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Mortality and complications after treatment of acute diabetic Charcot foot
Accepted Manuscript Mortality and complications after treatment of acute diabetic Charcot foot
Rasmus Bo Jansen, Bo Jørgensen, Per E. Holstein, Klaus Kirketerp Møller, Ole Lander Svendsen PII: DOI: Reference:
S1056-8727(18)30357-X doi:10.1016/j.jdiacomp.2018.09.013 JDC 7276
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
3 April 2018 13 September 2018 20 September 2018
Please cite this article as: Rasmus Bo Jansen, Bo Jørgensen, Per E. Holstein, Klaus Kirketerp Møller, Ole Lander Svendsen , Mortality and complications after treatment of acute diabetic Charcot foot. Jdc (2018), doi:10.1016/j.jdiacomp.2018.09.013
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ACCEPTED MANUSCRIPT Mortality and complications after treatment of acute diabetic Charcot foot
By Rasmus Bo Jansen1, Bo Jørgensen2, Per E. Holstein2, Klaus Kirketerp Møller2 and Ole Lander Svendsen1
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1) Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark 2) Center forWound Healing, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
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Word count: 4707 Reference count: 41
Corresponding author: Rasmus Bo Jansen, Ph.D. MD Address: Bispebjerg Hospital, Bispebjerg Bakke 23 ICamb, opg. 60, st. 2400 Kbh. NV, Denmark E-mail: [email protected] Phone: 0045 22 99 93 74
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ACCEPTED MANUSCRIPT Aims: Charcot foot is a rare but disabling complication to diabetic neuropathy, and can cause permanent, limb-threatening deformities. The aim of this study was to investigate a population of patients a Charcot foot on a case-by-case basis, in order to assess the consequences of an acute Charcot foot and its complications. Methods: The study was conducted a retrospective study of patients admitted to the Copenhagen Wound Healing Center between 1996-2015 with the diagnosis of Charcot foot (DM14.6) and diabetes mellitus type 1 or 2 (DE10.X and DE11.X). Physical and electronic records were used, and compared to data from the Danish Diabetes Registry.
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Results: In total 392 patients were identified of which 173 were included. There were 26% with type 1 diabetes (initial HbA1c 81.7 ±21.4 mmol/mol) and 74% with type 2 diabetes (initial HbA1c 66.5 ±20.3 mmol/mol). Primary off-loading was with a removable walker in 95% of the cases (average off-loading time 8.3 months). The 5-year mortality was 14% with a mean survival time of 12.7 years. There was an association between lack of compliance and occurrence of foot complications, as well as between having a Charcot foot and leaving the workforce.
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Conclusion: More patients had type 1 diabetes compared to the background population, and they had a higher HbA1c than the general population of diabetes patients. A total of 67% developed complications such as ulcers, while patients non-compliant to treatment did significantly worse than those being compliant. The 5-year mortality was low, 14%, and comparable to diabetes patients without Charcot foot.
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Keywords: Charcot foot ; retrospective follow-up ; complications ; mortality
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ACCEPTED MANUSCRIPT Introduction: Charcot foot is a rare complication to peripheral neuropathy (1–5). It manifests as an aseptic inflammation and bone degeneration located in one or both feet. If left untreated it can cause spontaneous fatigue bone fractures, resulting in deformity, ulcerations and possibly ultimately amputation. The majority of Charcot foot cases in the Western world today occur as a complication to diabetes mellitus, with a group incidence rate about 0.3% (2,6). Charcot foot is associated with a marked increase in morbidity (7,8), and patients with Charcot foot rate their life quality as "fair" or
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"poor" in standardized questionnaires (9–14). Treatment consists primarily of long-term off-loading, either with a total contact cast (TCC, "gold standard"), or as an alternative with a removable off-
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loading boot (e.g. Aircast) (15–19).
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Charcot foot is a major cause for ulceration and amputation in patients with diabetes (20,21). As such, correct and timely treatment is of vital importance. The diagnostic tools and treatment used
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for Charcot foot can vary extensively from hospital to hospital despite the rather uniform guidelines in the litterature (22–24). Furthermore, each patient treated often needs attention from several
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different medical specialties during their hospital admission.
This poses a challenge in the standard hospital environment where patients with Charcot foot are often admitted to an orthopedic surgery ward for stabilization and/or off-loading. Several groups
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have recommended employing a multi-disciplinary team in the diagnostics, treatment and follow-up
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of patients with Charcot foot (23,25,26). In 1996, a Danish center to employ this multidisciplinary strategy was established at the Copenhagen Wound Healing Center (CWHC). The center's main focus is off-loading, wound recovery and day-to-day surgery. Major Charcot reconstruction does
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not fall under the purview of the center.
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The aim of the present study was to describe a population with diabetes-related Charcot foot treated at the CWHC in the period of 1996-2015 (27). Several large studies have previously assessed populations with diabetes and Charcot foot (28–34). To complement these works, our main objective was to evaluate our population, their treatment and resolution on a case-by-case basis. We wanted to assess the consequences of an acute Charcot foot and its complications.
Methods: Materials: This study was conducted as a retrospective, longitudinal, observational study. The population consisted of all patients treated for acute Charcot foot as a complication to diabetes mellitus at the CWHC at Bispebjerg Hospital, Copenhagen, Denmark between 1996-2015 (figure 1). The 3/19
ACCEPTED MANUSCRIPT maximum possible follow-up was thus 19 years. The patients were identified using the electronic patient registration system, which logs all contacts to the hospital. The contacts are logged with a unique personal identifier in the form of each patients’ personal identification number from the Danish national civil registration system (CPR) and also include ICD-10 codes. All contacts with the ICD-10 code for neuropathic arthropathy (DM14.6) were reviewed for inclusion in the study. Only candidates also diagnosed with diabetes mellitus type 1 (T1DM) or 2 (T2DM) were included. The diagnosis was not always evident from the log, and each patient's
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medical charts and history was reviewed to confirm their diabetes status. Patients with diabetes due to other reasons (e.g. chronic pancreatitis) were excluded.
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Patients coded with DM14.6 without any evidence of Charcot foot diagnosis or treatment in their medical history were excluded. Furthermore, only patients with Charcot foot who were referred to
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the CWHC in the acute/initial phase (defined as <6 months from reported onset of the condition) were included. Patients already undergoing treatment at the CWHC for other reasons (e.g. foot
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ulcers) when the acute Charcot foot occured were also included in the study. All patients fitting the group above were considered for inclusion including those who, during parts
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of the follow-up period, already participated in other medical studies.
Data recording:
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All patients were followed up from first contact at the Copenhagen Wound Healing Center and until
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final discharge, death or the 1st of August 2015. The records date back to 1996 where the CWHC was established. The patients were followed up with medical records, both in paper and electronic format, and well as in the "Danish Register of Cause of Death". Mortality data was collected from
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first contact at the CWHC and until death or the 1st of August 2015. A secondary search was performed of the database program storing scanned versions of x-rays (both
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conventional and CT), MRIs and scintigraphies. These were assessed comparatively to determine the location of the Charcot activation. All anthropomorphic data were registered at baseline (as close to first contact to the CWHC as possible, within a margin of 6 months) including age, sex, weight, height, blood pressure, HbA1c, and smoking/alcohol consumption habits. Additionally, we registered each patients occupational situation at first contact, and any recorded changes during the treatment period. Finally, we registered all late stage diabetic complications at first contact, and again if they changed during the follow-up period.
Definitions: 4/19
ACCEPTED MANUSCRIPT Acute Charcot foot: Patients referred with a possible new, acute Charcot foot were considered for the diagnosis if they were seen for the first time at the CWHC within 6 months of discovering a red, warm foot (swelling or pain not mandatory) without another obvious cause (such as known, ongoing infection or x-ray confirming major traumatic fracture with a matching recent medical history). All patients also had the diagnosis confirmed by x-ray (conventional or CT) and either scintigraphy and/or MRI, either before referral or shortly after first visit to the CWHC (most cases).
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The acute phase of the Charcot foot was considered to be abated: When the foot temperature difference between the Charcot foot and the contralateral foot
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had dropped below 1.5 °C and the edema subsided.
When the patient were allowed full load-bearing (often with the removable off-loading boot
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as modfied support).
When a control scintigraphy/MRI showed no activity in the feet (primarily used in case of
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bilateral Charcot foot).
Foot ulcers were considered to be related to the Charcot foot if they fitted chronologically with this,
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and had a placement consistent with the skeletal damage or altered pressure patterns caused by the foot changes (based on records by doctors and podiatrists respectively). Age of diabetes refers to the time passed from first confirmed diabetes diagnosis, irrespective of
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onset of symptoms or use of antidiabetic drugs or insulins.
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Charcot foot recurrence was defined as new symptoms of swelling/reddening and an increase in foot skin temperature difference of more than 2 °C in the previously affected foot, occurring after
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full weight bearing was attempted for at least one month.
Late stage diabetic complications were registered if the records showed that the patient had been
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diagnosed with such, or if the records showed the following: Neuropathy: Impaired peripheral sensitivity as measured with biothesiometry and/or monofilament test.
Retinopathy: Diagnosed solely based on eye screening with fundusscopy. Macular edema, exudation, non-proliferative and/or proliferative diabetic retinopathy were all registered.
Nephropathy: Defined as macroalbuminuria (urine albumine/creatinine ratio >300 mg); progression from microalbuminuria (urine albumine/creatinine ratio between 30 - 299 mg) to macroalbuminuria; a persistent (two or more consecutive measurements at least a month apart) increase in p-creatinine (above twice the normal range) without another cause present in the records (such as severe infections/septicemia, trauma or hypovolemic shock); initiation of renal dialysis; or death from renal disease. 5/19
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Macrovascular disease: Recorded events of angina pectoris; peripheral vascular insufficiency (defined as ankle-brachial index <0.9 and/or toe-brachial index <0.7); performance of revascularization; pathological CAG; performed PCI/CABG procedure; or death from major cardiovascular event.
Occupation: To evaluate the possible effect of an acute Charcot foot on a patient's employment status, we also
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gathered data regarding the patients' occupation before, during and after the Charcot foot had abated. These data were based on notes in the medical records. The Danish welfare system
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distinguishes between several types of aid for chronically ill citizens including premature pension, early withdrawal for health reasons and part-time work subsidized by the state. For ease of reading,
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these have been categorized into:
Job (the patient returned to his/her ordinary job). This includes reschooling (the patient
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returned to the job market, but in another job with less load on the feet) and job at reduced time (the patient returned to the job market, but with a shorter-than-average work-week). Retirement (the patient retired but at the standard age 65 years or above). This includes all
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forms of early retirement and disability pension (the patient retired before the normal age of retirement in Denmark (65 years)).
Unemployed (the patient does not have a job for whatever reason, and does not qualify for
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retirement (early, disability or otherwise).
Statistical analysis:
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Data are expressed as means ±1SD or median and ranges. Missing values in the data were excluded by row in the relevant analysis. An α=0.05 was considered significant. Normal distribution in data
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was controlled by Shapiro-Wilks tests, and no transformations were used. ANOVA was used for variance analysis between groups in normally distributed subsets, while in ranked groups and groups not normally distributed, non-parametric tests in the form of the Mann-Whitney rank sum test and the Kruskal-Wallis one way analysis of variance on ranks were used. We tested for correlations using Pearson's r (continuous variables), Spearman's test (continuous and categorical data) and the chi-square test (categorical data). Paired/related dichotome 2 x 2 datasets (repeated measures) were compared using the McNemar test. Categorical and continuous data were compared using a logistic regression model. Survival analysis was performed with a Kaplan-Meier estimator. To counteract problems from multiple comparisons (mass significance), test results were adjusted using the Holm-Bonferroni correction on a test-by-test basis. Statistics and generel data handling was done using IBM SPSS Statistics v. 23 by IBM Corporation, 6/19
ACCEPTED MANUSCRIPT SIGMAPLOT v. 11.0.0.77 by Systat Software Inc., Microsoft Excel 2000 v. 9.0.2812 by Microsoft Corporation and Apache OpenOffice 4.0.1 by The Apache Software Foundation.
Control population: The results have been compared to data from the annual report from the national Danish Diabetes Registry (DDR) from 2014/2015 (35). The data used represent the entire population of diabetes patients, either type 1 or 2, treated at a hospital outpatient clinic the capital region of Greater
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Copenhagen (Denmark). This is also where the CWHC is located. The data from the DDR does not contain elaborate information regarding possible secondary
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diagnoses and/or concomittant diseases. Furthermore, it does not contain mortality data.
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Results: Inclusion process:
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We identified 313 patients coded with the ICD-10 codes for diabetes mellitus (DE10.X; DE11.X; DE13.X; DE14.X) and acute Charcot foot (DM14.6) between 1996-2015. Another 79 patients had
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been diagnosed with Charcot foot, but not with diabetes mellitus. Thus, 392 patients diagnosed with Charcot foot were screened for inclusion. The flow of patients for inclusion is shown in figure 1. Of these 392 patients, 91 (23%) had been coded with a Charcot foot diagnosis (DM14.6) in the
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system without their written records containing sufficient confirmation for this diagnosis, and were
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thus excluded. Most of these were due to the initial referral diagnosis of Charcot foot not being edited in the system as it was rejected by primary patient examination at the CWHC. Furthermore, 25 (6%) patients were diagnosed as having Charcot foot due to another source of
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neuropathy than diabetes mellitus, and were also excluded. The causes were alcoholism (n=15), spinal stenosis (n=2), spinal tumor (n=1), neurodevelopmental defect (n=1), Charcot-Marie-Tooth
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(n=3), side effect to anti-HIV medication (n=1) and unknown (n=2). Another 73 (19%) patients were excluded due to being admitted or seen >6 months after the reported onset of their acute Charcot foot. These patients were typically referred years after the active phase of their Charcot foot to receive treatment for foot deformities and ulcers. Finally, 30 (8%) were excluded due to missing data. Thus, of the 392 patients screened for inclusion 173 (44%) were included in the study.
Population characteristics: Mean follow-up time at the CWHC was 31 months (range 3-168 months). Anthropomorphic data for all included patients are listed in table 1. Of the population, 26% had T1DM and 74% had T2DM. None were diagnosed with other forms of diabetes. There was a higher proportion of 7/19
ACCEPTED MANUSCRIPT patients with T1DM (26%) than in the diabetic control population (around 10%), and in a population of patients with diabetes treated with below ankle level amputation from the CWHC (20% had T1DM) (36). Males made up the largest portion of both the T1DM and T2DM groups with 55% and 74% respectively. In the regional hospital data males make up 55% of the T1DM population and 61% of the T2DM population.
The Charcot population had an higher initial HbA1c of 81.7 ±21.4 mmol/mol (median 83
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mmol/mol) (9.7 ±4.1%; median 9.7%) for T1DM patients compared to the median level in the region of greater Copenhagen which is 61 mmol/mol (7.7%) (p<0.001).
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The T2DM Charcot patients also had a higher initial HbA1c of 66.5 ±20.3 mmol/mol for T2DM patients (median 66 mmol/mol) (8.2 ±4.0%; median 8.2%) compared to the median regional level
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of 59 mmol/mol (7.5%) (32).
The median blood pressure in the T1DM group was 151/80 mmHg, and 150/82 mmHg in the
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mmHg and 133/78 mmHg respectively (table 1).
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T2DM group. The median levels for diabetics in the region of greater Copenhagen are 130/77
The number of patients referred with acute Charcot foot to the CWHC each year from 1996 to 2015 is listed in figure 2. The distribution of age of onset of acute Charcot foot is shown for T1DM and
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T2DM in figure 3. For the T1DM patients, the peak in onset age was in the 50-59 year range, and
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for patients with T2DM the peak was in the 60-69 year range. Looking at gender distribution at first Charcot presentation, men presented at 57.4 years and women
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at 56.7 years (p=0.682).
Characteristics of the Charcot feet:
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The characteristics of the acute Charcot feet are listed in table 2. For 73% of the patients treated for acute Charcot foot (n=126), one or more possible causes for triggering the acute Charcot foot were listed in the medical records. Some patients presented with more than one possible cause. The primary cause given were minor traumatic events (such as hitting the foot, standing on a ladder or overloading while hiking) for 44% (n=56). This number does not include foot surgery. For 33% (n=41) foot ulcer treatment were given as a prelude to the Charcot breakout, off-loading of the contra-lateral foot prior to Charcot onset were recorded for 16% (n=20), and 10% (n=13) were registered as having poor glyemic control prior to the Charcot breakout.
In addition to this, prior (within 1 year) foot surgery or amputation were recorded for 29 patients. These were: Minor amputations (n=11), wound revision (including removal of foreign bodies 8/19
ACCEPTED MANUSCRIPT (n=9)), surgery for osteomyelitis (n=2), revascularisation (n=2), arthrodesis (n=2) and surgery related to fracture stabilisation (n=3).
The placement of the Charcot inflammation within the foot or ankle is shown schematically in figure 4. Cases have been divided into four zones comprised of phalanges, metatarses I-V, rear midfoot bones (oss. cuneiformes, cuboideum et naviculare) and the talus/calcaneus/ankle section. As several patients presented with an outbreak in more than one area, the total number of places
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exceeds the number of patients. Both the primary activation and possible recurrences are listed. The most prominent place of activation was around the Lisfranc joint. A total of 17 patients presented
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primarily with an ankle-Charcot. We were unable to determine a specific location of the Charcot
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activity in 22 cases.
A total of 164 patients (95%) received their primary off-loading with a removable off-loading
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device with a custom made insole with arch support, maintained by the CWHC, while the remaining 9 (5%) used other methods (such as a plaster cast or a wheelchair).
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Secondary off-loading in the form of an adapted stock sandal variant was used in 89 patients to transfer from the primary off-loading and into a form of new, permanent footwear. The remaining 84 patients transfered directly into the permanent footwear. This tertiary (long-term) footwear was:
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Handmade shoes by an out-of-hospital specialist (n=109); orthopedic or semi-orthopedic shoes
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(n=19); orthotic foot-ankle capsule boot (n=16); lower leg prosthesis (n=4); unknown (n=25).
There was no difference in the total duration of off-loading between patients with T1DM and
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T2DM (p=0.467). The average primary off-loading period was 8.3 months across the follow-up period, without any significant variations.
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A total of 51 recurrences of acute Charcot foot occured in the population. Of these 41 occured in the same foot, and 10 in the opposite foot (p<0.001) (table 2). Of these recurrences, 23 (45%) happened within 3 months of cessation of the primary off-loading. The total time from cessation in primary Charcot activity to recurrence was 17.7 months (range 1-103 months).
The frequency of complications to the acute Charcot foot was 67% (defined as ulcers and/or amputation due to ulcers, or ulcer risk after an acute Charcot foot where Charcot-related deformities played a role in the development of the ulcer). A total of 21 major amputations (above or below knee) were performed in 17 patients, meaning that ~10% of the patients with diabetes treated for an acute Charcot foot needed a major amputation. These were mostly performed due to uncontrollable infections years after the acute Charcot foot, and after extensive attempts at wound healing. 9/19
ACCEPTED MANUSCRIPT Apart from amputations, a total of 223 lesser surgical procedures were performed as part of the Charcot treatment at the CWHC. These mainly consisted of exostectomias and comprehensive wound debridements. Reconstructive surgery is not performed at the CWHC, but referred to another center when the foot is in a stable phase.
The medical records mentioned lacking compliance to the prescribed treatment by the CWHC
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(especially long-term off-loading) in 31 cases (18%). These patients had a significantly longer total duration of their acute Charcot condition (15.4 ±10.2 months) than patients who did not have any
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records of lacking compliance to the treatment (9.6 ±8.0 months)(p<0.001).
Furthermore, in the group with less-than-optimal complicance (n=31), 10 patients had one or more
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amputations (4 major and 11 minor), while 27 had one or more foot ulcers during the Charcot treatment. In the compliant group (n=142) there were 35 patients who received one or more
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amputations (17 major and 35 minor), while 89 had foot ulcers. This is a significant relationship between lacking compliance and the occurrence of complications (foot ulcers and/or amputation)
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(p=0.019).
Mortality and cause of death:
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During the 19 years included in the study, there were 68 deaths (39%) in the population. These 68
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patients lived for an average of 87 months (7.3 years) after first contact to the CWHC. The causes of death were: Cardiovascular (n=17), nephrological (n=12), cancer (n=10), infections (n=5), substance abuse (alchohol and/or opiates)(n=4), other (mainly pulmonal or traumatic)(n=8) or
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unknown (n=12).
A Kaplan-Meier plot (figure 5) shows a mean survival time of 152.4 months (12.7 years) from
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initial Charcot diagnosis, and a median survival of 166 months. This is an average life expectancy for patients with Charcot foot of 64.6 years (T1DM) and 71.3 years (T2DM). There were no differences in the time from first diagnosis to death between Charcot patients with T1DM and T2DM (p=0.222). The 5-year mortality from first diagnosis of acute Charcot foot was 14%.
Renal complications: Of the 173 patients included, 51 were diagnosed with nephropathy either before referral to the CWHC (n=25) or after (n=26). A total of 25 of these 51 patients required dialysis before the followup period ended.
Pharmacological data: 10/19
ACCEPTED MANUSCRIPT The most common antidiabetic drug used was insulin, with 48% of the patients in the T2DM group (and all in the T1DM group) using it. This is lower than in the regional control material, where 63% of the T2DM patients use insulin (p=0.017). A total of 60% of the T2DM patients used one or more types of oral antidiabetics, this is also significantly lower than in the control material (73%) (p=0.004). Seven patients (4%) with T2DM did not use any anti-diabetic medicine. For Charcot patients with T1DM, the use of antihypertensive medicine was more common (68%) than in the control material (44%) (p=0.001), while there was no difference in the use of statins
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(32% versus 42% respectively) (p=0.159). For Charcot patients with T2DM, there was no difference in the use of antihypertensives compared to the control material (79% versus 83%)
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(p=0.970), but there was a significantly lower use of statins in the T2DM Charcot population (49% versus 79%) (p<0.001).
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No patients received bisphosphonate for their Charcot feet at the CWHC.
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Employment status:
The work-situation was undisclosed in 23 cases. Of the remaining 150 patients, 67 (45%) were
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employed before the onset of their Charcot foot, 73 (49%) were on some form of retirement, while 10 (7%) were unemployed. At final discharge from the CWHC out-patient clinic, 26 (17%) remained employed, 101 (67%) had retired and 23 (15%) were unemployed.
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Thus, of the 67 initially employed 41 (61%) had lost their job during the Charcot treatment. This is
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a significant association between loss of employment and a Charcot foot (p<0.001). During their treatment, 78 (52%)(24 missing) patients had a disability leave signed by the CWHC. Of the remaining 71 without disability leave, 64 were retired for the entire treatment period, and 7
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of the 150 patients (5%) continued to work for the entirety of their treatment period. These 7 all had jobs assessed as "low-foot-impact", such as sedentary office work.
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There was a significant correlation between initial unemployment or retirement status, and a lack of compliance to the off-loading treatment (p=0.003). However, there was no correlation between initial employment status and risk of Charcot recurrence (p=0.401).
Discussion: We have conducted a retrospective, longitudinal study of 173 patients with diabetes mellitus related Charcot foot, treated at the CWHC between 1996-2015. We have described and assessed their treatment, compliance, complications, medicine use and employment status. We did not include patients diagnosed with Charcot foot on another basis than diabetes. This was mainly due to the heterogeneous nature of this group and to the small amount of data available.
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ACCEPTED MANUSCRIPT The population had a higher ratio of T1DM compared to T2DM than in both the background population and another other major group of patients referred to the CWHC (those with diabetes and minor amputation) (36). However, it is in line with the distribution reported by Game et al. (33). Both groups also had a high average HbA1c compared to the regional data. In the T1DM group 81% had an HbA1c above 59 mmol/mol (54% in regional data), in the T2DM group 61% had an HbA1c above 59 mmol/mol (48% in the regional data). The patients with T1DM were younger at onset of the Charcot foot, with a longer diabetes duration,
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a lower BMI, lower alcohol intake, a lower frequency of tobacco smoking and a higher HbA1c than
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the patients with T2DM.
Unexpectedly, the Charcot population had a low 5-year mortality of 14%. Previously published data
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from the CWHC on diabetes patients with a minor lower leg amputation showed a 5-year mortality of 43% (T1DM) and 52% (T2DM) (36). Furthermore, the average life expectancy in the Charcot
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foot population of 64.6 years (T1DM) and 71.3 years (T2DM) means that the population has a average life expectancy comparable to that of patients with diabetes in general (37).
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This mortality rate is lower than what has been reported by others (7,8,38), although Sohn et al. have also reported that foot ulcers have a higher mortality than Charcot foot, which might account for some of this difference. In addition, Fabrin et al. has also reported a very low mortality of 2 in
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115 Charcot patients over a median follow-up period of 48 months (2).
The resolution time of the primary Charcot outbreak was 8.3 months (table 2) which is in line with the CDUK study (33) and data published by Armstrong et. al (39), but longer than what was
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reported by Christensen et. al (18). There was a higher frequency of recurrences (24%) than reported by Christensen et al. (12%), and a longer resolution time of recurrences as well (9.9 versus
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2.3 months). These differences in resolution time might in part be due to differences in the patient populations, compliance to treatment and follow-up intensity, of which there is little data available in the litterature.
We found the self-reported possible primary triggering event to the Charcot foot to be traumatic in 44% of the cases, which is also similar to the CDUK study (estimated 36%). Regarding the lack of use of bisphosphonates for the Charcot patients, bisphosphonates have not been recommended for the treatment of acute Charcot foot in Denmark due to the insufficient evidence of their effect on this condition (33,40).
Regarding off-loading treatment, 95% of the population had been treated primarily with an Aircast. While a total contact cast is the golden standard, from our data a removable cast seems to be a 12/19
ACCEPTED MANUSCRIPT viable alternative. A high rate of use of off-loading and immobilisation is in line with several recommendations (23,24,33,41), and it is the best method of avoiding extensive damage to the foot bones. We found that lack of compliance to off-loading treatment had a significant correlation to the risk of developing complications from a Charcot foot. This was to be expected and underlines the importance of correct and sustained treatment, despite its possible longevity (39).
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In addition, we have shown that Charcot foot has a profound effect on the work-situation of the patients. Only 4% of the population were able (or allowed) to keep working throughout the period
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of off-loading, while 61% lost their job. We have not been able to adjust for regular retirement age, as this is somewhat flexible in Denmark, and we have no data to suggest whether someone beyond
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the normal retirement age stopped working due to their Charcot foot or for other reasons (planned
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or otherwise).
The main limitations of our study is in the design, as it is fully dependant on the medical records of
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the CWHC. The center employs a handful of highly specialized surgeons, meaning that all patients treated there have been evaluated by only a handful of doctors. Therefore, the records overall were kept to the same standard, and more easy to compare. However, data gathered from other databases
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and sources (such as blood samples) have not been accessable in all cases and are therefore lacking
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in some cases. In addition, data regarding specific parts of the treatment concerning for instance brand and type of secondary off-loading shoe wear, have not been accessible, as this is not described in the medical records.
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As can be seen by the high number of excluded patients, only about 50% of the patients registered with the diagnosis of Charcot foot (DM14.6) from the CWHC were actually included in this study.
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While this could affect data, it’s important to note that the main reasons for exclusion were erroneous/insufficiently described diagnosis or complications to a chronic Charcot foot, both of which would have negatively impacted the data quality.
Furthermore, all conclusions must be drawn with caution as the study is based on associations instead of cause-effect. All data, especially considering personal evaluations (such as lacking compliance) could have been influenced by registration bias by the clinicians. Furthermore, a few of the patients have been included in other, prospective, studies by the authors which could introduce observer bias. There are also several sources of inclusion bias. For instance, the fact that our population had a higher frequency of insulin treatment than the background diabetes population at large could mean 13/19
ACCEPTED MANUSCRIPT that they are more often followed at highly specialized centers instead of their family general practitioner, and therefore more likely to have their Charcot foot discovered and referred. Finally, as the CWHC is a highly specialized, multi-disciplinary center, the results here might mainly be generalisable to other populations of patients with diabetic Charcot foot treated at similar institutions.
In conclusion, we have conducted a large, retrospective, observational study of 173 patients with
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diabetes and acute Charcot foot, treated at a multi-disciplinary wound healing center between 1996 to 2015.
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In general, the patients were middle-aged at diagnosis, and more patients had T1DM and had a higher HbA1c and blood pressure than the overall population of diabetes patients in the region. A
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total of 67% developed complications such as ulcers, while non-compliant patients did significantly worse than those being compliant. However, the 5-year mortality was low, 14%, and comparable to
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diabetes patients without Charcot foot.
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Conflicts of interests:
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No conflicts of interests exists for any of the authors.
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References:
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ACCEPTED MANUSCRIPT Hartemann-Heurtier A, Van GH, Grimaldi A. The Charcot foot. Lancet. 2002 Nov 30;360(9347):1776–9.
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Fabrin J, Larsen K, Holstein PE. Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care. 2000 Jun;23(6):796–800.
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Lee L, Blume PA, Sumpio B. Charcot joint disease in diabetes mellitus. Ann Vasc Surg. 2003 Sep;17(5):571–80.
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Rogers LC, Frykberg RG. The charcot foot. Med Clin North Am. 2013 Sep;97(5):847–56.
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Boulton AJM. Diabetic neuropathy and foot complications. Handb Clin Neurol. 2014;126:97– 107.
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Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot neuroarthropathy in diabetes mellitus. Diabetologia. 2002 Aug;45(8):1085–96.
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van Baal J, Hubbard R, Game F, Jeffcoate W. Mortality associated with acute Charcot foot and neuropathic foot ulceration. Diabetes Care. 2010 May;33(5):1086–9.
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Sohn M-W, Lee TA, Stuck RM, Frykberg RG, Budiman-Mak E. Mortality risk of Charcot arthropathy compared with that of diabetic foot ulcer and diabetes alone. Diabetes Care. 2009 May;32(5):816–21.
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Pinzur MS, Evans A. Health-related quality of life in patients with Charcot foot. Am J Orthop Belle Mead NJ. 2003 Oct;32(10):492–6.
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10. Willrich A, Pinzur M, McNeil M, Juknelis D, Lavery L. Health related quality of life, cognitive function, and depression in diabetic patients with foot ulcer or amputation. A preliminary study. Foot Ankle Int Am Orthop Foot Ankle Soc Swiss Foot Ankle Soc. 2005 Feb;26(2):128–34.
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11. Sochocki MP, Verity S, Atherton PJ, Huntington JL, Sloan JA, Embil JM, et al. Health related quality of life in patients with Charcot arthropathy of the foot and ankle. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2008;14(1):11–5.
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12. Raspovic KM, Wukich DK. Self-reported quality of life in patients with diabetes: a comparison of patients with and without Charcot neuroarthropathy. Foot Ankle Int. 2014 Mar;35(3):195–200. 13. Kroin E, Schiff A, Pinzur MS, Davis ES, Chaharbakhshi E, DiSilvio FA. Functional Impairment of Patients Undergoing Surgical Correction for Charcot Foot Arthropathy. Foot Ankle Int. 2017 Jul;38(7):705–9. 14. Kroin E, Chaharbakhshi EO, Schiff A, Pinzur MS. Improvement in Quality of Life Following Operative Correction of Midtarsal Charcot Foot Deformity. Foot Ankle Int. 2018 Mar 1;1071100718762138. 15. Ramanujam CL, Facaros Z. An overview of conservative treatment options for diabetic Charcot foot neuroarthropathy. Diabet Foot Ankle. 2011;2. 16. Milne TE, Rogers JR, Kinnear EM, Martin HV, Lazzarini PA, Quinton TR, et al. Developing an evidence-based clinical pathway for the assessment, diagnosis and management of acute Charcot Neuro-Arthropathy: a systematic review. J Foot Ankle Res. 2013;6(1):30. 15/19
ACCEPTED MANUSCRIPT 17. Guyton GP. An analysis of iatrogenic complications from the total contact cast. Foot Ankle Int. 2005 Nov;26(11):903–7. 18. Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteo-arthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications. 2012 Oct;26(5):430–4. 19. Petrova NL, Edmonds ME. Medical management of Charcot arthropathy. Diabetes Obes Metab. 2013 Mar;15(3):193–7.
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20. Al-Rubeaan K, Al Derwish M, Ouizi S, Youssef AM, Subhani SN, Ibrahim HM, et al. Diabetic foot complications and their risk factors from a large retrospective cohort study. PloS One. 2015;10(5):e0124446.
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21. Larsen K, Fabrin J, Holstein PE. Incidence and management of ulcers in diabetic Charcot feet. J Wound Care. 2001 Sep;10(8):323–8.
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22. Pinzur MS, Shields N, Trepman E, Dawson P, Evans A. Current practice patterns in the treatment of Charcot foot. Foot Ankle Int. 2000 Nov;21(11):916–20.
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23. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg Off Publ Am Coll Foot Ankle Surg. 2006 Oct;45(5 Suppl):S1-66.
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24. Rogers LC, Frykberg RG, Armstrong DG, Boulton AJM, Edmonds M, Van GH, et al. The Charcot foot in diabetes. J Am Podiatr Med Assoc. 2011 Oct;101(5):437–46.
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25. Edmonds ME, Blundell MP, Morris ME, Thomas EM, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med. 1986 Aug;60(232):763–71. 26. Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev. 2000 Oct;16 Suppl 1:S75-83.
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27. Gottrup F. A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg. 2004 May;187(5A):38S–43S.
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28. Stuck RM, Sohn M-W, Budiman-Mak E, Lee TA, Weiss KB. Charcot arthropathy risk elevation in the obese diabetic population. Am J Med. 2008 Nov;121(11):1008–14. 29. Younis BB, Shahid A, Arshad R, Khurshid S, Masood J. Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital. BMC Endocr Disord. 2015;15:28. 30. Bergis D, Bergis PM, Hermanns N, Zink K, Haak T. Coronary artery disease as an independent predictor of survival in patients with type 2 diabetes and Charcot neuroosteoarthropathy. Acta Diabetol. 2014 Dec;51(6):1041–8. 31. Munson ME, Wrobel JS, Holmes CM, Hanauer DA. Data mining for identifying novel associations and temporal relationships with Charcot foot. J Diabetes Res. 2014;2014:214353. 32. Frykberg RG, Belczyk R. Epidemiology of the Charcot foot. Clin Podiatr Med Surg. 2008 Jan;25(1):17–28, v. 16/19
ACCEPTED MANUSCRIPT 33. Game FL, Catlow R, Jones GR, Edmonds ME, Jude EB, Rayman G, et al. Audit of acute Charcot’s disease in the UK: the CDUK study. Diabetologia. 2012 Jan;55(1):32–5. 34. Pakarinen T-K, Laine H-J, Mäenpää H, Mattila P, Lahtela J. Long-term outcome and quality of life in patients with Charcot foot. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2009;15(4):187–91. 35. The Danish Clinical Registries, http://www.rkkp.dk/in-english/. The Danish Diabetes Registry, Annual Report.
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36. Wilbek TE, Jansen RB, Jørgensen B, Svendsen OL. The Diabetic Foot in a Multidisciplinary Team Setting. Number of Amputations below Ankle Level and Mortality. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc. 2016 Jul 20;
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37. Leal J, Gray AM, Clarke PM. Development of life-expectancy tables for people with type 2 diabetes. Eur Heart J. 2009 Apr;30(7):834–9.
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38. Gazis A, Pound N, Macfarlane R, Treece K, Game F, Jeffcoate W. Mortality in patients with diabetic neuropathic osteoarthropathy (Charcot foot). Diabet Med J Br Diabet Assoc. 2004 Nov;21(11):1243–6.
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39. Armstrong DG, Todd WF, Lavery LA, Harkless LB, Bushman TR. The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. Diabet Med J Br Diabet Assoc. 1997 May;14(5):357–63.
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40. Pakarinen T-K, Laine H-J, Mäenpää H, Kähönen M, Mattila P, Lahtela J. Effect of immobilization, off-loading and zoledronic acid on bone mineral density in patients with acute Charcot neuroarthropathy: a prospective randomized trial. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2013 Jun;19(2):121–4.
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41. Sponer P, Kucera T, Brtková J, Srot J. The management of Charcot midfoot deformities in diabetic patients. Acta Medica Hradec Král Univ Carol Fac Medica Hradec Král. 2013;56(1):3–8.
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ACCEPTED MANUSCRIPT Table 1: Baseline data of included participants with T1DM or T2DM and acute Charcot foot. T2DM
P-value
Diabetes type
26%
74%
--
Sex (% m)
55%
74%
0.017*
Age at onset of Charcot foot (years)
51.9 ±11.6
58.6 ±8.6
<0.001*
Age of diabetes diagnosis at onset of Charcot foot (years)
31.2 ±10.4
11.4 ±8.2
<0.001*
BMI (median)
25.2
28.8
0.011*
Regular alcohol intake in excess of recommandations*
16%
41%
0.003*
Alcohol intake (units/week)
15.3 ±4.5
30.3 ±23.6
0.001*
Smoking status (current smoker)
18%
26%
Smoking status (ever smoked, yes/no)
20%
41%
Pack-years for current and former smokers (20 cigarettes/day/year)
26.1 ±11.4
41.5 ±27.4
0.010*
HbA1c (mmol/mol) (%)
81.7 ±21.4
66.5 ±20.3
0.001*
Systolic blood pressure (mmHg)
150 ±21
Diastolic blood pressure (mmHg)
79 ±10
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0.028*
8.2 ±4.0% 150 ±23
0.946
84 ±16
0.059
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9.7 ±4.1%
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T1DM
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n=167; 6 missing due to unknown diabetes type. Unless otherwise noted values are listed as mean ± 1SD or percentage of the population. + = 14 units/week for men or 7 units/week for women. * = Significant at chosen α-level of 0.05.
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ACCEPTED MANUSCRIPT Table 2: Data on the acute Charcot feet – duration and recurrences of off-loading for T1DM and T1DM (n=173). T1DM
T2DM
P-value
Affected foot (right/left/bilateral)
61% / 39% / 0%
54% / 44% / 2%
--
Mean temperature increase ( C)
3.5 ±1.3
3.6 ±1.6
0.905
Duration of primary off-loading (months)
8.6 ±6.5
8.4 ±6.5
0.796
Same side recurrences (1 time / >1 time)
16% / 7%
17% / 2%
--
Opposite side recurrences (1 time / >1 time)
7% / 2%
2% / 1%
--
Total duration of off-loading (primary Charcot + recurrence(s)) (months)
11.8 ±10.3
10.5 ±8.1
0.771
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Charcot foot characteristics:
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Unless otherwise noted values are listed as mean ± 1SD. Compared with Mann-Whitney rank sum tests. Data was missing for 6-14 patients in some parameters.
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Figure 1
Figure 2
Figure 3
Figure 4
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Rasmus Bo Jansen, Bo Jørgensen, Per E. Holstein, Klaus Kirketerp Møller, Ole Lander Svendsen PII: DOI: Reference:
S1056-8727(18)30357-X doi:10.1016/j.jdiacomp.2018.09.013 JDC 7276
To appear in:
Journal of Diabetes and Its Complications
Received date: Revised date: Accepted date:
3 April 2018 13 September 2018 20 September 2018
Please cite this article as: Rasmus Bo Jansen, Bo Jørgensen, Per E. Holstein, Klaus Kirketerp Møller, Ole Lander Svendsen , Mortality and complications after treatment of acute diabetic Charcot foot. Jdc (2018), doi:10.1016/j.jdiacomp.2018.09.013
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ACCEPTED MANUSCRIPT Mortality and complications after treatment of acute diabetic Charcot foot
By Rasmus Bo Jansen1, Bo Jørgensen2, Per E. Holstein2, Klaus Kirketerp Møller2 and Ole Lander Svendsen1
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1) Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark 2) Center forWound Healing, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen NV, Denmark
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Word count: 4707 Reference count: 41
Corresponding author: Rasmus Bo Jansen, Ph.D. MD Address: Bispebjerg Hospital, Bispebjerg Bakke 23 ICamb, opg. 60, st. 2400 Kbh. NV, Denmark E-mail: [email protected] Phone: 0045 22 99 93 74
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ACCEPTED MANUSCRIPT Aims: Charcot foot is a rare but disabling complication to diabetic neuropathy, and can cause permanent, limb-threatening deformities. The aim of this study was to investigate a population of patients a Charcot foot on a case-by-case basis, in order to assess the consequences of an acute Charcot foot and its complications. Methods: The study was conducted a retrospective study of patients admitted to the Copenhagen Wound Healing Center between 1996-2015 with the diagnosis of Charcot foot (DM14.6) and diabetes mellitus type 1 or 2 (DE10.X and DE11.X). Physical and electronic records were used, and compared to data from the Danish Diabetes Registry.
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Results: In total 392 patients were identified of which 173 were included. There were 26% with type 1 diabetes (initial HbA1c 81.7 ±21.4 mmol/mol) and 74% with type 2 diabetes (initial HbA1c 66.5 ±20.3 mmol/mol). Primary off-loading was with a removable walker in 95% of the cases (average off-loading time 8.3 months). The 5-year mortality was 14% with a mean survival time of 12.7 years. There was an association between lack of compliance and occurrence of foot complications, as well as between having a Charcot foot and leaving the workforce.
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Conclusion: More patients had type 1 diabetes compared to the background population, and they had a higher HbA1c than the general population of diabetes patients. A total of 67% developed complications such as ulcers, while patients non-compliant to treatment did significantly worse than those being compliant. The 5-year mortality was low, 14%, and comparable to diabetes patients without Charcot foot.
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Keywords: Charcot foot ; retrospective follow-up ; complications ; mortality
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ACCEPTED MANUSCRIPT Introduction: Charcot foot is a rare complication to peripheral neuropathy (1–5). It manifests as an aseptic inflammation and bone degeneration located in one or both feet. If left untreated it can cause spontaneous fatigue bone fractures, resulting in deformity, ulcerations and possibly ultimately amputation. The majority of Charcot foot cases in the Western world today occur as a complication to diabetes mellitus, with a group incidence rate about 0.3% (2,6). Charcot foot is associated with a marked increase in morbidity (7,8), and patients with Charcot foot rate their life quality as "fair" or
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"poor" in standardized questionnaires (9–14). Treatment consists primarily of long-term off-loading, either with a total contact cast (TCC, "gold standard"), or as an alternative with a removable off-
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loading boot (e.g. Aircast) (15–19).
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Charcot foot is a major cause for ulceration and amputation in patients with diabetes (20,21). As such, correct and timely treatment is of vital importance. The diagnostic tools and treatment used
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for Charcot foot can vary extensively from hospital to hospital despite the rather uniform guidelines in the litterature (22–24). Furthermore, each patient treated often needs attention from several
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different medical specialties during their hospital admission.
This poses a challenge in the standard hospital environment where patients with Charcot foot are often admitted to an orthopedic surgery ward for stabilization and/or off-loading. Several groups
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have recommended employing a multi-disciplinary team in the diagnostics, treatment and follow-up
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of patients with Charcot foot (23,25,26). In 1996, a Danish center to employ this multidisciplinary strategy was established at the Copenhagen Wound Healing Center (CWHC). The center's main focus is off-loading, wound recovery and day-to-day surgery. Major Charcot reconstruction does
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not fall under the purview of the center.
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The aim of the present study was to describe a population with diabetes-related Charcot foot treated at the CWHC in the period of 1996-2015 (27). Several large studies have previously assessed populations with diabetes and Charcot foot (28–34). To complement these works, our main objective was to evaluate our population, their treatment and resolution on a case-by-case basis. We wanted to assess the consequences of an acute Charcot foot and its complications.
Methods: Materials: This study was conducted as a retrospective, longitudinal, observational study. The population consisted of all patients treated for acute Charcot foot as a complication to diabetes mellitus at the CWHC at Bispebjerg Hospital, Copenhagen, Denmark between 1996-2015 (figure 1). The 3/19
ACCEPTED MANUSCRIPT maximum possible follow-up was thus 19 years. The patients were identified using the electronic patient registration system, which logs all contacts to the hospital. The contacts are logged with a unique personal identifier in the form of each patients’ personal identification number from the Danish national civil registration system (CPR) and also include ICD-10 codes. All contacts with the ICD-10 code for neuropathic arthropathy (DM14.6) were reviewed for inclusion in the study. Only candidates also diagnosed with diabetes mellitus type 1 (T1DM) or 2 (T2DM) were included. The diagnosis was not always evident from the log, and each patient's
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medical charts and history was reviewed to confirm their diabetes status. Patients with diabetes due to other reasons (e.g. chronic pancreatitis) were excluded.
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Patients coded with DM14.6 without any evidence of Charcot foot diagnosis or treatment in their medical history were excluded. Furthermore, only patients with Charcot foot who were referred to
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the CWHC in the acute/initial phase (defined as <6 months from reported onset of the condition) were included. Patients already undergoing treatment at the CWHC for other reasons (e.g. foot
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ulcers) when the acute Charcot foot occured were also included in the study. All patients fitting the group above were considered for inclusion including those who, during parts
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of the follow-up period, already participated in other medical studies.
Data recording:
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All patients were followed up from first contact at the Copenhagen Wound Healing Center and until
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final discharge, death or the 1st of August 2015. The records date back to 1996 where the CWHC was established. The patients were followed up with medical records, both in paper and electronic format, and well as in the "Danish Register of Cause of Death". Mortality data was collected from
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first contact at the CWHC and until death or the 1st of August 2015. A secondary search was performed of the database program storing scanned versions of x-rays (both
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conventional and CT), MRIs and scintigraphies. These were assessed comparatively to determine the location of the Charcot activation. All anthropomorphic data were registered at baseline (as close to first contact to the CWHC as possible, within a margin of 6 months) including age, sex, weight, height, blood pressure, HbA1c, and smoking/alcohol consumption habits. Additionally, we registered each patients occupational situation at first contact, and any recorded changes during the treatment period. Finally, we registered all late stage diabetic complications at first contact, and again if they changed during the follow-up period.
Definitions: 4/19
ACCEPTED MANUSCRIPT Acute Charcot foot: Patients referred with a possible new, acute Charcot foot were considered for the diagnosis if they were seen for the first time at the CWHC within 6 months of discovering a red, warm foot (swelling or pain not mandatory) without another obvious cause (such as known, ongoing infection or x-ray confirming major traumatic fracture with a matching recent medical history). All patients also had the diagnosis confirmed by x-ray (conventional or CT) and either scintigraphy and/or MRI, either before referral or shortly after first visit to the CWHC (most cases).
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The acute phase of the Charcot foot was considered to be abated: When the foot temperature difference between the Charcot foot and the contralateral foot
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had dropped below 1.5 °C and the edema subsided.
When the patient were allowed full load-bearing (often with the removable off-loading boot
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as modfied support).
When a control scintigraphy/MRI showed no activity in the feet (primarily used in case of
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bilateral Charcot foot).
Foot ulcers were considered to be related to the Charcot foot if they fitted chronologically with this,
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and had a placement consistent with the skeletal damage or altered pressure patterns caused by the foot changes (based on records by doctors and podiatrists respectively). Age of diabetes refers to the time passed from first confirmed diabetes diagnosis, irrespective of
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onset of symptoms or use of antidiabetic drugs or insulins.
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Charcot foot recurrence was defined as new symptoms of swelling/reddening and an increase in foot skin temperature difference of more than 2 °C in the previously affected foot, occurring after
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full weight bearing was attempted for at least one month.
Late stage diabetic complications were registered if the records showed that the patient had been
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diagnosed with such, or if the records showed the following: Neuropathy: Impaired peripheral sensitivity as measured with biothesiometry and/or monofilament test.
Retinopathy: Diagnosed solely based on eye screening with fundusscopy. Macular edema, exudation, non-proliferative and/or proliferative diabetic retinopathy were all registered.
Nephropathy: Defined as macroalbuminuria (urine albumine/creatinine ratio >300 mg); progression from microalbuminuria (urine albumine/creatinine ratio between 30 - 299 mg) to macroalbuminuria; a persistent (two or more consecutive measurements at least a month apart) increase in p-creatinine (above twice the normal range) without another cause present in the records (such as severe infections/septicemia, trauma or hypovolemic shock); initiation of renal dialysis; or death from renal disease. 5/19
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Macrovascular disease: Recorded events of angina pectoris; peripheral vascular insufficiency (defined as ankle-brachial index <0.9 and/or toe-brachial index <0.7); performance of revascularization; pathological CAG; performed PCI/CABG procedure; or death from major cardiovascular event.
Occupation: To evaluate the possible effect of an acute Charcot foot on a patient's employment status, we also
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gathered data regarding the patients' occupation before, during and after the Charcot foot had abated. These data were based on notes in the medical records. The Danish welfare system
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distinguishes between several types of aid for chronically ill citizens including premature pension, early withdrawal for health reasons and part-time work subsidized by the state. For ease of reading,
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these have been categorized into:
Job (the patient returned to his/her ordinary job). This includes reschooling (the patient
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returned to the job market, but in another job with less load on the feet) and job at reduced time (the patient returned to the job market, but with a shorter-than-average work-week). Retirement (the patient retired but at the standard age 65 years or above). This includes all
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forms of early retirement and disability pension (the patient retired before the normal age of retirement in Denmark (65 years)).
Unemployed (the patient does not have a job for whatever reason, and does not qualify for
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retirement (early, disability or otherwise).
Statistical analysis:
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Data are expressed as means ±1SD or median and ranges. Missing values in the data were excluded by row in the relevant analysis. An α=0.05 was considered significant. Normal distribution in data
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was controlled by Shapiro-Wilks tests, and no transformations were used. ANOVA was used for variance analysis between groups in normally distributed subsets, while in ranked groups and groups not normally distributed, non-parametric tests in the form of the Mann-Whitney rank sum test and the Kruskal-Wallis one way analysis of variance on ranks were used. We tested for correlations using Pearson's r (continuous variables), Spearman's test (continuous and categorical data) and the chi-square test (categorical data). Paired/related dichotome 2 x 2 datasets (repeated measures) were compared using the McNemar test. Categorical and continuous data were compared using a logistic regression model. Survival analysis was performed with a Kaplan-Meier estimator. To counteract problems from multiple comparisons (mass significance), test results were adjusted using the Holm-Bonferroni correction on a test-by-test basis. Statistics and generel data handling was done using IBM SPSS Statistics v. 23 by IBM Corporation, 6/19
ACCEPTED MANUSCRIPT SIGMAPLOT v. 11.0.0.77 by Systat Software Inc., Microsoft Excel 2000 v. 9.0.2812 by Microsoft Corporation and Apache OpenOffice 4.0.1 by The Apache Software Foundation.
Control population: The results have been compared to data from the annual report from the national Danish Diabetes Registry (DDR) from 2014/2015 (35). The data used represent the entire population of diabetes patients, either type 1 or 2, treated at a hospital outpatient clinic the capital region of Greater
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Copenhagen (Denmark). This is also where the CWHC is located. The data from the DDR does not contain elaborate information regarding possible secondary
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diagnoses and/or concomittant diseases. Furthermore, it does not contain mortality data.
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Results: Inclusion process:
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We identified 313 patients coded with the ICD-10 codes for diabetes mellitus (DE10.X; DE11.X; DE13.X; DE14.X) and acute Charcot foot (DM14.6) between 1996-2015. Another 79 patients had
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been diagnosed with Charcot foot, but not with diabetes mellitus. Thus, 392 patients diagnosed with Charcot foot were screened for inclusion. The flow of patients for inclusion is shown in figure 1. Of these 392 patients, 91 (23%) had been coded with a Charcot foot diagnosis (DM14.6) in the
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system without their written records containing sufficient confirmation for this diagnosis, and were
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thus excluded. Most of these were due to the initial referral diagnosis of Charcot foot not being edited in the system as it was rejected by primary patient examination at the CWHC. Furthermore, 25 (6%) patients were diagnosed as having Charcot foot due to another source of
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neuropathy than diabetes mellitus, and were also excluded. The causes were alcoholism (n=15), spinal stenosis (n=2), spinal tumor (n=1), neurodevelopmental defect (n=1), Charcot-Marie-Tooth
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(n=3), side effect to anti-HIV medication (n=1) and unknown (n=2). Another 73 (19%) patients were excluded due to being admitted or seen >6 months after the reported onset of their acute Charcot foot. These patients were typically referred years after the active phase of their Charcot foot to receive treatment for foot deformities and ulcers. Finally, 30 (8%) were excluded due to missing data. Thus, of the 392 patients screened for inclusion 173 (44%) were included in the study.
Population characteristics: Mean follow-up time at the CWHC was 31 months (range 3-168 months). Anthropomorphic data for all included patients are listed in table 1. Of the population, 26% had T1DM and 74% had T2DM. None were diagnosed with other forms of diabetes. There was a higher proportion of 7/19
ACCEPTED MANUSCRIPT patients with T1DM (26%) than in the diabetic control population (around 10%), and in a population of patients with diabetes treated with below ankle level amputation from the CWHC (20% had T1DM) (36). Males made up the largest portion of both the T1DM and T2DM groups with 55% and 74% respectively. In the regional hospital data males make up 55% of the T1DM population and 61% of the T2DM population.
The Charcot population had an higher initial HbA1c of 81.7 ±21.4 mmol/mol (median 83
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mmol/mol) (9.7 ±4.1%; median 9.7%) for T1DM patients compared to the median level in the region of greater Copenhagen which is 61 mmol/mol (7.7%) (p<0.001).
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The T2DM Charcot patients also had a higher initial HbA1c of 66.5 ±20.3 mmol/mol for T2DM patients (median 66 mmol/mol) (8.2 ±4.0%; median 8.2%) compared to the median regional level
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of 59 mmol/mol (7.5%) (32).
The median blood pressure in the T1DM group was 151/80 mmHg, and 150/82 mmHg in the
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mmHg and 133/78 mmHg respectively (table 1).
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T2DM group. The median levels for diabetics in the region of greater Copenhagen are 130/77
The number of patients referred with acute Charcot foot to the CWHC each year from 1996 to 2015 is listed in figure 2. The distribution of age of onset of acute Charcot foot is shown for T1DM and
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T2DM in figure 3. For the T1DM patients, the peak in onset age was in the 50-59 year range, and
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for patients with T2DM the peak was in the 60-69 year range. Looking at gender distribution at first Charcot presentation, men presented at 57.4 years and women
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at 56.7 years (p=0.682).
Characteristics of the Charcot feet:
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The characteristics of the acute Charcot feet are listed in table 2. For 73% of the patients treated for acute Charcot foot (n=126), one or more possible causes for triggering the acute Charcot foot were listed in the medical records. Some patients presented with more than one possible cause. The primary cause given were minor traumatic events (such as hitting the foot, standing on a ladder or overloading while hiking) for 44% (n=56). This number does not include foot surgery. For 33% (n=41) foot ulcer treatment were given as a prelude to the Charcot breakout, off-loading of the contra-lateral foot prior to Charcot onset were recorded for 16% (n=20), and 10% (n=13) were registered as having poor glyemic control prior to the Charcot breakout.
In addition to this, prior (within 1 year) foot surgery or amputation were recorded for 29 patients. These were: Minor amputations (n=11), wound revision (including removal of foreign bodies 8/19
ACCEPTED MANUSCRIPT (n=9)), surgery for osteomyelitis (n=2), revascularisation (n=2), arthrodesis (n=2) and surgery related to fracture stabilisation (n=3).
The placement of the Charcot inflammation within the foot or ankle is shown schematically in figure 4. Cases have been divided into four zones comprised of phalanges, metatarses I-V, rear midfoot bones (oss. cuneiformes, cuboideum et naviculare) and the talus/calcaneus/ankle section. As several patients presented with an outbreak in more than one area, the total number of places
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exceeds the number of patients. Both the primary activation and possible recurrences are listed. The most prominent place of activation was around the Lisfranc joint. A total of 17 patients presented
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primarily with an ankle-Charcot. We were unable to determine a specific location of the Charcot
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activity in 22 cases.
A total of 164 patients (95%) received their primary off-loading with a removable off-loading
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device with a custom made insole with arch support, maintained by the CWHC, while the remaining 9 (5%) used other methods (such as a plaster cast or a wheelchair).
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Secondary off-loading in the form of an adapted stock sandal variant was used in 89 patients to transfer from the primary off-loading and into a form of new, permanent footwear. The remaining 84 patients transfered directly into the permanent footwear. This tertiary (long-term) footwear was:
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Handmade shoes by an out-of-hospital specialist (n=109); orthopedic or semi-orthopedic shoes
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(n=19); orthotic foot-ankle capsule boot (n=16); lower leg prosthesis (n=4); unknown (n=25).
There was no difference in the total duration of off-loading between patients with T1DM and
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T2DM (p=0.467). The average primary off-loading period was 8.3 months across the follow-up period, without any significant variations.
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A total of 51 recurrences of acute Charcot foot occured in the population. Of these 41 occured in the same foot, and 10 in the opposite foot (p<0.001) (table 2). Of these recurrences, 23 (45%) happened within 3 months of cessation of the primary off-loading. The total time from cessation in primary Charcot activity to recurrence was 17.7 months (range 1-103 months).
The frequency of complications to the acute Charcot foot was 67% (defined as ulcers and/or amputation due to ulcers, or ulcer risk after an acute Charcot foot where Charcot-related deformities played a role in the development of the ulcer). A total of 21 major amputations (above or below knee) were performed in 17 patients, meaning that ~10% of the patients with diabetes treated for an acute Charcot foot needed a major amputation. These were mostly performed due to uncontrollable infections years after the acute Charcot foot, and after extensive attempts at wound healing. 9/19
ACCEPTED MANUSCRIPT Apart from amputations, a total of 223 lesser surgical procedures were performed as part of the Charcot treatment at the CWHC. These mainly consisted of exostectomias and comprehensive wound debridements. Reconstructive surgery is not performed at the CWHC, but referred to another center when the foot is in a stable phase.
The medical records mentioned lacking compliance to the prescribed treatment by the CWHC
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(especially long-term off-loading) in 31 cases (18%). These patients had a significantly longer total duration of their acute Charcot condition (15.4 ±10.2 months) than patients who did not have any
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records of lacking compliance to the treatment (9.6 ±8.0 months)(p<0.001).
Furthermore, in the group with less-than-optimal complicance (n=31), 10 patients had one or more
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amputations (4 major and 11 minor), while 27 had one or more foot ulcers during the Charcot treatment. In the compliant group (n=142) there were 35 patients who received one or more
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amputations (17 major and 35 minor), while 89 had foot ulcers. This is a significant relationship between lacking compliance and the occurrence of complications (foot ulcers and/or amputation)
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(p=0.019).
Mortality and cause of death:
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During the 19 years included in the study, there were 68 deaths (39%) in the population. These 68
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patients lived for an average of 87 months (7.3 years) after first contact to the CWHC. The causes of death were: Cardiovascular (n=17), nephrological (n=12), cancer (n=10), infections (n=5), substance abuse (alchohol and/or opiates)(n=4), other (mainly pulmonal or traumatic)(n=8) or
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unknown (n=12).
A Kaplan-Meier plot (figure 5) shows a mean survival time of 152.4 months (12.7 years) from
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initial Charcot diagnosis, and a median survival of 166 months. This is an average life expectancy for patients with Charcot foot of 64.6 years (T1DM) and 71.3 years (T2DM). There were no differences in the time from first diagnosis to death between Charcot patients with T1DM and T2DM (p=0.222). The 5-year mortality from first diagnosis of acute Charcot foot was 14%.
Renal complications: Of the 173 patients included, 51 were diagnosed with nephropathy either before referral to the CWHC (n=25) or after (n=26). A total of 25 of these 51 patients required dialysis before the followup period ended.
Pharmacological data: 10/19
ACCEPTED MANUSCRIPT The most common antidiabetic drug used was insulin, with 48% of the patients in the T2DM group (and all in the T1DM group) using it. This is lower than in the regional control material, where 63% of the T2DM patients use insulin (p=0.017). A total of 60% of the T2DM patients used one or more types of oral antidiabetics, this is also significantly lower than in the control material (73%) (p=0.004). Seven patients (4%) with T2DM did not use any anti-diabetic medicine. For Charcot patients with T1DM, the use of antihypertensive medicine was more common (68%) than in the control material (44%) (p=0.001), while there was no difference in the use of statins
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(32% versus 42% respectively) (p=0.159). For Charcot patients with T2DM, there was no difference in the use of antihypertensives compared to the control material (79% versus 83%)
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(p=0.970), but there was a significantly lower use of statins in the T2DM Charcot population (49% versus 79%) (p<0.001).
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No patients received bisphosphonate for their Charcot feet at the CWHC.
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Employment status:
The work-situation was undisclosed in 23 cases. Of the remaining 150 patients, 67 (45%) were
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employed before the onset of their Charcot foot, 73 (49%) were on some form of retirement, while 10 (7%) were unemployed. At final discharge from the CWHC out-patient clinic, 26 (17%) remained employed, 101 (67%) had retired and 23 (15%) were unemployed.
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Thus, of the 67 initially employed 41 (61%) had lost their job during the Charcot treatment. This is
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a significant association between loss of employment and a Charcot foot (p<0.001). During their treatment, 78 (52%)(24 missing) patients had a disability leave signed by the CWHC. Of the remaining 71 without disability leave, 64 were retired for the entire treatment period, and 7
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of the 150 patients (5%) continued to work for the entirety of their treatment period. These 7 all had jobs assessed as "low-foot-impact", such as sedentary office work.
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There was a significant correlation between initial unemployment or retirement status, and a lack of compliance to the off-loading treatment (p=0.003). However, there was no correlation between initial employment status and risk of Charcot recurrence (p=0.401).
Discussion: We have conducted a retrospective, longitudinal study of 173 patients with diabetes mellitus related Charcot foot, treated at the CWHC between 1996-2015. We have described and assessed their treatment, compliance, complications, medicine use and employment status. We did not include patients diagnosed with Charcot foot on another basis than diabetes. This was mainly due to the heterogeneous nature of this group and to the small amount of data available.
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ACCEPTED MANUSCRIPT The population had a higher ratio of T1DM compared to T2DM than in both the background population and another other major group of patients referred to the CWHC (those with diabetes and minor amputation) (36). However, it is in line with the distribution reported by Game et al. (33). Both groups also had a high average HbA1c compared to the regional data. In the T1DM group 81% had an HbA1c above 59 mmol/mol (54% in regional data), in the T2DM group 61% had an HbA1c above 59 mmol/mol (48% in the regional data). The patients with T1DM were younger at onset of the Charcot foot, with a longer diabetes duration,
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a lower BMI, lower alcohol intake, a lower frequency of tobacco smoking and a higher HbA1c than
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the patients with T2DM.
Unexpectedly, the Charcot population had a low 5-year mortality of 14%. Previously published data
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from the CWHC on diabetes patients with a minor lower leg amputation showed a 5-year mortality of 43% (T1DM) and 52% (T2DM) (36). Furthermore, the average life expectancy in the Charcot
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foot population of 64.6 years (T1DM) and 71.3 years (T2DM) means that the population has a average life expectancy comparable to that of patients with diabetes in general (37).
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This mortality rate is lower than what has been reported by others (7,8,38), although Sohn et al. have also reported that foot ulcers have a higher mortality than Charcot foot, which might account for some of this difference. In addition, Fabrin et al. has also reported a very low mortality of 2 in
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115 Charcot patients over a median follow-up period of 48 months (2).
The resolution time of the primary Charcot outbreak was 8.3 months (table 2) which is in line with the CDUK study (33) and data published by Armstrong et. al (39), but longer than what was
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reported by Christensen et. al (18). There was a higher frequency of recurrences (24%) than reported by Christensen et al. (12%), and a longer resolution time of recurrences as well (9.9 versus
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2.3 months). These differences in resolution time might in part be due to differences in the patient populations, compliance to treatment and follow-up intensity, of which there is little data available in the litterature.
We found the self-reported possible primary triggering event to the Charcot foot to be traumatic in 44% of the cases, which is also similar to the CDUK study (estimated 36%). Regarding the lack of use of bisphosphonates for the Charcot patients, bisphosphonates have not been recommended for the treatment of acute Charcot foot in Denmark due to the insufficient evidence of their effect on this condition (33,40).
Regarding off-loading treatment, 95% of the population had been treated primarily with an Aircast. While a total contact cast is the golden standard, from our data a removable cast seems to be a 12/19
ACCEPTED MANUSCRIPT viable alternative. A high rate of use of off-loading and immobilisation is in line with several recommendations (23,24,33,41), and it is the best method of avoiding extensive damage to the foot bones. We found that lack of compliance to off-loading treatment had a significant correlation to the risk of developing complications from a Charcot foot. This was to be expected and underlines the importance of correct and sustained treatment, despite its possible longevity (39).
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In addition, we have shown that Charcot foot has a profound effect on the work-situation of the patients. Only 4% of the population were able (or allowed) to keep working throughout the period
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of off-loading, while 61% lost their job. We have not been able to adjust for regular retirement age, as this is somewhat flexible in Denmark, and we have no data to suggest whether someone beyond
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the normal retirement age stopped working due to their Charcot foot or for other reasons (planned
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or otherwise).
The main limitations of our study is in the design, as it is fully dependant on the medical records of
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the CWHC. The center employs a handful of highly specialized surgeons, meaning that all patients treated there have been evaluated by only a handful of doctors. Therefore, the records overall were kept to the same standard, and more easy to compare. However, data gathered from other databases
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and sources (such as blood samples) have not been accessable in all cases and are therefore lacking
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in some cases. In addition, data regarding specific parts of the treatment concerning for instance brand and type of secondary off-loading shoe wear, have not been accessible, as this is not described in the medical records.
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As can be seen by the high number of excluded patients, only about 50% of the patients registered with the diagnosis of Charcot foot (DM14.6) from the CWHC were actually included in this study.
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While this could affect data, it’s important to note that the main reasons for exclusion were erroneous/insufficiently described diagnosis or complications to a chronic Charcot foot, both of which would have negatively impacted the data quality.
Furthermore, all conclusions must be drawn with caution as the study is based on associations instead of cause-effect. All data, especially considering personal evaluations (such as lacking compliance) could have been influenced by registration bias by the clinicians. Furthermore, a few of the patients have been included in other, prospective, studies by the authors which could introduce observer bias. There are also several sources of inclusion bias. For instance, the fact that our population had a higher frequency of insulin treatment than the background diabetes population at large could mean 13/19
ACCEPTED MANUSCRIPT that they are more often followed at highly specialized centers instead of their family general practitioner, and therefore more likely to have their Charcot foot discovered and referred. Finally, as the CWHC is a highly specialized, multi-disciplinary center, the results here might mainly be generalisable to other populations of patients with diabetic Charcot foot treated at similar institutions.
In conclusion, we have conducted a large, retrospective, observational study of 173 patients with
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diabetes and acute Charcot foot, treated at a multi-disciplinary wound healing center between 1996 to 2015.
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In general, the patients were middle-aged at diagnosis, and more patients had T1DM and had a higher HbA1c and blood pressure than the overall population of diabetes patients in the region. A
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total of 67% developed complications such as ulcers, while non-compliant patients did significantly worse than those being compliant. However, the 5-year mortality was low, 14%, and comparable to
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diabetes patients without Charcot foot.
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Conflicts of interests:
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No conflicts of interests exists for any of the authors.
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References:
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ACCEPTED MANUSCRIPT Hartemann-Heurtier A, Van GH, Grimaldi A. The Charcot foot. Lancet. 2002 Nov 30;360(9347):1776–9.
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Fabrin J, Larsen K, Holstein PE. Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care. 2000 Jun;23(6):796–800.
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Lee L, Blume PA, Sumpio B. Charcot joint disease in diabetes mellitus. Ann Vasc Surg. 2003 Sep;17(5):571–80.
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Rogers LC, Frykberg RG. The charcot foot. Med Clin North Am. 2013 Sep;97(5):847–56.
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Boulton AJM. Diabetic neuropathy and foot complications. Handb Clin Neurol. 2014;126:97– 107.
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Rajbhandari SM, Jenkins RC, Davies C, Tesfaye S. Charcot neuroarthropathy in diabetes mellitus. Diabetologia. 2002 Aug;45(8):1085–96.
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van Baal J, Hubbard R, Game F, Jeffcoate W. Mortality associated with acute Charcot foot and neuropathic foot ulceration. Diabetes Care. 2010 May;33(5):1086–9.
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Sohn M-W, Lee TA, Stuck RM, Frykberg RG, Budiman-Mak E. Mortality risk of Charcot arthropathy compared with that of diabetic foot ulcer and diabetes alone. Diabetes Care. 2009 May;32(5):816–21.
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Pinzur MS, Evans A. Health-related quality of life in patients with Charcot foot. Am J Orthop Belle Mead NJ. 2003 Oct;32(10):492–6.
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10. Willrich A, Pinzur M, McNeil M, Juknelis D, Lavery L. Health related quality of life, cognitive function, and depression in diabetic patients with foot ulcer or amputation. A preliminary study. Foot Ankle Int Am Orthop Foot Ankle Soc Swiss Foot Ankle Soc. 2005 Feb;26(2):128–34.
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11. Sochocki MP, Verity S, Atherton PJ, Huntington JL, Sloan JA, Embil JM, et al. Health related quality of life in patients with Charcot arthropathy of the foot and ankle. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2008;14(1):11–5.
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12. Raspovic KM, Wukich DK. Self-reported quality of life in patients with diabetes: a comparison of patients with and without Charcot neuroarthropathy. Foot Ankle Int. 2014 Mar;35(3):195–200. 13. Kroin E, Schiff A, Pinzur MS, Davis ES, Chaharbakhshi E, DiSilvio FA. Functional Impairment of Patients Undergoing Surgical Correction for Charcot Foot Arthropathy. Foot Ankle Int. 2017 Jul;38(7):705–9. 14. Kroin E, Chaharbakhshi EO, Schiff A, Pinzur MS. Improvement in Quality of Life Following Operative Correction of Midtarsal Charcot Foot Deformity. Foot Ankle Int. 2018 Mar 1;1071100718762138. 15. Ramanujam CL, Facaros Z. An overview of conservative treatment options for diabetic Charcot foot neuroarthropathy. Diabet Foot Ankle. 2011;2. 16. Milne TE, Rogers JR, Kinnear EM, Martin HV, Lazzarini PA, Quinton TR, et al. Developing an evidence-based clinical pathway for the assessment, diagnosis and management of acute Charcot Neuro-Arthropathy: a systematic review. J Foot Ankle Res. 2013;6(1):30. 15/19
ACCEPTED MANUSCRIPT 17. Guyton GP. An analysis of iatrogenic complications from the total contact cast. Foot Ankle Int. 2005 Nov;26(11):903–7. 18. Christensen TM, Gade-Rasmussen B, Pedersen LW, Hommel E, Holstein PE, Svendsen OL. Duration of off-loading and recurrence rate in Charcot osteo-arthropathy treated with less restrictive regimen with removable walker. J Diabetes Complications. 2012 Oct;26(5):430–4. 19. Petrova NL, Edmonds ME. Medical management of Charcot arthropathy. Diabetes Obes Metab. 2013 Mar;15(3):193–7.
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20. Al-Rubeaan K, Al Derwish M, Ouizi S, Youssef AM, Subhani SN, Ibrahim HM, et al. Diabetic foot complications and their risk factors from a large retrospective cohort study. PloS One. 2015;10(5):e0124446.
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21. Larsen K, Fabrin J, Holstein PE. Incidence and management of ulcers in diabetic Charcot feet. J Wound Care. 2001 Sep;10(8):323–8.
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22. Pinzur MS, Shields N, Trepman E, Dawson P, Evans A. Current practice patterns in the treatment of Charcot foot. Foot Ankle Int. 2000 Nov;21(11):916–20.
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23. Frykberg RG, Zgonis T, Armstrong DG, Driver VR, Giurini JM, Kravitz SR, et al. Diabetic foot disorders. A clinical practice guideline (2006 revision). J Foot Ankle Surg Off Publ Am Coll Foot Ankle Surg. 2006 Oct;45(5 Suppl):S1-66.
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24. Rogers LC, Frykberg RG, Armstrong DG, Boulton AJM, Edmonds M, Van GH, et al. The Charcot foot in diabetes. J Am Podiatr Med Assoc. 2011 Oct;101(5):437–46.
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25. Edmonds ME, Blundell MP, Morris ME, Thomas EM, Cotton LT, Watkins PJ. Improved survival of the diabetic foot: the role of a specialized foot clinic. Q J Med. 1986 Aug;60(232):763–71. 26. Apelqvist J, Larsson J. What is the most effective way to reduce incidence of amputation in the diabetic foot? Diabetes Metab Res Rev. 2000 Oct;16 Suppl 1:S75-83.
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27. Gottrup F. A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. Am J Surg. 2004 May;187(5A):38S–43S.
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28. Stuck RM, Sohn M-W, Budiman-Mak E, Lee TA, Weiss KB. Charcot arthropathy risk elevation in the obese diabetic population. Am J Med. 2008 Nov;121(11):1008–14. 29. Younis BB, Shahid A, Arshad R, Khurshid S, Masood J. Charcot osteoarthropathy in type 2 diabetes persons presenting to specialist diabetes clinic at a tertiary care hospital. BMC Endocr Disord. 2015;15:28. 30. Bergis D, Bergis PM, Hermanns N, Zink K, Haak T. Coronary artery disease as an independent predictor of survival in patients with type 2 diabetes and Charcot neuroosteoarthropathy. Acta Diabetol. 2014 Dec;51(6):1041–8. 31. Munson ME, Wrobel JS, Holmes CM, Hanauer DA. Data mining for identifying novel associations and temporal relationships with Charcot foot. J Diabetes Res. 2014;2014:214353. 32. Frykberg RG, Belczyk R. Epidemiology of the Charcot foot. Clin Podiatr Med Surg. 2008 Jan;25(1):17–28, v. 16/19
ACCEPTED MANUSCRIPT 33. Game FL, Catlow R, Jones GR, Edmonds ME, Jude EB, Rayman G, et al. Audit of acute Charcot’s disease in the UK: the CDUK study. Diabetologia. 2012 Jan;55(1):32–5. 34. Pakarinen T-K, Laine H-J, Mäenpää H, Mattila P, Lahtela J. Long-term outcome and quality of life in patients with Charcot foot. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2009;15(4):187–91. 35. The Danish Clinical Registries, http://www.rkkp.dk/in-english/. The Danish Diabetes Registry, Annual Report.
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36. Wilbek TE, Jansen RB, Jørgensen B, Svendsen OL. The Diabetic Foot in a Multidisciplinary Team Setting. Number of Amputations below Ankle Level and Mortality. Exp Clin Endocrinol Diabetes Off J Ger Soc Endocrinol Ger Diabetes Assoc. 2016 Jul 20;
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37. Leal J, Gray AM, Clarke PM. Development of life-expectancy tables for people with type 2 diabetes. Eur Heart J. 2009 Apr;30(7):834–9.
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38. Gazis A, Pound N, Macfarlane R, Treece K, Game F, Jeffcoate W. Mortality in patients with diabetic neuropathic osteoarthropathy (Charcot foot). Diabet Med J Br Diabet Assoc. 2004 Nov;21(11):1243–6.
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39. Armstrong DG, Todd WF, Lavery LA, Harkless LB, Bushman TR. The natural history of acute Charcot’s arthropathy in a diabetic foot specialty clinic. Diabet Med J Br Diabet Assoc. 1997 May;14(5):357–63.
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40. Pakarinen T-K, Laine H-J, Mäenpää H, Kähönen M, Mattila P, Lahtela J. Effect of immobilization, off-loading and zoledronic acid on bone mineral density in patients with acute Charcot neuroarthropathy: a prospective randomized trial. Foot Ankle Surg Off J Eur Soc Foot Ankle Surg. 2013 Jun;19(2):121–4.
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41. Sponer P, Kucera T, Brtková J, Srot J. The management of Charcot midfoot deformities in diabetic patients. Acta Medica Hradec Král Univ Carol Fac Medica Hradec Král. 2013;56(1):3–8.
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ACCEPTED MANUSCRIPT Table 1: Baseline data of included participants with T1DM or T2DM and acute Charcot foot. T2DM
P-value
Diabetes type
26%
74%
--
Sex (% m)
55%
74%
0.017*
Age at onset of Charcot foot (years)
51.9 ±11.6
58.6 ±8.6
<0.001*
Age of diabetes diagnosis at onset of Charcot foot (years)
31.2 ±10.4
11.4 ±8.2
<0.001*
BMI (median)
25.2
28.8
0.011*
Regular alcohol intake in excess of recommandations*
16%
41%
0.003*
Alcohol intake (units/week)
15.3 ±4.5
30.3 ±23.6
0.001*
Smoking status (current smoker)
18%
26%
Smoking status (ever smoked, yes/no)
20%
41%
Pack-years for current and former smokers (20 cigarettes/day/year)
26.1 ±11.4
41.5 ±27.4
0.010*
HbA1c (mmol/mol) (%)
81.7 ±21.4
66.5 ±20.3
0.001*
Systolic blood pressure (mmHg)
150 ±21
Diastolic blood pressure (mmHg)
79 ±10
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0.028*
8.2 ±4.0% 150 ±23
0.946
84 ±16
0.059
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9.7 ±4.1%
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T1DM
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n=167; 6 missing due to unknown diabetes type. Unless otherwise noted values are listed as mean ± 1SD or percentage of the population. + = 14 units/week for men or 7 units/week for women. * = Significant at chosen α-level of 0.05.
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ACCEPTED MANUSCRIPT Table 2: Data on the acute Charcot feet – duration and recurrences of off-loading for T1DM and T1DM (n=173). T1DM
T2DM
P-value
Affected foot (right/left/bilateral)
61% / 39% / 0%
54% / 44% / 2%
--
Mean temperature increase ( C)
3.5 ±1.3
3.6 ±1.6
0.905
Duration of primary off-loading (months)
8.6 ±6.5
8.4 ±6.5
0.796
Same side recurrences (1 time / >1 time)
16% / 7%
17% / 2%
--
Opposite side recurrences (1 time / >1 time)
7% / 2%
2% / 1%
--
Total duration of off-loading (primary Charcot + recurrence(s)) (months)
11.8 ±10.3
10.5 ±8.1
0.771
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Charcot foot characteristics:
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Unless otherwise noted values are listed as mean ± 1SD. Compared with Mann-Whitney rank sum tests. Data was missing for 6-14 patients in some parameters.
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Figure 1
Figure 2
Figure 3
Figure 4
Figure 5