Abstract Charcot neuro

-
osteoarthropathy (CN) is one of
the most challenging foot
complications in diabetes.
Common predisposing and
precipitating factors include
neuropathy and increased
mechanical forces, fracture and
bone resorption, trauma and
inflammation. In the last 15
years, considerable progress has
been made in the early
recognition of the acute Charcot
foot when the X ray is still
negative (stage 0 or incipient
Charcot foot). Recent advances in
imaging modalities have enabled
the detection of initial signs of
inflammation and underlying
bone damage before overt bone
and joint destruction has
occurred. Casting therapy
remains the mainstay of medical
therapy of acute CN. If timely
instituted, offloading can arrest
disease activity and prevent foot
deformity. In cases with severe
deformity, modern surgical
techniques can correct the
unstable deformity for improved
functional outcome and limb
survival. Emerging new studies
into the cellular mechanisms of
severe bone destruction have
furthered our understanding of
the mechanisms of pathological
bone and joint destruction in CN.
It is hoped that these studies may
provide a scientific basis for new
interventions with biological
agents. Copyright © 2016 John
Wiley & Sons, Ltd. Keywords
Charcot neuro-osteoarthropathy;
diabetes; magnetic resonance
imaging; casting therapy;
reconstructive surgery;
osteoclastic activity Introduction
Charcot neuro-osteoarthropathy
(CN) is one of the most
challenging foot complications in
diabetes. It is a severe osteolysis
that takes place on the
background of peripheral
neuropathy, and if not recognized
and treated promptly, it can
rapidly progress to extensive
bone and joint destruction
resulting in irreversible foot
deformity. It affects both type 1
and type 2 diabetes. Recently, a
relative preponderance of type 1
diabetes has been noted [1], and
the odds ratio for a patient with
type 1 diabetes to develop CN is
3.9 times greater than that of the
odds ratio for a patient with type
2 diabetes [2]. It is associated
with significant morbidity [3],
and patients often report a
reduced quality of life [4]. A high
index of suspicion, early
diagnosis and timely treatment
are the keys to arrest its
progression. This article will
discuss common predisposing
and precipitating factors. It will
describe the presentation,
diagnosis and current
management of the acute Charcot
foot. Finally, it will discuss recent
emerging studies looking into
possible new therapies.

Predisposing and precipitating
factors The pathogenesis of CN is
multifactorial. A novel
datamining approach identified
more than 100 associations that
had a significant temporal
relationship to the development
of CN [5]. Well established
predisposing and precipitating
factors of CN include neuropathy
and increased mechanical forces,
bone resorption and fractures,
trauma and inflammation.
Neuropathy Standard tests to
detect nerve damage demonstrate
a variable degree of impairment
in patients with CN. Numbness
of the extremity is one of the
most frequently reported
symptoms [6]. Abnormal
vibration sensation to 128
cycle/sec tuning fork was
observed in 93% of patients with
CN, whereas decreased ankle
jerks were noted in 25% and
absent in 30% of the patients [6].
Nerve damage in CN can affect
the large myelinated fibres (Aα),
the small myelinated fibres (Aδ)
and the unmyelinated fibres (C-
fibres). Patients with CN
demonstrate impaired sensation
to hot and cold stimuli (small
fibre neuropathy) and also
reduced vibration threshold (large
fibre neuropathy) when compared
with controls [7]. Evidence of
global neuropathy (small and
large fibre deficit) is more
frequently seen in type 2 diabetes
in contrast with patients with type
1 diabetes in whom a
predominant small fibre
neuropathy has been reported
[8,9]. Patients also exhibit
abnormal pain sensation. A recent
cross-sectional study
demonstrated that perception
thresholds for cutaneous pressure
pain (using calibrated von-Frey-
hairs with sharp non-injuring tip)
were significantly elevated in
patients with chronic CN
indicating a C-fibre deficit [10].
Nerve conduction velocity in the
affected Charcot foot was not
significantly different compared
with the non-affected
contralateral foot, indicating that
the foot involvement was
precipitated by the site of trauma
[7]. A further study of patients
presenting with unilateral CN
demonstrated that pinprick, light
touch and temperature sensations
were not significantly different
between the affected and non-
affected foot [11]. However, the
level of attenuation of vibration
sensation was more proximal in
the affected limb compared with
the unaffected limb, suggesting
that an asymmetrical attenuation
of vibration sensation may
predict the side that will develop
a Charcot joint [11]. All these
studies reiterate the role of
neuropathy, which is the common
denominator for all conditions
associated with Charcot joints.
Further studies are needed to
determine the specific
neurological deficit in patients
with diabetes presenting with this
devastating condition.

Trauma Patients with diabetic
neuropathy have limited joint
mobility, increased plantar
pressures and abnormal gait
predisposing them to frequently
traumatize their feet [12– 14].
Obesity in diabetic patients with
neuropathy can lead to increased
loading of the foot, although no
relationship between elevated
body mass index and acute CN
has been noted [2]. However,
mechanical pressures are signifi-
cantly elevated in patients with
neuropathy, and the highest peak
plantar pressures were reported in
patients with CN in the affected
and also in the contralateral foot
[15]. In a recent cohort of 288
cases of CN, a third of patients
recalled a particular episode of
preceding trauma [16], while in
others, the development of CN
had been noted shortly after foot
surgery or after an episode of foot
ulcer of infection [16]. However,
in the majority of cases, trauma
was not perceived by the patient
because of the underlying
neuropathy. Fractures Trauma on
the background of neuropathy
leads to bone fracture, a well-
recognized trigger event for the
development of CN [7,17,18].
Metatarsal fractures in patients
with severe neuropathy were
strongly associated with the
subsequent development of CN
[18]. Both type 1 and type 2
diabetes have increased risk for
fracture. In type 1 diabetes,
fractures are more frequently
associated with reduced bone
mineral density and preexisting
peripheral osteopenia [8,19],
whereas in type 2 diabetes,
fractures result from alteration of
weight bearing and load in the
foot [20]. The increased risk of
fractures in patients with type 2
diabetes is mainly attributed to
the increased risk of falling [21].
Patients who report falls have
multiple risk factors including
neuropathy, impaired balance,
advanced age and a history of
coronary disease [22]. Thus, the
pathway to foot fracture may be
different in patients with type 1
and type 2 diabetes, although its
role in the natural history of CN
is well recognized. Presentation
In diabetes, the foot is the most
common presentation, and very
rarely, the knee or the wrist can
be involved [23]. Based on
radiological features and foot
presentation, Eichenholtz
classified the evolution of the
Charcot joints into three stages:
development (I), coalescence (II)
and reconstruction and
reconstitution (III), (Eichenholtz
stages I–III). The anatomical sites
of bone and joint involvement in
the foot were described by
Sanders and Frykberg into five
patterns (pattern I – metatarsal/
phalangeal joints; pattern II –
metatarsal/ tarsal joints (Lisfranc
joints), pattern III – midtarsal
joints (Chopart joints), pattern IV
– ankle and subtalar joint, pattern
V – calcaneum), (Sanders and
Frykberg’s classification), [24].
Recent data from a web-based
survey of 288 new cases of acute
CN registered from 76 different
centres in the UK and Ireland
within 20 months reported that
the majority of lesions were in
the midfoot and hindfoot, [16].
The Charcot foot is usually
characterized by a unilateral
redness and swelling following
minor trauma, which may remain
unnoticed by the patient. At
presentation, the affected foot is
usually more than 2 °C warmer
compared with the non-affected
foot [25,26]. The acute
inflammatory response to trauma
in acute CN is local and is not
commonly associated with a rise
in systemic serum markers of
inflammation [27]. In acute CN,
C-reactive protein, white cell
count and erythrocytes
sedimentation rate are often
normal or non-specifically
elevated [27]. Patients may
present early in the acute active
phase with normal X ray or later
when there may be already
existing deformity and typical
radiological changes of bone and
joint destruction [23]. Early
recognition of CN when the X
ray is normal is extremely
important [23,28], and this has
been emphasized in a recent task
force document [29]. If not
recognized and managed at this
stage, extensive irreversible bone
and joint destruction can occur
[28] associated with severe foot
deformity, leading to ulceration
and possible amputation [29].

Diagnosis Because of the
underlying neuropathy, signs and
symptoms are often minimal, and
therefore, a high index of
suspicion is needed. At present,
there are no established
biochemical markers that can
help to diagnose the condition or
monitor disease activity. It is
important to differentiate
between the red, hot, swollen
Charcot foot and the red, hot,
swollen cellulitic foot. Cellulitis
is more likely in the presence of
an ulcer that may show typical
signs of infection. Presence of
gout and deep vein thrombosis
should also be ruled out by
measurement of serum uric acid
(which is usually raised in gout)
and duplex vein scan. Imaging is
the mainstay of diagnosis.
Standard weightbearing foot and
ankle radiographs should be
requested as the first line
investigation to assess bone
damage. Although evidence of
soft tissue inflammation can be
noted on foot and ankle
radiographs, in patients
presenting early, radiographs may
be normal [30]. It is now well
established that a normal foot
radiograph in a person with
diabetes presenting with a hot
swollen intact foot does not rule
out CN, and further imaging can
reveal the extent of pathology.
Imaging modalities including
technetium diphosphonate bone
scan, magnetic resonance
imaging (MRI) and positron
emission tomography–computed
tomography scanning have
enabled the detection of early
signs of inflammation and
underlying bone damage before
overt bone and joint destruction
has occurred [29,31,32]. The X-
ray negative stage is now well
recognized, and it is often
referred to stage 0, or sometimes
called ‘the incipient Charcot foot’
[28,30]. This X-ray negative/
MRI positive stage of
inflammatory bone marrow
oedema has been included into
the recently proposed modified
classification of CN in addition to
the Eichenholtz’s stages I–III
[33]. Stage 0 is characterized by
mild inflammation, soft tissue
oedema, normal X ray but
abnormal MRI scan showing
evidence of microfracture, bone
marrow oedema and bone
bruising [33]. Stage 1 is
characterized by severe
inflammation, soft tissue oedema,
abnormal X ray with
macrofractures and abnormal
MRI scan showing evidence of
macrofracture, bone marrow
oedema and bone bruising [33].
Recognition and management at
stage 0 could arrest disease
activity and prevent foot
deformity [28,34]. In a recent
series of cases, 69% of patients
presenting at stage 0 healed
without deformities in contrast
with only 7% of patients with a
delayed presentation at stage 1
[35]. Thus, the modern approach
to CN is to diagnose it as early as
possible to institute timely
offloading to avoid adverse
outcomes.

Management Casting therapy The
current standard of therapy
includes casting immobilization
until the inflammation subsides,
the fractures heal and the
deformity stabilizes [23,36]. Total
contact casting is well recognized
as a gold standard treatment for
CN, although it has not become a
standard treatment in many
diabetic foot clinics, because of
concern with complications.
Recently, we reported that in
experienced hands and regular
monitoring, total contact casting
was a safe treatment modality
and was associated with only
5.7% minor cast-related tissue
injuries [37]. Duration of casting
varies according to different
studies [36]. The median duration
of casting was 10 months based
on data from a recent audit in the
UK [16]. A further study reported
a significantly shorter duration
offloading of 5 months in a
removable cast and 2 crutches,
followed by a gradual
rehabilitation with a very low rate
of exacerbation (5%) and
recurrence (12%) [38].
Patients require close follow up
to monitor reduction of
inflammation usually by infrared
skin thermometry [29]. Foot
inflammation and swelling
characterize the acute active
phase (Eichenholtz stage I) and
subside in the stage of
coalescence (Eichenholtz stage
II). Foot swelling and skin foot
temperatures are traditionally
monitored within the course of
the disease to assess healing [39].
During the treatment phase, there
is a gradual cooling (on average
0.022 ± 0.0005 °C per day or 2.1
°C for every 100 days), [26]. A
more recent prospective
observational study in 28 patients
reported that skin temperature
difference between feet was a
good clinical parameter for
predicting disease outcome and
making decision on
immobilization withdrawal [40].
A variety of surface infrared
thermometers have been used to
measure skin temperature
difference at corresponding sites
of the feet. There is little
experience with the use of more
sophisticated infrared cameras in
the assessment of the Charcot
foot [41]. Thus the role of
thermography in the diagnosis
and monitoring of the acute CN is
yet to be established. In addition
to skin foot temperatures,
quantitative bone scanning
techniques have been also used to
assess healing and a strong
correlation between temperature
difference and the ratio of isotope
uptake has been reported [42].
More recently, dynamic MRI
scans have been used to
quantitate inflammation at
presentation and also on follow
up [43]. There was a strong
agreement between clinical and
MRI findings in definite lesion
healing, which was associated
with a significant reduction of the
contrast medium uptake rate in
all patients with improved
clinical findings [43]. A further
study, using Fluorine-18
Fluorodeoxyglucose positron
emission tomography–computed
tomography, indicated that an
inflammatory state may precede
bone damage in patients
presenting with CN [44]. Thus,
recent advances in imaging
modalities have not only helped
us to recognize better the early
presentation, but also show
promise as useful tools in the
assessment of disease activity.

Current and emerging
pharmacological therapies
Although casting therapy remains
the mainstay therapy of CN, the
role of pharmacological therapies
aiming to correct the imbalance
between bone resorption and
bone formation has been
investigated. Anti-resorptive
therapies including
bisphosphonates and calcitonin
have been used with some
success as an adjunct to casting
therapy [45–48], although
according to others, evidence to
support their use is weak [49].
Another method to improve bone
remodelling is to use an anabolic
agent, and at present, there is
early experience with the use of
human parathyroid hormone on
fracture healing in the
management of patients with CN
[36,50].

Emerging studies have identified
aberrantly activated osteoclasts as
key players of the pathological
bone destruction of the acute
Charcot foot [51]. A better
understanding of the cellular
mechanisms of increased
osteoclastic activity may lead to
novel therapies. Newly formed
osteoclasts derived from patients
with acute CN exhibit enhanced
resorbing activity in response to
the receptor activator of nuclear
factor-kβ ligand, an osteoclast
activator [52]. In addition,
osteoclastic activity is modulated
by the proinflammatory cytokine,
tumour necrosis alpha, [53]. Both
receptor activator of nuclear
factor-kβ ligand and tumour
necrosis alpha stimulate the
osteoclasts to produce cathepsin
K (the main lysosomal
collagenase responsible for the
degradation of type I collagen). If
shown that in CN the increased
osteoclastic activity is a result of
cathepsin K upregulation, this
mechanism may potentially
indicate a novel treatment target
to reduce the enhanced bone
resorption of the acute Charcot
foot by using cathepsin K
inhibitors [53]. Thus, a better
understanding of the cellular
mechanisms of the pathological
bone destruction of the acute
Charcot foot may provide a
scientific basis for novel
interventions with biological
agents.

Surgical treatment Non-operative
treatment with use of total
contact cast followed by an
appropriate bracing and footwear
is considered to be the gold
standard treatment for acute CN.
Surgical intervention in the
absence of ulceration or unstable
deformity may not be advisable,
as it is not without risk [54].
Operative treatment is indicated
for chronic recurrent ulcerations
and joint instability when patients
present with unstable or displaced
fracture-dislocations. Treatment
outcomes and complication rates
vary between centres. Late
corrective arthrodesis in non-
plantigrade diabetic Charcot foot
was associated with high
complication and reoperation
rates in a series of 19 patients
with severe CN [55]. However,
we reported recently the
outcomes of 20 patients (21 ft)
with CN who underwent
correction of deformities of the
ankle and hindfoot using
retrograde intramedullary nail
arthrodesis [56]. All were treated
with reconstructive surgery and
seven underwent simultaneous
midfoot fusion [56]. Limb
salvage was achieved in all
patients and all but one patient
regained independent
mobilization [56]. A multi-
disciplinary approach and a
dedicated diabetic foot clinic are
essential to achieve satisfactory
results.
Conclusion We describe common
predisposing and precipitating
factors of CN. Considerable
progress has been made in our
recognition of the acute Charcot
foot. Casting therapy remains the
mainstay of medical
management. Timely offloading
can arrest disease activity and
prevent foot deformity. Recent
advances in surgical
reconstruction techniques
together with close collaboration
within the multi-disciplinary
team can correct deformities and
improve limb survival. A better
understanding of the cellular
mechanisms of increased
osteoclastic activity may lead to
novel therapies for improved
outcome of this devastating
condition.