D i a b e t i c N e u ro p a t h y Pa r t 1

Overview and Symmetric Phenotypes

Mamatha Pasnoor, MDa,*, Mazen M. Dimachkie, MD

a
,
Patricia Kluding, PT, PhDb, Richard J. Barohn, MDa

KEYWORDS
 Diabetic neuropathy  Diabetes mellitus  Pathogenesis

KEY POINTS
 Diabetic neuropathy is the most common type of neuropathy.
 Various types of neuropathies are associated with diabetes mellitus.
 Metabolic, vascular, inflammatory, and immune theories have been suggested for
pathogenesis.
 Axonal and demyelination can be seen on electrophysiology and pathology.
 Treatment is mainly aimed at glycemic control and neuropathic pain management.

INTRODUCTION

Diabetes mellitus (DM) has 4 major complications: neuropathy, retinopathy, nephrop-

athy, and vasculopathy. The various neuropathies associated with DM can clinically
be divided into symmetric and asymmetric (focal and multifocal) forms (Box 1).1 In
addition, clinicians need to be aware of diabetic muscle infarction, a muscle disorder
that can occur in diabetic patients. A practical approach to the diagnosis and manage-
ment of diabetic symmetric neuropathies is discussed in this article.

EPIDEMIOLOGY

The estimated prevalence of DM in the United States in individuals 40 to 74 years old

is 12% if only fasting blood sugar (FBS) criteria are used, but 14% if both FBS and
glucose tolerance testing (GTT) criteria are used.2 It is estimated that about half the
adults with diabetes in the United States are undiagnosed.3 If the population is
considered, including children, DM has been reported to occur in 1% to 4%.4 In

a
Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA;
b
Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical
Center, Kansas City, KS, USA
* Corresponding author.
E-mail address: [email protected]

Neurol Clin 31 (2013) 425–445

http://dx.doi.org/10.1016/j.ncl.2013.02.004 neurologic.theclinics.com
0733-8619/13/$ – see front matter Ó 2013 Elsevier Inc. All rights reserved.
426 Pasnoor et al

Box 1
Clinical classification of diabetic neuropathies

I. Symmetric polyneuropathies:
Fixed deficits:
Distal sensory polyneuropathy (DSPN)
Variants
Acute, severe DSPN in early-onset diabetes
Pseudosyringomyelic neuropathy
Pseudotabetic neuropathy
Autonomic neuropathy
Episodic symptoms:
Diabetic neuropathic cachexia
Hyperglycemic neuropathy
Treatment-induced diabetic neuropathy
II. Asymmetric/focal and multifocal diabetic neuropathies:
Diabetic lumbosacral radiculoplexopathy (Bruns-Garland syndrome, diabetic amyotrophy,
proximal diabetic neuropathy)
Truncal neuropathies (thoracic radiculopathy)
Cranial neuropathies
Limb mononeuropathies

the Rochester, Minnesota, population-based study, 1.3% of the population had DM.4
According to the 2011 US Centers for Disease Control and Prevention National Dia-
betes Fact Sheet, diabetes affects 25.8 million Americans or 8.3% of the US popula-
tion. That estimate includes 7 million undiagnosed cases. Among US residents aged
65 years and older, 10.9 million, or 26.9%, had diabetes in 2010. In 2005 to 2008,
based on fasting glucose or hemoglobin A1c (HgbA1c) levels, 35% of US adults
aged 20 years or older and 50% of adults aged 65 years or older had prediabetes,
yielding an estimated 79 million American adults aged 20 years or older with predia-
betes. Almost 30% of people with diabetes aged 40 years or older have impaired
sensation in the feet.5
Approximately two-thirds of patients with insulin-dependent DM (IDDM) and non-
IDDM (NIDDM) had subclinical or clinical evidence of a peripheral neuropathy. Roughly
half of the diabetics had a symmetric polyneuropathy, a quarter had carpal tunnel
syndrome, about 5% had autonomic neuropathy, and 1% had asymmetric proximal
neuropathy. The occurrence of neuropathy correlates with the duration of DM, poor
glycemic control, and with the presence of retinopathy and nephropathy.4,6–11 In the
study by Picart,8 7.5% of patients had neuropathy at the time of diagnosis, and, after
20 years of DM, 50% had neuropathy. Partanen and colleagues9 showed that after
10 years of follow-up the percentage of diabetics with neuropathy increased from
8% at baseline to 42%.

DM Diagnostic Criteria
The American Diabetes Association (ADA) issued diagnostic criteria for DM in 1997,2
with follow-up in 200312 and 2010.13 The diagnosis is based on one of 4 abnormalities:
 Diabetic Neuropathy Part 1 427

HgbA1c, fasting plasma glucose (FPG), random increased glucose with symptoms, or
abnormal oral glucose tolerance test (OGTT) as follows:
1. HgbA1c greater than or equal to 6.5%. The test should be performed in a laboratory
using a method certified by the National Standardization Program (NGSP) and
standardized to the Diabetes Control and Complications (DCCT) assay.
2. FPG greater than or equal to 126 mg/dL (7.0 mmol/L) on repeat testing. Fasting is
defined as no caloric intake for at least 8 hours.
3. Two-hour plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during
an oral GTT. The test should be performed as described by the World Health Orga-
nization, using a glucose load containing the equivalent of 75 g anhydrous glucose
dissolved in water.
4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis,
a random glucose greater than or equal to 200 mg/dL (11.1 mmol/L).
In the absence of unequivocal hyperglycemia, criteria 1 to 3 should be confirmed by
repeat testing.
In evaluating a patient with a neuropathy, it is not sufficient to stop with the FBS in
excluding DM. Although the new criteria allow for the use of HgbA1c as sufficient to
diagnose DM, we still usually recommend OGTT in patients who are evaluated for
neuropathy to consider DM as a potential cause.

Pathogenesis of Diabetic Neuropathy

The pathologic basis for diabetic neuropathy remains controversial in spite of the
research efforts. There is evidence that both vascular and metabolic derangements
may be responsible for peripheral nerve disorders in diabetes.14–21 An overview of
these mechanisms is helpful in approaching the different clinical presentations of
diabetic neuropathies and in understanding the various experimental therapeutic
trials. A simplified pathophysiologic scheme would primarily attribute the focal
and multifocal neuropathies to a vascular basis, and the symmetric polyneuropa-
thies to a metabolic disorder. However, we think that there is a spectrum of possible
pathophysiologic cause of various diabetic neuropathies and evidence for either
vascular or metabolic dysfunction is not restricted to a particular neuropathy
(Fig. 1).22–26

Vascular Metabolic

Fig. 1. Spectrum of possible pathophysiologic causes of various diabetic neuropathies.

428 Pasnoor et al

Metabolic pathogenesis
Experimental models of acute, severe hyperglycemia can produce reduction in nerve
conduction velocity and axonal shrinkage.27 Glucose and myoinositol share a struc-
tural similarity and hyperglycemia may reduce myoinositol uptake in diabetic nerves.
This reduction secondarily impairs the function of membrane-bound sodium/potas-
sium ATPase, which can cause axoglial changes and alterations of conduction
velocity.28 However, in nerves from diabetic patients, endoneurial myoinositol was
not decreased and, in 2 clinical trials, there was no benefit to patients from myoinositol
supplementation.29–32
Another popular mechanism is an alteration of polyol metabolism. Persistent hyper-
glycemia activates the enzyme aldose reductase, thereby converting glucose to the
polyol, sorbitol, and ultimately to fructose. Sorbitol, a compound with a degree of
impermeability, accumulates in the nerve creating a hypertonic condition and subse-
quent water accumulation.

glucose sorbitol fructose

aldose reductase sorbitoldehydrogenase

The accumulation of sorbitol and fructose increases the distance between capil-
laries, producing endoneurial hypoxia and oxidative stress. Aldose reductase inhibi-
tors in animal models decrease sorbitol concentration in the sciatic nerve and
restore conduction velocities to normal. In addition, protection from sorbitol increase
in experimental diabetes using aldose reductase inhibitors prevents the loss of
myoinositol from the nerve, which may connect 2 possible pathogenic mechanisms.33
Alterations of fatty acid metabolism can result from chronic hyperglycemia. In
experimental diabetes there is a deficiency of gamma-linolenic acid that could lead
to abnormalities in endoneurial blood flow through secondary deficiencies in arachi-
donic acid and prostaglandins.34 This finding has led to clinical trials of diets enriched
in linolenic acid.35,36
Chronic hyperglycemia increases glycosylation of proteins.37–39 Glycation products
can accumulate in tissues, producing microvascular disease by direct deposition on
endothelial cell membranes or the generation of reactive oxygen species, which
adds to oxidative stress.40 Aminoguanidine, an inhibitor of advanced glycation, has
been used in experimental animal models of diabetes and is currently being studied
in humans.41

Vascular pathogenesis
It has been postulated that hypoxia or ischemia is involved in diabetic polyneurop-
athy.16,42–47 The ultrastructural studies of Dyck and colleagues44–46 have shown that
the increase in basement membrane area and endothelial cell degeneration is associ-
ated with severity of polyneuropathy. On a more macroscopic level, the study of the
distribution of fiber loss in diabetic nerves also suggests a vascular disorder.20,48–50
In the study by Dyck and colleagues,50 the multifocal pattern of fiber loss could still
be identified in the sural nerve. Johnson and colleagues20 identified changes in the
perineurium and surrounding epineurium that resembled those seen in peripheral
nerve vasculitis. Although these ultrastructural vessel changes could account for these
ischemic morphologic features, there is evidence that chronic hyperglycemia may
produce hypoxia or frank ischemia.47,51,52
Autopsy material from patients with diabetic cranial third nerve palsy reveals central
fascicular injury suggesting ischemia.53–55 Even diabetic patients who never experi-
enced third nerve palsy show microfasciculation on autopsy compared with
 Diabetic Neuropathy Part 1 429

controls.56 An autopsy study in diabetic asymmetric proximal lower extremity neurop-

athy by Raff and colleagues57,58 showed ischemic infarcts of the proximal major nerve
trunks of the leg and lumbosacral plexus with multiple areas of decreased myelinated
fiber density at these levels. Said and colleagues59,60 biopsied the cutaneous nerve of
the thigh in patients with this disorder and showed asymmetric fasicular loss in some
patients. In a study of sural nerve biopsies from patients with diabetic lumbosacral
radiculoplexopathy, there was multifocal variability in nerve fiber density with
nonrandom fiber loss between and within fascicles.61 In the Mayo Clinic series of
Pascoe and colleagues62 in 6 biopsied patients with diabetic proximal neuropathy,
a multifocal distribution of fiber loss was noted in 3 sural nerve specimens. In a recent
Mayo Clinic series, changes suggesting ischemia were found in the most of 33 nerve
biopsies with diabetic radiculoplexus neuropathy.63
Local sural nerve blood flow in patients with mild diabetic polyneuropathy was
assessed using laser Doppler flowmetry.64 Patients with peripheral nerve vasculitis
who showed abnormal sural nerve blood flow served as controls. No relationship
was found between sural nerve blood flow and the presence or development of distal
symmetric neuropathy. One study showed that activation of the complement pathway
and formation of the membrane attack complex could injure blood vessels and
adversely affect the circulation in the endoneurium.65

Immunologic/inflammatory pathogenesis
An immune-mediated pathogenesis has recently been advocated in some cases of
diabetic neuropathy.66 In a study of proximal asymmetric neuropathy that showed
asymmetric nerve fiber loss, an additional feature was lymphocytic epineurial inflam-
mation resembling vasculitis. Krendel and colleagues67 found similar perivascular
inflammation in 7 of 10 patients with asymmetric lumbosacral neuropathy. In
a Mayo Clinic study of diabetic proximal neuropathy, 2 out of 6 sural nerve bio-
psies showed perivascular mononuclear inflammatory infiltrates.62 Younger and
colleagues68 biopsied 20 patients with diabetic neuropathy, 6 with distal symmetric
and 14 with asymmetric neuropathy. Seven patients had epineurial vessel inflamma-
tion on routine paraffin sections, 2 with distal symmetric and 5 with asymmetric
neuropathy. With immunohistochemistry, the number of patients with T-cell microvas-
culitis increased to 12 (60% of biopsied patients) with the inflammatory cells being
predominantly CD81 T cells. The presence of tumor necrosis factor, interleukin-6,
interleukin-1b, interleukin-1a, and C5b-9 in several specimens further led the investi-
gators to suggest an immune-mediated pathogenesis of the neuropathy.
In the Mayo large series of patients with diabetic radiculoplexus neuropathy, peri-
vascular mononuclear cells were found in all 33 biopsied patients, most of whom
also showed changes of ischemia.63

Pathology and Pathophysiology

Axonal degeneration or segmental demyelination
There has been some debate regarding whether the primary lesion in diabetic neurop-
athy is the axon or Schwann cell/myelin. Ballin and Thomas69 identified onion bulbs
and teased nerve fiber, suggesting recurrent demyelination, and Vital70,71 reported
both segmental demyelination and axonal degeneration. Dyck and colleagues50
showed that the changes of axonal degeneration and regeneration were more
frequent than those of segmental demyelination and remyelination, and, in the setting
of multifocal fiber loss, they concluded that axonal degeneration was the primary
process. Studies by Said and coleagues72,73 of the sural nerves of patients with prom-
inent small-fiber sensory loss found pathologic evidence for axonal degeneration, as
430 Pasnoor et al

well as both primary and secondary segmental demyelination. Therefore, if a sural

nerve biopsy is obtained from a typical patient with distal symmetric diabetic neurop-
athy, a broad spectrum of axonal and myelin pathologic changes can be expected.
For this reason, the sural nerve biopsy is often not helpful in diabetic neuropathy in
attempting to determine whether the underlying process is axonal degeneration or
demyelination/remyelination.
The electrophysiologic studies can similarly show evidence of axonal degeneration
and demyelination. An early and characteristic feature of diabetic neuropathy is pro-
longed distal latencies and F waves, slow conduction velocity, and reduced amplitude
of potentials.7,74–76 Behse and colleagues77 thought that the conduction velocity slow-
ing was from loss of large fibers. However, another reason for slow conduction
velocity may be a functional alteration at nodes of Ranvier.16 Although frank conduc-
tion block and temporal dispersion are usually not found in diabetic neuropathies, the
degree of latency and velocity abnormalities can be so severe that so-called demye-
linating electrophysiologic criteria may be met.78 Krendel and colleagues67 found that
demyelinating electrophysiologic criteria were met in 6 of 21 patients with proximal
diabetic neuropathy. In the Mayo Clinic series of Pascoe and colleagues,62 28 of 42
patients with proximal diabetic neuropathy were classified as axonal and 14 as demy-
elinating. Temporal dispersion was noted in 14 patients, and conduction block in 2
patients. However, the patients with these demyelinating findings invariably had
axonal features as well.
Finding electrophysiologic changes that fulfill demyelinating criteria superimposed
on axonal degeneration in a diabetic patient needs to be interpreted with caution.
Chronic inflammatory demyelinating polyneuropathy (CIDP) can develop in diabetic
patients,79–81 but these cases are not thought to be related to the underlying diabetes.
In support of the lack of association, a recent Olmstead County epidemiologic study
identified DM in 4% of 23 CIDP cases and in 12% of matched controls.82 Electrophys-
iologic changes of demyelination in a diabetic patient with a symmetric distal or an
asymmetric proximal neuropathy may not necessarily imply an immune-mediated
neuropathy that will respond to immunosuppressive therapy. In cases of marked
demyelination, correlation with the clinical pattern and temporal profile are essential
to distinguish CIDP from distal symmetric peripheral polyneuropathy and avoid unnec-
essary therapies. Jaradeh and colleagues83 presented 15 patients with progressive
polyradiculoneuropathy in diabetes with presentation similar to CIDP. Electrophysi-
ology was predominantly axonal, and cerebrospinal fluid showed increased protein
in 14 and oligoconal bands in 5. Sural nerve biopsy performed in 14 patients showed
fiber loss, segmental demyelination, inflammatory infiltrates, and onion bulbs. All
patients had benefit with immunomodulating therapy.83

TYPES OF DIABETIC NEUROPATHIES

Symmetric Neuropathies
Symmetric neuropathies with fixed deficits
DSPN DSPN is the most common form of diabetic neuropathy. This is primarily
a length-dependent sensory neuropathy, and significant distal weakness is
uncommon. However, as with cryptogenic distal sensory neuropathy, there is usually
electrophysiologic evidence for subclinical motor involvement. The clinical and elec-
trophysiologic findings in both cryptogenic and diabetic distal sensory and sensori-
motor neuropathy are similar.84 However, because diabetic patients are often
monitored closely before they develop symptoms of neuropathy, the earliest signs
of neuropathy may be decreased distal vibration, touch, and pin sensation and ankle
 Diabetic Neuropathy Part 1 431

reflex loss on examination. The first symptoms are usually decreased feeling or tingling
in the toes. Dysesthesias, usually burning pain, may develop, although most diabetic
patients with a distal sensory neuropathy do not complain of significant discomfort. In
a population of 382 insulin-treated diabetic subjects, 41 (10.7%) had painful symp-
toms.85 In a 2-phase cross-sectional descriptive study of patients with type 2 diabetes
(postal survey followed by neurologic history and examination) up to 27% of diabetic
patients experienced neuropathic pain or mixed pain resulting in a significant negative
effect on quality of life.86 Sensory symptoms can eventually progress up the ankles
and knees and to the fingers, hands, and forearms. If sensory loss extends to the
elbows, patients can then develop a symmetric midline truncal wedge-shaped area
of sensory loss.87
Although there may be atrophy and weakness of the toe extensor and flexor
muscles, significant distal ankle weakness is uncommon. If profound distal upper
and lower extremity weakness is present in a diabetic patient, an evaluation for other
causes of neuropathy is warranted.
Progression of DSPN is usually slow. In the Rochester Diabetic Neuropathy Study,
none of the 380 diabetic patients had polyneuropathy that was disabling even when
followed for many years.4 An exception to this rule is the unusual cases of severe
sensory and autonomic neuropathy that can occur in the first several after the onset
of type 1 diabetes.73 It is not known why some patients develop this unusually severe
form of neuropathy in the early stages of the disease and there is no relationship
between the neuropathy and hyperglycemia or the initiation of insulin therapy.
Several examination scales have been developed to establish neuropathy.88,89
Most of these focus primarily on large-fiber function. The Utah Early Neuropathy Scale
was shown to be a sensitive clinical measure of sensory and small-fiber neuropathy.90
England and colleagues91,92 recently established the American Academy of Neurology
practice parameters for evaluation of distal symmetric polyneuropathy (DSP).93 In
routine clinical practice, documenting an abnormal sensory, reflex, and occasionally
a motor examination is sufficient to diagnose neuropathy in a diabetic patient with
appropriate symptoms. The use of monofilaments to assess touch-pressure sensation
has become important as well as the Rydell-Seifert semiquantitative tuning fork.94
Depending on the clinical context, it may be appropriate to perform screening blood
tests for other causes of neuropathy (complete blood count, chem 20, vitamin B12
level, Venereal Disease Research Laboratory test, serum immunofixation). Equipment
for detecting sensory loss, such as computerized quantitative sensory testing, and
both simple and complex grading systems have been developed for assessing dia-
betic neuropathy, and are primarily useful in the context of entering patients in
research protocols; they are not needed clinically in most patients.95,96 Skin biopsies
have become a tool to diagnose small-fiber neuropathy in patients with normal elec-
trodiagnostic testing.84,88
If severe foot ulcers and neurogenic arthropathies develop, this is often labeled
pseudosyringomyelic diabetic neuropathy. There is a selective loss of pain fibers
resulting in impaired cutaneous and deep pain and temperature sensation.72,97 Severe
proprioceptive loss is uncommon, but occasionally this can occur when there is prom-
inent large-fiber involvement. These patients develop sensory ataxia and autonomic
manifestations with impotence, bladder atony, and pupillary changes and thus have
been called the pseudotabetic form of diabetic neuropathy. However, severe propri-
oception deficits and ataxia are uncommon in diabetes, and when present should
lead to a search for other potential causes (syphilis, vitamin B12 deficiency, paraneo-
plastic or Sjogren syndrome sensory neuronopathy, CIDP). However, we think that the
pseudosyringomyelic, pseudotabetic, and the early-onset neuropathy described by
432 Pasnoor et al

Said and colleagues73 are all severe variants of diabetic DSPN and probably not
distinct forms of neuropathy.

Treatment of DSPN
Glucose control In general, patients with strict control of blood glucose have fewer
diabetic neuropathy complications.10,11,98 Several studies have shown that tight
glucose control with aggressive insulin therapy can reduce the risk for development
of neuropathy.7,99,100 The DCCT trial convincingly showed that intensive insulin
therapy with an insulin pump or 3 or more daily injections is more effective than
conventional therapy in reducing neuropathy.99 Neuropathy occurred in only 5% of
intensively treated patients compared with 13% of those conventionally treated. Over-
all neuropathy was reduced by 64% over 5 years in the intensively treated group. In
a follow-up 13 to 14 years after DCCT closeout, the prevalence of neuropathy
increased from 9% to 25% in the former intensive and from 17% to 35% in the former
conventional treatment groups (P<.001), and the incidence of neuropathy remained
lower among former intensive treatment subjects.101 This finding supports the impor-
tance and benefits of early intensive insulin treatment in reducing the risk of neurop-
athy, even more than a decade later.

Other experimental approaches Many different approaches to treat diabetic neurop-

athy and the other complications of diabetes have been attempted, but in general
there has been little success. Several of these experimental approaches were
described and referenced earlier. Despite numerous trials of various aldose reductase
inhibitors, none have been shown to prevent neuropathy or the progression of
deficits.11,102–104
In streptozotocin-induced diabetic rats, treatment with alpha-lipoic acid improved
nerve blood flow and improved conduction velocity. Alpha-lipoic acid (also known
as thioctic acid) may act as an antioxidant free-radical scavenger, and it may inhibit
nonenzymatic glycation.85,86,105,106 A placebo-controlled trial using intravenous
alpha-lipoic acid reduced neuropathic symptoms in diabetic patients.107 In a
5-week randomized controlled trial of oral alpha-lipoic acid 600, 1200, or 1800 mg
daily, there was a 50% pain reduction as measured by the Total Symptom Score,
including stabbing and burning pain, across all doses, which was statistically signifi-
cant compared with the placebo response (32%, P<.05).108 A more recent study sug-
gested that 4-year treatment with oral alpha-lipoic acid 600 mg once daily in mild to
moderate distal symmetric neuropathy did not influence the primary composite end
point of Neuropathy Impairment Score of the Lower Limbs and 7 neurophysiologic
tests.109 Besides being well tolerated, the investigators suggested a clinically mean-
ingful improvement and prevention of progression of neuropathic impairment, but
these results have yet to be duplicated by other investigators. Oral alpha-lipoic acid
can be obtained in health-food stores, and should be started at 300 mg daily and
increased to as much as 600 mg twice a day.
There has recently been interest in nerve growth factor (NGF) therapy as a treatment
of diabetic neuropathy.110 In experimental animal models of diabetes, there is some
evidence for decreased NGF expression in various target tissues, and NGF treatment
in these models prevented the manifestations of neuropathy.111–115 In humans with
diabetic neuropathy, NGF levels are reduced in skin biopsy specimens.116 In a phase
II placebo-controlled trial of subcutaneous NGF in 250 patients with diabetic neurop-
athy, the only end point that reached statistical significance was the patient’s overall
global symptom assessment that they felt improved. There was a trend toward
improvement in quantitative cold detection thresholds and in the small-fiber sensory
 Diabetic Neuropathy Part 1 433

components of neuropathy impairment score. However, in the larger phase III trial,
there was no benefit in the NGF group on any end point.

Symptomatic treatment If a patient’s with diabetic neuropathy does not complain of

pain, symptomatic treatment is of no value and is not necessary. Symptoms of numb-
ness and tingling should not be treated.
The most frequently used oral drugs for the symptomatic treatment of diabetic and
nondiabetic painful neuropathy are the tricyclic antidepressants, carbamazepine, gaba-
pentin, mexiletene, and, more recently, pregabalin and cymbalta.117–125 All physicians
have their own preferences for first-line, second-line, and third-line drugs. Our prefer-
ence and the doses are listed in Table 1. For further information on the treatment refer
to the article by Jaya Trivedi and colleagues elsewhere in this issue. Recent evidence-
based guidelines for treatment of pain in diabetic neuropathy were published by the
American Academy of Neurology.93 According to this, pregabalin is established as
effective and should be offered for relief of Diabetic Polyneuropathy (DPN). Venlafaxine,
duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol,
and oxycodone controlled release), and capsaicin are probably effective and should
be considered for treatment of PDN.123 Other treatments have less robust evidence
or the evidence is negative.124 Effective treatments for DPN are available, but many
have side effects that limit their usefulness, and few studies have sufficient information
on treatment effects on function and quality of life. For further review of neuropathic pain
management, the reader is referred to the article elsewhere in this issue.
Topical therapy with capsaicin and lidocaine creams can be tried.126,127 In our expe-
rience, few patients respond to these modalities and the creams are difficult to use
because they need to be applied several times a day. Lidoderm patches may be effec-
tive, but they are expensive and cumbersome to apply to the soles of both feet.128,129
Transcutaneous nerve stimulation is occasionally helpful. An unusual alternative-
medicine approach to painful neuropathies with magnetic inserts has received
some attention.130 A blinded controlled crossover study reported benefit with magnet
therapy.131 A larger multicenter study of repetitive and cumulative exposure to low-
frequency pulsed electromagnetic fields in 225 subjects with painful diabetic neurop-
athy did not show any effect on pain reduction.132 It did show in a subgroup of
27 subjects who completed serial biopsies that 29% of magnet-treated subjects
had an increase in distal leg ENFD of at least 0.5 standard deviations, whereas
none did in the sham group (P 5 .04).
Exercise therapy is being investigated as another treatment modality. A small pilot
study reported improvements in neuropathic pain and symptoms as well as cutaneous
nerve fiber branching on proximal skin biopsy following a 10-week supervised exer-
cise program in 17 patients with diabetic peripheral neuropathy. These findings are
particularly promising given the short duration of the intervention, but need to be vali-
dated by comparison with a control group in future studies.133

Autonomic neuropathy Autonomic manifestations can affect cardiovascular, genito-

urinary, or gastrointestinal organ systems so that patients develop orthostasis, tachy-
cardia/tachyarrhythmias, gastroparesis, impotence, bladder atony, or impotence.
Other autonomic manifestations include profuse nocturnal or postprandial sweating
and abnormal pupillary light responses. The nerve fibers that mediate sweating
undergo distal damage. One electrophysiologic technique for evaluating these nerve
fibers is to test for sympathetic skin responses.123 Diabetic diarrhea and incontinence
are rare but can be disabling. Gastrointestinal autonomic dysfunction is assessed with
various radiographic techniques, but the easiest is to show the abnormally slow
434 Pasnoor et al

Table 1
Pharmacologic therapy for neuropathic pain

Oral
Therapy Route Starting Doses Maintenance Doses
First Line
Tricyclic antidepressants Oral 10–25 mg at bedtime Increase by increments of
10–25 mg to 100–150 mg at
bedtime
Gabapentin (Neurontin) Oral 300 mg tid Increase by increments of
300–400 mg to 2400–6000
mg daily divided in 3–4 doses
Tramadol (Ultram) Oral 50 mg bid or tid Increase by 50-mg increments
to a maximum of 100 mg qid
Duloxetine (Cymabalta) Oral 30 mg/d Increase by increments of
30–60 mg up to 120 mg/d
Pregabalin (Lyrica) Oral 50 mg tid Increase to 300 mg/d
Second Line
Venlafaxine XR (Effexor) Oral 37.5–75 mg once a day Increase by 75-mg increments
to 150–225 mg a day
Valproate Oral 250 mg bid to tid Increase by 250-mg increments
up to 1500 mg/d
Carbamazepine Oral 200 mg bid Increase by 200-mg increments
to 200–400 mg 3 to 4 times
a day; follow drug levels on
doses greater than 600 mg/d
Oxcarbazepine (Trileptal) Oral 150–300 mg bid Increase by 300-mg increments
to 600–1200 mg 2 times a day
Lamotrigine (Lamictal) Oral 25 mg once a day or bid Increase by 25-mg increments
weekly to 100–200 mg bid
Topiramate (Topamax) Oral 25–50 mg at bedtime Increase by 50-mg increments
weekly to 200 mg bid
Third Line
Bupropion SR (Welbutrin) Oral 150 mg/d After 1 week, increase to
150 mg twice a day
Tiagabine hydrochloride Oral 4 mg/d Increase to 4–12 mg bid
(Gabitril)
Keppra (Levetiracetam) Oral 250 mg at bedtime Increase by increments of
250–500 mg to 1500 mg
2 times a day
Zonisamide (Zonegran) Oral 100 mg at bedtime Increase by 100-mg increments
to 400–600 mg at bedtime
Mexiletine Oral 200 mg once a day Increase by 200-mg increments
to a maximum of 200 mg tid
Phenytoin Oral 200 mg at bedtime Increase by 100-mg increments
to 300–400 mg daily divided
in 1–2 doses, following drug
levels
Newer Drugs
Savella Oral 12.5 mg at 12.5 mg bid  2 d then 25 mg
bedtime  1 d bid  4 d, then stay on 50 mg
bid. May increase up to
100 mg bid
(continued on next page)
 Diabetic Neuropathy Part 1 435

Table 1
(continued)

Oral
Therapy Route Starting Doses Maintenance Doses
Vimpat Oral 50 mg by mouth bid In 1 wk, go to 100 mg bid.
May increase up to
200 mg bid
Topical Agents
Over the Counter
Capsaicin 0.075% Topical Apply to affected region Continue with starting dose
tid to qid
Salicylate 10%–15% Topical Apply to affected region Continue with starting dose
tid to qid
Menthol 16%/ Topical Apply to affected Continue with starting dose
camphor 3% (1/ ) region tid to qid
By Prescription
Lidocaine 2.5%/ Topical Apply to affected Continue with starting dose
prilocaine 2.5% region tid to qid
Lidocaine patch 5% Topical Apply over adjacent, Increase up to 3 patches worn
intact skin for 12 h of 24-h period
Doxepin 5% (Zolopan) Topical Apply to affected Continue with starting dose
region bid
Diclofenac sodium gel Topical Apply to affected region Continue with starting dose
(Voltaren Gel 1%) tid to qid
By Prescription: Only at Compounding Pharmacies
Ketoprofen 5%/ Topicala Apply to affected Increase up to a schedule
amitriptyline 2%/ region bid of qid
tetracaine 1%
Ketoprofen 10%/ Topicala Apply to affected Increase up to a schedule
cyclobenzaprine 1%/ region bid of qid
lidocaine 5%
Ketamine 5%/ Topicala Apply to affected Increase up to a schedule
amitriptyline 4%/ region bid of tid
gabapentin 4%
Carbamazepine 5%/ Topicala Apply to affected Increase up to a schedule
lidocaine 5% region bid of qid
Amitriptyline 2%/ Topicala Apply to affected Continue with starting dose
lioresal 2% region tid to qid
a
Must be compounded by pharmacy (to locate your local compounding pharmacy, call the Inter-
national Academy of Compounding Pharmacists, 1-800-927-4227).

passage of barium through the gut.134 Impotence is the most common clinical mani-
festation of autonomic neuropathy, affecting more than 50% of men with diabetes.
Treatment Orthostatic symptoms can be treated with fludrocortisone (0.1 mg twice
a day), the nonsteroidal antiinflammatory agents ibuprofen and indomethacin, and the
oral sympathomimetic agent midodrine.105–107,135–137 Midodrine (ProAmatine) is an
alpha-adrenoreceptor agonist that increases blood pressure by producing arterial
and venous constriction. The recommended dose is 10 mg 3 times daily. Pharmaco-
therapy can be tried for delayed gastric emptying (metoclopramide; erythromycin)138,139
and diarrhea (clonidine).140 Impotence can be treated with oral phosphodieterase-5
436 Pasnoor et al

inhibitors such as sildenafil (Viagra)141 and, less commonly, with injectable (phentol-
amine/papervine) drug therapy or penile prosthesis.142,143

Symmetric neuropathies with episodic symptoms

Diabetic neuropathic cachexia Diabetic neuropathic cachexia is an uncommon
syndrome initially described by Ellenberg144 in 1974 in which patients develop
profound weight loss, a symmetric sensory peripheral neuropathy, and painful dyses-
thesias over the limbs and trunk, without associated weakness.144–149 Unlike other
symmetric neuropathies caused by diabetes, diabetic neuropathic cachexia is revers-
ible over a period of weeks to months. Most reported patients have been men, usually
in the sixth or seventh decades of life, but there have been 2 cases described in
women. All cases initially show a precipitous weight loss of up to 60% of total body
weight, leading at times to an incorrect suspicion of an underlying cancer. Patients
may experience intense contact hypersensitivity and may also describe intermittent
stabbing or shooting pains. The pain tends to be worse at night or during periods of
relaxation. The presence of proximal or truncal symmetric dysesthesias associated
with profound weight loss should be clinical clues that support the diagnosis of dia-
betic neuropathic cachexia rather than the more common DSPN of diabetes. Patients
may also experience depression, anorexia, and impotence. Sensory impairment asso-
ciated with diabetic neuropathic cachexia is generally minimal, by contrast with the
severity of the patient’s complaints of pain, and in some cases may not be clinically
detectable. Some reports describe associated muscle atrophy and weakness,
whereas others have reported normal strength.
Diabetic neuropathic cachexia can occur in patients with both type 1 and type 2 dia-
betes. There is a lack of correlation with other microvascular complications of diabetes
such as nephropathy or retinopathy. Most cases are associated with poor glucose
control. Some of these cases have been associated with malabsorption.150
Treatment of diabetic neuropathic cachexia can be difficult and strict diabetic
control is usually necessary. The usual drugs to treat neuropathic pain can be tried,
but they are often unsuccessful and the temporary use of narcotics is often needed.
The prognosis is usually good, and patients typically recover their baseline weight
with resolution of the painful sensory symptoms within 1 year. A residual sensorimotor
neuropathy is common. Recurrent diabetic neuropathic cachexia has also been re-
ported (Fig. 2).138

Fig. 2. Patient’s weight over time and the onset of neuropathic pain and initiation of diabetic
therapy. 1, initiation of oral hypoglycemic; *, initiation of insulin; Y, onset of pain. (From
Jackson CE, Barohn RJ. Diabetic neuropathic cachexia: report of a recurrent case. J Neurol Neu-
rosurg Psychiatry 1998;64:786; with permission.)
 Diabetic Neuropathy Part 1 437

The eventual resolution of diabetic neuropathic cachexia with concomitant weight

gain and the lack of correlation with other microvascular complications of diabetes
suggest a primarily dysmetabolic process (see Fig. 1). However, the pathophysiologic
basis of the disorder remains unknown.
Other possible transient symmetric sensory neuropathies Other cases of transient
distal sensory paresthesias and pain have been alleged to be caused by hyperglycemia
(hyperglycemic neuropathy) or insulin neuritis following the institution of
insulin.97,151,152 The insulin neuritis is usually characterized by acute severe pain,
peripheral nerve degeneration, and autonomic dysfunction after intensive glycemic
control, which often parallels worsening retinopathy and resolves in weeks or
months.153 Clinical features and objective measures of neuropathy can improve in
these patients despite a prolonged history of poor glucose control.151 So-called hyper-
glycemic neuropathy may occur at the time of diagnosis or may follow an episode of
ketotic coma, and the symptoms rapidly subside once the diabetes is controlled.
Llewelyn and colleagues152 reported similar symptoms within 6 weeks of establish-
ing good diabetic control with insulin, and pain persisted for 4 to 5 months.125 It is still
unclear whether these are distinct peripheral neuropathy entities.

Case study
A 42-year-old man developed numbness and tingling in the toes, progressing up to the ankles
over 2 years. He describes burning pain in his feet, mainly at night. He recently started noticing
symptoms of numbness and tingling in distal fingers. He denies any weakness. He was recently
diagnosed with diabetes.
Examination showed normal strength, with decreased pinprick and light touch sensations to
the ankles and distal fingers. Timed vibration is 0 seconds at the toes, 10 seconds at the ankles,
and proprioception is normal at the toes. Reflexes are normal in the arms and at the knees but
ankle reflexes are absent. Gait is normal.
Routine neuropathy laboratory studies were unremarkable except for mild increase of HgbA1c
6.0%, and 2-hour glucose tolerance test showed a 2-hour glucose of 250 mg/dL. Electrodiag-
nostic testing showed absent sural sensory responses and decreased peroneal and tibial motor
amplitudes, showing evidence of moderate axonal sensorimotor polyneuropathy.
He was started on gabapentin with initial improvement of pain. Over the next 2 years there was
progression of pain with mild worsening of weakness distally. Duloxetine was later started
because of worsening of the pain. He also developed diabetic retinopathy and diabetic medi-
cations had to be adjusted because of worsening blood sugar control.

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