Diabetic foot ulcers Part I. Pathophysiology and prevention

Abstract

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 diabetes mellitus will develop diabetic foot ulcers. Foot ulcer patients have an increased risk of amputation and increased mortality rate. The high-risk diabetic foot can be identified with a simplified screening, and subsequent foot ulcers can be prevented. Early recognition of the high-risk foot and timely treatment will save legs and improve patients' quality of life. Peripheral arterial disease, neuropathy, deformity, previous amputation, 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. An interprofessional approach (ie, physicians, nurses, and foot care specialists) is often needed to support patients' needs.

Full text

CONTINUING MEDICAL EDUCATION
Diabetic foot ulcers
Part 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
DavidG.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, PhD
j
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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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
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Learning Objectives
After completingthis learning activity, participants should be able to assess the
epidemiologyof diabetes mellitus and its complications; identifythe 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 control withelevated HbA1c levels,vascular compromise,
increased bacterial burden or deep and surrounding infection, increased plantar
pressure dueto neuropathyand foot deformities.); and describeclinical characteristics
and stage of DFUs based on depth and causative factors.
Date of release: January 2014
Expiration date: January 2017
Ó2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.06.055
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1.e1

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 diabetes
mellitus will develop diabetic foot ulcers. Foot ulcer patients have an increased risk of amputation and
increased mortality rate. The high-risk diabetic foot can be identified with a simplified screening, and
subsequent foot ulcers can be prevented. Early recognition of the high-risk foot and timely treatment will
save legs and improve patients’ quality of life. Peripheral arterial disease, neuropathy, deformity, previous
amputation, 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. An
interprofessional approach (ie, physicians, nurses, and foot care specialists) is often needed to support
patients’ needs. ( J Am Acad Dermatol 2014;70:1.e1-18.)
Key words: diabetes; diabetic foot ulcer; neuropathy; wounds.
The number of people with diabetes mellitus (DM)
has increased dramatically. DM is a serious, lifelong
condition that is the seventh leading cause of death in
North 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 rate
over the ensuing 5 years.
2-4
Early detection and
effective management can reduce the severity of
complications, including preventable amputations.
Dermatologists assessing and treating patients with
DM and DFUs can benefit from an interprofessional
team to optimize patient management and outcomes.
THE BURDEN OF DIABETES MELLITUS
AND COMMON DIABETIC
COMPLICATIONS
Key points
dMore than half of persons with diabetes
mellitus are unaware of their disease
d2.5% to 15% of annual global health care
budgets are spent on diabetes mellitus
dDiabetes mellitus is the seventh leading cause of
death in the United States
dDiabetes mellitus is the leading cause of
kidney failure, nontraumatic lower extrem-
ity amputations, and new cases of blindness
in adult Americans
dDiabetic foot ulcers are often preventable,
and treatment is frequently suboptimal
DM is an increasing problem in both developed
and developing nations. The majority of persons
with DM have type 2 DM, with only 5% to 10% of
patients diagnosed with type 1 DM.
5,6
Several studies
have concluded that [50% of people with DM
(according to World Health Organization criteria)
are unaware of their disease.
7,8
Early DM detection
and treatment can improve overall quality of life
(QOL) and increase the life expectancy of persons
with 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 of
age.
1,9
Worldwide estimates have calculated that
2.5% to 15% of global annual health care budgets
are spent on DM, and the annual direct medical cost
worldwide is as high as $241 billion.
7
In their 2009 report, the Canadian Diabetes
Association labeled the increased prevalence of
DM an ‘‘economical tsunami,’’ with a doubling of
the number of people diagnosed in the past de-
cade.
10
In 2010, 26.9% of US residents above 65
years of age (10.9 million) had DM.
1
DM is the
leading American cause of kidney failure, non-
traumatic lower extremity amputations, and new
cases of adult blindness.
1
DM is a serious, lifelong metabolic condition that
is the seventh leading cause of death in North
America.
1
By 2025, it is predicted that $333 million
people will develop DM worldwide; this increase
creates growing health and economic issue.
11-13
In
the developing world, the rise in the number of
persons with DM will have a devastating negative
impact on health care systems and individual health.
1
Every year, 1 million people worldwide lose their
lives to DM-associated complications, with most of
these deaths being preventable.
7
Chronic wounds, including DFUs, are a common
yet challenging problem. These ulcers often display
From the Departments of Medicine (Dermatology)
a
and Public
Health,
b
University of Toronto; Clinic for Cardiovascular Sur-
gery,
c
University Hospital of Zurich; Wound-Healing Clinic,
d
Mississauga; Wound Care Centre,
e
Women’s College Hospital,
Toronto; Department of Surgery,
f
the University of Arizona
College of Medicine/SALSA, Tucson; Faculty of Nursing,
g
Queen’s University, Kingston; Department of Prosthetics and
Orthotics,
h
University of Zurich; Excelsior College,
i
School of
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
JAMACAD DERMATOL
JANUARY 2014
1.e2 Alavi et al

suboptimal healing particularly when the underlying
disease and cause have not been treated and the
patient has not received holistic interprofessional
care.
The importance of routine foot examination in
persons with DM and the identification of the
high-risk foot are underestimated in both inpatient
and outpatient settings because of the asymptomatic
nature of the disease. There is often a reluctance
to conduct foot screening for patients with DM
because of a perceived lack of time in busy prac-
tices.
14
The early recognition of the high-risk foot
and timely treatment may prevent foot ulcers, save
limbs, potentially save lives, and improve patient
QOL. These individuals often have a history of
previous foot ulcer or lower limb minor or major
amputation.
Once a foot ulcer develops, optimal care for
persons with DFU includes the assessment of
adequate arterial blood supply to heal, the
assessment of neuropathy, and the diagnosis and
treatment of infection.
Many of the requirements for holistic DFU care
are beyond the expertise of the practicing
dermatologist. There is also often an overall lack of
interprofessional networking required for optimal
management.
15
This gap is related to a lack of
knowledge, routine practice procedures, and health
care organizational barriers.
RISK OF DIABETIC FOOT ULCERS AND
LOWER LIMB AMPUTATIONS
Key points
dDiabetic foot ulcers precede 85% of lower
limb amputations
dDiabetic foot ulcers are the most costly and
preventable complication of diabetes
mellitus
dThe average lower limb amputation and
rehabilitation costs $44,790
DM has a vast range of short- and long-term
complications, and up to 85% of nontraumatic lower
extremity amputations are attributed to DM.
16-18
A
foot ulcer diminishes QOL. Persons suffering from a
nonhealing DFU have approximately 10% to 40%
lower QOL scores than the general population. For
example, the DFU impact on QOL is equivalent to
chronic lung disease, myocardial infarction, and
breast cancer.
19-21
The development of DFU and the subsequent,
often preventable nontraumatic lower extremity
amputations are among the most costly complica-
tions of DM. A Canadian study on the cost of
complications of DM found that major events,
including lower limb amputations, generate a greater
financial burden than DFU treatment alone.
22
The
rate of foot ulcer development in persons with
diabetic neuropathy is increased, and peripheral
neuropathy is the most significant risk factor for
DFU.
2,23-25
Once an ulcer develops, healing is often
slow, with the average estimate being [2 months for
simple ulcers in specialized DFU centers.
25
In addition, with standard care, only 33% of DFUs
will heal despite an organized approach to diagnosis
and treatment.
26
Twenty to 25% of all hospital
admission days for patients with DM are related to
foot complications.
6,27
American statistics in 2006
estimate that 65,700 nontraumatic lower limb ampu-
tations were performed in patients with DM, a
number that continues to rise.
5
There is evidence
that some measures can prevent DFUs and save
nontraumatic amputations. Interprofessional teams
are needed to provide detailed and early patient
assessment, aggressive treatment, and education.
There is substantial economic and clinical benefit to
an organized approach for the high-risk patients.
28
The risk of lower extremity amputation in the diabetic
population is 15 to 46 times higher than their
nondiabetic counterparts.
27,29,30
After an initial
amputation, the risk of the contralateral extremity
amputation ranges between 9% and 17% in the
first year, increasing to 25% to 68% within 3 to
5 years.
2,27,29,30
Several studies have found a 41% to 70% decrease
in the 5-year survival rate after a lower extremity
amputation.
2,31,32
Iversen et al
33
also reported a 50%
higher risk of mortality for patients with DM with a
history of DFUs compared to a diabetic population
without DFUs.
33
The following list emphasizes the economic
burden of DFUs
34,35
in the United States:
dIncreased cost associated with the severity of
DFU, with higher-grade DFUs (according to the
MeggitteWagner classification [Table I]) having
more costly disease
dPersons with DM and foot complications had
Medicare claims that were 3 times higher than
the general population ($15,309 vs $5,226
between 1995 and 1996)
36
dHealing costs after an amputation averaged
$44,790; healing without amputation averaged
$6,664
37
dAccess to limb-preserving interventions is sub-
optimal, leading to an increased amputation
rate especially among nonwhite, low-income
populations on Medicare/Medicaid compared to
individuals with higher economic status and
private insurance (extracted data between 1998
and 2002)
38
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VOLUME 70, NUMBER 1
Alavi et al 1.e3

The Pan American Health Organization (PAHO)
reported 3 key cost-saving health service interven-
tions needed to fight noncommunicable disease in
the Americas
39
: educating diabetic patients on recog-
nizing and treating minor foot injuries, the use of
appropriate footwear, and accessing knowledgeable
health care personnel. Narayan et al
40
outlined that
for developing countries, the highest priorities that
could also be cost savings to health care systems
included 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 a
target for HbA1c\0.07 and blood pressure \130 /85
mm Hg are suggested. The annual projected benefits
per intervention for individuals with high-risk DM
are shown in Table II.
41
Pathophysiology of the diabetic foot
Several biochemical abnormalities may accelerate
neuropathy and vascular foot changes, including
hyperglycemia that inhibits the production and
activation of endothelial nitric oxide synthase and
the reaction of protein with sugars (Maillard
reaction) that is linked to diabetic complications
and aging. DFUs are caused by neuropathy,
ischemia, or both.
The pathophysiology of DFUs requires an
appreciation of the role of several contributory
factors, including peripheral neuropathy, vascular
disease (arterial circulation), and inflammatory
cytokines and susceptibility to infection.
Neuropathy. Persons with DM are susceptible to
peripheral neuropathy with sensory, autonomic, and
motor components. There are several proposed
mechanisms associated with this neuropathy,
including nitric oxide blocking and the Maillard
reaction between sugars and amino acids (Fig 1).
Nitric oxide blocking. Hyperglycemia, dyslipide-
mia, insulin resistance, and oxidative stress can
lead to cellular damage, endothelial dysfunction,
and various diabetes-associated complications
through a number of pathways. Hyperglycemia
inhibits the production of nitric oxide by blocking
endothelial nitric oxide synthase activation, which
can lead to higher levels of reactive oxygen
species, particularly superoxide. Superoxide is
then converted enzymatically to hydrogen peroxide
by superoxide dismutases. In the presence of
ferrous or cuprous ions, hydrogen peroxide is
converted to the highly reactive and damaging
hydroxyl radical. In addition, the superoxide anion
also binds to nitric oxide (a potent vasodilator),
producing peroxynitrite and thereby limiting the
bioavailability of a potent endothelium-derived
vasodilator. The peroxynitrite anion has a role in
the oxidization of sulfhydryl groups in proteins,
lipid peroxidation, the generation of reactive
aldehydes/nitrogen oxides, and the production of
proatherogenic low density lipoproteins. The
disruption of the endothelium-regulated vascular
function not only affects the vasoconstriction
response but also causes platelet aggregation,
abnormal intimal growth, inflammation, and
atherothrombosis formation.
37-39
Glucoxidation
and lipoxidation of vascular wall structural proteins
might facilitate atherogenesis through the effect on
vessel wall characteristics and the interaction of
inflammatory cytokines. This atherogenesis of the
small vessels supplying the peripheral nerves
contributes to the neuropathy.
Maillard reaction. The Maillard reaction is a slow
but complex reaction between reducing sugars and
amino groups of biomolecules leading to the
production of a complex structures known as
advanced glycation endproducts (AGEs).
40,42,43
This reaction has been hypothesized to be an
important mechanism in the pathophysiology of
diabetes complications. It has been linked to protein
modifications found during aging and diabetes.
43
AGE-modified proteins and lipoproteins have roles
in the pathogenesis of atherosclerosis.
Excess glucose is converted to sorbital by aldose
reductase through the polyol metabolic pathway
that consumes nicotinamide adenine dinucleotide
phosphate (NADPH).
41
NADPH is further reduced
by the activation of the hexosamine biosynthetic
pathway that limits the conversion of nicotinamide
adenine dinucleotide to NADPH by inhibiting
the enzymatic activity of glucose-6-phosphate
Table I. Diabetic foot ulcer cost as determined by
the MeggitteWagner classification
37
Wagner grade Retrospective cost analysis per ulcer (average)
1 or 2 $1,929
3 $3,980
4 or 5 $15,792
Table II. Projected annual cost benefits and
amputation reduction with interventions for high-
risk persons with diabetes
70,71
Potential
savings
Amputation
reduction
Detailed educational intervention $1.1 million 72%
Multiprofessional team approach
to diabetes mellitus care
$750,000 47%
Therapeutic footwear $850,000 53%
JAMACAD DERMATOL
JANUARY 2014
1.e4 Alavi et al

dehydrogenase.
42
The end result is the depletion of
NADPH that in turn affects the normal synthesis of
key antioxidants, such as glutathione. Decreased
antioxidant and increased production of reactive
oxygen species play a crucial mediatory role in the
pathogenesis and progression of complications in
diabetes.
Neuropathy leads to foot deformity or limited
joint mobility, resulting in abnormal foot pressure
and subsequent callus formation over pressure
points (Fig 2). The callus further increases
the local pressure and when combined with unde-
tected repetitive injury leads to local tissue injury,
inflammation, tissue death (necrosis), and finally
ulceration
44
(Fig 3).
Neuropathy is one of the main contributory fac-
tors in the pathogenesis of DFUs. In the absence of
neuropathy, pain limits the repetitive injury needed
for a full-thickness ulcer to develop.
Diabetic neuropathy can affect the production of
neuropeptides, such as nerve growth factor,
substance P, and calcitonin geneerelated peptide.
45
Neuropeptides are relevant to wound healing
because they promote cell chemotaxis, prompt
growth factor production, and stimulate the
proliferation of cells. In addition, sensory nerves
play a role in modulating immune defense
mechanisms, with denervated skin showing reduced
leukocyte infiltration.
46
For example, the rate of
wound healing in 1-cm excisional wounds on
rats created with denervated skin flaps was
significantly reduced compared with control
wounds.
47
Immunohistochemical studies identified
significantly reduced monocyte, macrophage, and
Fig 1. Pathophysiology of diabetic foot ulcers.
Fig 2. Diabetic neuropathic feet. Callus formation as a
presentation of neuropathy.
JAMACAD DERMATOL
VOLUME 70, NUMBER 1
Alavi et al 1.e5

T-lymphocyte counts in the denervated wounds.
Capsaicin injections induced sensory denervation
in rats has been associated with delayed reepitheli-
alization and wound healing.
48
Murray et al
49
indicated an 11-fold higher risk of developing ulcers
in the presence of callus.
Vascular disease. Micro- and macrovascular
disease in persons with DM may impair healing of
the ulcers and is critically important. Ischemia has
been reported as a contributing factor in 90% of
diabetic patients undergoing major amputation.
50,51
Prolonged inflammatory response within the
microcirculation can lead to thickening of capillary
basement membranes with arteriolar hyalinization,
compromising the normal movements of nutrients
and activated leukocytes between the capillary lu-
men and the interstitium. The relatively inelastic
capillary walls may explain the limited capacity for
vasodilatation in response to local injury, leading to
functional ischemia.
Inflammatory cytokines and susceptibility
to infection. Once an ulcer develops, susceptibil-
ity to infection exists because of a loss of innate
barrier function. In chronic wounds, microorganisms
aggregate together and grow within communities
where they encase themselves within extracellular
polymeric substances containing polysaccharides
and lipids. This encased collection of microorgan-
isms, known as a biofilm, increases resistance to
antimicrobial, immunologic, and chemical attacks.
52
Bacterial biofilms contribute to a delay in healing
and the occurrence of chronic inflammation and
recurrent infections with the intermittent release of
single (planktonic) organisms.
52
DM also affects normal leukocyte function and
immune functions, decreasing host resistance and
rendering this patient population more susceptible
to superficial increased bacterial burden in the
wound base and deep or surrounding skin
infection.
53,54
For example, Mowat et al
55
docu-
mented an in vitro leukocyte chemotaxis defect in
persons with diabetes. Phagocytosis and bactericidal
capacity was significantly reduced in the presence of
hyperglycemia.
55
Once DFUs have formed, they are
often slow to heal because of impaired cell
migration.
43
Stojadinovic et al
56
identified that
overexpression of c-Myc and b-catenin at the edge
of chronic DFUs may lead to impairment of
keratinocyte migration and inhibition of healing
in DFUs. A number of wound fluid studies have
identified an elevated level of matrix metalloprotei-
nases in the exudate associated with DFUs. These
elevated levels may result in sustained inflammation
with a net destruction of the collagen matrix required
for healing.
INCREASED PLANTAR PRESSURE AND ITS
CONSEQUENCES
Key points
dAll patients with DM should undergo a
thorough examination with both shoes and
socks off
dThe presence of callus is associated with an
increase in local pressure because of the
loss of protective sensation associated
with neuropathy. It is of utmost importance
to remove the callus at regular intervals
(ideally at every visit) to prevent pressure
ulcers
dA blister may be the result of friction and
shear (movement between the foot and the
shoe, orthotic, or special device)
dDeformities and limited range of motion of
the foot and ankle joints can alter foot
mechanics and cause critical pressure and
ulceration
Once an ulcer develops, there are different
techniques that can be used to deflect increased
plantar pressure, including a total contact cast, a
removable cast walker, half shoes, and custom
orthotics. However, before ulcer development, it
is necessary that all patients with DM and potential
diabetic foot changes should have a thorough
examination with the removal of both the patient’s
shoes and socks. The presence of callus is
Fig 3. Diabetic neuropathic foot ulcers overlying the
metatarsal head.
JAMACAD DERMATOL
JANUARY 2014
1.e6 Alavi et al

associated with an increase in local pressure. Motor
neuropathy causes unequal muscle pull. The
plantar muscles are affected first; the loss of distal
innervation creates unequal pull from the proximal
muscles on the dorsal surface of the foot. This
pressure differential results in a ‘‘cocked up’’ toe,
but unequal pressure can cause additional
deformities, such as claw toes (dorsiflexion of the
proximal phalanx on the lesser metatarsophalan-
geal joint, combined with flexion of both
the proximal and distal interphalangeal joints;
Fig 4).
57,58
The claw toe is distinguished from the
hammertoe, which has a deformity of proximal
metacarpophalangeal joint and interphalangeal
joint of the toe, causing consistent flexure like a
hammer (Fig 5).
58
The deformity results in
prominent plantar surface metatarsal heads and
clawed toes. These deformities are often associated
with skin breakdown on the doral or plantar surface
of the forefoot from poorly fitting shoes with an
inadequately sized toe box. As the metatarsal heads
drop, the corresponding fat pads herniate distally
under the base of the toes. The pressure from the
collapsed bone close to the plantar surface results
in local callus formation over the metatarsal heads.
These changes can be recognized by a thorough
examination of the base of the toes with the
metatarsal heads becoming easily palpated just
below the plantar surface. Callus is associated
with increased risk of ulceration.
A blister may be the result of friction and shear
(movement between the plantar surface of the
foot and the sole of the shoe), and this is also a
potential break in the skin barrier, leading to an
increased risk of infection. Bunions caused by
halluxvalgusareimportantfootdeformities
associated with a wide forefoot and an additional
risk site at the sides of the foot for ulcer
formation.
Glycosylation of collagen by hyperglycemia leads
to stiffness of connective tissues (ie, joint capsules
and ligaments). This impairs joint function and
results in restricted range of motion.
59
An example
is the equinus deformity, with restriction of
dorsiflexion of the ankle joint often associated with
fixed toes, leading to critical plantar pressure in the
forefoot and toe area. Patients may be referred for
ankle tendon lengthening to correct this deformity
or, in some cases, to promote the healing of
persistent forefoot plantar ulcers.
Evaluation of the risk factors and risk stratification
is an important guide for prognosis and diabetic foot
care. The International Working Group on the
Diabetic Foot (IWGDF) risk categorization tool
is a useful system to classify these patients
(Table III).
60,61
Fig 5. A and B, Hammer toes. Note the deformity of the
proximal metatarsophalangeal and interphalangeal joints
of the toes, causing consistent flexure like a hammer.
Fig 4. A and B, Claw toes. Dorsiflexion of the proximal
phalanx on the lesser metatarsophalangeal joint
combined with flexion of both the proximal and distal
interphalangeal joints that cause pressure. Claw toe can
affect the second, third, fourth, or fifth toes.
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WHY USE A SCREENING TEST?
Key points
dIdentification of the high-risk foot is an
essential component of diabetes care
dA simplified screening can detect the
high-risk foot
dAn interprofessional approach can reduce
the amputation rate by 40% to 85%
dNeuropathy, peripheral arterial disease, and a
previous foot ulcer or amputations are major
risk factors for developing a foot ulcer
The high-risk diabetic foot can be identified with
simplified screening tests, and subsequent foot
ulcers may be prevented.
62
One recently developed
and validated test is a simplified 60-second screening
test (video available at www.WoundPedia.com or
www.diabeticfootscreen.com;Fig 6).
62
Referral to
a foot specialist may prevent ulceration and
possibly decrease the risk of lower extremity
amputation.
Many specialists, including dermatologists, fre-
quently encounter patients with DM, and there is the
opportunity to screen these patients when they are in
the office for a routine visit. In fact, dermatologists
are more likely to survey a patient’s skin than any
other specialist and may have a special opportunity
to identify at-risk patients or early DFUs. Overall,
this screen can identify a large percentage of
persons with DMs at high risk of foot ulceration
and subsequent preventable lower limb amputa-
tion.
37,63-65
Several studies have shown that
amputation could be reduced by 40% to 85%
through the detection of high-risk patients and a
subsequent interprofessional approach that focuses
on preventive measures.
66-68
Screening may also detect foot ulcers and other
lesions that the patient is not aware of, including
blisters, calluses, fissures, tinea pedis, and ingrown
toenails.
62,67
Previous studies of persons with DM have
identified neuropathy, peripheral arterial disease
(PAD), a previous foot ulcer, or previous ampu-
tation as risk factors for developing a foot
ulcer.
14,69
Lavery et al
61
and Peters et al,
69
as
part of the IWGDF, identified the yearly
incidence ulceration rate. If a person has DM
and no other complication, such as neuropathy
or PAD, they have a 2% risk of developing a foot
ulcer. With neuropathy, the incidence increases
to 4.5% and with additional PAD to 13.8% annu-
ally. The incidence of foot ulceration is increased
32.2% 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 essential
component of diabetes care. It focuses attention
and provides a means to direct limited resources
to those patients most at risk of developing a DFU.
The approach to the cutaneous changes associated
with DM can be optimized when professionals work
toward a standardized plan.
CLINICAL PRESENTATIONS
The presence of a DFU is a consequence of
multiple factors and is not usually the result of a
single pathology.
Neuropathy
Key points
dIncreased plantar pressure resulting from
neuropathy is the major risk factor for
diabetic foot ulcers
dDiabetic neuropathy has 3 components:
sensory, autonomic, and motor neuropathy
dLoss of protective sensation can be
measured with a 10-g monofilament
(the SemmeseWeinstein monofilament test)
dAutonomic neuropathy causes dryness of the
skin, and motor neuropathy results in a claw
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 year
1 Sensory neuropathy 6-9% 0 Podiatry/chiropody every 6 months; over the
counter shoes and insoles
2 Sensory neuropathy and foot deformity
or peripheral vascular disease
8-17% 1-3% Podiatry/chiropody every 2-3 months;
therapeutic shoes and insoles; patient
education
3 Previous ulcer or amputation 26-78% 10-18% Podiatry/chiropody every 1-2 months;
therapeutic shoes and insoles; patient
education
Derived from Johnson et al
58
and Birke et al.
59
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toe deformity, loss of reflexes, and muscle
atrophy
dDiabetic sensorimotor polyneuropathy will
develop within 10 years of the onset of
diabetes 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 of
neuropathy and other factors, such as repetitive
unperceived trauma from excessive ambulation,
poorly fitting shoes, walking in stockings without
shoes, or walking barefoot, along with callus
formation over areas of increased pressure.
The 3 main mechanisms of injury are as follows
27
:
(1) footwear (ill-fitting shoes resulting in
low but prolonged pressure); (2) weight-bearing
(repetitive moderate pressure and friction or shear
forces that result in blister formation); and (3) trauma
(including penetrating injury, meaning high pressure
with a single or repetitive exposure of direct pressure).
The biomechanics of the foot are altered such that
the claw toe results in the metatarsal heads moving
close to the skin surface and the fat pads herniate
Fig 6. The 60-second screening tool. Continued on next page.
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upward, obliterating the space just below the toe
webs.
The resulting increased trauma from pressure
associated with calluses or friction/shear-
associated blisters (ie, vesicles, bullae, and
hemorrhagic bullae) leads to subsequent tissue
injury. Sensory neuropathy contributes to the lack
of perceived tissue injury (loss of protective
sensation).
26,70,71
Diabetic sensorimotor polyneu-
ropathy will develop sooner with poor glycemic
control, but often within 10 years of the onset of
diabetes in 40% to 50% of patients with type 1 or
type2DM.
72,73
The onset of diabetic neuropathy is insidious, and
many patients are unaware of the process. Although
neuropathy is associated with a loss of protective
sensation, neuropathic pain may decrease quality
of life. This pain may present spontaneously as
burning, stabbing, shooting, stinging, hyperesthesia,
or even allodynia (an increased response to normal
stimuli, such as light touch). This represents sensory
neuropathy, which is 1 of the 3 components of
neuropathy represented by the mnemonic SAM
(sensory, autonomic, and motor).
A thorough physical examination, including the
removal of shoes and socks, is a more reliable tool to
Fig 6. Continued.
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detect neuropathy than patient history. The physical
examination 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) SemmeseWeinstein
monofilament
34,71
and a 128-Hz tuning fork
for perception of vibration sensory stimuli. The
monofilament test is a simple bedside screening
test that has been widely used in clinical practice.
The inability to feel a 10-g (5.07) monofilament is a
sensitive predictor for neuropathy and ulceration.
74
With their eyes closed, the patient is asked if they
feel the monofilament while the monofilament is
placed against the intact skin (with no callus) and
allowed to buckle.
75
Most authors suggest testing 10
sites; the absence of sensation in 3 to 4 sites is
consistent with a loss of protective sensation.
76
Other techniques exist to detect sensory neuropathy,
including a simple prototype robotic monofilament
inspector that has been used to diagnose
neuropathy.
77
Neuropathy impairs the ability to perceive injury
because of a loss of protective sensation. Autonomic
neuropathy involves the sympathetic nervous
system and presents as anhidrosis with dry skin
and fissures that needs to be distinguished from
other causes of dry plantar skin. These changes must
be distinguished from fungal infection, because the
fourth and fifth web spaces are common areas for
fungal intertrigo while the plantar surface and the
sides of the foot are common areas for a moccasin
distribution. The nail changes include distal
streaking or more complete nail plate asymmetric
nail changes of fungal infections. Any patient with a
suspicion of fungal infection should have a potas-
sium hydroxide microscopic examination and/or
fungal culture to confirm the diagnosis. Because of
the increased risk for complications of bacterial
infection, the presence of superficial fungal infection
in patients with DM may lead to a greater risk for
associated bacterial infections.
Motor neuropathy can be detected with a loss of
ankle reflexes.
24,78
Motor neuropathy is tested with
ankle reflex, and a loss of reflexes is associated with
deformity, wasting of intrinsic muscles, and muscle
imbalance with cocked up toes.
Education for persons with DM regarding proper
foot care may help prevent DFU and amputations,
especially for those who are at high risk.
79,80
PERIPHERAL VASCULAR DISEASE
Key points
dDiabetic foot ulcers can be divided into
neuropathic, ischemic, and neuroischemic
foot ulcers, with the latter 2 having a less
favorable prognosis
dAssessment of the vascular status requires a
thorough history and physical examination;
however, definitive diagnoses require more
advanced, technical examinations
dA palpable pulse in the foot indicates a
pressure of at least 80 mm Hg; however, a
palpable pulse, especially in diabetes
mellitus (because of medial sclerosis) does
not exclude poor perfusion
dSegmental continuous wave Doppler exami-
nation and ideally toe pressure measure-
ment of the large toe (toeebrachial
pressure index) are regarded as the criterion
standard for the evaluation of limb
perfusion in persons with diabetes mellitus
dDuplex ultrasonography may aid in the
morphologic diagnosis of occlusions and
planning of interventions
dTranscutaneous oxygen tension measure-
ment may be of important value, especially
in patients with diabetic foot ulcers, because
it reflects oxygen supply to the end organ
(the skin) by macro- and microcirculation
dIschemic disease increases the risk for
limb loss. If vascular (ischemic) signs and
symptoms are present, refer immediately to
a vascular surgeon for proper testing and
possible revascularization
PAD is another important contributory factor in
DFUs. In some populations, PAD is present in [50%
of patients with DFUs.
81,82
DFUs can be divided into
3 main categories: diabetic neuropathic, diabetic
ischemic, and diabetic neuroischemic foot
ulcers (Table IV).
41,42
This ischemia represents
macrovascular disease. Individuals with ischemic
and neuroischemic foot ulcers have a poorer
prognosis, and vascular procedures are often
warranted.
83-88
Friction and trauma in an ischemic
foot can cause skin breakdown, especially when
complicated by infection (Fig 7).
The assessment of vascular status requires a
thorough history and physical examination,
including any history of previous PAD, intermittent
claudication, or rest pain (in persons with DM, often
not present because of neuropathy). Examination
for clinical signs should include the following:
inspection for pallor, dependent rubor, decreased
skin temperature, hair loss, atrophic shiny skin,
and palpation of the dorsalis pedis or posterior
tibial pulses. Although the physical examination
provides important qualitative information, the
sensitivity of the clinical tests is limited. The
absence of the dorsalis pedis pulse has a sensitivity
of 50%, a specificity of 73.1%, and a low positive
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predictive value of 17.7%.
89
In 8% of healthy
individuals, the dorsalis pedis is absent; the tibialis
posterior pulse is absent in 3% of cases.
90,91
A
palpable pulse in the foot represents the presence
of at least 80 mm Hg pressure.
92
However, a
palpable pulse does not rule out PAD, especially in
diabetic patients suffering from medial calcinosis
(abnormal deposition of calcium of the vessel
wall).
93
Generally, significant arterial disease is
most often excluded when the dorsalis pedis or
posterior tibial pulses are clearly palpable. The more
accurate technical tests to rule out PAD include
qualitative segmental Doppler waveforms or
quantitative 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 ankle
pressure could not be measured in 109 (41.8%)
patients because of occlusion of both tibial arteries
in 75 (28.7%) patients or because of the presence of
arterial calcification in 34 (13.0%) patients.
95
In
diabetic patients, the toeebrachial pressure index
(TBPI) is the screening test of choice rather than
ABPI because of the common occurrence of medial
calcinosis. However, in a recent study, it has been
shown 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 the
ABPI or the TBPI.
88
Therefore, color-coded Duplex
ultrasonography represents the criterion standard of
noninvasive vascular assessment once relevant PAD
is suspected and/or simple examination is not
possible.
Because of the presence of arteriovenous shunt-
ing, an ischemic foot might appear pink and
even warm in the presence of impaired perfusion.
There may be a localized arterial block; angiosomal
defects should be referred to a vascular surgeon.
Angiography can verify the real anatomic correlates
for nonhealing ulcers and assist in planning the
best intervention.
84-87
The foot can be divided into 6
anatomic regions corresponding to the 6 proposed
angiosomes.
75,76,84,87
A distinct source artery feeds
each angiosome.
84
Wounds may fail to heal because
of inadequate local vascular supply despite having
palpable pulses. Early referral to a vascular surgeon
or specialist is recommended for targeted primary
angioplasty following this angiosomal model and
can therefore improve clinical success.
86,87
Skin perfusion pressure is a good indicator of
lower extremity microcirculation.
96
Transcutaneous
oxygen tension reflects the amount of oxygen that
has diffused from the capillaries through the
epidermis to an electrode at the measuring site. It
provides instant, continuous information about the
body’s ability to deliver oxygen to the tissue. This test
is usually conducted in a vascular laboratory and has
recently been shown to be an indicator for critical
limb ischemia (CLI).
88
Faglia et al
88
concluded that if
diabetic patients presented with rest pain and/or foot
lesions, it is essential to measure the foot oxygen
tension for the diagnosis of CLI, and that this was true
not only when arterial pressure was not measurable
but also when arterial pressure was $70 mm Hg.
CHARCOT FOOT
Key points
dDiabetes mellitus is the most common cause
of Charcot deformity in the Western world
dCharcot foot may present with redness,
swelling, deformity, and increased foot
temperature
dIn the acute phase, differentiating Charcot
disease from cellulitis and the chronic phase
of osteomyelitis may be difficult
dNoneweight-bearing and immobilization
is the key treatment choice in the acute stage
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 of
toes and foot
Plantar and/or dorsal aspect of
toes and foot
Morphology Surrounding callus Punched out, black eschar Necrosis and callus
Pain Mild Severe Dull pain
Type of pain Neuropathic; sharp, stabbing,
or burning
Nociceptive and claudication;
dull pain or persistent sharp
pain
Combination of both
Callus 111 e11(1)
Bone deformity 111 e11(1)
Pulses Present Weak or absent Weak or absent
Skin temperature Warm Cool Cool
Surrounding skin Loss of sensation, callus Pallor, shiny, rubor, or pale; cool Both
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Charcot foot is a late complication of peripheral
motor neuropathy of any cause. Charcot foot results
from repetitive trauma to insensitive bones and joints
of the foot (Fig 8). DM is the most common cause of
Charcot deformity in the Western world and should
be considered in any patient who presents with a
warm swollen foot, even in the absence of
ulceration. A diagnosis of osteomyelitis is more likely
if there is ulceration, although both Charcot foot
and osteomyelitis can exist simultaneously.
97,98
Dislocation of bones and joints without a
preceding known trauma is the characteristic of
Charcot foot caused by long-standing diabetic
neuropathy.
99
Charcot foot may present as redness,
swelling, deformity, increased foot temperature, and
ulceration (Fig 9). In the acute phase of Charcot
disease, differentiating it from cellulitis and
osteomyelitis is difficult. Chronic osteomyelitis usu-
ally has an insidious presentation and is refractory to
treatment. The acute radiographic changes of
osteomyelitis include focal osteopenia and lucency
in the cortex or medullary bone, while chronic
changes may lead to the sequestration of dead
bone.
77
The differentiation of osteomyelitis from
osteopathy is difficult. The radiographic changes
of chronic osteopathy include fractures, bone
destruction, and periosteal new bone formation.
77
In the chronic phase of Charcot foot, deformity is
more predominant. The exact pathogenesis remains
to be determined. Multiple recurrent stress fractures
develop because of osteopenia. The expression of a
polypeptide cytokine (a specific receptor activator of
a nuclear factorekb ligand [RANKL]) has been
described as a possible mechanism for osteopenia
and neuropathy.
99-101
Inflammation mediated by the
release of proinflammatory cytokines also increases
osteolysis.
The healing process may last more than 6 to 9
months, during which the foot (without off-loading
and immobilization) usually becomes distorted and
turns into a ‘‘clinically visible’’ Charcot foot. The
resultant fixed deformity may include a rocker
bottom foot. The clinician should examine the foot
for abnormal contours and compare both feet to
monitor any differences in the bony contours. The
changes can be present in the forefoot, midfoot, hind
foot, or heel area as well as the ankle. Chronically,
these deformities lead to an increased susceptibility
to ulceration.
Fig 7. Diabetic neuroischemic foot. Minor trauma from
footwear led to gangrene of the fifth toe and tissue loss on
the laterodorsal surface of the foot. Without rapid arterial
revascularization, progression of gangrene and infection
will usually occur, resulting in below the knee amputation
or sepsis.
Fig 8. Charcot foot.
Fig 9. Charcot foot. Note the typical ‘‘rocker bottom
deformity,’’ with an ulcer at the area of maximal pressure
of the foot because of the loss of arch integrity.
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A high index of suspicion and early diagnosis
with appropriate diagnostics can play a key role in
management. A radiograph of the foot may be
useful, and the most commonly affected joints are
in the midfoot region (ie, the cuneiform/metatarsal
area). A swollen foot with increased temperature
and no ulcer in a patient with DM is most likely
a Charcot foot, but if there is an ulcer present,
osteomyelitis is more likely. Occasionally, both
conditions coexist.
A bone scan reveals increased blood flow and
bone intake. In limited cases, magnetic resonance
imaging or white cell scans aid in the differentiation
from osteomyelitis. Careful weight-bearing limitation
is imperative to stop the cycle of structural damage
and inflammation. Management includes using a
total contact cast, potential medical treatment
with bisphosphonates, and surgical management
of resultant deformity once the foot has been
stabilized.
102
Differential diagnosis
Although the vast majority of DFUs in diabetic
patients are caused by neuropathy, the differential
diagnosis includes traumatic ulcers, inflammatory
ulcers (vasculitis/ pyoderma gangrenosum), vascu-
lopathies, and malignancies. In 2 studies by Kong
et al,
103,104
7 cases of melanoma presenting as
foot ulcers have been reported. Acral melanoma
is frequently misdiagnosed and commonly
presents with amelanotic and ulcerated lesions.
105
Skin biopsy specimens will be diagnostic.
Nonmelanoma skin cancers (Fig 10) and metastatic
lesions may present as DFUs in patients with DM.
106
CLASSIFICATION OF DIABETIC FOOT
ULCERS
Key points
dThe MeggitteWagner classification is mainly
based on the wound depth and presence and
location of infection, with grades ranging
from 0 to 6
dThe University of Texas classification
categorizes wounds with 4 grades based on
the wound depth, presence of infection, and
presence of ischemia
Should an ulcer develop, clinical staging is
critical because it portends prognosis. One of the
most commonly used classification systems for
diabetic foot ulcers is the MeggitteWagner classifi-
cation. The system is primarily based on the wound
depth and presence and location of wound
infection, with grades ranging from 0 to 6. The
first 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) based
on the wound severity. Grade 0 represents a pre-
or postulcerative site. Grade I ulcers are superficial,
grade II ulcers penetrate to the tendon or joint
capsule, and grade III ulcers penetrate the bone or
into the joint. With each wound grade, there are 4
stages: nonischemic clean (A), nonischemic in-
fected (B), ischemic wounds (C), and infected
ischemic wound (D).
63,108
Various classification systems have been pro-
posed for DFUs, with no single universally
accepted system. In addition to the staging
systems listed above, the IWGDF has developed a
classification system for all ulcers according to the 5
categories of perfusion, extent/size, depth/tissue
Fig 10. A, Squamous cell carcinoma presenting as a foot
ulcer in a patient with a long history of diabetes.
B, Histopathology shows nests of atypical keratinocytes
within the dermis. (Hematoxylin-eosin stain; Original
magnification: X200.)
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loss, infection, and sensation (PEDIS).
64
Several
studies have shown a link between poor outcomes
and increased severity of disease (higher stage or
grade).
63
All 3 classifications are compared in
Table V. The University of Texas classification is the
classification that is most commonly used in wound
care clinics. While classification systems are
important and are focused on wound characteristics,
the anatomic location of a diabetic neuropathic or
ischemic ulcer can also relate to healing potential.
Forefoot wounds have a higher chance of healing
compared to more proximal wound locations.
Specifically, heel region ulcers are associated with
higher amputation rates and a greater difficulty in
healing.
107
CONCLUSION
Diabetic 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 are
the main factors contributing to the development of
DFU. Early recognition of the high-risk foot is
imperative to decrease morbidity and mortality
associated with amputations. An interprofessional
approach (ie, physicians, nurses, and foot care
specialists) can support patients and their circle of
care. The management of DFUs will be further
addressed in part II of this continuing medical
education article, where we will review the role
of 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.
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 superficial
ulceration
Grade I-C—Ischemic, noninfected superficial
ulceration
Grade I-D—Ischemic and infected superficial
ulceration
Perfusion
Grade 1—Superficial ulcer involving the full
skin thickness but not underlying tissues
Extent/size
Grade 2—Deep ulcer, penetrating down to
ligaments and muscle, but no bone
involvement or abscess formation
Grade II-A—Noninfected, nonischemic ulcer
that penetrates to capsule or bone
Grade II-B—Infected, nonischemic ulcer that
penetrates to capsule or bone
Grade II-C—Ischemic, noninfected ulcer that
penetrates to capsule or bone
Grade II-D—Ischemic and infected ulcer that
penetrates to capsule or bone
Depth/ tissue loss
Grade 3—Deep ulcer with cellulitis or abscess
formation, often with osteomyelitis
Infection
Grade 4—Localized gangrene Grade III-A—Noninfected, nonischemic ulcer
that penetrates to bone or a deep abscess
Grade III-B—Infected, nonischemic ulcer that
penetrates to bone or a deep abscess
Grade III-C—Ischemic, noninfected ulcer that
penetrates to bone or a deep abscess
Grade III-D—Ischemic and infected ulcer that
penetrates to bone or a deep abscess
Sensation
Grade 5—Extensive gangrene involving the
entire foot
PEDIS, Perfusion, extent/size, depth/tissue loss, infection, and sensation.
JAMACAD DERMATOL
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Alavi et al 1.e15

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 in Ontario,Canada. Can J Diabetes 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
JAMACAD DERMATOL
JANUARY 2014
1.e16 Alavi et al

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 e2010. 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.
JAMACAD DERMATOL
VOLUME 70, NUMBER 1
Alavi et al 1.e17

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.
JAMACAD DERMATOL
JANUARY 2014
1.e18 Alavi et al