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Role of Body Mass Index in Acute Charcot Neuroarthropathy
The Journal of Foot & Ankle Surgery 52 (2013) 6–8
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Role of Body Mass Index in Acute Charcot Neuroarthropathy Adrianne J. Ross, DPM 1, Robert W. Mendicino, DPM, FACFAS 2, Alan R. Catanzariti, DPM, FACFAS 3 1
Resident, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA Chief, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA 3 Director of Residency Training, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA 2
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 3 Keywords: diabetes foot logistic regression neuropathy obesity peripheral vascular disease
Obesity has been posited as a predictor for the development of Charcot neuroarthropathy, a severe form of degenerative joint disease associated with peripheral neuropathy and diabetes mellitus. The present casecontrol study investigated the relationship between elevated (overweight and obese) body mass index and acute Charcot neuroarthropathy in a diabetic population. The final data set consisted of 49 patients, 20 (40.82%) of whom had Charcot foot and 29 (59.18%) who served as controls. In the present investigation, no statistically significant association was found between an elevated body mass index and the development of acute Charcot neuroarthropathy involving the foot. Ó 2013 by the American College of Foot and Ankle Surgeons. All rights reserved.
The prevalence of obesity in the U.S. population has been reported to have increased steadily since the 1980s (1). Several reports have suggested an association between obesity and the development of chronic diseases such as diabetes and cardiovascular disease (1,2) and lower extremity repetitive strain injuries such as posterior tibial tendon dysfunction and heel pain (3–5). Vela et al (6) demonstrated that in the presence of deformities and limited joint mobility, increased body weight could significantly increase plantar foot pressure. Charcot neuroarthropathy (CN), a severe form of degenerative joint disease in the foot and ankle, has a prevalence of 0.1% to 0.4% in the diabetic population (3). Overload on a structurally abnormal foot has been thought to accelerate or incite the formation of CN, and obesity has been associated with an increased incidence of CN, independent of other risk factors (3). The body mass index (BMI), a ratio of height to weight, has been used to determine an individual’s risk of developing heel pain and as a predictor for postoperative complications of fracture care (2,3,7–9). The objective of the present case-control study was to investigate the relationship between an increased BMI and development of acute CN involving the foot in diabetic patients. We hypothesized a greater prevalence of elevated (overweight or obese) BMI in a group of patients with acute CN (ACN) compared with the BMI of a group of patients with diabetes but without CN. Elevated BMI was defined in the study as being overweight or obese, specifically a BMI of 25.0 or greater (10). Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Robert W. Mendicino, DPM, FACFAS, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, 4800 Friendship Avenue, N1, Pittsburgh, PA 15224. E-mail address: [email protected] (R.W. Mendicino).
Patients and Methods The medical records were reviewed after the institutional review board of the Western Pennsylvania Hospital (Pittsburgh, PA) approved the study. We reviewed the data from all patients seen at the Foot and Ankle Institute of the Western Pennsylvania Hospital from July 2006 to November 2011, who had been diagnosed with diabetic peripheral neuropathy (International Classification of Diseases, 9th revision, code 250.60) and/or CN of the foot (International Classification of Diseases, 9th revision, code 713.50). Information from the records was abstracted by the primary author (A.J.R.), who also participated in the care of some of the patients. The patients were selected from an initial computer-generated pool of patient records according to the following inclusion criteria: availability of complete medical records relative to the variables of interest (provided in subsequent paragraphs), documented diabetic peripheral neuropathy with or without the diagnosis of Charcot foot, and documented BMI or height and weight. We excluded patients with a documented history of non–diabetes-related neuropathy (e.g., alcoholic neuropathy, drug- or chemical-induced neuropathy, inherited sensorimotor neuropathy, or the presence of a previously documented brain or spinal cord lesion), recent ( 6 months before the date of chart review) infection, and recent ( 6 months before the date of chart review) trauma or surgery that might otherwise have incited an ACN event. Patients with a pedal ulceration were not excluded unless the documentation was indicative of an infection (e.g., active antibiotic therapy). Patients with ACN, in contrast to chronic, remodeled, and quiescent Charcot foot, were identified by documentation in the medical record that indicated the acute nature of the CN. For the purposes of the present study, patients were considered to have ACN if 1 of the attending physicians made the diagnosis and provided subsequent documentation in the medical records. The diagnosis of Charcot foot was determined from the radiographic evidence, clinical presentation, and physical examination findings. Because the attending physicians routinely used serial skin temperature monitoring, an objective tool to detect signs of subtle inflammation, a skin temperature of 6 C to 8 C higher than the contralateral foot was considered suggestive of ACN in the foot (11). The following independent variables were also extracted from the medical records: gender, ethnicity (defined as African American, Caucasian, or other), age, and comorbidities (categorized as insulin- and noninsulin-dependent diabetes, osteoporosis [defined as a severe reduction in bone density evident on radiographic exam], chronic renal insufficiency [CRI], or renal failure [defined as diminished renal function characterized by the need for dialysis or renal transplant], peripheral vascular disease [PVD]
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A.J. Ross et al. / The Journal of Foot & Ankle Surgery 52 (2013) 6–8 [defined as nonpalpable pulses and ankle/brachial index <0.7] (12-14), and tobacco use [active or not]. Diabetic peripheral neuropathy was defined as abnormal neurologic examination findings of the lower extremities (e.g., a Semmes-Weinstein monofilament test, the presence of gross motor or sensory abnormalities). Vascular disease was defined as nonpalpable pedal pulses and/or documentation of abnormal findings from noninvasive vascular studies. CRI/CRF was defined by decreased creatinine clearance and/or the need for hemodialysis (determined from the patient’s primary care physician’s report). Tobacco use was defined as active or a history of regular tobacco use. All statistical analyses were performed using SPSS, version 19.0 (IBM SPSS, Armonk, NY). Descriptive statistics were reported as frequencies (percentages), accompanied by means (standard deviations) where appropriate. A logistic regression was conducted to determine the influence of BMI and other predictors in the development of Charcot foot. Preliminary diagnostic analyses eliminated all independent variables with the exception of age, gender, PVD, diabetes, and BMI. Following the logistic regression, a power analysis was conducted in order to characterize the observed power of the study.
Results A total of 55 neuropathic diabetic patients who met the inclusion criteria were selected from the initial computer-generated pool of 98 patient records. Two patients (3.64%) with Charcot foot were not included in the analyses because of a lack of information pertaining to age, and another patient (1.82%) was excluded because of a lack of information used to determine the status of PVD, CRI, CRF, and/or osteoporosis. Also, 3 Charcot-positive patients (5.46%) were excluded because of a lack of information used to determine the specific classification of diabetes. Therefore, the final data set included 20 Charcot-positive patients (40.82%) and 29 neuropathic diabetic patients (59.18%) without Charcot foot, who served as controls. Among all patients, 28 (57%) were insulin dependent, with 15 (75%) of all ACN patients and 13 (45%) of all non-ACN patients exhibiting insulin independence. Nineteen (39%) patients were male and 30 (61%) were female. For all patients, mean age was 63.16 10.28 years, with mean age for ACN patients 62.05 9.44 years and mean age for non-ACN patients 63.93 10.91 years. Among all patients, mean BMI was 32.26 6.76, 32.84 6.99 among ACN patients and 31.87 6.69 among non ACN patients. Fisher’s exact test was conducted to test for differences in the proportion of cases between ACN and non ACN patients for all categorical variables, and independent samples t tests were conduced to test for differences in cases of continuous variables. The Holm-Bonferonni (15) correction for multiple comparisons was use to adjust all significant levels. After these adjustments there were no observed significant differences ACN and non ACN patients with regards to any of the tested variables (Table 1).
Table 1 Demographic and clinical characteristics Variable Diabetes mellitus Insulin dependent Non-insulin dependent PVD Gender Male Female Age (y) BMI (kg/m2)
All Patients (n ¼ 49)
7
In preparation for the logistic regression analyses, a number of independent variables had to be removed from the list of possible predictors because of a lack of data that precluded the calculation of an odds ratios. Specifically, ethnicity (16 patients [32.65%]) and tobacco use (12 patients [24.49%]) were excluded for this reason. Moreover, because CRI and CRF were observed only in those patients with ACN (patients), they were also excluded from the regression models. Similarly, because osteoporosis was also observed only in the Charcot foot group (2 patients [4.08%]), it was removed from the regression models. There were 4 (8.1%) cases of CKD/CKI. CKD was removed from the list of dependent variables as all cases of CKD were among Charcot patients precluding the calculation of odds ratios, as well as the small number of CKD cases (4). The cutoff probability for inclusion in the final multiple variable logistic regression model was p .1 (10% level of statistical significance), as determined by univariate logistic regression analysis. Furthermore, analysis of residual error related to the associations between height and weight (r ¼ 0.46, p < .01) and between weight and BMI (r ¼ 0.85, p < .001) indicated shared variance and multicolinearity; hence, these variables were also excluded from the list of independent variables used in the adjusted logistic regression model. The final list of independent variables (exposures and risk factors) used in the adjusted (multivariate) logistic regression model included patient age, the presence of lower extremity PVD, type of diabetes mellitus, and BMI. The presence of Charcot foot was the dependent (outcome) variable. Logistic regression models (Table 2) were used to determine the relationship between BMI and Charcot status after accounting for the relationship between Charcot status and the independent variables, as described in the previous paragraph. Age, PVD, and diabetes status were entered in block 1 and BMI in block 2. Combined, the independent variables entered in block 1 were not significantly associated statistically with Charcot status [G2 (4, N ¼ 49) ¼ 6.10, p < .191; Cox and Snell R2 ¼ .117; Table 2]. Of the individual predictors, only diabetes classification was statistically significantly related to Charcot status [chi-square Wald (1, N ¼ 49) ¼ 4.29, p < .05], with the odds of a patient with insulin-dependent diabetes mellitus (type 1 diabetes) having ACN involving the foot 3.90 times greater than the odds of a patient with non–insulin-dependent diabetes mellitus (type 2 diabetes) having ACN of the foot. No other statistically significant relationships were observed between the block 1 variables and Charcot status. The relationship between BMI and Charcot status was evaluated after controlling for all variables entered in block 1. The addition of BMI failed to account for a significant amount of additional variance in the model [G2 (1, N ¼ 49) ¼ 0.963, p > .5]. Power Analysis
ACN (n ¼ 20)
No ACN (n ¼ 29)
p Value
*
y,z
28 (57) 21 (43) 13 (27)
15 (75) 5 (25) 4 (31)
13 (45) 16 (55) 9 (69)
19 (39) 30 (61) 63.16 10.28 32.26 6.76
9 (47) 11 (37) 62.05 9.44 32.84 6.99
10 (53) 19 (63) 63.93 10.91 31.87 6.69
.225 NA NA .516y .555y NA NA .534x .625x
Abbreviations: ACN, acute Charcot neuroarthropathy; BMI, body mass index; NA, not available; PVD, peripheral vascular disease. Data presented as n (%) or mean standard deviation. * Comparing patients with and without acute Charcot foot, using Wilcoxon rank sum (Mann-Whitney U) nonparametric test of the null hypothesis for categorical data and the unpaired Student’s t test for continuous variables. y Fisher’s exact test. z After application of Holm-Bonferroni (15) correction for multiple comparisons t test. x Independent samples Student’s t test.
A post hoc power analysis was conducted to determine the observed power, given the observed effect sizes. The independent variable with the lowest observed p value (i.e., diabetes type) was selected as the focus of the power analysis. The odds ratio/effect size
Table 2 Results of logistic regression analysis with Charcot foot as dependent variable (n ¼ 49) Variable
Omnibus Statistic
Block 1 Age Gender PVD Diabetes Block 2 BMI
G2 (4, N ¼ 49) ¼ 6.11
G2 (1, N ¼ 49) ¼ .96
Wald Chi-square
p Value
OR
95% CI
0.003 0.509 0.80 4.29
.96 .48 .37 .04
0.99 1.57 0.50 3.90
0.935–1.07 0.45–5.46 0.11–2.28 1.08–14.13
0.95
.33
1.05
0.95–1.15
Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; PVD, peripheral vascular disease.
8
A.J. Ross et al. / The Journal of Foot & Ankle Surgery 52 (2013) 6–8
estimated was that observed for the distribution of the diabetes type within the Charcot-positive sample compared with the control sample (odds ratio 3.90). The distribution was specified as a binomial distribution, with the R2 correction estimated as 0 and the test set as 2-tailed. The observed power of the logistic regression analysis using the observed sample size of 49 was 0.55.
In conclusion, the results of the present study challenge the understanding of the role of BMI in the development of ACN of the foot in the presence of diabetic peripheral neuropathy. Although it was expected that a greater BMI would be related to an increased risk of ACN, no such relationship was observed. Of all analyzed predictors, only diabetes classification was significantly related to Charcot status, with insulin dependence coinciding with a greater risk of ACN.
Discussion Obesity, in particular abdominal obesity, has been linked to insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, and hypertension, collectively known as the metabolic syndrome (16,17). A longer duration of diabetes, greater levels of glycosylated hemoglobin, older age, and insulin use are considered risk factors for diabetic peripheral neuropathy (18). Although a causal relationship between obesity and neuropathy has also been posited, the published biomedical data have provided only mixed support for such a connection (19), and causality has been difficult to show with observational studies. In a meta-analysis of controlled clinical trials, Boule et al (16) found that exercise training reduced glycosylated hemoglobin by 0.66%, an amount expected to decrease the risk of developing diabetic complications. They concluded that a normal BMI and weight control should be regarded as vital components of diabetic therapy. We hypothesized that after accounting for diabetes type, a high BMI would be statistically significantly related to ACN. Our investigation, however, did not find a correlation between an elevated BMI and the presence of ACN. The research design had several limitations. The present study was retrospective, which limited the accuracy of the data collected to the integrity of the reviewed medical records and the abstracting investigator’s interpretation of the information. We did not consider a number of clinical variables that reasonable clinicians might consider important in regard to Charcot foot, such as unilateral versus bilateral ACN, ankle equinus, activity level, and so forth. Also, we did not undertake a sensitivity analysis to test the resistance of our findings to unmeasured variables. Moreover, the BMI, calculated from self-reported height and weight, was also subject to selfpresentational biases, and this likely affected some of the measurements reported in the records. Specifically, some patients might have underestimated their weight or overestimated their height to represent a more fit physique, if these measurements were not actually made by the examining clinician and recorded. There was also the possibility of clinical misdiagnosis of acute versus chronic Charcot. Furthermore, the small sample size yielded power only for the observed significant relationship equal to 0.55, and our claim of a nonstatistically significant association between BMI and ACN of the foot could represent a type 2 statistical error. The presumably complex process by which the Charcot foot develops, coupled with the limitations of the study design, could have contributed to failure to observe the predicted relationship. Additional research is needed to fully explore the nature of the relationship between obesity and ACN. We have continued to recommend weight loss to all patients with diabetic peripheral neuropathy and consider weight loss a fundamental component of diabetic therapy. Diabetic patients with obesity have multiple health risks, and supervised weight management can help to mitigate those risks without introducing other potential health risks (16).
Acknowledgment The authors would like to thank Clinton R. Irvin, PhD, of Western Pennsylvania Hospital, Pittsburgh, PA, for performing the analyses for this study.
References 1. Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991–1998. JAMA 282:1519–1522, 1999. 2. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289:76–79, 2003. 3. Coughlin MJ, Mann RA, Saltzman C. Surgery of the Foot and Ankle, ed 8, volume II, Mosby, Philadelphia, 2007, p 1014. 4. Pinzur M, Freeland R, Juknelis D. The association between body mass index and foot disorders in diabetic patients. Foot Ankle Int 26:375–377, 2005. 5. Rano JA, Fallat LM, Savoy-Moore RT. Correlation of heel pain with body mass index and other characteristics of heel pain. J Foot Ankle Surg 40:351–356, 2001. 6. Vela SA, Lavery LA, Armstrong DG, Anaim AA. The effect of increased weight on peak pressures: implications for obesity and diabetic foot pathology. J Foot Ankle Surg 37:416–420, 1998. 7. Karunakar MA, Shah SN, Jerabek S. Body mass index as a predictor of complications after operative treatment of acetabular fractures. J Bone Joint Surg Am 87:1498–1502, 2005. 8. Sabharwal S, Caixia Z, McClemens E. Correlation of body mass index and radiographic deformities in children with Blount disease. J Bone Joint Surg Am 89:1275–1283, 2007. 9. Stuck RM, Sohn M, Budiman-Mak E, Lee TA, Weiss KB. Charcot arthropathy: risk elevation in the obese diabetic population. Am J Med 121:1008–1014, 2008. 10. Centers for Disease Control and Prevention. Healthy WeightdIt’s Not a Diet, It’s a Lifestyle. Available at: http://www.cdc.gov/healthyweight/assessing/bmi/adult_ BMI/index.html. Accessed September 27, 2012. 11. Fabrin J, Larsen K, Holstein P. Long-term follow-up in diabetic Charcot feet with spontaneous onset. Diabetes Care 23:796–800, 2000. 12. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey: Osteoporosis. Available at: http://www.cdc.gov/nchs/data/ nhanes/databriefs/osteoporosis.pdf. Accessed November 1, 2012. 13. Centers for Disease Control and Prevention. Incidence of Treatment for End-Stage Renal Disease Attributed to Diabetes MellitusdUnited States, 1980-1989. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/00017927.htm. Accessed November 1, 2012. 14. Cook J, Cook E, Landsman AS, Basile P, Dinh T, Lyons T, Rosenblum B, Giurini J. A retrospective assessment of partial calcanectomies and factors influencing postoperative course. J Foot Ankle Surg 46:248–255, 2007. 15. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat 6:65– 70, 1979. 16. Boule NG, Haddad E, Kenny GP, Wells GA, Sigal RJ. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. JAMA 286:1218–1227, 2001. 17. Looker HC, Knowler WC, Hanson RL. Changes in BMI and weight before and after the development of type 2 diabetes. Diabetes Care 24:1917–1922, 2001. 18. Dyck PJ, Davies JL, Wilson DM, Melton LJ, O’Brien PC. Risk factors for severity of diabetic polyneuropathy: intensive longitudinal assessment of the Rochester Diabetic Neuropathy study cohort. Diabetes Care 22:1479–1486, 1999. 19. Frykberg RG, Belczyk R. Epidemiology of the Charcot foot. Clin Podiatr Med Surg 25:17–28, 2008.
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Role of Body Mass Index in Acute Charcot Neuroarthropathy Adrianne J. Ross, DPM 1, Robert W. Mendicino, DPM, FACFAS 2, Alan R. Catanzariti, DPM, FACFAS 3 1
Resident, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA Chief, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA 3 Director of Residency Training, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, Pittsburgh, PA 2
a r t i c l e i n f o
a b s t r a c t
Level of Clinical Evidence: 3 Keywords: diabetes foot logistic regression neuropathy obesity peripheral vascular disease
Obesity has been posited as a predictor for the development of Charcot neuroarthropathy, a severe form of degenerative joint disease associated with peripheral neuropathy and diabetes mellitus. The present casecontrol study investigated the relationship between elevated (overweight and obese) body mass index and acute Charcot neuroarthropathy in a diabetic population. The final data set consisted of 49 patients, 20 (40.82%) of whom had Charcot foot and 29 (59.18%) who served as controls. In the present investigation, no statistically significant association was found between an elevated body mass index and the development of acute Charcot neuroarthropathy involving the foot. Ó 2013 by the American College of Foot and Ankle Surgeons. All rights reserved.
The prevalence of obesity in the U.S. population has been reported to have increased steadily since the 1980s (1). Several reports have suggested an association between obesity and the development of chronic diseases such as diabetes and cardiovascular disease (1,2) and lower extremity repetitive strain injuries such as posterior tibial tendon dysfunction and heel pain (3–5). Vela et al (6) demonstrated that in the presence of deformities and limited joint mobility, increased body weight could significantly increase plantar foot pressure. Charcot neuroarthropathy (CN), a severe form of degenerative joint disease in the foot and ankle, has a prevalence of 0.1% to 0.4% in the diabetic population (3). Overload on a structurally abnormal foot has been thought to accelerate or incite the formation of CN, and obesity has been associated with an increased incidence of CN, independent of other risk factors (3). The body mass index (BMI), a ratio of height to weight, has been used to determine an individual’s risk of developing heel pain and as a predictor for postoperative complications of fracture care (2,3,7–9). The objective of the present case-control study was to investigate the relationship between an increased BMI and development of acute CN involving the foot in diabetic patients. We hypothesized a greater prevalence of elevated (overweight or obese) BMI in a group of patients with acute CN (ACN) compared with the BMI of a group of patients with diabetes but without CN. Elevated BMI was defined in the study as being overweight or obese, specifically a BMI of 25.0 or greater (10). Financial Disclosure: None reported. Conflict of Interest: None reported. Address correspondence to: Robert W. Mendicino, DPM, FACFAS, Division of Foot and Ankle Surgery, Western Pennsylvania Hospital, 4800 Friendship Avenue, N1, Pittsburgh, PA 15224. E-mail address: [email protected] (R.W. Mendicino).
Patients and Methods The medical records were reviewed after the institutional review board of the Western Pennsylvania Hospital (Pittsburgh, PA) approved the study. We reviewed the data from all patients seen at the Foot and Ankle Institute of the Western Pennsylvania Hospital from July 2006 to November 2011, who had been diagnosed with diabetic peripheral neuropathy (International Classification of Diseases, 9th revision, code 250.60) and/or CN of the foot (International Classification of Diseases, 9th revision, code 713.50). Information from the records was abstracted by the primary author (A.J.R.), who also participated in the care of some of the patients. The patients were selected from an initial computer-generated pool of patient records according to the following inclusion criteria: availability of complete medical records relative to the variables of interest (provided in subsequent paragraphs), documented diabetic peripheral neuropathy with or without the diagnosis of Charcot foot, and documented BMI or height and weight. We excluded patients with a documented history of non–diabetes-related neuropathy (e.g., alcoholic neuropathy, drug- or chemical-induced neuropathy, inherited sensorimotor neuropathy, or the presence of a previously documented brain or spinal cord lesion), recent ( 6 months before the date of chart review) infection, and recent ( 6 months before the date of chart review) trauma or surgery that might otherwise have incited an ACN event. Patients with a pedal ulceration were not excluded unless the documentation was indicative of an infection (e.g., active antibiotic therapy). Patients with ACN, in contrast to chronic, remodeled, and quiescent Charcot foot, were identified by documentation in the medical record that indicated the acute nature of the CN. For the purposes of the present study, patients were considered to have ACN if 1 of the attending physicians made the diagnosis and provided subsequent documentation in the medical records. The diagnosis of Charcot foot was determined from the radiographic evidence, clinical presentation, and physical examination findings. Because the attending physicians routinely used serial skin temperature monitoring, an objective tool to detect signs of subtle inflammation, a skin temperature of 6 C to 8 C higher than the contralateral foot was considered suggestive of ACN in the foot (11). The following independent variables were also extracted from the medical records: gender, ethnicity (defined as African American, Caucasian, or other), age, and comorbidities (categorized as insulin- and noninsulin-dependent diabetes, osteoporosis [defined as a severe reduction in bone density evident on radiographic exam], chronic renal insufficiency [CRI], or renal failure [defined as diminished renal function characterized by the need for dialysis or renal transplant], peripheral vascular disease [PVD]
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A.J. Ross et al. / The Journal of Foot & Ankle Surgery 52 (2013) 6–8 [defined as nonpalpable pulses and ankle/brachial index <0.7] (12-14), and tobacco use [active or not]. Diabetic peripheral neuropathy was defined as abnormal neurologic examination findings of the lower extremities (e.g., a Semmes-Weinstein monofilament test, the presence of gross motor or sensory abnormalities). Vascular disease was defined as nonpalpable pedal pulses and/or documentation of abnormal findings from noninvasive vascular studies. CRI/CRF was defined by decreased creatinine clearance and/or the need for hemodialysis (determined from the patient’s primary care physician’s report). Tobacco use was defined as active or a history of regular tobacco use. All statistical analyses were performed using SPSS, version 19.0 (IBM SPSS, Armonk, NY). Descriptive statistics were reported as frequencies (percentages), accompanied by means (standard deviations) where appropriate. A logistic regression was conducted to determine the influence of BMI and other predictors in the development of Charcot foot. Preliminary diagnostic analyses eliminated all independent variables with the exception of age, gender, PVD, diabetes, and BMI. Following the logistic regression, a power analysis was conducted in order to characterize the observed power of the study.
Results A total of 55 neuropathic diabetic patients who met the inclusion criteria were selected from the initial computer-generated pool of 98 patient records. Two patients (3.64%) with Charcot foot were not included in the analyses because of a lack of information pertaining to age, and another patient (1.82%) was excluded because of a lack of information used to determine the status of PVD, CRI, CRF, and/or osteoporosis. Also, 3 Charcot-positive patients (5.46%) were excluded because of a lack of information used to determine the specific classification of diabetes. Therefore, the final data set included 20 Charcot-positive patients (40.82%) and 29 neuropathic diabetic patients (59.18%) without Charcot foot, who served as controls. Among all patients, 28 (57%) were insulin dependent, with 15 (75%) of all ACN patients and 13 (45%) of all non-ACN patients exhibiting insulin independence. Nineteen (39%) patients were male and 30 (61%) were female. For all patients, mean age was 63.16 10.28 years, with mean age for ACN patients 62.05 9.44 years and mean age for non-ACN patients 63.93 10.91 years. Among all patients, mean BMI was 32.26 6.76, 32.84 6.99 among ACN patients and 31.87 6.69 among non ACN patients. Fisher’s exact test was conducted to test for differences in the proportion of cases between ACN and non ACN patients for all categorical variables, and independent samples t tests were conduced to test for differences in cases of continuous variables. The Holm-Bonferonni (15) correction for multiple comparisons was use to adjust all significant levels. After these adjustments there were no observed significant differences ACN and non ACN patients with regards to any of the tested variables (Table 1).
Table 1 Demographic and clinical characteristics Variable Diabetes mellitus Insulin dependent Non-insulin dependent PVD Gender Male Female Age (y) BMI (kg/m2)
All Patients (n ¼ 49)
7
In preparation for the logistic regression analyses, a number of independent variables had to be removed from the list of possible predictors because of a lack of data that precluded the calculation of an odds ratios. Specifically, ethnicity (16 patients [32.65%]) and tobacco use (12 patients [24.49%]) were excluded for this reason. Moreover, because CRI and CRF were observed only in those patients with ACN (patients), they were also excluded from the regression models. Similarly, because osteoporosis was also observed only in the Charcot foot group (2 patients [4.08%]), it was removed from the regression models. There were 4 (8.1%) cases of CKD/CKI. CKD was removed from the list of dependent variables as all cases of CKD were among Charcot patients precluding the calculation of odds ratios, as well as the small number of CKD cases (4). The cutoff probability for inclusion in the final multiple variable logistic regression model was p .1 (10% level of statistical significance), as determined by univariate logistic regression analysis. Furthermore, analysis of residual error related to the associations between height and weight (r ¼ 0.46, p < .01) and between weight and BMI (r ¼ 0.85, p < .001) indicated shared variance and multicolinearity; hence, these variables were also excluded from the list of independent variables used in the adjusted logistic regression model. The final list of independent variables (exposures and risk factors) used in the adjusted (multivariate) logistic regression model included patient age, the presence of lower extremity PVD, type of diabetes mellitus, and BMI. The presence of Charcot foot was the dependent (outcome) variable. Logistic regression models (Table 2) were used to determine the relationship between BMI and Charcot status after accounting for the relationship between Charcot status and the independent variables, as described in the previous paragraph. Age, PVD, and diabetes status were entered in block 1 and BMI in block 2. Combined, the independent variables entered in block 1 were not significantly associated statistically with Charcot status [G2 (4, N ¼ 49) ¼ 6.10, p < .191; Cox and Snell R2 ¼ .117; Table 2]. Of the individual predictors, only diabetes classification was statistically significantly related to Charcot status [chi-square Wald (1, N ¼ 49) ¼ 4.29, p < .05], with the odds of a patient with insulin-dependent diabetes mellitus (type 1 diabetes) having ACN involving the foot 3.90 times greater than the odds of a patient with non–insulin-dependent diabetes mellitus (type 2 diabetes) having ACN of the foot. No other statistically significant relationships were observed between the block 1 variables and Charcot status. The relationship between BMI and Charcot status was evaluated after controlling for all variables entered in block 1. The addition of BMI failed to account for a significant amount of additional variance in the model [G2 (1, N ¼ 49) ¼ 0.963, p > .5]. Power Analysis
ACN (n ¼ 20)
No ACN (n ¼ 29)
p Value
*
y,z
28 (57) 21 (43) 13 (27)
15 (75) 5 (25) 4 (31)
13 (45) 16 (55) 9 (69)
19 (39) 30 (61) 63.16 10.28 32.26 6.76
9 (47) 11 (37) 62.05 9.44 32.84 6.99
10 (53) 19 (63) 63.93 10.91 31.87 6.69
.225 NA NA .516y .555y NA NA .534x .625x
Abbreviations: ACN, acute Charcot neuroarthropathy; BMI, body mass index; NA, not available; PVD, peripheral vascular disease. Data presented as n (%) or mean standard deviation. * Comparing patients with and without acute Charcot foot, using Wilcoxon rank sum (Mann-Whitney U) nonparametric test of the null hypothesis for categorical data and the unpaired Student’s t test for continuous variables. y Fisher’s exact test. z After application of Holm-Bonferroni (15) correction for multiple comparisons t test. x Independent samples Student’s t test.
A post hoc power analysis was conducted to determine the observed power, given the observed effect sizes. The independent variable with the lowest observed p value (i.e., diabetes type) was selected as the focus of the power analysis. The odds ratio/effect size
Table 2 Results of logistic regression analysis with Charcot foot as dependent variable (n ¼ 49) Variable
Omnibus Statistic
Block 1 Age Gender PVD Diabetes Block 2 BMI
G2 (4, N ¼ 49) ¼ 6.11
G2 (1, N ¼ 49) ¼ .96
Wald Chi-square
p Value
OR
95% CI
0.003 0.509 0.80 4.29
.96 .48 .37 .04
0.99 1.57 0.50 3.90
0.935–1.07 0.45–5.46 0.11–2.28 1.08–14.13
0.95
.33
1.05
0.95–1.15
Abbreviations: BMI, body mass index; CI, confidence interval; OR, odds ratio; PVD, peripheral vascular disease.
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estimated was that observed for the distribution of the diabetes type within the Charcot-positive sample compared with the control sample (odds ratio 3.90). The distribution was specified as a binomial distribution, with the R2 correction estimated as 0 and the test set as 2-tailed. The observed power of the logistic regression analysis using the observed sample size of 49 was 0.55.
In conclusion, the results of the present study challenge the understanding of the role of BMI in the development of ACN of the foot in the presence of diabetic peripheral neuropathy. Although it was expected that a greater BMI would be related to an increased risk of ACN, no such relationship was observed. Of all analyzed predictors, only diabetes classification was significantly related to Charcot status, with insulin dependence coinciding with a greater risk of ACN.
Discussion Obesity, in particular abdominal obesity, has been linked to insulin resistance, hyperinsulinemia, hyperglycemia, dyslipidemia, and hypertension, collectively known as the metabolic syndrome (16,17). A longer duration of diabetes, greater levels of glycosylated hemoglobin, older age, and insulin use are considered risk factors for diabetic peripheral neuropathy (18). Although a causal relationship between obesity and neuropathy has also been posited, the published biomedical data have provided only mixed support for such a connection (19), and causality has been difficult to show with observational studies. In a meta-analysis of controlled clinical trials, Boule et al (16) found that exercise training reduced glycosylated hemoglobin by 0.66%, an amount expected to decrease the risk of developing diabetic complications. They concluded that a normal BMI and weight control should be regarded as vital components of diabetic therapy. We hypothesized that after accounting for diabetes type, a high BMI would be statistically significantly related to ACN. Our investigation, however, did not find a correlation between an elevated BMI and the presence of ACN. The research design had several limitations. The present study was retrospective, which limited the accuracy of the data collected to the integrity of the reviewed medical records and the abstracting investigator’s interpretation of the information. We did not consider a number of clinical variables that reasonable clinicians might consider important in regard to Charcot foot, such as unilateral versus bilateral ACN, ankle equinus, activity level, and so forth. Also, we did not undertake a sensitivity analysis to test the resistance of our findings to unmeasured variables. Moreover, the BMI, calculated from self-reported height and weight, was also subject to selfpresentational biases, and this likely affected some of the measurements reported in the records. Specifically, some patients might have underestimated their weight or overestimated their height to represent a more fit physique, if these measurements were not actually made by the examining clinician and recorded. There was also the possibility of clinical misdiagnosis of acute versus chronic Charcot. Furthermore, the small sample size yielded power only for the observed significant relationship equal to 0.55, and our claim of a nonstatistically significant association between BMI and ACN of the foot could represent a type 2 statistical error. The presumably complex process by which the Charcot foot develops, coupled with the limitations of the study design, could have contributed to failure to observe the predicted relationship. Additional research is needed to fully explore the nature of the relationship between obesity and ACN. We have continued to recommend weight loss to all patients with diabetic peripheral neuropathy and consider weight loss a fundamental component of diabetic therapy. Diabetic patients with obesity have multiple health risks, and supervised weight management can help to mitigate those risks without introducing other potential health risks (16).
Acknowledgment The authors would like to thank Clinton R. Irvin, PhD, of Western Pennsylvania Hospital, Pittsburgh, PA, for performing the analyses for this study.
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