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Review Article

Charcot Neuroarthropathy of the Foot and Ankle

van der Ven, Alexander MD, MBA; Chapman, Cary B. MD; Bowker, John H. MD

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Journal of the American Academy of Orthopaedic Surgeons: September 2009 - Volume 17 - Issue 9 - p 562-571
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Abstract

Charcot neuroarthropathy is a progressive, noninfectious, destructive disease of the bones and joints in persons with sensory neuropathy. It has been hypothesized that inadequate or delayed treatment may lead to instability and severe deformity, with secondary bony prominences and ulceration. Shoe wear modifications and accommodative orthoses may prevent ulceration over these prominences. Chronic ulceration may eventually occur, leading to soft-tissue and bone infections, sometimes resulting in amputation.

In the developed world, diabetic neuropathy is the most frequent cause of Charcot neuroarthropathy, with the foot and ankle the most commonly affected sites. Other conditions that may be implicated in the occurrence of Charcot neuroarthropathy in the foot and ankle include alcoholism, leprosy, tabes dorsalis, myelomeningocele, and congenital insensitivity to pain.1–7 After reviewing a series of patients with tertiary syphilis in 1868, Jean-Martin Charcot8 gave a detailed description of the condition that now bears his name. In 1936, Jordan9 described its occurrence in patients with diabetes mellitus.

The precise incidence of Charcot neuroarthropathy in persons with diabetes had been previously estimated to be between 0.1% and 0.4%,10,11 but a recent review of data from the Department of Veterans Affairs estimated the incidence in 2003 to be 0.12%.12 In a large retrospective review of 456 patients with diabetes, Charcot changes were noted radiographically in 1.4%.13 Older studies have found the incidence of diabetesrelated Charcot neuroarthropathy to be quite low,10,14 but more recent studies have noted higher rates,15 indicating either an actual increase in the incidence of Charcot neuroarthropathy or an increased awareness of this condition among physicians treating patients with diabetes.10,11,14,16

Etiology

The pathogenesis of Charcot neuroarthropathy is not well understood, and there is no unifying theory for the pathologic processes that cause Charcot neuroarthropathy. It is likely that multiple mechanisms are responsible.

The neurotraumatic theory suggests that Charcot neuroarthropathy is an exaggerated overuse injury in which insensate joints are subjected to either repetitive microtrauma or a single traumatic event that leads to typical Charcot changes. Abnormal sensation prevents the affected individual from adopting normal protective mechanisms, specifically offloading and activity modification, and from seeking medical attention. This theory has been supported by several studies using experimental animals with insensate limbs.17–19 Investigators denervated joints through division of the spinal cord or peripheral nerves and then subjected the animals to trauma or repetitive overuse.20 This experimental model often resulted in the changes seen in Charcot neuroarthropathy. However, reports of Charcot changes in nonweight-bearing joints, such as the shoulder, as well as in the hips of bedridden patients, have cast doubt on this theory as an explanation for the primary cause of Charcot neuroarthropathy.20

The neurovascular theory proposes that autonomic dysfunction leads to increased blood flow via arteriovenous shunting, resulting in bone resorption and weakening.21 Bone turnover markers have been found to be elevated in acute Charcot neuroarthropathy compared with controls, whereas bone formation markers have been found to be unchanged, indicating increased osteoclastic activity.22 Several studies also have shown an increase in bone resorption markers.23,24 Bone density analysis confirms the presence of osteopenia and indicates an increased risk for neuropathic fracture.25,26

More recent theories implicate the role of inflammatory cytokines such as tumor necrosis factor-α and interleukin-1 in the pathogenesis of Charcot neuroarthropathy. On the molecular level, these factors lead to increased expression of nuclear transcription factor-?B, which in turn stimulates osteoclast formation.27,28 In 2006, Baumhauer et al29 confirmed the increased presence of osteoclasts, tumor necrosis factor-α, and interleukin-1 through examination of pathologic specimens and immunohistologic staining of surgical specimens from patients with Charcot neuroarthropathy.

Clinical Presentation and Classification

Charcot neuroarthropathy has been associated with the advanced sequelae of diabetes, specifically, diabetic nephropathy, retinopathy, and obesity,12 and has been reported in recipients of solid organ transplantation.7,30–32 In persons with type 1 diabetes, Charcot neuroarthropathy most frequently presents in the fifth decade, after an average duration of diabetes of 20 to 24 years; in those with type 2 diabetes, Charcot neuroarthropathy typically presents in the sixth decade, after an average duration of diabetes of 5 to 9 years.33 In one series that evaluated patients with bilateral involvement, the median time of onset in the second foot was reported to be 2 years.16 Simultaneous bilateral involvement was rare, occurring in only 1 of 115 patients.

Acute Charcot neuroarthropathy manifests as a hot and swollen foot or ankle, with bounding distal pulses. A misconception is that the condition is typically painless; in fact, Brodsky34 found pain to be present in approximately one half of patients with Charcot neuroarthropathy. A careful history may reveal an unrecognized traumatic event. Clohisy and Thompson31 noted a 5-week delay in presentation from a recognized injury. Skin temperature of the affected leg has been found to be an average of 3.3°C higher than that of the unaffected extremity.35 The progression of Charcot neuroarthropathy most often follows a predictable clinical and radiographic pattern, and the widely recognized Eichenholtz classification continues to help guide the practitioner through the treatment process36 (Table 1).

Table 1
Table 1:
Modified Eichenholtz Classification for the Progression of Charcot Neuroarthropathy 36,37

Stage 0, although not initially described by Eichenholtz, refers to findings based on clinical examination alone with normal radiographs.37 The clinician may often suspect either deep infection or cellulitis, given the marked swelling and erythema. A simple method of distinguishing the dependent rubor of Charcot neuroarthropathy from infection involves elevating the leg and watching for a decrease in erythema.34 The practitioner must maintain a high index of suspicion during this phase so as to initiate early treatment, if appropriate, because doing so has been hypothesized to prevent catastrophic late deformity; however, the data supporting this have not been clearly defined.38

Stage I is the fragmentation phase; it is also called the dissolution phase. Plain radiographs demonstrate osteopenia, periarticular fragmentation, and subluxation or frank dislocation of joints. Clinically, the foot continues to be warm and edematous and may demonstrate increased ligamentous laxity.

The coalescence period, stage II, represents the early healing phase. Edema and warmth decrease. Absorption of debris, fusion of bony fragments, and early sclerosis of bone are evident on radiographs.

Stage III, reconstruction, is characterized by an absence of inflammation and a progression to a more stable, although often deformed, foot or ankle. Radiographically, osteophytes and subchondral sclerosis are often present, along with narrowing of joint spaces.36,39

In an effort to guide treatment, Brodsky34 identified a specific pattern of collapse occurring in Charcot neuroarthropathy based on anatomic location (Figures 1 and 2). Type 1 collapse occurs in the tarsometatarsal joint; this is the most common location of Charcot neuroarthropathy, accounting for approximately 60% of cases.1 Collapse often leads to a fixed rocker-bottom foot with valgus angulation. The patient with type 1 collapse also tends to develop bony exostosis, a risk factor for recurrent ulcerations. Type 2 collapse affects the subtalar and Chopart joints, either individually or together, and accounts for up to 10% of Charcot neuroarthropathy cases.1 This deformity is often unstable and may require periods of immobilization averaging 2 years.34 Type 3A collapse affects the ankle joint in 20% of cases. Late deformities include severe varus or valgus collapse, leading to recurrent ulceration and osteomyelitis over the malleoli. Type 3B deformities occur following fracture of the calcaneal tuberosity, with late deformity resulting in more distal foot changes or proximal migration of the tuberosity.3,24 The classification system was later modified by Trepman et al40 to include types 4 and 5 deformity. In type 4, a combination of areas is affected, either concurrently or sequentially, whereas type 5 deformity occurs solely within the forefoot.40

Figure 1
Figure 1:
AP (A) and lateral (B) drawings demonstrating Brodsky's anatomic classification of the Charcot foot. Type 1 involves the tarsometatarsal and naviculocuneiform joints. Type 2 involves the subtalar and/or the Chopart joint. Type 3A involves the ankle joint. Type 3B involves fracture of the posterior calcaneal tuberosity. (Reproduced with permission from Brodsky JW: The diabetic foot, in Coughlin MJ, Mann RA, Saltzman CL, eds: Surgery of the Foot and Ankle, ed 8. St. Louis, MO, Mosby, 2006, p 1341.)
Figure 2
Figure 2:
Lateral radiographs demonstrating the progression of Brodsky type 1 Charcot neuroarthropathy of the foot through the Eichenholtz stages. This patient developed rocker-bottom deformity. A, Stage 0 or early stage I, with no evidence of fragmentation or osteopenia. B, Late stage I, with fragmentation of bone around the Lisfranc joint (arrow). C, Stage II, bone debris begins to resorb and consolidate. D, Stage III, further consolidation and remodeling of fracture fragments, with increasing bony sclerosis.

Schon et al1 provided a classification system based on their experience with a cohort of 221 neuropathic fractures. With the Lisfranc pattern, breakdown initially occurs along the medial column, with late changes progressing to the lateral column. The arch abducts and prominences develop, leading to deformity, fullness, and ulceration. The naviculocuneiform pattern leads to collapse at the naviculocuneiform joint, with development of a lateral rocker-bottom deformity. The perinavicular pattern is caused by osteonecrosis or fracture of the navicular. The lateral arch height decreases, leading to a lateral rocker and shortening of the medial column. Eventually this breakdown progresses to the central aspect of the foot, with severe plantar flexion of the talus and eventual ulceration. The transverse tarsal pattern is caused by lateral subluxation of the navicular on the talus and abduction of the foot with a valgus calcaneus. Calcaneal pitch eventually decreases, and a central rocker develops at the calcaneocuboid joint. In late stages, the talus is completely dislocated from the navicular, and ulceration develops at the calcaneocuboid interval. All four patterns eventually progress to a rocker-bottom deformity and chronic ulceration.

Diagnostic Imaging

Clinical and radiographic signs of Charcot neuroarthropathy and osteomyelitis may overlap significantly, especially in the setting of an adjacent open wound. One challenge in managing Charcot neuroarthropathy is determining whether there is superimposed osteomyelitis. The presence or absence of systemic signs of infection, such as fever, leukocytosis, elevated inflammatory markers, and increased blood glucose or insulin requirement, may not always be a reliable indicator. An underlying ulcer, particularly one that probes to bone, will provide an important clue because deep infection without evidence of skin compromise is rare.

Although plain radiography has been shown to be only 50% specific in detecting osteomyelitis, it is an essential tool in detecting the characteristic deformities associated with Charcot neuroarthropathy.41 When superimposed osteomyelitis in the setting of Charcot neuroarthropathy is suspected, more detailed imaging may be needed. There is no definitive imaging test to distinguish Charcot neuroarthropathy from osteomyelitis. However, three-phase technetium Tc-99m methylene diphosphonate scintigraphy, followed by indium In111-labeled leukocyte scintigraphy, has been found to have a sensitivity of 93% to 100% and a specificity of approximately 80%.42–47 This combination allows for the detection and localization of osteomyelitis and enables the surgeon to distinguish it from adjacent soft-tissue infection. MRI has been found to be less specific than combined bone scintigraphy with tagged leukocytes; however, it may be useful in the detection of abscess.45

Management

Management is based on a variety of factors, including location, phase of the disease process, presence of infection, deformity, and comorbidities. Treatment should be guided by specific and realistic goals, depending on the severity of the disease and the patient's functional capacity. This can vary from basic shoe modifications to major limb amputation. Most treatments have been guided by level IV studies. Few randomized trials have been conducted.

Nonsurgical

Immobilization is the mainstay of treatment in the unstable phases of Charcot neuroarthropathy, and the total-contact cast is the most widely used and accessible modality for maintaining stability and decreasing swelling. The cast should encase the entire foot and ankle, with all major bony prominences padded with foam or felt. Frequent cast changes are critical in reducing complications because settling can lead to instability and ulceration within the cast. Cast changes accommodate reductions in swelling and avoid the problem of excessive padding.34 Total-contact casts have been found to reduce total loads on the foot by about one third of the normal load.39,46

Eichenholtz stage I Charcot neuroarthropathy traditionally has been treated with immobilization and non-weight bearing in a totalcontact cast.47 This stage is usually maintained until the practitioner believes that the involved joints will be able to sustain physiologic stresses. The actual duration depends on the progression of the disease rather than on a preset time frame, but in our experience, it can last for 2 to 4 months. Typical indicators are resolution of fragmentation on radiographs and normal skin temperature, indicating the absence of inflammation.34,39 Stage II is typically treated with a molded total-contact polypropylene ankle-foot orthosis (ie, Charcot restraint orthotic walker) or a bivalved ankle-foot orthosis.34,48 These orthoses allow for continued immobilization and weight bearing but are less restrictive than a total-contact cast. In stage III the patient can progress to an appropriate accommodative shoe and insole.34

Fracture of the contralateral limb was reported in 72% of patients in a high-risk population.31 Prophylactic immobilization of the unaffected limb was recommended to reduce the risk of contralateral fracture. Based on this finding as well as the lack of documented evidence to support a non-weight-bearing treatment plan, some investigators have suggested allowing weight bearing in the early stages of Charcot neuroarthropathy.47,49,50 Sinacore49 retrospectively reviewed outcomes following partial weight bearing. Although the results were comparable to those of a nonweight-bearing protocol, Sinacore demonstrated that adherence to a partial-weight-bearing program was poor, with only 28% compliance. Pinzur et al47 reported on 10 patients with stage I arthropathy of the midfoot who underwent biweekly total contact cast changes and were allowed full weight bearing. The average cast duration was 6 weeks, with progression to therapeutic footwear at 12 weeks. All patients in this group progressed to healing with a stable foot. A recent retrospective case series by de Souza50 demonstrated similar results.

Anatomic location also affects the treatment algorithm. Longer immobilization, ranging from 90 days to >1 year, is recommended when joints of the hindfoot and ankle are affected; midfoot joints typically require a less lengthy period of immobilization.34

Surgical

No comparative studies have been published regarding surgical choices for Charcot neuroarthropathy. The decision for surgical intervention is multifactorial and is typically influenced by patient comorbidities and compliance, deformity location and severity, and the presence of infection, pain, or instability.39

Exostectomy

When ulceration occurs following failed nonsurgical treatment, exostectomy of an ulcer-inciting bony prominence can be considered. Typically, these prominences are not newly formed bone but rather are tarsal bones that have shifted into a nonanatomic position, leading to chronic ulceration. Exostectomy followed by protective bracing and, if necessary, antibiotic therapy can lead to a good result. In two separate studies, limb-salvage rates reached 90% with this procedure,51,52 although revision surgery was required in 25% of one group.52 Exostectomy is usually most effective for Brodsky type 1 (ie, tarsometatarsal) deformity).51 Achilles tendon lengthening should be considered for the patient with concomitant recurrent plantar ulceration with equinus contracture.53

Arthrodesis

With more severe deformity, fusion may be the only option short of amputation.39 Procedure selection is dependent on the location of the arthropathy and surgeon preference. Timing of surgery has traditionally been reserved for Eichenholtz coalescence or reconstruction phases. However, Simon et al54 showed promising results with fusion during the fragmentation stage, with no major complications and a return to regular shoe wear in a mean of 27 weeks.

Effective internal fixation techniques include screw, pin, and plate fixation. These can be single or staged procedures, based on the presence of infection, and may require osteotomy with autograft.55,56 Tibiocalcaneal intramedullary devices offer an alternative for Brodsky type 2 and 3 deformities.57–59 With internal fixation, the average time to fusion is 11 to 22 weeks.54,59 Most fusion techniques require an extended course of rigid immobilization and no or minimal weight bearing for 3 months, which is typically followed by prolonged or permanent protective bracing.54,59,60

Most published series are small, with short to intermediate follow-up. Complication rates are high, reaching 69% in one series.60 Common complications are infection, both superficial and deep, hardware malposition requiring removal, recurrent ulceration, and fracture. Most studies have 1 to 4 years of follow-up, and postoperative amputation rates have been reported to range from zero to 10% during that time frame.55,58 Although bony union is desirable and is achievable in 36%61 to 100%59 of patients, a stable fibrous union may lead to an acceptable result with adequate bracing and follow-up.59,61 In contrast, failure to appropriately manage an unstable fibrous union or uncontrolled infection often leads to amputation.60

External fixation recently has gained popularity as a less invasive treatment of Charcot deformities. Potential advantages include singlestage treatment in the presence of osteomyelitis or ulceration, easy monitoring of soft-tissue healing, and the ability to protect somewhat against noncompliance with postoperative non-weight-bearing instruction. Indications include ulcers with underlying osteomyelitis, poor soft-tissue envelope, poor bone quality, and morbid obesity.62,63

Good results have been reported with external fixation techniques in patients who were not suited for internal fixation and who otherwise may have required amputation61,62,64–67 (Figure 3). Limb salvage rates were >90%, and new or recurrent ulceration was rare.62–64 Pin-tract infection was the most common complication. In the largest study, Cooper64 treated 83 patients with Charcot neuroarthropathy of the midfoot and hindfoot with static and dynamic ring external fixation. The average follow-up was 22 months, and the overall limb salvage rate was 96%. Three patients required amputation because of uncontrolled infection or unstable pseudarthrosis. There were two recurrent ulcers.

Figure 3
Figure 3:
Preoperative lateral hindfoot (A) and AP hindfoot (B) radiographs of a patient with Brodsky type 2 Charcot neuroarthropathy involving the subtalar and talonavicular joints as well as chronic ulceration and osteomyelitis. The patient was treated with a single-stage reconstruction procedure and circular ring external fixation. C, Intraoperative photograph demonstrating significant abduction deformity of the foot. D, Immediate postoperative photograph after correction of deformity and application of the circular external fixator. Standing lateral (E) and AP (F) radiographs of the foot at 12-month follow-up demonstrating correction of abduction deformity and bony union of the talonavicular joint.

Most recently, Pinzur62 reported the results of a neutrally applied ring external fixator for nonplantigrade midfoot Charcot neuroarthropathy. This simple neutralization frame was used on 26 Charcot feet in 26 patients after deformity correction through limited incisions and other adjuvant procedures, such as tendon lengthening. At a minimum 1-year follow-up, 24 patients were ulcer-free and ambulating in extradepth shoes with accommodative foot orthoses. One patient required a transtibial amputation for recurrent infection.

Amputation

Limb amputation has typically been reserved for failed previous surgery and has been performed because of unstable arthrodesis or recurrent ulceration or infection.55,57,60,64 In a retrospective review of multimodal management of patients with known Charcot deformities, Saltzman et al68 noted a 2.7% annual rate of amputation. We are not aware of any specific outcome study related to primary amputation for Charcot deformities. However, anecdotal accounts from some authors with significant experience treating patients with Charcot neuroarthropathy report satisfactory results.69 Given the lack of objective data, the surgeon must consider many factors when determining whether to perform primary amputation. These include but are not limited to the general health and functional status of the patient, who may not be able to tolerate a complex surgery or extended periods of non-weight bearing or who may be unlikely to ambulate even with a limb-salvage procedure.

Pharmacologic

Marked osteopenia has been noted in patients with Charcot neuroarthropathy, and several randomized pharmacologic trials have been undertaken in an attempt to identify a pharmacologic treatment. Bisphosphonates have shown promising short-term results in preventing bone resorption. Their mechanism is based on the promotion of osteoclast apoptosis and the inhibition of osteoclast activity.70

Jude et al71 randomized 39 patients with Charcot neuroarthropathy to receive either a single infusion of pamidronate 90 mg or placebo. Symptomatic relief remained significantly higher in the medicated group at 12 months compared with placebo (P < 0.001). At 6-week follow-up, those who received pamidronate showed a significant reduction in bone turnover markers (bonespecific alkaline phosphate, P < 0.03: deoxypyridinoline, P < 0.01). After 3 months, these differences were no longer significant, suggesting that interval doses may be necessary. Similarly, Pitocco et al72 randomized 20 patients to receive weekly oral alendronate or placebo for 6 months. Those receiving alendronate showed significant improvements in bone turnover markers (P < 0.05), bone mineral density (P < 0.05), and pain scale scores (P < 0.05).

Calcitonin has been similarly studied in relation to the Charcot neuroarthropathy process. Bem et al73 monitored 32 patients with acute Charcot neuroarthropathy over a 6-month period. A statistically significant decrease in bone turnover markers was noted in patients who received a daily dose of 200 IU intranasal calcitonin for the first 3 months of treatment (P < 0.05), but no statistical significance was evident by 6 months. No differences in skin temperature were found.

Treatment with pharmacologic agents remains theoretic, with most studies evaluating only secondary clinical markers. We cannot make any recommendations on appropriate dosages or duration of therapy.

Summary

Diabetes-related Charcot neuroarthropathy is a destructive process of the bones and joints; it is found most commonly in the feet of persons with advanced sensory neuropathy. Although Charcot neuroarthropathy is a relatively rare condition, evidence suggests that it is more common than previously thought. Without proper evaluation and prompt management, potentially devastating consequences, such as amputation, can occur.

A high index of suspicion is required in the patient with diabetes and neuropathy who has an acutely warm and swollen foot, particularly when radiographs appear to be normal. The cause is not precisely understood, but advances in understanding of Charcot neuroarthropathy on the molecular level may lead to breakthroughs in the medical treatment of this disease.

Most patients with Charcot neuroarthropathy can be treated with immobilization and protected weight bearing. Use of a total-contact cast is the preferred method of nonsurgical management. Progression to protective bracing or extra-depth shoes with accommodative orthoses is based on clinical and radiographic examination and may take many months to achieve. Surgical treatment is reserved for recurrent ulceration, unbraceable deformity, acute fracture or dislocation, and infection. Pharmacologic agents such as bisphosphonates have shown promise in their effect on secondary markers, but clinical efficacy has not been established.

References

Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, references 71 and 72 are level I studies. References 18 (animal), 21, 22, 35, 46, and 73 are level II studies. References 17 (animal), 23–26, 30, 33, 38, and 42–45 are level III studies. References 1–7, 9–15, 29, 31, 32, 37, 41, 47–63, and 65–68 are level IV studies. References 8, 20, 27, 28, 36, 64, 69, and 70 are level V expert opinion.

Citation numbers printed in bold type indicate references published within the past 5 years.

1. Schon LC, Easley ME, Weinfeld SB: Charcot neuroarthropathy of the foot and ankle. Clin Orthop Relat Res 1998; 349:116-131.
2. Shibuya N, La Fontaine J, Frania SJ: Alcohol-induced neuroarthropathy in the foot: A case series and review of literature. J Foot Ankle Surg 2008;47: 118-124.
3. Horibe S, Tada K, Nagano J: Neuroarthropathy of the foot in leprosy. J Bone Joint Surg Br 1988;70:481-485.’
4. Henderson VE: Joint affections in tabes dorsalis. J Pathol 1905;10:211-263.
5. Nagarkatti DG, Banta JV, Thomson JD: Charcot arthropathy in spina bifida. J Pediatr Orthop 2000;20:82-87.
6. Bar-On E, Weigl D, Parvari R, Katz K, Weitz R, Steinberg T: Congenital insensitivity to pain: Orthopaedic manifestations. J Bone Joint Surg Br 2002:84:252-257.
7. Matricali GA, Bammens B, Kuypers D, Flour M, Mathieu C: High rate of Charcot foot attacks early after simultaneous pancreas-kidney transplantation. Transplantation 2007; 83:245-246.
8. Charcot JM: Leçons sur les maladies du système nerveux, in Archives de Physiologie, 1868.
9. Jordan WR: Neuritic manifestations in diabetes mellitus. Arch Intern Med 1936; 57:307-366.
10. Sinha S, Munichoodappa CS, Kozak GP: Neuro-arthropathy (Charcot joints) in diabetes mellitus (clinical study of 101 cases). Medicine (Baltimore) 1972;51: 191-210.
11. Klenerman L: The Charcot joint in diabetes. Diabet Med 1996;13(suppl 1):S52-S54.
12. Stuck RM, Soh, MW, Budiman-Mak E, Lee TA, Weiss KB: Charcot arthropathy risk elevation in the obese diabetic population. Am J Med 2008;121:1008-1014.
13. Smith DG, Barnes BC, Sands AK, Boyko EJ, Ahroni JH: Prevalence of radiographic foot abnormalities in patients with diabetes. Foot Ankle Int 1997;18:342-346.
14. Bailey CC, Root HF: Neuropathic foot lesions in diabetes mellitus. N Engl J Med 1947;236:397-401.
15. Lavery LA, Armstrong DG, Wunderlich RP, Mohler MJ, Wendel CS, Lipsky BA: Risk ractors for foot infections in individuals with diabetes. Diabetes Care 2006;29:1288-1293.
16. Fabrin J, Larsen K, Holstein PE: Longterm follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care 2000;23:796-800.
17. Eloesser L: On the nature of neuropathic affections of the joints. Ann Surg 1917; 66:201-207.
18. O'Connor BL, Palmoski MJ, Brandt KD: Neurogenic acceleration of degenerative joint lesions. J Bone Joint Surg Am 1985; 67:562-572.
19. Salo PT, Theriault E, Wiley RG: Selective ablation of rat knee joint innervation with injected immunotoxin: A potential new model for the study of neuropathic arthritis. J Orthop Res 1997;15:622-628.
20. Johnson LC: In discussion of Williams LE, Bland JH, Lipson RL: Cervical spine subluxations and massive osteolysis in the upper extremities in rheumatoid arthritis. Arthritis Rheum 1966;9:348-359.
21. Edmonds ME, Roberts VC, Watkins PJ: Blood flow in the diabetic neuropathic foot. Diabetologia 1982;22:9-15.
22. Gough A, Abraha H, Li F, et al: Measurement markers of osteoclast and osteoblast activity in patients with acute and chronic diabetic Charcot neuroarthropathy. Diabet Med 1997;14: 527-531.
23. Edelson GW, Jensen KL, Kaczynski R: Identifying acute Charcot arthropathy through urinary crosslinked N-telopeptides. Diabetes 1996;45(suppl 2):108A.
24. Selby PL, Jude EB, Burgess J, et al: Bone turnover markers in acute Charcot neuroarthropathy. Diabetologia 1999; 41(suppl 1):A275.
25. Jirkovská A, Kasalický P, Boucek P, Hosová J, Skibová J: Calcaneal ultrasonometry in patients with Charcot osteoarthropathy and its relationship with densitometry in the lumbar spine and femoral neck and with markers of bone turnover. Diabet Med 2001;18: 495-500.
26. Young MJ, Marshall A, Adams JE, Selby PL, Boulton AJ: Osteopenia, neurological dysfunction, and the development of Charcot neuroarthropathy. Diabetes Care 1995; 18:34-38.
27. Jeffcoate WJ, Game F, Cavanagh PR: The role of proinflammatory cytokines in the cause of neuropathic osteoarthropathy (acute Charcot foot) in diabetes. Lancet 2005;366:2058-2061.
28. Jeffcoate WJ: Theories concerning the pathogenesis of the acute Charcot foot suggest future therapy. Curr Diab Rep 2005;5:430-435.
29. Baumhauer JF, O'Keefe RJ, Schon LC, Pinzur MS: Cytokine-induced osteoclastic bone resorption in charcot arthropathy: An immunohistochemical study. Foot Ankle Int 2006;27:797-800.
30. Gazis A, Pound N, Macfarlane R, Treece K, Game F, Jeffcoate W: Mortality in patients with diabetic neuropathic osteoarthropathy (Charcot foot). Diabet Med 2004;21:1243-1246.
31. Clohisy DR, Thompson RC Jr: Fractures associated with neuropathic arthropathy in adults who have juvenile-onset diabetes. J Bone Joint Surg Am 1998;70: 1192-1200.
32. Cofield RH, Morrison MJ, Beabout JW: Diabetic neuroarthropathy in the foot: Patient characteristics and patterns of radiographic change. Foot Ankle 1983;4: 15-22.
33. Petrova NL, Foster AV, Edmonds ME: Difference in presentation of charcot osteoarthropathy in type 1 compared with type 2 diabetes. Diabetes Care 2004;27:1235-1236.
34. Brodsky JW: The diabetic foot, in Coughlin MJ, Mann RA, Saltzman CL, eds: Surgery of the Foot and Ankle, ed 8. St. Louis, MO, Mosby, 2006, pp 1281-1368.
35. McGill M, Molyneaux L, Bolton T, Ioannou K, Uren R, Yue DK: Response of Charcot's arthropathy to contact casting: Assessment by quantitative techniques. Diabetologia 2000;43:481-484.
36. Eichenholtz S: Charcot Joints. Springfield, IL, Charles C. Thomas, 1966.
37. Shibata T, Tada K, Hashizume C: The results of arthrodesis in the ankle for leprotic neuroarthropathy. J Bone Joint Surg Am 1990;72:749-756.
38. Chantelau E: The perils of procrastination: Effects of early vs. delayed detection and treatment of incipient Charcot fracture. Diabet Med 2005;22:1707-1712.
39. Sanders LJ, Frykberg RG: The Charcot foot, in Bowker JH, Pfeifer MA, eds: Levin and O'Neal's The Diabetic Foot, ed 7. Philadelphia, PA, Mosby Elsevier, 2007, p 258.
40. Trepman E, Nihal A, Pinzur MS: Current concepts review: Charcot neuroarthropathy of the foot and ankle. Foot Ankle Int 2005;26:46-63.
41. Segall GM, Nino-Murcia M, Jacobs T, Chang K: The role of bone scan and radiography in the diagnostic evaluation of suspected pedal osteomyelitis. Clin Nucl Med 1989;14:255-260.
42. Crerand S, Dolan M, Laing P, Bird M, Smith ML, Klenerman L: Diagnosis of osteomyelitis in neuropathic foot ulcers. J Bone Joint Surg Br 1996;78:51-55.
43. Schauwecker DS, Park HM, Burt RW, Mock BH, Wellman HN: Combined bone scintigraphy and indium-111 leukocyte scans in neuropathic foot disease. J Nucl Med 1988;29:1651-1655.
44. Johnson JE, Kennedy EJ, Shereff MJ, Patel NC, Collier BD: Prospective study of bone, indium-111-labeled white blood cell, and gallium-67 scanning for the evaluation of osteomyelitis in the diabetic foot. Foot Ankle Int 1996;17: 10-16.
45. Lipman BT, Collier BD, Carrera GF, et al: Detection of osteomyelitis in the neuropathic foot: Nuclear medicine, MRI and conventional radiography. Clin Nucl Med 1998;23:77-82.
46. Shaw JE, Hsi WL, Ulbrecht JS, Norkitis A, Becker MB, Cavanagh PR: The mechanism of plantar unloading in total contact casts: Implications for design and clinical use. Foot Ankle Int 1997;18:809-817.
47. Pinzur MS, Lio T, Posner M: Treatment of Eichenholtz stage I Charcot foot arthropathy with a weightbearing total contact cast. Foot Ankle Int 2006;27: 324-329.
48. Morgan JM, Biehl WC III, Wagner FW Jr: Management of neuropathic arthropathy with the Charcot Restraint Orthotic Walker. Clin Orthop Relat Res 1993;296:58-63.
49. Sinacore DR: Acute Charcot arthropathy in patients with diabetes mellitus: Healing times by foot location. J Diabetes Complications 1998;12:287-293.
50. de Souza LJ: Charcot arthropathy and immobilzation in a weight-bearing total contact cast. J Bone Joint Surg Am 2008; 90:754-759.
51. Brodsky JW, Rouse AM: Exostectomy for symptomatic bony prominences in diabetic charcot feet. Clin Orthop Relat Res 1993;296:21-26.
52. Rosenblum BI, Giurini JM, Miller LB, Chzran JS, Habershaw GM: Neuropathic ulcerations plantar to the lateral column in patients with Charcot foot deformity: A flexible approach to limb salvage. J Foot Ankle Surg 1997;36: 360-363.
53. Armstrong DG, Stacpoole-Shea S, Nguyen H, Harkless LB: Lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot. J Bone Joint Surg Am 1999;81:535-538.
54. Simon SR, Tejwani SG, Wilson DL, Santner TJ, Denniston NL: Arthrodesis as an early alternative to nonoperative management of charcot arthropathy of the diabetic foot. J Bone Joint Surg Am 2000;82:939-950.
55. Stone NC, Daniels TR: Midfoot and hindfoot arthrodesis in diabetic Charcot arthropathy. Can J Surg 2000;43:449-455.
56. Hockenbury RT, Gruttadauria M, McKinney I: Use of implantable bone growth stimulation in Charcot ankle arthrodesis. Foot Ankle Int 2007;28: 971-976.
57. Caravaggi C, Cimmino M, Caruso S, Dalla Noce S: Intramedullary compression nail fixation for the treatment of severe Charcot deformity of the ankle and rear foot. J Foot Ankle Surg 2006;45:20-24.
58. Dalla Paola L, Volpe A, Varotto D, et al: Use of a retrograde nail for ankle arthrodesis in Charcot neuroarthropathy: A limb salvage procedure. Foot Ankle Int 2007;28:967-970.
59. Pinzur MS, Noonan T: Ankle arthrodesis with a retrograde femoral nail for Charcot ankle arthropathy. Foot Ankle Int 2005;26:545-549.
60. Papa J, Myerson M, Girard P: Salvage, with arthrodesis, in intractable diabetic neuropathic arthropathy of the foot and ankle. J Bone Joint Surg Am 1993;75: 1056-1066.
61. Farber DC, Juliano PJ, Cavanagh PR, Ulbrecht J, Caputo G: Single stage correction with external fixation of the ulcerated foot in individuals with Charcot neuroarthropathy. Foot Ankle Int 2002;23:130-134.
62. Pinzur MS: Neutral ring fixation for high-risk nonplantigrade Charcot midfoot deformity. Foot Ankle Int 2007; 28:961-966.
63. Conway JD: Charcot salvage of the foot and ankle using external fixation. Foot Ankle Clin 2008;13:157-173.
64. Cooper PS: Application of external fixators for management of Charcot deformities of the foot and ankle. Foot Ankle Clin 2002;7:207-254.
65. Fabrin J, Larsen K, Holstein PE: Arthrodesis with external fixation in the unstable and misaligned Charcot ankle in patients with diabetes mellitus. Int J Low Extrem Wounds 2007;6:102-107.
66. Wang JC, Le AW, Tsukuda RK: A new technique for Charcot's foot reconstruction. J Am Podiatr Med Assoc 2002;92:429-436.
67. Zarutsky E, Rush SM, Schuberth JM: The use of circular wire external fixation in the treatment of salvage ankle arthrodesis. J Foot Ankle Surg 2005;44: 22-31.
68. Saltzman CL, Hagy ML, Zimmerman B, Estin M, Cooper R: How effective is intensive nonoperative initial treatment of patients with diabetes and Charcot arthropathy of the feet? Clin Orthop Relat Res 2005;435:185-190.
69. Pinzur MS: Current concepts review: Charcot arthropathy of the foot and ankle. Foot Ankle Int 2007;28:952-959.
70. Rogers MJ: New insights into the molecular mechanisms of action of bisphosphonates. Curr Pharm Des 2003; 9:2643-2658.
71. Jude EB, Selby PL, Burgess J, et al: Bisphosphonates in the treatment of Charcot neuroarthropathy: A doubleblind randomised controlled trial. Diabetologia 2001;44:2032-2037.
72. Pitocco D, Ruotolo V, Caputo S, et al: Six-month treatment with alendronate in acute Charcot neuroarthropathy: A randomized controlled trial. Diabetes Care 2005;28:1214-1215.
73. Bem R, Jirkovská A, Fejfarová V, Skibová J, Jude EB: Intranasal calcitonin in the treatment of Charcot neuroosteoarthropathy: A randomized controlled trial. Diabetes Care 2006;29: 1392-1394.
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