Peripheral Neuropathy Diabetic Neuropathy

Diabetic Neuropathy
A. Gordon Smith, MD; J. Robinson Singleton, MD

ABSTRACT
Purpose of Review: Diabetes is the most common cause of peripheral neuropathy in
the world. More than half of patients with diabetes have neuropathy, and half of pa-
tients with neuropathy have diabetes. Diabetic neuropathy is a major cause of disability
and health care expense. This article reviews the various forms of diabetic neuropathy
with a focus on diagnosis and treatment.
Recent Findings: Diabetes causes a wide variety of peripheral nerve problems. These
can be divided into chronic neuropathies, of which distal symmetric polyneuropathy is
the most common, and acute neuropathies, such as diabetic amyotrophy. There is
growing evidence suggesting that prediabetic levels of hyperglycemia and other con-
sequences of obesity and dyslipidemia contribute to neuropathy risk. Evolving literature
suggests that many of the acute diabetic neuropathies are related to inflammatory
mechanisms. An important exception is treatment-related neuropathy, previously known
as insulin neuritis.
Summary: While disease-altering therapy continues to prove elusive, our understand-
ing of basic disease mechanisms is improving, and new diagnostic and research tools
will hopefully lead to novel therapies for distal symmetric diabetic polyneuropathy.
Continuum Lifelong Learning Neurol 2012;18(1):6084.
INTRODUCTION AND
CLASSIFICATION
It can be reasonably argued that to know
diabetes is to know neuropathy. Distal
symmetric polyneuropathy (DSP) is the
most common neuropathic complica-
tion of diabetes and the most common
form of peripheral neuropathy world-
wide. Diabetes also causes a wide range
of both chronic and acute neuropathies
that affect the full anatomic breadth of
the peripheral nervous system from the
nerve root to the skin, mirroring the
spectrum of peripheral nerve diseases in
general. Diabetic neuropathies can be
classified in several ways. One system
divides them into chronic neuropathies
(DSP, autonomic neuropathy) and acute
neuropathies (diabetic amyotrophy,
treatment-related neuropathy). They can
also be divided based on focal (mono-
neuropathies), multifocal (diabetic amyo-
trophy), or generalized and symmetric
(DSP) patterns. From a clinicians per-
spective, perhaps the most useful classi-
fication is division between typical DSP
and atypical neuropathies. Typical DSP
is chronic, distal, symmetric, sensory pre-
dominant, and often painful. Any varia-
tion (eg, acute, asymmetric, proximal, or
motor involvement) suggests an atypi-
cal neuropathy.
1
The diabetic neuropathies are a ma-
jor cause of morbidity and mortality.
Approximately 20%of patients with DSP
experience severe pain. DSP is a leading
risk factor for foot ulceration and even-
tual limb amputation. In 2003 the an-
nual health care costs in the United
States directly attributable to diabetic
neuropathy and its consequences were
$10.9 billion,
2
and patients with severe
pain have 80% greater costs than those
with only mild pain.
3
While less common
than polyneuropathy, acute diabetic neu-
ropathies such as diabetic amyotrophy
(diabetic lumbosacral radiculoplexus
neuropathy) cause substantial pain and
Address correspondence to
Dr A. Gordon Smith,
University of Utah
Department of Neurology, 30
North 1900 East SOM 3R242,
Salt Lake City, UT 84132,
gordon.smith@hsc.utah.edu.
Relationship Disclosure:
Dr Smith has received
compensation for consulting
activities from Baxter
Bioscience, Talecris,
NeurogesX, Allergan, and
Merz. Dr Smith has received
compensation in an editorial
capacity for AAN.com and
receives grant support from
the NIH and the American
Diabetes Association.
Dr Singleton provides medical
review for Medical Review
Institute of America, Inc.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Smith and Singleton
report no disclosure.
Copyright * 2012,
American Academy
of Neurology. All rights
reserved.
60 www.aan.com/continuum February 2012
Review Article
Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
weakness, often leading to wheelchair
dependence and severe disability. While
effective disease-altering therapies have
proven elusive, a great deal is known
about disease pathogenesis, and a wide
array of symptomatic approaches are
available.
DEFINITION AND DIAGNOSIS
OF DIABETES
Diabetes mellitus encompasses a spec-
trum of different disorders all having the
common symptom of hyperglycemia.
Diabetes is divided into four groups.
Type 1 diabetes is due to autoimmune
destruction of pancreatic " cells, leading
to insulin dependency. Type 1 diabetes
most often presents in childhood or
adolescence. Type 2 diabetes results
from resistance to insulin. Type 3 dia-
betes comprises all other types, in-
cluding genetic defects, diseases of the
exocrine pancreas (eg, cystic fibrosis),
and drug-induced. The fourth type is
gestational. Neuropathy may occur in
any of the first three types of diabetes,
although it occurs most often with type 1
or 2. While some differences do exist in
the clinical spectrum of neuropathies
between the two types and there are
likely differences in underlying patho-
biology, there is much greater overlap
in mechanism and clinical features. In-
terest in the relationship between pe-
ripheral neuropathy and prediabetes is
increasing. The diagnosis of diabetes
and prediabetes has traditionally been
made by fasting and oral glucose tol-
erance testing (OGTT), respectively,
although recent criteria establish diag-
nostic values based on hemoglobin A
1c
measurement (Table 3-1). The diagnos-
tic sensitivity of hemoglobin A
1c
for pre-
diabetes in a clinical setting is unclear,
although the specificity is likely very
high. Given the ease with which hemo-
globin A
1c
can be measured compared
to OGTT, it is a logical first diagnostic
step; however, OGTT is recommended
for screening patients at high risk for
diabetes or prediabetes.
DISTAL SYMMETRIC
POLYNEUROPATHY
Clinical Features
DSP is the most common neuropathic
complication of diabetes. Depending
on how neuropathy is defined, at least
50% of patients with diabetes will de-
velop DSP, and up to 20% have DSP
at the time of diabetes diagnosis. DSP
causes a variety of positive and nega-
tive sensory symptoms, or it may be
asymptomatic. Positive symptoms con-
sist of abnormal excessive sensations,
such as pricking, tingling, or burning.
These may be relatively innocuous, al-
though in one in five patients they are
painful, often causing substantial dis-
ability. Most patients with DSP also have
negative symptoms such as numbness
or sensory loss. Those with severe neu-
ropathy may have painless injury. Some
patients with DSP are unaware of their
sensory loss.
TABLE 3-1
Diagnostic Criteria for Diabetes and Prediabetes
Diagnosis Fasting Plasma Glucose
2-Hour Oral Glucose
Tolerance Test Hemoglobin A
1C
Normal G 100 mg/dL (5.6 mmol/L) G 140 mg/dL (7.8 mmol/L) G 5.7%
Prediabetes 100 mg/dL to 125 mg/dL (5.6 mmol/L
to 6.9 mmol/L)
140 mg/dL to 199 mg/dL
(7.8 mmol/L to 11.0 mmol/L)
5.7% to 6.4%
Diabetes Q 126 mg/dL (7.0 mmol/L) Q 200 mg/dL (11.1 mmol/L) Q 6.5%
KEY POINT
h Peripheral neuropathy is
the most common
complication of diabetes.
61 Continuum Lifelong Learning Neurol 2012;18(1):6084 www.aan.com/continuum
DSP is a major cause of disability and
reduced quality of life. The most feared
complication of DSP is foot ulceration
and eventual foot or limb amputation.
DSP increases the risk of ulceration sev-
enfold and contributes to over 60% of
lower extremity amputations in patients
with diabetes.
4
The increased risk is due
to a combination of lack of protective
sensation, abnormalities in blood flow
(that are often compounded by periph-
eral artery disease), abnormal sweating,
and poor wound healing. Ulceration
and amputation risk is also related to
the duration of the neuropathy and the
severity of the hyperglycemia. It is rare
for ulceration to occur early in neurop-
athys course.
In contrast, painful DSP is frequently
observed early in the course of diabetes
(Case 3-1). This may be in part due to
an ascertainment bias (those with pain-
ful neuropathy will present for evalua-
tion earlier and therefore have an earlier
diagnosis than those without painful
neuropathy), although other mecha-
nisms are almost certainly involved.
The pain is length dependent, involving
the feet, toes, calves, and hands. The
pain is often described as deep ach-
ing, burning, electric, tingling, or
sharp. While pain frequently limits ac-
tivities and is worse with walking, it is
most severe at night. Pain severity is
typically moderate to severe. In a survey
of 105 patients with painful DSP, the
average pain intensity was 5.8 out of 10.
6
Falls are an often unappreciated risk
of DSP. Patients with peripheral neuro-
pathy are at higher risk of falling, and
this problem may be particularly signifi-
cant in those with diabetes. Among 60
patients with diabetes over the age of
55, more than one-third had fallen in
KEY POINT
h Diabetic neuropathy
increases fall risk
sevenfold.
Case 3-1
A 57-year-old man presented to his primary care physician with reports of
6 months of severe burning in his feet. The pain was rated as 8 out of 10 in
severity and was worst in the evening. Physical examination revealed reduced
sensation to pinprick and cold temperature in both feet. Vibration was mildly
reduced at the toes. Ankle reflexes were normal. Nerve conduction studies
revealed an antidromic sural sensory amplitude of 3 HVand a peroneal motor
conduction velocity of 38 m/s with an amplitude of 3 HV. Serologic evaluation
revealed a fasting plasma glucose of 120 mg/dL and a hemoglobin A
1c
of
6.7%. The patient was provided diet and exercise counseling and was
started on gabapentin titrated to a dose of 900 mg 3 times a day with
moderate improvement in pain. Tramadol was added at a dose of 50 mg
every 6 to 8 hours with additional improvement in pain.
Comment. While traditional dogma held that distal symmetric
polyneuropathy developed only after many years of sustained
hyperglycemia, it has long been recognized that 10% to 20% of patients
with diabetes have neuropathy at presentation and that many present with
neuropathy, as in this case. While only 20% of patients with diabetic
neuropathy experience significant pain, it is likely this number is higher early
in the disease course. This is probably due to a combination of ascertainment
bias (patients with pain are more likely to present for evaluation) and the
fact that early neuropathy appears to preferentially injure small fibers. In this
case, the diagnosis of diabetes was made based on hemoglobin A
1c
criteria,
which were revised by the American Diabetes Association in 2010.
5
Treatment of pain is challenging and often requires multiple agents, as
demonstrated in this case.
Diabetic Neuropathy
the past year. Neuropathy, sensory loss,
and distal weakness were major risk
factors.
7
Bedside gait examination may
be a relatively insensitive predictor of
fall risk. Patients with neuropathy often
fall when walking on uneven or irreg-
ular surfaces, and formal gait evalua-
tion should include these conditions.
8
Any patient with DSP or diabetes with
poor lower extremity strength or vibra-
tion perception should be counseled
regarding fall risk, and gait evaluation,
walking aids, and physical therapy in-
tervention should be considered.
Diagnostic Evaluation
Early diagnosis of DSP is essential for
several reasons. Early recognition allows
for implementation of strategies in-
tended to prevent development of fu-
ture complications such as ulceration
and falls. It is likely that neuropathy
begins with potentially reversible phys-
iologic abnormalities that progress to
irreversible structural axonal damage.
Thus, early diagnosis facilitates effective
therapy. Diagnosis of peripheral neurop-
athy in general, including DSP, relies on
recognition of a combination of symp-
toms and signs and confirmatory testing.
Nerve conduction studies (NCSs) are the
most frequently used diagnostic tool for
DSP. As with most other axonal neu-
ropathies, the central feature of DSP is
reduced distal lower extremity sensory
nerve action potential amplitudes. Dia-
betic neuropathy is often associated with
mild motor conduction slowing, a find-
ing less frequently observed in other
neuropathies.
The Toronto Consensus Conference
reviewed diagnostic measures of DSP
in the fall of 2009 and recommended
new criteria.
1
Confirmed DSP requires
abnormal NCSs with symptoms or signs.
Probable clinical DSP requires both
symptoms and signs of neuropathy.
Signs include reduced distal sensation
and reduced or absent reflexes. Possi-
ble clinical DSP requires symptoms or
signs. Diagnosis of DSP, which preferen-
tially involves small nerve fibers, can be
challenging. While patients often have
severe symptoms of pain and numbness,
NCSs may be normal. Diagnosis in this
situation may rely on one of several
measures of small nerve fiber function
such as sudomotor testing or skin biopsy
with measurement of intraepidermal
nerve fiber density (IENFD). IENFD is a
well-tolerated and reliable tool for diag-
nosis of small fiber neuropathy.
9
Age and
gender normative data are published.
10
The Toronto Consensus Conference ac-
cepted use of validated measures of
small fiber function (eg, IENFD) in lieu
of NCSs in patients with suspected small
fiber neuropathy with normal NCSs.
Having made a diagnosis of DSP, it
is important to consider potential alter-
native etiologies (Case 3-2). Given the
high independent population preva-
lence of neuropathy and diabetes, a
sizable percentage of patients with neu-
ropathy and diabetes have a different or
contributing etiology. In a retrospective
analysis of 103 sequential patients with
DSP, more than 50% had at least one
additional potential cause of or contrib-
utor to neuropathy. Half of these diag-
noses were apparent by taking a careful
history (eg, heavy alcohol use), and the
rest were discovered on thorough labo-
ratory evaluation.
13
Vitamin B
12
level,
serum protein electrophoresis, and im-
munofixation should be assessed in all
patients with neuropathy, and an eval-
uation for connective tissue disease
(eg, Sjogren syndrome) or infection
(eg, hepatitis C or HIV) should be pur-
sued in appropriately selected at-risk
patients.
14
Pathophysiology
The pathophysiology of DSP is incom-
pletely understood, although a number
of important mechanistic pathways have
been identified. Neuropathy likely
KEY POINTS
h Nerve conduction studies
are frequently normal in
patients with small
fiberYspecific diabetic
neuropathy. Skin biopsy
for intraepidermal nerve
fiber density or sudomotor
function testing may be
necessary to confirm
the diagnosis.
h Up to 50% of patients
with peripheral
neuropathy and diabetes
have an additional
potential neuropathy
risk factor.
Case 3-2
A 67-year-old man with a 12-year history of type 2 diabetes presented with progressive tingling of his feet
and gait imbalance. He first noted bilateral sensory loss in his toes 7 years ago, which was associated with
mild intermittent burning discomfort. His diabetes was diet controlled until 6 years earlier when metformin
was initiated at a dose of 500 mg twice daily. For the past 4 years he had been taking 1000 mg twice daily
with excellent glycemic control. Neurologic examination revealed normal strength. Sensation to vibration
was absent beneath the ankle, and joint position sense was absent in the toes. Lower extremity deep tendon
reflexes were absent. His gait was ataxic with a positive Romberg sign. Plantar responses were extensor.
Comment. This patient developed a typical distal symmetric diabetic peripheral polyneuropathy.
While neuropathy may progress despite excellent glycemic control, the relatively rapid progression with
gait instability and proprioceptive loss would be atypical, and the extensor plantar responses suggest a
myelopathic component. This clinical pattern is typical for the subacute combined degeneration of
vitamin B
12
deficiency. It has long been recognized that
metformin may interfere with cobalamin absorption.
Several recent studies have demonstrated an increased
risk of vitamin B
12
deficiency and elevated plasma
homocysteine and methylmalonic acid levels. These
biochemical changes are associated with greater
neuropathy severity. This problem is more likely in those
who have been taking metformin for a prolonged
period at high doses (Figure 3-1).
11
In one prospective
trial, one of nine patients treated with metformin
developed vitamin B
12
deficiency (Figure 3-2).
12
Patients with new or worsening neuropathy symptoms
while on metformin should have serum vitamin B
12
,
homocysteine, and methylmalonic acid levels assessed.
FIGURE 3-1
Among 59 patients with diabetes
receiving metformin, a significant
relationship existed between the cumulative metformin
dose and serumhomocysteine (and methylmalonic acid)
levels (A). A significant correlation between cumulative
dose and neuropathy severity, here measured by the
Neuropathy Impairment Score, also existed (B).
NIS = Neuropathy Impairment Score.
Modified with permission from Wile DJ, Toth C. Association of
metformin, elevated homocysteine, and methylmalonic acid levels
and clinically worsened diabetic peripheral neuropathy. Diabetes
Care 2010;33(1):156Y161.
FIGURE 3-2
In a prospective randomized trial, those
receiving metformin experienced a
progressive decline in serum vitamin B
12
levels. Patients taking metformin should be observed carefully
for vitamin B
12
deficiency, particularly if they develop new
neuropathy symptoms.
Modified from de Jager J, Kooy A, Lehert P, et al. Long term treatment with
metformin in patients with type 2 diabetes and risk of vitamin B-12
deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181.
Copyright B 2010, with permission from BMJ Publishing Group Ltd.
Diabetic Neuropathy
results from a combination of direct ax-
onal injury due to the metabolic con-
sequences of hyperglycemia, insulin
resistance, and toxic adiposity, and en-
dothelial injury and microvascular dys-
function leading to nerve ischemia. Di-
abetes causes functional deficits in nitric
oxideYmediated microvascular reactivity
as well as a structural microangiopathy
that shares pathologic features with
microvascular injury to the retina. Addi-
tional relevant metabolic pathways in-
clude oxidative stress, accumulation of
advanced glycation end products, and
increased flux through the polyol path-
way.
15
Growing evidence indicates that
factors other than hyperglycemia play
a role in neuropathy risk and patho-
genesis. Obesity-related complications,
including dyslipidemia, may be particu-
larly important. Among 28,700 patients
with diabetes, serum triglyceride level
was an independent stepwise risk factor
for lower extremity amputation.
16
Among
1172 patients with type 1 diabetes
without baseline neuropathy followed
in the Eurodiab study, hypertension,
smoking, obesity, and serum triglycer-
ides were independent risk factors for
neuropathy.
17
Treatment
Despite a number of promising thera-
pies in cell culture and animal models of
diabetic neuropathy, no treatment has
proven effective at preventing or slow-
ing the progression of DSP. Multiple
trials of aldose reductase inhibitors have
failed to result in clinical response,
18
as
did a large trial of recombinant human
nerve growth factor.
19
Antioxidant ther-
apy with alpha-lipoic acid has reduced
pain in some trials
20
but not others,
and several additional studies are un-
derway. A number of novel therapeutic
approaches, including gene therapy, are
under development. For example, one
study of IM injection of a plasmid con-
taining the vascular endothelial growth
factor A gene, VEGFA, demonstrated a
small benefit. Another example is sub-
cutaneous injection of a replication-
deficient herpesvirus containing thera-
peutic genes of interest. The herpes
gene is transported to the dorsal root
ganglion neuron, where the therapeu-
tic gene is expressed. A recent phase I
study of injection of a herpes simplex
virus vector expressing the proenke-
phalin gene, PENK (an opiate precur-
sor), in patients with cancer-related
pain showed good tolerance and sug-
gested dose-dependent pain reduction
(Figure 3-3).
21
The same investigators
have used this technique in animal mod-
els of diabetic and toxic neuropathies.
These molecular approaches are appeal-
ing because of their theoretical ability to
target a therapy specifically to the nerve
or neuron without encountering off-
target side effects.
It is often said the only proven
therapy for reducing risk and slowing
progression of diabetic neuropathy is
aggressive glycemic control. The Dia-
betes Control and Complications Trial
(DCCT) randomized 1441 patients with
type 1 diabetes to receive either inten-
sive or standard glucose control. The
intensive therapy reduced the develop-
ment of clinical neuropathy by 65%after
5 years of follow-up.
22
The DCCT pa-
tients have been followed as part of the
Epidemiology of Diabetes Interventions
and Complications (EDIC) study. Dur-
ing the long-term follow-up, glycemic
control was similar among patients ini-
tially randomized to the different treat-
ment groups. Despite this fact, those
who had 5 years of intensive control
during the DCCT were less likely to
have neuropathy 14 years later than
those who had standard control (25%
versus 35%, PG.001).
23
While these and other studies pro-
vide clear evidence that aggressive gly-
cemic control reduces neuropathy risk
in type 1 diabetes, data from studies of
type 2 diabetes are less convincing. The
Action to Control Cardiovascular Risk in
Diabetes (ACCORD) study randomized
10,251 patients with type 2 diabetes and
a hemoglobin A
1c
of greater than 7.4%
to two diabetic regimens: an intensive
protocol with a goal hemoglobin A
1c
of
6.5% and a standard protocol with a
goal hemoglobin A
1c
of 7.0% to 7.9%.
Neuropathy was assessed using the
Michigan Neuropathy Screening Instru-
ment (MNSI) and examination find-
ings of vibration, ankle jerk, or 10-g
monofilament loss. The intensive ther-
apy arm was stopped because of in-
creased mortality. Data compared prior
to stopping the intensive arm showed
only a minimally reduced risk of new
sensory loss and no reduction in the risk
of new neuropathy based on the MNSI
(Figure 3-4).
24
The United Kingdom
Prospective Diabetes Study (UKPDS)
randomized 3642 newly diagnosed pa-
tients with type 2 diabetes to receive
either intensive or conventional glyce-
mic control. Neuropathy was defined
based on a biothesiometer, which as-
sessed vibration perception. The risk of
neuropathy was significantly reduced in
the group receiving intensive glycemic
control (Figure 3-5). In aggregate, the
literature supports a modest improve-
ment in neuropathy outcomes with ag-
gressive glycemic control. These data
suggest that other risk factors (such as
obesity anddyslipidemia) may prove par-
ticularly important in neuropathy risk in
patients with type 2 diabetes. This ob-
servation may provide clues regarding
the apparent relationship between pre-
diabetic levels of glucose dysregulation
and neuropathy.
Beyond glycemic control and man-
agement of other vascular risk factors,
current therapy focuses on symptom
management. For more information on
the management of neuropathic pain,
refer to the article Neuropathic Pain:
Mechanisms, Therapeutic Approach,
and Interpretation of Clinical Trials in
this issue of . Early rec-
ognition of patients at risk for foot
KEY POINT
h Aggressive bloodglucose
control remains the only
proven therapy to
slow painful diabetic
neuropathy progression
but carries risks
of hypoglycemia.
FIGURE 3-3
Ten subjects with focal cancer-related pain were treated with a replication-deficient
herpes simplex virus expressing the proenkephalin gene, PENK, which encodes an
opiate precursor. The agent was injected in the region of pain. The results
suggested treatment was safe and associated with a significant improvement in pain severity using a
numeric rating scale. Those receiving the highest dose had a sustained improvement of approximately
80% compared to baseline (A). There appeared to be a dose-response relationship of greater pain
relief with a higher dose (B).
NRS = numeric rating scale; MPE = maximum potential effect.
Reprinted with permission fromFink DJ, Wechuck J, Mata M, et al. Gene therapy for pain: results of a phase I clinical trial. Ann
Neurol 2011;70(2):207Y212.
Diabetic Neuropathy
ulceration is a major priority. Risk factors
include a history of ulceration, severe
neuropathy, insensitivity to a 10-g mono-
filament, and reduced pulses.
25
Patients
who have any of these risk factors
should be formally evaluated by a po-
diatrist with expertise in DSP and neu-
ropathy prevention. Patients at risk for
falls should be referred for physical
therapy evaluation. Specific gait assess-
ment on uneven surfaces should be
encouraged.
DIABETIC AUTONOMIC
NEUROPATHY
Autonomic neuropathy is a common but
underrecognized complication of dia-
betes that increases the risk of cardiac
death and can result in disability due to
orthostasis, erectile dysfunction, gastro-
paresis, and hypoglycemia (Case 3-3).
Studies to determine the prevalence of
diabetic autonomic neuropathy (DAN)
have been frustrated by the lack of a
generally accepted definition, referral
bias, and widely different methodolo-
gies for its measurement. Cardiovascu-
lar autonomic dysfunction (CAD) has
been associated with greater all-cause
mortality and cardiac death, and rela-
tively simple clinical tests for its detec-
tion exist. As a result, CAD has been a
popular common point of reference for
measurement of DAN, yet studies fo-
cusing on CAD have still yielded a wide
spectrum of predicted prevalence. For
FIGURE 3-4
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study examined the benefit of intensive glucose
control. This aspect of the study was stopped early because of increased mortality among those in the intensive
treatment arm. This figure shows the hazard ratios for developing microvascular outcomes among those in the
intensively treated group at the time this treatment was stopped. While there was a mildly reduced risk of developing examination
findings of neuropathy, there was no reduction in the development of neuropathy symptoms.
a
Defined as Snellen fraction G 20/200.
NNT = number needed to treat; ESRD= end-stage renal disease; SCr = serumcreatinine; eGFR = estimated glomerular filtration rate;
MNSI = Michigan Neuropathy Screening Instrument.
Reprinted from Ismail-Beigi F, Craven T, Banerji MA, et al; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in
type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet 2010;376(9739):419Y430. Copyright B 2010, with permission from Elsevier.
KEY POINT
h Patients who fail 10-g
monofilament testing
are at increased risk
for foot ulceration and
should be evaluated
by a podiatrist with
expertise in distal
symmetric polyneuropathy
and wound prevention.
instance, a study of 1170 patients with
type 1 and type 2 diabetes recruited
at random from European diabetes
centers found abnormalities on at least
three of six cardiovascular autonomic
function tests in 20% of patients.
26
In
contrast, the DCCT used similar meth-
ods in a pure type 1 diabetes popula-
tion of 1441 and found dysautonomia
in only 6% of patients.
22
Isolated syn-
dromes with a component of auto-
nomic dysfunction may be much more
common and may occur earlier in the
course of altered glucose regulation.
FIGURE 3-5
The only therapy proven effective for reducing risk for diabetic complications is
glycemic control. The United Kingdom Prospective Diabetes Study (UKPDS)
evaluated complication risk among 3642 patients with type 2 diabetes over a
median of 10 years. The risk of diabetic complications was significantly associated with the mean
hemoglobin A
1c
level over length of follow-up. However, the benefit of aggressive glycemic control
on reduction of neuropathy risk is at best minimal, and other metabolic factors appear to be
very important.
Reprinted from Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular
complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000;321(7258):405Y412.
Copyright B 2000, with permission from BMJ Publishing Group Ltd.
Diabetic Neuropathy
Erectile dysfunction is reported by 27%
of men with newly diagnosed diabetes
and by 20% to 40% of men with met-
abolic syndrome and prediabetes. Sen-
sitive tests for defects in peripheral
sweat generation in response to acetyl-
choline find reduced responsiveness in
one-quarter of newly diagnosed pa-
tients with diabetes.
Symptoms and Evaluation
DAN is clinically heterogeneous: skin
and essentially every internal organ re-
ceive autonomic innervation and are
thus potential targets of dysautonomia.
However, few patients present with all,
or even most, of the symptoms of dys-
autonomia listed in Table 3-2. Instead,
most patients are asymptomatic or pres-
ent with vague symptoms, such as diz-
ziness, poor balance, nausea, abdominal
pain, or sexual dysfunction. Thus, a
high index of suspicion for DAN is
required in patients with diabetes.
Patients with prolonged diabetes, poor
glucose control, or peripheral neurop-
athy are at particular risk for DAN and
should be specifically queried for possi-
ble symptoms of dysautonomia. Use of
a validated self-report clinical question-
naire such as the Survey of Autonomic
Symptoms can improve diagnostic sen-
sitivity.
27
However, because symptoms
are vague, consensus statements regard-
ing evaluation of DAN have stressed
that symptoms reflecting possible DAN
should not by themselves confirm the
diagnosis.
28
Once suspected, simple diagnostic
testing can confirm dysautonomia. Many
of the simplest tests evaluate cardiac
and vagal function, but functional tests
of other systems are available. Diagnos-
tic guidelines suggest evaluating more
than one organ system and both sym-
pathetic and parasympathetic pathways
and repeating testing to confirm DAN.
KEY POINT
h Use of a validated
self-report clinical
questionnaire for
autonomic symptoms
can improve diagnostic
sensitivity for diabetic
dysautonomia.
Case 3-3
A 36-year-old woman was admitted to the medical intensive care unit
following sudden cardiac arrest due to myocardial infarction. She was
diagnosed with type 1 diabetes at age 17, which was complicated by
persistent poor glucose control. She was unable to walk long distances or
exercise because of nausea and fatigue. Episodes of orthostatic hypotension
and syncope resulted in a fractured ankle and clavicle at age 30, and the
patient preferred to move around using a motorized cart. Gastroparesis and
extended bouts of diarrhea resulted in inanition and weight loss. During
a period of attempted insulin pump therapy, she experienced recurrent
episodes of hypoglycemia of which she was often unaware, resulting in
generalized seizures on two occasions. She denied angina or palpitations,
and at the time of her myocardial infarction she had neither dyslipidemia
nor obesity.
Comment. Autonomic neuropathy is a common but underrecognized
complication of diabetes that can result in disability due to orthostasis,
erectile dysfunction, gastroparesis, and hypoglycemia. Cardiovascular
dysautonomia, typically identified as a defect in variability of heart rate to
deep breathing or Valsalva maneuver, has been clearly associated with a
twofold to fivefold increase in risk of all-cause mortality. Alack of physiologic
discomfort induced by hypoglycemia in these patients increases the risk
of seizure and potentiates vascular injury. Dysautonomia is often present
in association with somatic peripheral neuropathy but can be the first
manifestation of hyperglycemia.
Medications and drugs that may alter
autonomic function (eg, aspirin, cough
and cold medicines, diuretics, antide-
pressants, caffeine) should be stopped
24 hours prior to testing if possible, and
confounders of age and other illness
should be considered.
Forms of DAN
Cardiac dysautonomia. Damage to the
innervation of the heart and central
blood vessels disrupts control of heart
rate and blood pressure regulation, par-
ticularly the inputs to cardiac output
control from carotid baroreceptors me-
diated by the vagus nerve. Orthostatic
hypotension is the most easily recog-
nized consequence. Patients experience
a failure of positive inotropy and blood
pressure maintenance after standing or
with exercise, which may be exacer-
bated by postprandial blood pooling
and the hypotensive effects of insulin.
Although presyncopal lightheadedness
is the classic symptom, patients often
have difficulty describing this phenom-
enon and may present with fatigue, vi-
sual blurring, weakness, vertiginous
dizziness, or neck pain.
Cardiac dysautonomia also contrib-
utes to exercise intolerance and altered
blood pressure regulation.
29
Patients
often report rapid fatigue, shortness of
breath, or presyncope with sustained
exercise. Treadmill testing demonstrates
a failure of appropriate increase in heart
rate and cardiac output in response to
aerobic exercise. It is important that
these patients understand that they
must limit exercise by perceived effort
TABLE 3-2
Symptoms and Tests for Aspects of Diabetic Dysautonomia
Category Symptoms/Signs Diagnostic Tests
Cardiovascular Orthostasis Heart rate variation to deep breathing/Valsalva
maneuver
Arrhythmia
Blood pressure variability to grip, standing, tilt
Silent ischemia
PET cardiac scintigraphy
Reduced exercise tolerance
Gastrointestinal Nausea Gastric emptying study
Early satiety Colonoscopy
Constipation/diarrhea
Genitourinary Erectile dysfunction Nocturnal penile plethysmography
Retrograde ejaculation Postvoid residual
Reduced vaginal lubrication
Neurogenic bladder
Cutaneous/sudomotor Anhidrosis Quantitative sudomotor axon reflex testing
Dry skin Sympathetic skin response
Heat intolerance Thermoregulatory sweat testing
Pupillary Argyll Robertson pupil
Central, integrative Hypoglycemic unawareness
Reduced hypoxia-induced
ventilatory drive
KEY POINT
h Orthostatic hypotension,
presyncope, or exercise
intolerance should
suggest cardiac
dysautonomia.
Diabetic Neuropathy
rather than by heart rate. Because
length-dependent nerve injury often
affects parasympathetic vagal fibers
first, patients with DAN may initially
have a relative predominance of sym-
pathetic outflow that contributes to
hypertension, especially at night. As
dysautonomia progresses, blood pres-
sure lability may increase anesthesia
and postoperative risk and complicate
postinfarction critical care. Finally, pa-
tients with cardiac dysautonomia often
do not report angina in association with
myocardial infarction or ischemia.
Chest pain may be variable, minimal,
atypically located, or absent. In these
patients, abrupt fatigue, confusion, nau-
sea, diaphoresis, dyspnea, or cough
should suggest cardiac ischemia.
Detection is critical because cardio-
vascular dysautonomia increases the
risk of cardiac and all-cause mortality
(Figure 3-6). Large epidemiologic stud-
ies have consistently demonstrated a
twofold to fivefold increased mortality
risk among those with two or more
confirmatory abnormalities of cardiac
dysautonomia compared to patients
with diabetes without these risk fac-
tors.
30
Sudden death, myocardial infarc-
tion, and congestive heart failure are
also more common. Increased preva-
lence of ventricular and malignant ar-
rhythmias, clinically silent infarction, and
blunted inotropic response to stress all
represent primary cardiac contributors
to this increased mortality. The Eurodiab
study of type 1 diabetes showed greater
QT interval prolongation in those with
dysautonomia
31
and found that dysau-
tonomia was the single strongest pre-
dictor of mortality during the 7-year
follow-up period, greater than age, glu-
cose control, or common cardiovascu-
lar risk factors.
32
A number of studies
have found increased rates of symp-
tomatic and malignant arrhythmias.
However, increased cardiac risk may
not simply reflect cardiac dysfunction:
hypoglycemic unawareness, height-
ened sympathetic outflow resulting in
nocturnal hypertension, and altered
respiratory response to stress may
predispose to cardiac ischemia. In ad-
dition, dysautonomia appears to accel-
erate nephropathy, a cardiac risk fac-
tor, and postinfarction critical care is
complicated by blood pressure lability
that increases mortality in those with
dysautonomia.
Several simple, noninvasive proce-
dures evaluate control of heart rate in
response to physiologic changes in tho-
racic pressure, blood volume, and car-
diac preload (see Vinik and colleagues
for discussion and specific instruc-
tions).
33
Paced deep breathing at a rate
of six complete cycles a minute max-
imizes variability of heart rate response,
and the expiration (bradycardia) to in-
spiration (tachycardia) ratio of the R-R
interval can be calculated using a basic
ECG strip recording (Figure 3-7). This
FIGURE 3-6
Abnormal cardiovascular reflex tests predict
increased mortality from all causes in a
population of 612 patients with type 2
diabetes. The baseline prevalence of abnormal CVR tests was
46% in patients with less than 5 years of diabetes and
approached 70% in those with more than 20 years of diabetes.
CVR = cardiovascular reflex.
Reprinted with permission from Chen HS, Hwu CM, Kuo BI, et al. Abnormal
cardiovascular reflex tests are predictors of mortality in type 2 diabetes mellitus.
Diabet Med 2001;18(4):268Y273.
KEY POINTS
h Painless myocardial
infarction is more
common with diabetic
dysautonomia and
should be suspected in
patients reporting abrupt
fatigue, confusion,
nausea, diaphoresis,
dyspnea, or cough.
h Cardiac dysautonomia
increases all-cause
mortality risk twofold
to fivefold.
h Heart rate variability to
deep breathing or
Valsalva maneuver
can be evaluated in
clinical practice.
test measures primarily parasympathetic
function. Standing from a supine posi-
tion causes maximum tachycardia at 15
seconds followed by slowest reflex bra-
dycardia at 30 seconds and is primarily a
test of sympathetic function. Finally, the
R-R interval to Valsalva maneuver tests
both sympathetic and parasympathetic
outflow. Each test can be performed in
routine practice. Valsalva has the highest
sensitivity for dysautonomia (98% com-
pared to 93% for cycled deep breathing)
but is more technically difficult to perform.
Power spectral analysis of the R-R
interval and blood pressure response to
standing, upright tilt, or sustained iso-
metric hand grip are measures that re-
quire more specialized equipment, but
as a whole they can improve the spe-
cificity of confirmatory dysautonomia
testing. Even more specialized tests in-
clude quantitative scintigraphy of heart
sympathetic innervation using PET and
quantification of peripheral neuronal
sympathetic bursts using noninvasive
radial or peroneal microneurography.
Peripheral dysautonomia. DAN is of-
ten present in association with somatic
DSP. Like DSP, DAN affects distal nerves
first. Patients may remark on reduced
foot sweating or cool extremities due to
distal loss of vascular regulation. Dry
skin, hair loss, and trophic skin changes
that reflect reduced sweating and invo-
lution of sweat glands over the feet and
lower legs are common findings on
examination.
Quantitative sudomotor axon reflex
testing (QSART) measures change in
baseline cutaneous sweat production in
response to acetylcholine iontophore-
sis. QSART is reproducible, and because
it can examine the longest cholinergic
sympathetic fibers innervating skin of
the lower leg, it is probably the most
sensitive measure of early systemic
dysautonomia.
34
Sympathetic skin re-
sponse can be performed with readily
available nerve conduction equipment
but is less sensitive. Thermoregulatory
sweat testing, in which sweat produc-
tion changes the color of a marker
FIGURE 3-7
Marked blunting of heart rate response to deep breathing is shown in a
25-year-old woman with type 1 diabetes and dysautonomia compared to normal
response in an age-matched control. Beat-to-beat RR interval is shown.
BPM = beats per minute.
Reprinted fromPfeifer M. Cardiovascular assessment. In: Dyck PJ, Thomas PK, editors. Diabetic neuropathy. 2nd ed. Philadelphia:
Saunders, 1999:177. Copyright B 1999, with permission from Elsevier.
Diabetic Neuropathy
powder sprinkled on the skin, requires
substantial dedicated equipment and is
messy and uncomfortable for patients
but is excellent for identifying focal
regions of reduced sweat (as from a
thoracic radiculopathy).
Gastrointestinal. Gastric emptying
and gut peristalsis depend on parasym-
pathetic vagal activity. Patients with dia-
betes often experience gastroparesis,
defined as retained food in the stomach
8 hours after a meal. Nausea, early sa-
tiety, vomiting, and diminished appetite
are typical symptoms, often occurring
in cycles of days or months. Gastro-
paresis retards small intestinal absorp-
tion of glucose and other nutrients, so
scheduled postprandial insulin may
intermittently cause bouts of hypogly-
cemia and large swings in glucose levels
for these patients. Evaluation of gastro-
paresis symptoms may include upper
endoscopy, gastropyloric manometry,
or radiographic studies using barium-
laced solids to look for retained gastric
food and rule out structural causes.
Diarrhea may alternate with constipa-
tion and occurs in one-quarter of pa-
tients with diabetes. In addition, diarrhea
is often potentiated by poor anal sphinc-
ter tone that may also reflect reduced
autonomic control or sensation. Evalua-
tion usually requires colonoscopy. Diar-
rhea due to medications, psychogenic
factors, celiac and inflammatory bowel
disease, bile acid excess, and bacterial
colitis must also be considered.
35
Para-
doxically, diarrhea may be exacerbated
by colonic bacterial overgrowth due to
bowel stasis; treatment with a constipat-
ing agent only increases stasis and risks
secondary superinfection. Instead, dia-
betic cyclic diarrhea often responds to a
prokinetic agent. Rotating antibiotics to
reduce colitis and restricting gluten may
also be helpful.
Genitourinary. Activation of post-
ganglionic fibers innervating the urinary
bladder from parasympathetic sacral
efferents results in bladder contraction.
Parasympathetic dysfunction causes uri-
nary hesitancy and dribbling and, when
more severe, can lead to bladder dis-
tention and urinary retention. Neuro-
genic bladder is potentiated by poor
somatic sensation that elevates the vol-
ume threshold for urinary urgency.
Together these features increase the
risk of urinary tract infections and py-
elonephritis, which in turn may accel-
erate renal failure. Twenty percent of
patients with diabetes have symptoms
of urinary dysautonomia, and a larger
number show abnormalities of bladder
distension and volume urgency.
36
Eval-
uation of diabetic bladder dysfunction
should be considered in patients with
urinary incontinence, recurrent urinary
tract infections, or pyelonephritis. Re-
nal function tests, ultrasound measure-
ment of postvoid residual, and voiding
cystometrography can be used to eval-
uate bladder sensation to filling and pres-
sure changes and to rule out renal injury.
Patients who demonstrate unawareness
to bladder filling of more than 500 mL to
800 mL may require temporary catheter
drainage to improve bladder contractility,
followed by scheduled voiding.
Erectile dysfunction (ED), the consis-
tent inability to achieve or maintain erec-
tion adequate for sexual intercourse, is
the most common symptom of dysau-
tonomia in men with diabetes, with a
prevalence of 23% in type 1 diabetes
37
and between 40% and 75% in type 2
diabetes. Risk for ED is particularly
closely linked to the duration of dia-
betes and the hemoglobin A
1c
level.
However, dysautonomia is just one of
numerous factors that can cause ED,
some of which include hypertension,
somatic neuropathy, peripheral vascular
disease, depression and other psycho-
genic features, and medication effects,
particularly from ethanol and other sed-
atives, antidepressants, and antihyper-
tensives. Dysautonomia also contributes
KEY POINT
h Gastroparesis retards
intestinal absorption of
glucose and nutrients
and can be an
important occult cause
of inconsistent response
to insulin and large
swings in glucose
control.
to other aspects of sexual dysfunction,
such as retrograde ejaculation in men
and diminished vaginal lubrication, re-
duced sexual drive, and dyspareunia in
women. Questions about ED and sexual
function are appropriate as part of a
routine neurologic evaluation because
effective symptomatic treatment is avail-
able and because ED is a potent marker
for endothelial dysfunction and macro-
vascular disease. Patients with ED have
a threefold to fourfold increased risk for
myocardial infarction and other cardio-
vascular events.
38
Patients who fail to
respond to sildenafil or other phospho-
diesterase 5 inhibitors may benefit from
nocturnal penile tumescence evaluation;
significant psychogenic contribution can
be suspected in those with nocturnal
erections.
Hypoglycemic unawareness and
counterregulatory failure. Hypoglycemia
induces both an uncomfortable, jittery
sensation and release of counterregula-
tory hormones, particularly epinephrine,
that mobilize intracellular glycogen and
free fatty acids to raise blood glucose.
Dysautonomia, especially in patients
with type 1 diabetes under strict glyce-
mic control, may lead to a damaging
cycle of hypoglycemia, blunted epineph-
rine response, and poor recognition of
low blood glucose, leading to further
autonomic nerve injury. However, many
patients with hypoglycemic unaware-
ness have neither dysautonomia by
heart rate variability testing nor altered
epinephrine response to hypoglycemia.
NEUROPATHY ASSOCIATED
WITH IMPAIRED GLUCOSE
TOLERANCE AND
METABOLIC SYNDROME
Epidemiology and Risk Factors
NCSs are abnormal in nearly 20% of
patients at the time of diabetes diagno-
sis,
39
suggesting that length-dependent
nerve injury can predate the develop-
ment of diabetes. Epidemiologic studies
and case series establish an association
between features of metabolic syn-
drome, including impaired glucose tol-
erance (IGT), and increased risk of
neuropathy (Case 3-4). Methodical pro-
spective screening of patients with oth-
erwise idiopathic neuropathy shows
that 30% to 50% have IGT,
14
which is
three times the background rate.
40
Pa-
tients with idiopathic neuropathy are
also more likely than the general popu-
lation to be obese, hypertensive, and
dyslipidemic, regardless of their glucose
control.
42
Conversely, in patients with
diabetes, features of metabolic syn-
drome confer additional independent
risk for developing neuropathy.
43
The
Eurodiab study followed 3000 patients
with type 1 diabetes for up to 7 years.
Among the 1200 patients without neurop-
athy at baseline, hypertension, serum lip-
ids and triglycerides, body mass index
(BMI), and smoking were each indepen-
dently associated with an increased risk
of developing neuropathy at follow-up.
17
The Steno-2 trial demonstrated that ag-
gressive therapy to normalize hyperten-
sion and lipid abnormalities in patients
with type 2 diabetes reduced the risk of
coronary, cerebral, or peripheral vascular
occlusive disease but also reduced the
risk of nephropathy, retinopathy, and
autonomic neuropathy, independent of
glucose control.
44
The nature of the relationship among
prediabetes, metabolic syndrome, and
neuropathy remains to be defined.
While data suggest a risk relationship
and supportive animal models exist, the
extent to which prediabetic levels of
hyperglycemia cause neuropathy is
not known. However, given that predia-
betes and metabolic syndrome are both
significant risk factors for stroke, heart
attack, and overt diabetes, all patients
with neuropathy should be appropri-
ately screened to facilitate suitable pre-
ventive care.
KEY POINTS
h Erectile dysfunction is
a potent marker for
cardiovascular risk and
should prompt
consideration of a
cardiac evaluation.
h Two-hour oral glucose
tolerance testing should
be performed in the
evaluation of patients
with idiopathic
neuropathy.
h Large epidemiologic
studies have identified
obesity and dyslipidemia
as risk factors for
neuropathy in diabetes,
independent of glucose
control.
Diabetic Neuropathy
Prognosis in diabetic neuropathy has
been characterized as a one-way street,
with the best outcome of glucose-low-
ering treatment being slowed progres-
sion. For example, complete resolution
of type 1 diabetes following pancreatic
transplant resulted in stabilization, but
not significant improvement, in neuro-
pathy signs by quantitative examina-
tion.
45
However, some aspects of early
neuropathy associated with prediabetes
and features of metabolic syndrome
may improve with treatment. Patients
with IGT neuropathy enrolled in a diet
and exercise counseling program with
goals of losing 7% of body weight (or
normalizing BMI) and moderate aerobic
exercise for 150 minutes a week showed
significant improvement in blood glu-
cose control and lipid metabolism.
46
This metabolic improvement was asso-
ciated with a significant increase in the
number of cutaneous nerve fibers by
IENFD and significant improvement in
neuropathic pain over a 2-year period
(Figure 3-8).
Clinical Presentation
and Evaluation
Most patients with IGT and neuropathy
have a symmetric, distal sensory neuro-
pathy with neuropathic pain very similar
to that commonly seen in early dia-
betes.
47
Sensory loss in the feet is typi-
cally accompanied by positive symptoms
of uncomfortable tingling, lancinating,
or burning paresthesia. Nocturnal foot
pain often prevents falling asleep. Pa-
tients describe allodynia from blankets
and sheets and may sleep with their feet
on top of the covers or construct foot
tents. Patients may have symptoms of
leg restlessness at rest consistent with
restless legs syndrome. Men often de-
scribe ED, but other overt manifesta-
tions of autonomic neuropathy are rare.
Distal weakness is rare and may be
Case 3-4
A 62-year-old woman with a 10-year history of hypertension and hypertriglyceridemia reported
bilateral burning foot pain. Symptoms began 3 years ago with warm paresthesia of her great toes,
which gradually increased in severity and extent so that it affected the entire lower leg to midankle.
Pain was the most troublesome feature, limiting activity, and was worst in the evenings. She was unable
to wear shoes with any heel, preferring light sandals, and could not tolerate the sensation of sheets on
her feet in bed. She denied foot weakness or sensory loss, symptoms in her hands, or back pain.
On examination, the patient was obese, with a body mass index (BMI) of 35 kg/m
2
. Mild pitting edema
was present in the feet bilaterally. Strength and muscle bulk were full throughout, but deep tendon
reflexes were trace at the ankles. Pin sensation was absent to the dorsum of the midfoot and was reduced
to the lower ankle. Vibration sense was intact. Nerve conduction studies were normal. Skin biopsy at
the distal leg showed a reduced intraepidermal nerve fiber density with frequent axonal swellings.
Laboratory evaluation showed a fasting glucose of 110 mg/dL and a glucose of 165 mg/dL 2 hours after
a 75-g oral load of glucola. Triglycerides were 240 mg/dL. Vitamin B
12
, thyroid-stimulating hormone,
serum protein electrophoresis, antinuclear antibody, and rheumatoid factor were negative or normal.
Comment. Eleven percent to 14% of Americans aged 50 to 75 have prediabetes as defined by the
American Diabetes Association (ADA).
40
Interest in prediabetes has escalated in the last decade
because it is a marker for the metabolic syndrome, which consists of obesity, dyslipidemia,
hyperglycemia, and hypertension. Patients with prediabetes are at increased risk for cardiovascular
and peripheral vascular occlusive disease, independent of risk for diabetes.
41
Because of these risks,
the ADA recommends screening for prediabetes and metabolic syndrome in all patients more than
45 years old and in younger patients with a BMI more than 27 kg/m
2
and additional risk factors for
diabetes (eg, family history). Screening can be accomplished with either fasting plasma glucose or
a 2-hour glucose tolerance test, as described in Table 3-1.
KEY POINT
h Structured diet and
exercise counseling or
metformin should be
offered for treatment of
patients with neuropathy
associated with
prediabetes as well as
in early diabetes.
absent or minimal even after years of
sensory symptoms.
Evaluation of patients with clini-
cally evident distal polyneuropathy and
known IGT should include an examina-
tion specific to small fiber neuropathy.
Assessing sensation to pin at the toe and
foot and timed vibration extinction using
a 128-Hz tuning fork are easy tests to
perform and have a markedly better
sensitivity and specificity profile in detec-
tion of hyperglycemic neuropathy by
receiver operating characteristic analysis
than does 10-g monofilament testing.
48
As with DSP, a search for other causes of
neuropathy is appropriate.
14
Treatment
to normalize hyperglycemia through diet
and exercise counseling is a standard of
care for those with IGT, but in those
who cannot obtain or do not comply
with counseling, glucose control with
metformin or another insulin-sensitizing
agent is probably warranted when neu-
ropathy is present. Prediabetic (and
diabetic) patients with neuropathy are
often reluctant to exercise because
they fear it will increase foot pain. Im-
paired Glucose Tolerance Neuropathy
study data found that exercise adher-
ence strongly predicted decreased neu-
ropathic pain; patients should be re-
assured and guided toward low-impact
aerobic exercise.
ACUTE DIABETIC NEUROPATHIES
Diabetes causes or is associated with a
variety of acute or subacute peripheral
nerve disorders. While none are as fre-
quent as DSP, they are not rare and their
importance outweighs their prevalence.
Some are preventable (eg, treatment-
related neuropathy), and most are dis-
abling. They are often not recognized,
which may lead to inappropriate diagnos-
tic evaluation or unnecessary treatments
or surgeries. Effective therapies may be
available for some. Unlike DSP, they are
not related to chronic hyperglycemia.
Treatment-Related Neuropathy
(Insulin Neuritis)
Some patients with poorly controlled
diabetes experience an acute, very pain-
ful, sensory neuropathy after initiation of
intensive glucose control (Case 3-5).
This entity has traditionally been labeled
insulin neuritis, although no evidence
indicates that it is an inflammatory con-
dition. While it is most common in type
FIGURE 3-8
Diet and exercise resulted in improvement in pain and intraepidermal nerve fiber
density (IENFD) among 32 patients with neuropathy associated with impaired
glucose tolerance. Reinnervation was observed at the proximal site in most patients.
In this patient, the baseline IENFD was 8.2 fibers/mm (A). After 1 year of diet and exercise, IENFD
at the same site had increased to 15.1 fibers/mm (B).
Modified from Smith AG, Rose K, Singleton JR. Idiopathic neuropathy patients are at high risk for metabolic syndrome.
J Neurol Sci 2008;273(1Y2):25Y28. Copyright B 2008, with permission from Elsevier.
Diabetic Neuropathy
1 diabetes, it also occurs in type 2
diabetes. The pain is generally length
dependent, but one-third of patients
experience widespread pain, which is
often very severe. Autonomic dysfunc-
tion is common. The condition is self-
limited, with improvement over subse-
quent months, although it may recur if
diabetic control lapses and is once again
rapidly initiated. Patients who have a
history of diabetic anorexia (intention-
ally withholding insulin for weight loss)
may be at particularly high risk. Neurop-
athy is associated with worsening retin-
opathy, and it has been hypothesized
that rapid vascular proliferation leads to
Case 3-5
A 22-year-old college student with longstanding type 1 diabetes presented with subacute progressive
pain. She was treated with insulin throughout high school but during college became nonadherent
to her medication regimen. She confessed that for the past 3 years she had intentionally been
withholding insulin in order to maintain weight loss. One month prior to presentation she was seen by
the student health service and restarted on insulin after her hemoglobin A
1c
was found to be 14.3%. Her
glycemic control improved rapidly and dramatically. Her symptoms began with tingling in both feet
that rapidly became severe burning pain that spread from the toes to the knees. The pain was intense
enough to prevent walking, and she began
using a wheelchair. Examination revealed
diminished pinprick and temperature sensation
to the level of the knees and reduced vibration
in the toes with absent ankle reflexes. Motor
examination was normal. Skin biopsy
demonstrated absent epidermal nerve fibers
at the distal leg. Retinal examination
revealed moderately severe nonproliferative
retinopathy. She was treated with gabapentin
and oral long-acting opiates and experienced
gradual improvement of her pain over the
subsequent 18 months.
Comment. This patient has a
treatment-induced painful peripheral
neuropathy, often referred to as insulin
neuritis. Patients with very poorly controlled
diabetes whose hyperglycemia is rapidly
corrected are at risk for this very painful
disabling condition (Figure 3-9). Women with
diabetic anorexia (intentionally withholding
insulin for weight loss) may be at particular
risk. The etiology is unknown, although it has
been hypothesized that vascular proliferation
results in shunting and nerve ischemia. It is
interesting that patients with treatment-
induced neuropathy also frequently experience
worsening retinopathy, another microvascular
complication of diabetes. Treatment is
supportive. This disorder may be prevented by
a more gradual initiation of insulin therapy in
patients who are chronically nonadherent or
whose diabetes is poorly controlled.
49
FIGURE 3-9
Patients with type 1 (red) and type 2 (black)
diabetes are both at risk for developing
treatment-related painful neuropathy. The top
lines represent hemoglobin A1c levels and the bottom lines
represent pain severity on a 0- to 10-point Likert scale. Severe
10/10 pain developed in nearly all patients within weeks of rapid
glycemic control. While pain uniformly improved, this often
required more than 1 year of follow-up.
Reprinted with permission from Gibbons CH, Freeman R. Treatment-induced
diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol
2010;67(4):534Y541.
KEY POINT
h Diabetic anorexia
(abstaining from insulin
therapy to encourage
weight loss) increases risk
for bouts of painful
treatment-related
neuropathy and cachexia.
a transient steal phenomenon, although
a number of other mechanisms have
been postulated.
49
Diabetic Neuropathic Cachexia
Diabetic neuropathic cachexia (DNC) is
closely related to treatment-related neu-
ropathy.
50
Its clinical features are nearly
identical, with the addition of severe
weight loss (Figure 3-10). Pain is fre-
quently nonYlength-dependent and gen-
eralized. DNC may occur in the context
of treatment-related neuropathy or may
occur independently. It is more frequent
in type 2 diabetes. Like treatment-related
neuropathy, DNC improves spontane-
ously, and therapy is focused on pain
control.
51
Diabetic Lumbosacral
Radiculoplexus Neuropathy
(Diabetic Amyotrophy)
The most common acute neuropathy
associated with diabetes is diabetic
lumbosacral radiculoplexus neuropathy
(DLRPN) (Case 3-6). DLRPN was first
described by Bruns in 1890 and redis-
covered by Garland in 1950. It has been
called Bruns-Garland syndrome in their
honor, as well as a large number of
other monikers, including diabetic my-
elopathy, diabetic myopathy, and prox-
imal diabetic neuropathy, to name only
a few. The most commonly used term
is diabetic amyotrophy. The variety of
different names for this condition re-
flects the historical uncertainty regard-
ing pathogenesis and localization. DLRPN
is therefore preferred given its anat-
omic specificity.
DLRPN typically presents with the ab-
rupt onset of severe unilateral thigh pain
that may be deep and aching as well as
burning and tingling. This is followed by
progressive atrophy and weakness. The
symptoms typically spread throughout
the limb, and in most patients the con-
tralateral side becomes involved after
several months. Most patients experience
dramatic weight loss and many become
wheelchair dependent.
53
While proximal
symptoms often predominate early in
the disease course, distal involvement is
the rule rather than the exception, and a
significant number of patients experi-
ence disease onset in distal segments.
DLRPN is often associated with mild
upper extremity involvement, although
some patients may have more severe
upper extremity symptoms.
54
A variant
of DLRPN with motor predominance,
absence of pain, and greater clinical
symmetry has recently been described,
further broadening the spectrum of this
disorder.
55
Most patients experience pro-
gression over many months with subse-
quent improvement. While the natural
history of DLRPN is self-limited, most pa-
tients are left with permanent deficits.
53
DLRPN typically affects older patients
with type 2 diabetes. Unlike DSP, DLRPN
risk is not related to glycemic control or
duration of diabetes. Indeed, patients
with DLRPN typically have shorter dia-
betes duration than those with DSP.
Electrodiagnostic studies demonstrate
evidence of a polyradiculoneuropathy.
CSF examination is characterized by
KEY POINT
h Diabetic lumbosacral
radiculoplexus
neuropathy should be
considered in the
differential diagnosis of
radiating back pain,
focal leg weakness,
or lumbosacral
radiculopathy in
patients with diabetes.
FIGURE 3-10
Two patients from Ellenbergs classic
description of diabetic neuropathic cachexia
(DNC) (A and BYC are two different patients).
B and C compare a patients appearance at the time of
presentation (B) to that after recovery from DNC (C).
49
Modified with permission from Ellenberg M. Diabetic neuropathic cachexia.
Diabetes 1974;23(5):418Y423.
Diabetic Neuropathy
elevated protein without pleocytosis.
Nerve biopsies demonstrate a micro-
vasculitis (Figure 3-11).
56,57
The natural
history, CSF findings, pathologic data,
and lack of relationship to metabolic
severity all support an autoimmune eti-
ology. It has been hypothesized that im-
munosuppression or modulation therapy
may be effective, but definitive studies
are lacking.
52
Chronic Inflammatory
Demyelinating
Polyradiculoneuropathy
The relationship between chronic in-
flammatory demyelinating polyradiculo-
neuropathy (CIDP) and diabetes has
been controversial. It has been argued
that diabetes increases the likelihood of
CIDP and is associated with greater
disease severity. In one study of 1127
Case 3-6
A74-year-old man presented withprogressive leg weakness andpain. He first
noted aching pain in the right thigh followed by tingling and burning that
extended throughout the right leg. This progressed over several weeks and
was followed by progressive right leg weakness. He developed difficulty
rising froma chair or climbing stairs. He also noted weakness in the right foot
that caused him to stumble. Three weeks later he noticed similar pain in
the left thigh as well as tingling in both hands. He required the use of a
wheelchair for any prolonged ambulation. He had a 3-year history of
diet-controlled diabetes, hypertension, and peptic ulcer disease. The pain
was severe enough that he was taking scheduled oral opiate medications.
Examination revealed atrophy of intrinsic hand muscles bilaterally and in the
right more than the left quadriceps. There was mildhandweakness andmore
severe weakness of the right leg (compared to the left leg) that involved
proximal muscles but also ankle dorsiflexion. He had a waddling gait
and was unable to stand on his heels. Sensation was reduced to vibration
belowthe right knee and left ankle with reduced pin sensation to the midcalf
and in the fingertips. Reflexes were absent in the legs. Laboratory evaluation
included a CSF examination that revealed no white or red blood cells and
a protein of 120 mg/dL. His pain improved over the next 6 months.
Comment. Diabetes is associated with several types of acute or subacute
neuropathies. While these neuropathies are much less common than distal
symmetric polyneuropathy, their recognition is important as it facilitates
appropriate early treatment and prevents unnecessary tests and treatments,
particularly unneeded lumbar surgeries. This patient has a diabetic
lumbosacral radiculoplexus neuropathy (DLRPN), a conditionoften referredto
as diabetic amyotrophy. There is some evidence that DLRPN results from a
microvasculitis involving the nerve roots, plexus, and peripheral nerves. While
the lower extremities are preferentially affected, some upper extremity
involvement is not uncommon. Unlike distal symmetric polyneuropathy, the
risk for DLRPN is not associated with the severity of diabetes or its duration,
although it is predominantly observed in type 2 diabetes. The diagnostic
evaluation typically includes electrodiagnostic testing, which confirms an
axonal polyradiculoneuropathy, and CSF examination, which frequently
reveals an elevated protein. Most patients require aggressive pain control,
frequently with opiate medications. It has been hypothesized that
immunosuppressant therapy may be useful, although evidence is lacking
and further study is required.
52
patients seen in an academic electro-
diagnostic laboratory, patients with dia-
betes had an 11-fold increased risk of
CIDP compared to those without diabe-
tes.
58
However, several more recent epi-
demiologic studies have failed to show
an increased risk of CIDP in diabetic
populations.
59,60
Reports of a higher risk
of CIDP in patients with diabetes are
likely due to the fact that patients with
severe diabetic neuropathy, particularly
in association with chronic renal failure,
may have substantial motor conduction
slowing. Patients with diabetes are also
at high risk for asymptomatic focal slow-
ing at sites of common compression.
These features may lead to diagnostic
confusion, emphasizing the need to
base CIDP diagnosis on clinical history
and neurologic examination.
FOCAL DIABETIC
NEUROPATHIES
In addition to the generalized and multi-
focal neuropathies described above,
diabetes is associated with a number of
focal peripheral neuropathies. Up to 1%
of patients with diabetes develop a
cranial neuropathy. A partial oculomo-
tor palsy, typically with pupillary sparing,
is most common. Diabetic third nerve
palsies may be related to a vasculopathy
or microvasculitis (similar to DLRPN,
with which they may be temporally as-
sociated), although detailed pathologic
studies are understandably lacking. The
relationship between diabetes and other
cranial neuropathies (eg, facial neurop-
athy) is less clear.
61
Truncal (thoracic) radiculopathy is a
recognized complication of diabetes. As
with DLRPN and cranial neuropathy, it
is most common in type 2 diabetes. Pa-
tients present with acute pain in a tho-
racic dermatome, often with associated
weakness of abdominal wall muscles
(which bulge during Valsalva maneu-
ver). The clinical presentation may be
confused with herpes zoster or struc-
tural disease of the spine given the
severity of the pain. Truncal radiculop-
athy may occur in association with
DLRPN, suggesting an inflammatory
etiology. The natural history is gradual
improvement and return to baseline.
62
Compressive mononeuropathies, es-
pecially of ulnar, median, and peroneal
nerves, occur more frequently in patients
KEY POINT
h Severe diabetic
neuropathy closely
resembles chronic
inflammatory
demyelinating
polyradiculoneuropathy
electrodiagnostically.
FIGURE 3-11
A sural nerve biopsy (A, hematoxin
eosin stain; B, trichrome stain) from a
patient with diabetic lumbosacral
radiculoplexus neuropathy (DLRPN) demonstrates a
microscopic vasculitis involving epineurial small
vessels. This finding indicates DLRPN is probably an
inflammatory vasculitis involving small vessels and
suggests that early anti-inflammatory therapy may have
therapeutic potential. The arrows show hemosiderin
deposition (old blood), the asterisk shows fresh blood,
and the arrowhead shows intimal proliferation.
Reprinted from Dyck PJ, Norell JE, Dyck PJ. Microvasculitis and
ischemia in diabetic lumbosacral radiculoplexus neuropathy.
Neurology 1999;53(9):2113Y2121. Copyright B 1999, with
permission from AAN Enterprises, Inc. All rights reserved.
Diabetic Neuropathy
withdiabetes. Bilateral and nondominant
median mononeuropathy at the wrist are
more common in patients with diabe-
tes,
63
although obesity, rather than dia-
betes, may be the primary contributor
to increased risk of carpal tunnel syn-
drome.
64
In the evaluation of patients
with a distal diabetic neuropathy, symp-
toms of numbness in the hands should
prompt consideration of bilateral median
mononeuropathies at the wrist (carpal
tunnel syndrome) or ulnar mono-
neuropathy at the elbow (cubital tun-
nel syndrome) before consideration of
length-dependent metabolic injury to
the upper extremities. Hand examina-
tion often demonstrates selective atro-
phy of the thenar muscle (abductor
pollicis brevis) in distal median mono-
neuropathy or the first dorsal inteross-
eous muscle in the web space between
the thumb and index finger, supplied
by the ulnar nerve. NCSs should be
performed to confirm compressive ul-
nar or median mononeuropathies and
to screen for associated axonal injury.
Those with only demyelinating injury
may respond to nocturnal neutral posi-
tion wrist splints and a regimen of stu-
dious avoidance for positional carpal
or cubital tunnel compression. Patients
with disabling symptoms, weakness and
muscle atrophy, or electrophysiologic
evidence of active denervation should
be referred for carpal tunnel decom-
pression, which is nearly as effective for
patients with diabetes as for normogly-
cemic controls, improving digital sensa-
tion in two-thirds.
65
Ulnar transposition
from the cubital tunnel improves symp-
toms in only 50% to 60% of ulnar com-
pression patients.
CONCLUSION
Neuropathy may occur early in the
course of insulin resistance in associa-
tion with obesity and dyslipidemia, ulti-
mately affects half of patients with
diabetes, and is among the most costly
and disabling of diabetic complications.
Symptoms of diabetic peripheral nerve
injury are protean, and the neurologist
should be alert not only for distal sym-
metrical sensory loss but also for cranial
or compressive limb mononeuropa-
thies (eg, carpal tunnel syndrome) and
symptoms or findings suggesting dys-
autonomia. CAD increases the risk of
myocardial infarction and death fromall
causes and should prompt a referral for
cardiac evaluation. Early treatment of
painful diabetic neuropathy to reduce
neuropathic pain, increase aerobic exer-
cise, and limit risk for falls and foot
ulceration can markedly improve prog-
nosis and quality of life.
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Diabetic Neuropathy

A. Gordon Smith, MD; J. Robinson Singleton, MD

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