Infrared thermography and ulcer prevention in the high-risk diabetic foot: data from a single-blind multicentre controlled clinical trial.

AIM: To assess the usefulness of monthly thermography and standard foot care to reduce diabetic foot ulcer recurrence. METHODS: People with diabetes (n = 110), neuropathy and history of ≥ 1 foot ulcer participated in a single-blind multicentre clinical trial. Feet were imaged with a novel thermal imaging device (Diabetic Foot Ulcer Prevention System). Participants were randomized to intervention (active thermography + standard foot care) or control (blinded thermography + standard foot care) and were followed up monthly until ulcer recurrence or for 12 months. Foot thermograms of participants from the intervention group were assessed for hot spots (areas with temperature ≥ 2.2°C higher than the corresponding contralateral site) and acted upon as per local standards. RESULTS: After 12 months, 62% of participants were ulcer-free in the intervention group and 56% in the control group. The odds ratios of ulcer recurrence (intervention vs control) were 0.82 (95% CI 0.38, 1.8; P = 0.62) and 0.55 (95% CI 0.21, 1.4; P = 0.22) in univariate and multivariate logistic regression analyses, respectively. The hazard ratios for the time to ulcer recurrence (intervention vs control) were 0.84 (95% CI 0.45, 1.6; P = 0.58) and 0.67 (95% CI 0.34, 1.3; P = 0.24) in univariate and multivariate Cox regression analyses, respectively. CONCLUSIONS: Monthly intervention with thermal imaging did not result in a significant reduction in ulcer recurrence rate or increased ulcer-free survival in this cohort at high risk of foot ulcers. This trial has, however, informed the design of a refined study with longer follow-up and group stratification, further aiming to assess the efficacy of thermography to reduce ulcer recurrence.

Reliability of a novel thermal imaging system for temperature assessment of healthy feet.

BACKGROUND: Thermal imaging is a useful modality for identifying preulcerative lesions ("hot spots") in diabetic foot patients. Despite its recognised potential, at present, there is no readily available instrument for routine podiatric assessment of patients at risk. To address this need, a novel thermal imaging system was recently developed. This paper reports the reliability of this device for temperature assessment of healthy feet. METHODS: Plantar skin foot temperatures were measured with the novel thermal imaging device (Diabetic Foot Ulcer Prevention System (DFUPS), constructed by Photometrix Imaging Ltd) and also with a hand-held infrared spot thermometer (Thermofocus® 01500A3, Tecnimed, Italy) after 20 min of barefoot resting with legs supported and extended in 105 subjects (52 males and 53 females; age range 18 to 69 years) as part of a multicentre clinical trial. The temperature differences between the right and left foot at five regions of interest (ROIs), including 1st and 4th toes, 1st, 3rd and 5th metatarsal heads were calculated. The intra-instrument agreement (three repeated measures) and the inter-instrument agreement (hand-held thermometer and thermal imaging device) were quantified using intra-class correlation coefficients (ICCs) and the 95% confidence intervals (CI). RESULTS: Both devices showed almost perfect agreement in replication by instrument. The intra-instrument ICCs for the thermal imaging device at all five ROIs ranged from 0.95 to 0.97 and the intra-instrument ICCs for the hand-held-thermometer ranged from 0.94 to 0.97. There was substantial to perfect inter-instrument agreement between the hand-held thermometer and the thermal imaging device and the ICCs at all five ROIs ranged between 0.94 and 0.97. CONCLUSIONS: This study reports the performance of a novel thermal imaging device in the assessment of foot temperatures in healthy volunteers in comparison with a hand-held infrared thermometer. The newly developed thermal imaging device showed very good agreement in repeated temperature assessments at defined ROIs as well as substantial to perfect agreement in temperature assessment with the hand-held infrared thermometer. In addition to the reported non-inferior performance in temperature assessment, the thermal imaging device holds the potential to provide an instantaneous thermal image of all sites of the feet (plantar, dorsal, lateral and medial views). TRIAL REGISTRATION: Diabetic Foot Ulcer Prevention System NCT02317835, registered December 10, 2014.

Novel Semiquantitative Bone Marrow Oedema Score and Fracture Score for the Magnetic Resonance Imaging Assessment of the Active Charcot Foot in Diabetes.

There are no accepted methods to grade bone marrow oedema (BMO) and fracture on magnetic resonance imaging (MRI) scans in Charcot osteoarthropathy. The aim was to devise semiquantitative BMO and fracture scores on foot and ankle MRI scans in diabetic patients with active osteoarthropathy and to assess the agreement in using these scores. Three radiologists assessed 45 scans (Siemens Avanto 1.5T, dedicated foot and ankle coil) and scored independently twenty-two bones (proximal phalanges, medial and lateral sesamoids, metatarsals, tarsals, distal tibial plafond, and medial and lateral malleoli) for BMO (0-no oedema, 1-oedema < 50% of bone volume, and 2-oedema > 50% of bone volume) and fracture (0-no fracture, 1-fracture, and 2-collapse/fragmentation). Interobserver agreement and intraobserver agreement were measured using multilevel modelling and intraclass correlation (ICC). The interobserver agreement for the total BMO and fracture scores was very good (ICC = 0.83, 95% confidence intervals (CI) 0.76, 0.91) and good (ICC = 0.62; 95% CI 0.48, 0.76), respectively. The intraobserver agreement for the total BMO and fracture scores was good (ICC = 0.78, 95% CI 0.6, 0.95) and fair to moderate (ICC = 0.44; 95% CI 0.14, 0.74), respectively. The proposed BMO and fracture scores are reliable and can be used to grade the extent of bone damage in the active Charcot foot.

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.

Inflammatory and bone turnover markers in a cross-sectional and prospective study of acute Charcot osteoarthropathy.

AIMS: To assess markers of inflammation and bone turnover at presentation and at resolution of Charcot osteoarthropathy. METHODS: We measured serum inflammatory and bone turnover markers in a cross-sectional study of 35 people with Charcot osteoarthropathy, together with 34 people with diabetes and 12 people without diabetes. In addition, a prospective study of the subjects with Charcot osteoarthropathy was conducted until clinical resolution. RESULTS: At presentation, C-reactive protein (P = 0.007), tumour necrosis factor-α (P = 0.010) and interleukin-6 (P = 0.002), but not interleukin-1ß, (P = 0.254) were significantly higher in people with Charcot osteoarthropathy than in people with and without diabetes. Serum C-terminal telopeptide (P = 0.004), bone alkaline phosphatase (P = 0.006) and osteoprotegerin (P < 0.001), but not tartrate-resistant acid phosphatase (P = 0.126) and soluble receptor activator of nuclear factor-κß ligand (P = 0.915), were significantly higher in people with Charcot osteoarthropathy than in people with and without diabetes. At follow-up it was found that tumour necrosis factor-α (P = 0.012) and interleukin-6 (P = 0.003), but not C-reactive protein (P = 0.101), interleukin-1ß (P = 0.457), C-terminal telopeptide (P = 0.743), bone alkaline phosphatase (P = 0.193), tartrate-resistant acid phosphatase (P = 0.856), osteoprotegerin (P = 0.372) or soluble receptor activator of nuclear factor-kß ligand (P = 0.889), had significantly decreased between presentation and the 3 months of casting therapy time point, and all analytes remained unchanged from 3 months of casting therapy until resolution. In people with Charcot osteoarthropathy, there was a positive correlation between interleukin-6 and C-terminal telopeptide (P = 0.028) and tumour necrosis factor-α and C-terminal telopeptide (P = 0.013) only at presentation. CONCLUSIONS: At the onset of acute Charcot foot, serum concentrations of tumour necrosis factor-α and interleukin-6 were elevated; however, there was a significant reduction in these markers at resolution and these markers may be useful in the assessment of disease activity.

Neuropathy and the vascular-bone axis in diabetes: lessons from Charcot osteoarthropathy.

Emerging evidence from the last two decades has shown that vascular calcification (VC) is a regulated, cell-mediated process orchestrated by vascular smooth muscle cells (VSMCs) and that this process bears many similarities to bone mineralization. While many of the mechanisms driving VSMC calcification have been well established, it remains unclear what factors in specific disease states act to promote vascular calcification and in parallel, bone loss. Diabetes is a condition most commonly associated with VC and bone abnormalities. In this review, we describe how factors associated with the diabetic milieu impact on VSMCs, focusing on the role of oxidative stress, inflammation, impairment of the advanced glycation end product (AGE)/receptor for AGE system and, importantly, diabetic neuropathy. We also explore the link between bone and VC in diabetes with a specific emphasis on the receptor activator of nuclear factor κß ligand/osteoprotegerin system. Finally, we describe what insights can be gleaned from studying Charcot osteoarthropathy, a rare complication of diabetic neuropathy, in which the occurrence of VC is frequent and where bone lysis is extreme.

Medical management of Charcot arthropathy.

Charcot arthropathy is a major complication of diabetes and it poses management challenges to health care professionals. Early diagnosis and timely intervention are essential for improved outlook of these patients. Casting therapy has been accepted as the mainstay treatment of the acute Charcot foot, although there are still controversies regarding its duration, the choice of removable and non-removable device and weight-bearing casts vs. non-weight-bearing casts. Two groups of antiresorptive therapies have been evaluated in the treatment of the acute Charcot foot, bisphosphonates (intravenous and oral) and calcitonin. These therapies have clearly shown a reduction of bone turnover, although, they have not shown a significant effect on temperature reduction. Current evidence to support their use is weak. An anabolic agent to speed up clinical resolution and fracture healing may be helpful and a clinical trial to evaluate the possible benefit of 1-84 recombinant human parathyroid hormone on fracture healing in the acute Charcot foot is in progress. This paper summarises the current approach to medical management of acute Charcot arthropathy with specific emphasis on casting and pharmacological therapy. Emerging new studies of the pathogenesis of this condition are also discussed.

Charcot neuro-osteoarthropathy-current standards.

It is extremely important to have a high index of suspicion for Charcot neuro-osteoarthropathy (CN) and to encourage early presentation of the patient. This should be followed by a rapid diagnosis and early intervention, and with such a modern approach many CN can now be healed and deformity prevented. CN can be divided into two phases: acute active phase and chronic stable phase. The acute active phase includes those patients presenting early with normal X-ray and those presenting later with deformity and radiological changes of CN. The acute phase is characterized by unilateral erythema and oedema. The foot is at least 2 degrees C hotter than the contralateral foot. Patients should have initially an X-ray examination which, at this time, may be normal. We then proceed to two investigations: initially a technetium diphosphonate bone scan, which will detect early evidence of bone damage and also locate the site of this damage. If the result of the bone scan is positive, we would proceed to magnetic resonance imaging (MRI) examination, which would describe in more detail the nature of the bony damage. The aim of treatment is immobilization in a plaster cast until there is no longer evidence on X-ray of continuing bone destruction, and the foot temperature is within 2 degrees C of the contralateral foot. An alternative treatment is a prefabricated walking cast, such as the Aircast. A randomized controlled study of a single 90 mg pamidronate infusion has shown a significant reduction of the markers of bone turnover and skin temperature in treated, compared with control subjects although the fall in skin temperature was similar in both groups. There was a similar finding in a recent study with alendronate. Calcitonin has also been used in the acute stage and there was a more rapid transition to the stable chronic phase in the treated group compared with controls. In the chronic stable phase, the foot is no longer warm and red. There may still be oedema but the difference in skin temperature between the feet is usually less than 2 degrees C. The X-ray shows fracture healing, sclerosis and bone remodelling. The patient must now be rehabilitated and gradually moved from cast treatment to suitable footwear. The patient needs close observation to detect any relapse, which will be evident from further swelling and heat in the foot. Careful rehabilitation is always necessary after a long period in a cast.

Increased osteoclastic activity in acute Charcot's osteoarthropathy: the role of receptor activator of nuclear factor-kappaB ligand.

AIMS/HYPOTHESIS: Our aims were to compare osteoclastic activity between patients with acute Charcot's osteoarthropathy and diabetic and healthy controls, and to determine the effect of the receptor activator of nuclear factor-kappaB ligand (RANKL) and its decoy receptor osteoprotegerin (OPG). METHODS: Peripheral blood monocytes isolated from nine diabetic Charcot patients, eight diabetic control and eight healthy control participants were cultured in the presence of macrophage-colony stimulating factor (M-CSF) alone, M-CSF and RANKL, and also M-CSF and RANKL with excess concentrations of OPG. Osteoclast formation was assessed by expression of tartrate-resistant acid phosphatase on glass coverslips and resorption on dentine slices. RESULTS: In cultures with M-CSF, there was a significant increase in osteoclast formation in Charcot patients compared with healthy and diabetic control participants (p=0.008). A significant increase in bone resorption was also seen in the former, compared with healthy and diabetic control participants (p<0.0001). The addition of RANKL to the cultures with M-CSF led to marked increase in osteoclastic resorption in Charcot (from 0.264+/-0.06% to 41.6+/-8.1%, p<0.0001) and diabetic control (0.000+/-0.00% to 14.2+/-16.5%, p<0.0001) patients, and also in healthy control participants (0.004+/-0.01% to 10.5+/-1.9%, p<0.0001). Although the addition of OPG to cultures with M-CSF and RANKL led to a marked reduction of resorption in Charcot patients (41.6+/-8.1% to 5.9+/-2.4%, p=0.001), this suppression was not as complete as in diabetic control patients (14.2+/-16.5% to 0.45+/-0.31%, p=0.001) and in healthy control participants (from 10.5+/-1.9% to 0.00+/-0.00%, p<0.0001). CONCLUSIONS/INTERPRETATION: These results indicate that RANKL-mediated osteoclastic resorption occurs in acute Charcot's osteoarthropathy. However, the incomplete inhibition of RANKL after addition of OPG also suggests the existence of a RANKL-independent pathway.

Calcaneal bone mineral density in patients with Charcot neuropathic osteoarthropathy: differences between Type 1 and Type 2 diabetes.

AIMS: To measure bone density and neuropathy in both feet in Type 1 and Type 2 patients with unilateral Charcot osteoarthropathy and controls. METHODS: Calcaneal bone density, temperature and vibration thresholds were compared between 17 Type 1 diabetic patients with osteoarthropathy and 47 Type 1 controls and between 18 Type 2 diabetic patients and 48 Type 2 controls. As well as the Charcot foot, the non-Charcot foot was studied to assess osteopenia at onset of osteoarthropathy. RESULTS: In Type 1 diabetes, bone density was reduced in the non-Charcot foot compared with controls [Z-score: -1.7 ({-1.9}-{-1.4}) vs. -0.2 ({-1.1}-{0.5}), P < 0.0001, median (interquartile range)]; but not in Type 2 diabetes [Z-score: 0.15 ({-0.45}-{0.85}) vs. 0.3 ({-0.5}-{0.9}), P = 0.675]. Bone density in the Charcot foot was lower compared with the non-Charcot foot in both Type 1 [Z-score: -2.0 ({-2.8}-{-1.4}) vs. -1.7 ({-1.9}-{-1.4}), P = 0.018] and Type 2 diabetes [Z-score: -0.2 ({-1.4}-{0.1}) vs. 0.3 ({-0.5}-{0.9}), P = 0.001]. In Type 1 diabetes, bone density of the non-Charcot foot was reduced compared with that in Type 2 (P < 0.0001). Body mass index was lower in Type 1 than in Type 2 Charcot patients (P = 0.007). Type 2 patients had high temperature (P = 0.001) and vibration thresholds (P < 0.0001) in the non-Charcot foot compared with Type 2 controls whereas Type 1 patients had a high temperature threshold (P = 0.01) but not vibration threshold compared with Type 1 controls (P = 0.077). CONCLUSION: Bone density was reduced in the non-Charcot foot in Type 1 but not in Type 2 diabetes. Type 2 patients had high temperature and vibration thresholds in contrast to Type 1 patients who had a high temperature threshold only.