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 C H A P T E R

3
N EUROPATHIC P ROBLEMS OF
THE L OWER L IMBS IN
D IABETIC PATIENTS
ROBERT J. TANENBERG AND PETER D. DONOFRIO

severe DPN (defined as the inability to sense a 5.07

Introduction monofilament) were not identified by this same group of
primary care providers.
This chapter defines diabetic neuropathy and reviews the Either a disinterest in the condition or an inability of
pivotal role this complication plays in lower-limb disease health care providers to diagnose DPN is reflected in a
and disability. Although diabetic peripheral neuropathy similar lack of appreciation of the condition by patients
(DPN) is common and a frequent cause of morbidity and with diabetes. A recent ADA telephone survey of over
disability, early assessment and management of diabetic 8000 respondents who claimed to have diabetes (ADA
neuropathy are often overlooked or forgotten. The Diabetic Neuropathy Campaign) confirms a general lack
American Diabetes Association (ADA) has been recom- of recognition of the term neuropathy and the cause of
mending a neurologic examination on the initial patient their neuropathic symptoms.5 The key findings of this
visit for over 10 years and currently recommends annual survey included the following:
screening for DPN in all patients with diabetes.1,2
1. Only 42% of the two thirds of survey respondents who
Unfortunately, neuropathy screening has not become a
experience symptoms of DPN had been told by their
universal standard of care in the United States, as is illus-
doctor that diabetes was the cause.
trated by its exclusion in the 2002 Health Employer Data
2. Only 25% of survey respondents who experience symp-
and Information Set criteria for diabetes management
toms of DPN had been diagnosed with the condition.
for U.S. health plans.
3. Fewer than 50% of those with DPN symptoms were
A 2005 study of 20 health plans found two thirds of
aware of the term diabetic neuropathy.
health care providers in compliance with all six of their
diabetes management criteria (e.g., measuring hemo- This widespread failure by both patients and physi-
globin A1C, lipids, and microalbuminuria and referring cians to understand and appreciate the importance of
patients for dilated retina exams).3 In contradistinction, DPN is not without consequence. Furthermore, the
a recent study of over 2000 primary care providers in the common omission of a neurologic exam of the lower
United States found that these practitioners were able limbs in the physician’s office or at the bedside often
to correctly identify the presence of mild to moderate leads to a failure to diagnose DPN. When the DPN is not
neuropathy in only 31% of their patients.4 This study diagnosed in the early stages, a window of opportunity is
(The Underdiagnosis of Peripheral Neuropathy in Type missed to ameliorate symptoms and prevent the develop-
2 Diabetes) also found that one third of patients with ment of the major clinical neuropathic endpoints of the
33
34 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

lower limb: the chronic painful foot, the insensate foot, demiology, and recommendations for treatment, manage-
the Charcot foot, and the neuropathic ulcer. ment, and screening.6 They reiterated the definition of
This chapter reviews the epidemiology, pathogenesis, diabetic neuropathy as “the presence of symptoms,
and classification of DPN. The evidence base supporting and/or signs of peripheral nerve dysfunction in people
“tight” glycemic control to prevent or delay the onset or with diabetes after the exclusion of other causes.”7 Clinical
progression of DPN is presented. The chapter presents a diabetic neuropathy requires the presence of an abnormal
practical approach to the evaluation and treatment of neurologic examination done by a physician skilled in
the patient with DPN for the clinician. The approach the proper examination technique and the finding that
focuses on the lower limb and includes (1) neurologic the abnormal neurologic exam is consistent with nerve
history, (2) neurologic examination, (3) use of ancillary damage from diabetes.
testing, (4) pharmacologic treatment of the patient with Confirmed clinical neuropathy is defined as clinical
painful neuropathy, and (5) office management of the neuropathy plus confirmation by abnormal quantitative
insensate foot. The authors’ goal for this chapter is to neurologic function tests (e.g., electrophysiologic tests,
improve the reader’s understanding of DPN as a critical quantitative sensory testing, or autonomic function tests)
cause of the lower-limb morbidity that, when detected in two or more nerves. “Subclinical diabetic neuropathy”
and addressed in the early stages, can reduce pain and is the presence of abnormal quantitative neurologic
suffering and improve the lives of patients with diabetes. function tests with little or no evidence of clinical neu-
ropathy by exam.8 There are sensory nerves (controlling
sensation), motor nerves (controlling the musculature),
Definition, Pain Overview and Stages and autonomic nerves (controlling functions such as
of Diabetic Neuropathy sweating, vascular flow, heart rate, gastric emptying, and
other visceral organs).
Illustrations of the major types of diabetic neuropathy
Definition are depicted in Figure 3-1. Sensory neuropathy can result
In 2005, the American Diabetes Association published in abnormal sensations, such as pain or lack of sensation
a statement on diabetic neuropathies that reviewed (numbness), typically in the glove and stocking distribu-
accepted definitions, classification, diagnostic criteria, epi- tion (Fig. 3-2).

III VI

Truncal

Ulnar

Lateral
Median
popliteal

Large-Fiber Small-Fiber Proximal Motor Acute Mono- Pressure

neuropathy neuropathy neuropathy neuropathies palsies

Sensory loss: 0 ˜  Sensory loss: 0 ˜  Sensory loss: 0 ˜  Sensory loss: 0 ˜  Sensory loss in nerve
(touch, vibration) (thermal, allodynia) Pain:  ˜  Pain:  ˜  distribution:  ˜ 
Pain:  ˜  Pain:  ˜  Tendon reflex: ŒŒ Tendon reflex: N Pain:  ˜ 
Tendon reflex: N ˜ Tendon reflex: N ˜ Œ Proximal motor deficit: Motor deficit: Tendon reflex: N
ŒŒŒ Motor deficit: 0  ˜   ˜  Motor deficit:  ˜ 
Motor deficit: 0 ˜ 

Figure 3–1 Five clinical presentations of DPN. Schematic representation of five different clinical presentations of peripheral diabetic
neuropathy with both sensory and motor components. DPN may predominantly affect large fibers or small fibers (see text). Proximal
motor deficits in diabetic patients may be from another etiology and will require a full neurologic evaluation. Proximal diabetic
neuropathy, also known as diabetic amyotrophy, may be associated with weight loss and a progressive disability. Mononeuropathies may
be acute or chronic, are generally unilateral, and can involve various peripheral nerves, such as the median (carpal tunnel), ulnar, truncal,
and lateral popliteal nerves. (Redrawn from Vinik AI, Mehrabyan A: Diabetic neuropathies. Med Clin N Am 88:947–999, 2004.)
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 35

D D
D

D D

D
Figure 3–3 Development of claw toe deformity. As the
flexor muscles of the foot become weakened disproportionately
to the extensor muscles, the toes are pulled into a claw deformity.
This action pulls the fat pad off the metatarsal heads of the foot.
The pressure is no longer distributed along a wide base but rather
Figure 3–2 Stocking-and-glove distribution. Stocking-and- at a narrow point beneath the metatarsal heads, which no longer
glove distribution of diabetic distal symmetrical polyneuropathy. have any fat padding. The plantar surface of the metatarsal
Diabetic distal symmetrical polyneuropathy involves both sides heads, the cocked-up toe knuckle (more likely to hit the top of the
relatively equally, involves feet more than hands, is distal rather toe box), and the tip of the toe are at increased risk for ulceration
than proximal, and involves multiple nerves. There is a distal with this common deformity.
dying of the nerve fiber. This results in a dying-back clinical
picture. Thus, the involvement of hands and feet presents as a
stocking-and-glove pattern.
importance of pain and the need for providers to ask
about it at every patient encounter.10 It is important that
Motor neuropathy can result in muscle atrophy. This physicians and other health care providers understand
may lead to imbalances between muscle groups in the that diabetic neuropathy can occur with no pain or with
foot. These imbalances can result in foot deformities. A an insensate foot or may present with pain in the form of
common example is the claw toe deformity, which is dysesthesias and paresthesias as described below (see the
caused by the constant flexion of the toes (Figs. 3-3, 3-4). section entitled “Epidemiology and Risk Factors”). It is
Autonomic neuropathy may lead to decreased sudo- estimated that 15% of individuals with diabetes will
motor function and dry feet or abnormal blood flow in present with painful DPN.11 The most recent data from
the soles of the feet. the Centers for Disease Control and Prevention give the
prevalence for diabetes as approximately 22 million
people, which would translate to over 3 million people in
Pain Overview the United States suffering from painful neuropathy.12
In 1931, Charles Mayo once remarked that “of all the However, patients may have nonneuropathic or nocicep-
symptoms for which physicians are consulted, pain in tive pain or conditions with both elements. Nociceptive
one form or another, is the most common and most pain arises from a stimulus outside the nervous system
urgent.”9 In 1995, the American Pain Society created the and is proportionate to receptor stimulation. When noci-
phrase “Pain: The 5th Vital Sign”™ to emphasize the ceptive pain is acute, it serves as a protective function.
36 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

Figure 3–4 Photos of claw

toes. Claw foot deformity (green
arrow), callus on the first
metatarsal head (yellow arrows),
and neuropathic ulcer (orange
arrows) in a patient with
insensate feet.

TRANSMISSION MODULATION Figure 3–5 Normal pain

pathways. Left, The ascending
pathway of pain transmission.
F C Messages are transduced by the
C Cortex F peripheral ending of the primary
A afferent nociceptor and then
SS H transmitted to the spinal cord.
Subsequently, messages are
Key: Thalamus relayed via the thalamus to the
RVM  rostroventral medulla PAG
frontal cortex and somatosensory
PAG  periaqueductal grey Midbrain
cortex. Right, The descending
C  cingulate cortex
pathway of pain modulation. Pain-
F  frontal cortex
SS  somatosensory cortex modulating impulses from the
A  amygdala Medulla frontal cortex and hypothalamus
H  hypothalamus ultimately suppress spinal pain
Ascending pathway transmission. (Adapted with
Descending pathway RVM permission of the publisher, from The
Spinothalamic Placebo Effect: An Interdisciplinary
tract Exploration, edited by A. Harrington,
p.106, Cambridge, Mass: Harvard
Injury
University Press. Copyright © 1997 by
Spinal cord the President and Fellows of Harvard
College.)

Examples of nociceptive pain include arthritis, sports Fields. In Figure 3-5, the diagram on the left demon-
injuries, postoperative pain, and mechanical low back strates the normal ascending pathway of pain transmis-
pain. These pains fit the official definition of the sions described by Fields. Messages are transduced by the
International Association for the Study of Pain. They peripheral ending of the primary afferent nociceptor
have defined pain as “an unpleasant sensory and emo- and then transmitted to the spinal cord and then relayed
tional experience associated with actual or potential through the thalamus to the frontal and the somatosen-
tissue damage or described in terms of such damage.”13 sory cortex.15 The diagram on the right of Figure 3-5
In contradistinction, neuropathic pain arises from a pri- illustrates the normal descending pathway of pain modu-
mary lesion or dysfunction in the nervous system and is lation. In this case, pain-modulating impulses from the
disproportionate to receptor stimulation.14 Neuropathic frontal cortex and hypothalamus ultimately suppress
pain does not require nociceptive stimulation, and there spinal pain transmission.16 These paradigms are invalu-
is often other evidence of nerve damage. In addition to able to clinicians in improving their understanding of
DPN, other examples of neuropathic pain include post- pain transmission in neuropathies such as DPN.
herpetic neuralgia, trigeminal neuralgia, neuropathic
low back pain, complex regional pain syndrome, and
distal HIV polyneuropathy. Clinical entities with both
Stages
nociceptive and neuropathic pain include fibromyalgia, A useful staging method is the one described by the
certain cancer pain, and various neck and back pains. Mayo Clinic.17 Stage 0 is no evidence of neuropathy.
Our understanding of neuropathic pain was greatly Stage 1 is subclinical neuropathy defined as no signs or
enhanced with neurobiological models described by symptoms of neuropathic problems but abnormal quan-
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 37

TABLE 3-1 Stages of Diabetic Neuropathy

BOX 3–1 Classification of Diabetic Neuropathy
Abnormal
Signs or Quantitative
Stage Description Symptoms Tests
0 No neuropathy No No
1 Subclinical neuropathy No Yes
2 Clinically evident neuropathy Yes Yes
3 Debilitating neuropathy Yes Yes

titative neurologic function tests. Stage 2 is clinical neu-

ropathy (i.e., findings of signs and symptoms consistent From Dyck PJ, Kratz KM, Karnes JL, et al: The prevalence by staged severity of
with diabetic neuropathy). Usually, this can be confirmed various types of diabetic neuropathy, retinopathy, and nephropathy in a population-
based cohort: The Rochester Diabetic Neuropathy Study. Neurology 43:817–824,
by evaluating quantitative neurologic function tests. 1993.
Stage 3 is end-stage, debilitating neuropathy. Typically,
people with stage 3 neuropathy have an abnormal gait,
cannot walk on their heels, or have had a foot ulcer.
BOX 3–2 Types of Diabetic Neuropathy
Table 3-1 summarizes these stages.
I. Focal neuropathies
A. Ischemic neuropathies
Classification of Diabetic Neuropathy 1. Sudden onset
2. Asymmetrical
3. Ischemic etiology
Diabetic neuropathy can be classified in several ways: 4. Self-limited
clinical presentation (symmetrical, focal, or multifocal 5. Examples
or painful, paralytic, and ataxic), predominant type of a. Mononeuropathies
fibers affected (motor, sensory, autonomic), or painful b. Femoral neuropathies
c. Radiculopathies
or nonpainful. d. Plexopathies
The classification by P. K. Thomas was the first attempt e. Cranial neuropathies
to separate diabetic neuropathy into symmetrical, focal, B. Entrapment neuropathies
or multifocal. Symmetric neuropathies were sensory or 1. Gradual onset
sensorimotor, acute or subacute, or autonomic. Focal 2. Usually asymmetrical but can be bilateral
3. Compression etiology
or multifocal neuropathies were cranial, trunk or limb, 4. Waxing and waning progressive course without
or proximal.18 A popular classification is the one created spontaneous recovery
by Dyck and colleagues in 1987; it groups neuropathies 5. Examples
by the predominant clinical presentation (Box 3-1). It a. Carpal tunnel syndrome
can be appreciated as a modification of the classification b. Ulnar entrapment (tennis elbow)
c. Lateral cutaneous femoral nerve entrapment
proposed by P. K. Thomas earlier. Neuropathies are d. Tarsal tunnel syndrome
grouped as symmetrical, asymmetrical, or both.19 Box 3-2
briefly describes the various types of neuropathy in terms II. Diffuse neuropathies
of their onset, symmetry, and clinical course. A. Insidious onset
A symmetrical distal neuropathy is the most common B. Symmetrical
C. Abnormalities secondary to vascular, metabolic, structural,
presentation of diabetic neuropathy. It can be symp- and autoimmune aberrations
tomatic in a patient complaining of numbness, tingling, D. Progressive without spontaneous recovery
and burning in the feet and lower shins or it can be E. Examples
asymptomatic, first detected on neurologic examination 1. Distal-symmetrical polyneuropathy
or electrophysiologic testing. The symmetrical proximal 2. Autonomic neuropathies
neuropathies are extremely rare and are typically observed
in the setting of a distal symmetrical neuropathy. The
asymmetrical neuropathies are clustered together, each with a symmetrical distal neuropathy. In Dyck’s classifi-
with its unique presentation of ocular involvement, pain cation, autonomic involvement would be grouped with
over the chest or abdomen, lumbosacral distribution of the symmetrical distal neuropathy.
weakness and pain, or a mononeuropathy at a common The Consensus Panel Report and Recommendations
entrapment site or in the setting of severe prolonged of the San Antonio Conference on Diabetic Neuropathy
ischemia. The final term in Dyck’s classification describes in 1988 grouped neuropathies into symptomatic and
the common occurrence of an asymmetrical neuropathy asymptomatic and whether the patient had signs of neu-
and the common symmetrical distal neuropathy, for ropathy or only symptoms. Feldman adapted this classifi-
example, diabetic amyotrophy superimposed on a patient cation so that class I or subclinical neuropathies were
38 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

subgrouped into those that had abnormal nerve con-

duction results, abnormal quantitative sensory testing, or
abnormal autonomic testing. Class II or clinical neu-
ropathies were divided into diffuse and focal neu-
ropathies. Diffuse neuropathies were grouped again into MPN
the predominant fiber type abnormality (small, large, or
mixed fibers) or the type of autonomic neuropathy.
LPN
Focal neuropathies were mononeuropathies, mononeu-
ropathy multiplex, cranial neuropathies, plexopathies,
or polyradiculopathy.20 Focal neuropathies can also be
divided into ischemic and entrapment neuropathies.
Focal ischemic neuropathies are believed to be due to
an acute ischemic event to a nerve, a plexus of nerves, or
a nerve root. As a result, this type of neuropathy tends to
have a sudden onset, to be asymmetrical in distribution,
and to have a self-limiting course. Examples of acute
A
ischemic focal neuropathies include mononeuropathies,
femoral neuropathies, radiculopathies, plexopathies, Medial plantar nerve (MPN)
and cranial neuropathies. Diagnosis is typically via clinical
examination and symptoms. Therapy relates to time. Lateral plantar nerve (LPN)
Cranial neuropathies (e.g., third-nerve palsy) may improve
in days to a few weeks, whereas femoral neuropathies
may take months to a year and a half to improve. No Calcaneal branch
known therapy has been proven to shorten the time
to recovery. Posterior tibial nerve

Focal Entrapment Neuropathies

B
(Tarsal Tunnel Syndrome)
Figure 3–6 Tarsal tunnel. Compression of either the
Focal entrapment neuropathies occur when a nerve is posterior tibial nerve at the tarsal tunnel or the plantar nerves
compressed in a specific body compartment. They tend causes a combination of sensory impairment of the sole and
to have a gradual onset, to occur in an asymmetrical dis- intrinsic weakness of the pedal musculature. (Adapted from
Aguayo AJ: Neuropathy due to compression and entrapment. In Dyck
tribution (but can occur bilaterally), and often have a
PJ, Thomas PK, Lambert EH (eds): Peripheral Neuropathy.
progressive course. Examples include carpal tunnel syn- Philadelphia, W.B. Saunders, 1975.)
drome, ulnar entrapment, and tarsal tunnel syndrome.
Tarsal tunnel syndrome occurs when the tibial nerve
becomes entrapped in the tarsal tunnel. The tarsal condyle of the ankle as you would tap for a carpal tunnel
tunnel is located on the medial surface and just below Tinel’s sign at the wrist. If the test is positive, the patient
the medial malleolus. As the tibial nerve traverses into notes a tingling in the sole of the foot. In addition, there
the foot, it splits into two branches, one to the heel and may be loss of flexibility of the metatarsophalangeal joint
the other to the remainder of the foot. The split of the (inability to hold a pencil with toes or inability to grab a
tibial nerve can occur before or within the tarsal tunnel handkerchief placed flat on the floor with the toes). A
(Fig. 3-6). Thus, people with tarsal tunnel syndrome may gait disturbance is occasionally observed. The diagnosis
have a variety of symptoms. Symptoms may include of the tarsal tunnel syndrome is made via appropriate
paresthesias or numbness in the distal foot with the heel signs and symptoms and confirmed by electrodiagnostic
spared, or the heel may be involved as well. Pain from measures above and below the tarsal tunnel. Therapy may
tarsal tunnel entrapment generally worsens throughout include surgery or steroid injections (see the Surgery
the day, as there is increased pain with activity. Thus, section later in this chapter).
the pain is typically worse at the end of the day and
improves on resting the foot. This pain scenario is very
different from the pain associated with distal symmetrical Epidemiology and Risk Factors
polyneuropathy.
Examination findings of the tarsal tunnel syndrome
include an abnormal two-point discrimination test,
Epidemiologic Perspective
abnormal vibratory sensation, and weakness and wasting Only a few studies have addressed the prevalence of dia-
of foot muscles and a positive Tinel’s sign. To perform betic neuropathy, with varying results. Some of the best
the Tinel’s test, one taps posterior to the medial epi- information on the prevalence of diabetic neuropathy is
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 39

from the population-based Rochester Diabetic Neuropathy sponding increase in all complications, including dia-
Study conducted by epidemiologists from the Mayo betic neuropathy.27,28
Clinic in Rochester, Minnesota.21 This study noted that
between 60% and 65% of patients with either type 1
or type 2 diabetes had some (any) neuropathy. Forty Risk Factors
percent to 45% had symmetrical distal polyneuropathy There are both modifiable and nonmodifiable risk
(see the definition of this type of diabetic neuropathy factors for the development of diabetic neuropathy (Box
below). Approximately 30% had carpal tunnel syndrome. 3-3). Only hyperglycemia has been proven to be a risk
Six percent had autonomic neuropathy. Fewer than 5% factor via prospective, randomized, multicenter, parallel
had “other” neuropathies (including plexopathies, mono- design clinical trials.1 The other factors are considered to
neuropathies, cranial neuropathies, and radiculopathies). be risk factors via retrospective or cross-sectional data
There was no statistically significant difference in the analysis. Nonmodifiable risk factors include older age,
prevalence of neuropathy between the two types of dia- longer duration of diabetes, HLA DR 3/4 genotype, and
betes mellitus. height. Many studies have found that men are at greater
In a household-based population survey of neuro- risk for neuropathy than are females, but reanalysis of
pathic symptoms in 2400 subjects, Harris and coworkers these data shows it to be height rather than gender that
with the NIH estimated the prevalence of neuropathic is significant. It is hypothesized that longer nerves are
symptoms to be about 30% in patients with type 1 dia- more prone to nerve damage.29,30
betes. In respondents with type 2 diabetes, they estimated Age, duration of diabetes, and the DR 3/4 genotype
a prevalence of 36% for men and 40% for women com- are also risk factors for the other two microvascular com-
pared to 10% to 12% in a control group of matched non- plications of diabetes: retinopathy and nephropathy.
diabetic men and women.22 In addition, the prevalence Genetic investigations into the polymorphisms of the
of neuropathic symptoms increased twofold with the aldose reductase gene have revealed various suscepti-
duration of diabetes over 20 years compared to subjects bilities to microvascular complications including neu-
at 0 to 4 years since diagnosis. This finding confirms ropathy. Initial work on the Z-2 gene was promising, but
previous results published by Pirart, who analyzed the at this time, one can only conclude that more work is
findings of a large population of patients with diabetes necessary to further define the role of the polymor-
over many years.23 He found an increase in the pre- phisms of the aldose reductase gene and their role in the
valence of neuropathy with both increased duration of pathogenesis of diabetic neuropathy.31
diabetes and worse glycemic control.
In a longitudinal study from Finland, Partenen and
colleagues performed nerve conduction testing in 133
Hyperglycemia
patients with newly diagnosed type 2 diabetes.24 The Modifiable risk factors include hyperglycemia, hyperten-
baseline prevalence of definite or probable DPN was sion, elevated cholesterol, smoking, and heavy alcohol
8.3% versus 2.1% in a control group. The prevalence of use. The Diabetes Control and Complications Trial
DPN in the group with diabetes increased to 16.7% after (DCCT) and the United Kingdom Prospective Diabetes
5 years and 41.9% after 10 years. The prevalence of DPN Study have demonstrated conclusively that better glucose
was increased in patients with higher fasting glucose and control prevents or slows the progression of diabetic
A1C values and lower fasting plasma insulin concentra- neuropathy8,32,33 (Table 3-2). The recent EDIC Study
tions. A cross-sectional study from Turkey evaluated 866 confirms that this effect persists in slowing the progres-
patients with type 2 diabetes for a mean duration of sion of microvascular disease, including diabetic neu-
8.5 years.25 These investigators defined neuropathy as ropathy, even after the improved glycemic control is no
the presence of (a) abnormal neurologic symptom scale, longer present (“metabolic memory”)34,35 (Fig. 3-7).
(b) abnormal neurologic disability score, (c) abnormal
sensory or motor signs and symptoms, and (d) decreased
toe vibration perception. The prevalence of DPN in their
BOX 3–3 Risk Factors for Diabetic Neuropathy
patients according to these criteria was 60%. The part of
the world reporting the highest prevalence of DPN is Nonmodifiable risk factors
South India. Mohan and colleagues, defining neuropathy Older age
as bilateral absence of ankle jerks and/or vibratory loss Longer duration of diabetes
HLA DR 3/4 genotype
using biothesiometry, reported a 69.8% prevalence of
Greater height
DPN in 726 patients with type 2 diabetes of over 25 years’ Modifiable risk factors
duration.26 Unfortunately, this trend toward a higher Hyperglycemia
prevalence of DPN will most likely continue. As the Hypertension
worldwide prevalence of diabetes increases from an esti- Elevated cholesterol levels
Smoking
mated 200 million people in 2005 to 333 million people
Heavy alcohol use
by 2025, epidemiologists have already predicted a corre-
40 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

TABLE 3-2 DCCT and UKPDS Landmark Clinical 7%

Trials of Glucose Control
6%
DCCT UKPDS
Type of diabetic patients 1 2 5%

Percent positive
Number of patients 1441 4209
Length of study (years) 10 20 4%
Average length of patient follow-up (years) 5 10
Average HbA1C (%) 3%
Standard therapy 8.9 7.9
Intensive therapy 7.1 7.0 2%
Average glucose level (mg/dL)
Standard therapy 231 177 1%
Intensive therapy 155 147
Reduction in retinopathy (%) 76 21
Reduction in nephropathy (%) 56 34 0%
Reduction in neuropathy (%) 60 25 1 2 3 4 5 6 7 8
EDIC year
DCCT, Diabetes Control and Complications Trial; UKPDS, United Kingdom
Figure 3–7 EDIC study. Frequency of neuropathy-positive
Prospective Diabetes Study; HbA1C, glycosylated hemoglobin.
questionnaires across 8 years of the EDIC among former DCCT
conventional therapy (yellow dots) and intensive therapy (blue
The EDIC Study also recently demonstrated a statis- dots) without confirmed DPN at the end of the DCCT. ( p <.0001
on average for all EDIC years combined.) (Redrawn with permission
tical reduction in the number of foot or leg ulcers in the from Martin C, Albers J, Herman W, et al: Neuropathy among the
DCCT intensive versus the conventional therapy group Diabetes Control and Complications Trial cohort 8 years after trial
(4 versus 11, p = .01).36 The authors of this prospective completion. Diabetes Care 29:340–344, 2006.)
epidemiologic trial call for “the implementation of inten-
sive therapy as early as is safely possible and the mainte- cholesterol, triglycerides, body mass index, a history of
nance of such therapy for as long as possible, with the smoking, hypertension, the presence of microalbumin-
expectation that a prolonged period of nearly normal uria, and cardiovascular disease. Noting that only aggres-
blood glucose levels will result in an even greater reduc- sive medical treatment to control glucose has been
tion in the risk of complications in patients with type 1 demonstrated to reduce the progression of neuropathy,
diabetes.”37 Since the etiology of DPN in type 2 diabetes the authors of this study propose clinical trials to
is presumably the same as that in type 1 diabetes, early “confirm the efficacy of antihypertensive agents and pos-
intensive glycemic control with a target A1C of 6.5% sibly other strategies for cardiovascular risk reduction in
should be the goal of clinicians who treat these patients. slowing progression of neuropathy.”24
The same target A1C of 6.5% is recommended by the
investigators of the Kumamoto Study.38 In this 10-year
prospective study, 110 patients with type 2 diabetes were
Alcoholism, Uremia, and Organ Transplantation
randomly assigned to one of two groups: a multiple Alcoholism, a common cause of polyneuropathy in non-
insulin injection therapy group or a conventional insulin diabetic individuals, is, like DPN, often associated with
injection therapy group. The multiple-injection therapy prominent neuropathic pain.41 Alcoholic neuropathy is
group maintained a 64% risk reduction in diabetic neu- considered to result from a direct neurotoxic effect of
ropathy as defined by significant improvement in nerve ethanol independent of thiamine deficiency.42 Therefore,
conduction velocity and vibration threshold.39 listing it as an independent risk factor for the develop-
ment of diabetic neuropathy is problematic.43,44 It would
be reasonable to postulate that the increased incidence
Vascular Risk Factors of neuropathy in diabetic patients who are heavy alcohol
A recent publication of a large prospective study of users is no more than a combination of two neuropathies
patients with type 1 diabetes, the EURODAIB IDDM occurring in the same individual. In an individual
Complications Study, has expanded our understanding patient, it can be very difficult if not impossible to deter-
of the role of vascular risk factors in diabetic neu- mine which condition is responsible for the clinical
ropathy.40 In this prospective multicenter study, new- findings. It is of interest to note that a reversal of
onset neuropathy developed in 276 of 1172 patients with alcoholic neuropathy has been described in patients
type 1 diabetes during an average follow-up of 7.3 years. with end-stage liver disease following successful liver
As expected, the development of DPN was highly corre- transplantation.45
lated with both the duration of diabetes and the level of The situation of mixed etiologies for neuropathy with
the hemoglobin A1C. Using a multivariate logistic- ethanol is similar to patients with diabetes who develop
regression model to adjust for duration of diabetes and end-stage renal failure. Uremic polyneuropathy “occurs
glycemic control, these investigators noted the following in about half of patients undergoing dialysis and is
risk factors to be statistically significant for the develop- characterized by axonal degeneration with secondary
ment of DPN: total cholesterol, low-density lipoprotein segmental demyelination.”46 Diabetic patients with renal
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 41

failure are more likely to have greater sensory involve- Both these trials were prospective randomized studies
ment with uremia than are nondiabetic individuals, and comparing groups utilizing intensive versus conventional
diabetic patients are less likely to respond to newer treat- therapy to achieve “tighter” glycemic control. In both of
ments such as erythropoietin therapy.47 these trials, patients who were randomized to the inten-
Hemodialysis or peritoneal dialysis typically halts the sive control group had better nerve conduction velocity
progress of polyneuropathy but usually does not bring tests. Furthermore, the DCCT demonstrated better auto-
improvement. However, clinical improvement in DPN nomic nervous tests and less “confirmed clinical” neu-
and overall prognosis in both patients with diabetes and ropathy in patients with better glucose control. As was
patients without diabetes is much greater with successful previously noted, long-term follow-up of the DCCT
renal transplantation than with either hemodialysis or patients has finally demonstrated that 5 years of better
peritoneal dialysis.48 glucose control early in the course of diabetes results in
The most dramatic change in uremic and diabetic fewer neuropathic foot ulcers.22
neuropathy in patients with diabetes occurs after
successful simultaneous pancreas and kidney trans-
plantation. Numerous studies have demonstrated that
Neuropathy Associated with Prediabetes
restoration of normoglycemia with successful pancreas In 1997, the ADA changed the diagnostic criteria for
transplantation is not only able to halt the progression of diabetes, lowering the fasting glucose from 140 mg/dL
diabetic polyneuropathy but also may lead to objective (7.8 mmol/L) to 126 mg/dL (7.0 mmol/L).52 They also
improvement.49,50 created new categories called impaired fasting glucose
(plasma glucose fasting 110 to 125 mg/dL) and impaired
glucose tolerance (IGT), defined as patients with a 2-hour
Pathogenesis postprandial glucose between 140 and 199 mg/dL.53
More recently, the ADA cutoff for the fasting glucose has
Much information as to the etiology of the diffuse neu- been lowered to 100 mg/dL for impaired fasting glucose,
ropathies has been established in the last 30 years. After and this group and the IGT group are now sometimes
reviewing the risk factors, it would be of interest to ask lumped together under the term prediabetes.54,55
four important questions about neuropathy that have The clinician needs to be cognizant that neuropathy
stymied clinicians for years: can frequently be the presenting symptom of these
patients who are not diabetic but meet the diagnostic cri-
1. How do the various pathogenic mechanisms of dia-
teria of IGT or prediabetes.56 These patients may present
betic complications explain the link between hyper-
with a “length-dependent polyneuropathy that typically
glycemia and neuropathy?
is sensory predominant and painful.”57 Typical symptoms
2. Why do patients develop neuropathy with only min-
of this condition include paresthesias and dysesthesia of
imal hyperglycemia, for example, impaired glucose
the toes and fingers in which the only objective findings
tolerance?
are neurologic signs limited to those of small-caliber
3. Why do neuropathic symptoms often become exacer-
sensory nerve fiber involvement: reduced distal pinprick
bated after glycemic control is improved?
sensation. However, vibratory sensation and reflexes
4. Why do some individuals seem less likely to develop
(which require large fibers) are intact. Although nerve
neuropathy than others despite worse glycemic
conduction velocity (NCV) studies will be normal, distal
control?
leg skin biopsies show loss of small-caliber nerve fibers.58
Clearly, these questions would apply to all the Most patients with neuropathy associated with predia-
microvascular complications, not just to diabetic neu- betes are typical of people with the metabolic syndrome.
ropathy. At this time, at least theoretical answers to these They are obese with a preponderance of visceral fat;
elusive questions are finally appearing in the medical exhibit the classic metabolic manifestations of insulin
literature. The authors will attempt to answer these four resistance, including diabetes or prediabetes, dyslipidemia,
questions in this section on the pathogenesis of diabetic and hypertension; and have an increased risk for premature
neuropathy. cardiovascular disease.59 In general, neuropathy associated
with prediabetes is thought to be less severe and more
likely to be reversible than is the classic neuropathy occur-
Hyperglycemia ring in patients with diabetes.43 Thus, early diagnosis will
As with most diabetic complications, insulin deficiency be important for the physician to institute treatment for
and hyperglycemia are considered the initiating factors. neuropathic pain and to address the manifestations of
Although there are multiple retrospective studies that metabolic syndrome by treating obesity, postprandial
support this hypothesis, the results of the DCCT51 and hyperglycemia, dyslipidemia, and associated hyperten-
the United Kingdom Prospective Diabetes Study18,19 are sion. A final caveat for clinicians is to consider the diag-
the strongest evidence supporting this mechanism in nosis of prediabetes in patients presenting with a painful
both type 1 and type 2 diabetic patients (see Table 3-2). distal symmetrical polyneuropathy of no obvious etiology.
42 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

If the fasting glucose is between 100 and 125 mg/dL, a Other work has suggested that the increased aldose
simple 2-hour oral glucose tolerance test will confirm the reductase activity secondary to hyperglycemia competes
diagnosis of IGT or prediabetes. If no other etiology of with nitric oxide synthetase for NADPH, resulting in
the DPN is found, the patient can be presumed to have decreased nitric oxide. The reduction in nitric oxide
neuropathy associated with prediabetes.43 reduces nerve blood flow, resulting in nerve ischemia. In
A recent publication from Germany has given new experimental diabetic animals, a nitric oxide synthetase
insight into the possible etiology of neuropathy asso- inhibitor was able to block the beneficial effect of sorbinil
ciated with prediabetes in these patients who are only (an aldose reductase inhibitor [ARI]) on NCV.68,69 This
minimally hyperglycemic.60 In a pilot study, sural nerve implies that the beneficial effects on DPN of sorbinil and
biopsies were found to stain positively for the receptor other experimental drugs in this class (ARIs) seen in dia-
for advanced glycation end-products (RAGE) in the betic animals and humans might be secondary to their
perineurium, in the epineurial vessels, and in part in vascular effects on the nerve. Sural nerve biopsies from
endoneurial vessels. Control patients with another neuro- patients with DPN consistently demonstrate defects in
logic disorder had no significant staining for this antigen. the endoneurial vessels, including thickening of the
These investigators believe that their preliminary data basement membrane, endothelial cell proliferation, and
“suggest that activation of the RAGE pathway may be one hypertrophy that often closes the vessels70 (Fig. 3-9).
of the first steps in the pathogenesis of diabetic polyneu- Using a sophisticated experimental technique of fluo-
ropathy even before chronic hyperglycemia occurs.”60 rescein angiography and nerve photography, a group
of investigators in Britain was able to demonstrate
abnormal epineural vessel (vaso nervorum) anatomy and
Vasa Nervorum arteriovenous shunting in subjects with chronic sensory
It has been proposed that an abnormal vasa nervorum motor neuropathy.71 A more recent work from this group
causing local nerve ischemia will lead to poor nerve has demonstrated arteriovenous shunting and prolifer-
function (NCV, nerve conduction amplitude, quantita- ating new vessels in so-called insulin neuritis.72 This is an
tive sensory tests, and abnormal autonomic function uncommon disorder of acute neuropathic pain that is seen
tests) and nerve morphometry. in patients shortly after rapid improvement of glycemic
This concept is illustrated in a medical cartoon control (usually with the initial institution of insulin
comparing healthy and normal nerves and vessels (Fig. therapy). Using their nerve photography-fluorescein
3-8). Several studies lend credence to these mecha- angiography technique, these investigators were able to
nisms.61–63 One study demonstrated that treatment with a demonstrate proliferation of new leaky epineural vessels
prostaglandin I2 analogue (beraprost sodium) resulted analogous to those seen fundoscopically with prolifera-
in improved nerve function by theoretically inducing tive diabetic retinopathy. The authors postulate the
relaxation of vascular smooth muscle and reducing nerve epineural new vessel “lead to a ‘steal’ effect rendering
ischemia.64 Furthermore, lisinopril, an angiotensin- the endoneurium ischemic.”59
converting enzyme inhibitor, has shown an improvement
in nerve conduction velocity (NCV) both in experimental
studies with rats and in individuals with DPN. The
Protein Kinase C Pathway Activation
improvement of NCV by lisinopril was hypothesized to The diacylglycerol–protein kinase C (PKC) pathway
be secondary to vasodilatation secondary to increase in activation has been proposed to explain some of the
nitric oxide.65–67 complications of diabetes and might help to explain the

Figure 3–8 Normal and damaged

Healthy Damaged nerves. Examination of tissues from
patients with diabetes reveals
capillary damage, neovascularization,
and occlusion in the vasa nervorum.
Reduced blood supply to the neural
tissue results in impairments in
neurotransmission that affect both
sensory and motor conduction.
(References: Cameron NE, et al:
Diabetologia 44:1973–1988, 2001. Dyck
PJ, Giannini C: J Neuropathol Exp Neurol
55:1181–1193, 1996. Copyright 2005
International Medical Press.)

Vaso nevorum
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 43

Figure 3–9 Photomicrographs

of endoneurial capillaries.
Photomicrographs of endoneurial
capillaries from sural nerve
biopsies showing (A) a normal
capillary from a diabetic subject
without neuropathy and (B) a
closed capillary from a subject with
diabetic neuropathy with basement
membrane (BM) thickening and
endothelial cell (e) proliferation.
(Courtesy of RA Malik, University of
Manchester, Manchester, U.K.
Reprinted with permission from
Cameron NE, Eaton SE, Cotter MA,
et al: Vascular factors and metabolic
interactions in the pathogenesis of
diabetic neuropathy. Diabetologia
A B
44:1973–1988, 2001.)

above findings in a unified hypothesis. Hyperglycemia sion of evening primrose oil and a-lipoic acid will follow
increases the formation and the metabolism of diacyl- in the section on treatment of painful DPN.
glycerol, which in turn activates PKC.73 In addition,
hyperglycemia activates the polyol pathway, which in
turn decreases myo-inositol (see below).74 The altered Polyol Pathway
inositol phospholipid metabolism also increases PKC The polyol pathway consists of converting glucose to sor-
activity.75 PKC mediates a vascular response to hyper- bitol via aldose reductase and then converting sorbitol to
glycemia that involves both the endothelium and smooth fructose via sorbitol dehydrogenase. The pathway is rela-
muscle tissue. PKC regulates vascular permeability, con- tively dormant at normal glucose levels and activated
tractility, basement membrane synthesis, and cellular during hyperglycemia owing to the Km of the aldose
proliferation.76–79 Inhibition of the b form of PKC with reductase enzyme. Besides the competitive consumption
LY333531 appears to decrease vascular endothelial growth of NADPH and the theoretical decrease in nitric oxide
factor in the retina and transforming growth factor beta synthetase activity, the increased activity of the polyol
(TGF-b) in the kidney.80,81 Vascular endothelial growth pathway also decreases nerve myo-inositol through mech-
factor and TGF-b are believed to play pivotal roles in the anisms that are not well understood.88–90
development of diabetic retinopathy and nephropathy, Shunting of glucose into the polyol pathway leads to
respectively.82,83 Recent clinical trials of protein kinase an accumulation of fructose and sorbitol and an increase
inhibitor LY333531 (now know as ruboxistaurin) for dia- in intracellular osmolality. As cells accommodate to
betic microvascular complications, including DPN, are maintain osmotic balance, there may be a compensatory
currently under way.84 depletion of other intracellular compounds such as
endoneurial myo-inositol and taurine. The decrease in
nerve myo-inositol may also lead to a decrease in nerve
Abnormal Fatty Acid Metabolism function (i.e., NCV) and to abnormal morphometry.91
Linoleic acid is converted to g-linolenic acid, which is con- The role of taurine in neuropathy and other diabetic
verted to dihomo-g-linolenic acid. Dihomo-g-linolenic complications is currently under investigation.92
acid will eventually be converted (through several more Clinical studies with ARIs have documented improved
steps) to arachidonic acid, which helps to dilate blood morphometry and an improvement in NCV.93 Only one
vessels. In diabetes, the d-6-desaturation of linoleic acid study using an ARI has attempted to prevent the develop-
to g-linolenic acid is impaired. This forces prostaglandin ment of diabetic neuropathy. In this double-blind, ran-
metabolism down an alternative pathway, leading to a domized, placebo-controlled, multicenter study, results
decrease in nerve function either directly or indirectly showed an improvement in peroneal motor, median motor,
via nerve ischemia as a result of altered prostaglandin and median sensory NCV, but prevention of confirmed
metabolism (see above).85,86 When patients were given clinical neuropathy was not statistically different between
evening primrose oil, which is high in g-linolenic acid, in the ARI group and the placebo group.94 However, the
a double-blind, placebo-controlled, randomized, multi- statistical power of the study was noted to be inadequate.
center study, both peroneal and median motor NCV and In a small, single-center, longitudinal study, long-term
thermal perception threshold improved in the patients treatment with the ARI sorbinil prevented the deteriora-
who were randomized to g-linolenic acid treatment com- tion of tactile and thermal perception threshold.95
pared to the control patients.87 However, clinical signs In summary, therapy with an ARI is associated with both
and symptoms were unchanged. A more detailed discus- an improvement of NCV and morphometry, presumably
44 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

via a restoration of nerve myo-inositol concentration and colleagues present a strong case for the importance of
improved nerve blood flow. However, clinical efficacy of neural antibodies in diabetic autonomic neuropathy but
this class of medicines has not been established. This admit that evidence for an etiologic role of antibodies in
may be due to clinical trial design rather than lack of somatic neuropathy has not yet been convincingly
efficacy. demonstrated.110
Investigators are still interested in this area of
research, and one group has recently stated that
“renewed efforts to develop aldose reductase inhibitors
Nerve Growth Factors
for the treatment and prevention of diabetic complica- Distal dying back of nerves is a common morphometric
tions are warranted.”96 finding in patients with diabetic neuropathy. Efforts to
reverse this process with nerve growth factor and gan-
gliosides have been attempted in clinical trials. Both
Myo-inositol nerve growth factor and ganglioside treatment result
Hyperglycemia, per se, competitively inhibits neural in axonal sprouting and could theoretically improve
uptake of myo-inositol (in addition to the polyol pathway nerve function, especially in small nerve fibers. To
decreasing nerve myo-inositol). It is hypothesized that date, results of these trials have been inconsistent and
Na+-K+-ATPase activity is decreased by lower myo-inositol disappointing.111,112
concentrations and thus presumably slows NCV.97 In some One of the neurotrophic factors is nerve growth factor
studies, patients and animals placed on a high-myo-inositol (NGF). In a recent review of the subject, Pittenger and
diet showed improvement in NCV, but in other studies, Vinik state that “there is increasing evidence that there
the results were contradictory.98–100 Improvement in is a deficiency of NGF in diabetes, as well as the
nerve morphometry and autonomic neuropathy has been dependent neuropeptides substance P (SP) and calci-
shown in animals placed on high-myo-inositol diets.101–104 tonin gene-related peptide (CGRP) that may also con-
tribute to the clinical symptoms resulting from small
fiber dysfunction.”113
Advanced Glycated End-Products
Increased levels of glycosylated neural proteins have also
been attributed to hyperglycemia. The first step in glyco-
Delineating the Etiologies
sylation of proteins is bonding of glucose to a free amino It is clear that many etiologies can lead to the common
group. Subsequent glycosylated neural protein can cross- clinical manifestation of diabetic neuropathy (Fig. 3-10).
link, leading to the formation of advanced glycosylated Although all the pathways are feasible and appear to be
end-products (AGEs). Cross-linking changes the three- valid in animal studies, confirmation in human clinical
dimensional configuration of the proteins, and the pro- trials, with the exception of hyperglycemia, is generally
teins may become dysfunctional. This might account for lacking. In a recent review article, Cameron and col-
the slowing of axonal transport that is observed in dia- leagues note that although “it is clear that impaired
betic neuropathy. Aminoguanidine prevents this cross- blood flow and endoneurial hypoxia play a major role in
linking from occurring. Future studies might show that causing diabetic neuropathy in human and animal
aminoguanidine or similar products may be useful in the models,” the “link between vascular dysfunction and
prevention of the development of diabetic neuropathy. long-term degenerative changes is not entirely clear and
In addition, aminoguanidine appears to have ARI prop- merits future attention.”114
erties and effects on nitric oxide and vascular flow in Clinical trials of the chronic complications of diabetes
animal models of diabetes.105,106 However, these latter require demonstrating that the progression of the
effects of aminoguanidine have not been confirmed by specific complications can be slowed or prevented. This
other studies. requires adequate time for the control group to develop
the complication or demonstrate a worsening of the
condition. In diabetic individuals with stage 0 or 1 neu-
Antibodies to Neural Tissue ropathy, the rate of progression is very slow. It has been
Although antibodies to nerve tissue are associated with estimated that NCV (one of the most reliable and precise
the presence of neuropathy in both type 1 and type 2 dia- measurements) deteriorates at a rate of 0.5 m/sec/yr.
betic patients, it is not clear that these antibodies play an This would imply that the minimum worsening in NCV
initial etiologic role. These antibodies could simply be a that would be considered clinically significant (2 to
response by the immune system to damaged nerves. 3 m/sec) in the control group would take 4 to 6 years.
However, once the autoantibodies have been produced, This is compounded by the fact that physiologic changes
it is certainly feasible that they might further impair in NCV can be as much as 2 to 3 m/sec. For instance, one
nerve integrity and function.107–109 Clinical trials of study showed that an improvement in plasma glucose
immune suppression therapy for diabetic neuropathy levels via a 20-minute intravenous insulin infusion can
have not been conducted. In a recent review, Vinik and improve NCV by 2 m/sec.115,116 Furthermore, there appear
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 45

Figure 3–10 Proposed

Hyperglycemia/Insulin deficiency etiologies of diffuse diabetic
neuropathy. Abnormal vasa
nervorum, insulin deficiency,
hyperglycemia, abnormal fatty
Abnormal Abnormal Ø Polyol Œ Uptake Ø Glycosylation acid metabolism, increased
vaso fatty acid activity myo-inositol of neural proteins
Smoking nervorum metabolism polyol activity, decreased nerve
myo-inositol, increased
glycosylation of neural proteins,
and neural autoantibodies have
ΠNitric oxide ΠNerve ΠAxonal transport all been suggested as etiologies
synthase myo-inositol of diabetic neuropathy. There
activity and taurine appears to be a common end
Painful
foot result: confirmed clinical
neuropathy. In a single individual,
one or more of these pathways
may be prominent. In another
Nerve ΠNerve Diabetic
ischemia neuropathy individual, other pathways may
function
play a more predominant role.
(Redrawn with permission from
Pfeifer MA, Schumer MP: Clinical
Abnormal morphology Insensate foot trials of diabetic neuropathy: Past,
present and future. Diabetes
44:1355–1361, 1995.)
Neural antibodies

3.5
Change in peroneal NCV (msec)

2.5

1.5

0.5

0
Better High Aldose g-linolenic Pancreatic Lisinopril
glucose myo-inositol reductase acid transplant
control diet inhibitor supplement
Figure 3–11 Change in peroneal NCV. Change in peroneal NCV in human diabetic individuals in various clinical trials. Better glucose
control, a high-myo-inositol diet, use of an aldose reductase inhibitor, g-linolenic acid oral supplementation, pancreatic transplant, and
use of an angiotensin-converting enzyme inhibitor (lisinopril) have been evaluated in human clinical trials. Interestingly, the change in
peroneal nerve conduction velocity has been very similar (an increase of 1 to 2 m/sec) in all these well-done, controlled clinical trials.
Therefore, it would not appear that one of the etiologic pathways plays a consistently dominant role. Combined-therapies clinical trials
have not been done. (References: Reja A, Tesfaye S, Harris ND, Ward JD: Is ACE inhibition with lisinopril helpful in diabetic neuropathy? Diabet
Med 12:307–309, 1995. The -Linolenic Acid Multicenter Trial Group: Treatment of diabetic neuropathy with  -linolenic acid. Diabetes Care
16:8–15, 1993. Obrosova I, Faller A, Burgan J, et al: Glycolytic pathway, redox state of NAD (P)-couples and energy metabolism in lens in
galactose-fed rats: Effect of an aldose reductase inhibitor. Curr Eye Res 16:34–43, 1997.)

to be a metabolic component and a structural compo- NCV. Figure 3-11 compares change in NCV in various
nent to diabetic neuropathy. The metabolic component clinical trials.67,87,90,118–121
could be the result of any of the proposed etiologies It is interesting that this improvement is very consis-
listed above. tent among the various trials and methods. This implies
Theoretically, this component is reversible if the that most, if not all, of the proposed mechanisms play
underlying abnormality is corrected. In fact, many of the a similar contributing role or that they interplay in a
clinical trials that test the various hypothesized patho- single common pathogenic mechanism. The most likely
genic mechanisms demonstrate a small (1 to 2 m/sec) common mechanism might be the vascular component.
statistical but not clinically meaningful improvement in The structural component does not appear to be
46 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

single hyperglycemia-induced process of overproduction

of superoxide by mitochondrial electron-transport
chain.”107 Furthermore, Brownlee speculates that the
phenomenon of hyperglycemia-induced mitochondrial
superoxide production may provide an explanation for
the “metabolic memory” phenomenon described in the
EDIC trial, that is, the development or exacerbation of
75% Normal 50% Normal 25% Normal diabetic complications during years of improved
function function function
glycemic control after years of poor control. In the same
Time Banting lecture, Brownlee also suggests a potential
answer to the question posed about individual suscepti-
bility to neuropathy at the beginning of this section.107
He describes familial clustering of microvascular and
Reversible Irreversible Normal
component of component of
macrovascular complications, although most of these
abnormality abnormality reports from clinical trials have been described for
Figure 3–12 Reversible and irreversible components of
retinopathy and nephropathy.
DPN. Reversible and irreversible components of diabetic A further link between the four mechanisms of hyper-
neuropathy as a function of time. There appear to be both a glycemic complications noted by Brownlee and DPN is
reversible (metabolic) and an irreversible (structural) component suggested in a recent review titled “Neural Redox Stress
to diabetic neuropathy. The reversible component appears to play and Remodeling in Metabolic Syndrome, Type 2 Diabetes
a greater role earlier in the natural history of diabetic neuropathy.
In contrast, the irreversible component appears to play a greater
Mellitus, and Diabetic Neuropathy.”123 The authors review
role later. The response of any treatment modality would be the data indicating that a compromise of antioxidant
limited to the reversible component. Thus, early prevention and reserve and toxicities from excessive glucose, free fatty
consistent treatment of the reversible components appear to be acids, amylin, AGEs, homocysteine, and other metabolic
the only practical approach for the therapy of diabetic substrates are associated with an abundance of reactive
neuropathy. It is unlikely that reversibility of advanced neuropathy
is any more likely than is reversibility of the other chronic
oxygen species (ROS). They note that elevated tension
complications of diabetes (retinopathy or nephropathy). By of redox stress and ROS have been reported to lead to an
controlling blood glucose level, the DCCT (see text) was able to increase in matrix metalloproteinase (MMP) activity.124
prevent the development of diabetic neuropathy in patients They postulate that a key link to DPN would be a pro-
without neuropathy at the beginning of the trial. However, some posed “robust activation of MMP-9,” which could result
patients already had neuropathy at the beginning of the DCCT,
and there was no difference in the reversibility of neuropathy in
in a “complete disconnection of the neuronal microvas-
these patients with better glucose control compared to the less cular cells within the neuronal unit.”109 These associa-
well-controlled patients. tions might help to explain the proclivity of patients with
the metabolic syndrome to develop DPN before they are
diagnosed with overt type 2 diabetes.
reversible and might represent a greater portion of the
sum total nerve abnormality and damage over time (Fig.
3-12). Therefore, even small reversibility of late stage 2 or Documentation of Neuropathy
3 neuropathy is probably not feasible.
Delineation of etiologies also requires clear-cut end
points. However, with the exception of the DCCT, clinical
Clinical Presentation
trials of diabetic neuropathy have been too short, under- Symptoms of a distal diabetic polyneuropathy vary from
powered, and conducted in patients with advanced patient to patient, but common complaints are numb-
disease and without clear-cut demonstrable end points. ness, tingling, and pain beginning in the toes and soles
In the future, further delineation of the causes of dia- of the feet, progressing over months to years to affect the
betic neuropathy will be possible only by meeting this top of the feet, ankles, and lower shins. Patients often
requirement. volunteer a variety of other descriptions including a dead
feeling in the feet, burning sensation, and pins and
needles in the feet (paresthesias). Some patients state
A Unifying Hypothesis of Diabetic Complications their feet feel as if immersed in cold water or a block of
In the 2004 Banting Lecture, Brownlee proposed that ice. In addition to a baseline burning pain or discomfort,
the four major pathogenic mechanisms of hyperglycemic superimposed shock-like, electric, or ice-pick pains
damage may result from a single mechanism.122 The four frequently complicate the lives of patients with diabetic
known mechanisms are (1) increased polyol pathway flux, neuropathy and commonly are the most concerning
(2) increased intracellular formation of AGEs, (3) activa- complaints during an office visit. Other descriptors used
tion of protein kinase C and (4) increased hexosamine by patients include jabbing, icy cold, formication (sensa-
pathway flux. All of these mechanisms “seem to reflect a tion of bugs crawling on the skin), cramping, sunburn,
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 47

frostbite, intense itching, and the perception of walking may use with this type of pain are “burning sensation,”
on broken glass. Sensory symptoms are commonly worse “sunburn-like,” “skin tingles,” or “painful sensation when
at night, particularly when the patient is trying to fall something touches me” that normally would not hurt,
asleep. Often, patients with diabetic neuropathy state such as bed sheets or stockings.
that movement, walking, or standing lessens the pain, a Paresthesic pain is thought to occur from several pos-
characteristic that is unusual in patients with nociceptive sible etiologies: (1) spontaneous activity and increased
pain such as osteoarthritis of the feet or plantar fasciitis. mechanosensitivity near the cell body of damaged afferent
Unclear is the explanation for the seemingly paradoxical axons in the dorsal root ganglion; (2) loss of segmental
worsening of pain at night. It might relate to the absence
of distractibility, which is present during the day but not
when one is trying to fall asleep. TABLE 3-3 Descriptors of Different Types of
Neuropathic Pain
Dysesthesia Paresthesia Muscular Pain
Types of Pain
Burning sensation Pins and needles Dull ache
Three types of pain have been described in patients with Sunburn-like Electric-like Night cramps
Skin tingles Numb but achy Band-like sensation
painful diabetic neuropathy: According to the pain Painful sensation Like feet in ice water Drawing sensation
model developed by David Ross, the three categories are when something
dysesthesia, paresthesia, and muscular pain125 (Table 3-3, touches me that
normally would not
Fig. 3-13). Dysesthetic pain has been attributed to a hurt (e.g., bedsheets
cutaneous or subcutaneous distribution and may be or stockings)
attributable to increased firing of damaged or abnor- Knife-like Deep aches
Shooting pain Spasms
mally excitable nociceptive fibers, particularly sprouting Lancinating pain Toothache-like
regenerating fibers. The pain descriptors that a patient

Demylinated Muscle
patch

Skin

Normal

A B C D

Pain Muscle Painful

transmission spasm stimuli
neuron Skin
; :
Inhibitor
cell
:
;
;
Swollen
Normal

E F G
Figure 3–13 Three types of pain. The proposed etiologies of the different types. A, Dysesthesia pain. Increases firing of damaged
or abnormally excited nociceptive fibers, particularly sprouting regenerating fibers in the cutaneous tissue. B, Paresthesia pain.
Spontaneous activity and increased mechanosensitivity near the cell body of damaged afferents in the dorsal root ganglion.
C, Paresthesia pain. Ectopic impulses generated from demyelinated patches of myelinated axons. D, Muscular pain. Ectopic impulses to
the muscle generated from demyelinated patches resulting in muscle spasms and pain. E, Paresthesia pain. Loss of large myelinated
fibers on the effects of the small unmyelinated fibers (modified gate control hypothesis). Pain signals are transmitted from the spinal cord
pain transmission neuron as a result of the input from the unmyelinated, myelinated, and inhibitor cells. F, Paresthesia pain. Increased
firing of endings of nociceptive afferents that innervate the nerve sheaths themselves (nervi nervorum). The endoneurial swelling is
secondary to endoneurial sodium accumulation and marked nerve hydration. G, Muscular pain. Reflex loop (Livingston’s vicious cycle)
involving a nociceptive input that activates the motor neuron within the spinal cord causing muscle spasms that in turn activate the
muscle nociceptors and feeds back to the spinal cord to sustain the spasm. (Redrawn with permission from Pfeifer MA, Ross D, Schrage J,
et al: A highly successful and novel model for the treatment of chronic painful diabetic peripheral neuropathy. Diabetes Care 16:1103–1115, 1993.)
48 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

inhibition of large myelinated fibers on small unmyeli- Leg weakness is typically a late feature of diabetic neu-
nated fibers (modified gate control in which pain signals ropathy, as patients usually do not complain of toe weak-
are transmitted from the spinal cord transmission ness, the first body region affected by weakness in most
neuron as a result of the input from the unmyelinated, people with diabetic neuropathy. Ankle weakness or foot
myelinated, and inhibitor cells); (3) ectopic impulses drop is typically the first motor symptom of diabetic neu-
generated from demyelinated patches of myelinated ropathy noted by patients. Intuitively, one would predict
axons; or (4) increased firing caused by physiologic that the weakness or foot drop would be symmetrical, but
stimulation of endings of nociceptive afferents that inner- commonly, it presents in one leg before the other. Not
vate the nerve sheaths themselves (nervi nervorum). infrequently, the foot drop also affects foot eversion,
Morphologic changes in affected nerves include nerve a clinical presentation that is more in keeping with a
fiber loss, axonal atrophy, nodal swelling, and endoneurial common peroneal palsy, one of the common compres-
swelling.126 These abnormalities may lead to other struc- sion mononeuropathies observed in diabetic neuropathy.
tural changes (e.g., axonal degeneration, myelin wrin- Over time, the asymmetrical foot drop spreads to the
kling, and Wallerian degeneration). The endoneurial contralateral foot. When the weakness moves to the
swelling may be secondary to endoneurial sodium accu- hands, patients often complain about dropping of
mulation and marked increase in nerve hydration. The objects, deteriorating handwriting, and loss of muscle
pain descriptors that are used to describe paresthesia mass in the hands. Entrapment neuropathies are
include “pins and needles,” “electric-like,” “numb,” “aching common in diabetic neuropathy. Patients with a super-
feet,” “feel as if my feet have been in ice water,” “knife- imposed carpal tunnel syndrome will have complaints
like,” “shooting pains,” or “lancinating pains.” that are unique to that diagnosis, such as atrophy and
The third type of pain is muscular pain. This is weakness of thumb abduction, numbness and pain in the
believed to be secondary to injury to the motor neurons distribution of the median nerve, and worsening hand
(e.g., demyelinated patches) or “Livingston’s vicious pain at night.
cycle.”127 Ectopic neural impulses to the muscle may be
generated from the demyelinated patches in motor
nerves. These ectopic impulses would result in muscle
Symptoms of Autonomic Neuropathy
spasms and pain. Livingston’s “vicious cycle” is a reflex Symptoms of autonomic neuropathy frequently parallel
loop involving a nociceptive input that activates the somatic complaints. Autonomic neuropathy in diabetes
motor neuron within the spinal cord causing muscle affects many organ systems, including the skin, the con-
spasms that in turn activate the muscle nociceptors and duction system of the heart, gastric and bowel motility,
feed back to the spinal cord to sustain the loop and the urinary bladder, and sexual function. Patients complain
spasms and pain. Muscular pain descriptors include “dull of a range of symptoms from dry, cracked, and mottled
ache,” “night cramps,” “band-like sensation,” “drawing skin, orthostatic dizziness, and syncope to abdominal
sensation,” “spasms,” and “toothache-like.” Physical bloating after eating, diarrhea or constipation, urinary
examination often reveals tight, contracted foot exten- retention or incontinence, and penile erection and
sors and gastrocnemius muscles. Treatment for muscular ejaculation impairment. The most common cardiac com-
pain includes lower-limb stretching exercises twice a day plaint is orthostatic hypotension, yet it is well known that
and proper footwear, including custom shoes and resting tachycardia and silent myocardial infarction are
metatarsal bars where necessary. Patients are encouraged common in diabetic patients, reflecting underlying auto-
to avoid high heels because they cause undue strain on nomic system disease.
the gastrocnemius muscles. If the muscular pain con-
tinues after 2 weeks of exercise, a muscle relaxant
should be considered. Alternatively, a nonsteroidal anti- Neurologic Examination
inflammatory drug could be used to break “Livingston’s
vicious cycle.”
Overview
The physical examination of a patient with diabetic
neuropathy often begins with the vital signs and the need
Motor Signs and Symptoms for pulse and blood pressure measurements in several
Imbalance of walking is a commonly elicited complaint positions (supine, sitting, and standing) to assess for
even if not volunteered by the patient initially. It often orthostasis and pulse change. Patients with symptoms
begins with difficulty maintaining balance in the shower that are suggestive of orthostatic hypotension should be
when washing hair and the feet are close together. The tested supine, sitting, and standing, delaying measure-
patient may have gait ataxia walking in the dark yet no ments until at least 1 minute after the position change.
ataxia during the day. This symptom relates to the loss of In the setting of profound orthostasis, patients with auto-
proprioception in the toes and ankles, a sign that is nomic neuropathy might have little or no change in
commonly confirmed on testing of joint position sense pulse, reflecting sinoatrial node disease and the inability
in the feet. to generate a tachycardia during position changes and
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 49

stress. In contradistinction, patients with hypovolemia gradient loss is detected to cold perception in patients
and normal cardiac function should have a rise of pulse with small sensory fiber involvement. This writer has
of 20 to 30 when the patient changes position. found with experience that a cold perception gradient loss
Observation of the lower limbs and particularly the is easier to define than is loss of pin and pain perception.
feet often gives clues to abnormalities betraying an under- Loss of joint position sense (proprioception) is usually
lying neuropathy. Patients often have dry and cracked the last sensory modality to become abnormal in a distal
skin, nail changes, and skin discoloration, raising the gradient loss neuropathy but is commonly detected in
possibility of autonomic disease. Feet are most often cold patients with long-standing diabetic neuropathy.
to touch, yet at other times, they may be warm. Even
though patients and physicians often attribute excessive
coldness to “poor circulation,” foot pulses are often
Sense of Touch: Monofilament Testing
easily palpated, since the underlying mechanism is auto- Performing monofilament testing on the plantar surface
nomic impairment and not large vessel disease. of the great toe and the pulp of the index finger bilat-
In mild diabetic distal neuropathy, the two most erally can assess the sense of touch. They are often used
prominent changes on neurologic examination will be a as screening devices for determining whether patients
reduced or lost ankle reflex and a distal gradient loss of have neuropathy or have lost their protective sensation,
large and small sensory fiber modalities; the latter is rendering them much more prone to ulceration. The
often referred to as “stocking-and-glove” sensory loss. currently available instruments are known as the Semmes-
Examination with a 128-Hz tuning fork is the most prac- Weinstein monofilaments. They are usually made of fine
tical way to check for the presence or absence of vibra- nylon and designed so that the amount of pressure
tory sensation in the feet (Fig. 3-14). Most often, patients administered to the plantar surface is a function of
show deficits in vibration perception at the great toe. the instrument and not the examiner. Each of the 24
Over time, the deficits move proximally to the metatarsal- available nylon monofilaments is calibrated to deliver a
phalangeal joints, dorsum of the foot, ankle, and the different bowing force (buckling stress). Each mono-
mid-shin region. In typical cases, patients have similar filament is marked with a number that represents the
but less severe abnormalities in the fingers by the time decimal log of 10 times the force in milligrams ranging
deficits are found at the mid-shin or knee. A similar distal from 1.65 (000.45 g) to 6.65 (447 g) of linear force (Fig.
3-15). The various sites for monofilament testing on the
plantar surface of the feet are illustrated in Figure 3-16.
In examining the foot, a series of monofilaments that
range in size from 2.83 to 6.65 are typically used. The tip
of the monofilament is gently placed perpendicularly on
the surface until the monofilament buckles (Fig. 3-17).
The approach, skin contact, and departure of the monofila-
ment should be approximately 1.5 seconds. Examiners
should not allow the filament to slide across the skin or
make repetitive contact to the site. Examiners should
also be sure to avoid callused areas. The patient should
be able to sense the monofilament by the time the
monofilament buckles. The thicker (higher the number)
the monofilament, the more force is required to cause
the buckle. Patients without neuropathy should be able
to sense the 3.61 monofilament (equivalent to 0.4 gram
of linear force). The inability to sense monofilaments of
4.17 (equivalent of 1 gram of linear pressure) or higher
is considered consistent with neuropathy (large fiber
Figure 3–14 Vibration sense. It is difficult to establish a modality). Inability to sense a monofilament of 5.07
quantitative assessment, so a 128-Hz tuning fork is commonly (equivalent to 10 grams of linear force) is consistent with
used. Have the patient close his or her eyes. Demonstrate the severe neuropathy and loss of protective sensation (see
feeling to be expected to the patient by touching his/her jaw with
the vibrating tuning fork. Make the tuning fork vibrate by hitting it
Fig. 3-17). Custom footwear is indicated for diabetic
close to the base of the tines with the heel of your hand. Place people who cannot feel the 5.07 monofilament.
the tuning fork at the base of the great toenail for at least 10
seconds. The response should be present or absent. The test is
repeated in the other foot and at the base of both thumbnails. Deep Tendon Reflexes
The inability to feel the tuning fork at the base of the great toenail
carries the same significance as the inability to feel a 5.07
Documentation of the presence or absence of the knee
monofilament, and the patient should be referred for custom and ankle (Achilles) reflexes are an essential part of
footwear. This is considered to be a large nerve fiber function. the physical examination in the patient with known or
50 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

Target force Plantar

Evaluator size
in grams thresholds
1.65 0.008
2.36 0.02
2.44 0.04
Normal
2.83 0.07
3.22 0.16
3.61 0.4
3.84 0.6
4.08 1 Diminished
4.17 1.4 light touch
4.31 2
4.56 4 Diminished
4.74 6 protective
4.93 8 sensation
5.07 10
5.18 15
5.46 26 Loss of
protective
5.88 60 sensation
6.10 100
6.45 180
Deep pressure
6.65 300
sensation only

Figure 3–15 Monofilament Table. This table lists 20 of the

24 Semmes-Weinstein monofilaments by size and grams of linear
force. The most important calibrations: 3.61, 431, 4.56, 5.07 and
6.65 are marked (✪). Commercially available kits of six typically
include these plus the 2.83 evaluator size.
Patients who are able to sense the 3.61 size (0.4 grams of
force) are presumed not to have small fiber neuropathy. Patients
who are able to sense the 5.07 monofilament (10 grams target
force) have retained protective sensation even if they have may
have mild small fiber neuropathy. Inability to sense the 5.07 size Figure 3–16 Monofilament sites on plantar surface. The
is: (1) consistent with severe neuropathy, (2) greatly increases the photo demonstrates various sites on the plantar surface of the
possibility of a neuropathic ulcer and (3) is one of the five foot that have been standardized for examination with the
indications for custom insoles/footwear for the diabetic patient Semmes-Weinstein monofilaments (see text).
(ses text and Pearls).
Monofilaments with an evaluator size smaller than the 3.61 are
primarily utilized for the evaluation of the hands. Evaluation of
sensation of the hands requires different thresholds than those
of CIDP in a diabetic patient is crucial, since treatment
illustrated for the foot (plantar). differs from the usual approach of diet control, exercise,
and glycemic control. CIDP can be treated with a variety
of agents from corticosteroids to other immunosup-
suspected peripheral neuropathy (Fig. 3-18). Deep pressant agents, plasma exchange, and intravenous
tendon or muscle stretch reflexes are reduced or absent immunoglobulins. CIDP is estimated to be 11 times more
in a length-dependent pattern such that the ankle reflex common in patients with type 2 diabetes than in nondia-
is typically lost first followed by the knee reflex. Upper- betic individuals.129
limb reflexes are usually preserved in early diabetic neu-
ropathy yet become reduced or absent as the disease
progresses. It is common for patients with diabetes for 15
Motor Function
to 20 years to be areflexic. If a patient with recent-onset Loss of motor function most commonly follows the
diabetes and a rapidly progressive peripheral neuropathy changes in sensation and reflexes. Many patients will
is areflexic in the arms and legs, the neuropathy is likely have no demonstrable weakness in the lower limbs on
to arise from another cause. The leading consideration formal strength testing after years of diabetic neuropathy.
would be chronic inflammatory demyelinating polyneu- Typically, weakness will first be detected in the toe exten-
ropathy (CIDP), a chronic inflammatory polyneuropathy sors followed by the toe flexors, a pattern that follows the
that bears some resemblance to Guillain-Barré syndrome length-dependent nature of diabetic neuropathy. As the
in pathogenesis and pathophysiology.128 The recognition disease progresses, patients develop weakness of ankle
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 51

Figure 3–17 Monofilament on the great toe. This photo

Figure 3–18 Ankle jerk. Have the patient kneel on the edge
demonstrates the correct usage of the Semmes-Weinstein
of a high-backed, stable chair with his or her back toward you.
monofilament to detect the presence or absence of neuropathy
Gently apply pressure on the sole of the foot (causing some
and the retention or loss of protective sensation The latter is
dorsiflexion and muscle stretching). Strike the Achilles tendon.
measured with the 5.07 monofilament (as shown here). The
Observe plantar flexion of the foot via muscle contraction of the
patient should be comfortable and have his or her eyes closed.
gastrocnemius and soleus muscles. Alternatively, the patient can
Note that the monofilament buckles when the 10 grams of linear
be examined while sitting on the exam table or at the bedside (as
force are applied by the examiner for about 10 seconds. Note that
illustrated). Patients who are hospitalized or who are disabled and
this patient has early claw toe deformities. He was insensate to
cannot sit up can be examined while lying on their back with their
the 5.07 and even the 6.65 monofilament.
head at about 45 degrees for maximum comfort. The examiner
holds the foot just off the bed as he or she strikes the Achilles
tendon. Note that the photograph illustrates the Traumner reflex
dorsiflexion and eversion before ankle plantar flexion hammer. This is an excellent hammer because of its ideal weight
and inversion, deficits that are explainable by the rela- and shape. It also has a smaller head, which is very useful for the
tively smaller muscle mass of the tibialis anterior and upper-limb deep tendon reflexes or with children.
peroneal longus muscles compared to the posterior
tibial and gastrocnemius group. Proximal muscles of the
legs are often spared unless the diabetic neuropathy is It can assess whether a superimposed process is present,
unusually long-standing, for example, 25 to 30 years, if it such as a mononeuropathy, mononeuritis multiplex,
is rapidly progressive, or if another illness is superim- brachial or lumbosacral plexopathy, or a polyradicu-
posed. If proximal weakness is observed in one leg and lopathy. Common mononeuropathies that are observed
the patient complains of pain in the same region, the in diabetic patients are median mononeuropathy at the
examiner should consider diabetic amyotrophy, one of wrist (carpal tunnel syndrome), ulnar neuropathy at the
the focal diabetic neuropathies that affect the lum- elbow or cubital tunnel, facial mononeuropathy (Bell’s
bosacral roots or plexus, or multiple proximal mononeu- palsy), and common peroneal palsy.
ropathies. Much information can be gleaned from the testing of
Once diabetic neuropathy advances to the level of the a few nerves that are carefully chosen by clinical examina-
knee, patients begin to complain of hand weakness, and tion. As is true in most neuropathies, the sensory nerves
the examination often confirms the deficits. In most will be more affected than will motor nerves. Little infor-
cases, the examiner will find weakness of the dorsal and mation is gained from the testing of severely affected
ventral interossei muscles and the abductor digiti nerves such as the sural, peroneal, or tibial nerves in a
minimi. Over time, weakness will progress to the thumb patient with long-standing diabetic neuropathy. In that
abductors and finger extensors. situation, the action potentials are usually unrecordable,
so the electromyographer cannot determine whether the
primary process is axon loss or demyelination. A rule of
Electrophysiologic Testing thumb is to test lower-limb nerves in a patient who is
Electrophysiologic testing plays a major role in the eval- thought to have a mild neuropathy and to focus testing
uation of patients with both suspected distal symmetrical on upper-limb nerves in a patient with a suspected severe
neuropathy and well-documented neuropathy, using neuropathy. The amplitude of the motor compound
motor and sensory nerve conduction studies, the needle muscle action potentials and the sensory nerve action
examination, and autonomic testing. Electrophysiologic potentials can be used to estimate the number of intact
testing can document that the neuropathy is present, motor and sensory nerve fibers, respectively, unless a
define the fibers that are affected (motor, sensory, and demyelinating process is present between the point of
autonomic), render a gross estimate of the duration of stimulation and the recording electrode. A good correla-
the neuropathy, and even give insight into the prognosis. tion exists between the severity and number of the nerve
52 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

conduction study abnormalities and the severity of the Extensive testing and retesting are usually not neces-
clinical neuropathy. Nerve conduction studies primarily sary; the repeated measurement of one or two nerves
measure the function of large myelinated fibers, so it is often suffices.132 Reeves and colleagues studied the medial
possible for a diabetic patient to have a painful small plantar sensory nerve in 10 diabetic patients who under-
fiber neuropathy and to have a normal nerve conduction went a 6-month program of intensification of therapy to
study. It is estimated that approximately 5% of patients with treat diabetes. Near normalization of glucose levels led to
neuropathy will have normal nerve conduction studies. a return of the sensory nerve action potentials in 7 of 10
Electromyography (EMG) can be a useful exami- patients and a normalization of the sensory distal latency
nation in diabetic neuropathy to detect denervation in all patients.133
and to decipher chronicity, the latter by analyzing the
morphology of motor units. Electromyography can detect
active or chronic denervation in patients with diabetes Prevention and Treatment
who have normal nerve conduction studies and thus
verify the diagnosis. The needle examination can test for
superimposed processes such as a brachial plexopathy,
Pain Management
lumbosacral plexopathy (diabetic amyotrophy), thora- Pain is a common complication of diabetic neuropathy.
columbar radiculopathy, or motor neuron disease such From a clinical and pathologic standpoint, pain can be
as amyotrophic lateral sclerosis or progressive muscular divided into nociceptive and neuropathic pain. The
atrophy. former arises from the presence of a pathologic process
Nerve conduction studies are often abnormal in dia- that produces continuing tissue damage. Examples include
betic patients who clinically do not have a neuropathy. osteoarthritis, cholecystitis, phlebitis, cellulitis, and
Hendriksen and colleagues studied 88 diabetic patients abscess. Conversely, neuropathic pain stems from injury
for subclinical neuropathy who had no clinical evidence to the peripheral nerve or central somatosensory pathways.
for polyneuropathy using nerve conduction studies, Neuropathic pain is commonly constant and associated
papillary latency and diameter testing, and single fiber with paroxysms of pain that do not follow a specific
electromyography. Of the group, 52 patients had type 1 pattern. Pain is experienced by over 10% of patients with
diabetes and 36 had type 2 diabetes. The authors found diabetic polyneuropathy, and management of this pain
a high percentage of abnormalities. The tibial nerve and can be a challenge for even the most skilled physician.
the tibial H-reflex were abnormal in 69% to 81% of Once it has been determined that the pain is sec-
patients, the sural nerve was abnormal in 56% to 64% ondary to distal symmetrical polyneuropathy, the pain is
of patients, the ulnar sensory nerve in 33% to 40%, and classified as acute or chronic painful neuropathy (Table
the ulnar motor nerve in 9% to 31% of patients. Pupil 3-4). Acute painful neuropathy lasts less than 12 months
constriction latency and pupil diameter percentage was and is mostly attributable to metabolic abnormalities
abnormal in 62% to 69% of patients. The severity of the rather than to structural abnormalities. Proposed etiolo-
polyneuropathy electrophysiologically was equal in gies include decreased nerve taurine concentration and
patients with type 1 diabetes and those with type 2 dia- endoneurial swelling. The typical scenario is the newly
betes when the results were corrected for age, height, diagnosed diabetic patient who has just been started on
and duration of the illness.130 insulin. Acute, painful diabetic neuropathy is self-limited.
The results of nerve conduction studies can be used to The patient often responds well to analgesic therapy with
monitor the course of diabetic patients treated with nonsteroidal anti-inflammatory drugs.
insulin or oral hypoglycemic agents, treated with inten- Chronic, painful diabetic neuropathy typically occurs
sive insulin therapy, or enrolled in clinical trials. In the in patients with intermediate duration (8 to 12 years)
DCCT, velocities of the sural and median sensory nerves of diabetes. It has a gradual and insidious onset, and
increased modestly in the first year of therapy in patients the pain typically lasts more than 12 months. There are
in the primary convention cohort who received intensive structural abnormalities (see below). The pain may persist
therapy, and the median sensory velocities returned to for years, and relapses occur. Treatment of chronic,
baseline by year 5. In the motor nerves, conduction painful diabetic neuropathy requires a more complex
velocities remained steady or increased slightly in the
intensive therapy group compared to the conventional
therapy group where motor nerve conduction velocities TABLE 3-4 Compendium of Treatments for
consistently decreased. Amplitudes of the motor and sen- Neuropathic Pain
sory nerves did not change significantly in the two treat- NSAIDs Transdermal clonidine
Tricyclic antidepressants Tramadol hydrochloride
ment groups. Changes favoring the intensive therapy SSRIs Antiarrhythmics
group were also recorded in autonomic testing. The Anticonvulsants Antispasticity medications
intensive therapy group experienced slower worsening Topical capsaicin Narcotics
Lidocaine cream a-Lipoic acid
of the R-R variation, reflecting some delay in the progres- Epidural spinal cord stimulation
sion of cardiac autonomic neuropathy.131
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 53

approach but can be greatly or moderately successful in Those fibers enter the dorsal root and synapse in laminae
patients who do not have motives for treatment failure I and II within the dorsal horn of the spinal cord. Many
(e.g., sympathy-seeking behavior, narcotic-seeking behavior, of the fine afferents terminating in the dorsal horn con-
wishing to gain or maintain disability). tain neuropeptides such as substance P, cholecystokinin,
Although improved glycemic control is advocated for and somatostatin. Opiate receptors are also found on the
all patients with DPN, the pain response might not cor- terminals of the primary afferents and dorsal horn neu-
relate with achievement of an ideal A1C level. An inter- rons. Consequently, both presynaptic and postsynaptic
esting paradox is the exacerbation of pain in some mechanisms are important in the analgesic effect of
patients as better glucose control is achieved. opiates at the spinal level.
Figure 3-19 demonstrates the relationship between To comprehend the effect of drugs that reduce norep-
nerve function and painful neuropathic symptoms. As inephrine and serotonin reuptake on pain, one needs
nerve function worsens, the pain threshold may be to understand the two major descending pathways for
exceeded. Once this occurs, the pain continues until the pain modulation. The first is the reticulospinal tract that
nerve becomes so dysfunctional that pain signals are not originates in the periaqueductal gray region and gives
easily transmitted to the central nervous system. Even- rise to serotonergic fibers that synapse on the dorsal
tually, nerve function worsens and sensation decreases to horn. The second descending pathways begin in the
the point that the foot becomes numb. Some individuals locus coeruleus of the medulla oblongata and send nora-
get numb or insensate feet without ever breaching the drenergic fibers to the dorsal horn. The periaqueductal
pain threshold (see Fig. 3-19). gray region of the midbrain, the raphe nuclei of the
Depending on the location of the patient on the pain medulla, and the dorsal horn contain a high density of
curve, an improvement in nerve function could either endogenous opiate peptides and receptors. In animals,
cause the pain to drop below the pain threshold or stimulation of the periaqueductal gray region inhibits
increase pain. Glucose control can improve nerve function the discharge of nociceptive neurons at spinal levels. At
enough to cause such changes. This would explain the the level of the spinal cord, the descending tracks from
decreased pain in some patients (located on the left side the periaqueductal gray region and raphe nuclei directly
of the curve) and increased pain in other patients (located inhibit pain-responsive neurons, some of which contain
on the right side of the curve) with better glucose control. endogenous opioid transmitters.
Regardless of the change in pain symptoms, glucose con- Current knowledge suggests that both central and
trol is still desirable and should be initiated in all patients. peripheral mechanisms play a role in initiating and per-
To understand the use of a vast array of treatments petuating neuropathic pain. Peripheral mechanisms
for neuropathic pain, a fundamental understanding of include sensitization and abnormal ectopic discharges;
pain pathways within the peripheral and central nervous both phenomena are thought to result from an increase
system is necessary. Pain is carried primarily by unmyeli- in the number of sodium channels that develop on
nated C-fibers within the peripheral sensory axons. peripheral nerves after trauma or toxic or metabolic
derangement to a nerve. Peripheral sensitization refers
to an increased sensitivity of the peripheral nociceptors
Onset of to stimuli and a lower threshold of the nociceptors to
diabetes Pain
fire. Ectopic pacemakers arise in injured peripheral
Pain

nerves and fire spontaneously to a broad series of phys-

ical, chemical, and metabolic stimuli. Central sensitiza-
tion refers to the phenomenon by which peripheral nerve
Pain injury causes release of various neurotransmitters at the
threshold
dorsal horn region, which in turn leads to increased cal-
e
No pain

cium influx into a cell, an activation of nitric oxide syn-

Tim

Numb thase, an expression of early genes, and activation of

(insensate) phosphatases. The latter results in a lower threshold for
depolarization and spontaneous discharges of the spinal
cord dorsal horns. Consequently, the spinal cord
Good Neural function Bad becomes hypersensitive to afferent fibers. An under-
Figure 3–19 Neural functions. This figure demonstrates the
standing of the central and peripheral mechanism for
relationship between nerve function and painful neuropathic neuropathic pain gives relevance to why different classes
symptoms. As nerve function worsens, the pain threshold may be of drugs can be beneficial for treating neuropathic pain.
exceeded. Once this occurs, the pain continues until the nerve
becomes so dysfunctional that pain signals are not easily
transmitted to the central nervous system. Eventually, nerve
function worsens such that sensation decreases to the point that *From Dwight C. McGoon: Ecstasy, a basis for meaning in the world. In
the foot becomes numb. Some individuals get numb or insensate Huth EJ, Murray TJ (eds): Medicine Quotations: Views of Health and Disease
feet without ever breaching the pain threshold. Through the Ages:. Philadelphia: American College of Physicians, 2000.
54 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

Treatment of Neuropathic Pain eight patients were particularly good responders to the
nonsteroidal anti-inflammatory agents. During the course
The authors strongly recommend that physicians and of the study, there was no change in glucose control or
other health care providers who are entrusted to relieve renal function that might have influenced the results.
the pain and suffering of patients with painful neuropathy Although not helpful for many patients with neuropathic
should abide by two important dictums: Primum non pain, anti-inflammatory agents may be useful in a small
nocere (“First, do no harm”) and “Your compassion for group and should be considered for initial therapy if
your patients—trying to do the best for them—must be renal function is normal.
the major motivating force in your effort to remain com-
petent.”* The authors are of the opinion that clinicians
who follow these principles will have a greater chance of
Tricyclic Antidepressants
success while they garner the respect of both their Tricyclic antidepressant (TCA) medications serve as
patients and their colleagues. a mainstay of treatment for neuropathic pain. They can
The treatment of neuropathic pain includes pharmaco- be divided into secondary and tertiary amine agents.
logic and psychological approaches. The clinician should The secondary amines nortriptyline, desipramine, and
understand the difficulty in completely eliminating pain maprotiline are selective inhibitors of norepinephrine,
associated with diabetic neuropathy. Some patients whereas the tertiary amines amitriptyline, imipramine,
respond poorly to these drugs; others develop adverse and clomipramine block the reuptake of both serotonin
effects even at the lowest dosages. In some patients, a and norepinephrine. The most effective agents are those
reduction of pain of 30% to 40% is appreciated and is that inhibit the reuptake of both norepinephrine and
considered a good response. In most instances, the drugs serotonin yet have a good adverse effect profile. Many
listed below are started slowly and titrated upward until studies have demonstrated the efficacy of these agents
satisfactory pain relief is achieved or side effects develop.134 for the treatment of painful diabetic neuropathy.138 The
Figure 3-20 is an algorithm that the authors have therapeutic dosage range is 25 to 150 mg per day with
found effective for providing guidance to clinicians who most or all of the drug taken at night. It is best to start
are neither specialists in pain management nor familiar with a low dosage in treating elderly patients and to
with treatment of this condition. This algorithm condenses advance in weekly increments of 10 to 25 mg. Relief of
and simplifies a practical approach to the management pain might not occur until several weeks after the treat-
of patients utilizing one or more of the agents described ment with TCAs is initiated.
in this section. A recent study by Gilron and associates The efficacy of antidepressants for the management
underscores patients’ attitudes toward the treatment of of neuropathic pain is separate from its antidepressive
neuropathy and the relative undertreatment of their effect.139 Commonly observed side effects include drowsi-
condition. In a study of 151 patients with neuropathic ness, dry eyes and mouth, increased appetite, weight
pain, of whom more than half had painful diabetic neu- gain, urinary retention, and constipation. In the elderly,
ropathy, 72.8% complained of inadequate pain control, moderate doses of antidepressants may cause disorien-
and more than 25% had never been treated with a drug tation, confusion, and excessive sleepiness. An under-
whose mechanism was directed at neuropathic pain. The standing of the different types of antidepressants and
mean daily pain score was 7.6 on a 10-point scale. New their side effect profiles allows selection of an agent that
agents, such as gabapentin, had been prescribed for only has an either greater or lesser effect on norepinephrine
16.6% of patients. Opioids, tricyclic antidepressants, and and serotonin reuptake as well as a minimal tendency to
anticonvulsants had never been prescribed for 41% of produce anticholinergic side effects. TCAs should be
patients. Approximately 32% of patients expressed fear used with caution in patients with a history of coronary
of addiction and adverse effect from medications pre- artery disease and cardiac conduction defects, as TCAs
scribed.135 Data that are often reported in studies of can incite cardiac arrhythmias or heart block.
painful diabetic neuropathy are the number of patients Mitchel Max and colleagues showed that amitripty-
needed to treat (NNT) to achieve a beneficial effect and line and desipramine provided moderate to good
the number needed to treat before an adverse event or relief of pain in 61% to 71% of patients with painful dia-
harm results (NNH). An ideal medication has a low NNT betic neuropathy.140 Amitriptyline and desipramine were
and a high NNH.136 Table 3-4 overviews a compendium as effective in nondepressed patients as in depressed
of treatments for neuropathic pain. patients. The authors identified a linear relationship
between pain relief and dosage of the antidepressive agent.
Little information from human studies is available
Nonsteroidal Anti-Inflammatory Drugs comparing the analgesic potency of one antidepressant
In 1987, Cohen and associates published a single-blind to that of another. In animal studies using response to a
study of 18 patients with DPN who were treated with painful stimulus, amitriptyline was more potent than nor-
placebo, ibuprofen, or sulindac.137 They showed that the triptyline, imipramine, and desipramine. Amitriptyline
response to both ibuprofen and sulindac was better than was judged to be approximately 70 times more potent
that to placebo for the entire group. Within the group, than aspirin as an analgesic.141
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 55

Algorithm for treatment of painful DPN 1

Painful feet

DPN Non-DPN etiologies

Modify risk factors Chronic pain Acute pain

Treat based on pain score

Add first agent

Retreat if necessary
Not improved—increase dose

Not improved—add 2nd agent

Dysesthesia

Paresthesia

Muscular pain

Continued with number 2

A Risk factors: hyperglycemia, hypertension, hyperlipidemia, smoking, ethanol intake

Algorithm for treatment of painful DPN 2 Figure 3–20 Algorithm for the treatment of painful diabetic neuropathy.
This algorithm has proven to be successful in a prospective clinical trial.
It requires the health care professional to query the patient as to the type of
neuropathic pain. Therapy is then directed toward the specific type of pain
First-line agents:
(dysesthesia, paresthesia, muscular pain, or combinations of the three).
1) Amitriptyline or nortriptyline
(Redrawn with permission from Pfeifer MA, Ross D, Schrage J, et al: A highly
2) Gabapentin or pregabalin
successful and novel model for the treatment of chronic painful diabetic peripheral
neuropathy. Diabetes Care 16:1103–1115, 1993.)

Second-line agents:
1) Duloxetine
2) Carbamazepine

Third-line agents Fourth-line agents

1) Phenytoin 1) Venlafaxine
2) Lamotrigine 2) Levetiracetam
3) Topiramate 3) Oxcarbaxepine
4) Zonisamide
5) Mexiletine
Fifth-line agents
1) Capsaicin cream
2) Lidocaine cream 5%
3) Sports creams
B

placebo, amitriptyline, and desipramine, fluoxetine was

Selective Serotonin Reuptake Inhibitors no better than placebo in relieving the pain associated
The neurologic literature supports marginal benefit with diabetic neuropathy. SSRIs may play a greater role
from using selective serotonin reuptake inhibitors in treating the depression of patients with painful neu-
(SSRIs) to treat neuropathic pain. Although better toler- ropathies. Common adverse effects of SSRIs are sweating,
ated than TCAs, in a study of fluoxetine compared to insomnia, dizziness, headache, visual disturbances, and
56 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

Placebo (n108)
0
Duloxetine 60 mg qd (n114)

Mean change in 24-hour average

0.5 Duloxetine 60 mg bid (n112)

1 *

pain severity score

1.5
*
*
2
* *
* * * * * * * * *
2.5
* *
3
* * * * * * * *
3.5
0 1 2 3 4 5 6 7 8 9 10 11 12
Week
*p  .001 vs. placebo.
Figure 3–21 Duloxetine graph. In a recent 12-week study, patients with diabetic neuropathic pain and without comorbid depression
were randomized to treatment with duloxetine 60 mg four times a day (n = 114), duloxetine 60 mg twice a day (n = 112), or placebo (n =
108). The primary outcome in this study was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Both
dosages of duloxetine were superior to placebo in reducing pain as measured by the weekly 24-hour average pain severity score, with
statistically significant separation from placebo occurring at week 1 and continuing throughout the 12-week period ( p < .001). Duloxetine
was also superior to placebo for almost all secondary outcomes (e.g., Brief Pain Inventory severity scores), with no significant
differences between the two dosages. (Redrawn with permission from Wernicke J, Lu Y, D’Souza D, Waninger A, Tran P: Duloxetine at doses of
60 mg QD and 60 mg BID is effective in treatment of diabetic neuropathic pain (DNP) [abstract]. J Pain 5(suppl 1):48, 2004.)

sexual dysfunction. SSRIs can be used with TCAs only than 20% of patients discontinued duloxetine because of
with great caution, as both paroxetine and adverse events.144 Figure 3-21 illustrates the pain score
fluoxetine block the cytochrome P450 2D isoenzyme that response to duloxetine in a double-blind randomized
is integral to the metabolism of TCAs. Blood levels of clinical trial.145
TCAs can rise as much as sevenfold when used in the
setting of SSRIs.
The efficacy and safety of venlafaxine was studied in a
Anticonvulsants
6-week trial in a multicenter, double-blind, randomized, Many anticonvulsants have been shown to be effective
placebo-controlled study of 244 patients with diabetic in the management of neuropathic pain (Table 3-5).
neuropathy. Patients received either the 75-mg ER or the Although the exact mechanism of their benefit remains
150- to 225-mg ER tablets. The reduction of the visual unknown for some of the drugs, these agents probably
analogue scale for pain intensity statistically favored the work by modulating sodium channels, stabilizing nerve
groups that received the active drug. The visual analogue
scale for pain relief was statistically better than placebo
for the 150- to 225-mg dosing. The number needed to TABLE 3-5 Anticonvulsants for Neuropathic Pain
treat (NNT) for the higher dose of venlafaxine was Generic Name Trade Name
comparable to those of tricyclic antidepressants and
First-Generation
gabapentin.142 Phenytoin Dilantin 
Duloxetine is the newest compound in this group of Phenobarbital
reuptake inhibitors. It is considered a balanced selective Primidone Mysoline
Ethosuximide Zarontin
serotonin and norepinephrine reuptake inhibitor and is Carbamazepine Tegretol 
approved for use in the treatment of painful DPN. The Valproic acid Depakote
half-life of the drug is 12 hours, and the maximum
plasma concentration is reached in 6 hours.143 In a Second-Generation
Gabapentin Neurontin 
12-week, multicenter, double-blind study of 457 patients Pregabalin Lyrica  ☺
with DPN pain randomized to duloxetine 20, 60, or Lamotrigine Lamictal 
120 mg per day or placebo, Goldstein and colleagues Topiramate Topamax 
Tiagabine Gabitrol
showed benefit in the groups receiving the two highest Levetiracetam Keppra
doses. Statistically significant improvement was observed Oxcarbazepine Trileptal 
in the primary efficacy measure of the 24-hour average Zonisamide Zanegran
Felbamate Felbatol
pain score and in nearly all the secondary measures
including the health-related outcome measures. Fewer , clinically prescribed or studied for painful DPN; ☺, FDA approved for DPN.
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 57

fiber membranes, and suppressing ectopic discharges Oxcarbazepine

that give rise to the paroxysms of pain. Phenytoin, carba-
mazepine, gabapentin, pregabalin, lamotrigine, valproic Oxcarbazepine is a metabolite of carbamazepine and
acid, and topiramate have been studied in uncontrolled shares many of the antiepileptic properties of the drug.
and controlled patient populations. In a 9-week, open-label trial of oxcarbazepine in the
treatment of painful diabetic neuropathy, Beydoun and
colleagues studied 30 patients. The drug was initiated at
Phenytoin a dose of 150 mg per day and titrated up to 1200 mg per
The response rate to phenytoin has been reported to day or maximum tolerated dose. The mean daily dose
be as high as 68% in patients taking 100 mg three times taken was 814 mg. The mean visual analogue scale drop
per day for 2 weeks.146,147 When successful, the response was 66.3 during the screening phase to 34.3 at the end of
usually occurs within 1 to 4 days after the initiation of the trial for a mean reduction of 48.3%. Significant
therapy. In another study of only 12 patients, using a improvement was also observed in the total pain score
study design in which patients received either active drug and present pain intensity.151 In a multicenter, random-
or placebo on alternate weeks for a total of 4 weeks, no ized placebo-controlled 16 week trial of oxcarbazepine in
statistical significance was found between the group that patients with painful diabetic neuropathy, significant
was prescribed 300 mg daily and placebo. The results improvement was observed in the average change in the
were confounded by the observation that blood glucose visual analogue score, the number of patients experi-
levels were elevated in the diabetic patients taking pheny- encing a greater than 50% reduction in pain, and global
toin.148 Phenytoin can be an attractive choice to treat assessment of therapeutic effect. Most adverse effects
neuropathic pain because of its low cost, well-known side were mild to moderate and transient.152
effect profile, and ease of use (nighttime dosing), but in
this author’s opinion, it rarely leads to impressive pain
relief in most patients with painful diabetic neuropathy. Gabapentin
Gabapentin is related structurally to the inhibitory
amino acid g-aminobutyric acid, yet the mechanism of its
Carbamazepine effect on modulating neuropathic pain is not completely
In a double-blind-crossover study of carbamazepine com- understood. Recently, Gu and Huang showed that
pared to placebo in the treatment of painful diabetic gabapentin’s action on the N-methyl-D-aspartate receptor
neuropathy, Rull and colleagues recorded symptomatic is protein kinase C–dependent. This response indirectly
improvement in 28 of 30 patients taking 200 mg three suggests a possible inflammatory component at the
times per day.149 Adverse effects were recorded in over dorsal horn, since in inflammation, endogenous PKC is
50% of patients, but those effects were often mild and elevated.153 Although gabapentin has been used to treat
transient. Mean improvement in pain varied between neuropathic pain for years, the first controlled study
56% and 75%. In another crossover study conducted of gabapentin in diabetic neuropathy was published in
over 2 weeks, Wilton and colleagues showed that carba- December 1998.154 In that protocol, 165 patients were
mazepine was effective in relieving pain by the second tested, 84 receiving gabapentin and 81 receiving placebo.
week of treatment in 40 patients with painful diabetic As tolerated, patients were titrated up to a daily dose of
neuropathy. No benefit was observed in the reversal of 3600 mg during the first 4 weeks of the study and main-
numbness or improvement in sleep.150 tained on the achieved dose for 4 additional weeks. The
Carbamazepine is most effective in relieving the authors reported statistically significant lower daily pain
sharp, lancinating component of neuropathic pain rather scores (primary efficacy measure) and improved secondary
than the dull, constant pain. Although it is well tolerated measures of efficacy in the group taking gabapentin. At
initially, approximately 30% to 40% of patients discon- the end of the trial, the mean reduction of pain scores was
tinue carbamazepine within 1 year because of side effects. 39% in the gabapentin-treated group compared to 22% in
Common adverse effects include dizziness, drowsiness, the group taking placebo (p < .001). Patients who received
diplopia, unsteady gait, impaired cognition, nausea, and gabapentin but not placebo reported improved sleep and
vomiting. A rash occurs in 10% to 15% of patients who quality of life. All secondary measures of pain showed sta-
take carbamazepine. In prescribing carbamazepine, a tistical significance. The most frequently recorded adverse
complete blood count (CBC) with differential, serum effects to gabapentin were dizziness and somnolence.
sodium, and liver function tests should be drawn at the Gorson and colleagues reported their results in
onset of treatment and at 3 and 6 months to screen for 40 patients using a placebo-controlled, double-blind,
the rare complications of aplastic anemia, hepatitis, and crossover trial. The maximum dose of gabapentin
the syndrome of inappropriate antidiuretic hormone secre- prescribed was 900 mg per day. Statistical improvement
tion (SIADH). Approximately 3 weeks after beginning was observed only in one of four end points, the McGill
therapy, carbamazepine tends to induce its own metabo- Pain Questionnaire, between the initial and final study
lism, often necessitating an increase in drug dosing. visits. The most common adverse effects were drowsiness,
58 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

fatigue, and imbalance. The authors concluded that disturbance, and several McGill Pain Questionnaires.
gabapentin at a dose of 900 mg per day was ineffective Pregabalin was well tolerated. The most common
or only minimally effective for the treatment of painful adverse effects were dizziness and somnolence, which
diabetic neuropathy.155 were judged to be mild to moderate in severity.160
In 2003, Backonja and Glanzman reviewed the data In a review of three randomized clinical trials of 5 to 8
on the efficacy and tolerability of gabapentin for the weeks’ duration and two clinical trials of 12 weeks’ dura-
treatment of neuropathic pain and to determine the tion, pregabalin at fixed dosages of 300 and 600 mg per
optimal dosing. They accepted only randomized con- day produced superior pain relief and improved pain-
trolled studies of more than 100 patients per treatment related sleep disturbance. The most common side effects
arm. Gabapentin was effective in the treatment of associated with the medication were dizziness, somno-
painful diabetic neuropathy, postherpetic neuralgia, and lence, and peripheral edema.161 In the largest study to
other pain syndromes, relieving symptoms of shooting date (246 patients), Richter and colleagues showed that
pain, burning pain, allodynia, and hyperesthesia. Most pregabalin 600 mg per day over 6 weeks significantly
adverse effects abated after 10 days of treatment. The reduced the mean pain score, sleep interference, past
authors advocated starting gabapentin at a dosage of week and present pain intensity, and sensory and affec-
900 mg per day in three divided doses and titrating the tive pain scores. At the dose of 150 mg per day, pregab-
dose upward to 1800 mg per day. Some patients needed alin was no different from placebo, although this is the
doses as high as 3600 mg per day for good pain relief.156 recommended starting dose.162 In the experience of
Dallocchio and colleagues compared the efficacy of these authors, many patients with painful DPN respond
gabapentin to that of amitriptyline in 25 patients with to this dose, but there is a clear minority that requires
painful diabetic neuropathy in an open-label, prospec- 300 mg or even 600 mg per day for the best response.
tive, randomized trial. Greater pain and paresthesia The advantage of this drug over gabapentin is the rapid
relief and fewer side effects were achieved in the group improvement in pain in only 1 to 2 days, which is a result
receiving gabapentin compared to the amitriptyline of the greater than 90% bioavailability of the pregabalin
group.157 In a similar small but randomized prospective, compared to only about 33% bioavailability of gabapentin
double-blind, double-dummy, crossover study in 28 at doses of 2400 mg or more.163 Figure 3-22 illustrates the
patients, Morello and colleagues reported moderate or
greater pain relief after treatment with gabapentin or
p .001
amitriptyline and no statistical difference between the p .001 vs placebo
50 vs placebo
two groups.158
Treatment with gabapentin should begin with a bed-
40
time dose of 300 mg. The dose can be increased by
Percent of patients

300 mg every 3 to 5 days with the eventual goal of

30
achieving a thrice-daily dosing schedule. Many patients
respond to a total dosage of 900 to 1200 mg per day,
whereas others need 3600 or 4800 mg per day for good 20
pain relief. An attractive feature of gabapentin is its lack
of interaction with other medications. 10

0
Pregabalin Placebo Pregabalin 75 Pregabalin 300 Pregabalin 600
(n 97) (n 77) (n 81) (n 81)
Pregabalin is an analogue of the neurotransmitter
*Last observation carried forward (LOCF) analysis.
g-aminobutyric acid, which possesses anticonvulsant, All pregabalin doses in mg/d.
anxiolytic activity, and analgesic properties. It interacts
Figure 3–22 Pregabalin 50% reduction. In this clinical trial,
with the a2-delta protein subunit of the voltage-gated cal- the 50% responder rates (i.e., the percentage of patients who
cium channel. The latter characteristic makes it attrac- achieved at least 50% reduction in mean pain score from baseline
tive for treating neuropathic pain, particularly for central to end point) in the 300 mg/d and 600 mg/d pregabalin groups
sensitization pain. Peak plasma levels occur 1 hour after were significantly higher than in the placebo group (p = .001) in
an oral dose; the half-life is 6 hours. Pregabalin is usually last observation carried forward (LOCF) analysis. The 50%
responder rate in the 75 mg/d pregabalin group was not
excreted unchanged in the urine.159 Rosenstock and col- significantly different from that in the placebo group. A response
leagues studied its effect on painful diabetic polyneu- of 30% from baseline has been shown to be clinically meaningful.
ropathy in 146 patients in a randomized, double-blind, In Study 029, 33% of placebo patients, 38% of 75 mg/d
placebo-controlled, parallel-group study. At a dosage of pregabalin patients, 62% of 300 mg/d pregabalin patients, and
300 mg per day, pregabalin produced clinically signifi- 65% of 600 mg/d pregabalin patients had a response of 30% or
greater in the LOCF analysis. (Redrawn with permission from
cant improvement compared to placebo in the primary Lesser H, Sharma U, LaMoreaux L, Poole RM: Pregabalin relieves
efficacy measure of the mean pain score as well as symptoms of painful diabetic neuropathy: A randomized controlled
secondary efficacy measures of sleep interference, mood trial. Neurology 63:2104–2110, 2004.)
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 59

10 Placebo (n 69) Figure 3–23 Pregabalin and sleep.

Pregabalin 300 mg/d (n 75) Pregabalin effects on mean weekly sleep
9
interference scores in DPN are noted. After only
Mean sleep interference score*

8 1 week of 300 mg pregabalin, the mean sleep

7 interference index fell from approximately 6 to 3,
a 50% improvement. The effect continued at this
6 improved level throughout the duration of the trial.
5 (Redrawn with permission from Rosenstock J et al:
Pain 110:628–638, 2004.)
4
3
† † † † † †
2 † † †

1
0
0 1 2 3 4 5 6 7 8
End
Weeks point
(LOCF)
*Least squares means claculated from the model. †p .001.

50% responder rates (i.e., the percentage of patients study because of adverse effects (rash, dizziness, and
who achieved at least 50% reduction in mean pain ataxia). Most patients continued to use lamotrigine 6
score from baseline to end point) in the 300 mg/d and months after the open study was completed.165 In a ran-
600 mg/d pregabalin groups.164 These rates were signifi- domized, controlled study in 59 patients, the same
cantly higher than that in the placebo group (p = .001) authors showed statistically significant improvement in
in last observation carried forward analysis. The 50% several pain profiles in the group receiving lamotrigine
responder rate in the 75 mg/d pregabalin group was not at dosages of 200, 300, and 400 mg per day. More adverse
significantly different from that in the placebo group. effects were reported in the placebo group than in the
In general, a 50% reduction of pain score from baseline lamotrigine group.166
by 30% or more of the subjects in a study is considered Side effects reported from lamotrigine use are
clinically meaningful. Figure 3-23 demonstrates the effect headache, somnolence, diplopia, ataxia, asthenia, and a
of 300 mg pregabalin on the mean weekly sleep inter- rash. Most feared is a Stevens-Johnson syndrome. The
ference scores of subjects with DPN.160 drug should be started at 25 mg per day and slowly
Finally in using pregabalin, it is important to note that increased by 25 mg weekly to 200 to 400 mg total dose
the drug is cleared by the kidney. Patients with a pretreat- taken on a twice per day schedule.
ment creatinine clearance of less than 60 mL/min need
to have a reduced dose of the drug (as is noted in the
package insert from the manufacturer). One of the authors
Valproic Acid
has achieved successful pain reduction for DPN with only Kochar and associates reported the first study of valproic
25 mg per day in patients on chronic hemodialysis. acid in the treatment of painful DPN. They assessed
valproic acid (1200 mg per day) in 60 patients with type
2 diabetes in a randomized clinical trial, assessing the
Lamotrigine benefit using the short form of the McGill Pain
Only a few studies have been conducted using lamotrigine Questionnaire and nerve conduction studies. At the end
to treat neuropathic pain. In a small placebo-controlled of 1 month, significant improvement was observed in
crossover trial of 14 patients, lamotrigine was added to the group receiving valproic acid in the short form of
either phenytoin or carbamazepine to manage patients the McGill Pain Questionnaire, and no changes were
with intractable postherpetic neuralgia. Eleven of the 13 detected in the electrophysiologic testing. The drug was
patients experienced greater pain relief when lamo- well tolerated except for one patient whose liver function
trigine (added to phenytoin or carbamazepine) was com- studies rose to abnormal levels.167 In a contrasting study
pared to placebo. from Denmark in 31 patients, no difference in total pain
In the first open study of lamotrigine as the sole anal- was recorded in patients taking 1500 mg of valproic acid
gesic in painful diabetic neuropathy, Eisenberg and col- per day compared to the placebo group.168
leagues studied 15 patients and showed a reduction in
the visual analogue and numeric pain scales compared
to pretreatment measurements. In the study, patients
Topiramate
were titrated from 25 mg to 400 mg per day, and pain Edwards and colleagues reported the results of their study
profiles and sensory testing were performed on seven investigating the efficacy of topiramate in treating painful
subsequent office visits. Two patients withdrew from the diabetic neuropathy. In this single-center, randomized,
60 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

controlled trial of 27 subjects, patients were prescribed studies using capsaicin to treat diabetic neuropathy, post-
either topiramate or placebo and were titrated up to mastectomy pain syndrome, and postherpetic neuralgia.
their maximum tolerated dose or 200 mg twice daily. One study showed statistically greater improvement at
Patients were maintained on a stable dosage for 4 weeks. the final visit in patients with painful diabetic neuropathy
At the conclusion of the study, patients taking topiramate who used capsaicin cream four times per day compared
had significantly less pain than did the placebo group to patients who applied an inactive cream.173 Those
and significantly lower scores on the short form of the results were not replicated in a much smaller study of
McGill Pain Questionnaire. Although topiramate was patients with various types of neuropathies. The major
generally well tolerated, more than 25% of the patients adverse effect of capsaicin cream is its tendency to
in the topiramate group discontinued the study because produce burning, stinging, erythema, and warmth at the
of adverse effects.169 site of application. Even though this reaction tends to
In a large 12-week randomized clinical trial of topira- wane after 1 to 2 weeks, the intensity of the reaction
mate compared to placebo in 323 patients, Raskin and frequently leads to premature discontinuation of the
colleagues showed that the group receiving topiramate agent and poor patient compliance. At best, if tolerated,
experienced statistically significant reductions of visual capsaicin cream produces only mild to moderate pain
analog scale scores. Patients were titrated up to 400 mg relief and often serves best as adjunctive therapy with
per day or maximum tolerated dose. Fifty percent of other agents.
patients receiving topiramate and 34% of patients
receiving placebo responded to treatment defined as a
greater than 30% reduction of the pain visual analogue
Lidocaine
(PVA) scale. Topiramate also reduced worst pain inten- White and colleagues studied the effectiveness and safety
sity and sleep disruption. The most commonly reported of a 5% lidocaine patch in patients with postherpetic
adverse effects were diarrhea, loss of appetite, and neuralgia, patients with low back pain, and 49 patients
somnolence.170 with painful diabetic neuropathy. The patch was applied
Topiramate has the attractive benefit of causing on up to four areas of maximum peripheral pain for
weight loss without disrupting glucose control.170 In an 2 weeks. Significant improvements in the Brief Pain
extension of this trial, 205 patients participated in a Inventory were measured in general activity, mood,
26-week open-label study in which patients initially given walking ability, normal work, relationships with others,
placebo were started on topiramate and those taking the and sleep and enjoyment of life in patients with painful
active drug continued it. Approximately 60% of patients diabetic neuropathy. The patch was well tolerated and
completed the study. At the final visit, PVA scales, current considered safe.174 In a similar study of the 5% lidocaine
pain, and sleep disruption scores did not differ sig- patch, 41 patients with painful diabetic neuropathy
nificantly between the former topiramate and former improved in four composite measures of neuropathic
placebo groups, implying that pain relief from topira- pain.175
mate is effective and long lasting. Mean weight loss was
over 5 kilograms in both groups taking topiramate.
Approximately 40% of the subjects discontinued the
Clonidine
study, primarily because of side effects.171 Zeigler and colleagues studied the efficacy of transdermal
Collins and colleagues studied the relative efficacy clonidine in patients with painful diabetic neuropathy.176
and adverse effect of antidepressants and anticonvulsants Twenty-four patients received either transdermal cloni-
in diabetic neuropathy using published reports from sev- dine (0.3 mg per day) or placebo patches in a two-period
eral electronic databases. The NNT to achieve at least crossover study in which each patch was applied for 6
50% pain relief with antidepressants was 3.4, and that weeks. The mean pain score diminished by only 13% in
with anticonvulsants was 2.7. Antidepressants and anti- the clonidine group compared to placebo, a result that
convulsants showed the same efficacy and only minor was not statistically significant (p = .11). Nine patients
side effects in the treatment of diabetic neuropathy.172 requested to continue the clonidine patch treatment and
were subjected to single or multiple challenges and with-
drawals. Seven of the nine patients reported return of
Topical Agents pain on withdrawal of the clonidine patch and relief of
pain when the patch was reapplied, suggesting that a
Capsaicin subset of patients with diabetic neuropathy experience
Capsaicin is the active agent in hot peppers. When pain relief from topical clonidine patches.157 In a similar
applied to skin over a prolonged period of time, it study design, Byas-Smith and colleagues showed little dif-
depletes substance P, an endogenous neuropeptide nec- ference in pain relief between the active drug (titrated
essary for the propagation of pain. This depletion occurs from 0.1 to 0.3 mg per day) and placebo group in
subcutaneously and in the dorsal root ganglia and dorsal 41 patients with painful diabetic neuropathy. As in the
horn. The discovery of this phenomenon led to several previous study, several patients (12 patients) requested
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 61

continuation of the clonidine patches. Analysis of this 10 patients with painful diabetic neuropathy. Few
subgroup showed 20% less pain after treatment with patients improved, and the authors concluded that
clonidine patches than after treatment with placebo.177 baclofen has little utility as a conventional analgesic for
On the basis of these two studies, clonidine patches may neuropathic pain.184
be beneficial in a subset of patients with painful diabetic
neuropathy.
Narcotics
Controversy exists over the place of narcotics in the treat-
Tramadol Hydrochloride ment of chronic pain, especially long-term neuropathic
Tramadol hydrochloride is a unique pharmacologic pain. Many physicians avoid their use on the basis of the
agent that acts in two ways: as an opioid agonist and as an belief that they are not effective or that their addictive
activator of monoaminergic spinal inhibition of pain. potential is too great. Conversely, other pain experts
Although approved only for oral use in the United States, believe that the potential for addiction is low and that
tramadol can be administered intravenously, intramus- opioid analgesics can be used safely if the amount and
cularly, and rectally. Its potency is equivalent to that of frequency of use are carefully monitored.185 In a ran-
meperidine. Respiratory depression and addiction are domized, double-blind, crossover trial of controlled-
rare complications of tramadol. Adverse effects include release oxycodone, patients with postherpetic neuralgia
dizziness, nausea, sedation, dry mouth, and sweating. who were treated with 30 mg twice per day experienced
In a multicenter, randomized, double-blind placebo- improvement in their pain.186 Watson stated that chronic
controlled study comparing tramadol hydrochloride to opioid use is acceptable in chronic refractory cases of
placebo, tramadol was shown to be statistically better at neuropathic pain if proper guidelines are followed.187
reducing pain intensity and producing greater pain
relief within the study population. The average daily
dose tolerated was 210 mg.178 Patients receiving tramadol Antioxidants
scored significantly better on physical and social func-
tioning scales. Treatment with tramadol should begin at
␣-Lipoic Acid
50 mg per day and be slowly advanced to the maximum Many studies have shown that a-lipoic acid given par-
dose of 100 mg four times a day. In an extension of the enterally at a dose of 600 mg per day reduces neuro-
previous study, the authors demonstrated duration of pathic symptoms and deficits.188 Conversely, the results
pain relief over 6 months.179 from oral use of a-lipoic acid have not been convincing.
In the ALADIN II study of a-lipoic acid, using 600 and
1200 mg per day in 65 patients, no improvement was
Antiarrhythmics observed in the Neuropathy Disability Score even though
statistically significant changes were recorded in the
Mexiletine nerve conduction velocity compared to placebo.189 In
Mexiletine is an antiarrhythmic agent and an orally ALADIN III, neuropathic deficits were significantly
active local anesthetic agent that is structurally related to reduced in patients during the parenteral 3-week phase
lidocaine. Dejgard and colleagues studied 16 patients of the study, yet statistically significant reductions of
with painful diabetic neuropathy. Mexiletine was com- the neuropathic impairment scores were not noted after
pared to placebo at a dosage of 10 mg/kg/d. Patients 6 months of the subsequent oral phase.190
receiving mexiletine reported statistically better control The opposite results occurred in the ORPIL study of
of pain, dysesthesia, paresthesia, and nightly exacerbation oral a-lipoic acid. Patients taking 1800 mg per day expe-
of pain and better sleep than when taking placebo.180 rienced a reduction of neurologic symptoms and deficits
Two other studies showed no benefit when mexiletine over 3 weeks of treatment. This study has been criticized
therapy was used to treat neuropathic pain arising from for the small number of patients who completed the
diabetic neuropathy.181,182 In a fourth study, only patients study (22 patients).191 a-Lipoic acid is well tolerated by
who were able to take a high dose of mexiletine (675 mg) most patients. The most common side effects are
achieved significant relief from nocturnal pain and headache, rash, and gastrointestinal upset.
improved sleep. Many patients (13% to 50%) develop side
effects when prescribed mexiletine, including nausea,
vomiting, headache, chest pain, and palpitations.183
Experimental Agents
In addition to the above agents, many new compounds
are currently undergoing phase 2 and 3 clinical trials.
Antispasticity Medications Unfortunately, there are many other compounds that
In an animal model of pain, baclofen has shown some were promising but have been withdrawn from testing
analgesic properties. Terrence and colleagues tested because of ineffectiveness or serious adverse events.
baclofen in 15 patients with postherpetic neuralgia and Table 3-6 summarizes some of the current and potential
62 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

TABLE 3-6 Treatment of DPN: Putative Pathogenic Mechanisms*

Abnormality Compound Aim of Treatment Status of RCTs
Polyol pathway앖 Aldose reductase inhibitors Nerve sorbitol앗
Sorbinil Withdrawn (AE)
Tolrestat Withdrawn (AE)
Ponalrestat Ineffective
Zopolrestat Withdrawn (marginal effects)
Zenarestat Withdrawn (AE)
Lidorestat Withdrawn (AE)
Fidarestat Effective in RCTs, trials ongoing
AS-3201 Effective in RCTs, trials ongoing
Epalrestat Marketed in Japan
Myo-inositol앗 Myo-inositol Nerve myo-inositol앖 Equivocal
Oxidative stress앖 Alpha-lipoic acid Oxygen free radicals앗 Effective in RCTs, trials ongoing
Nerve hypoxia앖 Vasodilators NBF앖
ACE inhibitors Effective in one RCT
Prostaglandin analogues Effective in one RCT
phVEGF165 gene transfer Angiogenesis앖 RCTs ongoing
Protein kinase C앖 Protein kinase C-b inhibitor (ruboxistaurin) NBF앖 RCTs ongoing
C-peptide앗 C-peptide NBF앖 Studies ongoing
Neurotrophism앗 Nerve growth factor (NGF) Nerve regeneration, growth앖 Ineffective
BDNF Nerve regeneration, growth앖 Ineffective
LCFA metabolism앗 Acetyl-L-carnitine LCFA accumulation앗 Ineffective
GLA synthesis앗 Gamma-linolenic acid (GLA) EFA metabolism앖 Withdrawn
NEG앖 Aminoguanidine AGE accumulation앗 Withdrawn

*List of compounds and compound status of randomized clinical trials was current only as of April 2005.
AE, adverse event; AGE, advanced glycation end product; BDNF, brain-derived neurotrophic factor; EFA, essential fatty acid; GLA, gamma-linolenic acid; LCFA, long-chain
fatty acid; NBF, nerve blood flow; NEG, nonenzymatic glycation; RCT, randomized clinical trial; VEGF, vascular endothelial growth factor.
From Boulton AJM, Vinik AI, Arezzo J, et al: Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care: 28:956–962, 2005.

treatments for diabetic neuropathy based on “putative skin peeling under the transmitter site and electrode
pathogenic mechanisms.”6 damage from trauma.193

Spinal Cord Stimulation Surgery

In extremely refractory patients, neurosurgical proce- Recently, surgical decompression of nerves in the foot
dures can be performed to relieve pain. Tesfaye and his has been promoted as a treatment of pain in patients
group reported their results using spinal cord stimula- with diabetic neuropathy. Impressive results have been
tion of the thoracic or lumbar epidural space in patients published, the percentage amelioration of pain being as
with painful DPN. They studied 10 patients, all of whom high as 85% and 92% and improvement of two-point dis-
had experienced a poor response to previous pharmaco- crimination of 72%.194–196 Since the presence of a posi-
logic therapies. The investigators reported better pain tive percussion sign (Tinel’s) at the level of the tarsal
control in 8 of 10 patients. There was improvement of tunnel is used to determine candidacy for the operation,
both background and peak pain at 3, 6, and 14 months it appears that the surgery is performed in most cases
and better exercise tolerance at 3 and 6 months. In to correct a decompressed nerve rather than to treat a
six patients, spinal cord stimulation alone controlled diffuse symmetrical polyneuropathy. The American
the pain. In those six patients, their neuropathic pain Academy of Neurology recently published a practice
increased dramatically when the stimulator was turned advisory stating that only class IV studies (uncontrolled
off, and pain relief returned when the stimulator was studies, case series, case reports, or expert opinions)
reactivated. One patient died 2 months after the start of exist for the utility of surgical decompression for the
the study from unrelated causes, and another patient treatment of diabetic neuropathy.197 This review con-
ceased to experience pain relief after 4 months of cluded that the data are insufficient to support or refute
treatment.192 the procedure. The organization recommended the per-
The same investigators restudied the six benefiting formance of randomized controlled clinical trials and
patients a mean of 3.3 years post-implantation and once emphasized the need to distinguish between entrapment
again found dramatic improvement of pain when the neuropathy and peripheral sensorimotor neuropathy.
stimulator was turned on compared to when it was
turned off. Four of the patients were reassessed at 7.5
years with similar impressive results. Two patients had
Cost and Treatment Summary
died in the interim from cardiovascular causes. Two com- The cost of medications to manage neuropathic pain
plications ensued between the 3.3- and 7.5-year periods: must be considered, particularly for patients on fixed
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 63

BOX 3–4 Summary of Treatment Scheme

for Neuropathic Pain
● Discuss the frequent refractoriness of pain to various agents
● Explain trial and error method of using drugs
● Simple to complex medications
● Cheap to expensive medications
● Explain side effects
● Single daily dosing preferred to multiple doses
● Begin with a small dose; titrate judiciously
● Titrate one drug at a time
● Careful dosing in the elderly

budgets taking large numbers of expensive drugs. The

least expensive drugs used to treat neuropathic pain are
ibuprofen, doxepin, phenytoin, carbamazepine, amitripty-
line, and imipramine.
In summary, treatment of neuropathic pain is a chal-
lenge for both the physician and patient. Many aspects of
care should be considered in choosing an appropriate
medication, including the severity of pain, age of the
patient, potential drug interactions, coexistent medical
and surgical disorders, allergies, medication intolerances,
and ability to pay for the treatment. Box 3-4 lists a time-
proven and effective scheme that this author has found
to be helpful to treat neuropathic pain.

Routine Assessment by the Figure 3–24 “Happy Foot” poster. This poster is
Health Care Professional prominently displayed on the walls of all the exam rooms of the
Diabetes Clinic of the Brody School of Medicine at the East
Carolina University in Greenville, North Carolina. The
Early identification and appropriate therapy of the endocrinologists in this clinic have found that patients are much
patient who is at increased risk of ulceration and ampu- more likely to already have their shoes and socks off when the
tation require routine assessment and examination by physician enters the exam room. This poster definitely facilitates
the foot examination and speeds up the visit. Patients with
the health care professional. The health care provider
disabilities are assisted in this effort by the clinic’s able and
is responsible for lifelong surveillance, examination of friendly medical assistants.
the feet at each office visit, risk stratification, and referral
for therapeutic footwear and orthoses when needed. The
patient’s responsibilities include daily foot inspection assistance in removing their socks and shoes. We have
and obtaining patient education on self-care practices. found that when patients expect to have their feet exam-
The ADA has estimated that 50% of the limbs with foot ined at every visit, their personal foot hygiene, nail care,
ulcers can be saved if both the health care provider and and overall concern with their feet improves.
the patient fulfill their respective responsibilities. An important part of the office exam in the neuro-
pathic patient is to check for foot deformities. Motor
neuropathy can lead to foot deformities from muscle
Routine Office Visit Exam atrophy and imbalance of the muscles. A common defor-
At each office visit the health care provider should mity is the claw toe deformity (see Figs 3-3 and 3-4). The
examine the patient’s feet. To help expedite the exam loss of foot flexor strength allows the foot extensors to
in the office of nonpodiatric providers, our diabetes contract relatively unopposed. Even at rest, the toes are
clinic has a poster on the wall of each exam room that pulled into a claw position. As this occurs the fat pad is
states: “if you have diabetes, please remove your socks pulled off the metatarsal heads. This may lead to high
and shoes before the doctor comes in” (Fig. 3-24). We pressure points under the metatarsal heads, the tips of
have found this “happy foot” poster to be very effective in the toes, and the knuckle of the toe. These are common
ensuring that patients have their feet examined every time areas for ulceration. Metatarsal bar orthoses help to pull
they are seen by the provider. In addition to improving the fat pad back into place and straighten the toes. Thus,
patient care, the poster saves the provider time, since the metatarsal bar can help to prevent ulceration in
many elderly and disabled patients need extra time or patients with claw toe deformity.
64 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

Other deformities that the health care provider monofilament (insensate) were at greater risk of ulcera-
should evaluate include hammer toes, hallux limitus, tion at any duration of diabetes.200 For this reason, dia-
bunions, Charcot arthropathy, limited joint mobility, betic individuals with insensate feet should obtain custom
abnormal toe position, calluses, and partial foot amputa- footwear. Lack of vibration sense over the great toenail
tions. Bunions do not allow for proper shoe fitting. carries a similar risk. Monofilaments and tuning fork
Callus formation is secondary to repeated insult from evaluation should be determined on an annual basis.
increased pressure. Thus, shoes that fit poorly, shoes that In addition to sensory and motor neuropathy, patients
have poor cushioning, going barefoot, and foot defor- with diabetes typically have autonomic neuropathy. Two
mities can result in heavy callus formation. Although common consequences of autonomic neuropathy in the
calluses form to better protect the foot, calluses are diabetic foot are sudomotor dysfunction and changes in
unyielding, fixed tissue that is more prone to injury from vascular flow within the skin of the sole of the foot. Both
shearing and can actually increase the pressure under of these abnormalities lead to dry feet. Dry, cracked, or
the callus even more. It is not uncommon to find an fissured skin in the feet is a common problem in people
ulcer under a callus.198 with diabetes. The reason is twofold: lack of skin lubrica-
Charcot foot (see Chapter 12) is a progressive destruc- tion and redirection of blood flow in the microscopic
tion of the bones in the foot. The arch of the foot is blood vessels in the skin (Fig. 3-26).
usually lost. The misshapen foot and bony protrusions Skin lubrication is maintained by oil and sweat secre-
lead to increased pressure points in unusual places on tion by the sebaceous glands. These sweat glands atrophy
the foot.199 Any foot deformity contributes to increased in the presence of autonomic neuropathy. This natural
pressure and shear stress over the bony prominence, put- lubrication is important for maintaining the health of
ting the foot at increased risk of ulceration. Foot defor- the skin. The other reason for dry feet is because the AV
mities should be sought, noted, and evaluated at each shunts, which are located in the soles (but not the
office visit. These and other foot deformities are dis- dorsum) of the feet, are inappropriately dilated. Normally,
cussed in detail elsewhere in this book. the sympathetic nerves to these channels keep them
Sensory neuropathy can easily be evaluated via mono- tightly shut, and the blood flows to the skin surface
filament testing (see Sense of Touch: Monofilament through the nutrient capillaries. These channels (AV
Testing earlier in this chapter). shunts) are normally used by the body to help protect an
Figure 3-25 details the importance of monofilament individual from very cold weather.
testing. Individuals who were unable to feel the 5.07 During extreme cold, the body allows these channels
to open up and redirects the blood away from the sur-
face of the skin back toward the central (core) part of the
Rate/1000 diabetic person-years

p .00075 body. These channels are located in the earlobes, the

600 fingers, the tip of the nose, and the soles of the feet.
500 Therefore, frostbite occurs in these places first. When
400 the nerves to these channels are damaged from auto-
300 p .00016 nomic neuropathy, the channels are not kept consis-
200 p .011 tently shut (i.e., the AV shunts dilate). This allows the
100 blood to bypass the surface of the skin. Bypassing of the
0 surface of the skin causes a lack of integrity to the skin
0–9 10–19 20 and aids in its becoming dry.
Duration of diabetes in years This is also a common reason for cold feet. The com-
bination of poor natural lubrication and reduction in
Sensate Insensate blood flow in the soles of the feet allows the skin to
become dry, crack, form fissures, and become hard. The
Figure 3–25 Ulceration and monofilament score. In a study
of the incidence of plantar ulceration by duration of diabetes and
skin serves to protect the feet from injury. If the skin is
sensitivity to 5.07 monofilament, 358 American Indians were dry and has lost its integrity for any reason, the foot is at
screened with the Semmes-Weinstein 5.07 monofilament. The increased risk for damage, sores, lesions, ulcers, infec-
patients were followed prospectively for lower-limb events and tions, and even amputation. Therefore, keeping the feet
changes in sensation. Insensitivity to the 5.07 monofilament well lubricated (not wet) is an essential part of prophy-
occurred in 19% of the patients screened. Among the insensate
group, the odds ratio of subsequent ulceration was 9.9 (95% CI,
lactic foot care.
4.8 to 21.0) and amputation was 17.0 (95% CI, 4.5 to 95.0) In choosing an agent to help maintain or replace skin
compared to those individuals who were able to feel the 5.07 moisture, the health care provider must read the label of
monofilament. These relationships were maintained when the product. Sometimes agents added to creams, oint-
controlling for the duration of diabetes and vascular indices. ment, and lotions are not the best for feet. Many of the
(Redrawn with permission from Rith-Najarian SJ, Stolusky T, Gohdes
DM: Identifying diabetic patients at high risk for lower-extremity
fragrances that are used in these products are alcohol
amputation in a primary health care setting: A prospective evaluation of based. As alcohols evaporate, they can dry the skin fur-
simple screening criteria. Diabetes Care 15:1386–1389, 1992.) ther. The patient should be instructed that words ending
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 65

Venous
plexus
(VP) Arteriole Venule

AVS

Subpapillary Arteriovenous
plexus anastomosis-
(SPP) A-V shunt
(AVS)
Artery

Cutaneous
arterial Vein
plexus
(CAP)

Sympathetic nerves
Sympathetic nerves
A B
Increased Figure 3–26 AV shunts. Plantar AV shunts in normal and
edema and neuropathic diabetic individuals. A, The microvasculature of the
decreased skin sole of the foot. Small subcutaneous arteries penetrate the dermis
temperature and anastomoses in the cutaneous arterial plexus (CAP).
Arterioles arise from this plexus and ascend to form the
subpapillary plexus (SPP). Arteriovenous anastomosis (AV shunts
[AVS]) are richly innervated, are under rigid sympathetic control,
and connect small arteries and arterioles to small veins and
venules, which form a venous plexus (VP). B, A schematic model
of the normal artery, arteriole, venule, vein, and sympathetically
Arteriole Venule
innervated AV shunt. Under normal circumstances, the AV shunt
is closed, and blood flow is through the nutrient capillaries.
C, Proposed mechanism of AV shunting in diabetic neuropathy.
A decrease in sympathetic innervation of the richly innervated AV
shunts and less innervated arterioles results in relatively greater
dilatation of the AV shunt and only a modest dilatation of the
arteriole. This leads to a shunting of blood away from the capillary
Arteriovenous dermal papillae loops (nutrient capillary), a decrease in
anastomosis- transcutaneous oxygen tension at the skin, an increase in foot
A-V shunt venous oxygen tension, and low skin temperature. (References:
(AVS) DCCT Research Group: The effect of intensive diabetes therapy on the
Artery development and progression of neuropathy. Ann Intern Med
122:561–568, 1995. Harris M, Eastman R, Cowie C: Symptoms of
sensory neuropathy in adults with NIDDM in the U.S. population.
Diabetes Care 16:1446–1452, 1993. Ohkubo Y, Kishikawa H, Araki E,
Vein et al: Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with non-insulin-
dependent diabetes mellitus: A randomized prospective 6-year study.
Diabetes Res Clin Pract 28(2):103–117, 1995. Hassan K, Simri W,
Rubenchik I, et al: Effect of erythropoietin therapy on polyneuropathy in
Diabetic neuropathy
of the sympathetic predialytic patients. J Nephrol 16(1):121–125, 2003.)
C nerves
66 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

A B
Figure 3–27 Xerosis before and after treatment. A, The foot of a subject with grade 7 xerosis prior to treatment with 10% urea and
4% lactic acid in a nongreasy emulsion base (Atrac-Tain cream, available online at http://www.sweenstore.com/atractain.html). Note the
presence of fissures. B, After 4 weeks of treatment with this product, there was marked improvement. The contralateral foot (not shown),
which was treated with only the vehicle (placebo), had no significant change in 4 weeks. (Data from Pham HT, Exelbert L, Segal-Owens AC,
et al: A prospective, randomized, controlled double-blind study of a moisturizer for xerosis of the feet in patients with diabetes. Ostomy Wound
Manage 48(5):30–36. 2002.)

with “-ol” are often alcohols. If any of the first four items and creams. Urea appears to be fairly efficacious and safe
on the label ends with the last two letters “-ol,” another as a moisturizer. In the opinion of this author, a 20-40
product should be chosen. Furthermore, words such as cream or gel of urea available by prescription (Carmol)
“natural,” “intensive,” “nature’s,” “diabetic,” “diabetes,” is one of the better pure lubricants on the market.
“pure,” “prevention,” “dermal,” “the best,” “formulated,” Patients with severe dryness from diabetic autonomic
“formula,” “secret,” “oldest,” “doctors,” and “physicians” neuropathy will often have xerosis. This term, derived
have no bearing on the quality of the product. In addi- from the Greek xeros, meaning “dry,” is often associated
tion, petroleum-based products seal the surface of the with flaking of the skin and is often recalcitrant to the
skin. They keep what little lubrication is made from evap- usual lubricant therapies. A recent prospective random-
orating too quickly but do not penetrate past the surface ized, double-blind clinical trial compared the efficacy of
of the skin. Thus, petroleum-based products do not a test moisturizer containing 10% urea and 4% lactic
replace the moisture in the skin. acid to that of a placebo emulsion base vehicle in 40
Creams or lotions with substances that are known to patients with severe xerosis.201 Subjects had one foot
help replace the moisture to the skin surface and just treated with the test product and the other with the
below the surface of the skin are better than perfumed placebo for 4 weeks, and the xerosis was documented by
lotions or petroleum-based products. Most ointments photographs and graded on a seven-point scale. The test
are petroleum based. Animal oils (e.g., lanolin), urea (a product, marketed as Atrac-Tain Cream (available online
substance commonly found in urine), and fats (e.g., at www.sweenstore.com/atractain), led to a statistically
stearates) tend to penetrate deep into the skin and mois- greater improvement in the treated foot. In some
turize dry skin well. There are many excellent creams patients, deep heel fissures were healed with this product
and lotions on the market. One lotion that is commonly within 4 weeks (Fig 3-27). The authors noted that unfor-
used is called Lansinoh. This lotion is a form of lanolin tunately, 25% of their subjects did not apply the cream
and is often used by nursing mothers to avoid cracking of daily and failed to complete the study. Nonetheless, this
their nipples when breast-feeding. study represents the only randomized trial to demon-
Other commonly used lanolin-based products include strate a significant improvement in xerosis by a moistur-
Bag Balm and Udder Butter, which were first used to izing product in a diabetic population.
keep cows’ udders soft and pliable. These lanolin-based
products appear to be safe and work reasonably well.
However, Bag Balm and Udder Butter contain an antibi-
Risk Stratification
otic that some health care professionals find less than Several classification schemes for foot risk stratification
desirable. Urea is found in many over-the-counter lotions have been proposed and are discussed elsewhere in this
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 67

TABLE 3-7 Treatment-Based Diabetic Foot Index

Category Presentation
0 Minimal or no pathology present
1 Insensate foot
2 Insensate foot with deformity
3 Neuropathy with deformity plus history of prior foot
ulcer
4 Insensate injury
5 Infected diabetic foot
6 Dysvascular foot

book. Table 3-7 is a convenient, evidence-based classifi-

cation.202 In this system, patients are stratified according
to the presence or absence of sensation, deformity, neu-
ropathic ulceration, infection, and vascular disease. Each
category corresponds to a recommended treatment
regimen and is discussed in Chapters 9, 15, and 28.
Evidence exists that the odds ratio of developing a foot
ulcer increases as patients exhibit more of the following
characteristics: severe peripheral neuropathy (inability
Figure 3–28 Harris Foot Mat. Harris Foot Mat results before
to feel a monofilament of 5.07), advanced peripheral vas-
and after wearing a cushioned stocking. The Harris Foot Mat is an
cular disease (absence of pedal pulses, dependent rubor, inexpensive method to document the presence of increased
pallor on elevation, or history of intermittent claudica- pressure points in an individual. This person had increased
tion or rest pain), foot deformity, history of previous foot pressure points over the first metatarsal head and great toe on
ulcer or amputation, presence of plantar callus, and/or the right foot. Use of a cushioned sock (Thor-Lo) greatly
decreased the presence of these pressure points. Harris mat
limited joint mobility syndrome.59 Health care profes-
determinations are recommended for all diabetic patients on a
sionals need to identify feet that are at risk for ulceration routine basis. This serves as both information for the health care
and seek methods (see below) to prevent the same. provider and education and motivation for patients.

Proper Footwear
Chapter 13 describes appropriate footwear for people In addition to special shoes, socks are very important
with diabetes in detail. Because of the presence of neu- in protecting insensate feet.
ropathy, special protective shoes are often necessary.203 Figure 3-28 illustrates impressions generated utilizing
Custom or modified footwear is important for healing Harris mats. The figure clearly demonstrates the advan-
(e.g., total contact casting, removable walker, half-shoe) tage of a cushioned sock (Thor-Lo) over a standard sock.
and for prevention (e.g., extra-depth shoe, custom- Even in people without neuropathy or foot deformity,
molded shoes, custom insoles). Metatarsal bars are com- well-fitting shoes, especially jogging, tennis, or other
monly used in custom insoles and help to correct the cushioned shoes, are essential for avoiding blisters and
claw toe deformity (see above). Rocker-bottom shoes are other foot lesions. Simple habits such as changing the
also commonly used. The rocker-bottom shoe enables shoes every 4 to 6 hours, breaking in new shoes slowly,
the individual to rock or roll the foot from heel to toe and inspecting shoes before wearing each time are also
without bending the shoe or creating undue pressures effective preventive measures.
on the foot.
Custom shoes can decrease the reulceration rate from
60% over 3 years to 20% over 3 years.204 The benefit of
Patient Education
special shoes and insoles has been recognized and sup- Chapter 30 details the importance and techniques for
ported by Medicare. The Medicare-supported Therapeutic proper patient education. Table 3-8 summarizes the gen-
Shoe Bill allows for payment for special footwear and eral principles. Foot soaks; “bathroom surgery”; going
insoles made for people with diabetes. The ADA states barefoot; heating pads; astringents; plastic shoes; and
that the objectives of prescription footwear include (1) to over-the-counter preparations for corns, calluses, and
relieve areas of excessive plantar pressure, (2) to reduce nails should be avoided. It is important for the patient to
shock, (3) to reduce shear stress, (4) to accommodate be actively involved in his or her own care. Proper foot
deformities, (5) to stabilize and support deformities, and care should be demonstrated by the health care educator
(6) to limit motion of joints. and in turn by the patient.
68 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

TABLE 3-8 Education for Diabetic Patients Autonomic neuropathy also contributes to many compli-
with Neuropathy cations that increase morbidity in patients with diabetic
Appropriate type of exercise Good communication with health neuropathy. These include poor papillary dark adapta-
care provider tion, gastroparesis, enteropathy, colonic hypomotility,
Wash feet carefully Dry feet carefully (especially
between toes)
constipation, urinary incontinence, erectile dysfunction,
Inspect feet every day Look for changes in skin color retrograde ejaculation, cold hands and feet, and hypo-
(especially between toes) glycemic unawareness.
Feel for increased skin Avoid extremes in temperature
temperature
Trim toenails straight across Wear proper footwear
Stop smoking Avoid minor trauma (i.e., no bare
Avoidance of Future Complications
feet) of Diabetic Neuropathy
Good nutrition Learn (read pamphlet or watch
video) about proper foot care The ultimate consequences of diabetic neuropathy can
be pain or foot ulcers and amputation. The management
of neuropathic pain was discussed above. The greatest
challenge to practitioners who care for patients with dia-
The use of a nonbreakable mirror enables the patient betes is management of the patient with an insensate
to inspect the soles of his or her feet with ease. Specific foot. The avoidance of ulceration and possible amputa-
instructions (such as “Don’t go barefoot”) are often tion in the care of the neuropathic patient includes three
more practical than are generalities (such as “Avoid essential components: regular assessment of the foot, use
hurting your feet”). Liberal use of films, booklets, pam- of properly prescribed footwear, and patient education.
phlets, videos, and handouts is important. The impor- In addition, offering these methods and tools to improve
tance of patient education was well illustrated in one the quality of life for patients with diabetic neuropathy
study, which showed that simple interventions (patient should be considered part of good clinical care.
foot care education provided with written information
about proper foot care) reduced serious foot problems
by 60% in 1 year.205 Summary
Although patient education is important in all people
with diabetes, it is especially important to provide patient In summary, diabetic neuropathy is a major public health
education to individuals with diabetic neuropathy. problem that is often overlooked by physicians and
Devices for activities of daily living, including buttoners, patients. In the previous edition of this text and in an
zipper assist devices, mirrors, and bathwater thermome- article that was published in Diabetes Forecast, we labeled
ters, can be helpful to a patient when diabetic neu- neuropathy the “forgotten complication” of diabetes.208
ropathy is advanced. As was previously stated in this chapter, the current situ-
ation regarding appreciation for the true prevalence and
clinical significance of DPN has not changed signifi-
Prognosis and Avoidance cantly since the sixth edition was published. Fortunately,
of Future Complications our understanding of the pathogenesis, clinical manifes-
tations, and treatment of DPN is far advanced over
that of clinicians in 2001. However, further research is
Prognosis needed to expand our knowledge of the etiologies and
Most of the information about the prognosis of diabetic pathogenesis of DPN and to discover better methods to
neuropathy can be found from the results of the DCCT prevent the onset and progression of this disorder, inde-
trial, which compared the prognosis of patients with dia- pendent of glucose control.
betic neuropathy treated with routine insulin to that of Even if diabetes could miraculously be cured or pre-
patients treated with an aggressive course of four insulin vented, neuropathy would continue to exist as an impor-
injections per day. Patients who received aggressive treat- tant clinical problem for millions of people in the United
ment achieved stabilization of the neuropathy and fewer States and throughout the world. This is one complica-
progressed to autonomic neuropathy. Several studies tion of diabetes that should never be forgotten.
have shown that patients with autonomic neuropathy,
especially cardiac autonomic neuropathy, have excessive
mortality. Cardiac autonomic neuropathy is the most fre- ACKNOWLEDGMENTS
quent autonomic complication of diabetic neuropathy.206 The authors wish to thank Kenneth Stone and Amy Long for
It leads to orthostatic hypotension, exercise intolerance, their assistance with the footnotes, tables, and figures. Also
and enhanced intraoperative instability, and it has been thanks to Mary P. Schumer and to Drs. Michael Pfeifer and
hypothesized to cause an increased incidence of silent Douglas Green for their contributions to the sixth edition of
myocardial infarction, ischemia, and sudden death.207 this text.
 CHAPTER 3 Neuropathic Problems of the Lower Limbs in Diabetic Patients 69

Pearls
● Suspect an alternative (or additional ) diagnosis to diffuse diabetic polyneuropathy (DPN) when the patient’s symptoms or signs are
◆ More unilateral than bilateral
◆ More proximal than distal
◆ More motor than sensory
◆ More localized than diffuse
◆ More pronounced with walking than at rest
◆ More common in the morning than the evening
◆ When there is associated edema
● Weight loss and depression are important manifestations of DPN.
● DPN symptoms and signs may precede the onset of diabetes.
● When treating neuropathic pain, remember that you are managing a patient. Begin medication carefully and in low doses, advancing
as tolerated. Try inexpensive medications before prescribing the newest and, most likely, the most expensive therapy. Explain poten-
tial side effects at the time of the first visit. Emphasize that complete relief of pain is rare and pain relief of 50% to 75% is considered
substantial improvement.
● Pearls regarding reflexes:
◆ When the sensory deficit is present proximal to the knees (including loss of knee jerks) the hands are usually involved with DPN.
◆ Normal people over age 60 years often lose their Achilles reflexes (ankle jerks).
◆ Patients with pain from small fiber DPN may still have normal deep tendon reflexes.
◆ Diminished knee and ankle jerks may be reinforced by using the Jendrassik’s maneuver (the patient hooks the hands together by
the flexed fingers and tries to pull them apart).
● Claw feet are a significant problem because the metatarsal heads bear much of the weight, resulting in a biomechanical instability with
a predisposition for callus and ulcers to occur on the metatarsal heads.
● Neuropathic ulcers are typically painless, are generally round in shape with a “punched out” appearance, and almost always form at
pressure points.
● Be sure to spread the toes to look for “kissing ulcers” in patients with insensate feet.
● When the patient’s pain persists for more than 6 months after therapy is begun:
◆ Check to be sure the patient is not smoking.
◆ Check to be sure the patient’s glucose, blood pressure, and lipids are at target levels.
◆ Increase medication to maximal dose and add a second or third medication to the regimen if needed.
● The five indications for custom diabetic shoes are:
1. Inability to feel the 5.07 monofilament
2. Deformities
3. Prior foot ulcer
4. Any history of amputation
5. Arterial insufficiency

Pitfalls
● Not all pain in the hands and feet of a diabetic patient is neuropathic pain. Patients with diabetes may have other disorders producing
pain in the hands and feet.
● Remember that a patient who feels the 5.07 monofilament might still have DPN but protective sensation is intact.
● The unilateral swollen foot that is painless in the presence of good pulses should not be dismissed without an evaluation for an early
Charcot foot.
● Do not assume that focal tenderness is related to DPN. Patients who have an area of focal tenderness should be referred to
a podiatrist to rule out another pathologic process (e.g., Morton’s neuroma, stress fracture(s), tarsal tunnel syndrome, or plantar
fasciitis).
● It is important to note the paradox of severe neuropathic pain in patients who have insensate feet.
● Patients with classic nonhealing neuropathic ulcers may also have an ischemic component, and one should not forget to order an
evaluation of their peripheral circulation.
● Gait abnormalities may be from large fiber DPN, but central nervous system disorders need to be ruled out with a complete neurologic
evaluation.
70 SECTION A THE FOUNDATIONS OF DIABETIC FOOT MANAGEMENT

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