Charcot osteoarthropathy in diabetes: A brief review with an emphasis on clinical practice

Abstract

Charcot osteoarthropathy (COA) is a potentially limbthreatening condition that mainly affects diabetic patients with neuropathy. In everyday practice, it presents as a red, hot, swollen foot, usually painless, and is frequently triggered by trivial injury. Its etiology is traditionally attributed to impairment of either the autonomic nervous system, leading to increased blood flow and bone resorption, or of the peripheral nervous system, whereby loss of pain and protective sensation render the foot susceptible to repeated injury. More recently, excessive local inflammation is thought to play a decisive role. Diagnosis is based on clinical manifestation and imaging studies (plain X-rays, bone scan, Magnetic Resonance Imaging). The mainstay of management is immediate off-loading, while surgery is usually reserved for chronic cases with irreversible deformities and/or joint instability. The aim of this review is to provide an overview of COA in terms of pathogenesis, classification and clinical presentation, diagnosis and treatment, with an emphasis on the high suspicion required by clinicians for timely recognition to avoid further complications.

Key Words: Charcot osteoarthropathy; Diabetes mellitus; Diabetic neuropathy; Diabetic foot

INTRODUCTION

In diabetes, Charcot osteoarthropathy (COA) is a specific manifestation of neuropathy. It is named after Jean-Martin Charcot, who first described it in 1868. Although the arthropathy described by Charcot was associated with tabes dorsalis, the most common cause of COA today is diabetic neuropathy[1]. Less common causes include leprosy, poliomyelitis, syringomyelia, alcohol abuse, traumatic injury, heavy metal poisoning, multiple sclerosis, congenital neuropathy and rheumatoid arthritis[2-4].

COA is a potentially limb-threatening condition which, beyond the emotional and social burden of physical dysfunction[5], has been associated with increased mortality[6,7]. Given the rising prevalence of diabetes, a high index of suspicion is required from both diabetic patients (especially those with neuropathy) and their physicians for the early diagnosis and treatment to prevent major complications[3,8]. The aim of this review is to provide an overview of COA in terms of pathogenesis, classification and clinical presentation, diagnosis and treatment.

EPIDEMIOLOGY

Although COA is a well established complication of diabetes mellitus recognized by specialists, it is not easily diagnosed by non-specialists[9], particularly in its early stages. Therefore, its true prevalence and incidence are unknown but it is estimated to affect 0.8%-8% of diabetic populations[10,11]. This frequency increases up to 10% of diabetic patients with neuropathy when radiographic findings are used[12,13]. Although prospective studies are limited, incidence rates ranging from 3 to 11.7/1000 patients per year have been reported[3,14].

Importantly, the incidence of COA is reported to be increasing[10]. This increase is attributable to both improved diagnosis with the use of the new imaging modalities and decreased rates of hospital admission, fewer amputations and increasing number of diabetic patients with foot ulcers being treated as outpatients with early mobilization[10,15].

Patients with COA are usually in their fifth and sixth decades of life, 80% of them having had diabetes for at least 10 years[16]. Bilateral COA has been reported as present in 9% of patients with acute COA[17]. However, in another study, when feet were prospectively examined by computerized tomography, bilateral changes of neuroarthropathy were found in 75% of patients[18].

The prevalence of COA does not differ between men and women, but differences have been reported between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). In the former, COA presents during their fifth decade of life, while the latter develop this condition during their sixth decade (42 ± 10.2 vs 59 ± 7.8 years, P < 0.001)[19]. Moreover, longer diabetes duration has been reported among T1DM patients as compared to T2DM patients (24 ± 8.4 vs 13 ± 8.1 years, P < 0.001)[19]. Interestingly, peripheral arterial disease seems to protect patients from developing COA[10]. This is probably due to limited inflammatory response as a result of ischemia[3].

PATHOGENESIS

The neurovascular and neurotraumatic theories have classically been proposed to explain the pathogenesis of COA. However, recent evidence suggests that a combination of the two theories is likely to provide the most accurate explanation for disease pathogenesis[1,4,14].

Neurovascular theory (French theory)

Mitchell and Charcot proposed increased blood supply to bone as the principal etiological factor. Increased blood flow mainly occurs through arteriovenous shunting, which is a manifestation of autonomic neuropathy (hence the term neurovascular). Increased blood flow could lead to bone resorption and mechanical weakening, ultimately resulting in fractures and deformity[1,20]. At the same time, increased blood flow becomes clinically manifest as a warm foot with dilated veins[1,20].

Neurotraumatic theory (German theory)

Volkman and Virchow suggested that peripheral neuropathy leading to loss of protective sensation may render the foot susceptible to injury from either repeated or acute trauma[1,10]. Pathology worsens with continued weight-bearing (hence the term neurotraumatic)[1,20]. Thus, fractures might ensue and, in the case of continued activity, patients could end up with severe deformities[1,10].

Additional potentially contributory factors:

Bone pathology: Reduced bone density in the lower limbs has been observed in patients with COA. Such patients appear to exhibit increased osteoclastic activity[21], predisposing to fracture even after minimal trauma[22].

Atypical neuropathy: It could, possibly, explain why not every neuropathic patient invariably develops COA[23]. A specific form of neuropathy with preservation of light touch and hot sensation but loss of cold sensation has been reported. However, these findings have never been replicated.

Non-enzymatic collagen glycation: It could contribute to Achilles tendon shortening and also render joints prone to abnormal pressure distribution, resulting in deformity and Charcot foot[24].

Increased plantar pressures: In comparison to diabetic patients without COA, increased plantar pressures were found in those developing COA, leading to excessive mechanical stress on the forefoot, which is, in turn, transmitted to the Lisfranc region[10].

Excessive local inflammation: The most recent view focuses on the presence of excessive and uncontrollable local inflammatory response to trauma[25-28]. Patients with COA are believed to harbor a grossly increased inflammatory response with excess production of pro-inflammatory cytokines (Tumor necrosis factor alpha, TNF-α; Interleukin 1beta, IL-1β)[25-28]. These, in turn, lead to elevation of RANKL (receptor activator of nuclear factor kappa B ligand), thereby activating NF-κΒ (Nuclear factor κΒ). The latter is a potent promoter of osteoclastic activity[25-28]. Hence, the predilection of COA for joints held together with ligaments, notably the Lisfranc and Chopart joints, may be accounted for by the inflammatory infiltration of these ligaments. In the same context, temperature elevation in acute COA provides further evidence of excess inflammation[25-28].

In a combined interpretation of the pathogenesis of COA, this condition is rare because there are several prerequisite factors. Autonomic neuropathy with increased blood flow to bones and peripheral neuropathy with loss of protective sensation may be, to a variable degree, combined. The condition may be triggered by trauma and, importantly, there may be an excessive inflammatory response to the latter[2,14,29].

Predisposing factors for the development of COA include pronounced peripheral and autonomic neuropathy, normal circulation, osteopenia in T1DM but not in T2DM[30], trauma (often minor, including foot deformities, joint infections or surgery)[14] and renal impairment, with a medical history of renal transplantation being associated with a high risk for Charcot osteoarthropathy[31]. Trauma has been reported in 22-53% of cases and may require a very detailed medical history to be disclosed[13].

ANATOMICAL CLASSIFICATION

COA can be classified into five different patterns according to the involvement of several foot joints (Table 1)[32]. It almost exclusively affects the foot and ankle, other locations being extremely rare[33,34]. (1) Pattern I (15%) involves the forefoot, i.e. the metatarsophalangeal (MTP) and interphalangeal (IP) joints; (2) Pattern II (40%) involves the tarso-metatarsal (TMT) (Lisfranc’s) joints; (3) Pattern III (30%) involves the naviculocuneiform, talonavicular and calcaneocuboid joints; (4) Pattern IV (10%) involves ankle and subtalar joints; and (5) Pattern V (5%) involves the calcaneum[10].

Table 1 Anatomical classification of charcot osteoarthropathy.

Anatomical classification of charcot osteoarthropathy
Pattern	Foot joints involved
I	Metatarsophalangeal and interphalangeal joints
II	Tarso-metatarsal (Lisfranc’s) joints
III	Naviculocuneiform, talonavicular and calcaneocuboid joints
IV	Ankle and subtalar joints
V	Calcaneum

According to another classification system[35], COA can be divided into: (1) forefoot COA involving the IP and MTP joints; (2) midfoot COA involving the TMT and tarsal joints; and (3) hindfoot COA, including lesions of the ankle joint and calcaneum. The midfoot (particularly pattern II) is the most commonly affected area (60%)[10].

Anatomical classifications could be clinically important as they have been reported to predict outcomes. For example, forefoot COA seems to have a better prognosis than hindfoot arthropathy, since lesions of the calcaneum may have detrimental effects on weight distribution during walking[10].

CLINICAL PRESENTATION

COA arthropathy can present either as an acute or a chronic condition but sometimes these two phases seem to overlap[9,10].

Acute COA

The acute phase is usually characterized by the presence of a warm, red, edematous foot and ankle, usually the midfoot[10]. The affected foot is usually painless. Even when pain is reported, it is less than might be anticipated based on the physical findings[1,14]. Skin temperature is elevated by 2-6°C in comparison to the contralateral foot[1,36]. Hyperemia may persist for months or years[9], but in some cases the acute phase rapidly progresses to the chronic one, sometimes in less than 6 months, resulting in irreversible deformity[10].

Chronic COA

Temperature elevation and redness gradually subside, while permanent deformities may develop[9,10]. Typically, the latter include arch collapse with rocker bottom deformity and medial convexity[9,10]. As a result, pressures during standing and walking are redistributed so that areas of deformity develop high pressure and become prone to ulceration. Finally, ulcerated areas may become infected and infection may spread to the bone, leading to osteomyelitis[9,10].

Natural course

COA is usually of a self-limiting nature. Nonetheless, it may induce localized osteoporosis in the affected foot[37]. Long-term complications such as deformity, ulceration and osteomyelitis[1] may now be preventable thanks to an improved early diagnosis. COA practically never re-activates but may later affect the contralateral foot[1,9]. Of note, current evidence confirms that long-term survival of patients with acute COA is diminished even after successful treatment. The reduced survival is generally attributable to morbidity associated with distal symmetrical neuropathy[6,7].

THE COURSE OF COA: EICHENHOLTZ STAGES

Progression of COA from onset to consolidation runs through three stages, as described by Eichenholtz (Table 2)[38]. Progression from one stage to the other may last from weeks or months to several years, although sometimes the process is arrested in the early stages[1,38].

Table 2 The course of charcot osteoarthropathy according to the clinical presentation of the foot: modified Eichenholtz classifica.

The course of Charcot osteoarthropathy: Eichenholtz stages
Stage	Clinical presentation
0: Patients at risk for COA	Diabetic neuropathy and an acute sprain or fracture
I: Development-Fragmentation	Erythema, edema and increased warmth, usually absence of pain
II: Coalescence	Diminution of erythema, edema and warmth; Decreased joint mobility
III: Reconstruction-Consolidation	Erythema, edema and warmth are no longer present; Ulcers at sites of residual deformity

COA: charcot osteoarthropathy.

Stage I: Development-fragmentation

The foot is red, hot and swollen. Initial radiographs may be normal. However, if the foot is not immobilized, radiographic findings such as bony debris at joints, fragmentation of subchondral bone, subluxation and dislocation can subsequently develop[39].

Stage II: Coalescence

Erythema, warmth and swelling are decreased in this stage and radiography findings include absorption of fine debris, formation of new bone, coalescence of larger fragments and sclerosis of bone ends. This results in decreased joint mobility and increased stabilization[38,39].

Stage III: Reconstruction-consolidation

Clinically, edema, erythema and warmth are not present, unless fractures have not healed. Ulcers may develop at sites of residual deformity, while X-rays reveal bony remodeling, rounding of bone ends and decreased sclerosis[38,39].

Furthermore, a “prodromal” stage 0 or “pre-stage I” has been described. This stage includes diabetic patients with neuropathy who have an acute sprain or fracture and are, therefore, at high risk of acute COA[1,40].

DIAGNOSIS

Diagnosis of COA is based on medical history and clinical examination, radiographic features, bone scintigraphy and magnetic resonance imaging (MRI).

Clinical presentation

Diagnosis of COA is primarily based on clinical presentation, as described above[1,3]. A red, hot, swollen, usually painless foot in patients with diabetic neuropathy should prompt the diagnosis of COA until proven otherwise[3]. Temperature elevation usually over 2°C in comparison to the contralateral foot is clinically demonstrable[1,3]. Mild antecedent trauma makes the diagnosis more likely, but it may not be recalled by the patient[41].

Radiographic features

Plain radiographs may initially be negative, for a few days up to three weeks, and the only finding in acute COA may be soft tissue swelling[1,3,42]. However, as the disease progresses, radiographic features appear. These can be divided into atrophic (bony resorption and little fragmentation) or hypertrophic (bony proliferation and destruction of joints, fragmentation and new bone formation)[1]. Osteophytes, subchondral sclerosis and narrowing of joint spaces are often seen in radiographs[42]. Specifically, radiographic features of the forefoot include demineralization, bone destruction and periosteal reaction, making the differential diagnosis from uncomplicated osteomyelitis difficult[42,43]. Furthermore, “pencil and cup” deformity at the MTP joints or fragmentation of the metatarsal heads can also occur[10,43]. In the midfoot, Lisfranc fracture or dislocation develops with bony fragmentation of the TMT joints and collapse of the longitudinal arch[10,43]. These changes in X-rays may occur very rapidly (within a few weeks)[10,43]. Finally, in the hindfoot, talocalcaneal dislocation with talar collapse and atypical calcaneal fractures may occur[10].

Bone scintigraphy

Bone scintigraphy is very sensitive but not specific enough for the diagnosis of COA. The three-phase technetium-99m methylene diphosphonate bone scan is positive in all phases[10]. Thus, differential diagnosis from osteomyelitis is difficult as increased bone turnover characterizes both entities[1,44]. Neither are indium-111-labeled leukocyte scans specific, given that labeled leukocytes may be found in both infected and non-infected joints[44]. It has been suggested that the combination of technetium-99m methylene diphosphonate scintigraphy with indium-111-labeled leukocyte scintigraphy may improve sensitivity (93-100%) and specificity (almost 80%) in the differential diagnosis from osteomyelitis[1,10,44-46].

Magnetic resonance imaging

MRI is being increasingly used for the diagnosis of COA due to its diagnostic accuracy[47], especially in the early stages when radiographic findings are absent[1,48]. Acute COA is characterized by reduced signal intensity on T1 sequence and increased signal intensity on T2 sequence[42,47,48]. Chronic COA is characterized by diffusely diminished marrow signal intensity and cyst formation. MRI is valuable both for the differential diagnosis from osteomyelitis and for the detection of superimposed osteomyelitis on pre-existing COA[10,42].

DIFFERENTIAL DIAGNOSIS

Acute COA needs to be differentiated from other conditions that cause pain and swelling, notably cellulitis, trauma or sprain, acute gout, deep vein thrombosis and osteomyelitis[49]. Accurate diagnosis is not always easy and can be a considerable clinical challenge. It is important to exclude infection, i.e. cellulitis or osteomyelitis. This is usually ruled out when there is no presence or history of foot ulceration[10,39]. Furthermore, in order to distinguish whether the redness appearing in acute COA is due to infection or to COA, a simple method could be used: keeping the affected leg elevated, a decrease in erythema suggests COA[42]. Positive systemic signs of infection like fever, leukocytosis, elevated C-reactive protein or erythrocyte sedimentation rate levels are more likely to be found in infection than COA, but some overlap exists[42,50]. As a rule of thumb though, patients with acute COA only exhibit local signs of inflammation (increased skin temperature) without systemic signs and symptoms[50].

Imaging techniques are helpful in the differential diagnosis of COA. Plain X-rays are normal in acute COA[3] as opposed to typical changes seen in gouty and rheumatoid arthritis[1]. Nevertheless, plain X-rays are not reliable in order to differentiate COA from osteomyelitis[10]. Instead, nuclear modalities (phase technetium-99m methylene diphosphonate and indium-111-labeled leukocyte scintigraphy) may be required[6].

MRI may be also used in differentiating acute COA from osteomyelitis. The former is characterized by periarticular and subchondral marrow edema[47], whereas the latter exhibits bone marrow typically affecting a single bone with diffuse marrow involvement. Furthermore, COA affects several joints while osteomyelitis mostly occurs in weight-bearing surfaces of the toes, metatarsal heads or calcaneum[51].

TREATMENT

Treatment of COA depends on many factors including clinical stage, location of involvement, degree of deformity and patient comorbidities. The mainstay of treatment is off-loading, while surgery is usually reserved for chronic cases with joint instability or severe deformity[3,39,42].

Non-surgical treatment

Off-loading is essential when acute COA is suspected, even if not proven, in order to prevent disease progression and foot deformity[3,39,42]. In stage I, non weight-bearing of the affected limb allows healing of joint fractures. The gold standard of off-loading is the total contact cast (TCC)[3,39,42]. It is made of stockinette, low-density foam, elastic plaster and fiberglass, with a rocker bottom sole created by layering standard plaster on the bottom of the cast from the heel to an area just proximal to the metatarsal heads, facilitating movement[52]. The TCC is usually necessary for 2 to 4 mo[1,42] until resolution of fragmentation on radiographs is seen and normal skin temperature is observed. The TCC should be checked regularly as edema might decrease and the cast might become loose[52]. A disadvantage of the TCC is that it requires specialized personnel to construct and fit it[52]. A more practical alternative is the Aircast walker, a bivalved cast, lined with four air cells and inflated by a hand pump to ensure a close fit[52]. For maximal reduction of weight-bearing, patients may, additionally, use crutches, wheelchairs and Zimmer frames[1,13]. Immobilization may last from 3 mo to over a year when the hindfoot and ankle are affected[42]. Afterwards, the cast might be removed and replaced by a protective bracing combined with the use of appropriate footwear. The latter must be designed to relieve high-pressure areas, ensure joint stability and accommodate any pre-existing deformity, so that gradual weight bearing on the affected foot will not pose any risk of ulceration or COA re-activation[13].

In stage II, when swelling has been controlled, the Charcot Restraint Orthotic Walker (CROW) is preferred. CROW is a total contact ankle-foot orthosis which resembles to TCC but is removable. However, in stage III, use of suitable therapeutic shoes with rigid shank and rocker bottom sole to minimize instability is recommended[1,13,42].

Protection of the contralateral extremity, although practically difficult, should not be neglected because contralateral fracture may occur in almost 80% of cases[1,42].

Additional pharmacological treatment: As osteopenia is observed in COA, bisphosphonates have been used to inhibit osteoclast activity[13,53]. Short-term results are promising but these agents are not yet recommended for routine use[13,53]. Similarly, use of calcitonin and non-steroidal anti-inflammatory drugs has been reported as adjunct treatment to conventional therapy[10,42,53,54]. Recently, new anti-inflammatory therapeutic agents such as corticosteroids, TNF-α antagonists (infliximab, etanercept) and RANK-L antagonists (denosumab) have been proposed, but further research is needed[28].

Surgical treatment

Surgical treatment should be considered in chronic cases with joint instability or severe deformity failing a conservative approach[1,13,39]. Surgical interventions include:

Exostectomy: When a patient with stable COA develops a bony prominence leading to recurrent skin ulceration and infection. It is a common off-loading surgical procedure performed to simply remove the bony prominence which is held responsible for the ulcer[39]. After exostectomy, a protective bracing and antibiotics are used[39,55].

Achilles tendon lengthening: When there is contracture of the Achilles tendon leading to abnormal plantar pressure distribution[39,55].

Arthrodesis: When the deformity cannot be appropriately treated with bracing[39,55].

Internal fixation techniques (single or staged procedure) are used and should be followed by non-weight-bearing, which continues until radiographic evidence of bony consolidation (from 6 wk up to 3 mo)[39] and bracing for a long time[42,56]. Complications include deep wound infection, recurrent ulceration, unstable non-union or mal-union, fracture and hardware failure[1,39]. External fixation (single-stage procedure) can also be used, especially when underlying osteomyelitis is present. Recurrence of ulceration has been rarely reported[57,58].

Amputation: Regrettably, this may be inevitable when surgery has failed due to recurrent ulceration/infection or unstable arthrodesis. It has been reported that 2.7% of Charcot deformities annually lead to amputation[59].

SIX PRACTICAL POINTS FOR CLINICIANS

Increased clinician alertness is required for the early detection and management of COA and the following points are of practical importance[3,60]: (1) COA should always be suspected in every diabetic patient with peripheral neuropathy who presents with a red, hot, swollen foot. The virtual absence of pain and the diffuse redness may help differentiate this condition from cellulitis or deep venous thrombosis; (2) Even when the diagnosis is only suspected, immediate immobilization and off-loading is the wisest practice; (3) Initially, plain X-rays may be normal but this should not deter off-loading; (4) Education of both patients and physicians to increased early detection and diagnosis of COA will be helpful; (5) Ulceration or infection in the plantar aspect of the foot should be avoided; and (6) Surgical intervention may be required, mainly in chronic cases with joint instability or severe deformity.

CONCLUSION

In everyday practice, clinicians need to consider COA in every patient with diabetic neuropathy who presents with a red, hot, swollen, usually painless, foot[1,3,9,13]. Currently, diagnosis remains clinical but may be confirmed by appropriate imaging studies[1,3,9,13]. Prompt immobilization and off-loading are indispensible when COA is suspected and should be pursued until confirmation of diagnosis[1,3,9,10,13,29]. In cases of uncertainty or suspected osteomyelitis, antibiotics may be administered as well[1,3,9,13,29]. Surgery is usually reserved for chronic cases with severe deformity or joint instability. Finally, the importance of patient and physician awareness to enable prompt diagnosis cannot be emphasized enough in an endeavor to reduce the burden of foot complications[1,3,9,10,13,29].