Diabetic neuroarthropathy

INTRODUCTION — In patients with diabetes mellitus, the loss of sensation in a joint may lead to 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 idiopathic neuropathy and syringomyelia, although diabetes is the most common cause of neuropathic (Charcot) arthropathy in the western world. Other names for diabetic neuroarthropathy include Charcot arthropathy and diabetic osteoarthropathy.

Diabetic neuroarthropathy will be reviewed here. 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. These conditions 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 is likely 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].

The neuropathic joint likely develops in two phases: an initial resorptive phase followed by a hypertrophic repair phase [5]. The initial resorptive phase is induced by proinflammatory cytokines, which are produced in response to joint damage.

●Resorptive phase

•Diabetic peripheral neuropathy predisposes to joint damage – Peripheral neuropathy is associated with loss of proprioception and autonomic neuropathy.

-Loss of proprioception – Loss of proprioception may lead to minor trauma that damages the joint. This joint damage increases the range of joint movement, leading to joint instability and ligament laxity. The resulting changes to joint architecture also changes the mechanical axis of the foot, which makes the patient susceptible to further joint damage.

-Autonomic neuropathy – Autonomic neuropathy may result in vasomotor changes and the formation of arteriovenous shunts. These, in turn, reduce skin and bone blood flow, despite normal foot pulses in these patients. The reduction in blood flow impedes the ability to repair the damaged joints.

•Joint damage induces pro-inflammatory cytokines – Trauma to the neuropathic foot may trigger an exaggerated local inflammatory response, mediated by proinflammatory cytokines (eg, tumor necrosis factor [TNF], interleukin 1 [IL-1] beta, and IL-6), resulting in the osteoarthropathy [4,6]. These cytokines may induce enhanced osteoclastic activity, which has been seen in surgical specimens from patients with neuroarthropathy [7].

Other laboratory studies suggest that both receptor activator of nuclear factor (NF) kappa B ligand (RANKL)-dependent and -independent pathways may be involved in the increased bone resorption seen in this condition [8].

●Hypertrophic repair phase – During the hypertrophic repair phase, the damaged joint is replaced with abnormal bone and cartilage, which often results in ankylosis. The altered anatomy of the joint places stress on the plantar fascia and surrounding tendons, predisposing the joint to additional damage [9].

EPIDEMIOLOGY AND RISK FACTORS

●Prevalence – Diabetic neuroarthropathy is uncommon among the general diabetic population. The prevalence of diabetic neuroarthropathy in a study of 205,033 patients with diabetes was 0.04 percent [10].

●Incidence – The annual incidence of diabetic neuroarthropathy ranges from 0.12 to 0.3 percent [11,12]. However, the incidence of diabetic neuroarthropathy is difficult to determine accurately, as reports are often from specialty centers that treat more severe cases of diabetes, and diagnostic criteria for diabetic neuroarthropathy vary between series [11-14].

●Risk factors

•Pancreas/kidney transplant – A high prevalence of diabetic neuroarthropathy (12 percent) has been reported in patients following simultaneous pancreatic and kidney transplantation, a group characterized by severe and longstanding diabetes [14].

A retrospective study of 487 patients with diabetes who underwent solid organ transplant found a greater incidence of diabetic neuroarthropathy in patients who had undergone kidney-pancreas transplant compared with those who had kidney 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 [15].

•Obesity – Obesity was found to be a risk factor for diabetic neuroarthropathy in a population of veterans with diabetes [12].

•Type 1 diabetes – Patients with type 1 diabetes may present with diabetic neuroarthropathy at a younger age than patients with type 2 diabetes. In a series of 85 patients presenting to a diabetic foot clinic with acute diabetic neuroarthropathy, type 1 diabetics presented more frequently in their fifth decade, with an average duration of diabetes of 24 ± 8.4 years, while patients with type 2 diabetes tended to present in their sixth decade, with a mean duration of diabetes of 13 ± 8.1 years [13].

CLINICAL FEATURES

Time course — Diabetic neuroarthropathy generally presents acutely. However, some patients present over months or years, with a slowly progressing arthropathy associated with insidious swelling. Other patients may not be diagnosed until they have developed radiographic damage characteristic of chronic disease. (See 'Plain radiographs and classification' below.)

History and physical findings

Acute attack — An acute attack of diabetic neuroarthropathy may present as a red, hot, swollen foot, possibly following minor trauma. However, acute attacks may also be more subtle and may be associated with minimal symptoms.

●Common symptoms and signs – The clinical manifestations are variable, but patients classically present with unilateral warmth, redness, and edema over the foot or ankle [16]. The affected foot may be several degrees warmer than the contralateral foot. The erythema may resolve with elevation of the affected extremity.

Pain is variable but typically not prominent. Although pain is present in 76 percent of patients, it is generally less than might be expected from the clinical and radiologic appearance of the affected joint [17]. Some patients present with minimal pain.

Diabetic neuroarthropathy often presents without a wound or ulceration.

●Joint distribution

•Foot and ankle is most common – The most frequently involved joints in the patients with diabetes are the tarsometatarsal joints, followed by the hindfoot joints, metatarsophalangeal joints, and the ankle [3,18].

•Involvement of other joints is uncommon – Although unusual, involvement of upper-limb joints can also occur [19]. In one report, upper-extremity involvement occurred in the hand and wrist in three patients with diabetes who had received or were receiving treatment for diabetic neuroarthropathy [20]; 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 diabetic neuroarthropathy of the foot [21].

●Recurrence – Recurrent attacks are uncommon. In one series, only 10 percent of patients experienced recurrent attacks in the same foot, and in approximately 20 percent of patients attacks of diabetic neuroarthropathy occurred in the contralateral foot. Simultaneous bilateral attacks were rare [11]. In this series, there was a median of two years between attacks in the contralateral foot.

Chronic arthropathy — In patients who present later in their disease course, following resolution of acute changes, joint damage and disorganization can be severe and irreversible. Deformities are common and can result in transfer of weightbearing to areas that tolerate it poorly and/or that may lack sensation. Ulceration and infection commonly ensue.

Chronic untreated diabetic neuroarthropathy is characterized by deformity and collapse of the affected joints. Common deformities seen are the “rocker bottom foot” caused by collapse of the arch of the midfoot, with resulting prominence of bones on the plantar aspect potentially leading to pressure ulceration (picture 1), medial convexity deformity caused by medial displacement of the talonavicular joint, and tarsometatarsal dislocation [3].

Laboratory findings — In patients with diabetic neuroarthropathy uncomplicated by infection, the white blood cell count and acute phase reactants may be normal or mildly elevated.

In a study of 36 patients who presented with acute diabetic neuroarthropathy, the median erythrocyte sedimentation rate (ESR) was 21 mm/h and the median C-reactive protein (CRP) was 5.8 mg/L [22]. (See 'Excluding alternate diagnoses' below.)

Synovial fluid is not typically obtained. However, if available, it should be sterile, with few white blood cells, no crystals or organisms on microscopy, and no growth on culture.

IMAGING — Radiographic finding are variable, depending upon the stage and site of the arthropathy.

Plain radiographs and classification — We obtain a weightbearing radiograph when evaluating for diabetic neuroarthropathy, although initial radiographs may be normal. (See 'Evaluation' below.)

Radiograph findings can vary by stage of disease, as classified by the modified Eichenholtz system for diabetic neuroarthropathy [23]. The stages are:

●Stage 0: Early or inflammatory – In early acute disease, plain radiographs may be normal or nonspecific, showing only soft tissue swelling, loss of joint space, or osteopenia [16]. These findings are often best appreciated on a weightbearing plain radiograph, but a normal plain radiograph does not exclude early acute diabetic neuroarthropathy.

Clinically, this stage is characterized by localized swelling, erythema, and warmth.

●Stage 1: Development – Plain radiographs show bony changes such as fracture, subluxation/dislocation, and bony debris.

Clinically, this stage is characterized by increasing swelling, erythema, and warmth.

●Stage 2: Coalescence – Plain radiographs show osseous fragmentation, sclerosis, new bone formation, subluxation, and dislocation, most commonly seen in the midfoot and hindfoot (image 1A-C) [1,19]. In the forefoot, bone resorption can result in osteolysis of phalanges and a variety of further changes, including partial or complete disappearance of the metatarsal heads or “pencil-pointing” of phalangeal and metatarsal shafts.

Clinically, this stage is characterized by a reduction in inflammatory signs.

●Stage 3: Remodeling – Plain radiographs may show mature fracture callus and decreased sclerosis.

Clinically, this stage is characterized by resolution of the redness, warmth, and swelling, and the presence of bony deformities of the affected joints.

Magnetic resonance imaging — Magnetic resonance imaging (MRI) is generally used to evaluate for potential complications or alternative diagnoses. However, certain MRI findings are suggestive of the diabetic neuroarthropathy and may be useful if the diagnosis cannot be confirmed with plain radiographs alone. The use of contrast is not always necessary but may help to distinguish diabetic neuroarthropathy from osteomyelitis.

●Non-contrast MRI – We suggest a prompt non-contrast MRI to confirm an early diagnosis of diabetic neuroarthropathy when the clinician cannot confidently differentiate diabetic neuroarthropathy from cellulitis or inflammatory arthritis based on history and physical examination.

A non-contrast MRI in stage 0 diabetic neuroarthropathy (ie, early disease, plain radiographs are normal or show nonspecific changes) typically demonstrates subchondral bone marrow edema with or without microfracture [24]. A normal MRI in this situation makes a diagnosis of acute diabetic neuroarthropathy unlikely. A non-contrast MRI may also identify mimics of diabetic neuroarthropathy (eg, stress fracture, torn ligaments, intraarticular fragmentation).

A non-contrast MRI in stage 1, 2, or 3 diabetic neuropathy reflects the findings demonstrated on plain radiographs. (See 'Plain radiographs and classification' above.)

●Contrast MRI – We suggest a contrast MRI when the clinician is trying to distinguish diabetic neuroarthropathy from osteomyelitis. These diagnoses may be indistinguishable on non-contrast MRI [5,25]. However, because of the risk of developing nephrogenic systemic fibrosis, use of gadolinium-containing contrast agents should be avoided in patients with diminished kidney function. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease", section on 'Assessment of kidney function prior to gadolinium exposure'.)

In a retrospective study of 128 neuropathic joints (42 with concomitant osteomyelitis), the presence of one or more of the following features on contrast-enhanced MRI favored a diagnosis of osteomyelitis [26]:

•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 [26].

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".)

Other imaging modalities

●Ultrasound – Further work is needed to study the value of ultrasound in diagnosing diabetic neuroarthropathy and differentiating this diagnosis from other arthropathies.

A pilot study of 26 patients with modified Eichenholtz stage 0 Charcot diabetic neuroarthropathy (confirmed on MRI) showed synovitis, effusion, and high Doppler signal 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 [27].

●Positron emission tomography – Further study of positron emission tomography (PET) scanning is needed to determine the sensitivity and specificity of this imaging modality as a test to distinguish diabetic neuroarthropathy from osteomyelitis [28].

PET is sometimes used as an alternative to MRI, particularly when the presence of metal precludes MRI [29-31]. However, in the presence of regional or diffuse ischemic changes, MRI is more useful at identifying features indicative of alternate diagnoses.

●Bone scintigraphy and tagged white blood cell scan – In patients in whom MRI is unable to distinguish between infection and diabetic neuroarthropathy, bone scintigraphy and labelled white blood cell scanning can be more specific than MRI but should always be correlated with clinical findings [29].

●Computed tomography – Computed tomography (CT) is not recommended as the primary diagnostic modality since MRI is more useful. Unlike CT, MRI can demonstrate an altered bone marrow signal characteristic of acute diabetic neuroarthropathy. Additionally, CT is less reliable at differentiating osteomyelitis from diabetic neuroarthropathy [24].

DIAGNOSIS

Acute diabetic neuroarthropathy

Clinical diagnosis — Acute diabetic neuroarthropathy (ie, Eichenholz stage 0) is a clinical diagnosis based on the presence of two factors:

●Diabetic neuropathy

●A unilateral warm, swollen, erythematous foot without alternate explanation (see 'Evaluation' below)

In whom to suspect — Acute diabetic neuroarthropathy should be suspected in any patient with diabetic neuropathy who presents with a unilateral, warm, swollen, erythematous foot.

A high index of clinical suspicion is important to diagnose diabetic neuroarthropathy early. A delay in diagnosis is very common and can result in progression of diabetic neuroarthropathy and an increased risk of complications [32]. Without treatment, progression can be rapid, and irreversible damage can occur within six months or less [33].

A retrospective series of 27 patients with acute diabetic neuroarthropathy found misdiagnosis in 63 percent and a median delay in diagnosis of two months (interquartile range [IQR] one to six months) [34].

Evaluation — For all patients, we suggest a careful physical examination and the following laboratory tests:

●Complete blood count (CBC) with a white blood cell differential

●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)

When a joint effusion is present, arthrocentesis with synovial fluid analysis should be performed to rule out alternative diagnoses. For small joints, especially those with disrupted architecture, joint aspiration may require imaging guidance (eg, by ultrasound, fluoroscopy, or CT). Testing should include a Gram stain, cultures, cell count, white blood cell differential count, and crystal analysis. (See "Synovial fluid analysis", section on 'Routine components of synovial fluid analysis'.)

We also suggest obtaining a weightbearing radiograph of the affected joint. However, since radiographs cannot be used to exclude a diagnosis of acute diabetic neuroarthropathy, a normal radiograph should not delay the diagnosis and management. A baseline plain radiograph serves mainly to facilitate longitudinal evaluation of disease progression, not to establish an initial diagnosis. (See 'Plain radiographs and classification' above.)

Excluding alternate diagnoses — Acute diabetic neuroarthropathy is a clinical diagnosis. The goal of the evaluation is to identify characteristic features of acute diabetic neuroarthropathy and to recognize any atypical features that might suggest an alternate diagnosis. Features suggestive of alternate diagnoses include the following:

●Symmetry – Acute diabetic neuroarthropathy generally presents unilaterally. Bilateral joint involvement should suggest the possibility of inflammatory polyarthritis, such as rheumatoid arthritis, or crystalline arthritis, such as gout or pseudogout.

●Pain – Pain and tenderness to palpation are typically limited in acute diabetic neuroarthropathy. Significant pain and tenderness is more consistent with a crystalline arthritis, cellulitis, or complex regional pain syndrome.

●Joint effusion – Acute diabetic neuropathy is generally not associated with the development of a significant joint effusion. When present, joint fluid should be aspirated. (See 'Differential diagnosis' below.)

●Acute phase reactant elevation – A highly elevated ESR or CRP is more indicative of an inflammatory disorder, such as an inflammatory arthritis (eg, crystalline or rheumatoid arthritis) or infection (eg, septic arthritis, osteomyelitis); however, mild elevations in acute phase reactants can be seen in acute diabetic neuropathy and do not exclude the diagnosis of diabetic neuroarthropathy. (See 'Laboratory findings' above.)

●Leukocytosis – Leukocytosis may indicate the presence of an inflammatory disorder such as inflammatory arthritis or infection. An increased number of immature white blood cells (ie, “left shift”) is more consistent with infection.

When these features do not clearly exclude alternate diagnoses, we suggest additional imaging, preferably MRI (see 'Magnetic resonance imaging' above). When MRI is not feasible, alternate imaging modalities (eg, ultrasound, positron emission tomography [PET], bone scintigraphy, tagged white blood cell scan) may be useful to exclude alternative diagnoses and establish a diagnosis of acute diabetic neuropathy. (See 'Other imaging modalities' above and 'Differential diagnosis' below.)

However, additional imaging is unnecessary when a diagnosis of acute diabetic neuroarthropathy can be established on clinical grounds.

Chronic diabetic neuroarthropathy

●Diagnosis – Chronic diabetic neuroarthropathy (ie, Eichenholz stages 1 to 3) is diagnosed in a patient with a prior history of acute diabetic neuroarthropathy who has radiologic evidence of joint damage consistent with this diagnosis (eg, subluxation, bony debris, osteolysis, osseous fragmentation, sclerosis, new bone formation). (See 'Plain radiographs and classification' above.)

●In whom to suspect – We consider the diagnosis of chronic diabetic neuroarthropathy in any patient with diabetes who presents with pain or ulceration of the foot or ankle, even in the absence of signs or symptoms of an acute attack.

●Evaluation – A plain radiograph is adequate to establish a diagnosis of chronic (but not acute) diabetic neuroarthropathy.

The radiologic characteristics of chronic diabetic neuroarthropathy are described in detail elsewhere. (See 'Imaging' above.)

Differential diagnosis — Diabetes mellitus is a common condition that may be complicated by other diseases of the bones and joints. Furthermore, multiple causes of joint pain can affect patients with and without diabetes.

Physical findings during the early stages of diabetic neuroarthropathy often can be mistaken for those of cellulitis, osteomyelitis, septic arthritis, gout, osteoarthritis, and inflammatory arthritis. (See 'History and physical findings' above and 'Imaging' above.)

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".)

Particularly important diagnoses to consider include the following:

Infections

●Septic arthritis – Patients with either diabetic neuroarthropathy or septic arthritis may present with a warm and swollen ankle. (See 'Noninfectious disorders' below.)

Infection is a particular concern in patients with skin ulceration. In a patient with diabetic neuropathy, bacterial septic arthritis may be characterized by less pain and greater range of motion than in the absence of neuropathy.

Although most patients with septic arthritis are febrile, neither the absence of fever nor a normal peripheral white blood cell count excludes septic arthritis. Joint aspiration with analysis and culture of synovial fluid is necessary to investigate the possibility of joint infection. (See "Septic arthritis in adults", section on 'Diagnosis'.)

●Osteomyelitis – Symptoms of pain and tenderness, along with local signs of inflammation, such as warmth, erythema, and swelling, may be present in both osteomyelitis and diabetic neuroarthropathy [35].

Osteomyelitis should be suspected when skin ulcers are present, especially those that are deep to bone or can be probed to bone, or those of more than one to two weeks’ duration. However, although ulcers can also occur in diabetic neuroarthropathy, osteomyelitis may also coexist with diabetic neuroarthropathy.

In one web-based series of 288 patients with acute diabetic neuroarthropathy, 35 percent of patients had coexistent foot ulceration and one-fifth of these also had osteomyelitis [36].

Although patients with diabetic neuroarthropathy alone often lack fever, leukocytosis, or elevated acute phase reactants, the absence of these findings does not by itself exclude osteomyelitis.

Plain radiography and non-contrast MRI may not distinguish between these conditions [35], and the diagnosis of osteomyelitis may require further investigation (eg, contrast MRI, bone biopsy, culture). (See 'Magnetic resonance imaging' 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 diabetic neuroarthropathy and cellulitis can also present as warmth, redness, and tenderness of the foot. However, cellulitis typically is accompanied by signs of systemic toxicity, leukocytosis, and elevated acute phase reactants. Cellulitis may occur 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

●Crystalline arthritis – Acute flares of gout and pseudogout typically occur in the foot and ankle and may be difficult to distinguish from diabetic neuroarthropathy based upon appearance alone.

Joint aspiration and synovial fluid analysis may demonstrate the presence of monosodium urate (gout) or calcium pyrophosphate (pseudogout) crystals. However, because the presence of crystals in synovial fluid does not exclude coexistent septic arthritis, the fluid should always be cultured. (See 'Infections' above.)

•Gout – 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 diabetic neuroarthropathy. Acute flares of gout are usually more painful, and the joints are more tender than those of diabetic neuroarthropathy. In the appropriate clinical setting (chronic kidney disease, 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. (See "Clinical manifestations and diagnosis of gout".)

•Pseudogout – 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".)

●Osteoarthritis – Osteoarthritis, like diabetic neuroarthropathy, 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.

Joint 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 diabetic neuroarthropathy.

Obvious inflammatory features, such as erythema or soft tissue swelling and tenderness, are also uncommon in uncomplicated osteoarthritis. In addition, in diabetic neuroarthropathy, but not in osteoarthritis, the temperature often differs by several degrees between the two feet. (See "Clinical manifestations and diagnosis of osteoarthritis".)

●Inflammatory (non-crystalline) arthritis – Various sterile inflammatory arthritides (eg, rheumatoid arthritis, psoriatic arthritis, reactive or postinfectious arthritis) are considered in the differential diagnosis of swollen and painful joints and may present initially with a single inflamed joint. These are usually distinguished by careful history and physical examination.

Isolated unilateral midfoot involvement is highly unusual in inflammatory arthritis. Diabetic 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 occurs rarely in patients with diabetes and is usually characterized by severe pain in a hand or foot following physical trauma.

It can be associated with reduced range of movement, hypersensitivity to touch, and vasomotor changes, with the affected hand or foot most often exhibiting warmth and swelling, but occasionally it is cool to the touch and later reveals trophic changes.

Complex regional pain syndrome can be distinguished from diabetic neuroarthropathy by the presence of hypersensitivity. Patients with complex regional pain syndrome typically report greater levels of pain than do patients with diabetic neuroarthropathy. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis".)

●Stress fracture – Stress fractures may also present with pain and swelling of the forefoot. However, stress fractures may be difficult to visualize on plain radiographs [16]. An uncomplicated stress fracture that is not apparent on a plain radiograph may be detected by MRI, nuclear scintigraphy, or serial plain radiographs.

TREATMENT

Treatment considerations — Due to a paucity of randomized trials and studies of sufficient size, our management approach is based largely upon case series, expert opinion, and clinical experience [23,29,37,38].

Multidisciplinary care team — 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 mellitus, a podiatrist, a physiatrist, a physical therapist, and an orthopedic surgeon. Whenever possible, the treating clinicians should have experience in the care of patients with diabetic neuroarthropathy.

Glucose control — Control of glucose should be optimized (as in all patients with diabetes mellitus), but there is no evidence that this alters the course of diabetic neuroarthropathy once it is present. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus".)

Offloading the affected foot — Management of diabetic neuroarthropathy is focused on strategies to avoid unprotected weightbearing on the affected foot. When selecting a strategy, it is important to consider each patient’s treatment individually, taking into account comorbidities, balance, mobility, and risk of falls.

Patients presenting with joint inflammation (stages 0 to 2)

Initial casting to achieve stability — For patients with diabetic neuropathy who present with edema, redness, and/or warmth of the affected joint (ie, from stage 0, the early or inflammatory stage, to stage 2, the coalescence stage), we suggest use of a total contact cast for offloading and immobilization, with or without an initial period of non-weightbearing immobilization [23,38].

Opinion varies as to whether non-removable or removable devices should be used, but the use of a non-removable, total-contact cast is favored by many experts [29,37,39]. We prefer the use of a total-contact cast because it affords full-time stabilization. Limited observational data suggest that total-contact casting may protect the foot more completely. As an example, in a retrospective study, total-contact casting and protected weightbearing was associated with a lower rate of foot ulceration than among patients who had refused casting and were treated with orthopedic footwear and unprotected weightbearing [40]. Additionally, some experts are concerned that prolonged three-point weightbearing, using crutches and the unaffected (but also neuropathic) foot, can lead to falls, new ulcerations, or overuse injuries to the contralateral foot and can also be difficult for the overweight patient.

Nevertheless, one international consensus document supports non-weightbearing using either crutches or a wheelchair [29], although this practice is falling out of favor.

Duration and management of casting — The cast must initially be changed every one to two weeks due to a decrease in edema over time.

Casting should be continued until redness and swelling have resolved, the difference in skin temperature has decreased to within 1 to 2 degrees of that of the unaffected foot, and radiographic signs (eg, resolving resorptive changes, resorption of osseous debris, and evidence of repair), if initially present, have improved. The time necessary to achieve this result varies. In one web-based observational study, the duration for needing non-removable casts ranged from 3 to 25 months (median 9 months), and that for removable casts ranged from 3 to 36 months (median 12 months) [36].

Short duration of casting with early weightbearing (ie, 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 [41].

Transition from casting — For a successful transition from casting to weightbearing, 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. (See "Evaluation of the diabetic foot".)

Transition to protected weightbearing should occur when erythema, swelling, and warmth have subsided. After the total contact cast has been removed, an offloading device should be selected, based on the amount of external support required to promote continued healing of the affected foot. Options for offloading devices are discussed below. (See 'Patients presenting after resolution of joint inflammation (stage 3)' below.)

Patients presenting after resolution of joint inflammation (stage 3) — For patients with diabetic neuropathy who present following resolution of edema, redness, and warmth (ie, stage 3, the remodeling stage), we suggest use of an offloading device. We also suggest use of an offloading device in patients with diabetic neuroarthropathy who have already been treated with a total-contact cast. (See 'Transition from casting' above.)

Patients who present with a cool, non-inflamed foot and stable radiologic damage (ie, late stage 3 disease) can be treated with bracing or orthotic support, without first using an offloading device, if the foot is plantigrade. If well-fitting footwear is not available, the patient may benefit from custom bracing or surgical treatment. (See 'Transition from casting' above and 'Surgery for treatment failure' below.)

Options for offloading devices include:

●Total-contact prosthetic walkers – These include the CROW for hindfoot involvement

●Removable cast walkers – These include a pneumatic walking brace/walking boot, or similar removable cast walkers that have a cushioned foot bed or insole [38]

The patient then progresses to using footwear with orthotic or bracing support after several months. The decision to move the patient into footwear should be supported by evidence of healing on plain radiographs or MRI. Collaboration with podiatric or orthopedic experts is particularly important at this stage, and physical therapy expertise may also be helpful with mobility and walking aids.

Patient education — Information and education is important. Poor adherence to treatment recommendations, particularly offloading, may affect outcomes negatively. One long-term retrospective study showed that patients with suboptimal adherence had a longer duration of their acute diabetic neuroarthropathy, and an increased risk of foot ulceration and amputation, compared with those with better adherence [42].

Care of the contralateral foot — Routine care for the contralateral foot, including the use of supportive footwear, is important. The contralateral foot must be monitored carefully for ulcers or diabetic neuroarthropathy. One series of 130 patients reported that 46 percent developed an ulcer in the foot not affected by diabetic neuroarthropathy [43]. Diabetic neuroarthropathy developed in the contralateral foot in 19 percent. These outcomes may have been related to overuse of the unaffected foot due to total contact casting and offloading of the affected foot.

Limited role for adjunctive inhibitors of bone turnover — We do not routinely use inhibitors of bone turnover (eg, bisphosphonates, calcitonin, and denosumab) given the lack of conclusive proof of benefit [29]. It may be reasonable to consider these agents in patients with severe pain unresponsive to more established therapies. However, treatment with these agents has not been approved by regulatory agencies for use in diabetic neuroarthropathy, and the decision to use these treatments should be individualized. Additionally, these medications should be used only as adjuncts to offloading, not in place of such interventions.

Small clinical trials of antiresorptive agents, including bisphosphonates, have shown reduction in bone turnover markers. However, these studies are generally of short duration and provide no data on long-term efficacy and resolution of radiographic changes. In one study, treatment with zolendronic acid was associated with a longer time to clinical resolution (27 versus 20 weeks of total immobilization time) [44]. There is evidence in some, but not all studies that pain may be reduced [45]. In limited studies, pamidronate, but not zoledronic acid, has been beneficial, and the oral agent alendronate has also shown some benefit [44,46-48].

We do not use calcitonin. However, some providers believe that it may be useful in patients for whom bisphosphonates are contraindicated due to kidney function impairment. (See "Pamidronate: Drug information" and "Alendronate: Drug information" and "Calcitonin: Drug information".)

Surgery for treatment failure

Selection of patients for surgery — Surgical correction is best avoided in most patients. However, in carefully selected cases, surgery can provide acceptable alignment, thereby preserving soft tissue integrity and viability and avoiding amputation [49]. Patients with chronic diabetic neuroarthropathy and joint injury who fail to achieve a stable, painless, plantigrade foot should be referred for consultation with an orthopedic surgeon with experience in the management of diabetic neuroarthropathy to assess the individual risks and benefits of a surgical stabilization or other procedures.

Surgery tends to be considered for patients after the acute inflammatory changes have subsided and bony deformities are evident (ie, stage 3 disease), although it may be considered earlier in the setting of skin compromise or in ankle and hindfoot diabetic neuroarthropathy, which can be difficult to treat conservatively [29,50].

However, the decision to perform surgery is complex and is best made in consultation with a provider who has extensive experience with this diagnosis. Patient comorbidities limiting adherence to non-weightbearing (eg, ulceration, peripheral arterial disease) predict poor surgical outcomes.

Ulceration at the time of surgery and peripheral arterial disease are associated with poor surgical outcomes. In one retrospective series of 245 patients with diabetic neuroarthropathy who were treated by a foot and ankle surgeon at a tertiary center, 72 percent were treated surgically, and the presence of a diabetic neuroarthropathy-related foot wound at presentation was associated with a sixfold risk of amputation [51]. Peripheral arterial disease is associated with a twofold higher risk of delayed healing and a fourfold risk of major amputation [52].

Surgical options — Surgical procedures include:

●Removal of exostoses (prominent bone) to relieve bony pressure.

●Arthrodesis to improve pain and instability.

●Achilles tendon or gastrocnemius muscle lengthening to reduce forefoot pressure and improve alignment of the ankle and foot. These procedures may promote ulcer healing in selected patients with diabetes mellitus, ankle equinus, and forefoot ulcers, including some patients with midfoot diabetic neuroarthropathy [53].

●Amputation is typically reserved for patients with severe deformity, non-healing or recurrent ulceration, or chronic osteomyelitis. Good candidates for amputation include patients with severe involvement, poor healing potential, and difficulty maintaining prolonged protected weightbearing as well as those who require a faster return to activity.

MONITORING — Once a patient with diabetic neuroarthropathy demonstrates evidence of sclerosis, new bone formation, subluxation, or dislocation (ie, stage 2 or stage 3), the deformity is typically stable. Monitoring past that point must be tailored to the individual patient and the presence or absence of complications (eg, ulceration). In general, the patient may resume routine footcare, with a low threshold to return for reevaluation if the patient develops erythema, ulceration, or other findings concerning for relapse.

PROGNOSIS — Prognosis depends upon the rapidity of recognition and treatment of the diabetic neuroarthropathy [29,37]. 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 the course of disease, joint destruction and disorganization is often severe and irreversible. This may result in foot ulceration, with secondary infection, increasing the risk of amputation.

Diabetic neuroarthropathy can have a significant negative impact on self-reported quality of life in patients with diabetes [54], and, in people of working age, job loss is common [42].

Diabetic neuroarthropathy affecting the ankle and hindfoot is often more unstable and may require a longer period of immobilization than midfoot diabetic neuroarthropathy. Ankle/hindfoot diabetic neuroarthropathy is associated with a poor prognosis and is often difficult to treat nonsurgically.

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

●Prevalence and risk factors – Diabetic neuroarthropathy is uncommon and has been reported in approximately 0.04 percent of patients with diabetes. Risk factors for diabetic neuroarthropathy include simultaneous pancreatic and kidney transplantation, obesity, and type 1 diabetes. (See 'Epidemiology and risk factors' above.)

●Clinical features – Patients may present with the recent onset of unilateral warmth, redness, and edema over a foot or ankle, often following minor trauma. Most patients experience some pain, but typically of lesser severity than that which might be expected from the findings.

Patients eventually develop a chronic arthropathy, associated with collapse of the arch of the midfoot. This collapse creates bony prominences on the plantar aspect of the foot, which can lead to pressure ulcers (picture 1). (See 'Clinical features' above.)

●Evaluation of acute diabetic neuropathy – Acute diabetic neuroarthropathy is a clinical diagnosis. We diagnose acute diabetic neuroarthropathy in a patient with diabetic neuropathy who presents with a unilateral warm, swollen, erythematous foot that lacks an alternate explanation. (See 'Evaluation' above.)

The diagnostic evaluation is aimed at confirming the diagnosis by identifying characteristic clinical findings and excluding other conditions, including infection, which could be confused with diabetic neuroarthropathy. (See 'Excluding alternate diagnoses' above.)

In patients with a joint effusion, the joint should be aspirated and synovial fluid should be analyzed and cultured to exclude other conditions, including septic or crystalline arthropathy. (See 'Evaluation' above.)

A normal radiograph does not exclude a diagnosis of acute diabetic neuroarthropathy. However, MRI may be helpful to exclude other diagnoses that are difficult to confirm clinically and thus confirm the diagnosis clinically. (See 'Imaging' above.)

●Evaluation of chronic diabetic neuroarthropathy – Chronic diabetic neuroarthropathy is diagnosed in a patient with a prior history of acute diabetic neuroarthropathy who exhibits radiographic evidence of joint damage consistent with this diagnosis (eg, subluxation, bony debris, osteolysis, osseous fragmentation, sclerosis, new bone formation). The diagnosis is established based on history and the presence of typical changes on plain radiographs. (See 'Chronic diabetic neuroarthropathy' above.)

●Differential Diagnosis – Important considerations in the differential diagnosis of diabetic neuroarthropathy include septic arthritis, osteomyelitis, cellulitis, gout, pseudogout, osteoarthritis, inflammatory arthritis such as rheumatoid arthritis, osteomyelitis, complex regional pain syndrome, and stress fracture. (See 'Differential diagnosis' above.)

●Treatment of acute and chronic diabetic neuroarthropathy – 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 podiatry and foot and ankle surgery. Physical therapy expertise is also helpful with mobility and walking aids. (See 'Treatment' above.)

•Patients presenting with joint inflammation – For patients with diabetic neuroarthropathy who present with joint edema, swelling, or warmth (ie, stages 0 to 2), we suggest a non-removable, total-contact cast to offload the involved foot (Grade 2C). We also educate patients on the importance of offloading, and we monitor the contralateral foot for evidence of diabetic neuroarthropathy. (See 'Initial casting to achieve stability' above and 'Care of the contralateral foot' above.)

We continue casting until edema, erythema, and temperature of the affected foot have lessened. Patients may then progress to protected weightbearing with use of orthotics and other assistive devices. (See 'Duration and management of casting' above and 'Transition from casting' above.)

•Patients presenting following resolution of joint inflammation – For patients with diabetic neuroarthropathy who present following resolution of joint edema, swelling, or warmth (ie, stage 3), we suggest using an offloading device (eg, total-contact prosthetic walker, removable cast walker) instead of a total-contact cast.

For patients with diabetic neuroarthropathy who have a cool, non-inflamed foot and stable radiologic damage, we suggest treatment with bracing or orthotic support if the foot is plantigrade. If well-fitting footwear is not available, the patient may benefit from custom bracing or surgical treatment. (See 'Offloading the affected foot' above.)

•Inhibitors of bone turnover – We suggest not routinely using inhibitors of bone turnover (Grade 2C) given the lack of supportive data, but these may be reasonable to consider as an adjunctive therapy for patients with severe pain despite offloading. (See 'Limited role for adjunctive inhibitors of bone turnover' above.)

●Surgical options for treatment failure – Surgical correction is best avoided in most patients but may be undertaken in selected patients with instability, bony prominence or a non-plantigrade foot. Possible interventions include removal of exostoses, arthrodesis, Achilles tendon or gastrocnemius muscle lengthening, and amputation. (See 'Surgery for treatment failure' above.)

●Prognosis – 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 to ensure a good outcome. Disease involving the hindfoot and ankle appears to have a worse prognosis than disease involving the midfoot. In patients who present late in the disease course, joint disorganization is often severe and irreversible. (See 'Prognosis' above.)