CONTINUING MEDICAL EDUCATION

Diabetic foot ulcersPart I. Pathophysiology and prevention

Afsaneh Alavi, MD, FRCPC,a,e R. Gary Sibbald, MD,a,b,e Dieter Mayer, MD,c Laurie Goodman, RN, MScN,d

Mariam Botros, Dch,e David G. Armstrong, DPM, MD, PhD,f Kevin Woo, RN, PhD,g Thomas Boeni, MD,h

Elizabeth A. Ayello, RN, PhD,i and Robert S. Kirsner, MD, PhDj

Toronto, Mississauga, and Kingston, Ontario, Canada; Zurich, Switzerland; Tucson, Arizona; Albany,

New York; and Miami, Florida

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The following is a journal-based CME activity presented by the American Academy of

Dermatology and is made up of four phases:

1. Reading of the CME Information (delineated below)

2. Reading of the Source Article

3. Achievement of a 70% or higher on the online Case-based Post Test

4. Completion of the Journal CME Evaluation

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Statement of Need:

The American Academy of Dermatology bases its CME activities on the Academy’s

core curriculum, identified professional practice gaps, the educational needs which

underlie these gaps, and emerging clinical research findings. Learners should reflect

upon clinical and scientific information presented in the article and determine the

need for further study.

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Dermatologists and others involved in the delivery of dermatologic care.

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The American Academy of Dermatology designates this journal-based CME activity

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Editors

The editors involved with this CME activity and all content validation/peer reviewers

of this journal-based CME activity have reported no relevant financial relationships

with commercial interest(s).

Authors

Dr Robert Kirsner’s conflicts are relevant, but mitigated by unconflicted peer-review

and unconflicted editorial review. His relevant financial relationships follow: 3M

Pharmaceuticals, Advisory Board, Honoraria; GlaxoSmithKline, Other, Honoraria;

Healthpoint, Advisory Board, Honoraria; Healthpoint, Principle Investigator, Grants/

Research Funding Institution; KCI, Consultant, Honoraria; Keraderm, Consultant,

Honoraria; Molynecke, Advisory Board, Honoraria; National Healing Corp, Advisory

Board, Honoraria; Organogenesis, Inc, Advisory Board, Honoraria; Shire, Consultant,

Honoraria; Tissue Repair Company, Principle Investigator, Grants/Research Funding

Institution. The other authors of this journal-based CME activity have reported no

relevant financial relationships with commercial interest(s).

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The planners involvedwith this journal-based CME activity have reported no relevant

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involved with this journal-based CME activity have reported no relevant financial

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Learning Objectives

After completing this learning activity, participants should be able to assess the

epidemiology of diabetes mellitus and its complications; identify the high risk diabetic

foot; delineate diabetic foot ulcer (DFU) prevention strategies; outline

the pathophysiology of a DFU; review factors associated with delayed DFU

healing (suboptimaldiabetes controlwithelevatedHbA1c levels, vascular compromise,

increased bacterial burden or deep and surrounding infection, increased plantar

pressure due to neuropathy and foot deformities.); and describe clinical characteristics

and stage of DFUs based on depth and causative factors.

Date of release: January 2014

Expiration date: January 2017

� 2013 by the American Academy of Dermatology, Inc.

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JANUARY 20141.e2 Alavi et al

Diabetes mellitus is a serious, life-long condition that is the sixth leading cause of death in North America.Dermatologists frequently encounter patients with diabetes mellitus. Up to 25% of patients with diabetesmellitus will develop diabetic foot ulcers. Foot ulcer patients have an increased risk of amputation andincreased mortality rate. The high-risk diabetic foot can be identified with a simplified screening, andsubsequent foot ulcers can be prevented. Early recognition of the high-risk foot and timely treatment willsave legs and improve patients’ quality of life. Peripheral arterial disease, neuropathy, deformity, previousamputation, and infection are the main factors contributing to the development of diabetic foot ulcers.Early recognition of the high-risk foot is imperative to decrease the rates of mortality and morbidity. Aninterprofessional approach (ie, physicians, nurses, and foot care specialists) is often needed to supportpatients’ needs. ( J Am Acad Dermatol 2014;70:1.e1-18.)

Key words: diabetes; diabetic foot ulcer; neuropathy; wounds.

The number of people with diabetesmellitus (DM) have concluded that [50% of people with DM

has increased dramatically. DM is a serious, lifelongcondition that is the seventh leading cause of death inNorth America.1 Persons with DM have a 15% to 25%chance of developing a diabetic foot ulcer (DFU)during their lifetime, and a 50% to 70% recurrence rateover the ensuing 5 years.2-4 Early detection andeffective management can reduce the severity ofcomplications, including preventable amputations.Dermatologists assessing and treating patients withDM and DFUs can benefit from an interprofessionalteam to optimize patient management and outcomes.

THE BURDEN OF DIABETES MELLITUSAND COMMON DIABETICCOMPLICATIONSKey pointsd More than half of persons with diabetesmellitus are unaware of their disease

d 2.5% to 15% of annual global health carebudgets are spent on diabetes mellitus

d Diabetesmellitus is theseventh leadingcauseofdeath in the United States

d Diabetes mellitus is the leading cause ofkidney failure, nontraumatic lower extrem-ity amputations, and new cases of blindnessin adult Americans

d Diabetic foot ulcers are often preventable,and treatment is frequently suboptimal

DM is an increasing problem in both developedand developing nations. The majority of personswith DM have type 2 DM, with only 5% to 10% ofpatients diagnosed with type 1 DM.5,6 Several studies

the Departments of Medicine (Dermatology)a and Public

ealth,b University of Toronto; Clinic for Cardiovascular Sur-

ry,c University Hospital of Zurich; Wound-Healing Clinic,d

ississauga; Wound Care Centre,e Women’s College Hospital,

ronto; Department of Surgery,f the University of Arizona

ollege of Medicine/SALSA, Tucson; Faculty of Nursing,g

ueen’s University, Kingston; Department of Prosthetics and

rthotics,h University of Zurich; Excelsior College,i School of

(according to World Health Organization criteria)are unaware of their disease.7,8 Early DM detectionand treatment can improve overall quality of life(QOL) and increase the life expectancy of personswith DM. The prevalence of DM is also increasing.For example, in North America, DM affects up to 20%to 25% of the elderly population over 65 years ofage.1,9 Worldwide estimates have calculated that2.5% to 15% of global annual health care budgetsare spent on DM, and the annual direct medical costworldwide is as high as $241 billion.7

In their 2009 report, the Canadian DiabetesAssociation labeled the increased prevalence ofDM an ‘‘economical tsunami,’’ with a doubling ofthe number of people diagnosed in the past de-cade.10 In 2010, 26.9% of US residents above 65years of age (10.9 million) had DM.1 DM is theleading American cause of kidney failure, non-traumatic lower extremity amputations, and newcases of adult blindness.1

DM is a serious, lifelong metabolic condition thatis the seventh leading cause of death in NorthAmerica.1 By 2025, it is predicted that $ 333 millionpeople will develop DM worldwide; this increasecreates growing health and economic issue.11-13 Inthe developing world, the rise in the number ofpersons with DM will have a devastating negativeimpact on health care systems and individual health.1

Every year, 1 million people worldwide lose theirlives to DM-associated complications, with most ofthese deaths being preventable.7

Chronic wounds, including DFUs, are a commonyet challenging problem. These ulcers often display

Nursing, Albany; and the Department of Dermatology and

Cutaneous Surgery,j University of Miami.

Funding sources: None.

Reprint requests: Afsaneh Alavi, MD, FRCPC, University of Toronto,

Women’s College Hospital, 76 Grenville St, M5S 1B1, Toronto, ON,

Canada. E-mail: afsaneh.alavi@utoronto.ca.

0190-9622/$36.00

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VOLUME 70, NUMBER 1Alavi et al 1.e3

suboptimal healing particularly when the underlyingdisease and cause have not been treated and thepatient has not received holistic interprofessionalcare.

The importance of routine foot examination inpersons with DM and the identification of thehigh-risk foot are underestimated in both inpatientand outpatient settings because of the asymptomaticnature of the disease. There is often a reluctanceto conduct foot screening for patients with DMbecause of a perceived lack of time in busy prac-tices.14 The early recognition of the high-risk footand timely treatment may prevent foot ulcers, savelimbs, potentially save lives, and improve patientQOL. These individuals often have a history ofprevious foot ulcer or lower limb minor or majoramputation.

Once a foot ulcer develops, optimal care forpersons with DFU includes the assessment ofadequate arterial blood supply to heal, theassessment of neuropathy, and the diagnosis andtreatment of infection.

Many of the requirements for holistic DFU careare beyond the expertise of the practicingdermatologist. There is also often an overall lack ofinterprofessional networking required for optimalmanagement.15 This gap is related to a lack ofknowledge, routine practice procedures, and healthcare organizational barriers.

RISK OF DIABETIC FOOT ULCERS ANDLOWER LIMB AMPUTATIONSKey pointsd Diabetic foot ulcers precede 85% of lowerlimb amputations

d Diabetic foot ulcers are the most costly andpreventable complication of diabetesmellitus

d The average lower limb amputation andrehabilitation costs $44,790

DM has a vast range of short- and long-termcomplications, and up to 85% of nontraumatic lowerextremity amputations are attributed to DM.16-18 Afoot ulcer diminishes QOL. Persons suffering from anonhealing DFU have approximately 10% to 40%lower QOL scores than the general population. Forexample, the DFU impact on QOL is equivalent tochronic lung disease, myocardial infarction, andbreast cancer.19-21

The development of DFU and the subsequent,often preventable nontraumatic lower extremityamputations are among the most costly complica-tions of DM. A Canadian study on the cost ofcomplications of DM found that major events,

including lower limb amputations, generate a greaterfinancial burden than DFU treatment alone.22 Therate of foot ulcer development in persons withdiabetic neuropathy is increased, and peripheralneuropathy is the most significant risk factor forDFU.2,23-25 Once an ulcer develops, healing is oftenslow, with the average estimate being[2 months forsimple ulcers in specialized DFU centers.25

In addition, with standard care, only 33% of DFUswill heal despite an organized approach to diagnosisand treatment.26 Twenty to 25% of all hospitaladmission days for patients with DM are related tofoot complications.6,27 American statistics in 2006estimate that 65,700 nontraumatic lower limb ampu-tations were performed in patients with DM, anumber that continues to rise.5 There is evidencethat some measures can prevent DFUs and savenontraumatic amputations. Interprofessional teamsare needed to provide detailed and early patientassessment, aggressive treatment, and education.There is substantial economic and clinical benefit toan organized approach for the high-risk patients.28

The risk of lower extremity amputation in the diabeticpopulation is 15 to 46 times higher than theirnondiabetic counterparts.27,29,30 After an initialamputation, the risk of the contralateral extremityamputation ranges between 9% and 17% in thefirst year, increasing to 25% to 68% within 3 to5 years.2,27,29,30

Several studies have found a 41% to 70% decreasein the 5-year survival rate after a lower extremityamputation.2,31,32 Iversen et al33 also reported a 50%higher risk of mortality for patients with DM with ahistory of DFUs compared to a diabetic populationwithout DFUs.33

The following list emphasizes the economicburden of DFUs34,35 in the United States:d Increased cost associated with the severity ofDFU, with higher-grade DFUs (according to theMeggitteWagner classification [Table I]) havingmore costly disease

d Persons with DM and foot complications hadMedicare claims that were 3 times higher thanthe general population ($15,309 vs $5,226between 1995 and 1996)36

d Healing costs after an amputation averaged$44,790; healing without amputation averaged$6,66437

d Access to limb-preserving interventions is sub-optimal, leading to an increased amputationrate especially among nonwhite, low-incomepopulations on Medicare/Medicaid compared toindividuals with higher economic status andprivate insurance (extracted data between 1998and 2002)38

Table I. Diabetic foot ulcer cost as determined bythe MeggitteWagner classification37

Wagner grade Retrospective cost analysis per ulcer (average)

1 or 2 $1,9293 $3,9804 or 5 $15,792

Table II. Projected annual cost benefits andamputation reduction with interventions for high-risk persons with diabetes70,71

Potential

savings

Amputation

reduction

Detailed educational intervention $1.1 million 72%Multiprofessional team approachto diabetes mellitus care

$750,000 47%

Therapeutic footwear $850,000 53%

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The Pan American Health Organization (PAHO)reported 3 key cost-saving health service interven-tions needed to fight noncommunicable disease inthe Americas39: educating diabetic patients on recog-nizing and treating minor foot injuries, the use ofappropriate footwear, and accessing knowledgeablehealth care personnel. Narayan et al40 outlined thatfor developing countries, the highest priorities thatcould also be cost savings to health care systemsincluded foot care if high risk, glycated hemoglobin(HbA1c)\0.09, or blood pressure\160/95 mm Hg.However, in the Western world, tight control with atarget for HbA1c\0.07 and blood pressure\130 /85mmHg are suggested. The annual projected benefitsper intervention for individuals with high-risk DMare shown in Table II.41

Pathophysiology of the diabetic footSeveral biochemical abnormalities may accelerate

neuropathy and vascular foot changes, includinghyperglycemia that inhibits the production andactivation of endothelial nitric oxide synthase andthe reaction of protein with sugars (Maillardreaction) that is linked to diabetic complicationsand aging. DFUs are caused by neuropathy,ischemia, or both.

The pathophysiology of DFUs requires anappreciation of the role of several contributoryfactors, including peripheral neuropathy, vasculardisease (arterial circulation), and inflammatorycytokines and susceptibility to infection.

Neuropathy. Persons with DM are susceptible toperipheral neuropathy with sensory, autonomic, andmotor components. There are several proposed

mechanisms associated with this neuropathy,including nitric oxide blocking and the Maillardreaction between sugars and amino acids (Fig 1).

Nitric oxide blocking. Hyperglycemia, dyslipide-mia, insulin resistance, and oxidative stress canlead to cellular damage, endothelial dysfunction,and various diabetes-associated complicationsthrough a number of pathways. Hyperglycemiainhibits the production of nitric oxide by blockingendothelial nitric oxide synthase activation, whichcan lead to higher levels of reactive oxygenspecies, particularly superoxide. Superoxide isthen converted enzymatically to hydrogen peroxideby superoxide dismutases. In the presence offerrous or cuprous ions, hydrogen peroxide isconverted to the highly reactive and damaginghydroxyl radical. In addition, the superoxide anionalso binds to nitric oxide (a potent vasodilator),producing peroxynitrite and thereby limiting thebioavailability of a potent endothelium-derivedvasodilator. The peroxynitrite anion has a role inthe oxidization of sulfhydryl groups in proteins,lipid peroxidation, the generation of reactivealdehydes/nitrogen oxides, and the production ofproatherogenic low density lipoproteins. Thedisruption of the endothelium-regulated vascularfunction not only affects the vasoconstrictionresponse but also causes platelet aggregation,abnormal intimal growth, inflammation, andatherothrombosis formation.37-39 Glucoxidationand lipoxidation of vascular wall structural proteinsmight facilitate atherogenesis through the effect onvessel wall characteristics and the interaction ofinflammatory cytokines. This atherogenesis of thesmall vessels supplying the peripheral nervescontributes to the neuropathy.

Maillard reaction. The Maillard reaction is a slowbut complex reaction between reducing sugars andamino groups of biomolecules leading to theproduction of a complex structures known asadvanced glycation endproducts (AGEs).40,42,43

This reaction has been hypothesized to be animportant mechanism in the pathophysiology ofdiabetes complications. It has been linked to proteinmodifications found during aging and diabetes.43

AGE-modified proteins and lipoproteins have rolesin the pathogenesis of atherosclerosis.

Excess glucose is converted to sorbital by aldosereductase through the polyol metabolic pathwaythat consumes nicotinamide adenine dinucleotidephosphate (NADPH).41 NADPH is further reducedby the activation of the hexosamine biosyntheticpathway that limits the conversion of nicotinamideadenine dinucleotide to NADPH by inhibitingthe enzymatic activity of glucose-6-phosphate

Fig 1. Pathophysiology of diabetic foot ulcers.

Fig 2. Diabetic neuropathic feet. Callus formation as apresentation of neuropathy.

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dehydrogenase.42 The end result is the depletion ofNADPH that in turn affects the normal synthesis ofkey antioxidants, such as glutathione. Decreasedantioxidant and increased production of reactiveoxygen species play a crucial mediatory role in thepathogenesis and progression of complications indiabetes.

Neuropathy leads to foot deformity or limitedjoint mobility, resulting in abnormal foot pressureand subsequent callus formation over pressurepoints (Fig 2). The callus further increasesthe local pressure and when combined with unde-tected repetitive injury leads to local tissue injury,inflammation, tissue death (necrosis), and finallyulceration44 (Fig 3).

Neuropathy is one of the main contributory fac-tors in the pathogenesis of DFUs. In the absence ofneuropathy, pain limits the repetitive injury neededfor a full-thickness ulcer to develop.

Diabetic neuropathy can affect the production ofneuropeptides, such as nerve growth factor,substance P, and calcitonin geneerelated peptide.45

Neuropeptides are relevant to wound healingbecause they promote cell chemotaxis, promptgrowth factor production, and stimulate theproliferation of cells. In addition, sensory nervesplay a role in modulating immune defense

mechanisms, with denervated skin showing reducedleukocyte infiltration.46 For example, the rate ofwound healing in 1-cm excisional wounds onrats created with denervated skin flaps wassignificantly reduced compared with controlwounds.47 Immunohistochemical studies identifiedsignificantly reduced monocyte, macrophage, and

Fig 3. Diabetic neuropathic foot ulcers overlying themetatarsal head.

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T-lymphocyte counts in the denervated wounds.Capsaicin injections induced sensory denervationin rats has been associated with delayed reepitheli-alization and wound healing.48 Murray et al49

indicated an 11-fold higher risk of developing ulcersin the presence of callus.

Vascular disease. Micro- and macrovasculardisease in persons with DM may impair healing ofthe ulcers and is critically important. Ischemia hasbeen reported as a contributing factor in 90% ofdiabetic patients undergoing major amputation.50,51

Prolonged inflammatory response within themicrocirculation can lead to thickening of capillarybasement membranes with arteriolar hyalinization,compromising the normal movements of nutrientsand activated leukocytes between the capillary lu-men and the interstitium. The relatively inelasticcapillary walls may explain the limited capacity forvasodilatation in response to local injury, leading tofunctional ischemia.

Inflammatory cytokines and susceptibilityto infection. Once an ulcer develops, susceptibil-ity to infection exists because of a loss of innatebarrier function. In chronic wounds, microorganismsaggregate together and grow within communitieswhere they encase themselves within extracellularpolymeric substances containing polysaccharidesand lipids. This encased collection of microorgan-isms, known as a biofilm, increases resistance toantimicrobial, immunologic, and chemical attacks.52

Bacterial biofilms contribute to a delay in healing

and the occurrence of chronic inflammation andrecurrent infections with the intermittent release ofsingle (planktonic) organisms.52

DM also affects normal leukocyte function andimmune functions, decreasing host resistance andrendering this patient population more susceptibleto superficial increased bacterial burden in thewound base and deep or surrounding skininfection.53,54 For example, Mowat et al55 docu-mented an in vitro leukocyte chemotaxis defect inpersons with diabetes. Phagocytosis and bactericidalcapacity was significantly reduced in the presence ofhyperglycemia.55 Once DFUs have formed, they areoften slow to heal because of impaired cellmigration.43 Stojadinovic et al56 identified thatoverexpression of c-Myc and b-catenin at the edgeof chronic DFUs may lead to impairment ofkeratinocyte migration and inhibition of healingin DFUs. A number of wound fluid studies haveidentified an elevated level of matrix metalloprotei-nases in the exudate associated with DFUs. Theseelevated levels may result in sustained inflammationwith a net destruction of the collagenmatrix requiredfor healing.

INCREASED PLANTAR PRESSURE AND ITSCONSEQUENCESKey pointsd All patients with DM should undergo athorough examination with both shoes andsocks off

d The presence of callus is associated with anincrease in local pressure because of theloss of protective sensation associatedwith neuropathy. It is of utmost importanceto remove the callus at regular intervals(ideally at every visit) to prevent pressureulcers

d A blister may be the result of friction andshear (movement between the foot and theshoe, orthotic, or special device)

d Deformities and limited range of motion ofthe foot and ankle joints can alter footmechanics and cause critical pressure andulceration

Once an ulcer develops, there are differenttechniques that can be used to deflect increasedplantar pressure, including a total contact cast, aremovable cast walker, half shoes, and customorthotics. However, before ulcer development, itis necessary that all patients with DM and potentialdiabetic foot changes should have a thoroughexamination with the removal of both the patient’sshoes and socks. The presence of callus is

Fig 5. A and B, Hammer toes. Note the deformity of theproximal metatarsophalangeal and interphalangeal jointsof the toes, causing consistent flexure like a hammer.

Fig 4. A and B, Claw toes. Dorsiflexion of the proximalphalanx on the lesser metatarsophalangeal jointcombined with flexion of both the proximal and distalinterphalangeal joints that cause pressure. Claw toe canaffect the second, third, fourth, or fifth toes.

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associated with an increase in local pressure. Motorneuropathy causes unequal muscle pull. Theplantar muscles are affected first; the loss of distalinnervation creates unequal pull from the proximalmuscles on the dorsal surface of the foot. Thispressure differential results in a ‘‘cocked up’’ toe,but unequal pressure can cause additionaldeformities, such as claw toes (dorsiflexion of theproximal phalanx on the lesser metatarsophalan-geal joint, combined with flexion of boththe proximal and distal interphalangeal joints;Fig 4).57,58 The claw toe is distinguished from thehammertoe, which has a deformity of proximalmetacarpophalangeal joint and interphalangealjoint of the toe, causing consistent flexure like ahammer (Fig 5).58 The deformity results inprominent plantar surface metatarsal heads andclawed toes. These deformities are often associatedwith skin breakdown on the doral or plantar surfaceof the forefoot from poorly fitting shoes with aninadequately sized toe box. As the metatarsal headsdrop, the corresponding fat pads herniate distallyunder the base of the toes. The pressure from thecollapsed bone close to the plantar surface resultsin local callus formation over the metatarsal heads.These changes can be recognized by a thoroughexamination of the base of the toes with themetatarsal heads becoming easily palpated justbelow the plantar surface. Callus is associatedwith increased risk of ulceration.

A blister may be the result of friction and shear(movement between the plantar surface of thefoot and the sole of the shoe), and this is also apotential break in the skin barrier, leading to anincreased risk of infection. Bunions caused byhallux valgus are important foot deformitiesassociated with a wide forefoot and an additionalrisk site at the sides of the foot for ulcerformation.

Glycosylation of collagen by hyperglycemia leadsto stiffness of connective tissues (ie, joint capsulesand ligaments). This impairs joint function andresults in restricted range of motion.59 An exampleis the equinus deformity, with restriction ofdorsiflexion of the ankle joint often associated withfixed toes, leading to critical plantar pressure in theforefoot and toe area. Patients may be referred forankle tendon lengthening to correct this deformityor, in some cases, to promote the healing ofpersistent forefoot plantar ulcers.

Evaluation of the risk factors and risk stratificationis an important guide for prognosis and diabetic footcare. The International Working Group on theDiabetic Foot (IWGDF) risk categorization toolis a useful system to classify these patients(Table III).60,61

Table III. The International Working Group on the Diabetic Foot risk categorization tool

Category Risk factor

Ulcer

incidence

Amputation

incidence Prevention and treatment

0 No sensory neuropathy 2-6% 0 Reevaluation once a year1 Sensory neuropathy 6-9% 0 Podiatry/chiropody every 6 months; over the

counter shoes and insoles2 Sensory neuropathy and foot deformity

or peripheral vascular disease8-17% 1-3% Podiatry/chiropody every 2-3 months;

therapeutic shoes and insoles; patienteducation

3 Previous ulcer or amputation 26-78% 10-18% Podiatry/chiropody every 1-2 months;therapeutic shoes and insoles; patienteducation

Derived from Johnson et al58 and Birke et al.59

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WHY USE A SCREENING TEST?Key pointsd Identification of the high-risk foot is anessential component of diabetes care

d A simplified screening can detect thehigh-risk foot

d An interprofessional approach can reducethe amputation rate by 40% to 85%

d Neuropathy, peripheral arterial disease, and aprevious foot ulcer or amputations are majorrisk factors for developing a foot ulcer

The high-risk diabetic foot can be identified withsimplified screening tests, and subsequent footulcers may be prevented.62 One recently developedand validated test is a simplified 60-second screeningtest (video available at www.WoundPedia.com orwww.diabeticfootscreen.com; Fig 6).62 Referral toa foot specialist may prevent ulceration andpossibly decrease the risk of lower extremityamputation.

Many specialists, including dermatologists, fre-quently encounter patients with DM, and there is theopportunity to screen these patients when they are inthe office for a routine visit. In fact, dermatologistsare more likely to survey a patient’s skin than anyother specialist and may have a special opportunityto identify at-risk patients or early DFUs. Overall,this screen can identify a large percentage ofpersons with DMs at high risk of foot ulcerationand subsequent preventable lower limb amputa-tion.37,63-65 Several studies have shown thatamputation could be reduced by 40% to 85%through the detection of high-risk patients and asubsequent interprofessional approach that focuseson preventive measures.66-68

Screening may also detect foot ulcers and otherlesions that the patient is not aware of, includingblisters, calluses, fissures, tinea pedis, and ingrowntoenails.62,67

Previous studies of persons with DM haveidentified neuropathy, peripheral arterial disease(PAD), a previous foot ulcer, or previous ampu-tation as risk factors for developing a footulcer.14,69 Lavery et al61 and Peters et al,69 aspart of the IWGDF, identified the yearlyincidence ulceration rate. If a person has DMand no other complication, such as neuropathyor PAD, they have a 2% risk of developing a footulcer. With neuropathy, the incidence increasesto 4.5% and with additional PAD to 13.8% annu-ally. The incidence of foot ulceration is increased32.2% with any 2 of the following criteria:previous foot ulcer, previous amputation, PAD,and neuropathy.61,69

Identification of the high-risk foot is an essentialcomponent of diabetes care. It focuses attentionand provides a means to direct limited resourcesto those patients most at risk of developing a DFU.The approach to the cutaneous changes associatedwith DM can be optimized when professionals worktoward a standardized plan.

CLINICAL PRESENTATIONSThe presence of a DFU is a consequence of

multiple factors and is not usually the result of asingle pathology.

NeuropathyKey pointsd Increased plantar pressure resulting fromneuropathy is the major risk factor fordiabetic foot ulcers

d Diabetic neuropathy has 3 components:sensory, autonomic, and motor neuropathy

d Loss of protective sensation can bemeasured with a 10-g monofilament(the SemmeseWeinstein monofilament test)

d Autonomic neuropathy causes dryness of theskin, and motor neuropathy results in a claw

Fig 6. The 60-second screening tool. Continued on next page.

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toe deformity, loss of reflexes, and muscleatrophy

d Diabetic sensorimotor polyneuropathy willdevelop within 10 years of the onset ofdiabetes mellitus in 40% to 50% of patients

Neuropathy is a major predictor for ulceration.69

The neuropathic foot does not ulcerate spontane-ously, but ulcer formation is a combination ofneuropathy and other factors, such as repetitiveunperceived trauma from excessive ambulation,poorly fitting shoes, walking in stockings without

shoes, or walking barefoot, along with callusformation over areas of increased pressure.

The 3 main mechanisms of injury are as follows27:(1) footwear (ill-fitting shoes resulting inlow but prolonged pressure); (2) weight-bearing(repetitive moderate pressure and friction or shearforces that result in blister formation); and (3) trauma(including penetrating injury, meaning high pressurewith a single or repetitive exposure of direct pressure).

The biomechanics of the foot are altered such thatthe claw toe results in the metatarsal heads movingclose to the skin surface and the fat pads herniate

Fig 6. Continued.

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upward, obliterating the space just below the toewebs.

The resulting increased trauma from pressureassociated with calluses or friction/shear-associated blisters (ie, vesicles, bullae, andhemorrhagic bullae) leads to subsequent tissueinjury. Sensory neuropathy contributes to the lackof perceived tissue injury (loss of protectivesensation).26,70,71 Diabetic sensorimotor polyneu-ropathy will develop sooner with poor glycemiccontrol, but often within 10 years of the onset ofdiabetes in 40% to 50% of patients with type 1 ortype 2 DM.72,73

The onset of diabetic neuropathy is insidious, andmany patients are unaware of the process. Althoughneuropathy is associated with a loss of protectivesensation, neuropathic pain may decrease qualityof life. This pain may present spontaneously asburning, stabbing, shooting, stinging, hyperesthesia,or even allodynia (an increased response to normalstimuli, such as light touch). This represents sensoryneuropathy, which is 1 of the 3 components ofneuropathy represented by the mnemonic SAM(sensory, autonomic, and motor).

A thorough physical examination, including theremoval of shoes and socks, is a more reliable tool to

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detect neuropathy than patient history. The physicalexamination may reveal the characteristic claw toe,dry skin, and a loss of reflexes. The test for neurop-athy is with the 10-g (5.07) SemmeseWeinsteinmonofilament34,71 and a 128-Hz tuning forkfor perception of vibration sensory stimuli. Themonofilament test is a simple bedside screeningtest that has been widely used in clinical practice.The inability to feel a 10-g (5.07) monofilament is asensitive predictor for neuropathy and ulceration.74

With their eyes closed, the patient is asked if theyfeel the monofilament while the monofilament isplaced against the intact skin (with no callus) andallowed to buckle.75 Most authors suggest testing 10sites; the absence of sensation in 3 to 4 sites isconsistent with a loss of protective sensation.76

Other techniques exist to detect sensory neuropathy,including a simple prototype robotic monofilamentinspector that has been used to diagnoseneuropathy.77

Neuropathy impairs the ability to perceive injurybecause of a loss of protective sensation. Autonomicneuropathy involves the sympathetic nervoussystem and presents as anhidrosis with dry skinand fissures that needs to be distinguished fromother causes of dry plantar skin. These changes mustbe distinguished from fungal infection, because thefourth and fifth web spaces are common areas forfungal intertrigo while the plantar surface and thesides of the foot are common areas for a moccasindistribution. The nail changes include distalstreaking or more complete nail plate asymmetricnail changes of fungal infections. Any patient with asuspicion of fungal infection should have a potas-sium hydroxide microscopic examination and/orfungal culture to confirm the diagnosis. Because ofthe increased risk for complications of bacterialinfection, the presence of superficial fungal infectionin patients with DM may lead to a greater risk forassociated bacterial infections.

Motor neuropathy can be detected with a loss ofankle reflexes.24,78 Motor neuropathy is tested withankle reflex, and a loss of reflexes is associated withdeformity, wasting of intrinsic muscles, and muscleimbalance with cocked up toes.

Education for persons with DM regarding properfoot care may help prevent DFU and amputations,especially for those who are at high risk.79,80

PERIPHERAL VASCULAR DISEASEKey pointsd Diabetic foot ulcers can be divided intoneuropathic, ischemic, and neuroischemicfoot ulcers, with the latter 2 having a lessfavorable prognosis

d Assessment of the vascular status requires athorough history and physical examination;however, definitive diagnoses require moreadvanced, technical examinations

d A palpable pulse in the foot indicates apressure of at least 80 mm Hg; however, apalpable pulse, especially in diabetesmellitus (because of medial sclerosis) doesnot exclude poor perfusion

d Segmental continuous wave Doppler exami-nation and ideally toe pressure measure-ment of the large toe (toeebrachialpressure index) are regarded as the criterionstandard for the evaluation of limbperfusion in persons with diabetes mellitus

d Duplex ultrasonography may aid in themorphologic diagnosis of occlusions andplanning of interventions

d Transcutaneous oxygen tension measure-ment may be of important value, especiallyin patients with diabetic foot ulcers, becauseit reflects oxygen supply to the end organ(the skin) by macro- and microcirculation

d Ischemic disease increases the risk forlimb loss. If vascular (ischemic) signs andsymptoms are present, refer immediately toa vascular surgeon for proper testing andpossible revascularization

PAD is another important contributory factor inDFUs. In some populations, PAD is present in[50%of patients with DFUs.81,82 DFUs can be divided into3 main categories: diabetic neuropathic, diabeticischemic, and diabetic neuroischemic footulcers (Table IV).41,42 This ischemia representsmacrovascular disease. Individuals with ischemicand neuroischemic foot ulcers have a poorerprognosis, and vascular procedures are oftenwarranted.83-88 Friction and trauma in an ischemicfoot can cause skin breakdown, especially whencomplicated by infection (Fig 7).

The assessment of vascular status requires athorough history and physical examination,including any history of previous PAD, intermittentclaudication, or rest pain (in persons with DM, oftennot present because of neuropathy). Examinationfor clinical signs should include the following:inspection for pallor, dependent rubor, decreasedskin temperature, hair loss, atrophic shiny skin,and palpation of the dorsalis pedis or posteriortibial pulses. Although the physical examinationprovides important qualitative information, thesensitivity of the clinical tests is limited. Theabsence of the dorsalis pedis pulse has a sensitivityof 50%, a specificity of 73.1%, and a low positive

Table IV. Comparison of 3 major groups of foot ulcers (neuropathic, ischemic, and neuroischemic)

Ulcer characteristics Neuropathic Ischemic Neuroischemic

Common location Plantar Plantar and/or dorsal aspect oftoes and foot

Plantar and/or dorsal aspect oftoes and foot

Morphology Surrounding callus Punched out, black eschar Necrosis and callusPain Mild Severe Dull painType of pain Neuropathic; sharp, stabbing,

or burningNociceptive and claudication;dull pain or persistent sharppain

Combination of both

Callus 111 e 11(1)Bone deformity 111 e 11(1)Pulses Present Weak or absent Weak or absentSkin temperature Warm Cool CoolSurrounding skin Loss of sensation, callus Pallor, shiny, rubor, or pale; cool Both

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predictive value of 17.7%.89 In 8% of healthyindividuals, the dorsalis pedis is absent; the tibialisposterior pulse is absent in 3% of cases.90,91 Apalpable pulse in the foot represents the presenceof at least 80 mm Hg pressure.92 However, apalpable pulse does not rule out PAD, especially indiabetic patients suffering from medial calcinosis(abnormal deposition of calcium of the vesselwall).93 Generally, significant arterial disease ismost often excluded when the dorsalis pedis orposterior tibial pulses are clearly palpable. The moreaccurate technical tests to rule out PAD includequalitative segmental Doppler waveforms orquantitative ankleebrachial pressure index (ABPI)assessment, provided that the vessels are compres-sible and the ABPI is\1.4 or[0.8.

In a recent article by Faglia et al,94 the anklepressure could not be measured in 109 (41.8%)patients because of occlusion of both tibial arteriesin 75 (28.7%) patients or because of the presence ofarterial calcification in 34 (13.0%) patients.95 Indiabetic patients, the toeebrachial pressure index(TBPI) is the screening test of choice rather thanABPI because of the common occurrence of medialcalcinosis. However, in a recent study, it has beenshown that because of a lesion on the great toe and/or lesions the midfoot, 187 of 261 patients (71.6%)could not be examined properly by either theABPI or the TBPI.88 Therefore, color-coded Duplexultrasonography represents the criterion standard ofnoninvasive vascular assessment once relevant PADis suspected and/or simple examination is notpossible.

Because of the presence of arteriovenous shunt-ing, an ischemic foot might appear pink andeven warm in the presence of impaired perfusion.There may be a localized arterial block; angiosomaldefects should be referred to a vascular surgeon.Angiography can verify the real anatomic correlates

for nonhealing ulcers and assist in planning thebest intervention.84-87 The foot can be divided into 6anatomic regions corresponding to the 6 proposedangiosomes.75,76,84,87 A distinct source artery feedseach angiosome.84 Wounds may fail to heal becauseof inadequate local vascular supply despite havingpalpable pulses. Early referral to a vascular surgeonor specialist is recommended for targeted primaryangioplasty following this angiosomal model andcan therefore improve clinical success.86,87

Skin perfusion pressure is a good indicator oflower extremity microcirculation.96 Transcutaneousoxygen tension reflects the amount of oxygen thathas diffused from the capillaries through theepidermis to an electrode at the measuring site. Itprovides instant, continuous information about thebody’s ability to deliver oxygen to the tissue. This testis usually conducted in a vascular laboratory and hasrecently been shown to be an indicator for criticallimb ischemia (CLI).88 Faglia et al88 concluded that ifdiabetic patients presentedwith rest pain and/or footlesions, it is essential to measure the foot oxygentension for the diagnosis of CLI, and that this was truenot only when arterial pressure was not measurablebut also when arterial pressure was $ 70 mm Hg.

CHARCOT FOOTKey pointsd Diabetes mellitus is the most common causeof Charcot deformity in the Western world

d Charcot foot may present with redness,swelling, deformity, and increased foottemperature

d In the acute phase, differentiating Charcotdisease from cellulitis and the chronic phaseof osteomyelitis may be difficult

d Noneweight-bearing and immobilizationis the key treatment choice in the acute stage

Fig 7. Diabetic neuroischemic foot. Minor trauma fromfootwear led to gangrene of the fifth toe and tissue loss onthe laterodorsal surface of the foot. Without rapid arterialrevascularization, progression of gangrene and infectionwill usually occur, resulting in below the knee amputationor sepsis.

Fig 8. Charcot foot.

Fig 9. Charcot foot. Note the typical ‘‘rocker bottomdeformity,’’ with an ulcer at the area of maximal pressureof the foot because of the loss of arch integrity.

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Charcot foot is a late complication of peripheralmotor neuropathy of any cause. Charcot foot resultsfrom repetitive trauma to insensitive bones and jointsof the foot (Fig 8). DM is the most common cause ofCharcot deformity in the Western world and shouldbe considered in any patient who presents with awarm swollen foot, even in the absence ofulceration. A diagnosis of osteomyelitis is more likelyif there is ulceration, although both Charcot footand osteomyelitis can exist simultaneously.97,98

Dislocation of bones and joints without apreceding known trauma is the characteristic ofCharcot foot caused by long-standing diabeticneuropathy.99 Charcot foot may present as redness,swelling, deformity, increased foot temperature, andulceration (Fig 9). In the acute phase of Charcotdisease, differentiating it from cellulitis and

osteomyelitis is difficult. Chronic osteomyelitis usu-ally has an insidious presentation and is refractory totreatment. The acute radiographic changes ofosteomyelitis include focal osteopenia and lucencyin the cortex or medullary bone, while chronicchanges may lead to the sequestration of deadbone.77 The differentiation of osteomyelitis fromosteopathy is difficult. The radiographic changesof chronic osteopathy include fractures, bonedestruction, and periosteal new bone formation.77

In the chronic phase of Charcot foot, deformity ismore predominant. The exact pathogenesis remainsto be determined. Multiple recurrent stress fracturesdevelop because of osteopenia. The expression of apolypeptide cytokine (a specific receptor activator ofa nuclear factorekb ligand [RANKL]) has beendescribed as a possible mechanism for osteopeniaand neuropathy.99-101 Inflammation mediated by therelease of proinflammatory cytokines also increasesosteolysis.

The healing process may last more than 6 to 9months, during which the foot (without off-loadingand immobilization) usually becomes distorted andturns into a ‘‘clinically visible’’ Charcot foot. Theresultant fixed deformity may include a rockerbottom foot. The clinician should examine the footfor abnormal contours and compare both feet tomonitor any differences in the bony contours. Thechanges can be present in the forefoot, midfoot, hindfoot, or heel area as well as the ankle. Chronically,these deformities lead to an increased susceptibilityto ulceration.

Fig 10. A, Squamous cell carcinoma presenting as a footulcer in a patient with a long history of diabetes.B, Histopathology shows nests of atypical keratinocyteswithin the dermis. (Hematoxylin-eosin stain; Originalmagnification: X200.)

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A high index of suspicion and early diagnosiswith appropriate diagnostics can play a key role inmanagement. A radiograph of the foot may beuseful, and the most commonly affected joints arein the midfoot region (ie, the cuneiform/metatarsalarea). A swollen foot with increased temperatureand no ulcer in a patient with DM is most likelya Charcot foot, but if there is an ulcer present,osteomyelitis is more likely. Occasionally, bothconditions coexist.

A bone scan reveals increased blood flow andbone intake. In limited cases, magnetic resonanceimaging or white cell scans aid in the differentiationfrom osteomyelitis. Careful weight-bearing limitationis imperative to stop the cycle of structural damageand inflammation. Management includes using atotal contact cast, potential medical treatmentwith bisphosphonates, and surgical managementof resultant deformity once the foot has beenstabilized.102

Differential diagnosisAlthough the vast majority of DFUs in diabetic

patients are caused by neuropathy, the differentialdiagnosis includes traumatic ulcers, inflammatoryulcers (vasculitis/ pyoderma gangrenosum), vascu-lopathies, and malignancies. In 2 studies by Konget al,103,104 7 cases of melanoma presenting asfoot ulcers have been reported. Acral melanomais frequently misdiagnosed and commonlypresents with amelanotic and ulcerated lesions.105

Skin biopsy specimens will be diagnostic.Nonmelanoma skin cancers (Fig 10) and metastaticlesions may present as DFUs in patients with DM.106

CLASSIFICATION OF DIABETIC FOOTULCERSKey pointsd The MeggitteWagner classification is mainlybased on the wound depth and presence andlocation of infection, with grades rangingfrom 0 to 6

d The University of Texas classificationcategorizes wounds with 4 grades based onthe wound depth, presence of infection, andpresence of ischemia

Should an ulcer develop, clinical staging iscritical because it portends prognosis. One of themost commonly used classification systems fordiabetic foot ulcers is the MeggitteWagner classifi-cation. The system is primarily based on the wounddepth and presence and location of woundinfection, with grades ranging from 0 to 6. Thefirst 3 grades (0-2) are based on the depth of the

lesion through the soft tissue, and the last 3 grades(3-5) are based on the extent of foot infection.107

The University of Texas wound classification sys-tem categorizes wounds into 4 grades (0-III) basedon the wound severity. Grade 0 represents a pre-or postulcerative site. Grade I ulcers are superficial,grade II ulcers penetrate to the tendon or jointcapsule, and grade III ulcers penetrate the bone orinto the joint. With each wound grade, there are 4stages: nonischemic clean (A), nonischemic in-fected (B), ischemic wounds (C), and infectedischemic wound (D).63,108

Various classification systems have been pro-posed for DFUs, with no single universallyaccepted system. In addition to the stagingsystems listed above, the IWGDF has developed aclassification system for all ulcers according to the 5categories of perfusion, extent/size, depth/tissue

Table V. Comparison of 3 diabetic foot classifications

Classification

MeggitteWagner University of Texas PEDIS (research-oriented)

Grade 0—No ulcer in a high-risk foot Grade I-A—Noninfected, nonischemic superfi-cial ulceration

Grade I-B—Infected, nonischemic superficialulceration

Grade I-C—Ischemic, noninfected superficialulceration

Grade I-D—Ischemic and infected superficialulceration

PerfusionGrade 1—Superficial ulcer involving the fullskin thickness but not underlying tissues

Extent/size

Grade 2—Deep ulcer, penetrating down toligaments and muscle, but no boneinvolvement or abscess formation

Grade II-A—Noninfected, nonischemic ulcerthat penetrates to capsule or bone

Grade II-B—Infected, nonischemic ulcer thatpenetrates to capsule or bone

Grade II-C—Ischemic, noninfected ulcer thatpenetrates to capsule or bone

Grade II-D—Ischemic and infected ulcer thatpenetrates to capsule or bone

Depth/ tissue loss

Grade 3—Deep ulcer with cellulitis or abscessformation, often with osteomyelitis

Infection

Grade 4—Localized gangrene Grade III-A—Noninfected, nonischemic ulcerthat penetrates to bone or a deep abscess

Grade III-B—Infected, nonischemic ulcer thatpenetrates to bone or a deep abscess

Grade III-C—Ischemic, noninfected ulcer thatpenetrates to bone or a deep abscess

Grade III-D—Ischemic and infected ulcer thatpenetrates to bone or a deep abscess

SensationGrade 5—Extensive gangrene involving theentire foot

PEDIS, Perfusion, extent/size, depth/tissue loss, infection, and sensation.

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loss, infection, and sensation (PEDIS).64 Severalstudies have shown a link between poor outcomesand increased severity of disease (higher stage orgrade).63 All 3 classifications are compared inTable V. The University of Texas classification is theclassification that is most commonly used in woundcare clinics. While classification systems areimportant and are focused on wound characteristics,the anatomic location of a diabetic neuropathic orischemic ulcer can also relate to healing potential.Forefoot wounds have a higher chance of healingcompared to more proximal wound locations.Specifically, heel region ulcers are associated withhigher amputation rates and a greater difficulty inhealing.107

CONCLUSIONDiabetic foot screening should be completed in all

diabetic ambulatory care settings (ie, physician offices,diabetic education centers, and home care). PAD,neuropathy, deformity, and previous amputation arethe main factors contributing to the development ofDFU. Early recognition of the high-risk foot isimperative to decrease morbidity and mortalityassociated with amputations. An interprofessionalapproach (ie, physicians, nurses, and foot carespecialists) can support patients and their circle of

care. The management of DFUs will be furtheraddressed in part II of this continuing medicaleducation article, where we will review the roleof infection, plantar pressure redistribution, debride-ment, local wound dressings, and advanced (active)therapies.

REFERENCES

1. Centers for Disease Control and Prevention. National

diabetes fact sheet: national estimates and general

information on diabetes and prediabetes in the United

States, 2011. Atlanta (GA): U.S. Department of Health and

Human Services, Centers for Disease Control and Prevention;

2011.

2. Boulton AJ, Armstrong DG. Diabetic foot and ulceration:

epidemiology and pathophysiology. In: Falabella AF, Kirsner

RS, editors. London: Taylor & Francis; 2005.

3. Boulton AJ. The diabetic foot. Medicine 2010;38:644-8.

4. Snyder RJ, Kirsner RS, Warriner RA 3rd, Lavery LA, Hanft JR,

Sheehan P. Recommendations on advancing the standard of

care for treating diabetic neuropathic foot ulcers in patients

with diabetes. Ostomy Wound Manage 2010;56(4 suppl):

S1-24.

5. American Diabetes Association. Diagnosis and classifica-

tion of diabetes mellitus. Diabetes Care 2012;35(suppl 1):

S64-71.

6. Lavery LA, McGuire J. Diabteic foot ulcers. In: Baranoski S,

Ayello EA, editors. Wound care essentials: practice principles.

2nd ed. Philadelphia: Lippincott, Williams and Wilkins; 2008.

pp. 338-62.

J AM ACAD DERMATOL

JANUARY 20141.e16 Alavi et al

7. World Health Organization web site. Facts and figures about

diabetes. Available at: http://www.who.int/diabetes/facts/en/.

Accessed September 25, 2013.

8. Alavi A, Sanjari M, Haghdoost A, Sibbald RG. Common foot

examination features of 247 Iranian patients with diabetes.

Int Wound J 2009;6:117-22.

9. Vijan S, Stevens DL, Herman WH, Funnell MM, Standiford CJ.

Screening, prevention, counseling, and treatment for the

complications of type II diabetes mellitus. Putting evidence

into practice. J Gen Intern Med 1997;12:567-80.

10. Canadian Diabetes Association web site. An economic

tsunami: the cost of diabetes in Canada. Available at:

http://www.diabetes.ca/documents/get-involved/FINAL_Eco

nomic_Report.pdf. Accessed September 25, 2013.

11. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence

of diabetes: estimates for the year 2000 and projections for

2030. Diabetes Care 2004;27:1047-53.

12. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, William-

son DF. Lifetime risk for diabetes mellitus in the United

States. JAMA 2003;290:1884-90.

13. Honeycutt AA, Boyle JP, Broglio KR, Thompson TJ, Hoerger

TJ, Geiss LS, et al. A dynamic Markov model for forecasting

diabetes prevalence in the United States through 2050.

Health Care Manag Sci 2003;6:155-64.

14. Boulton AJ, Armstrong DG, Albert SF, Frykberg RG, Hellman

R, Kirkman MS, et al. Comprehensive foot examination and

risk assessment: a report of the task force of the foot care

interest group of the American Diabetes Association,

with endorsement by the American Association of Clinical

Endocrinologists. Diabetes Care 2008;31:1679-85.

15. American Diabetes Association. Standards of medical care in

diabetes—2007. Diabetes Care 2007;30(suppl 1):S4-41.

16. Armstrong DG, Lavery LA, Wu S, Boulton AJ. Evaluation of

removable and irremovable cast walkers in the healing of

diabetic foot wounds: a randomized controlled trial. Diabetes

Care 2005;28:551-4.

17. Orsted HL, Searles GE, Trowell H, Shapera L, Miller P, Rahman

J. Best practice recommendations for the prevention,

diagnosis, and treatment of diabetic foot ulcers: update

2006. Adv Skin Wound Care 2007;20:655-69.

18. Lavery LA, Peters EJ, Armstrong DG. What are the most

effective interventions in preventing diabetic foot ulcers? Int

Wound J 2008;5:425-33.

19. Armstrong DG. An overview of foot infections in diabetes.

Diabetes Technol Ther 2011;13:951-7.

20. Sanjari M, Safari S, Shokoohi M, Safizade H, Rashidinezhad H,

Mashrouteh M, et al. A cross-sectional study in Kerman, Iran,

on the effect of diabetic foot ulcer on health-related quality

of life. Int J Low Extrem Wounds 2011;10:200-6.

21. Armstrong DG, Lavery LA, Wrobel JS, Vileikyte L. Quality of

life in healing diabetic wounds: does the end justify the

means? J Foot Ankle Surg 2008;47:278-82.

22. Goeree R, Lim ME, Hopkins R, Blackhouse G, Tarride JE, Xie F,

et al. Prevalence, total and excess costs of diabetes and related

complications inOntario, Canada. Can JDiabetes 2009;33:35-45.

23. Gordon KA, Lebrun EA, Tomic-Canic M, Kirsner RS. The role of

surgical debridement in healing of diabetic foot ulcers.

Skinmed 2012;10:24-6.

24. 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. Diabetes Care 1999;22:1029-35.

25. Steed DL, Attinger C, Brem H, Colaizzi T, Crossland M, Franz

M, et al. Guidelines for the prevention of diabetic ulcers.

Wound Repair Regen 2008;16:169-74.

26. Jeffcoate WJ, Lipsky BA, Berendt AR, Cavanagh PR, Bus SA,

Peters EJ, et al. Unresolved issues in the management of

ulcers of the foot in diabetes. Diabet Med 2008;25:1380-9.

27. Reiber GE, Lipsky BA, Gibbons GW. The burden of diabetic

foot ulcers. Am J Surg 1998;176(2A suppl):5S-10S.

28. 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. Diabetes

Care 1998;21:1071-5.

29. Lavery LA, Lavery DC, Quebedeax-Farnham TL. Increased foot

pressures after great toe amputation in diabetes. Diabetes

Care 1995;18:1460-2.

30. Lavery LA, Armstrong DG, Vela SA, Quebedeaux TL, Fleischli

JG. Practical criteria for screening patients at high risk

for diabetic foot ulceration. Arch Intern Med 1998;158:157-62.

31. Lavery LA, van Houtum WH, Harkless LB. In-hospital mortality

and disposition of diabetic amputees in The Netherlands.

Diabet Med 1996;13:192-7.

32. Most R, Sinnock P. The epidemiology of lower extremity

amputations in diabetic individuals. Diabetes Care 1983;6:

87-91.

33. Iversen MM, Tell GS, Riise T, Hanestad BR, Ostbye T, Graue M,

et al. History of foot ulcer increases mortality among

individuals with diabetes: ten-year follow-up of the

Nord-Trondelag Health Study, Norway. Diabetes Care 2009;

32:2193-9.

34. Driver VR, Fabbi M, Lavery LA, Gibbons G. The costs of

diabetic foot: the economic case for the limb salvage team.

J Vasc Surg 2010;52(3 suppl):17S-22S.

35. 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. Clin Ther 1998;20:169-81.

36. Harrington C, Zagari MJ, Corea J, Klitenic J. A cost analysis of

diabetic lower-extremity ulcers. Diabetes Care 2000;23:

1333-8.

37. Apelqvist J, Ragnarson-Tennvall G, Persson U, Larsson J.

Diabetic foot ulcers in a multidisciplinary setting. An

economic analysis of primary healing and healing with

amputation. J Intern Med 1994;235:463-71.

38. Eslami MH, Zayaruzny M, Fitzgerald GA. The adverse effects

of race, insurance status, and low income on the rate of

amputation in patients presenting with lower extremity

ischemia. J Vasc Surg 2007;45:55-9.

39. Pan American Health Organization web site.

Non-communicable disease in the Americas: cost-effective

interventions for prevention and control. Available at: http://

www.paho.org/hq/index.php?option=com_docman&task=

doc_view&gid=16220&Itemid=. Accessed September 29,

2013.

40. Narayan KM, Zhang P, Williams D, Engelgau M, Imperatore G,

Kanaya A, et al. How should developing countries manage

diabetes? CMAJ 2006;175:733.

41. Ollendorf DA, Kotsanos JG, Wishner WJ, Friedman M, Cooper

T, Bittoni M, et al. Potential economic benefits of

lower-extremity amputation prevention strategies in

diabetes. Diabetes Care 1998;21:1240-5.

42. Erbersdobler HF, Faist V. Maillard reaction products: uptake,

metabolic transit and selected parameters of biopotency and

safety. Forum Nutr 2003;56:353-5.

43. Ferreira AE, Ponces Freire AM, Voit EO. A quantitative model

of the generation of N(epsilon)-(carboxymethyl)lysine in

the Maillard reaction between collagen and glucose.

Biochem J 2003;376(part 1):109-21.

44. Lavery LA, Higgins KR, Lanctot DR, Constantinides GP,

Zamorano RG, Athanasiou KA, et al. Preventing diabetic

J AM ACAD DERMATOL

VOLUME 70, NUMBER 1Alavi et al 1.e17

foot ulcer recurrence in high-risk patients: use of tempera-

ture monitoring as a self-assessment tool. Diabetes Care

2007;30:14-20.

45. Galkowska H, Wojewodzka U, Olszewski WL. Low recruitment

of immune cells with increased expression of endothelial

adhesion molecules in margins of the chronic diabetic foot

ulcers. Wound Repair Regen 2005;13:248-54.

46. Quattrini C, Jeziorska M, Malik RA. Small fiber neuropathy in

diabetes: clinical consequence and assessment. Int J Lower

Extrem Wounds 2004;3:16-21.

47. Richards AM, Mitsou J, Floyd DC, Terenghi G, McGrouther DA.

Neural innervation and healing. Lancet 1997;350:339-40.

48. Smith PG, Liu M. Impaired cutaneous wound healing

after sensory denervation in developing rats: effects on

cell proliferation and apoptosis. Cell Tissue Res 2002;307:

281-91.

49. Murray HJ, Young MJ, Hollis S, Boulton AJ. The association

between callus formation, high pressures and neuropathy in

diabetic foot ulceration. Diabet Med 1996;13:979-82.

50. Eskelinen E, Lepantalo M, Hietala EM, Sell H, Kauppila L,

Maenpaa I, et al. Lower limb amputations in Southern

Finland in 2000 and trends up to 2001. Eur J Vasc Endovasc

Surg 2004;27:193-200.

51. Snyder RJ. Controversies regarding vascular disease in the

patient with diabetes: a review of the literature. Ostomy

Wound Manage 2007;53:40-8.

52. Percival SL, Hill KE, Williams DW, Hooper SJ, Thomas DW,

Costerton JW. A review of the scientific evidence for biofilms

in wounds. Wound Repair Regen 2012;20:647-57.

53. Lebrun E, Tomic-Canic M, Kirsner RS. The role of surgical

debridement in healing of diabetic foot ulcers. Wound Repair

Regen 2010;18:433-8.

54. Calhoun JH, Overgaard KA, Stevens CM, Dowling JP, Mader

JT. Diabetic foot ulcers and infections: current concepts. Adv

Skin Wound Care 2002;15:31-42.

55. Mowat A, Baum J. Chemotaxis of polymorphonuclear

leukocytes from patients with diabetes mellitus. N Engl

J Med 1971;284:621-7.

56. Stojadinovic O, Brem H, Vouthounis C, Lee B, Fallon J,

Stallcup M, et al. Molecular pathogenesis of chronic wounds:

the role of beta-catenin and c-myc in the inhibition of

epithelialization and wound healing. AM J Pathol 2005;167:

59-69.

57. Cavanagh PR, Bus SA. Off-loading the diabetic foot for ulcer

prevention and healing. J Am Podiatr Med Assoc 2010;100:

360-8.

58. Johnson S, Branthwaite HR, Naemi R, Chockalingam N. The

effect of three different toe props on plantar pressure and

patient comfort. J Foot Ankle Res 2012;5:22.

59. Birke JA, Franks BD, Foto JG. First ray joint limitation,

pressure, and ulceration of the first metatarsal head in

diabetes mellitus. Foot Ankle Int 1995;16:277-84.

60. Peters EJ, Lipsky BA, Berendt AR, Embil JM, Lavery LA,

Senneville E, et al. A systematic review of the effectiveness

of interventions in the management of infection in the

diabetic foot. Diabetes Metab Res Rev 2012;28(suppl 1):

142-62.

61. Lavery LA, Peters EJ, Williams JR, Murdoch DP, Hudson A,

Lavery DC, et al. Reevaluating the way we classify the

diabetic foot: restructuring the diabetic foot risk classification

system of the International Working Group on the Diabetic

Foot. Diabetes Care 2008;31:154-6.

62. Sibbald RG, Ayello EA, Alavi A, Ostrow B, Lowe J, Botros M,

et al. Screening for the high-risk diabetic foot: a

60-second tool (2012). Adv Skin Wound Care 2012;25:465-76.

63. Sumpio BE, Armstrong DG, Lavery LA, Andros G; Society for

Vascular Surgery; American Podiatric Medical Association.

The role of interdisciplinary team approach in the manage-

ment of the diabetic foot: a joint statement from the

Society for Vascular Surgery and the American Podiatric

Medical Association. J Am Podiatr Med Assoc 2010;100:

309-11.

64. Lavery LA, Armstrong DG, Harkless LB. Classification of

diabetic foot wounds. J Foot Ankle Surg 1996;35:528-31.

65. Schaper NC, Apelqvist J, Bakker K. Reducing lower leg

amputations in diabetes: a challenge for patients, healthcare

providers and the healthcare system. Diabetologia 2012;55:

1869-72.

66. Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in

patients with diabetes. JAMA 2005;293:217-28.

67. Tan JS, Flanagan PJ, Donovan DL, File TM. Team approach in

the management of diabetic foot infections. J Foot Surg

1987;26(1 suppl):S12-6.

68. Peters EJ, Lavery LA, Armstrong DG. Diabetic lower extremity

infection: influence of physical, psychological, and social

factors. J Diabetes Complications 2005;19:107-12.

69. Peters EJ, Armstrong DG, Lavery LA. Risk factors for recurrent

diabetic foot ulcers: site matters. Diabetes Care 2007;30:

2077-9.

70. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli

JG. Choosing a practical screening instrument to identify

patients at risk for diabetic foot ulceration. Arch Intern Med

1998;158:289-92.

71. Canadian Diabetes Association web site. Clinical practice

guidelines for the prevention and management of diabetes

in Canada. Available at: http://guidelines.diabetes.ca/

App_Themes/CDACPG/resources/cpg_2013_full_en.pdf. Ac-

cessed September 29, 2013.

72. Singleton JR, Smith AG, Bromberg MB. Increased prevalence

of impaired glucose tolerance in patients with painful

sensory neuropathy. Diabetes Care 2001;24:1448-53.

73. Perkins BA, Bril V. Diagnosis and management of diabetic

neuropathy. Curr Diabetes Rep 2002;2:495-500.

74. Katon JG, Reiber GE, Nelson KM. Peripheral neuropathy

defined by monofilament insensitivity and diabetes status:

NHANES 1999-2004. Diabetes Care 2013;36:1604-6.

75. Rith-Najarian SJ, Stolusky T, Gohdes DM. Identifying

diabetic patients at high risk for lower-extremity

amputation in a primary health care setting. A prospective

evaluation of simple screening criteria. Diabetes Care 1992;

15:1386-9.

76. Rogers LC, Williams DV, Armstrong DG. Assessment of

the diabetic foot. In: Krasner DL, Sibbald RG, editors.

Chronic wound care: a clinical source book for health care

professionals. Malvern (PA): HMP Communications; 2007:

549-55.

77. Wilasrusmee C, Suthakorn J, Guerineau C, Itsarachaiyot Y,

Sa-Ing V, Proprom N, et al. A novel robotic monofilament test

for diabetic neuropathy. Asian J Surg/Asian Surgical

Association 2010;33:193-8.

78. American, Diabetes Association. Standards of medical care in

diabetes e 2010. Diabetes Care 2010;33(suppl 1):S11-61.

79. Dorresteijn JA, Valk GD. Patient education for preventing

diabetic foot ulceration. Diabetes Metab Res Rev 2012;

28(suppl 1):101-6.

80. Registered Nurses Association of Ontario web site. Nursing

best practice guideline: reducing foot complications for

people with diabetes. Available at: http://rnao.ca/fr/sites/

rnao-ca/files/Reducing_Foot_Complications_for_People_

with_Diabetes.pdf. Accessed September 29, 2013.

J AM ACAD DERMATOL

JANUARY 20141.e18 Alavi et al

81. Prompers L, Schaper N, Apelqvist J, Edmonds M, Jude E,

Mauricio D, et al. Prediction of outcome in individuals with

diabetic foot ulcers: focus on the differences between

individuals with and without peripheral arterial disease. The

EURODIALE Study. Diabetologia 2008;51:747-55.

82. Prompers L, Huijberts M, Apelqvist J, Jude E, Piaggesi A,

Bakker K, et al. High prevalence of ischaemia, infection and

serious comorbidity in patients with diabetic foot disease

in Europe. Baseline results from the Eurodiale study.

Diabetologia 2007;50:18-25.

83. Neville RF, Attinger CE, Bulan EJ, Ducic I, Thomassen M,

Sidawy AN. Revascularization of a specific angiosome for

limb salvage: does the target artery matter? Ann Vasc Surg

2009;23:367-73.

84. Attinger CE, Evans KK, Bulan E, Blume P, Cooper P.

Angiosomes of the foot and ankle and clinical implica-

tions for limb salvage: reconstruction, incisions, and

revascularization. Plast Reconstr Surg 2006;117(7 suppl):

261S-93S.

85. Clemens MW, Attinger CE. Angiosomes and wound care in

the diabetic foot. Foot Ankle Clin 2010;15:439-64.

86. Alexandrescu VA, Hubermont G, Philips Y, Guillaumie B,

Ngongang C, Vandenbossche P, et al. Selective primary

angioplasty following an angiosome model of reperfusion

in the treatment of Wagner 1-4 diabetic foot lesions: practice

in a multidisciplinary diabetic limb service. J Endovasc Ther

2008;15:580-93.

87. Alexandrescu V, Soderstrom M, Venermo M. Angiosome

theory: fact or fiction? Scand J Surg 2012;101:125-31.

88. Faglia E, Clerici G, Clerissi J, Mantero M, Caminiti M,

Quarantiello A, et al. When is a technically successful periph-

eral angioplasty effective in preventing above-the-ankle

amputation in diabetic patients with critical limb ischaemia?

Diabet Med 2007;24:823-9.

89. Criqui MH, Fronek A, Klauber MR, Barrett-Connor E, Gabriel S.

The sensitivity, specificity, and predictive value of traditional

clinical evaluation of peripheral arterial disease: results from

noninvasive testing in a defined population. Circulation 1985;

71:516-22.

90. Lepantalo M, Apelqvist J, Setacci C, Ricco JB, de Donato G,

Becker F, et al. Chapter V: diabetic foot. Eur J Vasc Endovasc

Surg 2011;42(suppl 2):S60-74.

91. McGee SR, Boyko EJ. Physical examination and chronic

lower-extremity ischemia: a critical review. Arch Intern Med

1998;158:1357-64.

92. Holloway GA. Arterial ulcers: assessment, classification and

management. In: Krasner D, Kane D, editors. Chronic wound

care. 2nd ed. Wayne (PA): Health Management Publications;

1997. pp. 158-64.

93. Miyazawa T, Nakagawa K, Shimasaki S, Nagai R. Lipid glyca-

tion and protein glycation in diabetes and atherosclerosis.

Amino Acids 2012;42:1163-70.

94. Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V,

Somalvico F. Evaluation of feasibility of ankle pressure and

foot oximetry values for the detection of critical limb

ischemia in diabetic patients. Vasc Endovasc Surg 2010;44:

184-9.

95. Faglia E, Clerici G, Mantero M, Caminiti M, Quarantiello A,

Curci V, et al. Incidence of critical limb ischemia and

amputation outcome in contralateral limb in diabetic

patients hospitalized for unilateral critical limb ischemia

during 1999-2003 and followed-up until 2005. Diabetes Res

Clin Pract 2007;77:445-50.

96. Kawarada O, Yokoi Y, Higashimori A, Waratani N, Fujihara M,

Kume T, et al. Assessment of macro- and microcirculation in

contemporary critical limb ischemia. Catheter Cardiovasc

Interv 2011;78:1051-8.

97. Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ,

Armstrong DG, et al. 2012 Infectious Diseases Society of

America clinical practice guideline for the diagnosis and

treatment of diabetic foot infections. Clin Infect Dis 2012;54:

e132-73.

98. Wukich DK, Sung W. Charcot arthropathy of the foot and

ankle: modern concepts and management review. J Diabetes

Complications 2009;23:409-26.

99. Jeffcoate WJ. Abnormalities of vasomotor regulation in the

pathogenesis of the acute Charcot foot of diabetes mellitus.

Int J Lower Extrem Wounds 2005;4:133-7.

100. Thompson P, Hanson D, Langemo DK, Hunter S, Anderson J.

Diabetic foot: Charcot neuropathic osteoarthropathy.

Adv Skin Wound Care 2009;22:72-3.

101. Molines L, Darmon P, Raccah D. Charcot’s foot: newest

findings on its pathophysiology, diagnosis and treatment.

Diabetes Metab 2010;36:251-5.

102. Naqvi A, Cuchacovich R, Saketkoo L, Espinoza LR. Acute

Charcot arthropathy successfully treated with pamidronate:

long-term follow-up. Am J Med Sci 2008;335:145-8.

103. Kong MF, Jogia R, Jackson S, Quinn M, McNally P, Davies M.

Malignant melanoma presenting as a foot ulcer. Lancet 2005;

366:1750.

104. Kong MF, Jogia R, Jackson S, Quinn M, McNally P, Davies M.

When to biopsy a foot ulcer? Seven cases of malignant

melanoma presenting as foot ulcers. Practical Diabetes

International 2008;25:5-8.

105. Metzger S, Ellwanger U, Stroebel W, Schiebel U, Rassner G,

Fierlbeck G. Extent and consequences of physician delay in

the diagnosis of acral melanoma. Melanoma Res 1998;8:

181-6.

106. Panda S, Khanna S, Singh SK, Gupta SK. Squamous cell

carcinoma developing in a diabetic foot ulcer. Int J Low

Extrem Wounds 2011;10:101-3.

107. Brodsky JW. Classification of foot lesions in diabetic

patients. In: Bowker JS, Pfeifer M, editors. Levin and

O’Neal’s The Diabetic Foot. Philadelphia: Mosby Elsevier;

2007. pp. 227-39.

108. Lavery LA, Armstrong DG, Harkless LB. Classification of

diabetic foot wounds. Ostomy Wound Manage 1997;43:

44-8, 50, 52-3.