Richard Bedlack, MD, PhD
1.75 hours
Activity Medical Director Associate Professor of Neurology Duke University School of Medicine Durham,
NC
Defining the Challenge
Definition and Prevalence
DPN is often defined as “the
presence of symptoms or signs of
peripheral nerve dysfunction in
patients with diabetes after the
exclusion of other causes.”3 There are
several challenges to using this definition.
Clinicians detect peripheral nerve
dysfunction based on patients’ presenting
symptoms and/or physical examination.4 
Most often, symptom- and/or physical
examination–based scales are used, but
these may lack sensitivity.4,5 Some experts
advocate using a large panel of different
tests together to maximize sensitivity, and
scales may be supplemented by electro
diagnostic studies such as nerve
conductions, electromyography (which is
sensitive for large-diameter sensory and
motor fiber dysfunction), autonomic testing,
and epidermal nerve fiber density testing
(which is sensitive for small fiber
dysfunction).6
A second challenge comes from the
“exclusion of other causes.”3 Diabetes
mellitus can affect sensory nerves, motor
nerves, and autonomic nerves. Distal
symmetric polyneuropathy typically leads
to both small and large nerve fiber damage.
Frequently, combinations of nerves are
affected in what is termed polyneuropathy.7
Classification systems have been proposed
based upon the types and patterns of
peripheral nerves involved.3 For every one
of these sites of pathology, there will be a
list of potential causes. A detailed
description of all the causes of every type of
peripheral nerve dysfunction that can be
seen in a patient with diabetes mellitus is
beyond the scope of this monograph.
However, there are certain patterns of
neuropathy that are highly unlikely to be
related to diabetes mellitus. The most
common presentation of DPN (and its
differential diagnoses) is presented later in
this monograph.
The challenges of the definition of DPN, as
the challenge of ascertainment bias, make
the true prevalence of DPN difficult to
know.  Dyck and colleagues attempted to
determine the extent of diabetic
neuropathies in a community-based study
of 380 patients with clinically recognized
diabetes mellitus.8 Of these patients, 102
had insulin-dependent diabetes mellitus
(IDDM), and 278 had non–insulin-
dependent diabetes mellitus (NIDDM).
Two-thirds of the IDDM patients had some
type of neuropathy; of these patients, 54%
had polyneuropathy, 22% had
asymptomatic carpal tunnel syndrome, 11%
had symptomatic carpal tunnel syndrome,
7% had visceral autonomic neuropathy, and
3% had other neuropathies. Patients with
NIDDM had similar rates of neuropathies:
polyneuropathy (45%), asymptomatic
carpal tunnel syndrome (29%),
symptomatic carpal tunnel syndrome (6%),
visceral autonomic neuropathy (5%), and
other neuropathies (3%).
DPN Presentation Is Typically Sensory and
Insidious in Onset
Chronic sensorimotor polyneuropathy is the
most common form of DPN.3 Up to 50% of
the patients with this type of neuropathy
experience painful symptoms such as
burning pain, electrical or stabbing
sensations, paresthesia, hyperesthesia, and
deep aching pain. From 10% to 20% have
symptoms severe enough to require
treatment.9 In most patients, the pain is
worse at nighttime.3
DPN presentation is mainly sensory and
insidious in onset.3 Symptoms begin in the
toes and the feet and gradually extend
proximally.10 Later, the fingers and hands
may become affected, again with proximal
spread. Usually, when extensive, the
anterior abdominal wall may be involved,
and sensory loss gradually spreads laterally
around the trunk. Patients may lose their
ability to feel, identify, or manipulate
smaller objects.11 They can gradually lose
the capacity to ascertain temperature or
sense painful or threatening stimuli. The
loss of innervation can lead to atrophy of
essential pedal muscles, resulting in
deformities (eg, hammertoes) that leave
patients vulnerable to ulceration.11,12
Sensorimotor neuropathy is the main risk
factor for developing diabetic foot ulcers,
which are the predominant risk factor for
lower-extremity amputations in diabetes
patients.
Motor involvement is less frequent than
sensory involvement.10 However, when
severe, this neuropathy causes weakness of
distal leg muscles.
Autonomic Neuropathies
The autonomic nervous system may
become widely involved itself in diabetic
neuropathy.11 Diabetic autonomic
neuropathy can develop in patients with
type 1 or type 2 diabetes. While autonomic
neuropathy can occur at any stage of
diabetes, those over age 40 years who have
had the disease for more than 25 years and
have difficulty control- ling their blood
sugar run the highest risk.13
Most patients have symptoms that are not
severe, but some have significant morbidity
and even mortality, especially with
cardiovascular autonomic neuropathy
(CAN).3 Symptoms of autonomic
neuropathy range from cardiac (ie, early
fatigue, weakness with exercise, and
postural hypotension) to gastrointestinal (ie,
gastroparesis, erratic glucose control,
abdominal pain, early satiety, nausea,
vomiting, constipation, and diarrhea). 
Other symptoms include sexual, bladder,
and sudomotor dysfunction.
Cardiovascular Autonomic Neuropathy
CAN affects both the sympathetic and
parasympathetic innervation of the heart
and coronary vessels.11 Primary symptoms
of CAN are orthostatic hypotension and
decreased heart rate variability, and CAN
may contribute to left ventricular
dysfunction, silent or asymptomatic
myocardial infarction, and exercise
intolerance.11,14 There is evidence that the
disease process may begin early in the
course of diabetes but remains
asymptomatic until later stages.11,14
Gastrointestinal Autonomic Neuropathy
Diabetic autonomic neuropathy can affect
the entire gastrointestinal system.
Symptoms range from mild discomfort to
disabling impairment of daily activities.
Gastroesophageal dysfunction manifests as
gastroesophageal reflux disease in roughly
30% of diabetes patients.15 Delayed gastric
emptying and gastric retention, which are
present in one-fourth of patients with
diabetes, can result in early satiety,
bloating, epigastric pain (heartburn),
nausea, vomiting, and anorexia.16 
Gastroparesis can also complicate
pharmacotherapy by delay- ing the
absorption of glucose or antidiabetic
medication.
Focal Neuropathies
Diabetic mononeuropathy has an acute
onset, usually is asymmetric, and involves
the cranial, truncal, and peripheralnerves.17 
The neuropathy generally resolves
spontaneously in 3 to 12 months, but in rare
cases may last for years.
Cranial Neuropathies
Cranial neuropathies are rare, and include
the III, IV,VI, and VII cranial nerves.3 
Cranial neuropathy affects the nerves
connected with the brain that control sight,
eye movement, hearing, and taste.18 Most
often, cranial neuropathy affects the nerves
that control the eye muscles. Neuropathy
starts with pain on one side of the face near
the affected eye. Later, the eye muscle
becomes paralyzed, resulting in double
vision. Nevertheless, symptoms of this type
of neuropathy usually resolve within 2 or 3
months.
Truncal Neuropathies
Truncal neuropathy usually presents
subacutely with painful paresthesia in
variable size patches in the trunk, either
unilaterally or bilaterally.19 Associated
involvement of motor nerve fibers can lead
to bulging of the abdominal wall in the
paresthetic areas. Clinicians should check
for a patch of sensory abnormality in the
region of the symptoms.
Proximal Neuropathies
Proximal neuropathies may develop in
long-standing diabetics with poor metabolic
control and may lead to weight loss.20 A
prominent feature is pain that is often
severe and located in the hips and thighs.20,21 
Proximal neuropathy causes weakness in
the legs and often leaves patients unable to
emerge from a sitting to a standing position
without aid. The length of the recovery
period varies, depending on the type of
nerve damage.
Diagnosing Diabetic Neuropathy
Diagnosing diabetic neuropathy requires
clinicians to perform a thorough physical
examination, elicit patient history, and use
clinical judgment; it does not necessarily
hinge on any particular neurologic test or
finding.17 Some patients present with severe
pain but only minimal neurologic deficits,
while others present with foot ulcers but
have no pain or neurologic symptoms.
A complete medical evaluation enables
clinicians to classify the diabetes, detect the
presence of diabetes complications, review
previous treatment and glycemic control in
patients with established diabetes, assist in
formulating a management plan, and
provide a basis for continuing care.4
challenge
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