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Diabetic Foot Disorders: A Clinical Practice Guideline (2006 Revision)

      Abstract

      The prevalence of diabetes mellitus is growing at epidemic proportions in the United States and worldwide. Most alarming is the steady increase in type 2 diabetes, especially among young and obese people. An estimated 7% of the US population has diabetes, and because of the increased longevity of this population, diabetes-associated complications are expected to rise in prevalence.
      Foot ulcerations, infections, Charcot neuroarthropathy, and peripheral arterial disease frequently result in gangrene and lower limb amputation. Consequently, foot disorders are leading causes of hospitalization for persons with diabetes and account for billion-dollar expenditures annually in the US. Although not all foot complications can be prevented, dramatic reductions in frequency have been achieved by taking a multidisciplinary approach to patient management. Using this concept, the authors present a clinical practice guideline for diabetic foot disorders based on currently available evidence, committee consensus, and current clinical practice. The pathophysiology and treatment of diabetic foot ulcers, infections, and the diabetic Charcot foot are reviewed. While these guidelines cannot and should not dictate the care of all affected patients, they provide evidence-based guidance for general patterns of practice. If these concepts are embraced and incorporated into patient management protocols, a major reduction in diabetic limb amputations is certainly an attainable goal.
      This clinical practice guideline (CPG) is based on the consensus of current clinical practice and review of the clinical literature. This guideline was developed by the Clinical Practice Guideline Diabetes Panel of the American College of Foot and Ankle Surgeons.

      Introduction

      The prevalence of diabetes mellitus is growing at epidemic proportions in the United States and worldwide (
      • Boulton AJ
      • Vileikyte L
      • Ragnarson-Tennvall G
      • Apelqvist J
      The global burden of diabetic foot disease.
      ). Most alarming is the steady increase in type 2 diabetes, especially among young and obese persons. An estimated 7% of Americans are afflicted with diabetes, and with the longevity of this population increasing, the prevalence of diabetes-related complications will continue to rise.
      Foot disorders are a major source of morbidity and a leading cause of hospitalization for persons with diabetes. Ulceration, infection, gangrene, and amputation are significant complications of the disease, estimated to cost billions of dollars each year. Charcot foot, which of itself can lead to limb-threatening disorders, is another serious complication of long-standing diabetes. In addition to improving the management of ulcers—the leading precursor to lower extremity amputation in diabetic patients (
      • Singh N
      • Armstrong DG
      • Lipsky BA
      Preventing foot ulcers in patients with diabetes.
      )—clinicians must determine how to more effectively prevent ulceration. Although not all diabetic foot disorders can be prevented, it is possible to effect dramatic reductions in their incidence and morbidity through appropriate evidence-based prevention and management protocols.
      Taking a multidisciplinary approach to diabetic foot disorders, many centers from around the world have noted consistent improvement in limb salvage rates. With this premise as our central theme, the authors present this clinical practice guideline based on currently available evidence. Three major pedal complications of diabetes are reviewed: diabetic foot ulcers, diabetic foot infections, and the diabetic Charcot foot. These guidelines are intended to provide evidence-based guidance for general patterns of practice and do not necessarily dictate the care of a particular patient.

      Epidemiology of Diabetic Foot Disorders

      Diabetes is one of the foremost causes of death in many countries and a leading cause of blindness, renal failure, and nontraumatic amputation. Global prevalence of diabetes in 2003 was estimated to be 194 million (

      International Diabetes Federation and International Working Group on the Diabetic Foot. Diabetes and Foot Care: Time to Act, International Diabetes Federation, Brussels, 2005.

      ). By 2030, this figure is predicted to rise to 366 million due to longer life expectancy and changing dietary habits (
      • Wild S
      • Roglic G
      • Green A
      • Sicree R
      • King H
      Global prevalence of diabetes: estimates for the year 2000 and projections for 2030.
      ).
      The estimated incidence of diabetes in the US exceeds 1.5 million new cases annually, with an overall prevalence of 20.8 million people or 7% of the nation's population (

      Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Centers for Disease Control and Prevention, Atlanta, 2005.

      ). An estimated 14.6 million persons are currently diagnosed with the disease, while an additional 6.2 million people who have diabetes remain undiagnosed; this represents a sixfold increase in the number of persons with diabetes over the past four decades (

      Centers for Disease Control and Prevention. Diabetes: a serious health problem. At-a-Glance 2000, Center for Disease Control and Prevention, 2000.

      ). A higher incidence of diabetes occurs among non-Hispanic blacks, Hispanic/Latino Americans, and Native Americans compared with non-Hispanic whites (

      Centers for Disease Control and Prevention. Diabetes: Disabling, Deadly, and on the Rise: At-a-Glance, 2005, Centers for Disease Control and Prevention, Atlanta, 2005.

      ). Diagnosed diabetes is most prevalent in middle-aged and elderly populations, with the highest rates occurring in persons aged 65 years and older (

      American Diabetes Association. Diabetes 1996 Vital Statistics, American Diabetes Association, Alexandria, VA, 1996.

      ,
      • Harris MI
      Diabetes in America: epidemiology and scope of the problem.
      ,

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ). As the sixth leading cause of death in the US, diabetes contributes to more than 224,000 deaths per year (

      Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Centers for Disease Control and Prevention, Atlanta, 2005.

      ).
      Four categories of diabetes are recognized (Table 1). Type 1, formerly insulin-dependent diabetes mellitus (IDDM), is an autoimmune disease affecting the pancreas. Individuals with type 1 diabetes are prone to ketosis and unable to produce endogenous insulin. Type 2, formerly non-insulin dependent diabetes mellitus (NIDDM), accounts for 90% to 95% of cases diagnosed. Type 2 diabetes is characterized by hyperglycemia in the presence of hyperinsulinemia due to peripheral insulin resistance. Gestational as well as genetic defects and endocrinopathies are recognized as other types of diabetes (
      • American Diabetes Association
      Report of the Expert Committee on the diagnosis and classification of diabetes mellitus.
      ).Diabetes is associated with numerous complications related to microvascular, macrovascular, and metabolic etiologies. These include cerebrovascular, cardiovascular, and peripheral arterial disease; retinopathy; neuropathy; and nephropathy. Currently, cardiovascular complications are the most common cause of premature death among patients with diabetes (
      • Harris MI
      Diabetes in America: epidemiology and scope of the problem.
      ,

      American Diabetes Association. Diabetes Facts and Figures, 2000, American Diabetes Association, Alexandria, VA, 2000.

      ). Rates of heart disease and stroke are 2 to 4 times higher among diabetic adults compared with nondiabetic adults, accounting for about 65% of deaths in people with diabetes (

      Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Centers for Disease Control and Prevention, Atlanta, 2005.

      ). Estimated total (direct and indirect) annual expenditures for diabetes management in 2002 was $132 billion, representing 1 of every 10 health care dollars spent in the US (
      • American Diabetes Association
      Economic costs of diabetes in the U.S. in 2002.
      ).
      Table 1Classification of Diabetes Mellitus
      adapted from: Therapy for Diabetes Mellitus and Related Disorders, 3rd edition, American Diabetes Association, 1998.
      Type 1 diabetes - absolute insulin deficiency
      Type 2 diabetes - insulin resistant +/− insulin deficiency
      Other types - genetic defects of β-cell function or insulin action endocrinopathies drug or chemical infections
      Gestational diabetes
      * adapted from: Therapy for Diabetes Mellitus and Related Disorders, 3rd edition, American Diabetes Association, 1998.
      One of the most common complications of diabetes in the lower extremity is the diabetic foot ulcer. An estimated 15% of patients with diabetes will develop a lower extremity ulcer during the course of their disease (
      • Palumbo PJ
      • Melton LJ
      Peripheral vascular disease and diabetes.
      ,
      • Reiber GE
      Epidemiology of foot ulcers and amputations in the diabetic foot.
      ,
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Frykberg RG
      • Habershaw GM
      • Chrzan JS
      Epidemiology of the diabetic foot: ulcerations and amputations.
      ). Several population-based studies indicate a 0.5% to 3% annual cumulative incidence of diabetic foot ulcers (
      • Moss SE
      • Klein R
      • Klein BEK
      The prevalence and incidence of lower extremity amputation in a diabetic population.
      ,
      • Ramsey SD
      • Newton K
      • Blough D
      • McCulloch DK
      • Sandhu N
      • Reiber GE
      • Wagner EH
      Incidence, outcomes, and cost of foot ulcers in patients with diabetes.
      ,
      • Kumar S
      • Ashe HA
      • Parnell LN
      • Fernando DJ
      • Tsigos C
      • Young RJ
      • Ward JD
      • Boulton AJ
      The prevalence of foot ulceration and its correlates in type 2 diabetic patients: a population-based study.
      ,
      • Moss SE
      • Klein R
      • Klein BE
      The 14-year incidence of lower extremity amputations in a diabetic population. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
      ). According to one large British study of neuropathic patients, the 1-year incidence of initial foot ulcer was 7% (
      • Abbott CA
      • Vileikyte L
      • Williamson S
      • Carrington AL
      • Boulton AJ
      Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration.
      ). The prevalence of foot ulcers reported for a variety of populations ranges from 2% to 10% (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Moss SE
      • Klein R
      • Klein BEK
      The prevalence and incidence of lower extremity amputation in a diabetic population.
      ,
      • Abbott CA
      • Vileikyte L
      • Williamson S
      • Carrington AL
      • Boulton AJ
      Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration.
      ,
      • Walters DP
      • Gatling W
      • Mullee MA
      • Hill RD
      The distribution and severity of diabetic foot disease: a community study with comparison to a non-diabetic group.
      ). Neuropathy, deformity, high plantar pressure, poor glucose control, duration of diabetes, and male gender are all contributory factors for foot ulceration (see the following section: “Risk for Ulceration”) (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Frykberg RG
      Diabetic foot ulcers: pathogenesis and management.
      ,
      • Frykberg RG
      • Lavery LA
      • Pham H
      • Harvey C
      • Harkless L
      • Veves A
      Role of neuropathy and high foot pressures in diabetic foot ulceration.
      ,
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Davignon DR
      • Smith DG
      A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.
      ). National hospital discharge data indicate that the average hospital length of stay (LOS) for diabetic patients with ulcer diagnoses was 59% longer than for diabetic patients without ulcers (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ). While 7% to 20% of patients with foot ulcers will subsequently require an amputation, foot ulceration is the precursor to approximately 85% of lower extremity of amputations in persons with diabetes (
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ,
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Margolis DJ
      • Allen-Taylor L
      • Hoffstad O
      • Berlin JA
      Diabetic neuropathic foot ulcers and amputation.
      ).
      Diabetes continues to be the most common underlying cause of nontraumatic lower extremity amputations (LEAs) in the US and Europe (
      • Boulton AJ
      • Vileikyte L
      • Ragnarson-Tennvall G
      • Apelqvist J
      The global burden of diabetic foot disease.
      ,
      • Jeffcoate WJ
      The incidence of amputation in diabetes.
      ). More than 60% of LEAs in the US occur in people with diabetes, averaging 82,000 per year (

      Centers for Disease Control and Prevention. National diabetes fact sheet: general information and national estimates on diabetes in the United States, Centers for Disease Control and Prevention, Atlanta, 2005.

      ,

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ). While the number of diabetes-related hospital discharges has progressively increased from 33,000 in 1980 to 84,000 in 1997, this number seems to have leveled off during the present decade. In 2002, there were 82,000 diabetes-related LEA discharges, accounting for 911,000 days of hospital stay with an average LOS of 11.2 days (

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ). The age-adjusted rate of amputation for that year was 5.2 per 1,000 persons with diabetes, a notable decrease from the highest rate of 8.1 per 1,000 in 1996.
      In terms of level of diabetes-related lower limb amputations, toe amputations comprise the majority of procedures. The age-adjusted LEA rate in 2002 among persons with diabetes was highest for toe LEA (2.6 per 1,000 persons), followed by below-knee LEA (1.6 per 1,000 persons). For foot LEA and above-knee LEA, the age-adjusted rate was 0.8 per 1,000 persons. These trends in amputation level have essentially remained the same since 1993 (

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ). Generally, the LEA rate is 15 to 40 times higher in the diabetic versus nondiabetic populations, and the rate is at least 50% higher in men versus women (

      American Diabetes Association. Diabetes 1996 Vital Statistics, American Diabetes Association, Alexandria, VA, 1996.

      ,

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ,

      American Diabetes Association. Diabetes Facts and Figures, 2000, American Diabetes Association, Alexandria, VA, 2000.

      ,
      • Frykberg RG
      Epidemiology of the diabetic foot: ulcerations and amputations.
      ). In 2002, the age-adjusted LEA rate among men was 7.0 per 1,000 persons with diabetes compared with to the rate among women reported at 3.3 per 1000 persons with diabetes (

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ).
      Several ethnic differences occur in the frequency of diabetes-related amputations. Mexican (Hispanic) Americans, Native Americans, and African Americans each have at least a 1.5- to 2-fold greater risk for diabetes-related amputation than age-matched diabetic Caucasians (

      American Diabetes Association. Diabetes 1996 Vital Statistics, American Diabetes Association, Alexandria, VA, 1996.

      ,

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ,
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Frykberg RG
      • Habershaw GM
      • Chrzan JS
      Epidemiology of the diabetic foot: ulcerations and amputations.
      ,
      • Lavery LA
      • Ashry HR
      • van Houtum W
      • Pugh JA
      • Harkless LB
      • Basu S
      Variation in the incidence and proportion of diabetes related amputations in minorities.
      ,
      • Resnick HE
      • Valsania P
      • Phillips CL
      Diabetes mellitus and nontraumatic lower extremity amputation in black and white Americans: the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, 1971–1992.
      ). When LEA risk is compared between diabetic and nondiabetic populations worldwide, it is apparent that both diabetes and ethnicity have profound implications on rates of lower limb amputation (
      • Boulton AJ
      • Vileikyte L
      • Ragnarson-Tennvall G
      • Apelqvist J
      The global burden of diabetic foot disease.
      ,
      • Frykberg RG
      • Habershaw GM
      • Chrzan JS
      Epidemiology of the diabetic foot: ulcerations and amputations.
      ).
      Survival rates after amputation are generally lower for diabetic versus nondiabetic patients (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Frykberg RG
      • Habershaw GM
      • Chrzan JS
      Epidemiology of the diabetic foot: ulcerations and amputations.
      ,
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ). The 3- and 5-year survival rates are about 50% and 40%, respectively, with cardiovascular disease being the major cause of death (

      American Diabetes Association. Diabetes 1996 Vital Statistics, American Diabetes Association, Alexandria, VA, 1996.

      ). Although mortality rates following major amputation are high among both diabetic and nondiabetic patients, a recent study reported no significant difference between these two populations. The mean survival was approximately 6.5 years, with a 68% mortality after 9 years regardless of diabetes status (
      • Tentolouris N
      • Al-Sabbagh S
      • Walker MG
      • Boulton AJ
      • Jude EB
      Mortality in diabetic and nondiabetic patients after amputations performed from 1990 to 1995: a 5-year follow-up study.
      ). An earlier study from Sweden reported a 5-year mortality rate of 68% after lower limb amputation, with survival rates lower among patients who underwent higher levels of amputation (
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ). Similar trends were found in a review of amputations within the Veterans Affairs system, but worse survival outcomes were observed for older patients, those with renal disease, and those with peripheral arterial disease (
      • Mayfield JA
      • Reiber GE
      • Maynard C
      • Czerniecki JM
      • Caps MT
      • Sangeorzan BJ
      Survival following lower-limb amputation in a veteran population.
      ). Researchers have reported a 50% incidence of serious contralateral foot lesion (ie, ulcer) following an LEA, and a 50% incidence of contralateral amputation within 2 to 5 years of an LEA (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ).
      Total (direct and indirect) annual health care costs for persons with diabetes were estimated to be $132 billion in 2002. Direct medical expenditures, including hospitalization, medical care, and supplies, accounted for $91.8 billion (
      • American Diabetes Association
      Economic costs of diabetes in the U.S. in 2002.
      ). The estimated cost for foot ulcer care in the US ranges from $4,595 per ulcer episode to nearly $28,000 for the 2 years after diagnosis (
      • Ramsey SD
      • Newton K
      • Blough D
      • McCulloch DK
      • Sandhu N
      • Reiber GE
      • Wagner EH
      Incidence, outcomes, and cost of foot ulcers in patients with diabetes.
      ,
      • Holzer SE
      • Camerota A
      • Martens L
      • Cuerdon T
      • Crystal-Peters J
      • Zagari M
      Costs and duration of care for lower extremity ulcers in patients with diabetes.
      ). One report estimates 800,000 prevalent ulcer cases in the US, with costs averaging $5,457 per year per patient or total national annual costs of $5 billion (

      Amato D PU, Lantin M, Basso K, Martens L. The cost of illness in patients with diabetic foot ulcers. Abstract, 59th Annual Meeting of the American Diabetes Association, San Diego, 1999.

      ). A study of Medicare claims data found that expenditures for patients with lower extremity ulcers averaged 3 times higher than expenditures for Medicare beneficiaries in general. With 24% of their total costs allocated to ulcer-related expenses, lower extremity ulcer patients cost the Medicare system $1.5 billion in 1995 (
      • Harrington C
      • Zagari MJ
      • Corea J
      • Klitenic J
      A cost analysis of diabetic lower-extremity ulcers.
      ). According to a large prospective study of diabetic patients with foot ulcers, about 7% will subsequently require a lower extremity amputation (
      • Margolis DJ
      • Allen-Taylor L
      • Hoffstad O
      • Berlin JA
      Diabetic neuropathic foot ulcers and amputation.
      ). While hospital LOSs for diabetes-related LEA have progressively decreased in the US, the overall direct costs remain high (

      Centers for Disease Control and Prevention. Data and Trends: National Diabetes Surveillance System, Vol. 2006, National Center for Chronic Disease Prevention and Health Promotion, Atlanta, 2005.

      ,
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ). Direct and indirect costs of LEA—which range from $20,000 to $40,000 per event—vary by year, payer, level of amputation, LOS, and attendant comorbidities (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ). If the lower figure is applied to the 82,000 amputations performed in 2002, estimated total costs of LEA might exceed $1.6 billion annually. When outpatient costs for ulcer care preceding these amputations is added, the estimated total costs in the US for diabetic foot disease can easily approach or exceed $6 billion annually.

       Risk for Ulceration

      Foot ulceration is the most common single precursor to lower extremity amputations among persons with diabetes (
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ,
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ). Treatment of infected foot wounds comprises up to one quarter of all diabetic hospital admissions in the US and Britain, making this the most common reason for diabetes-related hospitalization in these countries (
      • Gibbons GW
      • Eliopoulos GM
      Infection of the diabetic foot.
      ,
      • Shaw JE
      • Boulton AJ
      The pathogenesis of diabetic foot problems: an overview.
      ,
      • Boulton AJ
      • Meneses P
      • Ennis WJ
      Diabetic foot ulcers: a framework for prevention and care.
      ). The multifactorial nature of diabetic foot ulceration has been elucidated by numerous observational studies (
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Abbott CA
      • Vileikyte L
      • Williamson S
      • Carrington AL
      • Boulton AJ
      Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration.
      ,
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Frykberg RG
      • Lavery LA
      • Pham H
      • Harvey C
      • Harkless L
      • Veves A
      Role of neuropathy and high foot pressures in diabetic foot ulceration.
      ,
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Davignon DR
      • Smith DG
      A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.
      ,
      • Young MJ
      • Breddy JL
      • Veves A
      • Boulton AJ
      The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. A prospective study.
      ,
      • Pham HT
      • Armstrong DG
      • Harvey C
      • Harkless LB
      • Giurini JM
      • Veves A
      Screening techniques to identify the at risk patients for developing diabetic foot ulcers in a prospective multicenter trial.
      ,
      • Abbott CA
      • Carrington AL
      • Ashe H
      • Bath S
      • Every LC
      • Griffiths J
      • Hann AW
      • Hussein A
      • Jackson N
      • Johnson KE
      • Ryder CH
      • Torkington R
      • Van Ross ER
      • Whalley AM
      • Widdows P
      • Williamson S
      • Boulton AJ
      The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community based patient cohort.
      ,
      • McNeely MJ
      • Boyko EJ
      • Ahroni JH
      • Stensel VL
      • Reiber GE
      • Smith DG
      • Pecoraro RF
      The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration.
      ,
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ). Risk factors identified include peripheral neuropathy, vascular disease, limited joint mobility, foot deformities, abnormal foot pressures, minor trauma, a history of ulceration or amputation, and impaired visual acuity (
      • Frykberg RG
      Diabetic foot ulcers: pathogenesis and management.
      ,
      • Boulton AJ
      • Kirsner RS
      • Vileikyte L
      Clinical practice. Neuropathic diabetic foot ulcers.
      ,
      • Boulton AJ
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      ). These and other putative causative factors are shown in Figure 1.
      Figure thumbnail gr1
      Figure 1The risk factors for ulceration may be distinguished by general or systemic considerations versus those localized to the foot and its pathology.
      Peripheral sensory neuropathy in the face of unperceived trauma is the primary factor leading to diabetic foot ulcerations (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Davignon DR
      • Smith DG
      A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.
      ,
      • Abbott CA
      • Carrington AL
      • Ashe H
      • Bath S
      • Every LC
      • Griffiths J
      • Hann AW
      • Hussein A
      • Jackson N
      • Johnson KE
      • Ryder CH
      • Torkington R
      • Van Ross ER
      • Whalley AM
      • Widdows P
      • Williamson S
      • Boulton AJ
      The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community based patient cohort.
      ,
      • Boulton AJ
      • Kirsner RS
      • Vileikyte L
      Clinical practice. Neuropathic diabetic foot ulcers.
      ). Approximately 45% to 60% of all diabetic ulcerations are purely neuropathic, while up to 45% have neuropathic and ischemic components (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • 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.
      ). According to an important prospective multicenter study, sensory neuropathy was the most frequent component in the causal sequence to ulceration in diabetic patients (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ).
      Other forms of neuropathy may also play a role in foot ulceration. Motor neuropathy resulting in anterior crural muscle atrophy or intrinsic muscle wasting can lead to foot deformities such as foot drop, equinus, hammertoe, and prominent plantar metatarsal heads (
      • Frykberg RG
      Diabetic foot ulcers: pathogenesis and management.
      ,
      • Frykberg RG
      • Lavery LA
      • Pham H
      • Harvey C
      • Harkless L
      • Veves A
      Role of neuropathy and high foot pressures in diabetic foot ulceration.
      ,
      • Akbari CM
      • Macsata R
      • Smith BM
      • Sidawy AN
      Overview of the diabetic foot.
      ,
      • Bus SA
      • Yang QX
      • Wang JH
      • Smith MB
      • Wunderlich R
      • Cavanagh PR
      Intrinsic muscle atrophy and toe deformity in the diabetic neuropathic foot: a magnetic resonance imaging study.
      ,
      • Sumpio BE
      Foot ulcers.
      ). Ankle equinus with restricted dorsiflexory range of motion is fairly common in patients with diabetic neuropathy and can be a consequence of anterior crural muscle atrophy (
      • Van Gils CC
      • Roeder B
      The effect of ankle equinus upon the diabetic foot.
      ,
      • Lin SS
      • Lee TH
      • Wapner KL
      Plantar forefoot ulceration with equinus deformity of the ankle in diabetic patients: the effect of tendo-achilles lengthening and total contact casting.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Armstrong DG
      • Stacpoole-Shea S
      • Nguyen H
      • Harkless LB
      Lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot.
      ,
      • van Schie CH
      A review of the biomechanics of the diabetic foot.
      ,
      • Lavery LA
      • Armstrong DG
      • Boulton AJ
      Ankle equinus deformity and its relationship to high plantar pressure in a large population with dia betes mellitus.
      ). The decreased ankle motion, which confers higher-than-normal plantar pressures at the forefoot, has been implicated as a contributory cause of ulceration as well as recurrence or recalcitrance of existing ulcers (
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Armstrong DG
      • Stacpoole-Shea S
      • Nguyen H
      • Harkless LB
      Lengthening of the Achilles tendon in diabetic patients who are at high risk for ulceration of the foot.
      ,
      • Lavery LA
      • Armstrong DG
      • Boulton AJ
      Ankle equinus deformity and its relationship to high plantar pressure in a large population with dia betes mellitus.
      ,
      • Mueller MJ
      • Sinacore DR
      • Hastings MK
      • Strube MJ
      • Johnson JE
      Effect of achilles tendon lengthening on neuropathic plantar ulcers. A randomized clinical trial.
      ).
      Autonomic neuropathy often results in dry skin with cracking and fissuring, creating a portal of entry for bacteria (
      • Shaw JE
      • Boulton AJ
      The pathogenesis of diabetic foot problems: an overview.
      ,
      • Flynn MD
      • Tooke JE
      Aetiology of diabetic foot ulceration: a role for the microcirculation.
      ). Autosympathectomy with attendant sympathetic failure, arteriovenous shunting, and microvascular thermoregulatory dysfunction impairs normal tissue perfusion and microvascular responses to injury. These alterations can subsequently be implicated in the pathogenesis of ulceration (
      • Flynn MD
      • Tooke JE
      Aetiology of diabetic foot ulceration: a role for the microcirculation.
      ,
      • Parkhouse N
      • Le Quesne PM
      Impaired neurogenic vascular response in patients with diabetes and neuropathic foot lesions.
      ,
      • Boulton AJM
      • Vileikyte L
      Pathogenesis of diabetic foot ulceration and measurements of neuropathy.
      ,
      • Boulton AJ
      The pathogenesis of diabetic foot problems: an overview.
      ,
      • Nabuurs-Franssen MH
      • Houben AJ
      • Tooke JE
      • Schaper NC
      The effect of polyneuropathy on foot microcirculation in Type II diabetes.
      ).
      Foot deformities resulting from neuropathy, abnormal biomechanics, congenital disorders, or prior surgical intervention may result in high focal foot pressures and increased risk of ulceration (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ,
      • Boulton AJ
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Frykberg RG
      Biomechanical considerations of the diabetic foot.
      ,
      • Knox RC
      • Dutch W
      • Blume P
      • Sumpio BE
      Diabetic Foot Disease.
      ,
      • Veves A
      • Murray HJ
      • Young MJ
      • Boulton AJ
      The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study.
      ,
      • Robertson DD
      • Mueller MJ
      • Smith KE
      • Commean PK
      • Pilgram T
      • Johnson JE
      Structural changes in the forefoot of individuals with diabetes and a prior plantar ulcer.
      ). The effects of motor neuropathy occur relatively early and lead to foot muscle atrophy with consequent development of hammertoes, fat pad displacement, and associated increases in plantar forefoot pressures (
      • Bus SA
      • Yang QX
      • Wang JH
      • Smith MB
      • Wunderlich R
      • Cavanagh PR
      Intrinsic muscle atrophy and toe deformity in the diabetic neuropathic foot: a magnetic resonance imaging study.
      ,
      • Greenman RL
      • Khaodhiar L
      • Lima C
      • Dinh T
      • Giurini JM
      • Veves A
      Foot small muscle atrophy is present before the detection of clinical neuropathy.
      ,
      • Mueller MJ
      • Hastings M
      • Commean PK
      • Smith KE
      • Pilgram TK
      • Robertson D
      • Johnson J
      Forefoot structural predictors of plantar pressures during walking in people with diabetes and peripheral neuropathy.
      ,
      • Andersen H
      • Gjerstad MD
      • Jakobsen J
      Atrophy of foot muscles: a measure of diabetic neuropathy.
      ,
      • Bus SA
      • Maas M
      • Cavanagh PR
      • Michels RP
      • Levi M
      Plantar fat-pad displacement in neuropathic diabetic patients with toe deformity: a magnetic resonance imaging study.
      ). Although most deformities cause high plantar pressures and plantar foot ulcerations, medial and dorsal ulcerations may develop as a result of footwear irritation. Common deformities might include prior partial foot amputations, prominent metatarsal heads, hammertoes, Charcot arthropathy, or hallux valgus (
      • Knox RC
      • Dutch W
      • Blume P
      • Sumpio BE
      Diabetic Foot Disease.
      ,
      • Boulton AJ
      Pressure and the diabetic foot: clinical science and offloading techniques.
      ,
      • Caputo GM
      • Cavanagh PR
      • Ulbrecht JS
      • Gibbons GW
      • Karchmer AW
      Assessment and management of foot disease in patients with diabetes.
      ,
      • Armstrong DG
      • Lavery LA
      Elevated peak plantar pressures in patients who have Charcot arthropathy.
      ,
      • Frykberg RG
      Charcot arthropathy: pathogenesis and management.
      ). A large prospective population-based study found that elevated plantar foot pressures are significantly associated with neuropathic ulceration and amputation (
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Predictive value of foot pressure assessment as part of a population based diabetes disease management program.
      ). The study also revealed a trend for increased foot pressures as the number of pedal deformities increased.
      Trauma to the foot in the presence of sensory neuropathy is an important component cause of ulceration (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ). While trauma may include puncture wounds and blunt injury, a common injury leading to ulceration is moderate repetitive stress associated with walking or day-to-day activity (
      • Knox RC
      • Dutch W
      • Blume P
      • Sumpio BE
      Diabetic Foot Disease.
      ,
      • Boulton AJ
      Pressure and the diabetic foot: clinical science and offloading techniques.
      ,
      • Cavanagh PR
      • Ulbrecht JS
      • Caputo GM
      New developments in the bio mechanics of the diabetic foot.
      ). This is often manifested by callus formation under the metatarsal heads (
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ,
      • Murray HJ
      • Young MJ
      • Hollis S
      • Boulton AJ
      The association between callus formation, high pressures and neuropathy in diabetic foot ulceration.
      ,
      • Young MJ
      • Cavanagh PR
      • Thomas G
      • Johnson MM
      • Murray H
      • Boulton AJ
      The effect of callus removal on dynamic plantar foot pressures in diabetic patients.
      ). A recent report suggests that even with moderate activity, ulceration may be precipitated by a higher degree of variability in activity or periodic “bursts” of activity (
      • Armstrong DG
      • Lavery LA
      • Holtz-Neiderer K
      • Mohler MJ
      • Wendel CS
      • Nixon BP
      • Boulton AJM
      Variability in activity may precede diabetic foot lceration.
      ). Shoe-related trauma has also been identified as a frequent precursor to foot ulceration (
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • 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.
      ,
      • Sumpio BE
      Foot ulcers.
      ,
      • Apelqvist J
      • Larsson J
      • Agardh CD
      The influence of external precipitating factors and peripheral neuropathy on the development and outcome of diabetic foot ulcers.
      ,
      • Uccioli L
      • Faglia E
      • Monticone G
      • Favales F
      • Durola L
      • Aldeghi A
      • Quarantiello A
      • Calia P
      • Menzinger G
      Manufactured shoes in the prevention of diabetic foot ulcers.
      ).
      Peripheral arterial disease (PAD) rarely leads to foot ulcerations directly. However, once ulceration develops, arterial insufficiency will result in prolonged healing, imparting an elevated risk of amputation (
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Pecoraro RE
      Chronology and determinants of tissue repair in diabetic lower extremity ulcers.
      ,
      • Gibbons GW
      Lower extremity bypass in patients with diabetic foot ulcers.
      ). Additionally, attempts to resolve any infection will be impaired due to lack of oxygenation and difficulty in delivering antibiotics to the infection site. Therefore, early recognition and aggressive treatment of lower extremity ischemia are vital to lower limb salvage (
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Akbari CM
      • Macsata R
      • Smith BM
      • Sidawy AN
      Overview of the diabetic foot.
      ,
      • Sumpio BE
      • Lee T
      • Blume PA
      Vascular evaluation and arterial reconstruction of the diabetic foot.
      ,

      International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot, edited by J Apelqvist, K Bakker, WH Van Houtum, MH Nabuurs-Franssen, and NC Schaper. Vol. 2005. International Working Group on the Diabetic Foot, Maatricht, 1999.

      ,
      • Mills JLBW
      • Taylor SM
      The diabetic foot: Consequences of delayed treatment and referral.
      ).
      Limited joint mobility has also been described as a potential risk factor for ulceration (
      • Fernando DJ
      • Masson EA
      • Veves A
      • Boulton AJ
      Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration.
      ,
      • Boulton AJM
      The pathway to ulceration.
      ,
      • Mueller MJ
      • Diamond JE
      • Delitto A
      • Sinacore DR
      Insensitivity, limited joint mobility, and plantar ulcers in patients with diabetes mellitus.
      ). Glycosylation of collagen as a result of longstanding diabetes may lead to stiffening of capsular structures and ligaments (cheiroarthropathy) (
      • Brownlee M
      Glycation products and the pathogenesis of diabetic complications.
      ). The subsequent reduction in ankle, subtalar, and first metatarsophalangeal (MTP) joint mobility has been shown to result in high focal plantar pressures with increased ulceration risk in patients with neuropathy (
      • Fernando DJ
      • Masson EA
      • Veves A
      • Boulton AJ
      Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration.
      ,
      • Delbridge L
      • Perry P
      • Marr S
      • Arnold N
      • Yue DK
      • Turtle JR
      • Reeve TS
      Limited joint mobility in the diabetic foot: relationship to neuropathic ulceration.
      ,
      • Zimny S
      • Schatz H
      • Pfohl M
      The role of limited joint mobility in diabetic patients with an at-risk foot.
      ). Several reports also attribute glycosylation and altered arrangement of Achilles tendon collagen to the propensity for diabetic patients to develop ankle equinus (
      • Grant WP
      • Foreman EJ
      • Wilson AS
      • Jacobus DA
      • Kukla RM
      Evaluation of Young's modulus in Achilles tendons with diabetic neuroarthropathy.
      ,
      • Grant WP
      • Sullivan R
      • Soenshine DE
      • Adam M
      • Slusser JH
      • Carson KA
      • Vinik AI
      Electron microscopic investigation of the effects of diabetes mellitus on the achilles tendon.
      ).
      Other factors frequently associated with heightened ulceration risk include nephropathy, poor diabetes control, duration of diabetes, visual loss, and advanced age (
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ,
      • Knox RC
      • Dutch W
      • Blume P
      • Sumpio BE
      Diabetic Foot Disease.
      ,
      • Boulton AJM
      The pathway to ulceration.
      ,
      • Frykberg RG
      Diabetic foot ulcerations: management and adjunctive therapy.
      ). Soft tissue changes (other than cheiroarthropathy) in the feet of diabetic patients might also contribute to ulceration through the pathway of altered pressure distributions through the sole of the foot. Such alterations include a reported increased thickness of the plantar fascia with associated limitation of hallux dorsiflexion, decreased thickness of plantar soft tissue, accentuated hardness/stiffness of the skin, and a propensity to develop calluses (
      • Murray HJ
      • Young MJ
      • Hollis S
      • Boulton AJ
      The association between callus formation, high pressures and neuropathy in diabetic foot ulceration.
      ,
      • Delbridge L
      • Perry P
      • Marr S
      • Arnold N
      • Yue DK
      • Turtle JR
      • Reeve TS
      Limited joint mobility in the diabetic foot: relationship to neuropathic ulceration.
      ,
      • Abouaesha F
      • van Schie CH
      • Armstrong DG
      • Boulton AJ
      Plantar soft-tissue thickness predicts high peak plantar pressure in the diabetic foot.
      ,
      • Abouaesha F
      • van Schie CH
      • Griffths GD
      • Young RJ
      • Boulton AJ
      Plantar tissue thickness is related to peak plantar pressure in the high risk diabetic foot.
      ,
      • D'Ambrogi E
      • Giurato L
      • D'Agostino MA
      • Giacomozzi C
      • Macellari V
      • Caselli A
      • Uccioli L
      Contribution of plantar fascia to the increased forefoot pressures in diabetic patients.
      ,
      • D'Ambrogi E
      • Giacomozzi C
      • Macellari V
      • Uccioli L
      Abnormal foot function in diabetic patients: the altered onset of Windlass mechanism.
      ,
      • Piaggesi A
      • Romanelli M
      • Schipani E
      • Campi F
      • Magliaro A
      • Baccetti F
      • Navalesi R
      Hardness of plantar skin in diabetic neuropathic feet.
      ). While these changes are presumably caused by glycosylation of collagen, their sum effect is to enhance plantar pressures in gait. In the presence of neuropathy, the accentuated plantar pressures can be implicated in the development of ulceration (
      • Veves A
      • Murray HJ
      • Young MJ
      • Boulton AJ
      The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study.
      ,
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Predictive value of foot pressure assessment as part of a population based diabetes disease management program.
      ,
      • Fernando DJ
      • Masson EA
      • Veves A
      • Boulton AJ
      Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration.
      ,
      • Ahroni JH
      • Boyko EJ
      • Forsberg RC
      Clinical correlates of plantar pressure among diabetic veterans.
      ).

       Mechanisms of Injury

      The multifactorial etiology of diabetic foot ulcers is evidenced by the numerous pathophysiologic pathways that can potentially lead to this disorder (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Boulton AJ
      • Meneses P
      • Ennis WJ
      Diabetic foot ulcers: a framework for prevention and care.
      ,
      • Sumpio BE
      Foot ulcers.
      ,
      • Frykberg R
      Diabetic foot ulcerations.
      ,

      International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot, edited by J Apelqvist, K Bakker, WH Van Houtum, MH Nabuurs-Franssen, and NC Schaper. Vol. 2005. International Working Group on the Diabetic Foot, Maatricht, 1999.

      ,
      • Rathur HM
      • Boulton AJ
      Pathogenesis of foot ulcers and the need for offloading.
      ). Among these are two common mechanisms by which foot deformity and neuropathy may induce skin breakdown in persons with diabetes (
      • Knox RC
      • Dutch W
      • Blume P
      • Sumpio BE
      Diabetic Foot Disease.
      ,
      • Brand PW
      Repetitive stress in the development of diabetic foot ulcers.
      ,
      • Habershaw G
      • Chrzan JS
      Biomechanical considerations of the diabetic foot.
      ).
      The first mechanism of injury refers to prolonged low pressure over a bony prominence (ie, bunion or hammertoe deformity). This generally causes wounds over the medial, lateral, and dorsal aspects of the forefoot and is associated with tight or ill-fitting shoes. Shoe trauma, in concert with loss of protective sensation and concomitant foot deformity, is the leading event precipitating foot ulceration in persons with diabetes (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Apelqvist J
      • Larsson J
      • Agardh CD
      The influence of external precipitating factors and peripheral neuropathy on the development and outcome of diabetic foot ulcers.
      ).
      Regions of high pedal pressure are frequently associated with foot deformity (
      • Frykberg RG
      Biomechanical considerations of the diabetic foot.
      ,
      • Mueller MJ
      • Hastings M
      • Commean PK
      • Smith KE
      • Pilgram TK
      • Robertson D
      • Johnson J
      Forefoot structural predictors of plantar pressures during walking in people with diabetes and peripheral neuropathy.
      ,
      • Boulton AJ
      Pressure and the diabetic foot: clinical science and offloading techniques.
      ,
      • Caputo GM
      • Cavanagh PR
      • Ulbrecht JS
      • Gibbons GW
      • Karchmer AW
      Assessment and management of foot disease in patients with diabetes.
      ,
      • Ahroni JH
      • Boyko EJ
      • Forsberg RC
      Clinical correlates of plantar pressure among diabetic veterans.
      ,
      • Rathur HM
      • Boulton AJ
      Pathogenesis of foot ulcers and the need for offloading.
      ). When an abnormal focus of pressure is coupled with lack of protective sensation, the result can be development of a callus, blister, and ulcer (
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell JL
      • Boulton AJM
      Predictive value of foot pressure assessment as part of a population-based diabetes disease management program.
      ). The other common mechanism of ulceration involves prolonged repetitive moderate stress (
      • Brand PW
      Repetitive stress in the development of diabetic foot ulcers.
      ). This normally occurs on the sole of the foot and is related to prominent metatarsal heads, atrophied or anteriorly displaced fat pads, structural deformity of the lower extremity, and prolonged walking. Rigid deformities such as hallux valgus, hallux rigidus, hammertoe, Charcot arthropathy, and limited range of motion of the ankle (equinus), subtalar, and MTP joints have been linked to the development of diabetic foot ulcers (
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Davignon DR
      • Smith DG
      A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Robertson DD
      • Mueller MJ
      • Smith KE
      • Commean PK
      • Pilgram T
      • Johnson JE
      Structural changes in the forefoot of individuals with diabetes and a prior plantar ulcer.
      ,
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Predictive value of foot pressure assessment as part of a population based diabetes disease management program.
      ,
      • Mueller MJ
      • Diamond JE
      • Delitto A
      • Sinacore DR
      Insensitivity, limited joint mobility, and plantar ulcers in patients with diabetes mellitus.
      ,
      • Delbridge L
      • Perry P
      • Marr S
      • Arnold N
      • Yue DK
      • Turtle JR
      • Reeve TS
      Limited joint mobility in the diabetic foot: relationship to neuropathic ulceration.
      ). Numerous studies support the significant association between high plantar pressures and foot ulceration (
      • Frykberg RG
      • Lavery LA
      • Pham H
      • Harvey C
      • Harkless L
      • Veves A
      Role of neuropathy and high foot pressures in diabetic foot ulceration.
      ,
      • Veves A
      • Murray HJ
      • Young MJ
      • Boulton AJ
      The risk of foot ulceration in diabetic patients with high foot pressure: a prospective study.
      ,
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Predictive value of foot pressure assessment as part of a population based diabetes disease management program.
      ,
      • Fernando DJ
      • Masson EA
      • Veves A
      • Boulton AJ
      Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration.
      ,
      • Ahroni JH
      • Boyko EJ
      • Forsberg RC
      Clinical correlates of plantar pressure among diabetic veterans.
      ,
      • Pham H
      • Armstrong DG
      • Harvey C
      • Harkless LB
      • Giurini JM
      • Veves A
      Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial.
      ,
      • Armstrong DG
      • Peters EJ
      • Athanasiou KA
      • Lavery LA
      Is there a critical level of plantar foot pressure to identify patients at risk for neuropathic foot ulceration?.
      ). Other biomechanical perturbations, including partial foot amputations, have the same adverse effects (
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Frykberg RG
      Biomechanical considerations of the diabetic foot.
      ,
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Predictive value of foot pressure assessment as part of a population based diabetes disease management program.
      ,
      • Armstrong DG
      • Lavery LA
      Plantar pressures are higher in diabetic patients following partial foot amputation.
      ).
      Figure 2 summarizes the various pathways and contributing factors leading to diabetic foot complications.
      Figure thumbnail gr2
      Figure 2Diabetes mellitus is responsible for a variety of foot pathologies contributing to the complications of ulceration and amputation. Multiple pathologies may be implicated, from vascular disease to neuropathy to mechanical trauma.

       Risk for Infection

      Infections are common in diabetic patients and are often more severe than infections found in nondiabetic patients. Persons with diabetes have an increased risk for developing an infection of any kind and a several-fold risk for developing osteomyelitis (
      • Shah BR
      • Hux JE
      Quantifying the risk of infectious diseases for people with diabetes.
      ). With an incidence of 36.5 per 1,000 persons per year, foot infections are among the most common lower extremity complications in the diabetic population (excluding neuropathy), second only to foot ulcers in frequency (
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohort.
      ).
      It is well documented that diabetic foot infections are frequently polymicrobial in nature (
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Caputo GM
      • Joshi N
      • Weitekamp MR
      Foot infections in patients with diabetes.
      ,
      • Armstrong DG
      • Lipsky BA
      Diabetic foot infections: stepwise medical and surgical management.
      ,
      • Grayson ML
      • Gibbons GW
      • Habershaw GM
      • Freeman DV
      • Pomposelli FB
      • Rosenblum BI
      • Levin E
      • Karchmer AW
      Use of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients.
      ,
      • Grayson ML
      Diabetic foot infections. Antimicrobial therapy.
      ,
      • Sapico FL
      • Canawati HN
      • Witte JL
      • Montgomerie JZ
      • Wagner Jr, FW
      • Bessman AN
      Quantitative aerobic and anaerobic bacteriology of infected diabetic feet.
      ,
      • Goldstein EJ
      • Citron DM
      • Nesbit CA
      Diabetic foot infections. Bacteriology and activity of 10 oral antimicrobial agents against bacteria isolated from consecutive cases.
      ). Hyperglycemia, impaired immunologic responses, neuropathy, and peripheral arterial disease are the major predisposing factors leading to limb-threatening diabetic foot infections (
      • Lipsky BA
      A report from the international consensus on diagnosing and treating the infected diabetic foot.
      ,
      • Lipsky BA
      • Berendt AR
      • Deery HG
      • Embil JM
      • Joseph WS
      • Karchmer AW
      • LeFrock JL
      • Lew DP
      • Mader JT
      • Norden C
      • Tan JS
      Diagnosis and treatment of diabetic foot infections.
      ,
      • Calhoun JH
      • Cantrell J
      • Cobos J
      • Lacy J
      • Valdez RR
      • Hokanson J
      • Mader JT
      Treatment of diabetic foot infections: Wagner classification, therapy, and outcome.
      ). Uncontrolled diabetes results in impaired ability of host leukocytes to fight bacterial pathogens, and ischemia also affects the ability to fight infections because delivery of antibiotics to the site of infection is impaired. Consequently, infection can develop, spread rapidly, and produce significant and irreversible tissue damage (
      • Caputo GM
      The rational use of antimicrobial agents in diabetic foot infection.
      ). Even in the presence of adequate arterial perfusion, underlying peripheral sensory neuropathy will often allow the progression of infection through continued walking or delay in recognition (
      • Gibbons GW
      • Habershaw GM
      Diabetic foot infections. Anatomy and surgery.
      ,
      • Eneroth M
      • Larsson J
      • Apelqvist J
      Deep foot infections in patients with diabetes and foot ulcer: an entity with different characteristics, treatments, and prognosis.
      ).

       Risk for Charcot Joint Disease

      It has been estimated that less than 1% of persons with diabetes will develop Charcot joint disease (
      • Sinha S
      • Munichoodapa CS
      • Kozak GP
      Neuroarthropathy (Charcot joints) in diabetes mellitus.
      ,
      • Sanders LJ
      • Frykberg RG
      Diabetic neuropathic osteoarthropathy: The Charcot foot.
      ,
      • Jeffcoate W
      • Lima J
      • Nobrega L
      The Charcot foot.
      ). Data on the true incidence of neuroarthropathy in diabetes are limited by the paucity of prospective or population-based studies in the literature. One large population-based prospective study found an incidence of about 8.5 per 1,000 persons with diabetes per year (
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohort.
      ); this equates to 0.85% per year and is probably the most reliable figure currently available. Much of the data clinicians rely upon have been extracted from retrospective studies of small, single-center cohorts. The incidence of reported Charcot cases is likely to be underestimated because many cases go undetected, especially in the early stages (
      • Banks AS
      A clinical guide to Charcot foot.
      ,
      • Frykberg RG
      • Mendeszoon E
      Management of the diabetic Charcot foot.
      ,
      • Sanders L
      • Frykberg RG
      Charcot neuroarthropathy of the foot.
      ,
      • Frykberg RG
      • Kozak GP
      The diabetic Charcot foot.
      ).
      Primary risk factors for this potentially limb-threatening deformity are the presence of dense peripheral sensory neuropathy, normal circulation, and history of preceding trauma (often minor in nature) (
      • Boulton AJ
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      ,
      • Armstrong DG
      • Todd WF
      • Lavery LA
      • Harkless LB
      The natural history of acute Charcot's arthropathy in a diabetic foot specialty clinic.
      ,
      • Frykberg RG
      Charcot changes in the diabetic foot.
      ). Trauma is not limited to injuries such as sprains or contusions. Foot deformities, prior amputations, joint infections, or surgical trauma may result in sufficient stress that can lead to Charcot joint disease (
      • Giurini JM
      • Chrzan JS
      • Gibbons GW
      • Habershaw GM
      Charcot's disease in diabetic patients. Correct diagnosis can prevent progressive deformity.
      ,
      • Pakarinen TK
      • Laine HJ
      • Honkonen SE
      • Peltonen J
      • Oksala H
      • Lahtela J
      Charcot arthropathy of the diabetic foot. Current concepts and review of 36 cases.
      ,
      • Rajbhandari SM
      • Jenkins RC
      • Davies C
      • Tesfaye S
      Charcot neuroarthropathy in diabetes mellitus.
      ,
      • Trepman E
      • Nihal A
      • Pinzur MS
      Current topics review: Charcot neuroarthropathy of the foot and ankle.
      ).

       Risk for Amputation

      The reported risk of lower extremity amputations in diabetic patients ranges from 2% to 16%, depending on study design and the populations studied (
      • Ramsey SD
      • Newton K
      • Blough D
      • McCulloch DK
      • Sandhu N
      • Reiber GE
      • Wagner EH
      Incidence, outcomes, and cost of foot ulcers in patients with diabetes.
      ,
      • Moss SE
      • Klein R
      • Klein BE
      The 14-year incidence of lower extremity amputations in a diabetic population. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
      ,
      • Jeffcoate WJ
      The incidence of amputation in diabetes.
      ,
      • Lavery LA
      • Armstrong DG
      • Wunderlich RP
      • Tredwell J
      • Boulton AJ
      Diabetic foot syndrome: evaluating the prevalence and incidence of foot pathology in Mexican Americans and non-Hispanic whites from a diabetes disease management cohort.
      ,
      • Moss SE
      • Klein R
      • Klein BE
      The prevalence and incidence of lower extremity amputation in a diabetic population.
      ,
      • Adler AI
      • Boyko EJ
      • Ahroni JH
      • Smith DG
      Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers [In Process Citation].
      ,
      • Jeffcoate WJ
      • van Houtum WH
      Amputation as a marker of the quality of foot care in diabetes.
      ,
      • Resnick HE
      • Carter EA
      • Sosenko JM
      • Henly SJ
      • Fabsitz RR
      • Ness FK
      • Welty TK
      • Lee ET
      • Howard BV
      Incidence of lower-extremity amputation in American Indians: the Strong Heart Study.
      ). LEA rates can be 15 to 40 times higher among the diabetic versus nondiabetic populations (

      American Diabetes Association. Diabetes 1996 Vital Statistics, American Diabetes Association, Alexandria, VA, 1996.

      ,
      • Reiber GE
      • Boyko EJ
      • Smith DG
      Lower extremity foot ulcers and amputations in diabetes.
      ,
      • Lavery LA
      • Ashry HR
      • van Houtum W
      • Pugh JA
      • Harkless LB
      • Basu S
      Variation in the incidence and proportion of diabetes related amputations in minorities.
      ,
      • Resnick HE
      • Valsania P
      • Phillips CL
      Diabetes mellitus and nontraumatic lower extremity amputation in black and white Americans: the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, 1971–1992.
      ). Although one author suggests that amputation may be a marker not only for disease severity but also for disease management, it is clear that amputation remains a global problem for all persons with diabetes (
      • Jeffcoate WJ
      The incidence of amputation in diabetes.
      ,
      • Jeffcoate WJ
      • van Houtum WH
      Amputation as a marker of the quality of foot care in diabetes.
      ). The same risk factors that predispose to ulceration can also generally be considered contributing causes of amputation, albeit with several modifications (Fig 3).
      Figure thumbnail gr3
      Figure 3The risk factors for amputation are multifactorial and similar to those for ulceration.
      While peripheral arterial disease may not always be an independent risk factor for ulceration when controlling for neuropathy, it can be a significant risk factor for amputation (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Gibbons GW
      Lower extremity bypass in patients with diabetic foot ulcers.
      ,
      • Adler AI
      • Boyko EJ
      • Ahroni JH
      • Smith DG
      Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers [In Process Citation].
      ,
      • Moulik PK
      • Mtonga R
      • Gill GV
      Amputation and mortality in new-onset diabetic foot ulcers stratified by etiology.
      ,
      • Hennis AJ
      • Fraser HS
      • Jonnalagadda R
      • Fuller J
      • Chaturvedi N
      Explanations for the high risk of diabetes-related amputation in a Caribbean population of black african descent and potential for prevention.
      ). PAD affecting the feet and legs is present in 8% of adult diabetic patients at diagnosis and in 45 % after 20 years (
      • Melton LJ
      • Macken KM
      • Palumbo PJ
      • Elveback LR
      Incidence and prevalence of clinical peripheral vascular disease in a population based cohort of diabetic patients.
      ,
      • Pirart J
      Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973.
      ). The incidence of amputation is 4 to 7 times greater for diabetic men and women than for their nondiabetic counterparts. Impairment of arterial perfusion may be an isolated cause for amputation and a predisposing factor for gangrene. Early diagnosis, control of risk factors, and medical management as well as timely revascularization may aid in avoiding limb loss (
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Akbari CM
      • Macsata R
      • Smith BM
      • Sidawy AN
      Overview of the diabetic foot.
      ,
      • Caputo GM
      • Cavanagh PR
      • Ulbrecht JS
      • Gibbons GW
      • Karchmer AW
      Assessment and management of foot disease in patients with diabetes.
      ,
      • Gibbons GW
      Lower extremity bypass in patients with diabetic foot ulcers.
      ,
      • LoGerfo FW
      • Gibbons GW
      • Pomposelli Jr., FB
      • Campbell DR
      • Miller A
      • Freeman DV
      • Quist WC
      Trends in the care of the diabetic foot. Expanded role of arterial reconstruction.
      ).
      While infection is not often implicated in the pathway leading to ulceration, it is a significant risk factor in the causal pathway to amputation (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ). Lack of wound healing, systemic sepsis, or unresolved infection can lead to extensive tissue necrosis and gangrene, requiring amputation to prevent more proximal limb loss. This includes soft tissue infection with severe tissue destruction, deep space abscess, or osteomyelitis. Adequate debridement may require amputation at some level as a means of removing all infected material (
      • Caputo GM
      • Cavanagh PR
      • Ulbrecht JS
      • Gibbons GW
      • Karchmer AW
      Assessment and management of foot disease in patients with diabetes.
      ,
      • Lipsky BA
      • Berendt AR
      • Deery HG
      • Embil JM
      • Joseph WS
      • Karchmer AW
      • LeFrock JL
      • Lew DP
      • Mader JT
      • Norden C
      • Tan JS
      Diagnosis and treatment of diabetic foot infections.
      ,
      • Gibbons GW
      The diabetic foot: amputations and drainage of infection.
      ,
      • Frykberg RG
      An evidence-based approach to diabetic foot infections.
      ).
      Another frequently described risk factor for amputation is chronic hyperglycemia. Results of the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) support the long-held theory that chronic poor control of diabetes is associated with a host of systemic complications (
      • UK Prospective Diabetes Study Group
      Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group.
      ,
      • The Diabetes Control and Complications Trial Research Group
      The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependant diabetes mellitus.
      ). The link between degree of glucose control and incidence or progression of numerous diabetic complications has been well established by these and other studies (
      • American Diabetes Association
      Implications of the Diabetes Control and Complications Trial.
      ,
      • American Diabetes Association
      Implications of the United Kingdom Prospective Diabetes Study.
      ). Such complications include peripheral neuropathy, microangiopathy, microcirculatory disturbances, impaired leukocyte phagocytosis, and glycosylation of tissue proteins. Each has adverse effects on the diabetic foot: They can contribute to the etiology of foot ulceration, delay normal wound healing, and subsequently lead to amputation (
      • Frykberg RG
      Diabetic foot ulcers: pathogenesis and management.
      ,
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ,
      • Boulton AJ
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      ,
      • Greenman RL
      • Khaodhiar L
      • Lima C
      • Dinh T
      • Giurini JM
      • Veves A
      Foot small muscle atrophy is present before the detection of clinical neuropathy.
      ). Several studies have reported a significant correlation between elevated glucose and LEA (
      • Moss SE
      • Klein R
      • Klein BE
      The 14-year incidence of lower extremity amputations in a diabetic population. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
      ,
      • Moss SE
      • Klein R
      • Klein BE
      The prevalence and incidence of lower extremity amputation in a diabetic population.
      ,
      • Selby JV
      • Zhang D
      Risk factors for lower extremity amputation in persons with diabetes.
      ,
      • Reiber GE
      • Pecoraro RE
      • Koepsell TD
      Risk factors for amputation in patients with diabetes mellitus: a case control study.
      ,
      • Nelson RG
      • Gohdes DM
      • Everhart JE
      • Hartner JA
      • Zwemmer FL
      • Pettitt DJ
      • Knowler WC
      Lower extremity amputations in NIDDM: 12-year follow-up study in Pima Indians.
      ,
      • Lee JS
      • Lu M
      • Lee VS
      Lower extremity amputation: incidence, risk factors and mortality in the Oklahoma Indian diabetes study.
      ,
      • Lehto S
      • Ronnemaa T
      • Pyorala K
      • Laakso M
      Risk factors predicting lower extremity amputations in patients with NIDDM.
      ,
      • Humphrey AR
      • Dowse GK
      • Thoma K
      • Zimmet PZ
      Diabetes and nontraumatic lower extremity amputations. Incidence, risk factors, and prevention—a 12-year follow-up study in Nauru.
      ). Amputation has also been associated with other diabetes-related comorbidities such as nephropathy, retinopathy, and cardiovascular disease (
      • Moss SE
      • Klein R
      • Klein BE
      The 14-year incidence of lower extremity amputations in a diabetic population. The Wisconsin Epidemiologic Study of Diabetic Retinopathy.
      ,
      • Mayfield JA
      • Reiber GE
      • Sanders LJ
      • Janisse D
      • Pogach LM
      Preventive foot care in people with diabetes.
      ,
      • Resnick HE
      • Carter EA
      • Sosenko JM
      • Henly SJ
      • Fabsitz RR
      • Ness FK
      • Welty TK
      • Lee ET
      • Howard BV
      Incidence of lower-extremity amputation in American Indians: the Strong Heart Study.
      ). Aggressive glucose control, management of associated comorbidities, and appropriate lower extremity care coordinated in a team environment may indeed lower overall risk for amputation (
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,

      International Working Group on the Diabetic Foot. International Consensus on the Diabetic Foot, edited by J Apelqvist, K Bakker, WH Van Houtum, MH Nabuurs-Franssen, and NC Schaper. Vol. 2005. International Working Group on the Diabetic Foot, Maatricht, 1999.

      ,
      • Levin ME
      Preventing amputation in the patient with diabetes.
      ,
      • Frykberg RG
      Team approach toward lower extremity amputation prevention in diabetes.
      ,
      • Larsson J
      • Apelqvist J
      • Agardh CD
      • Stenstrom A
      Decreasing incidence of major amputation in diabetic patients: a consequence of a multidisciplinary foot care team approach?.
      ,
      • Driver VR
      • Madsen J
      • Goodman RA
      Reducing amputation rates in patients with diabetes at a military medical center: the limb preservation service model.
      ,
      • Van Gils CC
      • Wheeler LA
      • Mellstrom M
      • Brinton EA
      • Mason S
      • Wheeler CG
      Amputation prevention by vascular surgery and podiatry collaboration in high-risk diabetic and nondiabetic patients. The Operation Desert Foot experience.
      ).
      The best predictor of amputation is a history of previous amputation. A past history of a lower extremity ulceration or amputation increases the risk for further ulceration, infection, and subsequent amputation (
      • Larsson J
      • Agardh CD
      • Apelqvist J
      • Stenstrom A
      Long-term prognosis after healed amputation in patients with diabetes.
      ,
      • Adler AI
      • Boyko EJ
      • Ahroni JH
      • Smith DG
      Lower-extremity amputation in diabetes. The independent effects of peripheral vascular disease, sensory neuropathy, and foot ulcers [In Process Citation].
      ,
      • Reiber GE
      • Pecoraro RE
      • Koepsell TD
      Risk factors for amputation in patients with diabetes mellitus: a case control study.
      ,
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Heagerty PJ
      Prediction of diabetic foot ulcer using readily available clinical information: the Seattle Diabetic Foot Study.
      ). It may also be inferred that patients with previous ulceration possess all the risk factors for developing another ulceration, having demonstrated that they already have the component elements in the causal pathway (
      • Reiber GE
      • Vileikyte L
      • Boyko EJ
      • del Aguila M
      • Smith DG
      • Lavery LA
      • Boulton AJ
      Causal pathways for incident lower extremity ulcers in patients with diabetes from two settings.
      ,
      • Boyko EJ
      • Ahroni JH
      • Stensel V
      • Forsberg RC
      • Davignon DR
      • Smith DG
      A prospective study of risk factors for diabetic foot ulcer. The Seattle Diabetic Foot Study.
      ,
      • Pecoraro RE
      • Reiber GE
      • Burgess EM
      Pathways to diabetic limb amputation: basis for prevention.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ). Up to 34% of patients develop another ulcer within 1 year after healing an index wound, and the 5-year rate of developing a new ulcer is 70% (
      • Larsson J
      • Apelqvist J
      • Agardh CD
      • Stenstrom A
      Decreasing incidence of major amputation in diabetic patients: a consequence of a multidisciplinary foot care team approach?.
      ,
      • Apelqvist J
      • Larsson J
      • Agardh CD
      Long-term prognosis for diabetic patients with foot ulcers.
      ). The recurrence rate is higher for patients with a previous amputation because of abnormal distribution of plantar pressures and altered osseous architecture. The cumulative risks of neuropathy, deformity, high plantar pressure, poor glucose control, and male gender are all additive factors for pedal ulceration in these diabetic patients (
      • Frykberg RG
      • Lavery LA
      • Pham H
      • Harvey C
      • Harkless L
      • Veves A
      Role of neuropathy and high foot pressures in diabetic foot ulceration.
      ,
      • Abbott CA
      • Carrington AL
      • Ashe H
      • Bath S
      • Every LC
      • Griffiths J
      • Hann AW
      • Hussein A
      • Jackson N
      • Johnson KE
      • Ryder CH
      • Torkington R
      • Van Ross ER
      • Whalley AM
      • Widdows P
      • Williamson S
      • Boulton AJ
      The North-West Diabetes Foot Care Study: incidence of, and risk factors for, new diabetic foot ulceration in a community based patient cohort.
      ,
      • Boulton AJ
      The diabetic foot: from art to science. The 18th Camillo Golgi lecture.
      ,
      • Lavery LA
      • Armstrong DG
      • Vela SA
      • Quebedeaux TL
      • Fleischli JG
      Practical criteria for screening patients at high risk for diabetic foot ulceration.
      ,
      • Pham H
      • Armstrong DG
      • Harvey C
      • Harkless LB
      • Giurini JM
      • Veves A
      Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial.
      ). Re-amputation can be attributed to disease progression, nonhealing wounds, and additional risk factors for limb loss that develop as a result of the first amputation. Tragically, the 5-year survival rate after a diabetes-related LEA has been reported to be as low as 28% to 31% (
      • Ebskov LB
      Diabetic amputation and long-term survival.
      ,
      • Aulivola B
      • Hile CN
      • Hamdan AD
      • Sheahan MG
      • Veraldi JR
      • Skillman JJ
      • Campbell DR
      • Scovell SD
      • LoGerfo FW
      • Pomposelli Jr, FB
      Major lower extremity amputation: outcome of a modern series.
      ). Persons with renal failure or more proximal levels of amputation have a poor prognosis and higher mortality rate. Those who undergo a diabetes-related amputation have a 40% to 50 % chance of undergoing a contralateral amputation within 2 years (
      • Tentolouris N
      • Al-Sabbagh S
      • Walker MG
      • Boulton AJ
      • Jude EB
      Mortality in diabetic and nondiabetic patients after amputations performed from 1990 to 1995: a 5-year follow-up study.
      ,
      • Goldner MG
      The fate of the second leg in the diabetic amputee.
      ,
      • Bodily KC
      • Burgess EM
      Contralateral limb and patient survival after leg amputation.
      ).

      Assessment of the Diabetic Foot (Pathway 1)

      The pedal manifestations of diabetes are well documented and potentially limb-threatening when left untreated. Recognition of risk factors and treatment of diabetic foot disorders require the skill of a specialized practitioner to diagnose, manage, treat, and counsel the patient. Integration of knowledge and experience through a multidisciplinary team approach promotes more effective treatment, thereby improving outcomes and limiting the risk of lower extremity amputation (
      • American Diabetes Association
      Consensus Development Conference on Diabetic Foot Wound Care.
      ,
      • Sumpio BE
      • Aruny J
      • Blume PA
      The multidisciplinary approach to limb salvage.
      ).
      The evaluation of the diabetic foot involves careful assimilation of the patient's history and physical findings with the results of necessary diagnostic procedures (Pathway 1). Screening tools may be valuable in evaluating the patient and determining risk level (Appendix 1, Appendix 1). Early detection of foot pathology, especially in high-risk patients, can lead to earlier intervention and thereby reduce the potential for hospitalization and amputation (
      • Frykberg RG
      Diabetic foot ulcerations: management and adjunctive therapy.
      ). This is also facilitated by an understanding of the underlying pathophysiology of diabetic foot disorders and associated risk factors. Identification of abnormal historical and/or physical findings can therefore improve the prognosis for a favorable outcome through appropriate—and early—referral (
      • Mills JLBW
      • Taylor SM
      The diabetic foot: Consequences of delayed treatment and referral.
      ,
      • Del Aguila MA
      • Reiber GE
      • Koepsell TD
      How does provider and patient awareness of high-risk status for lower-extremity amputation influence foot-care practice?.
      ).

       History

      A thorough medical and foot history must be obtained from the patient. The history should address several specific diabetic foot issues (Table 2).
      Table 2Medical History
      Global HistoryFoot Specific History
      • Diabetes - duration
      • Glycemic management/control
      • Cardiovascular, renal and opthalmic evaluations
      • Other comorbidities
      • Treating physicians
      • Nutritional status
      • Social habits: alcohol, tobacco, drugs
      • Current medications
      • Allergies
      • Previous hospitalizations/surgery
      GeneralWound/Ulcer History
      • Daily activities, including work
      • Footwear
      • Chemical exposures
      • Callus formation
      • Foot deformites
      • Previous foot infections, surgery
      • Neuropathic symptoms
      • Claudication or rest pain
      • Location
      • Duration
      • Inciting event or trauma
      • Recurrence
      • Infection
      • Hospitalization
      • Wound care
      • Off-loading techniques
      • Wound response
      • Patient compliance
      • Interference with wound care (Family or social problems for patient)
      • Previous foot trauma or surgery
      • Presence of edema - unilateral vs bilateral
      • Charcot foot - previous or active
      • Charcot treatment

       Physical Examination

      All patients with diabetes require a pedal inspection whenever they present to any health care practitioner, and they should receive a thorough lower extremity examination at least once annually (
      • American Diabetes Association
      Preventative foot care in people with diabetes.
      ). Patients with complaints relating to the diabetic foot require more frequent detailed evaluations. The examination should be performed systematically so that important aspects are not overlooked (
      • Frykberg R
      Diabetic foot ulcerations.
      ). It begins with a gross evaluation of the patient and extremities. Any obvious problem can then receive closer scrutiny.
      Key components of the foot examination are presented in Table 3. Although not specifically mentioned in this section, it is assumed that a general medical assessment (including vital sign measurements) will be obtained.
      Table 3Lower Extremity Diabetic Foot Exam
      Vascular Examination
      • Palpation of pulses
        • Common femoral, popliteal
        • Dorsalis pedis, posterior tibial
      • Handheld Doppler examination
      • Skin/limb color changes
        • Cyanosis, erythema
        • Elevation pallor, dependent rubor
      • Presence of edema
      • Temperature gradient
        • (ipsilateral and contralateral extremity)
      • Dermal thermometry
      • Integementary changes
        • Skin atrophy - thin, smooth, parchment-like skin
        • Abnormal wrinkling
        • Absence of hair growth
        • Onychodystrophy
      • Previous hospitalizations/surgery
      Neurologic Examination
      • Vibration perception
        • Tuning fork 128 cps
        • Measurement of vibration perception threshold (biothesiometer)
      • Light pressure:
        • Semmes-Weinstein 10 gram monofilament
      • Light touch: cotton wool
      • Two point discrimination
      • Pain: pinprick (sterile needle)
      • Temperature perception: hot and cold
      • Deep tendon reflexes: patella, Achilles
      • Clonus testing
      • Babinski test
      • Romberg test
      Footwear Examination
      • Type of shoe (athletic, oxford, comfort, etc.)
      • Fit
      • Depth of toe box
      • Shoewear, patterns of wear
      • Lining wear
      • Foreign bodies
      • Insoles, orthoses
      Dermatologic Examination
      • Skin appearance
        • Color, texture, turgor, quality
        • Dry skin
      • Calluses
        • Discoloration/subcallus hemorrhage
      • Fissures (especially posterior heels)
      • Nail appearance
        • Onychomycosis, dystrophic, gryphotic
        • Atrophy or hypertrophy
        • Paronychia
      • Hair growth
      • Ulceration, gangrene, infection
        • Note location, size, depth, infection status, etc.
      • Interdigital lesions
      • Tinea pedis
      • Markers of diabetes
        • Shin spots - diabetic dermopathy
        • Necrobiosis lipoidica diabeticorum
        • Bullosum diabeticorum
        • Granuloma annulare
        • Acanthosis nigricans
      Musculoskeletal Examination
      • Biomechanical abnormalities
      • Structural deformities
        • Hammertoe, bunion, tailor's bunion
        • Hallux limitus/rigidus
        • Flat or high-arched feet
        • Charcot deformities
        • Postsurgical deformities (amputations)
      • Prior amputation
      • Limited joint mobility
      • Tendo-Achilles contractures/equinus
      • Gait evaluation
      • Muscle group strength testing
        • passive and active, non-weightbearing and weightbearing
        • Foot drop
        • Atrophy - intrinsic muscle atrophy
      • Plantar pressure assessment
        • Computerized devices
        • Harris ink mat, pressure sensitive foot mat

       Diagnostic Procedures

      Diagnostic procedures may be indicated in the assessment and care of the diabetic foot. Consideration should be given to the following tests in concert with those suggested by members of the consulting team. It should be noted that many of the following tests lack the ability to impart a definitive diagnosis, necessitating clinical correlation.

       Laboratory Tests

      Clinical laboratory tests that may be needed in appropriate clinical situations include fasting or random blood glucose, glycohemoglobin (HbA1c), complete blood count (CBC) with or without differential, erythrocyte sedimentation rate (ESR), serum chemistries, C-reactive protein, alkaline phosphatase, wound and blood cultures, and urinalysis. Caution must be exercised in the interpretation of laboratory tests in these patients, because several reports have documented the absence of leukocytosis in the presence of severe foot infections (
      • Armstrong DG
      • Lipsky BA
      Diabetic foot infections: stepwise medical and surgical management.
      ,
      • Lipsky BA
      A report from the international consensus on diagnosing and treating the infected diabetic foot.
      ,
      • Frykberg RG
      An evidence-based approach to diabetic foot infections.
      ,