it hurts, then that interrupts the release of the proinflammatory cytokines. Then that makes this process self-limiting. If however you've got sensory neuropathy and you don’t split the broken bone, then you will continue to stimulate osteoclast maturation, bone breakdown.
You reduce the integrity of the bones and joints, you then get worsening fracture and dislocation and the whole thing becomes a vicious cycle. This was the thought, this was the theory we put together. It’s a theory which a lot of people accept. There are no data really to demonstrate that the theory as correct, but let’s hope it is. It’s the process, particularly the elaboration of RANKL and NF-kappaB is regulated by a whole host of different agents acting in different ways. This one highlights calcitonin gene related peptide really just to come across another concept so the pathogenesis of disease. We think of peptides as being things. We don’t think the most of them as being hormones that are released by nerve terminals. We think nerve terminals release acetylcholine or catecholamines. Well, we don’t think of them as releasing peptides, but they do. When the nerve terminals die as in neuropathy, then the release of these peptides obviously goes down. CGRP is very important because CGRP actually suppresses this inflammatory pathway. It’s possible that the nerve terminal death would reduce CGRP release actually encourages this pathway. If you like, it’s a bit hyperexcitable and hence more likely to respond to an inflammatory stimulus. Diabetes itself also increases the expression of RANKL and NF-kappaB and the whole process that goes on to uncontrolled inflammation. Diabetes does it through oxidized lipids, reactive pid oxygen species and advanced glycation endproducts, all of which augment this pathway. But there’s a problem in our pathogens. I said, it only really affects 1% of person with neuropathy and yet everybody with diabetes and neuropathy could have all these things I’ve been talking about. So why is it so uncommon? One possible clue comes from three separate groups working over the last 10, 15 years looking at the vasomotor responsiveness of people who have had an acute Charcot in the past. They showed that whereas normally in people with neuropathy, if you warm the skin of the foot, there is impairment of vasodilatation. If you warm the skin afterwards, like in trying to stamp up the fire of the carpet which happened about 15 minutes ago, then you will get local vasodilatation. But if you got neuropathy, you don’t. But what these three groups independently showed is that in people who have had neuropathy, that vasodilatation in response to skin warming is preserved. This is a possible explanation for why Charcot is so uncommon. It’s only in that tiny minority who retain the capacity of inflammation who are able to actually trigger off this cascade. Now, this question about abnormal vasomotor control is one that interests me a lot. This is the foot of a man with neuropathy. As you can see, he's got one of those and he's had some callous debrided there. The other abnormality apart from the flaky skin and the loss of air is the distended vein. When we feel the dorsalis pedis pulse of someone like that, it will be going boing, boing, boing and all of us will think "Oh, I feel, that's okay. Pulse is thick." Well, it's not normal at all. It’s very abnormal and you can feel it easily because they got a widened pulse pressure and the reason why they got the distended veins is because as a result of neuropathy, they are AV shunting. The blood is going straight through from arterioles to venules transmitting the arteriole pressure to the veins which is why they distend widening the pulse pressure and that's why their pulses are very easy to feel in these people. This is not specific to Charcot, it happens in anybody with neuropathy. But when we think the pulses are palpable, therefore the blood flow is normal. We have to think it's not normal, it's actually abnormal. I’ll come back to that in a bit. But here's a little picture. Normally, we shunt blood to the skin as we want with depending on requirements and you have normal skin integrity. We tend to think of loss of sweating as being a specific abnormality or autonomic neuropathy for these reasons.
But if you lose the capacity to shunt blood to the more superficial levels of the skin and you're AV shunting, you can have relative ischemia of the skin which explains why in neuropathy, you get hair loss in the foot just as prevalent as hair loss from peripheral arterial disease if not more common and you'll also get loss of sweating. That’s just to try and illustrate the problem. Coming back again to other factors in this complicated thing that I'm trying to take you through is that you got this release of these things which is augmented for a variety of different reasons. You've got underlying maybe vasomotor neuropathy but maybe it only happens again in people who've got a particular inherent genetic predisposition. There have been two studies I'm aware of. Both show an odd ratio of about two to one for the Charcot versus controls. In one case, the actual polymorphism is the same. The others are different. I think the jury is still out on that one. We don’t know really whether this genetic predisposition is in fact a true factor making it more likely on the affected group. We don’t know not for ones who's trying to get money to study it. We’ve tried over and over again and it failed repeatedly. It’s a text simple study. If anybody can get the money, it’s dead easy to do a genome-wide association study and also to bring up all your friends who got patients with Charcot and take blood even though the Charcot occurred 10 years earlier. But there’s not a little bit here in this sort of cascade I’m going through and this is the question of arterial calcification. We all know that people, the population we see have Monckeberg sclerosis more often than not. The prevalence is about 50% in people with neuropathy whether or not they’ve got Charcot. It is actually this, what I’m about to talk about, about arterial calcification is a feature of neuropathy not of Charcot specifically. It can be seen on plain x-ray in about 50% and now you can see it quite clearly on that little picture even that tiny little picture. The reason for this is, there’s a picture of arterial calcification. When you see calcified arteries, you think, well, this may be this is faster than arterial sclerosis and in your mind, you link that with atheroma. It’s nothing to do with intimal calcification associated with atherosclerosis. What we’re talking about in Monckeberg sclerosis is medial calcification. In other words, here stained in alizarin red, the calcification occurs in the media of the arterial wall and just by the by, for your interest histologically that is not calcification. That is bone with people leech leach the bones out of the calcium, the bone if you like out of their bones, but they’re actually making new bone in their arterial wall in people who got neuropathy. There are various reviews on arterial calcification and if you try and read them, I’m not a calcium doctor. I’m trying to put together this review where it took ages and ages trying to understand what these calcium doctors were all talking about. But there are now three of them which are available looking at the complicated processes which lead to arterial calcification. In other words, new bone formation in the media of arterial walls. It is triggered by exactly the same pathways that we’ve been talking about RANKL and NF-kappa B are involved. Not only causing bone breakdown but bone formation in arterial walls and bone formation may also potentiated by calcium and phosphate for obvious reasons as a result of bone breakdown and especially in people who've got renal failure. As the bones become abnormal, x-ray, as the arteries become abnormal because their walls are not rigid, this will further increase the pulse pressure that I’ve been talking about because anyway, the body can maintain effective distal circulation, is by the left ventricle squirting harder to get the blood down there to maintain blood flow through the whole of the cardiac cycle because it no longer got the compliance of the large vessels. You have this abnormal blood flow which is not just a result of arteriovenous shunting in the periphery but also the result of having pipestem arteries if you’re like, going right down to the small arteries that we see on x-ray being calcified. All of which leads to altered blood flow. You can then start to hypothesize as Charcot did but actually you’ve got abnormal blood flow contributing to the integrity of the bones and joints.
I put another little arrow in there because of course we also get abnormal bones and renal failure partly mediated through vitamin D deficiency. If you’ve got autonomic neuropathy as we classically think of autonomic neuropathy, in particular with loss of catecholamine secretion, this also will lead to abnormal blood flow which could contribute to the reduced integrity of the bones and joints. It’s interesting that there is actually one study that has been looking at the count of sympathetic nerve terminals in the bones of people who’ve got a chronic Charcot foot and showing that it’s markedly depleted. One of the things I’m sure, we’re all going to learn an awful lot more about or be aware an awful lot more about in the coming decade is going to be importance of the nerve supply to the bones themselves and their relationship to this whole pathway in ways that we can only really guess at, at the moment. I mentioned CGRP before as being something that might mediate, this little class was a bit of the pathway. CGRP is also important because the nerves which innovate joint capsules are really rich in CGRP. One of the things I’ve never really understood is why you dislocate that joint. It’s so difficult. You got to put your foot under a bus to dislocate that joint normally. It’s immensely tough. Yet it seems that relatively easily just like someone who is affected, stepping, putting, still getting out of bed and standing up. It’s sufficient for that to occur when they’ve got this disease. Is this because the joint capsule is now the attachment to the adjacent bone is weakened and is that why the whole thing gives way? Or is it more specific? Is it that the integrity of the joint capsule is reduced because of the loss of innervation of the joint capsule and particular by CGRP? There are other candidates as well including substance P and VIP. As there’s another facet to this whole process about this complex disease. If you start exploring this whole idea, your mind suddenly stops getting sideways and you start thinking of all sorts of new ideas. It’s very complicated. We think that this is the process that’s involved in acute Charcot, but once you start speculating on all these ideas, you start thinking about what is innovation. You get away from just motor sensory autonomic and start thinking about what these nerves do and all the different tissues and how they modulate the cells of bones and other parts of soft tissue as well. The role also in inflammation in this case, pain sensation was obviously important arterial structure I described. Things I haven’t mentioned any more detail it’s also the relationship between bone hormones. Bone is also an endocrine organ. Osteocalcin in particular might also be involved because we know that osteocalcin actually modulates glucose resistance, insulin resistance and hence, links in with the pathogenesis of type 2 diabetes. It’s incredibly complicated and very, very exciting fields to start, once you open the crack in the door, you realize all the potentials that they are there for studying. That’s what I’ve been talking about. In a short while, you're just going to hear about the options for treating, I’m sorry, I’m not going to go through those at all. Although we all know that casting at the moment is the mainstay of what we do to try and control the disease. But while talking about understanding the disease which was my title, there’s just two things really that I think we just have to keep also in mind and the most important thing is not just think of the foot. If we get a new Charcot, we all go, “Look, a new Charcot,” do an MRI, and say, “Oh, am I clever.” We know what to do so that makes us feel good as well, but there are other things that we have to think about and one of them is mortality. We know the data now which suggest that anybody who presents with a foot ulcer, the chances of surviving five years is only 50% unrelated to age.
What people think is, well, that relates to widespread macrovascular disease, it doesn’t actually. It is just as common in people who got neuropathic disease as in people got ischemic ulcers. Anybody who comes to you with a neuropathic foot ulcer has got 50% five-year survival expectation on average. We looked at all the Charcot’s we had identified over a period of time and we could identify 117, we had age, gender, disease, duration match controls wherever we could and we had 109 of them and we looked at the median duration of followup the incidence of death and median survival. You will see that actually there’s no difference between Charcot and neuropathic ulcer. I’m mentioning it now because we’re talking about Charcot and people with Charcot have also got neuropathy so they're neuropaths. This population have got an extraordinarily high percentage of death and in a median followup of three to five years. In other words, they got 40% to 50% mortality in less than five years. If you look at the median survival of the two groups, it’s about eight years. Someone that comes to you has got a median survival of eight years even though they might be 52. We plotted those data out. These here are Charcot’s in green and neuropathic ulcers in blue, showing the cumulative survival going down from 100% just obviously everybody surviving to 50%, which is fair. These are normative UK data unselected populations which are corrected for age and gender and you will see that the 50% mortality, the average reduction and life expectancy between there and there is 14 years. When you’re managing these people, you need to think of that. The other aspect of treating the patient and not just the foot with all the clever things we might want to do with it is to think of depression. When we manage people with Charcot because they always, as the saying Charcot cheers us up to some extent, even though it gets a bit depressing when the inflammation doesn’t settle as fast as it should do, it might be depressing for you. It’s even more depressing for the person who's got the Charcot foot. Foot clinics tend to be quite jolly for some unknown reason and by and large when you’re there, there’s a great atmosphere, there's a whole lot of people buzzing around and the person comes back and they have their cast replaced, and you’ll say, “Oh, that’s good. How are you? Jolly good.” And you say, “Oh, it’s feeling a bit of temperature difference. Oh, well, we better put it back for another fortnight,“ or whatever it is. And you, there's sort of banter that goes on, well certainly now our clinic and I guess it’s true in many others actually can bury the extent of upset that the people have who we are managing and they might not be able to express their depression unless you go actively seeking it. But here’s a major problem and I think we probably all underestimate it and we probably all ought to be proactive in trying to identify it. That was all I was going to say. Thank you very much.