The Diabetic Foot: An Overview of Prevention and Treatment

THE DIABETIC FOOT:
AN OVERVIEW
September 2004
Andrew J M Boulton MD, DSc (Hon), FRCP
Professor of Medicine, University of Manchester
Consultant Physician, Manchester Royal
Infirmary, Manchester, UK.
Professor of Medicine, University of Miami,
Miami, Fl, USA

AN EXPERT
‘An expert is someone who
comes a long way
- and brings slides’
Henry Miller

A SPECIALIST
‘A Specialist is a man who
knows more and more about
less and less’
William Mayo

‘Mind like parachute –
Does not work if not
open.’
Charlie Chan

Diabetic foot care is the PITS:-
Prevention
Identification
Treatment
Service

THE DIABETIC FOOT:
Two decades of progress
1986: First Malvern Diabetic Foot Meeting
1987: Foot Council of ADA formed
1991: First International Diabetic Foot Meeting
1998: Diabetic Foot Study Group of EASD
founded
1998: Japanese and Alfadiem symposia on the
foot
1999: International Consensus group publishes
Guidelines on management

THE DIABETIC FOOT: no longer the
Cinderella of diabetic complications
Publications listed on Medline on the
diabetic foot / total diabetes publications
1979-1988: 0.7%
1989-1996: 1.4%
1997-2003: 2.7%

INTERNATIONAL MEETINGS ON THE
DIABETIC FOOT
1991 First meeting – 250 delegates
1995 Second meeting – 450 delegates
1999 Third meeting – 600 delegates
2003 Fourth meeting – 700 delegates

‘Diabetes itself may play an active
part in the causation of perforating
ulcers…….
..And it is abundantly evident that the
actual cause of the perforating ulcers
was a peripheral nerve degeneration

Paul Brand CBE, MD, FRCS
1914-2003
• The Gift of Pain
• Pain: the Gift nobody wants
• Surgeon and missionary: worked in
leprosy and diabetes
• He took the foot from art to science

Paul Brand CBE, MD, FRCS
1914-2003
• THE ART:
‘Remove the patient’s shoes and socks and
look at the feet’
• THE SCIENCE
Classic studies of the relationship between
pressure, time and ulceration in the canine
hind-limb

The Diabetic Foot
• Epidemiology
• Causal pathways
• Reducing foot pressures
• Charcot Foot
• Wound healing
• International perspective

AMPUTATIONS IN DIABETES: TRENDS 1995-2000
• US data: steady increase in major amputations
• UK: 50% increase in one health care district
• Germany: no evidence of decrease
• Sweden: 78% decrease in amputations
CDC, 1997
Anonymous, 1997
Stiegler et al, 1998
Larrson et al, 1995
Trautner et al, 2001

Prevalence of Foot Ulcers and
Amputations
in Diabetes
Prevalence
Author Yr Country Ulceration Amputation
Borssen 1990 Sweden 0.75%
Moss 1992 USA 3.6%
Kumar 1994 UK 1.4%
Carrington 1996 UK 4.8% 1.4%
Vozar 1997 Slovakia 2.5% 0.9%
Pendsey 1994 India 3.6% -
Van Rensbe 1995 S. Africa 11.2% -
U-Roven 1998 Slovenia 7.1% -
Belhadj 1998 Algeria 11.9% 6.7%

THE PAIN OF NEUROPATHY
‘Of a burning and unremitting
character’
F W Pavy, 1887

PAINFUL NEUROPATHY
‘I don’t like peripheral neuritis -
it interferes with work’
R D Lawrence, 1923

DIABETIC NEUROPATHY: PREVALENCE.
• UKPDS showed that >10% of patients had neuropathy
at the diagnosis of Type 2 diabetes
• Neuropathy may be asymptomatic in over 50% of
subjects.
• UK Community study of Type 2 patients (n=811),
mean age 65 yrs.
* 41.6% clinical evidence of neuropathy
* 11% peripheral vascular disease
• Over 50% of older Type 2 patients have risk factors
for foot ulceration
Kumar at al: 1994
UKPDS, 1998

Risk Factors for Neuropathy
in UKPDS
Irene M Stratton, Rury R Holman,
Andrew JM Boulton
for the UKPDS group

Background to UKPDS
• A multicentre, randomised clinical trial of therapies
in patients with newly diagnosed Type 2 diabetes
• 5,102 subjects, mean age 53 years
• Trial period 1977-1997
• Recruitment ended in 1991 with main study results
in 1998
• No sustained difference was seen in indices of
neuropathy between allocated treatment policies

Measures of neuropathy
• Patients were assessed at entry to the study,
and then every three years for:-
• vibration perception threshold (VPT)
• absence of one or both ankle reflexes
• erectile dysfunction (ED)

Aims
• To examine prevalence and incidence of new
neuropathy we examined:-
• Age
• Gender
• HbA1c
• Height
• Waist circumference
• Alcohol consumption
• Smoking status
• Weight

Vibration Perception
Threshold
• Biothesiometer used to assess VPT
at the lateral malleoli and at apex of
great toes
• Abnormal VPT defined here as
mean value for great toes >25 volts

Relative risk for VPT
in great toes >25
12.8% prevalence at diagnosis
______________________________________________________________________________________________________________________________________________________
__________
Age (per 5 years) 1.89 (1.73 to 2.07)
Height (per 5 cm) 1.40 (1.32 to 1.50)
Waist (per 5 cm) 1.05 (1.01 to 1.10)
13.3% incidence at 12 years
______________________________________________________________________________________________________________________________________________________
__________
Age (per 5 years) 1.58 (1.44 to 1.73)
Female 0.56 (0.44 to 0.70)
HbA1c (per 1%) 1.07 (1.01 to 1.14)

Years from entry
Age at entry
VPT in great toes >25
by age
0
10
20
30
40
50
60
70
0 3 6 9 12
Proportionwithevent(%)
<50 50-59 60+
Point prevalence at 12 years
37%

Conclusions
• The risk factors for these 3 indices of neuropathy
were similar for prevalent cases at diagnosis and
for subsequent incident cases
• For prevalence the most important risk factor was
age, but HbA1c, height, waist circumference and
alcohol were also significant
• For incidence age was the most important factor,
again height, HbA1c and measures of obesity were
important
• Twelve years from diagnosis 71% of men and 51%
of women have at least one of these indices of
neuropathy

Does Neuropathy Lead to
Ulceration? A Prospective
Study
–469 diabetic patients screened in 1988
–Vibration perception assessed by
biothesiometry
–All foot ulcers recorded
Young et al, Diabetes Care 1994;17:557

Prospective Foot Ulcer Study
Results — Foot Ulcers
VPT<15 VPT 16-24 VPT>25
Total ulcers 1988-92 6 2 41
Risk per patient 2.9% 3.4% 19.6%
Risk/patient/year 0.7% 0.9% 4.9%

Causal Pathways for Foot
Ulceration
• Neuropathy most important component
cause (78%)
• Critical triad: neuropathy, deformity,
and trauma present in 63%
• Ischemia component cause in 35%
• >80% of ulcers potentially preventable
Reiber, Vileikyte et al, 1999.

The Most Common Causal
Pathway to Incident Diabetic
Foot Ulcers

FOOTWEAR
• Controlled evidence for reduction of
recurrent ulceration
• evidence for footwear as part of
multidisciplinary approach
Uccioli et al, D.Care 1995; 18: 1376
Dargis et al, D. Care 1999; 22: 1428
Faglia et al, D. Care 2001; 245: 78

Predicting Neuropathic
Foot Ulcer Risk
• North West Diabetes Foot Care
Study (NWDFCS)
• Population-based prospective
study in NW UK – 6 health-care
districts
• 16,000 patients included in total
• First study on 9,710 diabetic
patients
Abbott et al, Diabetic Med
2002;19:377

NWDFCS: THE NDS
• 3 sensory modalities
Vibration (128 Hz tuning fork – hallux)
Pin-prick (Neurotip): dorsal distal hallux
Hot/cold rods : dorsal distal hallux
ALL: normal = 0, abnormal = 1
Ankle reflex: normal = 0, absent = 2,
reinforcement = 1
MAX TOTAL 5 each leg: =10
Abbott et al, 2002

NWDFCS: Results
• 9710 diabetic patients followed for 2 years
• 291 ulcers developed:
male to female: 1.6:1.0
• NDS best baseline predictor
NDS < 6: 1.1% annual ulcer incidence
NDS > 6: 6.3% annual ulcer incidence
Abbott et al, 2002

Foot Pressure Studies in
Diabetic Neuropathy
• High foot pressures associated with first and
recurrent plantar neuropathic ulcers
• Foot Pressure abnormalities precede the
appearance of neuropathy
• High foot pressures predict ulcers
• Plantar callus associated with high pressure
and predicts ulcer formation
Boulton et al, 1983, 1984, 1985,1986.
Veves et al, 1992.
Murray et al, 1996

Semi-Quantitative Foot
Pressure Assessment
• Podotrack (PressureStat): a dynamic
pressure print map system
• Inexpensive, easy to use in clinic or at home
• Validated by comparison with optical
pedobarograph
• All high pressure sites correctly identified by
trained observers
Van Schie et al: Diabetic Med 1999;16:154

‘Coming Events cast
their shadows before.’
Thomas Campbell

Reducing Foot Pressures
• Orthoses
• Padded Hosiery
• Removing callus
• Footwear
• Surgery
• Injected liquid silicone
Lavery et al, 1998
Veves et al, 1989, 1990
Young et al, 1992
Murray et al, 1996
Van Schie et al, 2001, 2002

Diabetic Foot 2000
• First randomized controlled trial
• Podosil/saline injected under callus
at high pressure areas
• Podosil: Increased plantar tissue
thickness: reduced pressures
• This treatment may reduce ulcer
rates in high risk patients
Van Schie et al, Diabetes Care
2000;23:634
New Treatment
Does injected liquid silicone reduce ulcer risk?

Silicone Injection in the
High Risk Diabetic Foot

Diabetic Foot Ulcer Prevention
• Who responds best to silicone?
• Podosil: Increased plantar tissue
thickness greatest in those with
highest baseline foot pressure
• Those at highest risk of foot
ulceration most likely to benefit
from silicone injection.
Van Schie et al, Wounds 2002;14:26
Potential New Treatment
Does injected liquid silicone reduce ulcer risk?

Diabetic Foot 2002
• Two year follow-up study
• Podosil/saline injected under callus
at high pressure areas
• Two year fu: pressure reduction
effects of ILS reduced: plantar
tissue thickness remained
increased
• This suggests that booster
injections may periodically be
required.
Van Schie et al, Arch Phys Med
Rehabil 2002;83:919-923
Injected Liquid Silicone (ILS)
Does silicone’s pressure reducing effect last?

Classification of Diabetic Foot
Ulcers
• Wagner Grades: 0-5: classical,
most frequently quoted
• San Antonio: Wagner Grades and
staging for ischaemia/infection
• Nottingham S(AD), SAD system
• King’s College SSS: Stages 1-6
Armstrong et al, 1998
Jeffcoate et al, 1999
Foster et al, 2000

UT Diabetic Wound Classification
System
0 1 2 3
A
Pre or
postulcerative
lesion
(epithelialized)
Superficial, not
involving
tendon, capsule
or bone
Penetrates to
tendon or
capsule
Penetrates to
Bone
B
INFECTION INFECTION INFECTION INFECTION
C
ISCHEMIA ISCHEMIA ISCHEMIA ISCHEMIA
D
INFECTION and
ISCHEMIA
INFECTION and
ISCHEMIA
INFECTION and
ISCHEMIA
INFECTION and
ISCHEMIA
Armstrong, et al, Diabetes Care, 1998Armstrong, et al, Diabetes Care, 1998

• 2 centre prospective observational
study
• 194 patients followed for 6 months
• Inclusion of stage (ischaemic
and/or infection) made San
Antonio (UT) system a better
predictor of outcome
Oyibo et al, Diabetes Care 2001;24:84
San Antonio vs Wagner
classifications in wound
healing prediction

Factors Affecting
Wound Healing

Some Factors That May
Influence Wound Healing
• Albumin concentration
• TCpO2 concentration
• Infection
• Hyperglycaemia
• Cytokine imbalance
• Protease and inhibitor imbalance
• Psychological stress

TGF-β distribution in Diabetic
Foot Ulcers
• TGF-β 1,2 and 3 and TGF-β receptor
distribution in foot ulcers compared with
diabetic and non-diabetic skin
• TGF-β 3 expression was increased in foot
ulcer biopsies
• TGF-β 1 expression not increased in foot
ulcers
• Lack of TGF-β1 upregulation may explain the
chronicity and retarded wound healing
Jude et al, Diabet Med 2002;19:440

NS DS DFU AG
TGF β1
TGF β2
TGF β3
Transforming growth factors in diabetic foot ulcers

Lack of IGF1 in Diabetic Foot
Ulcers
• IGF 1 & 2 distribution in foot ulcers compared
with diabetic and non-diabetic skin
• IGF 2 found throughout epidermis in all three
groups
• IGF 1: absent in basal layer at ulcer edge and
in fibroblasts
• Lack of expression of IGF1 may contribute to
retarded wound healing
Blakytny et al, J. Pathol 2000;190:606

Matrix metalloproteinases in
Diabetic Foot Ulcers
• Punch biopsies from 20 DFUs and 12 non-
diabetic traumatic wounds
• MMPs 1 (x65), 2 (x6), 8(x2) and 9(x14) all
increased in chronic DFUs compared to
controls
• Expression of TIMP-2 decreased twofold in
DFU
• These findings suggest that the increased
proteolytic environment may be contributory to
the chronicity of DFUs.
Lobmann et al, Diabetologia 2002;45:1011

Psychological stress and wound
healing
• Anxiety/depression more common in DN: may
impact adherence to off-loading
Vileikyte et al, 2003
• Psychological stress slows healing of acute
wounds
Kiecolt-Glaser et al 1995
• Chronic stress can lead to increased IL-6 and
altered MMP levels
Yang et al 2002,, Kiecolt-Glaser et al
2003

Factors That Enhance Wound
Healing
Correct underlying condition
• Control infection
• Vascular reconstruction for patients with
severely compromised peripheral circulation
• Adequate glycaemic control for patients
with diabetes
• Off-load pressure
• Maintain moist wound healing environment

Factors That Enhance Wound
Healing (continued)
Adequate debridement
– Removes infected and non-viable tissue
– May stimulate release of endogenous
growth factors

Effect of Debridement on
Healing of Diabetic Foot
Ulcers
Steed, et al.Steed, et al. J Am Coll SurgJ Am Coll Surg 1996;183:61-64.1996;183:61-64.
100
80
60
40
20
0
20 40 60 10080
PatientsHealed(%)PatientsHealed(%)
*100 µg rhPDGF-BB per gram sodium*100 µg rhPDGF-BB per gram sodium
carboxymethylcellulose gel.carboxymethylcellulose gel.
Office Visits at which debridementOffice Visits at which debridement
was performed (%)was performed (%)
rhPDGF-BB*rhPDGF-BB*
PlaceboPlacebo

Common Methods toCommon Methods to
“Off-Load” the Foot“Off-Load” the Foot
• Bed Rest
• Wheel Chair
• Crutch Assisted Gait
• Total Contact Casts
• Felted Foam
• “Half Shoes”
• Therapeutic Shoes
• Custom Splints
• Removable Cast
Walkers

Total Contact CastTotal Contact Cast
Advantages
• Forced compliance
• Shortens stride
length
• Decrease cadence
• Reduces activity
• Reduces peak
pressures

Offloading the DM Wound
Week of therapy
121086420
CumulativeSurvival
1.2
1.0
.8
.6
.4
.2
0.0
Device
TCC
Half Shoe
Aircast
Armstrong, et al, Diabetes Care, 2001Armstrong, et al, Diabetes Care, 2001

Activity Patterns of Persons with Diabetic Foot
Ulceration: Persons with Active Ulceration may not
Adhere to a Standard Pressure-Offloading
Regimen
DG Armstrong
LA Lavery
HR Kimbriel
BP Nixon
AJM Boulton
From the Department of Surgery, Southern Arizona
Veterans Affairs Medical Center, Tucson, AZ, USA, the
Department of Medicine, Manchester Royal Infirmary,
Manchester, United Kingdom, the Department of Surgery,
Texas A&M University, and the Department of Medicine,
University of Miami, Miami, FL, USA

Introduction
• Pressure-offloading is a critical component in
treating plantar diabetic foot wounds
• Gait lab plantar pressure analysis
demonstrated total contact casts (TCC)
equivalent to removable cast walkers (RCW)
• Yet TCCs have been shown to be clinically
superior to RCWs
Armstrong, et al, Diabetes Care, 2001
Frykberg, et al, J Foot Ankle Surg, 2000
Lavery et al, Diabetes Care, 1996

Purpose
• To evaluate the activity of persons with
diabetic foot ulcerations and their
adherence to their pressure offloading
device.

Methods
• 20 persons were treated for UT
Grade 1A neuropathic diabetic
foot wounds
• All were offloaded utilizing a
removable cast walker (RCW)
• Total activity was recorded
(measured in activity units or
steps per day) taken on a waist-
worn computerized
accelerometer
• We subsequently correlated this
to activity recorded on a RCW-
mounted accelerometer, which
was not readily accessible to the
patient

Results
• There were a mean 1219.1 ±
821.2 activity units (steps)
taken per patient per day
• Patients logged significantly
more daily activity units with
the protective removable
cast walker off than with it on
(873.7 ± 828.0 vs. 345.3 ±
219.1, p = 0.01)
• This amounts to only 28% of
total daily activity recorded
while patients were wearing
their removable cast walker
* p = 0.01

Conclusion
Armstrong, et al, J Amer Podiatr Med Assn, 2002Armstrong, et al, J Amer Podiatr Med Assn, 2002
• Modify RCW to make it less easily
removable
– “Instant” total contact cast

‘Instant Total-Contact Cast’
vs TCC: controlled trial
• TCC ‘gold standard’ but labor-intensive,
expensive and time-consuming
• 2 trials in progress
• a): TCC vs Instant TCC
• b): Instant TCC vs Cast walker
Boulton and Armstrong , 2003

‘Instant Total-Contact Cast’
vs TCC: controlled trial
• Randomized controlled trial: 38 plantar
neuropathic ulcer patients randomized to
instant or regular TCC
• No differences in healing times observed
• Instant TCC quicker to apply and cheaper for
the duration of treatment
• Any center can apply instant TCC without
casting experience
• This treatment could revolutionize the
management of plantar neuropathic ulcers
Katz et al , Diabetes 2004 (In

Studies of new therapies
for neuropathic foot ulcers:
time for a paradigm shift?
• Why have so many trials of dressings and
other new therapies failed?
• Few if any have attended to offloading
• Conclusions: we propose that all future trials
of therapies for plantar neuropathic ulcers
should have standardized offloading in all
treatment groups
Boulton and Jude, 2002,
Boulton and Armstrong,
2003, 2004

The effect of pressure relief
on the histopathology of
diabetic foot ulcers
• Randomized trial of patients with chronic
plantar diabetic neuropathic ulcers
• Group A: TCC for 20 days then ulcerectomy
Group B: Ulcerectomy
• Histological changes compared between the
two groups
Piaggesi et al, 2002, 2003

Histological Results
Hyperkeratosis 1.8 2.8 p<0.002
Fibrosis 1.8 2.8 p<0.007
Capillaries 2.5 0.5 p<0.001
Inflammation 1.1 3.0 P<0.001
Granulating 2.8 0.2 p<0.001

Effective offloading: histologic
evidence
Piaggesi, et al, Diabetes Care, 2003Piaggesi, et al, Diabetes Care, 2003
Removable offloadingRemovable offloading Irremovable offloadingIrremovable offloading

The effect of pressure relief on
the histopathology of diabetic
foot ulcers:
Conclusions
• Pressure not only has a direct effect on the
ulcer but also supports the chronic
inflammation
• After pressure relief, the diabetic foot ulcer in
many ways resembles an acute wound
• Prolonged repetitive pressure contributes to
the chronicity of diabetic neuropathic foot
ulcers
Piaggesi et al, 2002, 2003

Summary
• Wound healing in diabetes is impaired
• Multiple factors are impaired in diabetic
wound healing
• Cellular differences noted between
acute and chronic wound healing
• Failure to offload pressure from plantar
neuropathic ulcers is a major
contributory factor in ulcer chronicity

The future….
• Better understanding of the wound
healing process in diabetes is needed
• Possibly cocktail of GFs / TIMPs?
• Gene expression in chronic wound
healing
• Gene therapy of wound healing in the
not too distant future?

The future….
• Role of bone marrow-derived cells?
Preliminary evidence suggests that they can lead to
dermal rebuilding
Badiavas & Falanga, 2003
• Role of Oestrogen?
Oestrogen can enhance wound healing, possibly
through down-regulation of macrophage MIF
Ashcroft et al 2003
• Role of Androgens?
Testosterone inhibits cutaneous wound healing
response in males
Ashcroft &
Mills 2002

‘To live in one land
is captivity’
J. Donne

Save the diabetic foot project
Brasília, Brazil
1992-2002
(A ten year educational approach
to make professionals concerned
about foot problems and motivate
the implementation of foot
clinics)

Diabetic Foot
Clinics:
Implementation
in Brazil - 1992 Brasília

Diabetic Foot Clinics*
1992/2001
Implemented - 34
In implementation – 10
Total = 44
* outpatient basis

0
1
2
3
4
5
6
7
8
1992 1993 1994 1995 1996 1997 1998 1999 2000
DM - Female
DM - Male
Major amputation (1992/2000)
Female: 2.67±
1.72
Male: 1.11 ±
0.71
ns
Rate reduction
(92-94 / 98-00)
Female = 71,42%
Male = 50%

For one mistake made for
not knowing, ten mistakes
are made for not looking.
J A Lindsay

“Before I came to this lecture, I was
confused.
After hearing it I am still confused,
but on a higher level”
Enrico Fermi

“...It ought, however, to be remembered,
that more credit is due to the surgeon
who saves one limb, than to he who
amputates twenty.”
Edinburgh Med Surg J. 1805;1:187-193.

‘ Do not follow where the
path may lead,
go instead where there is
no path, and leave a trail ’
Anon

Inferior physicians treat the
full-blown disease
Good physicians treat the
disease before it appears
Superior physicians prevent
the disease
Chinese proverb

I hear and I forget
I see and I remember
I do and I understand
Chinese proverb

‘The surest way not to
fail is to be determined
to succeed’
R. Sheridan

‘If you always do what
you always did..
You will always get
what you always got
Liam Donaldson

Success consists of going
from failure to failure –
without loss of enthusiasm
Winston Churchill

‘Prediction is always
difficult – especially
when it concerns the
future.’
Wilde

The old believe everything
The middle-aged suspect
everything
The young know everything
Oscar Wilde

The truth is rarely
pure and never simple
Oscar Wilde

An ulcer is only a
symptom of an underlying
diathesis
Swartz, 1910

International Guidelines on the
Outpatient Management of
Patients with Peripheral
Neuropathy

Annual Review of the Diabetic
Patient
• Should include:
– Patient history
• Age diabetes, lifestyle,
social circumstances
symptoms
– Foot examination
• Skin status, sweating,
infection, blistering,
joint mobility, gait,
shoes
• Tests
– Pin prick test
– Light touch
– Vibration test
– Pressure perception
– Ankle reflex

I marvel that society would pay
a surgeon a large sum of
money to remove a person’s
leg — but nothing to save
it.
George Bernard Shaw

ConclusionConclusion
“If you don’t know where you’re
going, you’ll end up someplace
else.” -Yogi Berra

“The art of life is the art of
avoiding pain; and he is the
best pilot, who steers clearest
of the rocks and shoals with
which it is beset.”
Thomas Jefferson

Use of Apligraf (Graftskin) in
diabetic foot ulcers
• Randomized trial in 208 patients
• Graftskin vs saline gauze + standard
treatment
• 56% (Graftskin) vs 38% (control)
healing (p=0.004)
• Time to closure 65 vs 90 days
• Graftskin is a useful adjunct to best
standard care
Veves, Falanga, Armstrong, Sabolinski, Diabetes Care, 2001

A Study of Promogran in
Diabetic foot ulceration
• Randomized, 11 centre trial: 276 subjects,
neuropathic plantar ulcers, 12 week study
• Promogran vs. moistened gauze
• Offloading constant in each centre, but
technique ‘left to individual’
• Results: 37% Promogran healed vs 28%: ns
• Conclusions: Promogran safe and may be
useful for neuropathic ulcers!
Veves et al, Arch Surg 2002;137:822

Results
• 30% of the patients in the study
recorded more daily activity units while
wearing the device (best behaved)
– still only wore the device for a total of 60%
of their total daily activity

Camillo Golgi, 1898
• On the structure of nerve cells
• On the structure of the nerve cells of the
spinal ganglia
Golgi, Arch Ital Biol,
1898

PAIN
‘I shall never be free until I can
feel pain’
Leprosy patient in Madras:
cited by Dr Paul Brand

‘If I were to choose
between pain and
nothing ….. I would
choose pain’
William Faulkner

InflammationInflammation
Proliferation/Proliferation/
RegenerationRegeneration
RemodellingRemodelling
WoundWound
HealingHealing
Phases of Wound Healing

Inflammation Phase
InjuryInjury
Clot FormationClot Formation
(platelet aggregation)(platelet aggregation)
Release of chemotactic agentsRelease of chemotactic agents
(platelet degranulation)(platelet degranulation)
Orderly recruitment of cellsOrderly recruitment of cells
into wound siteinto wound site

Cell Influx Into Wound Site1
1. Pierce, et al1. Pierce, et al J Cell BiochemJ Cell Biochem 1991;45:319-1991;45:319-
NeutrophilsNeutrophils
MacrophagesMacrophages
FibroblastsFibroblasts
00 22 44 66 1414 2828 4242
Days Post-InjuryDays Post-Injury
88 1010

Wound Healing Cascade
Early CascadeEarly Cascade Late CascadeLate Cascade
PMNsPMNs
MacrophagesMacrophages
FibroblastsFibroblasts
Granulation TissueGranulation Tissue
Wound StrengthWound Strength
AutocrineAutocrine
AutocrineAutocrine
GFs PDGF TGF-ß1GFs PDGF TGF-ß1
PDGF-AA TGF-ß1PDGF-AA TGF-ß1
Procollagen 1Procollagen 1
Extracellular MatrixExtracellular Matrix
55 1010 151500
WoundingWounding
((DaysDays))

CONCLUSIONS
• Possible future studies with higher
doses
• Use of oral bisphosphonates?
• Earlier diagnosis essential
• Better diagnostic markers
• Do not forget the words of Dr Jean-
Martin Charcot ……………………….

CHARCOT NEUROARTHROPATHY
How often have I seen persons, not yet
familiar with this arthropathy,
misunderstand its real nature, and wholly
preoccupied with the local affection, even
absolutely forget that behind the disease
of the joint there was a disease far more
important in character and which really
dominated the situation
J M Charcot 1881

Chronic Non-healing Wounds
• Chronic non-healing wounds occur
when the normal healing process is
compromised
• Ultimately, chronic wounds may fail to
heal because of decreased growth
factor activity or increased protease
activity, or both

Roles of Growth Factors
in Wound Healing
• All three phases of wound healing
• Chemotaxis
• Mitogenesis
• Stimulate angiogenesis
• Influence synthesis and degradation
of extracellular matrix
• Influence synthesis of other
cytokines and growth factors

Nitric oxide in wound healing
• NO is important in the wound healing
Moncada 1991, Schaffer 1997
• Reduced NO production may impair
wound healing
Schaffer 1997, Boykin 1999
• NO and other nitrogenous free radicals
(superoxide, peroxynitrite) cause tissue
destruction
Radi 1991, Beckman 1990

Nitric Oxide Synthase and
Arginase in Diabetic Foot Ulcers
• L Arginine metabolized by NO synthase or
Arginase
• Enzyme activity measured in foot ulcers, diabetic
and normal skin
• NO synthase and Arginase activities increased
in foot ulcers. TGF beta 1 decreased in foot
ulcers
• These findings could explain impaired healing: ?
Arginase effect on callus
Jude et al, Diabetologia 1999;42:748

Adjunctive Wound Healing
Modalities
• Bioengineered Tissue
• Growth Factors
• Hyperbaric Oxygen
• Vacuum-assisted therapy
• Larvatherapy
• Antibiotic-impregnated beads

“In God we trust.
…all others must show data”
anon

Cultured Human Dermis
(Dermagraft)
31.7
38.5
50.8
0
10
20
30
40
50
60
Control (n =
126)
Cultured
Human Dermis
(n = 109)
Cultured
Human Dermis
TR (n = 61)
%Healedin12Weeks%Healedin12Weeks
Pollack,et. al. Wounds, 1997Pollack,et. al. Wounds, 1997

MANCHESTER
Loretta Vileikyte
Caroline Abbott
Frag Abouaesha
Gillian Ashcroft
Anne Carrington
Peter Cavanagh
Cuong Dang
Mark Ferguson
Devaka Fernando
Nicky Jackson
Ed Jude
Evangelos Katoulis
Ann Knowles
Sudhesh Kumar
Rayaz Malik
Ewan Masson
Sam Oyibo
Y Prasad
Anne Roscoe
Peter Selby
Nick Tentolouris
David Tomlinson
Steve Tomlinson
Carine Van Schie
Aris Veves
Matthew Young

United Kingdom
SHEFFIELD
John Ward
Bill Armstrong
Rick Betts
Chris Franks
Colin Hardisty
Graham Knight
Paul Newrick
John Scarpello
Solomon Tesfaye
ELSEWHERE
Paul Baker
Nish Chaturvedi
Henry Connor
Mollie Donohoe
Mike Edmonds
Ali Foster
Simon Page
PK Thomas
Bob Young

USA
MIAMI
Jay Skyler
John Bowker
Rick Cutfield
F Collado-Mesa
B Miranda-Palma
Mark Mizel
Jay Sosenko
ELSEWHERE
David Armstrong
Peter Cavanagh
Larry Harkless
Larry Lavery
Ben Lipsky
Mark Peyrot
Gary Pittenger
Gayle Reiber
Richard Rubin
Jan Ulbrecht
Arthur Vinik

THE WORLD
BELGIUM
Kristien Van Acker
BRAZIL
Hermelinda Pedrosa
GERMANY
Dan Ziegler
GREECE
Nicolas Katsilambros
Evangelos Katoulis
Christos Manes
Nicolas Tentolouris
Dimitris Voyatzaglou
ITALY
Guido Menzinger
Luigi Uccioli
LITHUANIA
Vytas Dargis
Vladimir Petrenko
NETHERLANDS
Karel Bakker
AUSTRALIA
Jonathan Shaw

DifferenDifferencesces in cellular infiltratein cellular infiltrate
between acute and chronicbetween acute and chronic
wounds?wounds?
• Cross-sectional study in acute
wounds vs. venous and diabetic
ulcers
• ECM molecules and cellular
infiltrates compared
• Prolonged presence of ECM
molecules noted in dermis of
chronic ulcers
• Decreased CD4 T cells, increased
B cells and macrophages in
chronic ulcers
Loots et al, J. Invest Dermatol, 1998;111:850

““EpidemiologyEpidemiology
is what you dois what you do
when you run outwhen you run out
of ideas”of ideas”
J.D.WardJ.D.Ward

Ethnicity and foot ulceration
and amputations
• Diabetic foot ulcers much less common
amongst Indian sub-continent Asians in the
Manchester area
Toledano et al, 1995
• Amputations 4x more common in Europids
compared to Asians in NW UK
Chaturvedi, Abbott et al, Diab Med 2002;19:99
• Ethnicity and Diabetic Neuropathy
Ongoing study in NW UK supported by Diabetes UK
Abbott, Chaturvedi et al, 2004

DIABETIC NEUROPATHY
‘PAIN – God’s greatest gift to mankind’
Paul Brand

Future MeetingsFuture Meetings
2nd
International Meeting on Chronic
Wounds: WUWHS meeting, Paris,
France, July 8 – 13th
2004
Cleveland Clinic International Meeting on
the Diabetic Foot, 2005
11th
Malvern Diabetic Foot Meeting,
May 2006

Charcot Foot
• Common in neuropathic patients
• frequently mis-diagnosed
• treatable if diagnosed early
• suspect in neuropathic patient with
warm, swollen foot
• AN UPDATE 2004

• Neuropathy - sensory/autonomic
• Increased blood flow
• Arteriovenous shunting
• Reduced BMD / Osteoporosis
• ?Osteoclast activation/bone resorption
Pathogenesis
• Trauma

1. To reduce disease activity
2. To achieve a stable joint
3. To reduce deformity
Treatment Goals

Treatment
• Casting
• Non-steroidals
• Immobilisation
• Radiotherapy
• Extra-depth shoes
• Pharmacotherapy
• Surgery

Pamidronate in Charcot
• Open-labelled trial
• 6 patients with acute CNA
• Pamidronate 60 mg 2-weekly x6
• At each time point:
- Skin temps measured (Mikron infrared
thermometer)
- Alkaline phosphatase
Selby Diabetic Med 1994

0
1
2
3
4
Temperaturedifference(°C)
Temperature difference between affected
and intact foot
2 4 10 126 8Basal
* * * * *
Weeks of therapy

-30
-25
-20
-15
-10
-5
0
5
Basal 2 4 6 8 10 12
Weeks of therapy
%agechangeinAP
Percentage change in plasma alkaline
phosphatase

Randomised double-blind
trial of Pamidronate in
Diabetic Charcot
Arthropathy
Jude et al Diabetologia 2001;44:2032

Exeter
London
Nottingham
Manchester

-3
-2
-1
0
1
0 2 4 6 8 10 12 24 36 52
Weeks
Temperaturedifference(°C)
Active
♦
Placebo
Effect of Pamidronate on disease activity

0
5
10
15
20
25
2 4 6 8 10 12 24 36 52
Weeks
BSAP(u/l)Effect of Pamidronate on Bone Specific
Alkaline Phosphatase
Active
♦
Placebo
* * * * *

0
2
4
6
8
0 2 4 6 8 10 12 24 36 52
Weeks
DPD(nM/mM)
* *
Active
♦
Placebo
Effect of Pamidronate on DPD crosslinks

Discussion
• Bone turnover markers are increased in
Charcot arthropathy
• Immobilisation is effective in reducing
Charcot activity
• Pamidronate is effective in reducing
both disease activity and bone turnover
markers

Peak pressure 2nd
MTH
0
2
4
6
8
10
12
14
0 500 1000 1500 2000
Peak plantar pressure (kPa)
Plantartissuethickness(mm)
r = - 0.53 (p<0.001)

Conclusions
• Plantar tissue thickness measurement is a
useful alternative method to study patients at
risk of foot ulceration
• Follow up of these patients will point to the
importance of these measurements in clinical
practice
Abouaesha et al, Diabetes Care 2001;24:1270

The ‘Instant Total-Contact
Cast’
• TCC ‘gold standard’ but labor-intensive,
expensive and time-consuming
• Why not use cast-walker or Scotchcast boot
made ‘irremovable’
• Removable device wrapped with cohesive
bandage (Coband) or plaster
• The device can then be re-attached weekly
after removal of bandage and wound
inspection
• Conclusions: an ‘instant’ or ‘poor man’s’ TCC
Armstrong et al, JAPMA, 2001

Why are trials of removable
devices so disappointing?
• When given specialist footwear, only 20% of
patients report wearing regularly
• DH walker offloads as well as TCC
• DH walker worn for only 28% of daily activity
• Conclusions: Despite all good intentions,
offloading devices are used for a minority of
daily walking activity
Knowles & Boulton 1996,
Lavery et al, 1996
Armstrong et al,

INTERNATIONAL MEETINGS ON THE
DIABETIC FOOT
DECEMBER 1988, Howard Johnson 57
Hotel, Boston, Mass, USA
Meeting on Diabetic Foot organized by
Bob Frykberg.
In Attendance: Karel Bakker, John
Dooren, Jan Rauwerda, Andrew
Boulton

‘I don’t like
peripheral neuritis – it
interferes with work
RD Lawrence, 1923

Neuropathy and Foot
Ulceration: Prospective Study
– 169 patients, 22 controls: Manchester, UK
– Spectrum of neuropathic deficits. Six year follow
up
– 37% ulcers, 11% amputation, 18% died
– MNCV best predictor of ulcers, arterial calcification
& PPT, amputation; MNCV,Creatinine & TcPO2
predicted mortality
CONCLUSION: MNCV is the best surrogate
endpoint for end-stage neuropathy
Carrington et al, Diabetes Care 2002;25:2010-2015

The Diabetic Foot: An Overview of Prevention and Treatment

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