Dr. Frykberg discusses the history of Charcot's foot and the current perceptions. He reviews the pathophysiology, methods of diagnosis and preferred treatments for the different stages of Charcot's foot.
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Release Date: 03/16/2018 Expiration Date: 12/31/2018
Robert Frykberg, , DPM, MPH,
PRESENT Editor - Diabetic Limb Salvage
Carl T Hayden VA Medical Center
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Male Speaker: Okay. We are going to move along with our Charcot Foot session. I think you've got several important talks here from entirely different perspectives, which is probably the best way to present this information. My job really is just to go over the current concepts about pathophysiology as well as diagnosis. You'll hear Dr. Shara [phonetic] talk about an overview of conservative treatment strategies and Dr. Laporto [phonetic] will be talking about surgical principles. Charcot first described this disorder really in his French paper 1868 which he called -- and he called it the arthropathy of locomotor ataxia subsequent to tabes dorsalis, tertiary lewis [phonetic] and it was first brought to the attention of the English speaking world by Charcot in the 7th International Medical Congress in 1881 in London and it was at that point that Sir James Paget named this disease Charcot's disease. Although we know there's several diseases by that name. However, he did not discuss fetal manifestations of this entity then. It wasn't until he published the paper in 1883 in the archives of neurology where he presented a typical Charcot foot. You could see the images here of the cartoons of that foot, which he termed Pied Tabetique. Interestingly, at the 7th International Medical Congress, Dr. Herbert Page, presented a case of what Charcot recognized as locomotor arthropathy or that he was describing in the foot. However, it was Charcot who made the first publication on this entity and Charcot is given also the credit not just for describing what we term Charcot arthropathy but also as Charcot arthropathy or the Charcot foot in 1883. And of course, we recognize that diabetes-related Charcot foot wasn't described in the literature until William Riley Jordan, a former Joslin Clinic fellow, presented in 1936 paper in the archives in internal medicine where it was-- he termed a rather typical appearing painless Charcot joint in the ankle of a diabetic patient number 10,000-something or something, it was a woman. From then on, it's become an increasingly more prevalent point of discussion in the medical literature and then certainly over the last 20 years. So if we go back to the future and use Charcot's own words, he said, as you could see, most usually the first phenomenon discernible is extreme tumefaction of the entire member or extremity. And the first symptoms of ataxia arthropathy appear suddenly and unexpectedly and we can use these same words to describe many of the Charcot feet or Charcot joints that we currently see. But yet, more than 100 years later, many questions still remain. There's confusion about Charcot's disease exists. Even the terminology is not standard, Charcot arthropathy, Charcot foot, diabetic, neuropathic osteoarthropathy, osteoarthropathy, osteolysis, et cetera. What exactly is it? What causes it? These are all questions that have been raised in our international consensus in 2011. Is it a disease or is it simply a syndrome comprising multiple manifestations and ideologies? How do we diagnose Charcot arthropathy properly? Is there a specific diagnostic test for this disorder? Is there -- can become a gold standard? Once diagnosed, how is it best treated? These are all still clinical conundrums that we don't have quite definitive answers for. And is surgery necessary? And if so, when is it necessary? And on what evidence do we use to guide our decision? So still many questions remain. And in 2011, January to February 2011, we convened in a national taskforce in Salpêtrière Hospital in Paris where Charcot practiced. And you could see some of the proceedings here in the picture. This was the -- the consensus was published in September of 2011 in diabetes care which gives our overall consensus on what the panel determined to be current concepts and diagnosis in pathophysiology as well as treatment. And I refer you to that paper. How do we define it? Well, we define it as a condition affecting the bones, joints and soft tissues of the foot and ankle.
But specifically, as you could see, characterized by inflammation. Now, 15 years ago, certainly not 30 years ago, we recognized inflammation but we didn't highlight it. Now, we highlight the importance of that acute sudden and really profound inflammatory reaction that is very typical for an acute Charcot foot. And while pain or discomfort maybe a feature of this disorder at the acute stage, we have to recognize that it is much less than would be expected for injuries or the nature that we see on common x-rays. Previously, Charcot joints were felt to be painless. Now, we recognize from several studies that there is usually some degree of pain or discomfort in an otherwise neuropathic or almost anesthetic limb and that becomes a diagnostic clue in and of itself. And the committee determined that the set of signs and symptoms more appropriately reflected a syndrome and therefore we recommended the overall terminology of Charcot foot syndrome, and also for the record, not recommended that the terminology Charcot neuropathic osteoarthropathy, abbreviated as CN or Charcot foot, really be the standard nomenclature used for this entity. Although, we recognize that many people still use other terms to describe it. We looked at numerous classification system and realized that most really do not have any prognostic value or direct treatment value as a whole. But the most important prognostic values came when we looked, when we classified the entity as either being active versus inactive or what we might consider acute versus chronic because there are distinctively different ways to approach the entity. But once again, there is no accepted way to define when is it not acute and when does it become chronic. There's no hard points in this syndrome, so it requires a great deal of clinical acumen, suspicion and knowledge of the underlying metabolic perturbations that are the sole characteristic of this disorder to really know when an acute or active Charcot foot becomes an inactive or chronic Charcot foot. We also recognize that many diseases have the potential for causing or predisposing patients to developing Charcot feet or Charcot joints and of course, if you see the list of these diseases, we recognize that they all are associated with peripheral neuropathies and peripheral neuropathy, of course, must be present in order for this neuropathic joint disease to develop. We certainly recognize now, as opposed to in Charcot's day diabetes mellitus is certainly the most commonly associated disease causing the neuropathy that is associated with Charcot foot disorders. I believe that second in my clinic, it would probably be alcoholism. If patients have Charcot feet and they are not overly diabetic, they usually have some degree of neuropathy related to alcohol dependents or alcohol toxicity and it can change depending on your clinical circumstances. I think I've only seen one with leprosy but in the third world, leprosy still remains a cause for Charcot feet and that was demonstrated in 1966 paper by Harrison and Brand where they were discussing the different types of patterns of disintegration of the neuropathic Charcot foot dealing with patients with leprosy and the neuropathy associated therein. Very interestingly, up until several years ago, we didn't have any data reflecting the effects on mortality for patients afflicted with the Charcot foot until Von Bauer [phonetic] out of William Jeffcoate's Group in Nottingham produced this paper which was their -- a single center experience of the diabetic foot ulcer patients and also those who had Charcot feet in the center. And they looked at five-year mortalities here or several year, five-year mortalities as well as the first and the third year mortalities. And as we can see in this bar graph here, the patients with Charcot foot disease had the same five-year mortality as to those patients with diabetic foot ulcer.
This followed a paper, a previous paper by Sewn [phonetic] which showed higher rates in patients than diabetic patients without ulcer but still less of a five-year mortality that ulcerative patients. But in this very important paper, the patients with Charcot foot had the same impact on their mortality as to the patients with diabetic foot ulcer. And as we know, diabetic foot ulcers patients have an impaired longevity once again and a lower survival rate compared to patients with diabetes who do not have that disorder. So for the first time, we're seeing that Charcot patients indeed have lower survival than diabetic patients who do not have ulcer or -- and just diabetes and they have the same survival rates, for the most part, as to patients with diabetic foot ulcers. Many of you have seen this type of a diagram in numerous publications. It actually came from Belcha's [phonetic] paper in 2003 where he was dealing with peripheral arterial diseases and how similar these major complications of diabetes were compared to different types of cancers. And as you could see here referring to Charcot foot from Von Bauer's paper that we see 41 percent five-year mortality rate which is higher than five-year mortalities of patients with colon rectal cancer, breast cancer, Hodgkin's and prostate cancers. So once again, the complications, the chronic complications of diabetes have an adverse effect on these patients' survivals. They don't die obviously of these problems but they die of associated comorbidity such as cardiac disease, renal disease and cardiac autonomic neuropathies. So what about the pathogenesis of Charcot foot? Well, once again, we recognize the very key role of inflammation in both this pathogenesis as well as the early diagnosis of the condition. Many of us were aware years ago the French theory versus the German theory or the neurotraumatic theory versus the neurovascular theory. And it was Steve Edelman in 1987 publishing in the archives of internal medicine whereby he combined this into what he called the modern theory or the combined theory. And as you can see in the graph here, if we look at the neurovascular theory which is really the nutritive [phonetic] theory of French theory proposed by Charcot really focused on a central nutritive defect as Charcot said, which really we know now to be related most closely to autonomic neuropathy, hyperemia of bone, weakening of bone and osteopenia which makes it very susceptible to injury. But equally important is the role of the neurotraumatic theory here or the German theory proposed by Volkman and Berkhow [phonetic] whereby underlying sensory and motor and neuropathy patients can sustain a trauma. They walk through the trauma and without that gift of pain that Andrew Bolton had mentioned earlier, they continue to walk and create this vicious cycle and walking in itself becomes traumatic, and this leads it further degeneration of these joints. We see this chronic development of spontaneous dislocations, neuropathic fractures and osteoarthropathy are what we recognize to be a Charcot feet. And it's at this stage that we find the acute inflammation. And due to neuropeptide, this regulation that we'll talk about, these patients develop further osteopenia, weakening of bone and further fracturing so we get this chronic vicious cycle has been talked about for many years which is just due to the underlying disease of the bone, of the excessive hyperemia and the continued act of walking, which is why it's so important to get these patients off their feet once the initial diagnosis is made. This comes from Jeffcoate once again. William Jeffcoate has done a lot of work in this area and has produced some very important papers. And once again, it's combining the neurotraumatic theory with the neurovascular therapy -- theory and also interposing the role of neuropeptide regulation. Here we see trauma to a neuropathic foot leads to increased forces resulting in dislocation and fracture leading to abnormal loading here in the presence of neuropathy.
However, in the presence of osteopenia, and this would be more of the inflammatory theory, the neurovascular theory in the presence of osteopenia, this continued walking leads to excessive osteoclastogenesis due to underlying metabolic perturbations of excessive RANKL production and increased levels of proinflammatory cytokines. So we see a vicious cycle of developing due to underlying bone disease and appear due to continued walking on this injured foot in the presence of neuropathy and also protective sensation. So we can see how this process just continues to get worse and worse and worse if we allow our patients to continue walking. Hence, the importance of early diagnosis. Many of you, by now, might be aware of the important role of NF-kappaB and RANKL as providing perhaps the missing link that we didn't really know about 30 years ago when we first really started to pay attention to this disease. So now, we recognize through much of the work that has been done by researchers and bone and mineral research whereby osteoclastogenesis, osteolysis or osteopenia is really dependent upon the activation of nuclear transcription factor kappaB. And if kappaB activation is subsequently dependent upon the increase expression of RANKL, which was RANKL's receptor activator of nuclear factor kappaB and the RANKL must bind with RANK on the surface of osteoclast precursor cells. And once they bind, there's enough regulation of NF-kappaB leading to up-regulation of osteoclast leading to excessive osteoclastogenesis and subsequent osteopenia. So that's basically the mechanism here. This cartoon by Melina [phonetic] is published in 2010 probably demonstrates this very simply. Where we have the acute trauma in anyone, there's enough regulation of TNF alpha and interleukin 1 beta, proinflammatory cytokines that stimulate on the -- from the osteoblast. The up-regulation of both RANKL as well osteoprotegerin, OPG, which is called the decoy receptor. Now, it's called the decoy receptor because when there's an up-regulation of RANKL, the body's counterbalance is the production of OPG to help bind the excessive production of RANKL to limit the amount of osteoclastogenesis and up-regulation of NF-kappaB. This puts a breaking system on this excessive boning osteolysis. However, in patients to go on to develop Charcot foot, the excessive production of RANKL causes a binding with RANK on the surface of the osteoclast precursor cells leading to activation of these cells and subsequent osteoclastogenesis leading to excessive bone loss. And that's about as simple as we can make it. So there's some kind of disregulation of this OPG and RANKL neuropeptide system which is tightly regulated. Something is altered in the patients who have neuropathy who go on to develop this severe destruction due to excessive RANKL production. And you'll -- we'll talk about this shortly, that there's probably a genetic predisposition in these patients whereby they have a deficient production of OPG. And there have been two recent genetic studies, one from Italy by Dario Pitocco [phonetic] and then subsequently one from Poland by Anna Borkowski [phonetic], I always get her name wrong, of course on Borkowski, showing that there are specific single nucleotide polymorphisms of the genes for OPG. Whereby, certain polymorphisms were highly and significantly associated in patients who had Charcot foot compared to diabetic patients without Charcot foot. So we know now that it's not just neuropathy and not just trauma in neuropathic patients because some of our neuropathic patients they sustain trauma, they'll go onto heal without developing Charcot feet. But in that small, let's say, 1 percent of the population who develop Charcot feet, they must have this signal in nucleotide polymorphism that predisposes them to excessive RANKL without appropriate up-regulation of OPG to put the breaks on this system.
So in these patients, we see that excessive osteoclastogenesis that is an abnormal response to injury. And remember these processes are normal in all of us. But in the patients who develop Charcot, they have that critical single nucleotide polymorphism that predisposes them to develop the Charcot osteoarthropathy. So most of us are fairly familiar with the clinical presentation and hopefully are able to make the diagnosis at its earliest stage. And the key is to really diagnosis our clinical suspicion, the patient history, the appropriate clinical findings and of course, radiographic studies. And this is not really difficult, you just need to have a high index of suspicion and a red hot swollen foot in the presence of neuropathy is key, inflammation is the earliest and the key finding especially when associated with their antecedent injury. But as an inception, we know the so-called stage zero foot that was put forth by Shibata in 1990 where it was more of a prodromal stage where you had the acute inflammation post-injury without evidence of radiographic changes, without fracture on the x-ray and it's this acute inflammation in the presence of extensively normal appearing x-ray that really defines this stage zero or this prodromal stage that if left unchecked will subsequently lead on to that classic acute Charcot foot that we talked about. We also recognize that the midfoot collapse or the so-called rocker bottom foot is the hallmark deformity of the Charcot foot, but it's a late finding usually associated with a chronic Charcot foot that has gone -- that has been misdiagnosed or gone undiagnosed because of lack of treatment or a lack of treatment being sought by the patient. So whenever we see a rocker bottom foot, we know that that's late in the course of the development stage of the Charcot foot. So once again, we need to have a high index of clinical suspicion. And if you have a high index of clinical suspicion in diabetic patients especially though as with preexisting neuropathy, you'll recognize that a red hot swollen foot in a neuropathic patient should be considered a Charcot foot until proven otherwise. It's really that simple. Patient with neuropathy whether unilateral, swollen foot, you need to automatically or immediately consider it to be a Charcot foot especially when there are no wounds present. These are often misdiagnosed as gout, often misdiagnosed as acute cellulitis or due to diabetic nephropathy but an acutely hot foot, inflamed foot with or without deformity in the presence of neuropathy especially in a diabetic patient needs to be considered early as having a Charcot foot. So our diagnostic recommendations from the Charcot taskforce, we recommended that the occurrence of the acute foot and ankle fractures or dislocations in the neuropathic individual needs to be considered an act of Charcot foot and treated appropriately. What does that mean? Proper immobilization and appropriate offloading, of course. X-rays needs to be the initial diagnostic imaging first and foremost. Generally, an x-ray can be diagnostic for an early Charcot foot except for that subtle stage zero injury. And if there's no obvious pathology available on an x-ray and you have a high degree of clinical suspicion for the appropriate patient, then we recommend moving onto MRI or nuclear imaging to confirm or refute your suspicions. But classically, one needs a high degree of clinical suspicion for this acutely inflamed foot, a positive x-ray and that's all you need to make the diagnosis. If the x-ray is negative, you proceed on with some type of advanced imaging especially MRI or even nuclear medicine imaging to make the final diagnosis. So here we see some classic examples of rather typical appearance for Charcot feet, there's no mystery on making these diagnoses. However, sometimes your x-ray might be negative and you -- with the high index of suspicion you get an MRI and you could see the appropriate changes with the bone marrow, edema going across multiple joints and when it goes across multiple joints or multiple bones across a single joint, that would be diagnostic in this setting for acute osteoarthropathy or acute Charcot foot.
We mentioned already the importance of making the diagnosis in stage zero, that prodromal stage whereby there are no radiographic findings evident, just a clinically inflamed foot in a neuropathic individual. This is the precursor to that classic I can hold stage 1 of acute development. So again, it's recognized, the MRI has been the most studied and is the most sensitive to detect the bone marrow edema which would be diagnostic in this case. This might be a picture of an acutely inflamed foot and if you'll look at the x-ray here on the right, it almost looks negative to be extensively normal and this would be missed by most patients. But this isn't quite a stage zero because if you look at right at the base of the second metatarsal and cuneiform, there's the diagnostic clue. Even a one millimeter step off at this spot is diagnostic for early Charcot foot. Many radiologists, many of us might call this an extensively normal x-ray, but this is diagnostic, it's one of the earliest signs that you can find on an early x-ray in an undeformed, non-deformed foot but acutely inflamed as we could see here. And in this situation again, an MRI would be recommended to make the definitive diagnosis. We recognize the stages of natural history, stage zero is that prodromal stage where you have radiographically no changes but an acute inflammation perhaps following an injury, then one would go on if undiagnosed to the classic stage 1 of development, the I could hold stage 1, which we would call an acute stage. Finally, you would move onto stage 2 which is a little bit harder to make that distinction and then finally the chronic stage of reconstruction where the inflammation subsides but you have residual deformity evident in the foot especially if it goes undiagnosed. So our goal is to always make the diagnosis a stage zero before deformity commences. That's our job and that's what is most critical about making the early diagnosis to prevent deformity. I only have a couple of words about treatment. Basically, our treatment goals would be to convert from the active to the inactive stage, to prevent further deformity, to provide protected ambulation once that chronic stage has been reached and the process is settled and to prevent recurrent ulcerations. Now, we did publish this diagnostic and management algorithm here as we could see. And initially, we have a clinical suspicion with Charcot foot, when x-rays are negative as we can see in the right panel, we proceed to take our MRIs. If we detect osteomyelitis, we treat for osteomyelitis. If we have Charcot foot that's diagnostic by that bone marrow edema in the absence of wounds, we will proceed to treat for a Charcot foot. If however, the x-ray is positive, the x-ray makes the diagnosis, as I've said, then we proceed with appropriate offloading and management conservatively. If conservative management fails to arrest the condition or if we have picked up the -- or the we have made the diagnosis late in the natural history of this disorder finding that ulcers become recurrent or there's severe instability, then one would proceed with evaluation for surgical intervention which Dr. Laporta will discuss later on in this symposium. So in conclusion, I like to use the words of Charcot himself, sera continue, to be continued. The story has expanded greatly in the last 30, 35 years since I've become interested in this disorder but we still do not have all the answers. We do not have the answers as to which specific patient is predisposed to developing this disease. And once a patient develops this problem or this syndrome, we do not know who is best treated conservatively or who is best treated surgically or which joints involved are best treated surgically, perhaps other than the ankle joint, and which joints are best treated through conservative measures that Dr. Shara will discuss. So with that and with several seconds to go...