INTRODUCTION — In patients with diabetes mellitus, the loss of sensation to a joint may result in a chronic, progressive, and destructive arthropathy. The prototype of this disorder was described by Charcot in relation to tabes dorsalis. Similar changes are seen with other neurologic disorders, such as syringomyelia, although diabetes is the most common cause of neuropathic (Charcot) arthropathy in the western world. It is commonly termed diabetic neuroarthropathy. Diabetic neuropathic arthropathy is also called diabetic osteoarthropathy.
A variety of other musculoskeletal conditions have also been associated with diabetes mellitus, including specific arthropathies of the hand and shoulder, limited joint mobility, and spontaneous infarction of skeletal muscle.
Diabetic neuroarthropathy will be reviewed here. Other musculoskeletal conditions associated with diabetes, limited joint mobility in diabetes, and diabetic muscle infarction are described separately. (See "Overview of the musculoskeletal complications of diabetes mellitus" and "Diabetic muscle infarction" and "Limited joint mobility in diabetes mellitus".)
PATHOGENESIS — The pathogenesis of this condition remains uncertain; it is likely to be multifactorial, due to a combination of mechanical and vascular factors resulting from diabetic peripheral and autonomic neuropathy and metabolic abnormalities of bone (algorithm 1) [1-4].
It is thought that lack of proprioception secondary to peripheral neuropathy may result in ligamentous laxity, increased range of joint movement, instability, and damage by minor trauma, to which the relatively insensitive neuropathic foot is prone. In addition, the resulting change in the architecture of the foot causes a change in weightbearing and subsequent localized trauma. Finally, autonomic neuropathy may result in vasomotor changes and in the formation of arteriovenous shunts. These, in turn, result in reductions in effective skin and bone blood flow, despite the good and sometimes bounding foot pulses in these patients.
Trauma to the neuropathic foot may trigger an exaggerated local inflammatory response, mediated by proinflammatory cytokines (eg, tumor necrosis factor-alpha and interleukin [IL]-1 beta), resulting in the osteoarthropathy [4]. A possible cytokine-associated effect is suggested by the finding of enhanced osteoclastic activity in surgical specimens from patients with neuropathic arthropathy [5]. Other laboratory studies suggested that both receptor activator of nuclear factor (NF) kappa B (RANK) Ligand (RANKL)-dependent and -independent pathways may be involved in the increased bone resorption seen in this condition [6]. Subsequent work showed increased serum concentrations of proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-6, correlating with raised bone turnover markers, at the presentation of acute neuropathic arthropathy [7].
Regardless of the initiating mechanism, an initial resorptive phase may occur in the development of a neuropathic joint, which is then followed by a hypertrophic repair phase [8].
EPIDEMIOLOGY — Neuroarthropathy is uncommon among the general diabetic population; however, the incidence of neuroarthropathy is difficult to determine accurately, as reported series are often from specialty centers that treat more severe cases of diabetes, and diagnostic criteria for neuroarthropathy vary between series [9-12].
As an example, one study from a specialist diabetic center reported an incidence of 0.3 percent per year in their patient population [9]. In another study, in a series of 85 patients presenting to a diabetic foot clinic with acute neuroarthropathy, type 1 diabetics presented more frequently in their fifth decade, with an average duration of diabetes of 24 ± 8.4 years, while type 2 diabetics tended to present in their sixth decade, with a mean duration of diabetes of 13 ± 8.1 years [10]. A study of 561,597 patients with diabetes, largely with type 2, from the US Department of Veterans Affairs inpatients and outpatients datasets for 2003 showed the frequency of newly diagnosed diabetic (Charcot) neuroarthropathy to be 0.12 percent, with obesity as well as the other factors noted here also increasing the risk [11]. A prospective study of active Charcot arthropathy in a British population of 205,033 patients with diabetes identified 90 cases, a prevalence of 0.04 percent [13].
A high prevalence of diabetic (Charcot) neuroarthropathy (12 percent) has been reported in patients following simultaneous pancreatic and kidney transplantation, a group characterized by severe and longstanding diabetes [12]. A more recent retrospective study of 487 diabetic transplant patients found a greater incidence of Charcot arthropathy in patients who had undergone kidney-pancreas transplant compared with those who had renal transplantation alone (18 versus 11 percent); the mean times to develop the arthropathy were 6.4±4.8 and 7.1±5.2 years, respectively [14].
CLINICAL FEATURES
History and physical findings — The clinical manifestations are variable, but patients classically present with sudden onset of unilateral warmth, redness, and edema over the foot or ankle, often with a history of minor trauma [15]. The affected foot may be discernably warmer to the touch and have a temperature that is several degrees (centigrade) greater than the contralateral foot. Sometimes, patients present instead with a slowly progressing arthropathy with insidious swelling over months or years, and occasionally recurrent acute attacks may occur. The most frequently involved joints in the diabetic patients are the tarsus and tarsometatarsal joints, followed by the metatarsophalangeal joints and the ankle [3,16].
In one series, a minority of patients (10 percent) experienced recurrent acute attacks in the same foot, and in about 20 percent of patients attacks of diabetic neuroarthropathy occurred in the contralateral foot. However, simultaneous bilateral attacks were rare [9]. In this series, there was a median of two years between occurrences in the contralateral foot.
Involvement of the foot is characterized by collapse of the arch of the midfoot and bony prominences in peculiar places, with bony prominences on the plantar aspect potentially leading to pressure ulceration (picture 1). A delay in diagnosis is very common and can lead to progression of the neuroarthropathy and an increased risk of complications [17]. A retrospective series of 27 patients with acute diabetic (Charcot) neuroarthropathy found misdiagnosis in 63 percent and a median delay of two months (interquartile range [IQR] one to six months) before presentation or referral to a high-risk foot service [18]. Without treatment, progression can be rapid, and irreversible damage can occur within six months or less [19].
The arthropathy has been described as relatively painless, although ill-defined pain is commonly reported, being present in one series in 76 percent of patients [20]. The severity of the pain was less than might have been expected from the clinical and radiologic appearance of the affected joint.
Most often, the skin is unbroken. However, early neuroarthropathy can coexist with foot ulceration, and ulceration can be a consequence of the foot deformity associated with late disease.
In patients who present later in their disease course, following resolution of acute changes, joint disorganization can be severe and irreversible. Deformities are common and can transfer weightbearing to areas that tolerate it poorly and/or that may lack sensation. Ulceration and infection commonly ensue. Common deformities seen are the “rocker bottom foot” caused by collapse of the medial arch (picture 1), medial convexity deformity caused by medial displacement of the talonavicular joint, and tarsometatarsal dislocation [3].
Although unusual, involvement of upper limb joints can also occur [21]. In one report, upper-extremity involvement occurred in the hand and wrist in three diabetic patients who had received or were receiving treatment for Charcot foot neuroarthropathy [22]; the hand abnormalities were bilateral in two patients. Rarely, diabetic neuroarthropathy can also affect the knee; in one report of three patients with knee involvement, all had been treated for Charcot disease of the foot [23]. By contrast, tabes dorsalis primarily affects the knees, hips, and ankles, and syringomyelia usually affects the shoulder or elbow.
Laboratory findings — In patients with diabetic (Charcot) neuroarthropathy uncomplicated by infection, the white blood cell count should be normal and acute phase reactants should be appropriate for the patient’s age, sex, and body weight. Synovial fluid, if obtained, should be sterile, with no crystals or organisms on microscopy and no growth on culture.
Imaging — Radiographic findings are variable, depending upon the stage and site of the arthropathy.
●In early acute disease, the plain film radiographic changes may be mild or nonspecific, showing only soft tissue swelling, loss of joint space, or osteopenia [15].
●In later stages, bone resorption may predominate in the forefoot, leading to osteolysis of phalanges and to a variety of further changes, including partial or complete disappearance of the metatarsal heads or “pencil-pointing” of phalangeal and metatarsal shafts. Osseous fragmentation, sclerosis, new bone formation, subluxation, and dislocation are more likely to occur in the midfoot and hindfoot (image 1A-C) [1,21].
●Stress fractures, which may be difficult to diagnose, can complicate the neuroarthropathy [15]. An uncomplicated stress fracture not apparent on a plain radiograph can be located by magnetic resonance imaging (MRI) or nuclear scintigraphy and can often be confirmed by MRI or serial radiography. However, both MRI and scintigraphy may show nonspecific abnormalities in the diabetic neuropathic foot, and delay in diagnosis may occur if one waits for the characteristic radiologic changes to become apparent. (See 'Clinical and radiographic staging' below and 'Initial diagnostic evaluation' below.)
Clinical and radiographic staging — Classification of diabetic (Charcot) neuroarthropathy into one of four stages by a modified Eichenholtz system is helpful for choosing appropriate treatment and prognosis and for clinical trials [24]. The stages are:
●Stage 0: Early or inflammatory – There is localized swelling, erythema, and warmth with little or no radiological abnormalities.
●Stage 1: Development – Swelling, redness, and warmth persist, and bony changes such as fracture, subluxation/dislocation, and bony debris are apparent on plain radiographs.
●Stage 2: Coalescence – The clinical signs of inflammation decrease, and radiological signs of fracture healing, resorption of bony debris, and new bone formation are evident.
●Stage 3: Remodelling – The redness, warmth, and swelling has resolved, and bony deformity, which may be stable or unstable, is present. Radiographs may show mature fracture callus and decreased sclerosis.
DIAGNOSIS
Diagnostic features — A high index of clinical suspicion is important to diagnose neuropathic arthropathy early. This diagnosis should always be considered in any patient with diabetes who presents with a unilateral warm, swollen, erythematous foot, particularly in the context of peripheral neuropathy and with longstanding diabetes. Physical findings during the early stages of neuroarthropathy often can be mistaken for cellulitis. (See 'Infections' below.)
The diagnosis is based upon the presence of characteristic symptoms and physical and radiographic findings, which depend upon the stage of the disease. Other conditions that may mimic neuropathic arthropathy must be excluded, including cellulitis, osteomyelitis, septic arthritis, gout, osteoarthritis, and inflammatory arthritis. (See 'History and physical findings' above and 'Imaging' above and 'Differential diagnosis' below.)
Initial diagnostic evaluation — The initial diagnostic evaluation in all patients includes:
●History and physical examination – A thorough medical history and physical examination is essential in making the diagnosis. It is important to confirm the presence of peripheral neuropathy and to look for potential portals of entry for a possible infection. The presence of foot ulceration, particularly a deep ulcer that probes to bone, should raise suspicion of osteomyelitis, which can coexist with Charcot arthropathy. (See "Evaluation of the diabetic foot" and 'Infections' below.)
●Laboratory testing – Laboratory testing in a patient suspected of neuropathic arthritis should include a complete blood count (CBC), white blood cell differential count, and testing for renal function (blood urea nitrogen and creatinine). Additional testing depends upon the clinical presentation and is useful primarily to exclude alternative diagnoses. (See 'Differential diagnosis' below.)
As an example, acute phase reactants are helpful when considering certain differential diagnoses. In neuroarthropathy uncomplicated by an infection such as osteomyelitis or septic arthritis, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should be appropriate for the patient’s age, sex, and body weight; elevated values should raise the possibility of infection (see 'Infections' below). Examination of synovial fluid for crystals may be helpful if a differential diagnosis of gout is being considered. In both gout and infection, acute phase reactants are usually elevated, and leukocytosis may be present. (See 'Noninfectious disorders' below.)
●Imaging – Plain radiographs of affected joints should be obtained. In patients with radiographs that are normal or inconclusive, a non-contrast magnetic resonance imaging (MRI) study should be obtained. While a second radiograph obtained several weeks after presentation may clarify the diagnosis of acute early neuropathic arthropathy, the use of plain radiography alone inevitably results in undesirable delays in diagnosis and treatment.
Bone scintigraphy is sometimes used as an alternative to MRI, particularly when there is limited availability of MRI, and can be utilized in patients when the presence of metal precludes MRI [25]; in the presence of regional or diffuse ischemic changes, MRI would be preferred.
In patients with normal radiographs and a low clinical suspicion of osteomyelitis, non-contrast MRI is very helpful for making an early diagnosis of Charcot neuroarthropathy, and a negative MRI in this situation indicates that acute Charcot neuroarthropathy is unlikely. Non-contrast MRI in stage 0 Charcot neuroarthropathy typically shows subchondral bone marrow edema with or without microfracture [26]. In later stages of Charcot neuroarthropathy, where radiographs already show abnormalities, the main value of MRI is in further investigation of possible infection or functional deterioration caused by mechanical derangement such as subluxation or tendon tears.
The situation is more complicated if the patient has skin ulceration and a high likelihood of infection. Whereas the diagnosis of stress fracture and visualization of torn ligaments and of intraarticular fragmentation may be facilitated by non-contrast MRI, the changes of acute neuropathic arthropathy may be indistinguishable from those of osteomyelitis [8,27].
Contrast-enhanced MRI may provide additional diagnostic value if safe to use in the individual patient. However, the decision to use contrast should be made with particular caution, and the use of gadolinium-based MRI contrast agents is relatively contraindicated in patients with diabetic nephropathy who have moderate or severe renal functional impairment, as use of these agents increases the likelihood of developing gadolinium-induced systemic fibrosis (also called nephrogenic systemic fibrosis), a systemic fibrosing disorder. Discussion of which imaging study would be most appropriate in difficult or complex patients should be undertaken with an experienced musculoskeletal radiologist.
The information potentially provided by use of contrast was illustrated in a retrospective study of 128 neuropathic joints (42 with concomitant osteomyelitis), of which the majority had joint effusions [28]. The presence of one or more of the following features on contrast-enhanced MRI favored osteomyelitis [28]:
•A sinus tract
•Replacement of soft tissue fat
•A fluid collection
•Extensive marrow abnormality
The absence of infection was associated with a thin rim of enhancement rather than diffuse signal throughout an effusion and with the presence of subchondral cysts or intraarticular bodies [28].
The diagnostic evaluation of possible osteomyelitis is presented in detail separately. (See "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis" and "Approach to imaging modalities in the setting of suspected nonvertebral osteomyelitis".)
Ultrasound studies may also be useful, but more research using these techniques is needed. A pilot study of 26 patients with modified Eichenholtz stage 0 Charcot neuroarthropathy, confirmed on MRI, showed synovitis and effusion and high Doppler activity in the midtarsal joints in all patients, along with a high prevalence of ankle effusions, peroneal and tibialis posterior tendonitis, and erosions in the distal fibula. However, further work is needed to study the value of ultrasound in differentiating between neuroarthropathy and other arthropathies [29].
Further testing in selected patients
●Evaluation of joint effusions – In patients with a joint effusion, joint fluid should be aspirated. For small joints, especially those with disrupted architecture, radiologic guidance (eg, by ultrasound, fluoroscopy, or computed tomography [CT]), may be necessary. Testing should include a Gram stain, cultures, cell count, differential white blood cell count, and crystal search.
●Plain radiography and MRI inadequate – In patients in whom MRI is unable to distinguish between infection and diabetic (Charcot) neuroarthropathy, labelled white blood cell scanning can be more specific, but should always be correlated with clinical findings [25]. Patients with metal implants that degrade the signal in the area of interest or those with other contraindications to MRI (eg, a pacemaker) may be assessed using ring positron emission tomography (PET) scan or PET/CT, if available [30,31]. Further study of PET scanning is needed to determine the sensitivity and specificity of this imaging modality as a test to distinguish neuropathic arthropathy from osteomyelitis [32].
Differential diagnosis — Multiple causes of joint pain can affect both diabetics and nondiabetics, and diabetes mellitus is a common condition that may be complicated by other diseases of the bones and joints. Conditions that are most likely to mimic diabetic neuropathic arthropathy and which are particularly important in the differential diagnosis of this condition will be described here. These include septic arthritis, gout, cellulitis, osteoarthritis, idiopathic inflammatory diseases, and osteomyelitis. Another disorder, complex regional pain syndrome (formerly referred to by various terms, including reflex sympathetic dystrophy, Sudeck’s atrophy, and algodystrophy), may also occur in the setting of diabetic neuropathy, and is briefly discussed.
The general approach to the adult with joint pain, the differential diagnosis of monoarthritis and polyarthritis, and the musculoskeletal conditions that may occur in patients with diabetes mellitus are presented in detail elsewhere. (See "Monoarthritis in adults: Etiology and evaluation" and "Evaluation of the adult with polyarticular pain" and "Overview of the musculoskeletal complications of diabetes mellitus".)
Those disorders of particular importance to consider in the differential diagnosis include both infections and noninfectious disorders:
Infections
●Septic arthritis – Patients with either diabetic neuropathic arthropathy or septic arthritis may present with a warm and swollen ankle, as may patients with gout (see 'Noninfectious disorders' below). Infection is a particular concern in patients with skin ulceration. Septic bacterial arthritis occurring in a patient with diabetic neuropathy may be less painful and may be associated with a greater range of joint motion than a similar infection in the absence of neuropathy. Although the majority of patients with septic arthritis are febrile, neither the absence of fever nor a normal peripheral white blood cell count excludes septic arthritis. If a joint effusion is apparent on physical examination or an imaging study, joint aspiration and synovial fluid analysis is necessary to exclude joint infection. (See "Septic arthritis in adults" and "Synovial fluid analysis" and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities".)
●Osteomyelitis – Symptoms of dull pain and tenderness, along with local signs of inflammation, such as warmth, erythema, and swelling, may be present in both osteomyelitis and diabetic neuropathic arthropathy [33]. Osteomyelitis should be suspected in the presence of ulcers, especially those that are deep to bone or can be probed to bone, or are of more than one to two weeks’ duration, although ulcers can also occur in neuropathic arthropathy, and osteomyelitis may also coexist with Charcot neuroarthropathy. In one web-based series of 288 patients with acute Charcot neuroarthropathy, 35 percent of patients had coexistent foot ulceration and one-fifth of these also had osteomyelitis [34]. Although patients with neuropathic joints alone usually lack fever, leukocytosis, and elevated acute phase reactants, the absence of these findings does not by itself exclude osteomyelitis. Plain radiography and non-contrast MRI may not distinguish the conditions [33], and the diagnosis of osteomyelitis may require further investigation, bone biopsy, and culture. (See 'Initial diagnostic evaluation' above and 'Further testing in selected patients' above and "Clinical manifestations, diagnosis, and management of diabetic infections of the lower extremities" and "Nonvertebral osteomyelitis in adults: Clinical manifestations and diagnosis".)
●Cellulitis – Both neuropathic arthropathy and cellulitis can also present as warmth, redness, and tenderness of the foot. However, cellulitis may be accompanied by signs of systemic toxicity, leukocytosis, and elevated acute phase reactants. Cellulitis usually occurs when there are breaks in the skin, particularly between the toes, and may be recurrent. The two conditions are usually distinguished on the basis of history and careful physical examination.
Noninfectious disorders
●Crystal-associated arthritis – Acute flares of gouty arthritis typically occur in the foot and ankle and may be difficult to distinguish from neuropathic joint disease based upon appearance alone, although acute flares of gout are usually more painful and the joints are more tender than those of neuropathic arthropathy. Joint aspiration and synovial fluid analysis can determine whether monosodium urate (gout) crystals are present. In the appropriate clinical setting (prior history of crystal-proven gouty arthritis, classic presentation in the first metatarsophalangeal joint), and in the absence of clinical features suspicious of infection (eg, foot ulcer, sinus tract), the diagnosis of gout should be suspected. Because the presence of crystals in synovial fluid does not exclude coexistent septic arthritis, the fluid should always be cultured. Gout is common among patients with diabetes, but the intense pain of gout, short duration of symptoms, and relatively rapid response to appropriate treatment help to distinguish gout clinically from Charcot neuroarthropathy. (See "Clinical manifestations and diagnosis of gout".)
The incidence of acute calcium pyrophosphate arthropathy (“pseudogout”) is increased in the older population with longstanding diabetes, but does not typically affect the ankle and foot and can be diagnosed by the identification of the characteristic positively birefringent crystals in the synovial fluid. (See "Clinical manifestations and diagnosis of calcium pyrophosphate crystal deposition (CPPD) disease".)
Calcium hydroxyapatite crystal deposition infrequently affects tendons and soft tissue structures in the foot, resulting in acute swelling and redness of the involved area. Radiographs may demonstrate calcific deposits in the corresponding area in such patients. Calcium hydroxyapatite crystals may be identified by light microscopic examination of synovial fluid stained with alizarin red S.
●Osteoarthritis – Osteoarthritis, like a neuropathic joint, can be associated with degenerative change and joint pain. However, pain is the principal symptom associated with osteoarthritis, and is typically exacerbated by activity and relieved by rest. With more advanced disease, pain may be experienced with progressively less activity, eventually occurring at rest and at night. Cartilage space narrowing and osteophyte formation are characteristic of osteoarthritis. In the absence of a history of significant trauma, bony fragmentation and callus formation are not seen in osteoarthritis but are observed in patients with a neuropathic joint. Obvious inflammatory features, such as erythema or soft tissue swelling and tenderness, are also uncommon in uncomplicated osteoarthritis. In addition, in neuroarthropathy there is often a temperature difference between the two feet of several degrees, which is not present in osteoarthritis. (See "Clinical manifestations and diagnosis of osteoarthritis".)
●Inflammatory (non-crystal) arthritis – Various sterile inflammatory arthritides (eg, rheumatoid arthritis, psoriatic arthritis, reactive or postinfectious arthritis) are considerations in the differential diagnosis of swollen and painful joints and may initially present with a single inflamed joint. These are usually distinguished by careful history and physical examination. Isolated unilateral midfoot involvement is unusual in inflammatory arthritis. Charcot neuroarthropathy should always be considered in a patient with diabetes and peripheral neuropathy who presents with a warm swollen foot or ankle. (See "Monoarthritis in adults: Etiology and evaluation", section on 'Systemic disorders'.)
●Complex regional pain syndrome – Complex regional pain syndrome can occur rarely in patients with diabetes and is usually characterized by severe pain in a hand or foot and is often triggered by injury. It can be associated with reduced range of movement, hypersensitivity to touch, and vasomotor changes, with the affected hand or foot most often showing warmth and swelling, but occasionally being cool and later showing trophic changes. Radiographs are usually normal initially but then may show patchy demineralization. Careful clinical assessment is necessary for diagnosis. The level of pain is usually greater than that seen in Charcot neuroarthropathy, and hypersensitivity is not usually a feature of the latter condition. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)
TREATMENT — Treatment of diabetic neuroarthropathy should be undertaken by a multidisciplinary team, which may include a rheumatologist or other clinician with expertise in the care of patients with joint disease, an expert in the care of patients with diabetes, a podiatrist, a physiatrist (physical medicine and rehabilitation specialist) and a physical therapist, and an orthopedic surgeon. Whenever possible, the clinicians should have experience, specifically in the care of patients with diabetic neuroarthropathy. Treatment includes the following:
●In its earlier stages, it is based upon strategies to avoid weightbearing and the use of casting to offload the affected foot. (See 'Acute and subacute disease' below.)
●Offloading is followed by the gradual progression to normal weightbearing with prescription footwear and close management as acute and subacute inflammatory changes resolve and bony fragments coalesce. (See 'Acute and subacute disease' below and 'Clinical and radiographic staging' above.)
●In patients in whom offloading is ineffective, and in those with chronic disease and joint injury, referral to an orthopedic surgeon is indicated to evaluate the potential risks and benefits of surgical intervention in the individual patient. (See 'Joint disorganization and surgical correction' below.)
●Some experts have advocated the use of antiresorptive therapies, such as bisphosphonates, although there is uncertainty and some disagreement regarding their efficacy in this condition (see 'Acute and subacute disease' below). We generally avoid these medications, especially in patients with chronic kidney disease. A group of patients that may benefit from these agents is the subset with severe pain unresponsive to more established therapies. These medications should be used only as adjuncts to offloading, not in place of such interventions.
●Control of glucose should be optimized, but there is no evidence that this alters the course of the arthropathy once it is present.
Due to a paucity of randomized trials and studies of sufficient size, treatment guidelines are largely based upon case series, expert opinion, and clinical experience [24,25,35,36].
The response to therapy depends upon the stage at which the condition is diagnosed (see 'Clinical and radiographic staging' above). As an example, a patient with diabetic neuroarthropathy diagnosed at Stage 0, with a warm, swollen, erythematous foot of relatively recent onset and before significant radiologic damage has occurred, is more likely to respond well to therapy, while patients presenting with more chronic joint deformities have already progressed to irreversible joint disintegration and damage.
Acute and subacute disease — In patients in the earlier stages of neuroarthropathy, in which edema, redness, and warmth are present (from Stage 0, the early or inflammatory stage, to Stage 2, the coalescence stage), treatment with casting is used to offload the affected foot. This should be continued until resolution of the redness and swelling occurs, skin temperature reduces to within one to two degrees of that of the unaffected foot, and there is improvement in radiologic signs, if present (eg, resolving resorptive changes, resorption of osseous debris, and evidence of repair).
Opinion varies as to whether non-removable or removable casts should be used, as to whether patients should be weightbearing or not, and regarding the length of time patients should wear a cast. The suggested duration of casting is very variable in the literature but ranges from an average of nine weeks to a median of 11 months, and the use of a non-removable, total-contact cast is favored by many experts [25,35,37]. The patient then progresses subsequently through removable bivalve casts or cast walkers into footwear [1]. A retrospective study noted a higher rate of foot ulceration in patients refusing casting and treated with orthopedic footwear and unprotected weightbearing compared with those treated with total-contact casting and protected weightbearing [38]. Coordination of care with a podiatrist or a foot and ankle orthopedist experienced in the care of such patients and the use of well-fitting shoes are essential at this stage. (See "Evaluation of the diabetic foot".)
The following issues should be addressed:
●Strategies for avoidance of weightbearing – It is important to consider each patient’s treatment individually, taking into account comorbidities, balance, mobility, and risk of falls in selecting the modality for avoidance of weightbearing, along with the clinical assessment of healing of the Charcot neuroarthropathy. Many patients can achieve non-weightbearing for the affected foot by use of crutches, but some experts are concerned that prolonged three-point weightbearing through crutches and the unaffected (but also neuropathic) foot can lead to problems and can also be difficult for the overweight patient. Thus, the total contact cast for offloading and immobilization is increasingly becoming the treatment of choice with or without an initial period of non-weightbearing immobilization [24,36]. Non-weightbearing using either crutches or a wheelchair is favored in one international consensus document [25], while some centers use a weightbearing total contact cast for early neuroarthropathy from the time of diagnosis. Wheelchairs may sometimes be necessary for mobility.
●Monitoring, ongoing care, and progression to normal weightbearing – Whether weightbearing or not, it is important that the cast be changed every one to two weeks to allow for the decrease in edema. There is progression to protected weightbearing when erythema, swelling, and warmth have subsided, usually with the aid of an assistive device, prior to returning to wearing permanent footwear after several months. However, the recommended duration of casting varies, ranging from 3 to 25 months (median 9 months) in one web- based observational study [34] when non-removable casts were used, and 3 to 36 months (median 12 months) with removable casting in the same study. Early weightbearing (total contact cast for approximately two weeks followed by a Charcot restraint orthotic walker [CROW]) was associated with a poor outcome (65 percent with ulceration and 26 percent undergoing amputation) in one long-term retrospective study [39].
After the total contact cast has been removed, a number of offloading modalities can be used. These include the Charcot restraint orthotic walkers (CROW) for hindfoot involvement, other total contact prosthetic walkers, a pneumatic walking brace/walking boot, or similar removable cast walker which might incorporate a cushioned foot bed or insole [36]. The duration and extent of offloading are guided by clinical assessment of healing based upon the degree of edema, erythema, and skin temperature changes, and the decision to move the patient into footwear should be supported by evidence of healing on plain radiography or magnetic resonance imaging (MRI). Collaboration with podiatric or orthopedic experts is of particular importance in this stage, and physical therapy expertise may also be helpful with mobility and walking aids.
Care of the contralateral foot is important. One study reported that 46.2 percent of a series of 130 patients developed an ulcer in the foot not affected by diabetic (Charcot) neuroarthropathy. The authors of the study attributed this to the overuse of the unaffected foot due to total contact casting and offloading of the affected foot. Neuroarthropathy developed in the contralateral foot in 19 percent of patients in this series [40].
Information and education is important. Poor adherence to treatment recommendations, particularly off-loading, may negatively affect outcome. One long-term retrospective study showed that patients with suboptimal compliance had a longer duration of their acute Charcot condition and an increased risk of foot ulceration and amputation, compared with those with better compliance [41].
●Role of inhibitors of bone turnover as adjunctive therapy – The role of bisphosphonates, calcitonin, and denosumab in acute Charcot neuroarthropathy remains uncertain. We generally do not use these therapies, given the lack of conclusive proof of benefit [25]. Such agents might be of benefit in a selected group of patients, such as individuals with severe pain unresponsive to other, better-established therapies, and some experts advocate their use more broadly. Further studies are needed.
Studies of antiresorptive agents, including bisphosphonates, have usually been of short duration, and contained no data on long-term efficacy and radiological resolution. While studies show reduction in bone turnover markers, immobilization time was increased in one study [42]. There is evidence in some, but not all studies that pain may be reduced [43]. If used, the treatment should be considered as an adjunct to and not as a substitute for offloading the affected limb. Bisphosphonate treatment has not been approved by regulatory agencies for use in this condition, and any decision to use this treatment should carefully consider the circumstances of the individual patient. Bisphosphonates have been used in some studies as part of acute therapy. In limited studies, pamidronate, but not zoledronic acid, has been beneficial, and the oral agent alendronate has also shown some benefit [42,44-46]. Calcitonin has also been evaluated in a small number of patients and may be useful in patients for whom bisphosphonates are contraindicated due to renal impairment. Further data are required before its use can be recommended.
•Bisphosphonates – In a series of six diabetic patients with the swollen, uncomfortable, hot foot of active Charcot arthropathy, all six showed marked improvement after pamidronate infusion, with three patients maintaining remission for over one year [44]. Subsequently, 39 such patients were randomly assigned to receive either pamidronate (a single intravenous infusion of 90 mg) or placebo. In addition, all patients received standard foot care with reduced weightbearing on the affected foot. Symptomatic improvement (eg, in patient-reported pain and discomfort) was significantly greater in the pamidronate group over 12 months of observation [45]. Skin temperature fell in both groups by 3.6 and 3.3 degrees Fahrenheit respectively, an insignificant intergroup difference. By contrast, a trial involving 39 patients with neuropathic arthropathy randomly assigned to either zoledronic acid infusions (4 mg monthly for three months) or to placebo found no benefit with drug therapy; the patients receiving zoledronate required a longer immobilization time before clinical resolution than did controls [42].
Oral bisphosphonates may also potentially be useful. In a randomized trial of 20 patients, patients received alendronate (70 mg once weekly) or placebo; both groups were also treated with total contact cast boots followed by use of a pneumatic walker [46]. After six months, the alendronate-treated group had decreases in pain and in a marker of bone turnover (urine C-terminal telopeptide of type I collagen) and had increases in bone mineralization in the foot as assessed by dual-emission radiograph absorptiometry, which were significantly better than those of the placebo group.
A web-based survey of 288 patients with acute Charcot neuroarthropathy of the foot treated in the United Kingdom found that 25.4 percent received intravenous and 19.4 percent received oral bisphosphonates. The median time to resolution in those receiving bisphosphonates was longer than in those who did not receive them (12 versus 10 months, p = 0.005). It is possible, however, that those with more severe disease had been selected to receive bisphosphonates [34].
•Calcitonin – Intranasal calcitonin has also been tried in acute Charcot arthropathy, but clinical benefit remains to be proven, and we do not use this therapy. In a randomized trial involving 32 patients, there was a significant reduction in urinary excretion of carboxyl (COOH)-terminal telopeptide of collagen and bone alkaline phosphatase in the treated group, suggesting decreased bone turnover compared with controls [47]. Both groups were also treated with standard offloading by removable contact cast or cast walkers. However there was no difference in clinical outcome as measured by skin temperature difference between groups. Calcitonin treatment might be useful in patients with both Charcot arthropathy and renal insufficiency (28 percent of their group) who have been unresponsive to other therapies and in whom bisphosphonates are contraindicated [47].
•Denosumab – The progress of 11 patients with diabetic (Charcot) neuroarthropathy receiving a single injection of denosumab was compared with that of 11 historical controls, 5 of whom had received alendronate. Controls were not well matched for sex and type of diabetes. Time to resolution of radiograph changes and cessation of total contact casting was shorter in the denosumab group [48].
Joint disorganization and surgical correction — Patients with chronic disease and joint injury who do not respond adequately to other interventions should be referred for consultation with an orthopedic surgeon with experience in the management of diabetic neuropathic arthropathy to assess the individual risks and benefits of a surgical stabilization or other procedures. The goal of treatment in patients with more chronic disease and joint injury is to maintain a stable plantigrade foot that is free of ulceration and infection; however, this can be difficult to achieve, even with good podiatry and with the use of specialized footwear and orthoses. Surgical correction is best avoided in most patients. However, in carefully selected cases, surgery can give acceptable alignment, thereby preserving soft tissue integrity and viability and avoiding amputation [49].
Surgery tends to be considered in Stage 3 when acute inflammatory changes have subsided, although it may be considered sooner in ankle Charcot neuroarthropathy, which can be difficult to treat conservatively [25,50]. Surgical procedures include removal of exostoses to relieve bony pressure, Achilles tendon lengthening to reduce forefoot pressure and improve alignment of the ankle and hindfoot to midfoot and forefoot, and arthrodesis to improve pain and instability [25]. The decision as to whether or not to perform surgery is complex and patient comorbidities, compliance with non-weightbearing, the location of the deformity, and the presence of pain, instability, and infection must all be considered. The presence of ulceration is associated with a worse prognosis. In one retrospective series of 245 patients with Charcot neuroarthropathy, treated surgically and nonsurgically by a foot and ankle surgeon at a tertiary center, the presence of a Charcot-related foot wound at presentation was associated with a sixfold risk of amputation [51]. The presence of peripheral arterial disease also gives a twofold risk of delayed healing and a fourfold risk of major amputation [52]. Consultation with a foot and ankle surgeon experienced in the treatment of these patients is essential.
Skeletal deformity resulting from nonunion of a fracture in a neuropathic foot can also be corrected by surgery, but this procedure has a relatively high failure rate of up to 27 percent [53]. Failure in one study occurred mainly in patients who had persistent ulceration associated with an uncorrectable skeletal deformity at the time of operation; as a result, surgery should be postponed until skin ulcers have healed. Even after successful surgery, orthotic devices are often still required.
Achilles tendon or gastrocnemius muscle lengthening has been successful in decreasing forefoot pressure to allow ulcer healing in selected diabetic patients with ankle equinus and forefoot ulcers, including some patients with midfoot neuroarthropathy [54]. Patients with hindfoot neuroarthropathy were excluded from this study, and some cases of heel ulceration were seen in response to the surgical treatment.
PROGNOSIS — The prognosis depends upon the rapidity of recognition and treatment of the diabetic (Charcot) neuroarthropathy [25,35]. Early presentation and confirmation of the diagnosis, with rapid offloading of the foot, are the most important factors in ensuring a good outcome. In patients who present later in disease, joint disorganization is often severe and irreversible. This may result in foot ulceration, with secondary infection leading to the risk of amputation.
Data are limited regarding whether bisphosphonate treatment improves the long-term outcome, and the available evidence is mixed (see 'Acute and subacute disease' above). Charcot neuroarthropathy of the hindfoot and ankle may require a longer period of immobilization than midfoot neuroarthropathy and has a worse prognosis. Lifetime surveillance is required to look for signs of recurrent or new Charcot episodes and to monitor for other diabetic foot complications. Charcot neuroarthropathy can have a significant negative impact on self-reported quality of life in patients with diabetes [55], and, in people of working age, job loss is common [41].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)
SUMMARY AND RECOMMENDATIONS
●Diabetes is the most common cause of neuropathic (Charcot) arthropathy in the western world. The pathogenesis of this condition is uncertain, but it is probably due to a combination of mechanical, neuropathic and vascular factors (algorithm 1). A major hypothesis is that lack of proprioception secondary to peripheral neuropathy may result in ligamentous laxity, increased range of joint movement, instability, and damage by minor trauma, to which the relatively insensitive neuropathic foot is prone. (See 'Introduction' above and 'Pathogenesis' above.)
●Diabetic neuropathic joint disease most commonly affects the joints of the foot and ankle, although the clinical presentation may vary. It typically affects patients with longstanding diabetes and peripheral neuropathy, affecting patients with both type 1 and type 2 diabetes. Patients may present with recent onset of unilateral warmth, redness, and edema over foot or ankle, often with a history of minor trauma, and occasionally recurrent acute attacks may occur. Bilateral involvement sometimes occurs. The majority of patients experience some pain, but the severity is typically less than might be expected from the findings. Rather than acute disease, some patients experience a slowly progressing arthropathy with insidious swelling over months or years.
Deformities are common and can transfer weightbearing to areas that tolerate it poorly and or that may lack sensation. Ulceration and infection commonly ensue. Collapse of the arch of the midfoot can lead to bony prominences on the plantar aspect with later pressure ulceration (picture 1). (See 'Clinical features' above.)
●Clinicians should have a high index of suspicion for this condition when a diabetic patient presents with a swollen foot. Diagnostic evaluation is aimed at confirming the diagnosis by identification of characteristic clinical and radiographic findings and by the exclusion of other conditions, including infection, which could be confused with neuropathic arthropathy. In patients with a joint effusion, we perform synovial fluid analysis to help rule out other conditions, including septic or crystalline arthropathy. Radiographic findings are variable, depending upon the stage and site of the arthropathy. Magnetic resonance imaging (MRI) may be helpful in some patients, but use of contrast is relatively contraindicated in patients with moderate or greater renal impairment. (See 'Diagnosis' above.)
●Important considerations in the differential diagnosis of diabetic neuroarthropathy include septic arthritis, cellulitis, gout, calcium pyrophosphate arthropathy, osteoarthritis, idiopathic inflammatory diseases, osteomyelitis, and complex regional pain syndrome. (See 'Differential diagnosis' above and 'Infections' above and 'Noninfectious disorders' above.)
●Treatment should be individualized and carried out by a multidisciplinary team with experience in this condition, including medical experts in joint disease and diabetes and specialists in foot and ankle surgery and podiatry. Physical therapy expertise may also be helpful with mobility and walking aids. In the acute active stage of diabetic neuroarthropathy, offloading the foot is the most important intervention, and is typically carried out by use of a non-removable, total contact cast. Alternative approaches include the use of crutches or a wheelchair.
The avoidance of weightbearing on the affected joint should be advised until resolution of edema and erythema occurs, with improvement of radiologic signs and reduction of temperature of the affected foot; patients may then progress to protected weightbearing with use of orthotics and other assistive devices. Treatment with a bisphosphonate may be an adjunct to therapy in selected patients but should not be considered as a substitute for offloading the affected limb. (See 'Acute and subacute disease' above.)
●The goal of treatment in patients with more chronic disease and joint injury is to maintain a stable plantigrade foot that is free of ulceration and infection. In patients in whom this cannot be achieved by good podiatry and the use of specialized footwear and orthoses, referral should be made for evaluation by an orthopedic foot and ankle surgeon with experience in this condition.
Surgical correction is best avoided in most patients but may be undertaken in selected patients. Surgical correction of skeletal deformity following nonunion of a fracture in a neuropathic foot has a relatively high failure rate, mainly in patients who have active ulceration relating to the deformity at the time of operation; thus, surgery should be postponed until the ulcers have healed. (See 'Joint disorganization and surgical correction' above.)
●The prognosis depends upon the rapidity of recognition and treatment. Early presentation and confirmation of the diagnosis of diabetic neuroarthropathy, with rapid offloading of the foot, are the most important factors in ensuring a good outcome. Disease of the hindfoot and ankle appears to have a worse prognosis than disease of the midfoot. In patients who present later in disease, joint disorganization is often severe and irreversible. (See 'Prognosis' above.)
