Diagnosis and treatment of active charcot neuro-osteoarthropathy in persons with diabetes mellitus: A systematic review.

BACKGROUND: There are uncertainties regarding the diagnostic criteria, optimal treatment methods, interventions, monitoring and determination of remission of Charcot neuro-osteoarthropathy (CNO) of the foot and ankle in people with diabetes mellitus (DM). The aims of this systematic review are to investigate the evidence for the diagnosis and subsequent treatment, to clarify the objective methods for determining remission and to evaluate the evidence for the prevention of re-activation in people with CNO, DM and intact skin. METHODS: We performed a systematic review based on clinical questions in the following categories: Diagnosis, Treatment, Identification of Remission and Prevention of Re-Activation in people with CNO, DM and intact skin. Included controlled studies were assessed for methodological quality and key data from all studies were extracted. RESULTS: We identified 37 studies for inclusion in this systematic review. Fourteen retrospective and observational studies relevant to the diagnosis of active CNO with respect to clinical examination, imaging and blood laboratory tests in patients with DM and intact skin were included. We identified 18 studies relevant to the treatment of active CNO. These studies included those focused on offloading (total contact cast, removable/non-removable knee high devices), medical treatment and surgical treatment in the setting of active CNO. Five observational studies were identified regarding the identification of remission in patients who had been treated for active CNO. We did not identify any studies that met our inclusion criteria for the prevention of re-activation in patients with DM and intact skin who had been previously treated for active CNO and were in remission. CONCLUSIONS: There is a paucity of high-quality data on the diagnosis, treatment, and prognosis of active CNO in people with DM and intact skin. Further research is warranted to address the issues surrounding this complex disease.

Guidelines on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes mellitus (IWGDF 2023).

The International Working Group on the Diabetic Foot (IWGDF) has published evidence-based guidelines on the prevention and management of diabetic foot disease since 1999. This is the first guideline on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes published by the IWGDF. We followed the GRADE Methodology to devise clinical questions in the PACO (Population, Assessment, Comparison, Outcome) and PICO (Population, Intervention, Comparison, Outcome) format, conducted a systematic review of the medical literature, and developed recommendations with the rationale. The recommendations are based on the evidence from our systematic review, expert opinion when evidence was not available, and also taking into account weighing of the benefits and harms, patient preferences, feasibility and applicability, and costs related to an intervention. We here present the 2023 Guidelines on the diagnosis and treatment of active Charcot neuro-osteoarthropathy in persons with diabetes mellitus and also suggest key future topics of research.

Rare complication of rheumatoid arthritis: Charcot Neuro-osteoarthropathy.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease.However, there are few cases of Charcot Neuro-osteoarthropathy (CN) caused by rheumatoid diseases in clinical reports. It is not easy to pay attention to the diagnosis of CN in the complications of rheumatoid disease, which greatly increases the probability of misdiagnosis and missed diagnosis. This case reported a rare complication of rheumatoid arthritis, Charcot arthritis, and the molecular mechanism and diagnosis and treatment of CN caused by RA were systematically discussed. CASE PRESENTATION: The patient, a 79-year-old woman, was hospitalized due to bilateral shoulder pain, limited activity for half a year, aggravated for 4 months to the hospital. During this period, the symptoms did not improve after treatment with acupuncture and Chinese medicine. The patient was previously diagnosed with rheumatoid arthritis for more than 3 years and intermittent irregular use of methylprednisolone and methotrexate for 2 years. She had a history of osteoporosis. PHYSICAL EXAMINATION: symmetrical malformed swelling of the finger joints of both hands; Bilateral supraspinatus and deltoid muscle atrophy, tenderness at the acromion, and attachment of the long head tendon of the biceps brachii were observed. The left Dugas test and the right Dugas test were positive.Blood test: anti-cyclic citrullinated peptide antibody (A-CCP) 33.10U/ml (normal range: 0-5RU/ml); antinuclear antibody quantification (ANA) 47.40AU/ml (normal range: Negative or < 32); anti-double stranded DNA IgG antibody quantification (dsDNA) 31.00 IU/ml (normal range: 0-100 IU/ml); D-Dimer 6.43 µg/ml (normal range: 0-0.5 mg/L); erythrocyte sedimentation rate (ESR) was 27 mm/h (normal range: < 20 mm/60 min). C-reactive protein (CRP) 39.06 mg/L(0.068-8 mg/L).MRI 3.0 T enhancement of bilateral shoulder joints, cervical spine and thoracic spine showed: 1.Large bone destruction, cartilage injury, multiple effusion, synovitis, obvious on the right side. 2.Intervertebral disc degeneration, cervical 3/4, 4/5, 5/6, 6/7 disc herniation, with cervical 3/4 obvious, posterior central herniation; CONCLUSIONS: Rheumatoid arthritis complicated with Charcot's joint is rare. Clinically, patients with rheumatoid diseases should not ignore Charcot's joint complications because of rareness. Early blood inflammatory markers, neuro electrophysiology, and imaging MRI of rheumatoid CN are of great significance for the diagnosis of this mild or early neurovascular inflammation. Early diagnosis and treatment are helpful to prevent further joint injury. The clinical diagnosis, treatment, and molecular mechanism of osteolysis in RA and peripheral sensory nerve injury remain to be further revealed.

Acute Charcot neuro-osteoarthropathy.

Charcot neuro-osteoarthropathy (CN) is one of the most challenging foot complications in diabetes. Common predisposing and precipitating factors include neuropathy and increased mechanical forces, fracture and bone resorption, trauma and inflammation. In the last 15 years, considerable progress has been made in the early recognition of the acute Charcot foot when the X ray is still negative (stage 0 or incipient Charcot foot). Recent advances in imaging modalities have enabled the detection of initial signs of inflammation and underlying bone damage before overt bone and joint destruction has occurred. Casting therapy remains the mainstay of medical therapy of acute CN. If timely instituted, offloading can arrest disease activity and prevent foot deformity. In cases with severe deformity, modern surgical techniques can correct the unstable deformity for improved functional outcome and limb survival. Emerging new studies into the cellular mechanisms of severe bone destruction have furthered our understanding of the mechanisms of pathological bone and joint destruction in CN. It is hoped that these studies may provide a scientific basis for new interventions with biological agents.

Charcot Neuro-Osteoarthropathy With Superimposed Osteomyelitis in a Nondiabetic Patient, as a Consequence of Cancer Chemotherapy: A MR-Monitored Case Report.

Charcot neuro-osteoarthropathy (CNO) is a manifestation of peripheral neuropathy as a chronic complication of diabetes mellitus but, less frequently, can be associated to other conditions such as alcoholism or neurotoxic therapies. An increasingly emerging cause of CNO is the use of oncological drugs which can cause neuropathic damage. The use of these therapies dramatically increased in recent years. CNO leads to a progressive degeneration of the foot's joints and to bone destruction and resorption which ends in deformities. These alterations in the foot's anatomy determine a high risk of ulceration, infection, and osteomyelitis. The superimposition of osteomyelitis on CNO increases the risk of major amputation, already high in patients suffering either from only CNO or osteomyelitis alone. We report the case of a 61-year old nondiabetic woman affected by CNO as a consequence of antiblastic therapy for breast cancer and the subsequent overlap of osteomyelitis, confirmed by magnetic resonance imaging. This case underlines how it is necessary to consider CNO as a possible complication of antiblastic therapy in the view of the severe consequences of missing its diagnosis.

Chronic Kidney Disease and Charcot Neuro-Osteoarthropathy of Foot in Diabetes.

INTRODUCTION: Charcot neuro-osteoarthropathy (CNO) occurs late in diabetes and may cause fracture, deformity, and higher mortality. Diabetic kidney disease (DKD) affects bone metabolism and contributes to mortality. However, there is no data on prevalence of CNO and its outcomes with coexisting DKD (or chronic kidney disease [CKD]). METHODS: To ascertain the prevalence of CKD (pick CKD or DKD) among patients with CNO and delineate the remission of active CNO and subsequent lower extremity amputation and all-cause mortality during prospective follow-up. Consecutive patients with diabetic CNO (active or inactive) were enrolled and subsequently divided into those with and without CKD (pick CKD or DKD) (Group A and Group B, respectively). A preestablished timeframe of 36 weeks was utilized to evaluate the remission proportion of active CNO. RESULTS: A total of 493 CNO patients were observed and 449 subjects (150 patients had active CNO) were further evaluated. The overall prevalence of diabetic nephropathy (DKD or CKD?) CNO was 43.7%. The proportion of patients achieving remission was significantly lower in Group A compared to Group B (OR 0.468, CI [0.239-0.934], P = .025), however, the median time for achieving remission was similar between the 2 groups (14 weeks vs 16 weeks, P = .885). Overall, all-cause mortality was notably higher Group A compared to Group B (OR 2.23, 95% CI [1.474-3.368]) over a median follow-up of 4 years. No significant differences were observed in rates of diabetic foot ulcers (58.2% vs 54.9%; P = .584) and amputations (17.4% vs 15.12%; P = .889) between Group A and Group B. CONCLUSION: Patients of CNO with coexisting CKD have poor prognosis both in terms of likelihood of active CNO remission and higher mortality.

Genetic Signature for the Causation of Charcot Neuro-osteoarthropathy of Foot in Diabetes: A Systematic Review.

Charcot neuro-osteoarthropathy (CNO) is a complication of diabetes occurring in people with diabetic neuropathy with a prevalence of 0.5% to 1% that may culminate to foot deformity, amputation, and early mortality. However, it is not known why only certain patients with diabetic neuropathy develop CNO. Hence, early recognition of risk factors, timely diagnosis, and appropriate intervention of CNO is pertinent. Recent understanding of the pathophysiology of CNO has expanded to suggest the involvement of RANKL-OPG pathways. But pharmaco-therapeutic interventions targeting bone metabolism predominantly inhibiting RANKL were not found to be useful. Moreover, there are not enough markers to help identify patients with diabetes who are at a higher risk of developing CNO. Hence, we explored the literature in the present systematic review of mainly case-control studies to identify genetic factors that could help in understanding the pathophysiology and risk factors for the development of CNO. We could identify 7 relevant studies identifying single nucleotide polymorphism of OPG and RANK genes. There is an isolated study identifying alterations of micro RNA associated with RANKL-OPG pathway. Another study found epigenetic alterations by performing whole methylome sequencing in people with CNO compared to control. These genetic factors can be used as a diagnostic marker and their functional counterparts as targets for future therapeutic interventions. However, we found that literature is sparse on the genetic risk factors for CNO in people with diabetic neuropathy and there is still a lot of scope for future studies towards finding the molecular and genetic markers for CNO.

Review and Evaluation of European National Clinical Practice Guidelines for the Treatment and Management of Active Charcot Neuro-Osteoarthropathy in Diabetes Using the AGREE-II Tool Identifies an Absence of Evidence-Based Recommendations.

Background: Charcot neuro-osteoarthropathy (CNO) is a rare but devastating complication of diabetes associated with high rates of morbidity; yet, many nonfoot specialists are unaware of it, resulting in missed and delayed diagnosis. Clinical practice guidelines (CPGs) have proven useful in improving quality of care and standardizing practice in diabetes and diabetic foot care. However, little is known about the consistency in recommendations for identification and management of active CNO. Aim: The aim of this study is to review European national diabetes CPGs for the diagnosis and management of active CNO and to assess their methodological rigor and transparency. Methods: A systematic search was performed to identify diabetes national CPGs across Europe. Guidelines in any language were reviewed to explore whether they provided a definition for active CNO and recommendations for diagnosis, monitoring, and management. Methodological rigor and transparency were assessed using the Appraisal of Guidelines for Research and Evaluation (AGREE-II) tool, which comprises 23 key items organized within six domains with an overall guideline assessment score of ≥ 60% considered to be of adequate quality to recommend use. Each guideline was assessed by two reviewers, and inter-rater agreement (Kendall's W) was calculated for AGREE-II scores. Results: Seventeen CPGs met the inclusion criteria. Breadth of CNO content varied across guidelines (median (IQR) word count: 327; Q1 = 151; Q3 = 790), and 53% provided a definition for active CNO. Recommendations for diagnosis and monitoring were provided by 82% and 53%, respectively, with offloading being the most common management recommendation (88%). Four guidelines (24%) reached threshold for recommendation for use in clinical practice (≥ 60%) with the scope and purpose domain scoring highest (mean (SD): 67%, ± 23%). The remaining domains had average scores ranging between 19% and 53%. Inter-rater agreement was strong (W = 0.882; p < 0.001). Conclusions: European national CPGs for diabetes provide limited recommendations on active CNO. All guidelines showcased deficits in their methodology, suggesting that more rigorous methods should be employed for diabetes CPG development across Europe.

Circular External Fixation as a New Offloading Standard of Treatment in Charcot Neuro-Osteoarthropathy Complicated by Midfoot Osteomyelitis: A Pilot, Prospective Case-Control Study.

After surgical treatment of Charcot neuro-osteoarthropathy (CNO) complicated by plantar ulcer and midtarsal osteomyelitis, offloading is mandatory to protect the surgical site. Total contact casting is, to date, the standard-of-care to offload the foot during the postoperative period. We have compared the application of external circular fixator, to the standard of care, with regard to surgical wound healing and time to healing. During the time period from January 2020 to December 2021, 71 consecutive patients admitted to our unit with diabetes and CNO complicated by plantar ulceration and midtarsal osteomyelitis were enrolled in our study. All patients were classified as stage 2, according to the Frykberg & Sanders classification. Wifi wound stage was W2 I0 FI2 in 43 of 71 patients (60.6%) and W2 I2 FI2 in 28 of 71 patients (39.4%). In cases where critical limb ischemia occurred, we performed an endovascular procedure to obtain patency in at least one of the tibial arteries. Localization of osteomyelitis was carried out with magnetic resonance imaging studies, and the degree of deformity was assessed using plain X-ray or computed tomography. A localized ostectomy through the ulceration was carried out with a fasciocutaneous flap to cover the surgical site. In 36 patients, an external circular fixator was applied intraoperatively (exfix+ group); the remaining 35 patients received fiberglass cast in the postoperative period (exfix- group). Complete healing of the surgical site was achieved in 36 of 36 patients in the exfix+ arm and in 22 of 35 in the exfix- arm (P < .02). Time to healing was 68 ± 28 days in exfix+ and 102 ± 88 days in exfix- (P = .05). Circular external frames should be considered as an effective offloading device that enhances the healing rate and reduces time to healing after surgical treatment of midfoot osteomyelitis in subjects affected by CNO.

Onset of an Active Charcot Foot in a Person with Longstanding Type 1 Diabetes and Normal Vibration Perception Threshold-A Case Report.

Charcot neuro-osteoarthropathy (CNO), or Charcot foot, is a disabling complication of diabetes, which is poorly understood and frequently overlooked. We describe an atypical presentation of an active Charcot foot in a woman with a long-standing type 1 diabetes who did not exhibit loss of protective sensation (sensate to a 10-gram monofilament) or loss of vibration sensation. These standard measures of large nerve fibre function ruled out "classical" neuropathy. However, additional testing showed reduced sweat gland function most likely related to degeneration of c-fibres (small fibre neuropathy). This case raises the awareness that in addition to the "textbook" description, in diabetes, Charcot foot can develop in individuals with "minimal" or "no signs" of clinical neuropathy. The onset of active Charcot foot should be suspected in every person with diabetes and history of trauma even when foot and ankle x-rays are normal. Offloading should be initiated until the diagnosis is proven otherwise.

Nonoperative Treatment of Charcot Neuro-osteoarthropathy.

Conservative treatment of Charcot neuro-osteoarthropathy (CN) aims to retain a stable, plantigrade, and ulcer-free foot, or to prevent progression of an already existing deformity. CN is treated with offloading in a total contact cast as long as CN activity is present. Transition to inactive CN is monitored by the resolution of clinical activity signs and by resolution of bony edema in MRI. Fitting of orthopedic depth insoles, orthopedic shoes, or ankle-foot orthosis should follow immediately after offloading has ended to prevent CN reactivation or ulcer development.

Comparison of the diagnostic accuracy of diffusion-weighted and dynamic contrast-enhanced MRI with 18F-FDG PET/CT to differentiate osteomyelitis from Charcot neuro-osteoarthropathy in diabetic foot.

PURPOSE: To compare the diagnostic accuracy of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) involving two region of interest (ROI) sizes with 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to differentiate diabetic foot osteomyelitis (DFO) from Charcot neuro-osteoarthropathy (CN). METHOD: Thirty-one diabetic patients were included in this prospective study. Two readers independently evaluated DWI (apparent diffusion coefficient [ADC] and high-b-value signal pathological-to-normal bone ratio [DWIr]) and DCE-MRI parameters (Ktrans, Kep, Ve, internal area under the gadolinium curve at 60 s [iAUC60] and time intensity curve [TIC]) using two different ROI sizes, and 18F-FDG PET/CT parameters (visual assessment, SUVmax, delayed SUVmax, and percentage changes between SUVmax and delayed SUVmax). Techniques were compared by univariate analysis using the area under the receiver operating characteristic curve [AUC]. Reliability was analyzed with Kappa and Intraclass correlation [ICC]. RESULTS: DWIr, Ktrans and iAUC60 showed better diagnostic accuracy (AUC = 0.814-0.830) and reliability (ICC > 0.9) for large than for small ROIs (AUC = 0.736-0.750; ICC = 0.6 in Ktrans, 0.8 in DWIr and iAUC60). TIC showed moderate diagnostic performance (AUC = 0.739-0.761) and reliability (κ 0.7). Visual assessment of 18F-FDG PET/CT demonstrated a significantly higher accuracy (AUC = 0.924) than MRI parameters. Semi-quantitative 18F-FDG PET/CT parameters did not provide significant improvement over visual analysis (AUC = 0.848-0.903). CONCLUSION: DWIr, Ktrans and iAUC60 allowed reliable differentiation of DFO and CN, particularly for large ROIs. Visual assessment of 18F-FDG PET/CT was the most accurate technique for differentiation.

Osteomyelitis or Charcot neuro-osteoarthropathy? Differentiating these disorders in diabetic patients with a foot problem.

Both osteomyelitis and Charcot neuro-osteoarthropathy (CN) are potentially limb-threatening complications of diabetic neuropathy, but they require quite different treatments. Almost all bone infections in the diabetic foot originate from an infected foot ulcer while diabetic osteoarthropathy is a non-infectious process in which peripheral neuropathy plays the critical role. Differentiating between diabetic foot osteomyelitis and CN requires careful evaluation of the patient, including the medical history, physical examination, selected laboratory findings, and imaging studies. Based on available studies, we review the approaches to the diagnostic differentiation of osteomyelitis from CN of the foot in diabetic patients.