DIABETICMedicine DOI: 10.1111/dme.12754
Invited Review Charcot foot syndrome W. J. Jeffcoate Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, Nottingham University Hospitals Trust, Nottingham, UK Accepted 19 March 2015
Abstract Charcot foot syndrome is an uncommon complication of diabetes but is potentially devastating in its consequences. Outcome is made worse by widespread professional ignorance leading to delayed diagnosis, but it is also hampered by lack of understanding of its causes and lack of treatments with proven effectiveness, other than offloading. There remains a desperate need for studies into its causes as well as comparative audit and trials designed to determine the best treatment for this difficult condition. Such work can probably only be effectively carried out through the establishment of multicentre networks. Nevertheless, improved understanding in recent years of the likely role of inflammatory pathways has raised awareness of the multiple ways in which the effects of neuropathy may be manifest in the development of the Charcot foot. This awareness is also leading to the realization that similar processes may conceivably contribute to the refractoriness of other foot diseases in diabetes, including both chronic unhealing ulcers and osteomyelitis. Diabet. Med. 32, 760–770 (2015)
Introduction Charcot foot syndrome is associated with very high morbidity and is frequently mismanaged. Its diagnosis is usually missed at first presentation and the resulting delay can lead to worsening structural damage, secondary ulceration, osteomyelitis and potentially avoidable limb loss [1]. It has been shown that there is a better functional outcome in those who are diagnosed within 3 months of disease onset [2]. Overall, the cost of care is enormous, having been recently estimated to be ~ $50,000 per episode in the USA, whether treatment is conservative or involves amputation [3]. The diagnosis of Charcot foot syndrome is often missed because most clinicians think that it is a rare condition and they are not likely to encounter it. It is certainly an uncommon complication of diabetes but, although there are no published data, the incidence is probably much higher than is usually thought and could be in the order of 0.1% per year: 20 cases per 20 000 people with diabetes. The Charcot foot is also neglected, however, because it is not emphasized in medical training. This reflects that fact that its causes are not fully understood, and there is no specific working definition for the condition nor are there firm criteria for diagnosis; the result is that the evidence base is currently too thin to justify the choice of approaches to clinical practice and many rely on professional opinion alone. There have been two multi-author reviews of Charcot foot syndrome in recent years [4,5]. The present article is a Correspondence to: William Jeffcoate. E-mail [email protected]
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non-systematic review that concentrates on the recent literature in an attempt to highlight new factors that could contribute to the onset of this complex disorder.
What’s in a name? Charcot foot syndrome is often referred to as neuropathic osteoarthropathy or neuro-osteoarthropathy, but these terms do not include the root ‘sarco-’, which refers to soft tissue, despite the fact that soft tissue inflammation is currently thought to be a universal feature of active disease and is, indeed, one of the main criteria for clinical diagnosis. Perhaps the most accurate term that could be used is ‘neuropathic inflammatory sarco-osteoarthropathy’, but it is easier to refer to the condition simply as the Charcot foot or Charcot foot syndrome. Similar inflammation-based changes were first described in larger joints of the lower limb and spine by Jean-Martin Charcot in 1868, but involvement of the foot was not described until 1881, by an English surgeon, Herbert William Page [6]. Charcot’s own description of the disease affecting the foot did not appear until 1883.
When does acute Charcot foot syndrome become chronic ?
The Charcot foot is also often referred to as being ‘acute’ when it first presents; however, given that the course of disease activity is always prolonged (see below) and many cases have been present for weeks or months before even being diagnosed, it is rarely ‘acute’ in the strict sense of the
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word. Chantelau and Grutzner [7] have recently suggested a new grading system in which the condition is described as either ‘active’ or ‘inactive’ (see below). There is much to support the suggestion that the word ‘active’ be adopted in preference to ‘acute’.
Disease definition Charcot foot has no definition but it is a complex syndrome, in which the occurrence of inflammation in the active phase is followed by variable degrees of destruction of the skeletal architecture. It seems that some cases are always limited in their extent, but others will progress. Any skeletal damage that occurs can lead to ulceration of the skin over new bone prominences, and such ulcers can become infected. If the secondary infection involves the bone, the limb is very much at risk; however, in the majority of cases of Charcot foot syndrome, the disease will eventually settle and the condition will become inactive. Any skeletal damage is permanent.
Histology Surprisingly, there have been almost no studies of the histology of the bone in the Charcot foot. La Fontaine et al. [8] compared findings in eight patients and described infiltration with inflammatory myxoid tissue and disorganised trabeculae. One other report, in an equally small series, was published only in abstract form [9]. There remains a clear need to study systematically the histology and microbiology (culture of bone specimens) of the bone, including cases of clinical osteomyelitis and of clinical Charcot syndrome whose disease process is assessed to be of a similar duration.
Pathogenesis Process
It is currently believed that Charcot foot syndrome occurs because the onset of an episode of inflammation in the foot becomes abnormally protracted as the result of underlying neuropathy. The inflammation in the foot may be triggered by any of a number of factors (see below), but the resultant expression of pro-inflammatory cytokines (such as interleukin-1ß, tumour necrosis factor-a) leads to activation of the receptor activator of nuclear factor j-B ligand (RANKLNFjB) pathway. The nuclear transcription factor NFjB triggers the maturation of osteoclasts and these cause bone lysis. Such activation of osteoclasts is part of the normal response to injury and facilitates the clearance of debris before the onset of wound repair, but the process is normally short-lived. If, however, the person’s sensation of pain is reduced, and they continue to walk on the inflamed foot, this
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initiates a cycle of uncontrolled inflammation with progressive osteolysis. This further weakens the pedal skeleton and encourages progressive fracture and dislocation [10–13]. It should, however, be noted that the evidence to confirm involvement of the RANKL/NFKB pathway in the pathogenesis of the Charcot foot is largely circumstantial. Mabilleau et al. [14] have also suggested that a RANKL-independent mechanism might be involved. There is some early interest in the osteoblast-dependent osteogenic mechanism mediated via the Wnt/b-catenin pathway and its endogenous inhibitors, sclerostin and dickkopf-1. The Wnt/b-catenin pathway is involved in osteoporotic disease and has been shown to be responsive to anti-sclerostin monoclonal antibodies [15]. It is particularly interesting to note that just like the RANKL/ NFKB pathway, the Wnt/b-catenin pathway is disordered in diabetes, and both have been implicated not only in abnormal bone breakdown but in parallel increases in macrovascular disease [16–18].
Dislocation
The Charcot foot is also characterized by joint dislocation, but this has received little attention hitherto. The joint dislocation may be because of reduced bone strength at the point of insertion of ligaments and joint capsules, but may also result from loss of nerve-derived peptides, such as calcitonin-gene-related peptide, and resultant weakness of the joint capsules which are normally richly innervated. This hypothesis has been described in detail elsewhere [10].
Predisposition as a result of sensory neuropathy Loss of protective sensation
The original description of the syndrome by Charcot concerned damage to larger joints of the lower body in people with tertiary syphilis and tabes dorsalis. Tabes dorsalis is associated with loss of deep pain sensation conducted via the dorsal column of the spinal cord. The condition was not described in people with distal neuropathy complicating diabetes until 1936 [19]. The neurological deficit in the distal neuropathy of diabetes is, however, very different: immediate sharp pain sensation is lost as a result of disruption of the ascending spinothalamic pathways, but deep pain sensation is typically intact. Many people with a Charcot foot in diabetes are aware of aching discomfort [20]. Similar inflammatory arthropathies have been described in association with a range of unrelated disorders and no common pattern has emerged to suggest the key involvement of any particular nerve pathway or fibre type. Nevertheless, all such disorders are associated with some degree of loss of protective sensation and this undoubtedly encourages continued weight-bearing and the resultant exposure of the affected foot to preventable trauma.
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Capacity to mount an inflammatory response
As it is thought that the onset of inflammation is central to the process of developing Charcot foot syndrome, the body must be capable of mounting an inflammatory response, and three separate groups have reported that, whereas people with diabetes complicated by neuropathy typically have loss of vasodilatation in response to warming [21–23], this response is not lost in those with a history of having had an active Charcot foot. This observation offers a possible explanation for the fact that the Charcot foot is uncommon when distal neuropathy is not.
Predisposition through other types of neuropathy Motor neuropathy
Wasting of the small muscles of the foot and imbalance of long flexor and extensors of the foot will lead to changes in posture and gait that will expose the foot to abnormal forces and increase the chances of injury.
the apoptosis of osteocytes and maintains bone strength [27]. There are three broad and overlapping paths by which changes in the normal expression of these agents could potentially contribute to the onset of Charcot foot syndrome: (1) reduction of premorbid bone strength; (2) potentiation of the expression of RANKL with activation of osteoclasts in the active phase; and (3) impairment of the prompt repair of any microfractures which occur. There is evidence to link calcitonin-gene-related peptide with some or all of these processes [28–31], as there is also for substance P [31,32] and nitric oxide [33,34]. The action of nitric oxide may, however, be biphasic [34]. Impairment of fracture healing has been noted by Mabilleau et al. [36]. While it is often suggested that premorbid reduction in bone strength may contribute to the onset of the active Charcot foot, the evidence for its involvement is mixed. The possibility is suggested by a reduction in bone mineral density in the contralateral limb [37], but this finding has not been confirmed by all [38].
Predisposition to Charcot foot syndrome through other aspects of diabetes
Neuropathy-mediated abnormalities of distal blood flow
Diabetes type
Abnormalities of distal blood flow, including vasomotor shunting, which involves the loss of neurally mediated regulation of small blood vessels, may lead to abnormal regional blood flow and, in particular, to arteriolar-venular shunting [24]. Selective abnormalities of this type could conceivably predispose particular individuals to the development of the condition. Medial arterial calcification, calcification of the media of the walls of small arteries, was first described by M€ onckeberg in 1902, and is now recognized to be associated with distal symmetrical neuropathy [16,17], although it is no more prevalent in people with Charcot foot syndrome than it is in those with neuropathic foot ulcers [25]. The resulting loss of compliance in the arterial wall will cause abnormalities of distal limb blood flow, with loss of triphasic pulsing and widening of pulse pressure, and these changes, too, could contribute to the onset of Charcot foot syndrome. There is evidence to suggest that abnormal pulsatility of distal blood flow could have an impact on bone structure [26].
As neuropathy is likely to be an essential prerequisite for the onset of the Charcot foot process, and as the onset of neuropathy is most dependent on the duration of any hyperglycaemia, it is obvious that the mean age of onset will be lower in people with Type 1 diabetes than in those with Type 2. It is also known that bone mineral density tends to be lower in Type 1 diabetes and is possibly elevated in Type 2 diabetes, despite a lack of any correlation with fracture risk [39]. It is also possible that the loss of islet cell peptides, such as glucagon and islet amyloid polypeptide (amylin), might have a negative impact on the integrity of bone in Type 1 disease. Despite all these potential mechanisms, however, there is no convincing evidence to suggest any difference—other than age of onset—between Type 1 and Type 2 diabetes in either the epidemiology or the clinical presentation of cases of the Charcot foot.
Loss of nerve-derived peptides and loss of innervation of bone
Axonal degeneration is associated with loss of peptides that are normally released by nerve terminals. Knowledge of the impact of these changes is currently in its infancy but the peptides which have attracted the greatest interest are calcitonin-gene related peptide and substance P. Interest has also focused on the possible effect of loss of innervation on the local release of nitric oxide, which normally inhibits
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Hypoglycaemic agents
While some hypoglycaemic agents are associated with an increased risk of fracture, there is currently no known link between any treatment and the onset of Charcot foot disease.
Body weight
Clinicians often believe that obesity makes the Charcot foot more likely, but while the biomechanical argument is easily understood, the evidence to suggest an overall link between BMI and Charcot incidence is not strong [40]. It is possible that any impact of obesity is countered by a protective effect
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of BMI on bone strength. It is also possible that perception of the importance of obesity relates more to the problems of achieving adequate offloading in established cases and the increased risks associated with surgery.
Associated eating disorders
The Charcot foot is occasionally seen in the young person (perhaps more often female) who has both poorly controlled Type 1 diabetes and an eating disorder. Of possible relevance is a recent report on a small series in which onset of a Charcot foot sydrome was reported to follow weight loss [41].
Effects of hyperglycaemia Metabolic effects
As the cycle of inflammation is thought to be largely mediated through activation of the RANKL/NFjB pathway, it is relevant that this pathway is already potentiated in diabetes; thus, it is well established that circulating concentrations of osteoprotegerin (a marker of activation of the RANKL/NFjB pathway) are higher in people with diabetes, probably as a result of the effect of oxidized lipids, advanced glycation endproducts and free radicals [10,42]. Glycation of connective tissue
The abnormal forces applied to the foot during standing and walking because of motor neuropathy will be exacerbated by shortening of tendons and connective tissue resulting from the glycation of collagen that can complicate chronic hyperglycaemia.
Chronic complications of diabetes, other than neuropathy,
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Nephropathy
Charcot disease also associates with nephropathy, simply because neuropathy and nephropathy are both microvascular complications of diabetes; however, the reduced hydroxylation of vitamin D and the hyperparathyroidism of advancing renal failure may possibly make expression of the disease more likely by their impact on bone strength. Kidney-pancreas transplantation
There is one group in which the Charcot foot appears to be especially common: patients with Type 1 diabetes who undergo combined renal-pancreas transplantation [45,46], and in whom it has also been suggested that the disease may differ clinically [47], although this remains to be confirmed. There are a number of reasons why this group may be at particularly high risk, including both the fact that they are selected for freedom from overt macrovascular disease before being considered for transplantation, as well as their exposure to immunosuppressive therapy. Although there are no precise details on incidence, the number of new cases appears anecdotally to be so high that counselling and surveillance should now be part of routine practice for people undergoing combined transplantation.
Genetic predisposition Two groups have reported small increases in odds ratio for the presence of certain candidate osteoprotegerin gene polymorphisms in selected populations of people with a history of Charcot foot syndrome [48,49]. The increases are small and the reported polymorphisms were not completely identical in the two studies but the observation is of interest, even though its clinical relevance is not certain.
and their treatment Other foot disease
Preceding foot ulcers may act as a trigger for the onset of Charcot foot sydrome and were reported in 35% of people presenting with an active Charcot foot in a recent report, the Charcot Disease in the UK (CDUK) study [43], even though it should be noted that the Charcot foot and ulceration occur in a similar sub-population of people with diabetes (with neuropathy, usually, preserved large arterial blood flow) and so it is possible their relationship is less causative than coincidental; however, a recent small observational series reported that patients with neuropathy and neuropathic ulcers had a reduction in pedal bone mass as assessed by quantitative ultrasonography, whereas those with neuropathy alone did not [44]. This might indicate that ulceration did indeed tend to trigger osteolysis, possibly through local inflammation, and this could be a factor leading to the later development of Charcot foot, as could be any associated immobilization, change of gait and weight-bearing.
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Potential predisposing factors in diseases other than diabetes Historically, tertiary syphilis with tabes dorsalis was the most frequently identified cause of Charcot foot syndrome, as in all of Charcot’s cases. Leprosy is a frequent cause in developing countries but diabetes is probably the most common cause worldwide today. The other main causative factor encountered in routine practice is the neuropathy associated with ethanol abuse, the presentation and management of which are just the same as for diabetes. The acute Charcot foot has also recently been reported as a complication of the neuropathy of rheumatoid disease [50]. Other causes are rare and include other causes of neuropathy [51], traumatic denervation and syringomyelia. A recent study of a large population has also reported some novel statistical associations with conditions not previously linked with the Charcot foot: cardiac dysrhythmia, pulmonary eosinophilia and volume depletion [52]. The significance of these findings will require further study.
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Clinical presentation Charcot foot syndrome may present with isolated inflammation of the foot (with or without discomfort), or the inflammation may be associated with varying degrees of destruction of the architecture of the foot. The distortion of the foot may lead to ulceration of the skin over areas exposed to abnormal forces and this may lead to infection. The bones and joints most often affected are those of the mid- and hind foot, with fractures accompanying medial dislocation of the medial cuneiform, lateral dislocation of the second to fifth tarsometatarsal joints and downward dislocation of the talonavicular joint. Any of these may lead to the classical infero-medial bulging of the foot with loss of the plantar arch, often referred to as the ‘rocker bottom foot’ (Fig.1). Other cases of what appear to be same process are much more limited in their extent, such as isolated fracture of one or two metatarsals. Overlap between these and so-called ‘stress fracture’ (even when it occurs without preceding stress) is blurred by limited medical understanding. If dislocation is a distinct part of the Charcot disease process, there may be similar aetiological overlap with cases of isolated dislocation of metatarsophalangeal or interphalangeal joints, which are not uncommon in people with neuropathy. The final definition of the Charcot foot will need to differentiate it from unrelated processes, which lead to a similar clinical presentation.
Triggers for the onset of active Charcot disease The majority of people who present with an active Charcot foot will recall seemingly minor trauma that they think
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triggered its onset. Sometimes this may have been very recent but sometimes it was weeks or months earlier. A recent webbased survey in Britain and Ireland, the CDUK study, reported that these episodes include minor accidental trauma (recalled in 36% of all presenting cases), preceding foot ulceration (35%), local surgery (12%) and osteomyelitis (7%) [43].
Diagnosis and differential diagnosis The main barrier to prompt diagnosis of Charcot foot syndrome is the failure of the clinician to consider the possibility. Most affected people present to non-specialists in primary care and in emergency departments where the commonest causes of foot inflammation are sprain, cellulitis, venous thrombosis and gout. It follows that many people with an active Charcot foot are investigated, and even treated, for one or more of these conditions before the correct diagnosis is made. This delay in diagnosis is likely to result in worsening of the disease and may increase the risk of eventual limb loss [2,53].
Confirmation of diagnosis
Once suspected, the clinician should do a plain X-ray (preferably performed with the subject weight-bearing to exaggerate possible changes). The association of the clinical presentation with radiological evidence of fracture and/or dislocation is usually sufficient to make the diagnosis and to start treatment. If the X-ray appears normal, it is essential that magnetic resonance imaging (MRI) be requested as soon as possible to show inflammation of soft tissue (which is not
FIGURE 1 The plantar aspect of the feet in a person with bilateral Charcot foot syndrome. Although no longer active, the disease process has caused bilateral ‘rocker-bottom’ deformity with the resultant change in weight distribution during walking leading to the build-up of callus under the midfoot on each side.
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diagnostic) and of bone marrow (which is strongly suggestive of active Charcot foot in a person who presents with inflammation that is otherwise unexplained). If the MRI is negative, it is usual to accept that the diagnosis is unlikely, although specialist teams will occasionally encounter cases in which the MRI later becomes abnormal. Fractures without displacement may be more apparent on computed tomography (CT) than on MRI.
that acute osteomyelitis can itself trigger the onset of secondary Charcot changes in the same foot. If a person has had surgery for osteomyelitis and there is a recurrence in an adjacent bone, the possibility of new, active Charcot disease may be as likely as that of persistence of bone infection. The same applies in cases in which the management of osteomyelitis with antibiotics alone is associated with a sudden deterioration accompanied by worsening inflammation.
Active Charcot foot syndrome and osteomyelitis
Classification
The appearances of Charcot foot and osteomyelitis on MRI are very similar and this can pose a problem with diagnosis in someone who has an associated ulcer, in whom the likelihood of osteomyelitis is much greater. Differentiation between the two conditions requires the careful input of a skilled musculoskeletal radiologist and may still be far from definite [54,55]. It should also be noted that the occurrence of bone marrow oedema may not be specific to Charcot foot syndrome and to osteomyelitis, and one study has suggested that such oedema may be observed in 30% subjects with neuropathic foot ulcers but without clinical evidence of, or progression to, either of these diseases [56]. If true, the use of MRI to confirm the diagnosis of Charcot foot in those presenting with suggestive symptoms and signs may sometimes prove to be misleading. More information is required on the MRI findings in people who simply have distal symmetrical neuropathy in diabetes. Labelled neutrophil scans may distinguish between bone infection and active Charcot foot but they are expensive and not always available. While blood-borne inflammatory makers are usually more markedly elevated in the presence of osteomyelitis, they may also be raised in cases of Charcot foot and are not sufficiently specific to be diagnostic. One clinical sign can, however, be useful and this is assessment of the response of the inflamed foot to immobilization in a nonremovable below-knee cast for 3–4 days. The inflammation of active Charcot foot will usually settle rapidly, while that of osteomyelitis will not. Imaging by fluorodeoxyglucose-positron emission tomography (PET) [57,58] and SPECT/CT [59–61] has been advocated but experience remains limited, partly because of cost and limited availability. Nevertheless, fluorodeoxyglucose-PET and other newer imaging techniques may prove to be of value in discriminating between osteomyelitis and Charcot foot syndrome; however, a conventional three-phase bone scan is rarely of any diagnostic value. The need for the careful differentiation between Charcot foot and osteomyelitis is obviously of importance when the skin is ulcerated as a result of Charcot deformity, and secondary osteomyelitis is a possible complication. In such circumstances it is generally accepted that a biopsy of bone may be needed to establish the diagnosis of infection, with the specimen being examined both histologically and microbiologically. It is also becoming increasingly recognized, however,
Two classifications of Charcot foot syndrome are widely quoted. The Eichenholtz classification—especially as later modified to include a stage 0—is essentially a summary of the theoretical stages through which the Charcot process is thought to progress: from inflammation without skeletal damage, to skeletal damage and to eventual resolution [62]. The more recent classification by Sanders and Frykberg [63] classifies disease on the basis of the affected joints and is found to be useful by many clinicians. The most recent classification is that of Chantelau and Grutzner [7], which divides affected feet into those that are either active or inactive as well as those that are or are not associated with full thickness cortical fractures.
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Non-surgical treatments: offloading There are two aims of offloading: (1) to splint the inflamed foot in order to try to break the cycle of damage and inflammation and thereby limit the extension of the inflammation-mediated damage and (2) to protect the skeleton of the foot while the bones and joints are vulnerable. International consensus recommends the use of a moulded below-knee fibreglass cast, which is easy to apply and strong enough to allow weight-bearing once it has set. Nonremovable casts should be changed within 1 week because if there is prompt reduction in local inflammation, they rapidly become loose. Thereafter, the casts need to be replaced every 1–3 weeks. Frequent replacement gives an opportunity for the foot to be checked – not least because the cast may cause abrasions of which the patient may be unaware, because of the underlying neuropathy. Those without ready access to casting facilities often use removable, commercially available ‘cast walkers’, and some have advocated making such walkers irremovable by the use of a band of fibreglass tape [64]. Neither fibreglass casting nor cast walkers are available in many communities, however, and while plaster of Paris can be used, clinicians will otherwise have to rely on the use of crutches, wheelchairs or whatever available approaches will achieve the desired effect.
Duration of offloading
Offloading is continued until the foot is judged to be in remission and until any fitted footwear (if prescribed) is
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available. There are few published data on the duration of offloading but the largest series comes from the CDUK webbased survey which reported that the median time to remission (defined as being ambulant in usual or fitted footwear) was between 9 and 12 months [43]. This contrasts with data from Denmark, Brazil, North America and the Czech Republic [53,65–67], which report a mean time in cast of < 6 months. The reason for this difference is not clear, but if the majority of people can be satisfactorily offloaded in other countries for < 6 months, it is likely that the duration of casting in the UK is longer than it needs to be. While there are a number of factors that may account for the observed difference, the main one may stem from the criteria used to define remission.
Recognition of remission
There are no firm criteria for deciding when the remission stage has been reached. It is generally said that remission can be assumed when there is a temperature difference of < 2°C between the feet (assuming the disease is not bilateral) and there are data to justify this [66]; however, a temperature difference of 2°C is quite obvious to the touch and many clinicians err on the side of caution and wait till the signs of inflammation regress even more. Quantitative bone scans have also been used to document changes in local scintigraphy and blood flow and have shown associations between both skin temperature and circulating bone turnover markers [68], but the use of this approach in routine clinical care is not yet clear. Zampa et al. [69] have reported that the mean time to recovery could be predicted by the extent of contract uptake using dynamic MRI, being some 5 months in those with lesser degrees of uptake, compared with 9 months in those with more. Some have suggested that MRI may be a valuable indicator of remission as it shows reduction in marrow oedema, but this is expensive and has yet to be validated. Moreover, the MRI changes in active Charcot foot syndrome are largely dependent on the replacement of marrow fat by inflammatory tissue, and it is quite possible that the process of re-establishing marrow fat will persist long into the postinflammatory phase of the disease. This has not been formally studied. Other imaging techniques may be more useful, as indicated in one recent report on the use of PET/CT [61], but such techniques will be of limited availability in most centres for the foreseeable future. Plain X-rays can also be used to define angles of alignment in order to document any continuing change in the extent of structural damage to the foot skeleton [70,71].
this, some have reported a relatively high incidence of recurrence [73,74]. One possible explanation is that the disease was not in complete remission in these series when offloading was discontinued. Another relates to the criteria used to define recurrence. It is quite common for the previously affected foot to become warm and swollen when non-removable casting is discontinued but it usually settles within days and it is possible that some groups regard this phase of transient swelling as a sign of continuing activity whereas others do not.
Potential adverse effects of prolonged casting
Prolonged casting is not without potential side-effects. These include abrasions on both the affected foot and the other one. It will also be associated with worsening osteopenia but clinically important consequences of this have not been described. There is also a theoretical risk of secondary thrombosis and appropriate preventive measures should be considered in those judged at highest risk even though secondary thrombosis seems to be an uncommon complication in routine practice. The most prevalent complication of prolonged immobilization is, however, the adverse effect on mobility, social functioning and mood.
Other non-surgical treatments Bisphosphonates (either oral or intravenous)
The use of bisphosphonates followed an encouraging unblinded observational study but a later small pilot randomized controlled trial failed to confirm the benefit with regard to the clinical course and showed only the predictable changes in bone turnover markers [75]. Observations made in the observational CDUK study [43] and, later, a second small but high-quality randomized controlled trial [76] did not confirm the benefit of bisphosphonates and even suggested that their use might be associated with a prolongation of the time to disease resolution. A systematic review concluded that there is currently no evidence to justify the use of bisphosphonates [77].
Salmon calcitonin
Data suggesting that salmon calcitonin may be beneficial have been published [78], but the product has since been withdrawn from the market.
Anti-inflammatory agents: anti-tumour necrosis factor, antiRANKL, glucocorticoids and non-steroidal anti-inflammatory drugs
Ipsilateral recurrence
It is generally thought that once a Charcot foot goes into remission, recurrence on the same side is rare [72]. Despite
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Studies are under way to assess the effect of agents that may interrupt RANKL/osteoprotegerin signalling, but there has been no formal study of systemic glucocorticoids or of
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non-steroidal anti-inflammatory drugs. Such studies are needed even though non-steroidal anti-inflammatory drugs would have to be used with care in those at risk of renal impairment.
mobility has been linked to a high incidence of anxiety and depression [82,83], even though this has not been a universal finding [84]. Any depression or anxiety that does occur appears to be resolve once the disease settles [85].
Recombinant parathyroid hormone
Long-term care
While there is no report of the use of the hormone fragment, teriparatide, a randomized clinical trial of the use of rh1-84 parathyroid hormone has been registered (EudraCT 2009016873-13). The results are not yet available.
Surgery: active phase Surgery in the active phase of Charcot foot syndrome is liable to be associated with delayed healing and secondary infection but there are no robust data on which to base a choice between surgical and non-surgical treatment for any individual. All the evidence identified in a recent systematic review was only of level 4 or 5: case report or expert opinion [79]; however, prevailing opinion was defined in the German-Austrian consensus statement [80], that (1) a deformed but plantigrade foot capable of full weight-bearing is not a candidate for surgery, and (2) surgery should be considered for cases with joint dislocation and significant instability because closed reduction and retention by means of casting is ineffective. The conclusion of the American Diabetes Association consensus panel [4] was rather more circumspect and recommended that, while fracture or dislocation at the level of the ankle should be treated surgically if feasible, the ‘initial management of acute neuropathic fractures should not differ from other fractures’. If, however, distortion at the level of the ankle is not reconstructable, the option of early transtibial amputation should be discussed because its early adoption may avoid months of fruitless treatment, observation and prevarication. Such elective amputation is often accompanied by a significant improvement in well-being [81].
Contralateral disease
The lifetime risk of both feet being affected is thought to be 20–25%. A total of 10–15% of patients with Charcot foot syndrome will have had contralateral disease by the time they present with a new episode, a small number have simultaneous bilateral disease and the remainder will develop contralateral disease in the future.
Maintenance of mobility and prevention of secondary ulceration
People who have had a chronic Charcot foot should be considered for long-term specialist surveillance, including regular podiatry and advice on the provision of appropriate footwear to minimize the risk of ulceration over abnormal bone prominences.
Cardiovascular mortality
The mortality rate reported in one cohort followed for 8 years was 29% [85]. Data from a second single-centre series of 117 patients, followed for a similar period, reported a mortality rate of ~ 40% at 5 years and a mean reduction in life expectancy of 14 years [86]. This reduction in survival was, however, no worse than that of people with neuropathic ulcers of the foot in diabetes and is thought to relate largely to an increased incidence of cardiovascular disease. It follows that cardiovascular risk reduction should remain a key aspect of the management of these groups.
Prevention
Once the condition has entered remission, reconstructive surgery should be considered to facilitate standing and walking on a plantigrade foot and to minimize secondary ulceration and may include arthrodesis, and either internal or external fixation.
It is not known how to reduce the onset of an active Charcot foot even in those who are most at risk. It follows that the only option is to make those at risk aware of the possibility of their developing the condition, and if they develop symptoms suggestive of Charcot foot, what they should do in order to ensure the diagnosis is confirmed as quickly as possible.
Complications
Need for agreed measures of outcome
Apart from the threat of limb loss and the complications of treatment (such as those of immobilization referred to above or of surgical intervention), the greatest complication of Charcot foot syndrome is the impact on well-being during the prolonged course of the active phase. The restriction on
Further information is desperately needed to guide management of the active phase of the Charcot foot. Given that the conduct of randomized trials in this condition poses particular difficulties (although these are not insurmountable), consideration should be given to the conduct of systematic
Surgery: inactive phase
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audits of performance, both within and between centres [87]. For both such audits and randomized trials, however, it is necessary to define disease severity at the time of first presentation to an expert service and to agree a choice of outcome measures. In addition to the incidence of major amputation and overall survival rates, these should include measures of physical functioning and mood during the active phase and the extent of residual deformity (using both radiological and gait-related measures).
Competing interests
None declared.
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56 Thorning C, Gedroye WM, Tyler PA, Dick EA, Hui E, Valabhji J. Midfoot and hindfoot bone marrow edema identified by magnetic resonance imaging in feet of subjects with diabetes and neuropathic ulceration is common but of unknown clinical significance. Diabetes Care 2010; 33: 1602–1603. 57 Hopfner S, Krolak C, Kessler S, Tiling R, Brinkbaumer K, Hahn K et al. Preoperative imaging of Charcot neuroarthropathy in diabetic patients: comparison of ring PET, hybrid PET and magnetic resonance imaging. Foot Ankle Int 2004; 25: 890–895. 58 Basu S, Zhuang H, Alavi A. Imaging of lower extremity artery atherosclerosis: FDG-PET and histopathological correlates. Clin Nucl Med 2007; 32: 567–568. 59 Pickwell KM, van Kroonenburgh MJ, Weijers RE, van Hirtum PV, Huijberts MS, Shaper NC. F-18 FDG PET/CT scanning in Charcot disease: a brief report. Nucl Med Rev Cent East Eur 2010; 36: 8–10. 60 Ergen FB, Sanverdi SE, Oznur A. Charcot foot in diabetes and an update on imaging. Diabet Foot Ankle 2013; 4: doi:10.3402/ dfa.v4i0.21884. 61 Ruotolo V, Di Pietro B, Giurato L, Masala S, Meloni M, Schillaci O et al. A new natural history of Charcot foot: clinical evolution and final outcome of Stage O Charcot neuroarthropathy in a tertiary referral diabetic foot clinic. Clin Nucl Med 2013; 38: 506–509. 62 Eichenholtz SN. Charcot joints. Springfield, IL: Charles C. Thomas, 1966. 63 Sanders LJ, Frykberg RG. Diabetic neuropathic osteoarthropathy: the Charcot foot. In: Frykberg RG ed. The high risk foot in diabetes mellitus. New York: Churchill Livingstone, 1991: 297–338. 64 Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: a randomized controlled trial. Diabetes Care 2005; 28: 551–554. 65 Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteoarthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications 2012; 26: 430–434. 66 Moura-Neto A, Fernandes TD, Zantut-Witmann DE, Trevisan RO, Sakaki MH, Santos AL et al. Charcot foot: skin temperature as a good clinical parameter for predicting disease outcome. Diabetes Res Clin Pract 2012; e11–4. 67 Armstrong DG, Todd WF, Lavery LA, Harkless LB, Bushman TR. The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. Diabet Med 1997; 14: 357–363. 68 Bem R, Jirkowsk a A, Dubskẏ M, Feifarova V, Buncova M, Skibova J et al. Role of quantitative bone scanning in the assessment of bone turnover in patients with Charcot foot. Diabetes Care 2010; 33: 348–349. 69 Zampa V, Bargellini I, Rizzo L, Turini F, Ortori S, Piaggesi A et al. Role of dynamic MRI in the follow-up of acute Charcot foot in patients with diabetes mellitus. Skeletal Radiol 2011; 40: 991–999. 70 Hastings MK, Sinacore DR, Mercer-Bolton N, McCormick J, Hildebolt CF, Prior FW et al. Precision of foot alignment measures in Charcot arthropathy. Foot Ankle Int 2011; 32: 867–872. 71 Sinacore DR, Gutekunst DJ, Hastings MK, Strube MJ, Bohnert KL, Prior FW, Johnson JE. Neuropathic midfoot deformity: associations with ankle and subtalar joint motion. J Foot Ankle Res 2013; 6: 11. 72 Rudrappa S, Game F, Jeffcoate W. Recurrence of acute Charcot foot in diabetes. Diabet Med 2012; 29: 819–821. 73 Fabrin J, Larsen K, Holstein PE. Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care 2000; 23: 796– 800. 74 Osterhof GG, Bono T, Berli M. Recurrence of acute Charcot neuropathic osteoarthropathy after conservative treatment. Foot Ankle Int 2013; 34: 359–364.
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75 Jude EB, Selby PL, Burgess J, Lilleystone P, Mawer EB, Page SR et al. Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Diabetologia 2001; 44: 2032–2037. 76 Pakarinen T-K, Laine H-J, Maenpaa H, Mattila P, Lahtela J. The effect of zoledronic acid on the clinical resolution of Charcot neuroarthropathy. Diabetes Care 2011; 34: 1514–1516. 77 Richard JL, Almasri M, Schuldiner S. Treatmet of acute Charcot foot with bisphosphonates: a systematic review of the literature. Diabetologia 2012; 55: 1258–1264. 78 Bem R, Jirkowska A, Fejfarova V, Skibova J, Jude EB. Intranasal calcitonin in the treatment of acute Charcot neuroosteoarthropathy: a randomized controlled trial. Diabetes Care 2006; 29: 1392– 1394. 79 Lowery NJ, Woods JB, Armstrong DG, Wukich DK. Surgical management of Charcot neuroarthropathy of the foot and ankle: a systematic review. Foot Ankle Int 2012; 33: 113–121. 80 Koller A, Springfeld R, Engels G, Fiedler R, Orther E, Schrinner S et al. German-Austrian consensus on operative treatment of Charcot neuroarthropathy: a Perspective by the Charcot task force of the German Association for Foot Surgery. Diabet Foot Ankle 2011; 2: doi:10.3402/dfa.v210.10207.
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Charcot foot syndrome W. J. Jeffcoate 81 Wukich DK, Pearson KT. Self-reported outcomes of trans-tibial amputations for nonreconstructable Charcot neuroarthropathy in patients with diabetes: a preliminary report. Diabet Med 2013; 30: e87–90. 82 Chapman Z, Shuttleworth CMJ, Huber JG. High levels of anxiety and depression in diabetic patients with Charcot foot. J Foot Ankl Res 2014; 7: 22. 83 Sochoki MP, Verity S, Atherton PJ, Huntington JL, Sloan JA, Embil JM et al. Health related quality of life in patients with Charcot arthropathy of the foot and ankle. Foot Ankle Surg 2008; 14: 11–15. 84 Raspovic KM, Wukich DK. Self-reported quality of life in patients with diabetes: a comparison of patients with and without Charcot neuroarthropathy. Foot Ankle Int 2014; 35: 195–200. 85 Pakarinen T-K, Laine H-J, Maenpaa H, Mattila P, Lahtela J. Longterm outcome and quality of life in patients with Charcot foot. Foot Ankle Surg 2009; 15: 187–191. 86 Van Baal J, Hubbard R, Game F, Jeffcoate W. Mortality associated with acute Charcot foot and neuropathic foot ulceration. Diabetes Care 201; 33: 1086–1089. 87 Boulton AJ, Jeffcoate WJ, Jones TL, Ulbrecht JS. International collaborative research on Charcot’s disease. Lancet 2009; 373: 105–106.
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Invited Review Charcot foot syndrome W. J. Jeffcoate Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, Nottingham University Hospitals Trust, Nottingham, UK Accepted 19 March 2015
Abstract Charcot foot syndrome is an uncommon complication of diabetes but is potentially devastating in its consequences. Outcome is made worse by widespread professional ignorance leading to delayed diagnosis, but it is also hampered by lack of understanding of its causes and lack of treatments with proven effectiveness, other than offloading. There remains a desperate need for studies into its causes as well as comparative audit and trials designed to determine the best treatment for this difficult condition. Such work can probably only be effectively carried out through the establishment of multicentre networks. Nevertheless, improved understanding in recent years of the likely role of inflammatory pathways has raised awareness of the multiple ways in which the effects of neuropathy may be manifest in the development of the Charcot foot. This awareness is also leading to the realization that similar processes may conceivably contribute to the refractoriness of other foot diseases in diabetes, including both chronic unhealing ulcers and osteomyelitis. Diabet. Med. 32, 760–770 (2015)
Introduction Charcot foot syndrome is associated with very high morbidity and is frequently mismanaged. Its diagnosis is usually missed at first presentation and the resulting delay can lead to worsening structural damage, secondary ulceration, osteomyelitis and potentially avoidable limb loss [1]. It has been shown that there is a better functional outcome in those who are diagnosed within 3 months of disease onset [2]. Overall, the cost of care is enormous, having been recently estimated to be ~ $50,000 per episode in the USA, whether treatment is conservative or involves amputation [3]. The diagnosis of Charcot foot syndrome is often missed because most clinicians think that it is a rare condition and they are not likely to encounter it. It is certainly an uncommon complication of diabetes but, although there are no published data, the incidence is probably much higher than is usually thought and could be in the order of 0.1% per year: 20 cases per 20 000 people with diabetes. The Charcot foot is also neglected, however, because it is not emphasized in medical training. This reflects that fact that its causes are not fully understood, and there is no specific working definition for the condition nor are there firm criteria for diagnosis; the result is that the evidence base is currently too thin to justify the choice of approaches to clinical practice and many rely on professional opinion alone. There have been two multi-author reviews of Charcot foot syndrome in recent years [4,5]. The present article is a Correspondence to: William Jeffcoate. E-mail [email protected]
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non-systematic review that concentrates on the recent literature in an attempt to highlight new factors that could contribute to the onset of this complex disorder.
What’s in a name? Charcot foot syndrome is often referred to as neuropathic osteoarthropathy or neuro-osteoarthropathy, but these terms do not include the root ‘sarco-’, which refers to soft tissue, despite the fact that soft tissue inflammation is currently thought to be a universal feature of active disease and is, indeed, one of the main criteria for clinical diagnosis. Perhaps the most accurate term that could be used is ‘neuropathic inflammatory sarco-osteoarthropathy’, but it is easier to refer to the condition simply as the Charcot foot or Charcot foot syndrome. Similar inflammation-based changes were first described in larger joints of the lower limb and spine by Jean-Martin Charcot in 1868, but involvement of the foot was not described until 1881, by an English surgeon, Herbert William Page [6]. Charcot’s own description of the disease affecting the foot did not appear until 1883.
When does acute Charcot foot syndrome become chronic ?
The Charcot foot is also often referred to as being ‘acute’ when it first presents; however, given that the course of disease activity is always prolonged (see below) and many cases have been present for weeks or months before even being diagnosed, it is rarely ‘acute’ in the strict sense of the
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word. Chantelau and Grutzner [7] have recently suggested a new grading system in which the condition is described as either ‘active’ or ‘inactive’ (see below). There is much to support the suggestion that the word ‘active’ be adopted in preference to ‘acute’.
Disease definition Charcot foot has no definition but it is a complex syndrome, in which the occurrence of inflammation in the active phase is followed by variable degrees of destruction of the skeletal architecture. It seems that some cases are always limited in their extent, but others will progress. Any skeletal damage that occurs can lead to ulceration of the skin over new bone prominences, and such ulcers can become infected. If the secondary infection involves the bone, the limb is very much at risk; however, in the majority of cases of Charcot foot syndrome, the disease will eventually settle and the condition will become inactive. Any skeletal damage is permanent.
Histology Surprisingly, there have been almost no studies of the histology of the bone in the Charcot foot. La Fontaine et al. [8] compared findings in eight patients and described infiltration with inflammatory myxoid tissue and disorganised trabeculae. One other report, in an equally small series, was published only in abstract form [9]. There remains a clear need to study systematically the histology and microbiology (culture of bone specimens) of the bone, including cases of clinical osteomyelitis and of clinical Charcot syndrome whose disease process is assessed to be of a similar duration.
Pathogenesis Process
It is currently believed that Charcot foot syndrome occurs because the onset of an episode of inflammation in the foot becomes abnormally protracted as the result of underlying neuropathy. The inflammation in the foot may be triggered by any of a number of factors (see below), but the resultant expression of pro-inflammatory cytokines (such as interleukin-1ß, tumour necrosis factor-a) leads to activation of the receptor activator of nuclear factor j-B ligand (RANKLNFjB) pathway. The nuclear transcription factor NFjB triggers the maturation of osteoclasts and these cause bone lysis. Such activation of osteoclasts is part of the normal response to injury and facilitates the clearance of debris before the onset of wound repair, but the process is normally short-lived. If, however, the person’s sensation of pain is reduced, and they continue to walk on the inflamed foot, this
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initiates a cycle of uncontrolled inflammation with progressive osteolysis. This further weakens the pedal skeleton and encourages progressive fracture and dislocation [10–13]. It should, however, be noted that the evidence to confirm involvement of the RANKL/NFKB pathway in the pathogenesis of the Charcot foot is largely circumstantial. Mabilleau et al. [14] have also suggested that a RANKL-independent mechanism might be involved. There is some early interest in the osteoblast-dependent osteogenic mechanism mediated via the Wnt/b-catenin pathway and its endogenous inhibitors, sclerostin and dickkopf-1. The Wnt/b-catenin pathway is involved in osteoporotic disease and has been shown to be responsive to anti-sclerostin monoclonal antibodies [15]. It is particularly interesting to note that just like the RANKL/ NFKB pathway, the Wnt/b-catenin pathway is disordered in diabetes, and both have been implicated not only in abnormal bone breakdown but in parallel increases in macrovascular disease [16–18].
Dislocation
The Charcot foot is also characterized by joint dislocation, but this has received little attention hitherto. The joint dislocation may be because of reduced bone strength at the point of insertion of ligaments and joint capsules, but may also result from loss of nerve-derived peptides, such as calcitonin-gene-related peptide, and resultant weakness of the joint capsules which are normally richly innervated. This hypothesis has been described in detail elsewhere [10].
Predisposition as a result of sensory neuropathy Loss of protective sensation
The original description of the syndrome by Charcot concerned damage to larger joints of the lower body in people with tertiary syphilis and tabes dorsalis. Tabes dorsalis is associated with loss of deep pain sensation conducted via the dorsal column of the spinal cord. The condition was not described in people with distal neuropathy complicating diabetes until 1936 [19]. The neurological deficit in the distal neuropathy of diabetes is, however, very different: immediate sharp pain sensation is lost as a result of disruption of the ascending spinothalamic pathways, but deep pain sensation is typically intact. Many people with a Charcot foot in diabetes are aware of aching discomfort [20]. Similar inflammatory arthropathies have been described in association with a range of unrelated disorders and no common pattern has emerged to suggest the key involvement of any particular nerve pathway or fibre type. Nevertheless, all such disorders are associated with some degree of loss of protective sensation and this undoubtedly encourages continued weight-bearing and the resultant exposure of the affected foot to preventable trauma.
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Capacity to mount an inflammatory response
As it is thought that the onset of inflammation is central to the process of developing Charcot foot syndrome, the body must be capable of mounting an inflammatory response, and three separate groups have reported that, whereas people with diabetes complicated by neuropathy typically have loss of vasodilatation in response to warming [21–23], this response is not lost in those with a history of having had an active Charcot foot. This observation offers a possible explanation for the fact that the Charcot foot is uncommon when distal neuropathy is not.
Predisposition through other types of neuropathy Motor neuropathy
Wasting of the small muscles of the foot and imbalance of long flexor and extensors of the foot will lead to changes in posture and gait that will expose the foot to abnormal forces and increase the chances of injury.
the apoptosis of osteocytes and maintains bone strength [27]. There are three broad and overlapping paths by which changes in the normal expression of these agents could potentially contribute to the onset of Charcot foot syndrome: (1) reduction of premorbid bone strength; (2) potentiation of the expression of RANKL with activation of osteoclasts in the active phase; and (3) impairment of the prompt repair of any microfractures which occur. There is evidence to link calcitonin-gene-related peptide with some or all of these processes [28–31], as there is also for substance P [31,32] and nitric oxide [33,34]. The action of nitric oxide may, however, be biphasic [34]. Impairment of fracture healing has been noted by Mabilleau et al. [36]. While it is often suggested that premorbid reduction in bone strength may contribute to the onset of the active Charcot foot, the evidence for its involvement is mixed. The possibility is suggested by a reduction in bone mineral density in the contralateral limb [37], but this finding has not been confirmed by all [38].
Predisposition to Charcot foot syndrome through other aspects of diabetes
Neuropathy-mediated abnormalities of distal blood flow
Diabetes type
Abnormalities of distal blood flow, including vasomotor shunting, which involves the loss of neurally mediated regulation of small blood vessels, may lead to abnormal regional blood flow and, in particular, to arteriolar-venular shunting [24]. Selective abnormalities of this type could conceivably predispose particular individuals to the development of the condition. Medial arterial calcification, calcification of the media of the walls of small arteries, was first described by M€ onckeberg in 1902, and is now recognized to be associated with distal symmetrical neuropathy [16,17], although it is no more prevalent in people with Charcot foot syndrome than it is in those with neuropathic foot ulcers [25]. The resulting loss of compliance in the arterial wall will cause abnormalities of distal limb blood flow, with loss of triphasic pulsing and widening of pulse pressure, and these changes, too, could contribute to the onset of Charcot foot syndrome. There is evidence to suggest that abnormal pulsatility of distal blood flow could have an impact on bone structure [26].
As neuropathy is likely to be an essential prerequisite for the onset of the Charcot foot process, and as the onset of neuropathy is most dependent on the duration of any hyperglycaemia, it is obvious that the mean age of onset will be lower in people with Type 1 diabetes than in those with Type 2. It is also known that bone mineral density tends to be lower in Type 1 diabetes and is possibly elevated in Type 2 diabetes, despite a lack of any correlation with fracture risk [39]. It is also possible that the loss of islet cell peptides, such as glucagon and islet amyloid polypeptide (amylin), might have a negative impact on the integrity of bone in Type 1 disease. Despite all these potential mechanisms, however, there is no convincing evidence to suggest any difference—other than age of onset—between Type 1 and Type 2 diabetes in either the epidemiology or the clinical presentation of cases of the Charcot foot.
Loss of nerve-derived peptides and loss of innervation of bone
Axonal degeneration is associated with loss of peptides that are normally released by nerve terminals. Knowledge of the impact of these changes is currently in its infancy but the peptides which have attracted the greatest interest are calcitonin-gene related peptide and substance P. Interest has also focused on the possible effect of loss of innervation on the local release of nitric oxide, which normally inhibits
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Hypoglycaemic agents
While some hypoglycaemic agents are associated with an increased risk of fracture, there is currently no known link between any treatment and the onset of Charcot foot disease.
Body weight
Clinicians often believe that obesity makes the Charcot foot more likely, but while the biomechanical argument is easily understood, the evidence to suggest an overall link between BMI and Charcot incidence is not strong [40]. It is possible that any impact of obesity is countered by a protective effect
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of BMI on bone strength. It is also possible that perception of the importance of obesity relates more to the problems of achieving adequate offloading in established cases and the increased risks associated with surgery.
Associated eating disorders
The Charcot foot is occasionally seen in the young person (perhaps more often female) who has both poorly controlled Type 1 diabetes and an eating disorder. Of possible relevance is a recent report on a small series in which onset of a Charcot foot sydrome was reported to follow weight loss [41].
Effects of hyperglycaemia Metabolic effects
As the cycle of inflammation is thought to be largely mediated through activation of the RANKL/NFjB pathway, it is relevant that this pathway is already potentiated in diabetes; thus, it is well established that circulating concentrations of osteoprotegerin (a marker of activation of the RANKL/NFjB pathway) are higher in people with diabetes, probably as a result of the effect of oxidized lipids, advanced glycation endproducts and free radicals [10,42]. Glycation of connective tissue
The abnormal forces applied to the foot during standing and walking because of motor neuropathy will be exacerbated by shortening of tendons and connective tissue resulting from the glycation of collagen that can complicate chronic hyperglycaemia.
Chronic complications of diabetes, other than neuropathy,
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Nephropathy
Charcot disease also associates with nephropathy, simply because neuropathy and nephropathy are both microvascular complications of diabetes; however, the reduced hydroxylation of vitamin D and the hyperparathyroidism of advancing renal failure may possibly make expression of the disease more likely by their impact on bone strength. Kidney-pancreas transplantation
There is one group in which the Charcot foot appears to be especially common: patients with Type 1 diabetes who undergo combined renal-pancreas transplantation [45,46], and in whom it has also been suggested that the disease may differ clinically [47], although this remains to be confirmed. There are a number of reasons why this group may be at particularly high risk, including both the fact that they are selected for freedom from overt macrovascular disease before being considered for transplantation, as well as their exposure to immunosuppressive therapy. Although there are no precise details on incidence, the number of new cases appears anecdotally to be so high that counselling and surveillance should now be part of routine practice for people undergoing combined transplantation.
Genetic predisposition Two groups have reported small increases in odds ratio for the presence of certain candidate osteoprotegerin gene polymorphisms in selected populations of people with a history of Charcot foot syndrome [48,49]. The increases are small and the reported polymorphisms were not completely identical in the two studies but the observation is of interest, even though its clinical relevance is not certain.
and their treatment Other foot disease
Preceding foot ulcers may act as a trigger for the onset of Charcot foot sydrome and were reported in 35% of people presenting with an active Charcot foot in a recent report, the Charcot Disease in the UK (CDUK) study [43], even though it should be noted that the Charcot foot and ulceration occur in a similar sub-population of people with diabetes (with neuropathy, usually, preserved large arterial blood flow) and so it is possible their relationship is less causative than coincidental; however, a recent small observational series reported that patients with neuropathy and neuropathic ulcers had a reduction in pedal bone mass as assessed by quantitative ultrasonography, whereas those with neuropathy alone did not [44]. This might indicate that ulceration did indeed tend to trigger osteolysis, possibly through local inflammation, and this could be a factor leading to the later development of Charcot foot, as could be any associated immobilization, change of gait and weight-bearing.
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Potential predisposing factors in diseases other than diabetes Historically, tertiary syphilis with tabes dorsalis was the most frequently identified cause of Charcot foot syndrome, as in all of Charcot’s cases. Leprosy is a frequent cause in developing countries but diabetes is probably the most common cause worldwide today. The other main causative factor encountered in routine practice is the neuropathy associated with ethanol abuse, the presentation and management of which are just the same as for diabetes. The acute Charcot foot has also recently been reported as a complication of the neuropathy of rheumatoid disease [50]. Other causes are rare and include other causes of neuropathy [51], traumatic denervation and syringomyelia. A recent study of a large population has also reported some novel statistical associations with conditions not previously linked with the Charcot foot: cardiac dysrhythmia, pulmonary eosinophilia and volume depletion [52]. The significance of these findings will require further study.
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Clinical presentation Charcot foot syndrome may present with isolated inflammation of the foot (with or without discomfort), or the inflammation may be associated with varying degrees of destruction of the architecture of the foot. The distortion of the foot may lead to ulceration of the skin over areas exposed to abnormal forces and this may lead to infection. The bones and joints most often affected are those of the mid- and hind foot, with fractures accompanying medial dislocation of the medial cuneiform, lateral dislocation of the second to fifth tarsometatarsal joints and downward dislocation of the talonavicular joint. Any of these may lead to the classical infero-medial bulging of the foot with loss of the plantar arch, often referred to as the ‘rocker bottom foot’ (Fig.1). Other cases of what appear to be same process are much more limited in their extent, such as isolated fracture of one or two metatarsals. Overlap between these and so-called ‘stress fracture’ (even when it occurs without preceding stress) is blurred by limited medical understanding. If dislocation is a distinct part of the Charcot disease process, there may be similar aetiological overlap with cases of isolated dislocation of metatarsophalangeal or interphalangeal joints, which are not uncommon in people with neuropathy. The final definition of the Charcot foot will need to differentiate it from unrelated processes, which lead to a similar clinical presentation.
Triggers for the onset of active Charcot disease The majority of people who present with an active Charcot foot will recall seemingly minor trauma that they think
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triggered its onset. Sometimes this may have been very recent but sometimes it was weeks or months earlier. A recent webbased survey in Britain and Ireland, the CDUK study, reported that these episodes include minor accidental trauma (recalled in 36% of all presenting cases), preceding foot ulceration (35%), local surgery (12%) and osteomyelitis (7%) [43].
Diagnosis and differential diagnosis The main barrier to prompt diagnosis of Charcot foot syndrome is the failure of the clinician to consider the possibility. Most affected people present to non-specialists in primary care and in emergency departments where the commonest causes of foot inflammation are sprain, cellulitis, venous thrombosis and gout. It follows that many people with an active Charcot foot are investigated, and even treated, for one or more of these conditions before the correct diagnosis is made. This delay in diagnosis is likely to result in worsening of the disease and may increase the risk of eventual limb loss [2,53].
Confirmation of diagnosis
Once suspected, the clinician should do a plain X-ray (preferably performed with the subject weight-bearing to exaggerate possible changes). The association of the clinical presentation with radiological evidence of fracture and/or dislocation is usually sufficient to make the diagnosis and to start treatment. If the X-ray appears normal, it is essential that magnetic resonance imaging (MRI) be requested as soon as possible to show inflammation of soft tissue (which is not
FIGURE 1 The plantar aspect of the feet in a person with bilateral Charcot foot syndrome. Although no longer active, the disease process has caused bilateral ‘rocker-bottom’ deformity with the resultant change in weight distribution during walking leading to the build-up of callus under the midfoot on each side.
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diagnostic) and of bone marrow (which is strongly suggestive of active Charcot foot in a person who presents with inflammation that is otherwise unexplained). If the MRI is negative, it is usual to accept that the diagnosis is unlikely, although specialist teams will occasionally encounter cases in which the MRI later becomes abnormal. Fractures without displacement may be more apparent on computed tomography (CT) than on MRI.
that acute osteomyelitis can itself trigger the onset of secondary Charcot changes in the same foot. If a person has had surgery for osteomyelitis and there is a recurrence in an adjacent bone, the possibility of new, active Charcot disease may be as likely as that of persistence of bone infection. The same applies in cases in which the management of osteomyelitis with antibiotics alone is associated with a sudden deterioration accompanied by worsening inflammation.
Active Charcot foot syndrome and osteomyelitis
Classification
The appearances of Charcot foot and osteomyelitis on MRI are very similar and this can pose a problem with diagnosis in someone who has an associated ulcer, in whom the likelihood of osteomyelitis is much greater. Differentiation between the two conditions requires the careful input of a skilled musculoskeletal radiologist and may still be far from definite [54,55]. It should also be noted that the occurrence of bone marrow oedema may not be specific to Charcot foot syndrome and to osteomyelitis, and one study has suggested that such oedema may be observed in 30% subjects with neuropathic foot ulcers but without clinical evidence of, or progression to, either of these diseases [56]. If true, the use of MRI to confirm the diagnosis of Charcot foot in those presenting with suggestive symptoms and signs may sometimes prove to be misleading. More information is required on the MRI findings in people who simply have distal symmetrical neuropathy in diabetes. Labelled neutrophil scans may distinguish between bone infection and active Charcot foot but they are expensive and not always available. While blood-borne inflammatory makers are usually more markedly elevated in the presence of osteomyelitis, they may also be raised in cases of Charcot foot and are not sufficiently specific to be diagnostic. One clinical sign can, however, be useful and this is assessment of the response of the inflamed foot to immobilization in a nonremovable below-knee cast for 3–4 days. The inflammation of active Charcot foot will usually settle rapidly, while that of osteomyelitis will not. Imaging by fluorodeoxyglucose-positron emission tomography (PET) [57,58] and SPECT/CT [59–61] has been advocated but experience remains limited, partly because of cost and limited availability. Nevertheless, fluorodeoxyglucose-PET and other newer imaging techniques may prove to be of value in discriminating between osteomyelitis and Charcot foot syndrome; however, a conventional three-phase bone scan is rarely of any diagnostic value. The need for the careful differentiation between Charcot foot and osteomyelitis is obviously of importance when the skin is ulcerated as a result of Charcot deformity, and secondary osteomyelitis is a possible complication. In such circumstances it is generally accepted that a biopsy of bone may be needed to establish the diagnosis of infection, with the specimen being examined both histologically and microbiologically. It is also becoming increasingly recognized, however,
Two classifications of Charcot foot syndrome are widely quoted. The Eichenholtz classification—especially as later modified to include a stage 0—is essentially a summary of the theoretical stages through which the Charcot process is thought to progress: from inflammation without skeletal damage, to skeletal damage and to eventual resolution [62]. The more recent classification by Sanders and Frykberg [63] classifies disease on the basis of the affected joints and is found to be useful by many clinicians. The most recent classification is that of Chantelau and Grutzner [7], which divides affected feet into those that are either active or inactive as well as those that are or are not associated with full thickness cortical fractures.
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Non-surgical treatments: offloading There are two aims of offloading: (1) to splint the inflamed foot in order to try to break the cycle of damage and inflammation and thereby limit the extension of the inflammation-mediated damage and (2) to protect the skeleton of the foot while the bones and joints are vulnerable. International consensus recommends the use of a moulded below-knee fibreglass cast, which is easy to apply and strong enough to allow weight-bearing once it has set. Nonremovable casts should be changed within 1 week because if there is prompt reduction in local inflammation, they rapidly become loose. Thereafter, the casts need to be replaced every 1–3 weeks. Frequent replacement gives an opportunity for the foot to be checked – not least because the cast may cause abrasions of which the patient may be unaware, because of the underlying neuropathy. Those without ready access to casting facilities often use removable, commercially available ‘cast walkers’, and some have advocated making such walkers irremovable by the use of a band of fibreglass tape [64]. Neither fibreglass casting nor cast walkers are available in many communities, however, and while plaster of Paris can be used, clinicians will otherwise have to rely on the use of crutches, wheelchairs or whatever available approaches will achieve the desired effect.
Duration of offloading
Offloading is continued until the foot is judged to be in remission and until any fitted footwear (if prescribed) is
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available. There are few published data on the duration of offloading but the largest series comes from the CDUK webbased survey which reported that the median time to remission (defined as being ambulant in usual or fitted footwear) was between 9 and 12 months [43]. This contrasts with data from Denmark, Brazil, North America and the Czech Republic [53,65–67], which report a mean time in cast of < 6 months. The reason for this difference is not clear, but if the majority of people can be satisfactorily offloaded in other countries for < 6 months, it is likely that the duration of casting in the UK is longer than it needs to be. While there are a number of factors that may account for the observed difference, the main one may stem from the criteria used to define remission.
Recognition of remission
There are no firm criteria for deciding when the remission stage has been reached. It is generally said that remission can be assumed when there is a temperature difference of < 2°C between the feet (assuming the disease is not bilateral) and there are data to justify this [66]; however, a temperature difference of 2°C is quite obvious to the touch and many clinicians err on the side of caution and wait till the signs of inflammation regress even more. Quantitative bone scans have also been used to document changes in local scintigraphy and blood flow and have shown associations between both skin temperature and circulating bone turnover markers [68], but the use of this approach in routine clinical care is not yet clear. Zampa et al. [69] have reported that the mean time to recovery could be predicted by the extent of contract uptake using dynamic MRI, being some 5 months in those with lesser degrees of uptake, compared with 9 months in those with more. Some have suggested that MRI may be a valuable indicator of remission as it shows reduction in marrow oedema, but this is expensive and has yet to be validated. Moreover, the MRI changes in active Charcot foot syndrome are largely dependent on the replacement of marrow fat by inflammatory tissue, and it is quite possible that the process of re-establishing marrow fat will persist long into the postinflammatory phase of the disease. This has not been formally studied. Other imaging techniques may be more useful, as indicated in one recent report on the use of PET/CT [61], but such techniques will be of limited availability in most centres for the foreseeable future. Plain X-rays can also be used to define angles of alignment in order to document any continuing change in the extent of structural damage to the foot skeleton [70,71].
this, some have reported a relatively high incidence of recurrence [73,74]. One possible explanation is that the disease was not in complete remission in these series when offloading was discontinued. Another relates to the criteria used to define recurrence. It is quite common for the previously affected foot to become warm and swollen when non-removable casting is discontinued but it usually settles within days and it is possible that some groups regard this phase of transient swelling as a sign of continuing activity whereas others do not.
Potential adverse effects of prolonged casting
Prolonged casting is not without potential side-effects. These include abrasions on both the affected foot and the other one. It will also be associated with worsening osteopenia but clinically important consequences of this have not been described. There is also a theoretical risk of secondary thrombosis and appropriate preventive measures should be considered in those judged at highest risk even though secondary thrombosis seems to be an uncommon complication in routine practice. The most prevalent complication of prolonged immobilization is, however, the adverse effect on mobility, social functioning and mood.
Other non-surgical treatments Bisphosphonates (either oral or intravenous)
The use of bisphosphonates followed an encouraging unblinded observational study but a later small pilot randomized controlled trial failed to confirm the benefit with regard to the clinical course and showed only the predictable changes in bone turnover markers [75]. Observations made in the observational CDUK study [43] and, later, a second small but high-quality randomized controlled trial [76] did not confirm the benefit of bisphosphonates and even suggested that their use might be associated with a prolongation of the time to disease resolution. A systematic review concluded that there is currently no evidence to justify the use of bisphosphonates [77].
Salmon calcitonin
Data suggesting that salmon calcitonin may be beneficial have been published [78], but the product has since been withdrawn from the market.
Anti-inflammatory agents: anti-tumour necrosis factor, antiRANKL, glucocorticoids and non-steroidal anti-inflammatory drugs
Ipsilateral recurrence
It is generally thought that once a Charcot foot goes into remission, recurrence on the same side is rare [72]. Despite
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Studies are under way to assess the effect of agents that may interrupt RANKL/osteoprotegerin signalling, but there has been no formal study of systemic glucocorticoids or of
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non-steroidal anti-inflammatory drugs. Such studies are needed even though non-steroidal anti-inflammatory drugs would have to be used with care in those at risk of renal impairment.
mobility has been linked to a high incidence of anxiety and depression [82,83], even though this has not been a universal finding [84]. Any depression or anxiety that does occur appears to be resolve once the disease settles [85].
Recombinant parathyroid hormone
Long-term care
While there is no report of the use of the hormone fragment, teriparatide, a randomized clinical trial of the use of rh1-84 parathyroid hormone has been registered (EudraCT 2009016873-13). The results are not yet available.
Surgery: active phase Surgery in the active phase of Charcot foot syndrome is liable to be associated with delayed healing and secondary infection but there are no robust data on which to base a choice between surgical and non-surgical treatment for any individual. All the evidence identified in a recent systematic review was only of level 4 or 5: case report or expert opinion [79]; however, prevailing opinion was defined in the German-Austrian consensus statement [80], that (1) a deformed but plantigrade foot capable of full weight-bearing is not a candidate for surgery, and (2) surgery should be considered for cases with joint dislocation and significant instability because closed reduction and retention by means of casting is ineffective. The conclusion of the American Diabetes Association consensus panel [4] was rather more circumspect and recommended that, while fracture or dislocation at the level of the ankle should be treated surgically if feasible, the ‘initial management of acute neuropathic fractures should not differ from other fractures’. If, however, distortion at the level of the ankle is not reconstructable, the option of early transtibial amputation should be discussed because its early adoption may avoid months of fruitless treatment, observation and prevarication. Such elective amputation is often accompanied by a significant improvement in well-being [81].
Contralateral disease
The lifetime risk of both feet being affected is thought to be 20–25%. A total of 10–15% of patients with Charcot foot syndrome will have had contralateral disease by the time they present with a new episode, a small number have simultaneous bilateral disease and the remainder will develop contralateral disease in the future.
Maintenance of mobility and prevention of secondary ulceration
People who have had a chronic Charcot foot should be considered for long-term specialist surveillance, including regular podiatry and advice on the provision of appropriate footwear to minimize the risk of ulceration over abnormal bone prominences.
Cardiovascular mortality
The mortality rate reported in one cohort followed for 8 years was 29% [85]. Data from a second single-centre series of 117 patients, followed for a similar period, reported a mortality rate of ~ 40% at 5 years and a mean reduction in life expectancy of 14 years [86]. This reduction in survival was, however, no worse than that of people with neuropathic ulcers of the foot in diabetes and is thought to relate largely to an increased incidence of cardiovascular disease. It follows that cardiovascular risk reduction should remain a key aspect of the management of these groups.
Prevention
Once the condition has entered remission, reconstructive surgery should be considered to facilitate standing and walking on a plantigrade foot and to minimize secondary ulceration and may include arthrodesis, and either internal or external fixation.
It is not known how to reduce the onset of an active Charcot foot even in those who are most at risk. It follows that the only option is to make those at risk aware of the possibility of their developing the condition, and if they develop symptoms suggestive of Charcot foot, what they should do in order to ensure the diagnosis is confirmed as quickly as possible.
Complications
Need for agreed measures of outcome
Apart from the threat of limb loss and the complications of treatment (such as those of immobilization referred to above or of surgical intervention), the greatest complication of Charcot foot syndrome is the impact on well-being during the prolonged course of the active phase. The restriction on
Further information is desperately needed to guide management of the active phase of the Charcot foot. Given that the conduct of randomized trials in this condition poses particular difficulties (although these are not insurmountable), consideration should be given to the conduct of systematic
Surgery: inactive phase
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audits of performance, both within and between centres [87]. For both such audits and randomized trials, however, it is necessary to define disease severity at the time of first presentation to an expert service and to agree a choice of outcome measures. In addition to the incidence of major amputation and overall survival rates, these should include measures of physical functioning and mood during the active phase and the extent of residual deformity (using both radiological and gait-related measures).
Competing interests
None declared.
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