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1.  Predictors of Barefoot Plantar Pressure during Walking in Patients with Diabetes, Peripheral Neuropathy and a History of Ulceration 
PLoS ONE  2015;10(2):e0117443.
Elevated dynamic plantar foot pressures significantly increase the risk of foot ulceration in diabetes mellitus. The aim was to determine which factors predict plantar pressures in a population of diabetic patients who are at high-risk of foot ulceration.
Patients with diabetes, peripheral neuropathy and a history of ulceration were eligible for inclusion in this cross sectional study. Demographic data, foot structure and function, and disease-related factors were recorded and used as potential predictor variables in the analyses. Barefoot peak pressures during walking were calculated for the heel, midfoot, forefoot, lesser toes, and hallux regions. Potential predictors were investigated using multivariate linear regression analyses. 167 participants with mean age of 63 years contributed 329 feet to the analyses.
The regression models were able to predict between 6% (heel) and 41% (midfoot) of the variation in peak plantar pressures. The largest contributing factor in the heel model was glycosylated haemoglobin concentration, in the midfoot Charcot deformity, in the forefoot prominent metatarsal heads, in the lesser toes hammer toe deformity and in the hallux previous ulceration. Variables with local effects (e.g. foot deformity) were stronger predictors of plantar pressure than global features (e.g. body mass, age, gender, or diabetes duration).
The presence of local deformity was the largest contributing factor to barefoot dynamic plantar pressure in high-risk diabetic patients and should therefore be adequately managed to reduce plantar pressure and ulcer risk. However, a significant amount of variance is unexplained by the models, which advocates the quantitative measurement of plantar pressures in the clinical risk assessment of the patient.
PMCID: PMC4315609  PMID: 25647421
2.  Increased osteoclastic activity in acute Charcot’s osteoarthopathy: the role of receptor activator of nuclear factor-kappaB ligand 
Diabetologia  2008;51(6):1035-1040.
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).
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.
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).
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.
PMCID: PMC2362134  PMID: 18389210
Charcot’s osteoarthropathy; OPG; Osteoclasts; Osteolysis; RANKL; Resorption
3.  Infrared Thermal Imaging for Automated Detection of Diabetic Foot Complications 
Although thermal imaging can be a valuable technology in the prevention and management of diabetic foot disease, it is not yet widely used in clinical practice. Technological advancement in infrared imaging increases its application range. The aim was to explore the first steps in the applicability of high-resolution infrared thermal imaging for noninvasive automated detection of signs of diabetic foot disease.
The plantar foot surfaces of 15 diabetes patients were imaged with an infrared camera (resolution, 1.2 mm/pixel): 5 patients had no visible signs of foot complications, 5 patients had local complications (e.g., abundant callus or neuropathic ulcer), and 5 patients had diffuse complications (e.g., Charcot foot, infected ulcer, or critical ischemia). Foot temperature was calculated as mean temperature across pixels for the whole foot and for specified regions of interest (ROIs).
No differences in mean temperature >1.5 °C between the ipsilateral and the contralateral foot were found in patients without complications. In patients with local complications, mean temperatures of the ipsilateral and the contralateral foot were similar, but temperature at the ROI was >2 °C higher compared with the corresponding region in the contralateral foot and to the mean of the whole ipsilateral foot. In patients with diffuse complications, mean temperature differences of >3 °C between ipsilateral and contralateral foot were found.
With an algorithm based on parameters that can be captured and analyzed with a high-resolution infrared camera and a computer, it is possible to detect signs of diabetic foot disease and to discriminate between no, local, or diffuse diabetic foot complications. As such, an intelligent telemedicine monitoring system for noninvasive automated detection of signs of diabetic foot disease is one step closer. Future studies are essential to confirm and extend these promising early findings.
PMCID: PMC3876354  PMID: 24124937
automatic detection; diabetic foot; infrared imaging; prevention; telemedicine; thermography
4.  Mortality Risk of Charcot Arthropathy Compared With That of Diabetic Foot Ulcer and Diabetes Alone 
Diabetes Care  2009;32(5):816-821.
The purpose of this study was to compare mortality risks of patients with Charcot arthropathy with those of patients with diabetic foot ulcer and those of patients with diabetes alone (no ulcer or Charcot arthropathy).
A retrospective cohort of 1,050 patients with incident Charcot arthropathy in 2003 in a large health care system was compared with patients with foot ulcer and those with diabetes alone. Mortality was determined during a 5-year follow-up period. Patients with Charcot arthropathy were matched to individuals in the other two groups using propensity score matching based on patient age, sex, race, marital status, diabetes duration, and diabetes control.
During follow-up, 28.0% of the sample died; 18.8% with diabetes alone and 37.0% with foot ulcer died compared with 28.3% with Charcot arthropathy. Multivariable Cox regression shows that, compared with Charcot arthropathy, foot ulcer was associated with 35% higher mortality risk (hazard ratio 1.35 [95% CI 1.18–1.54]) and diabetes alone with 23% lower risk (0.77 [0.66–0.90]). Of the patients with Charcot arthropathy, 63% experienced foot ulceration before or after the onset of the Charcot arthropathy. Stratified analyses suggest that Charcot arthropathy is associated with a significantly increased mortality risk independent of foot ulcer and other comorbidities.
Charcot arthropathy was significantly associated with higher mortality risk than diabetes alone and with lower risk than foot ulcer. Patients with foot ulcers tended to have a higher prevalence of peripheral vascular disease and macrovascular diseases than patients with Charcot arthropathy. This finding may explain the difference in mortality risks between the two groups.
PMCID: PMC2671113  PMID: 19196882
5.  The Effect of Zoledronic Acid on the Clinical Resolution of Charcot Neuroarthropathy 
Diabetes Care  2011;34(7):1514-1516.
To investigate the clinical efficacy of zoledronic acid in patients with diabetes and acute Charcot neuroarthropathy.
Thirty-nine consecutive patients were randomly assigned to placebo or three intravenous infusions of 4 mg zoledronic acid. The primary outcome was clinical resolution of acute Charcot neuroarthropathy determined by total immobilization time (casting plus orthosis).
At baseline, there was no significant difference between the randomly assigned groups with respect to Charcot disease activity or other baseline values. In the zoledronic acid group, the median time for total immobilization was 27 weeks (range 10–62), and in the placebo group it was 20 weeks (20–52) (P = 0.02).
Zoledronic acid had no beneficial effect on the clinical resolution of acute Charcot neuroarthropathy in terms of total immobilization time. It is possible that it may prolong the time to clinical resolution of Charcot neuroarthropathy.
PMCID: PMC3120211  PMID: 21593295
6.  Neuropathic midfoot deformity: associations with ankle and subtalar joint motion 
Neuropathic deformities impair foot and ankle joint mobility, often leading to abnormal stresses and impact forces. The purpose of our study was to determine differences in radiographic measures of hind foot alignment and ankle joint and subtalar joint motion in participants with and without neuropathic midfoot deformities and to determine the relationships between radiographic measures of hind foot alignment to ankle and subtalar joint motion in participants with and without neuropathic midfoot deformities.
Sixty participants were studied in three groups. Forty participants had diabetes mellitus (DM) and peripheral neuropathy (PN) with 20 participants having neuropathic midfoot deformity due to Charcot neuroarthropathy (CN), while 20 participants did not have deformity. Participants with diabetes and neuropathy with and without deformity were compared to 20 young control participants without DM, PN or deformity. Talar declination and calcaneal inclination angles were assessed on lateral view weight bearing radiograph. Ankle dorsiflexion, plantar flexion and subtalar inversion and eversion were assessed by goniometry.
Talar declination angle averaged 34±9, 26±4 and 23±3 degrees in participants with deformity, without deformity and young control participants, respectively (p< 0.010). Calcaneal inclination angle averaged 11±10, 18±9 and 21±4 degrees, respectively (p< 0.010). Ankle plantar flexion motion averaged 23±11, 38±10 and 47±7 degrees (p<0.010). The association between talar declination and calcaneal inclination angles with ankle plantar flexion range of motion is strongest in participants with neuropathic midfoot deformity. Participants with talonavicular and calcaneocuboid dislocations result in the most severe restrictions in ankle joint plantar flexion and subtalar joint inversion motions.
An increasing talar declination angle and decreasing calcaneal inclination angle is associated with decreases in ankle joint plantar flexion motion in individuals with neuropathic midfoot deformity due to CN that may contribute to excessive stresses and ultimately plantar ulceration of the midfoot.
PMCID: PMC3616933  PMID: 23531372
Foot alignment; Deformity; Ankle and foot joint goniometry; Limited joint mobility
7.  A Prospective Study of Calcaneal Bone Mineral Density in Acute Charcot Osteoarthropathy 
Diabetes Care  2010;33(10):2254-2256.
To measure prospectively bone mineral density (BMD) of the Charcot and non-Charcot foot in 36 diabetic patients presenting with acute Charcot osteoarthropathy.
Calcaneal BMD was measured with quantitative ultrasound at presentation, at 3 months of casting, and at the time of the clinical resolution.
BMD of the Charcot foot was significantly reduced compared with BMD of the non-Charcot foot at presentation (P = 0.001), at 3 months of casting (P < 0.001), and at the time of clinical resolution (P < 0.001). Overall, from the time of presentation to the time of resolution there was a significant fall of BMD of the Charcot foot (P < 0.001) but not of the non-Charcot foot (P = 0.439).
Although the Charcot foot was treated with casting until clinical resolution, there was a significant fall of BMD only from presentation up until 3 months of casting.
PMCID: PMC2945169  PMID: 20628091
8.  Pedal bone density, strength, orientation, and plantar loads preceding incipient metatarsal fracture after Charcot neuroarthropathy: 2 case reports 
Study Design
Case reports
Charcot neuroarthropathy (CN) is a progressive, non-infective, inflammatory destruction of bones and joints leading to foot deformities and plantar ulceration. Though individuals with CN typically have low areal bone mineral density (aBMD), little is known regarding changes in volumetric bone mineral density (vBMD), bone geometry, joint mal-alignment, and biomechanical loads preceding fracture.
Case Description
Two females, aged 45 and 54 years at the onset of an acute non-fracture CN event, received regular physical therapy with wound care and total contact casting. Both enrolled in a larger research study that included plantar pressure assessment and quantitative computed tomography (QCT) at enrollment and 3, 6, and 12 months later. The women sustained mid-diaphyseal fifth metatarsal fracture 10–11 months after enrollment. QCT image analysis techniques were used to measure vBMD; bone geometric indices reflecting strength in compression, bending, and cortical buckling; and 3-dimensional bone-to-bone orientation angles reflecting foot deformity.
Fifth metatarsal mid-diaphyseal vBMD decreased during off-loading treatment from 0 to 3 months, then increased to above baseline levels by 6 months. All geometric strength indices improved from baseline through 6 months. Plantar loading in the lateral midfoot increased preceding fracture, concomitant with alterations in bone orientation angles which suggest progressive development of metatarsus adductus and equinovarus foot deformity.
Fractures may occur when bone strength decreases or when biomechanical loading increases. Incipient fracture was preceded by increased loading in the lateral midfoot, but not by reductions in vBMD or geometric strength indices, suggesting that loading played a greater role in fracture. Moreover, the progression of foot deformities may be causally linked to the increased plantar loading.
Level of evidence
Therapy, level 4
PMCID: PMC3959983  PMID: 24256173
Diabetes; foot; plantar ulcers; fracture
9.  Comparative analysis of uniplanar external fixator and retrograde intramedullary nailing for ankle arthrodesis in diabetic Charcot's neuroarthropathy 
Indian Journal of Orthopaedics  2011;45(4):359-364.
Charcot's neuroarthropathy of ankle leads to instability, destruction of the joint with significant morbidity that may require an amputation. Aim of surgical treatment is to achieve painless stable plantigrade foot through arthrodesis. Achieving surgical arthrodesis in Charcot's neuroarthropathy has a high failure rate. This is a retrospective nonrandomized comparative study assessing the outcomes of tibio-talar arthrodesis for Charcot's neuroarthropathy treated by uniplanar external fixation assisted by external immobilization or retrograde intramedullary interlocked nailing.
Materials and Methods:
Records of the authors′ institution were reviewed to identify those patients who had undergone ankle fusion for diabetic neuroarthropathy from January 1998 to December 2008. A total of11 patients (six males and five females) with a mean age of 56 year and diabetes of a mean duration of 15.4 years with ankle tibio-talar arthrodesis using retrograde nailing or external fixator for Charcot's neuroarthropathy were enrolled for the analysis. Neuropathy was clinically diagnosed, documented and substantiated using the monofilament test. All procedures were performed in Eichenholz stage II/III.Six patients were treated with uniplanar external fixator, while the remaining five underwent retrograde intramedullary interlocking nail. The outcomes were measured for union radiologically, development of complications and clinical follow-up, according to digital archiving systems and old case notes.
All five (100%) patients treated by intramedullary nailing achieved radiological union on an average follow-up of 16 weeks. The external fixation group had significantly higher rate of complications with one amputation, four non unions (66.7%) and a delayed union which went on to full osseous union.
The retrograde intramedullary nailing for tibio-talar arthrodesis in Charcot's neuroarthropathy yielded significantly better outcomes as compared to the use of uniplanar external fixator.
PMCID: PMC3134023  PMID: 21772631
Charcot's diabetic neuropathy; retrograde intramedullary nailing; tibio-talar arthrodesis; uniplanar external fixator
10.  Mortality Associated With Acute Charcot Foot and Neuropathic Foot Ulceration 
Diabetes Care  2010;33(5):1086-1089.
To compare the mortality of patients with an acute Charcot foot with a matched population with uninfected neuropathic foot ulcers (NFUs).
Data were extracted from a specialist departmental database, supplemented by hospital records. The findings were compared with the results of earlier populations with Charcot foot and uninfected NFUs managed from 1980. Finally, the results of all patients with acute Charcot foot and all control subjects managed between 1980 and 2007 were compared with normative mortality data for the U.K. population.
A total of 70 patients presented with an acute Charcot foot (mean age 57.4 ± 12.0 years; 48 male [68.6%]) between 2001 and 2007; there were 66 matched control subjects. By 1 October 2008, 13 (eight male; 18.6%) patients with a Charcot foot had died, after a median of 2.1 years (interquartile range 1.1–3.3). Twenty-two (20 male; 33.3%) control subjects had also died after a median of 1.3 years (0.6–2.5). There was no difference in survival between the two groups (log-rank P > 0.05). Median survival of all 117 patients with acute Charcot foot managed between 1980 and 2007 was 7.88 years (4.0–15.4) and was not significantly different from the control NFU patients (8.43 years [3.4–15.8]). When compared with normative U.K. population data, life expectancy in the two groups was reduced by 14.4 and 13.9 years, respectively.
These data confirm that the mortality in patients presenting to our unit with either an acute Charcot foot and an uninfected neuropathic ulcer was unexpectedly high.
PMCID: PMC2858181  PMID: 20185744
11.  Effect of selected exercises on in-shoe plantar pressures in people with diabetes and peripheral neuropathy 
Foot (Edinburgh, Scotland)  2012;22(3):130-134.
In people with diabetes and peripheral neuropathy (DM+PN), injury risk is not clearly known for weight bearing (WB) vs. non-weight bearing (NWB) exercise. In-shoe peak plantar pressures (PPP) often are used as a surrogate indicator of injury to the insensitive foot.
Compare PPPs in people with DM+PN during selected WB and NWB exercises.
15 subjects with DM+PN participated. PPPs were recorded for the forefoot, midfoot, and heel during level walking and compared to; WB exercises - treadmill walking, heel and toe raises, sit to stands, stair climbing, single leg standing; and NWB exercises - stationary bicycling, balance ball exercise and plantar flexion exercise.
Compared to level walking; mean forefoot PPP during treadmill walking was 13% higher, but this difference was eliminated when walking speed was used as a covariate. Mean PPPs were similar or substantially lower for other exercises, except for higher forefoot PPP with heel raise exercises.
Slow progression and regular monitoring of insensitive feet are recommended for all exercises, but especially for heel raises, and increases in walking speed. The remaining WB and NWB exercises pose no greater risk to the insensitive foot due to increases in PPP compared to level walking.
PMCID: PMC3434274  PMID: 22677098
Diabetes; Peripheral Neuropathy; Plantar pressure; Exercise
12.  Impact of Charcot neuroarthropathy on metatarsal bone mineral density and geometric strength indices 
Bone  2012;52(1):407-413.
Charcot neuroarthropathy (CN), an inflammatory condition characterized by rapid and progressive destruction of pedal bones and joints, often leads to deformity and ulceration in individuals with diabetes mellitus (DM) and peripheral neuropathy (PN). Repetitive, unperceived joint trauma may trigger initial CN damage, causing a proinflammatory cascade that can result in osteolysis and contribute to subsequent neuropathic fracture. We aimed to characterize osteolytic changes related to development and progression of CN by measuring bone mineral density (BMD) and geometric strength indices using volumetric quantitative computed tomography. Twenty individuals with DM+PN were compared to twenty age-, sex-, and race-matched individuals with DM+PN and acute CN. We hypothesized that individuals with acute CN would have decreased BMD and decreased total area, cortical area, minimum section modulus, and cortical thickness in the diaphysis of the second and fifth metatarsals. Results showed BMD was lower in both involved and uninvolved feet of CN participants compared to DM+PN participants, with greater reductions in involved CN feet compared to uninvolved CN feet. There was a non-significant increase in total area and cortical area in the CN metatarsals, which helps explain the finding of similar minimum section modulus in DM+PN and CN subjects despite the CN group’s significantly lower BMD. Larger cortical area and section modulus are typically considered signs of greater bone strength due to higher resistance to compressive and bending loads, respectively. In CN metatarsals, however, these findings may reflect periosteal woven bone apposition, i.e., a hypertrophic response to injury rather than increased fracture resistance. Future research using these techniques will aid further understanding of the inflammation-mediated bony changes associated with development and progression of CN and other diseases.
PMCID: PMC3515650  PMID: 23117208
Charcot neuroarthropathy; bone mineral density; computed tomography; diabetes mellitus; peripheral neuropathy
13.  Lower-Extremity Amputation Risk After Charcot Arthropathy and Diabetic Foot Ulcer 
Diabetes Care  2009;33(1):98-100.
To compare risks of lower-extremity amputation between patients with Charcot arthropathy and those with diabetic foot ulcers.
A retrospective cohort of patients with incident Charcot arthropathy or diabetic foot ulcers in 2003 was followed for 5 years for any major and minor amputations in the lower extremities.
After a mean follow-up of 37 ± 20 and 43 ± 18 months, the Charcot and ulcer groups had 4.1 and 4.7 amputations per 100 person-years, respectively. Among patients <65 years old at the end of follow-up, amputation risk relative to patients with Charcot alone was 7 times higher for patients with ulcer alone and 12 times higher for patients with Charcot and ulcer.
Charcot arthropathy by itself does not pose a serious amputation risk, but ulcer complication multiplicatively increases the risk. Early surgical intervention for Charcot patients in the absence of deformity or ulceration may not be advisable.
PMCID: PMC2797995  PMID: 19825822
14.  Pressure pain perception in the diabetic Charcot foot: facts and hypotheses 
Diabetic Foot & Ankle  2013;4:10.3402/dfa.v4i0.20981.
Reduced traumatic and posttraumatic (nociceptive) pain is a key feature of diabetic neuropathy. Underlying condition is a gradual degeneration of endings of pain nerves (A-delta fibers and C-fibers), which operate as receivers of noxious stimuli (nociceptors). Hence, the absence of A-delta fiber mediated sharp pain (“first” pain), and of C-fiber mediated dull pain (“second” pain). However, patients with diabetic neuropathy and acute Charcot foot often experience deep dull aching in the Charcot foot while walking on it.
To create a unifying hypothesis on the kind of pain in an acute Charcot foot.
Absence of punctuate (pinprick) pain perception at the sole of a Charcot foot, as was shown recently, likely corresponds to vanished intraepidermal A-delta fiber endings. C-fiber nociceptors are reduced, according to histopathology studies. Both types of fibers contribute to posttraumatic hyperalgesia at the skin level, as studies show. Their deficiencies likely impact on posttraumatic hyperalgesia at the skin level and, probably, also at the skeletal level.
It is hypothesised that deep dull aching in an acute diabetic Charcot foot may represent faulty posttraumatic hyperalgesia involving cutaneous and skeletal tissues.
PMCID: PMC3661900  PMID: 23705057
pain perception; diabetic neuropathy; Charcot neuroarthropathy
15.  Ataxia and other data reviewed in Charcot-Marie-Tooth and Refsum's disease. 
The author reports his experience on Refsum's disease and that gained after personally examining in detail 64 patients with Charcot-Marie-Tooth disease over the past ten years. The "cerebellar" inco-ordination in Charcot-Marie-Tooth disease (with or without distal wasting) and in Refsum's disease is analysed. Some variations in the motor and sensory neuropathy of Charcot-Marie-Tooth disease and Refsum's disease are discussed. The adequacy of motor conduction velocity in genetically distinguishing types of the above mentioned familial peripheral neuropathies is reviewed. Data on the neuropathy assessed by modern techniques of three original patients of Roussy and Levy (1926) are given. The possibility of extensor plantar responses in patients with Charcot-Marie-Tooth and Refsum's disease without structural lesion of the pyramidal tract is pointed out. The existence of the association between Friedreich's ataxia and Charcot-Marie-Tooth disease is criticised. It is emphasised that spinocerebellar degeneration (other than Friedreich's ataxia) presenting with distal limb weakness and wasting and sensory impairment may mimic Charcot-Marie-Tooth disease.
PMCID: PMC491688  PMID: 6186770
16.  Association Between Osteoprotegerin G1181C and T245G Polymorphisms and Diabetic Charcot Neuroarthropathy 
Diabetes Care  2009;32(9):1694-1697.
Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role.
We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy.
Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3–4.1], P = 0.006; Ch vs. H, 2.10 [1.3–3.3], P = 0.002; and ND vs. H, 0.90 [0.7–1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2–19.7], P < 0.001; Ch vs. H, 3.56 [1.9–6.7], P = 0.001; and ND vs. H, 0.54 [0.6–5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06–0.5], P = 0.002) and with ND (0.17 [0.05–0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43–2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy.
This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy.
PMCID: PMC2732132  PMID: 19502537
17.  Correlation between Plantar Foot Temperature and Diabetic Neuropathy: A Case Study by Using an Infrared Thermal Imaging Technique 
Diabetic neuropathy consists of multiple clinical manifestations of which loss of sensation is most prominent. High temperatures under the foot coupled with reduced or complete loss of sensation can predispose the patient to foot ulceration. The aim of this study was to look at the correlation between plantar foot temperature and diabetic neuropathy using a noninvasive infrared thermal imaging technique.
Infrared thermal imaging, a remote and noncontact experimental tool, was used to study the plantar foot temperatures of 112 subjects with type 2 diabetes selected from a tertiary diabetes centre in South India.
Patients with diabetic neuropathy (defined as vibration perception threshold (VPT) values on biothesiometry greater than 20 V) had a higher foot temperature (32–35 °C) compared to patients without neuropathy (27–30 °C). Diabetic subjects with neuropathy also had higher mean foot temperature (MFT) (p = .001) compared to non-neuropathic subjects. MFT also showed a positive correlation with right great toe (r = 0.301, p = .001) and left great toe VPT values (r = 0.292, p = .002). However, there was no correlation between glycated hemoglobin and MFT.
Infrared thermal imaging may be used as an additional tool for evaluation of high risk diabetic feet.
PMCID: PMC3005049  PMID: 21129334
diabetic neuropathy; infrared thermal imaging; mean foot temperature; serum cholesterol; type 2 diabetes
18.  Etiology, pathophysiology and classifications of the diabetic Charcot foot 
Diabetic Foot & Ankle  2013;4:10.3402/dfa.v4i0.20872.
In people with diabetes mellitus, the Charcot foot is a specific manifestation of peripheral neuropathy that may involve autonomic neuropathy with high blood flow to the foot, leading to increased bone resorption. It may also involve peripheral somatic polyneuropathy with loss of protective sensation and high risk of unrecognized acute or chronic minor trauma. In both cases, there is excess local inflammatory response to foot injury, resulting in local osteoporosis. In the Charcot foot, the acute and chronic phases have been described. The former is characterized by local erythema, edema, and marked temperature elevation, while pain is not a prominent symptom. In the latter, signs of inflammation gradually recede and deformities may develop, increasing the risk of foot ulceration. The most common anatomical classification describes five patterns, according to the localization of bone and joint pathology. This review article aims to provide a brief overview of the diabetic Charcot foot in terms of etiology, pathophysiology, and classification.
PMCID: PMC3661901  PMID: 23705058
Charcot foot; classification; diabetes mellitus; diabetic foot; neuropathy; osteoarthropathy
19.  Plantar Foot Surface Temperatures with Use of Insoles 
Patients with diabetes are often prescribed foot orthoses to help prevent foot ulcer formation. Orthotics are used to redistribute normal and shear stress. Shear stresses are not easily measurable and considered to be responsible for skin breakdown. Local elevation of skin temperature has been implicated as an early sign of impending ulceration especially in regions of high shear stress. The purpose of this study was to measure the effects of commonly prescribed insole materials on local changes in plantar foot temperature during normal gait.
Six commonly used foot orthosis materials were tested using the Thermo Trace™ infrared thermometer to measure foot temperature. Ten healthy adult volunteers without any history of diabetes or abnormal sensation participated in the study. During each trial the subject walked on a treadmill with the test material in the dominant foot's shoe, for six minutes at a speed of four miles per hour and rested for six minutes between trials. Four locations on the foot (hallux, first and fifth metatarsal heads, and heel) and the contralateral bicep temperatures were measured at 0, 1, 3, 5 minutes during the rest period. The order of material and skin location testing was randomized.
Significant differences were found between baseline temperatures and foot temperatures for all materials. However, no differences were found between materials for any location on the foot.
Previous studies have attempted to characterize materials based on laboratory and clinical testing, while other studies have attempted to characterize the effect of pressure on skin temperature. However, no study has previously attempted to characterize foot orthosis materials based on foot temperatures. This study compared foot temperatures of healthy adults based on the material tested. Although this study was unable to distinguish between materials based on foot temperatures, it was able to show a rise in foot temperature with any material used. This study demonstrates a need to a larger study on a population with diabetes.
PMCID: PMC1888418  PMID: 15296210
20.  A comparative study of zoledronic acid and once weekly Alendronate in the management of acute Charcot arthropathy of foot in patients with diabetes mellitus 
The aim of this study was to assess and compare the response to two forms of treatment-immobilization with zoledronic acid injection and immobilization with oral weekly Alendronate, in patients with diabetes mellitus and acute Charcot arthropathy (CA) of foot in terms of clinical and radiological parameters.
Material and Methods:
Patients attending the endocrinology and podiatry clinic with history of diabetes mellitus and Acute CA were taken for study. The patients were randomized into two treatment groups. Group Z-zoledronic acid injection along with total contact cast (TCC). Group A-Tab. Alendronate 70 mg. once a week till the complete clinical resolution of acute CA along with TCC. Forty-five patients were randomized and 40 of them completed the study. The primary end point was complete clinical resolution of acute CA-defined as temperature difference between normal and affected foot <1°F.
Among the 40 patients, 30 (75%) had complete clinical resolution. The mean number of days taken for complete clinical resolution since the initiation of treatment (either Zoledronic acid or Alendronate) was approximately 122 days. There was no significant difference in a number of days required for complete clinical resolution, between the two forms of therapy. There was more than 50% reduction in the visual score between the baseline and the final scan. The target to non-target ratio in the skeletal phase also showed an average of 40% reduction from the baseline to the final skeletal scintigraphy.
Both Intravenous Zoledronic acid and oral alendronate had comparable efficacy with respect to the time taken for attaining complete clinical resolution of acute CA of foot. However, Alendronate therapy was cost effective among the two. 99mTc MDP bone scan can be used as an adjuvant to the clinical parameters in assessing the response to therapy.
PMCID: PMC3659876  PMID: 23776862
Arthropathy; alendronate; Charcot; resolution; zoledronic acid
21.  Neuroarthropathy of the hip following spinal cord injury 
Indian Journal of Orthopaedics  2011;45(1):87-90.
We present the case of a 33-year-old male who sustained a burst fracture D12 vertebrae with spinal cord injury (ASIA impairment scale A) and a right mid-diaphysial femoral shaft fracture around 1.5 years back. The patient reported 1.5 years later with a swelling over the right buttock. Arthrotomy revealed serous fluid and fragmented bone debris. The biopsy showed a normal bony architecture with no evidence of infection and malignant cells. Hence, a diagnosis of Charcot’s hip was made. Charcot’s neuroarthropathy of the feet is a well-recognized entity in the setting of insensate feet resulting from causes such as diabetes or spina bifida. Although Charcot’s disease of the hips has been described, it is uncommon in association with spinal cord injury, syphilis and even with the use of epidural injection. The present case highlights the fact that neuroarthropathy of the hip can occur in isolation in the setting of a spinal cord injury, and this can lead to considerable morbidity.
PMCID: PMC3004089  PMID: 21221231
Charcot’s hip; neuroarthropathy; spinal cord injury
22.  Syringomyelia with Chiari I Malformation Presenting as Hip Charcot Arthropathy: A Case Report and Literature Review 
Neuroarthropathy (neuropathic osteoarthropathy), also known as Charcot joint, is a condition characterized by a progressive articular surface destruction in the setting of impaired nociceptive and proprioceptive innervation of the involved joint. It is seen most commonly in the foot and ankle secondary to peripheral neuropathy associated with diabetes mellitus. Cases of hip (Charcot) neuroarthropathy are rare and almost exclusively reported in patients with neurosyphilis (tabes dorsalis). We report a case of a 36-year-old man who presented to the emergency department complaining of right hip pain. On physical examination, pain and thermal sensory deficits were noted in the upper torso with a cape-like distribution, as well as signs of an upper motor neuron lesion in the left upper and lower extremities. A magnetic resonance imaging study (MRI) of the right hip showed evidence of early articular surface destruction and periarticular edema consistent with hip Charcot arthropathy. An MRI of the spine revealed an Arnold-Chiari type I malformation with extensive syringohydromyelia of the cervical and thoracic spine.
PMCID: PMC4322850
23.  Effects of low-dye taping on plantar pressure pre and post exercise: an exploratory study 
Low-Dye taping is used for excessive pronation at the subtalar joint of the foot. Previous research has focused on the tape's immediate effect on plantar pressure. Its effectiveness following exercise has not been investigated. Peak plantar pressure distribution provides an indirect representation of subtalar joint kinematics. The objectives of the study were 1) To determine the effects of Low-Dye taping on peak plantar pressure immediately post-application. 2) To determine whether any initial effects are maintained following exercise.
12 asymptomatic subjects participated; each being screened for excessive pronation (navicular drop > 10 mm). Plantar pressure data was recorded, using the F-scan, at four intervals during the testing session: un-taped, baseline-taped, post-exercise session 1, and post-exercise session 2. Each exercise session consisted of a 10-minute walk at a normal pace. The foot was divided into 6 regions during data analysis. Repeated-measures analysis of variance (ANOVA) was used to assess regional pressure variations across the four testing conditions.
Reduced lateral forefoot peak plantar pressure was the only significant difference immediately post tape application (p = 0.039). This effect was lost after 10 minutes of exercise (p = 0.036). Each exercise session resulted in significantly higher medial forefoot peak pressure compared to un-taped; (p = 0.015) and (p = 0.014) respectively, and baseline-taped; (p = 0.036) and (p = 0.015) respectively. Medial and lateral rearfoot values had also increased after the second session (p = 0.004), following their non-significant reduction at baseline-taped. A trend towards a medial-to-lateral shift in pressure present in the midfoot immediately following tape application was still present after 20 minutes of exercise.
Low-Dye tape's initial effect of reduced lateral forefoot peak plantar pressure was lost after a 10-minute walk. However, the tape continued to have an effect on the medial forefoot after 20 minutes of exercise. Further studies with larger sample sizes are required to examine the important finding of the anti-pronatory trend present in the midfoot.
PMCID: PMC2676256  PMID: 19383160
24.  Testing the proficiency to distinguish locations with elevated plantar pressure within and between professional groups of foot therapists 
Identification of locations with elevated plantar pressures is important in daily foot care for patients with rheumatoid arthritis, metatarsalgia and diabetes. The purpose of the present study was to evaluate the proficiency of podiatrists, pedorthists and orthotists, to distinguish locations with elevated plantar pressure in patients with metatarsalgia.
Ten podiatrists, ten pedorthists and ten orthotists working in The Netherlands were asked to identify locations with excessively high plantar pressure in three patients with forefoot complaints. Therapists were instructed to examine the patients according to the methods used in their everyday clinical practice. Regions could be marked through hatching an illustration of a plantar aspect. A pressure sensitive platform was used to quantify the dynamic bare foot plantar pressures and was considered as 'Gold Standard' (GS). A pressure higher than 700 kPa was used as cut-off criterion for categorizing peak pressure into elevated or non-elevated pressure. This was done for both patient's feet and six separate forefoot regions: big toe and metatarsal one to five. Data were analysed by a mixed-model ANOVA and Generalizability Theory.
The proportions elevated/non-elevated pressure regions, based on clinical ratings of the therapists, show important discrepancies with the criterion values obtained through quantitative plantar pressure measurement. In general, plantar pressures in the big toe region were underrated and those in the metatarsal regions were overrated. The estimated method agreement on clinical judgement of plantar pressures with the GS was below an acceptable level: i.e. all intraclass correlation coefficient's equal or smaller than .60. The inter-observer agreement for each discipline demonstrated worrisome results: all below .18. The estimated mutual agreements showed that there was virtually no mutual agreement between the professional groups studied.
Identification of elevated plantar pressure through clinical evaluation is difficult, insufficient and may be potentially harmful. The process of clinical plantar pressure screening has to be re-evaluated. The results of this study point towards the merit of quantitative plantar pressure measurement for clinical practice.
PMCID: PMC1698918  PMID: 17140435
25.  Proinflammatory Modulation of the Surface and Cytokine Phenotype of Monocytes in Patients With Acute Charcot Foot 
Diabetes Care  2009;33(2):350-355.
Despite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed.
The immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects.
When compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot.
Together, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.
PMCID: PMC2809281  PMID: 19880584

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