Review Article

Neuromuscular
Address correspondence
to Dr Vera Bril, Toronto General
Hospital, 200 Elizabeth St,
5EC-309, Toronto, ON M5G 2C4,

Complications of Canada, vera.bril@utoronto.ca.

Relationship Disclosure:
Dr Bril has received grant

Diabetes Mellitus support and personal

compensation for consultancy
work from Dainippon
Sumitomo Pharma Co, Ltd;
Vera Bril, BSc, MD, FRCP(c) Eisai, Inc; Eli Lilly and Company;
Pfizer Inc; and Grifols, Canada,
Ltd. Dr Bril has also received
grant support from Cebix
ABSTRACT Incorporated, CSL Behring, and
Purpose of Review: Diabetes mellitus has become a modern global epidemic, with Novartis Corporation, as well
steadily increasing prevalence rates related to lifestyle such that 27% of individuals as unrestricted educational
fellow support from Grifols,
aged 65 years or older have diabetes mellitus, 95% of whom have type 2. This article Canada, Ltd.
reviews the effects of diabetes mellitus on the neuromuscular system. Unlabeled Use of
Recent Findings: Diabetes mellitus leads to diverse forms of peripheral neuropathy as Products/Investigational
Use Disclosure:
the major neuromuscular complication. Both focal and diffuse types of neuropathy can Dr Bril discusses the unlabeled
develop, with the most common form being diabetic sensorimotor polyneuropathy. use of gabapentin, amitriptyline,
Small fibers are damaged early in the development of diabetic sensorimotor morphine, and oxycodone for
the treatment of neuromuscular
polyneuropathy and are not assessed by nerve conduction studies. Small fiber damage complications of diabetes mellitus.
occurs even in the prediabetes stage. No disease-modifying therapy for diabetic * 2014, American Academy
sensorimotor polyneuropathy is available at this time, but this complication can be of Neurology.
limited in patients who have type 1 diabetes mellitus with strict glycemic control; the
same outcome is not clearly observed in patients who have type 2 diabetes mellitus.
Recently, the evidence base for symptomatic treatments of painful diabetic sensorimo-
tor polyneuropathy underwent systematic review. Effective evidence-based treatments
include some anticonvulsants (eg, pregabalin, gabapentin), antidepressants (eg,
amitriptyline, duloxetine), opioids (eg, morphine sulfate, oxycodone), capsaicin cream,
and transcutaneous electrical nerve stimulation.
Summary: This article reviews the increasing prevalence of diabetes mellitus and
diabetic sensorimotor polyneuropathy and discusses recent consensus opinion on the
objective confirmation needed for the diagnosis in the clinical research setting. The
evidence from clinical trials shows that intensive glycemic control reduces prevalence of
diabetic sensorimotor polyneuropathy in patients with type 1 diabetes mellitus, but
variable outcomes are observed in patients with type 2 diabetes mellitus. Finally,
despite the lack of disease-modifying treatment, effective evidence-based therapy can
control painful symptoms of diabetic sensorimotor polyneuropathy.

Continuum (Minneap Minn) 2014;20(3):531–544.

INTRODUCTION search studies have demonstrated

The effects of diabetes mellitus on the
neuromuscular system are widespread,
but the common clinical manifestations,
including peripheral sensorimotor
polyneuropathy, small fiber neuropathy,
mononeuropathy, lumbosacral radicu-
loplexus neuropathy, and autonomic
neuropathy, involve primarily the pe-
ripheral nervous system. Although re-
that diabetes mellitus affects skeletal
muscle metabolism and function, a
presentation of clinical myopathy is
not typical of patients with diabetes
mellitus. In fact, the presentation
of clinical myopathy in a diabetic
patient should alert the treating
physician to an alternate diagnosis,
such as statin-induced myopathy,

Continuum (Minneap Minn) 2014;20(3):531–544 www.ContinuumJournal.com 531

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Diabetes Mellitus
KEY POINTS
h Diabetes mellitus produces
clinical peripheral
neuropathies as the
major neuromuscular
complication; symptoms
suggestive of myopathies
or myoneural junction
disorders should raise
other diagnostic concerns.
h An epidemic of type 2
diabetes mellitus related
to lifestyle predicts that
one-third of adults will
have this disorder, and
one-half of these will
develop diabetic
sensorimotor
polyneuropathy during
their lifetime. No effective
disease-modifying agent
is available, and only strict
glycemic control may help
prevent progression of
neuropathy in patients
with type 1 diabetes
mellitus.
532 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
polymyositis, muscular dystrophy, or
inclusion body myositis, among others.
The most common form of neuropathy
in diabetes mellitus is diabetic sensori-
motor polyneuropathy (DSP), and, in
fact, DSP is the most common form of
polyneuropathy in the world today. A
diagnosis of DSP should be considered
in anyone presenting to the neurologist
with polyneuropathy, and appropriate
investigation to exclude diabetes mellitus
or prediabetes, including a 2-hour
glucose tolerance test, should be done.
DSP leads to insensate feet, foot ulcera-
tion, gangrene and amputation, and
sensory ataxia.1 Patients may present with
isolated small fiber involvement and
neuropathic pain early in the course of
diabetic neuropathy or even in the
prediabetic state.2,3 Involvement of au-
tonomic nerve fibers occurs commonly
as part of DSP, producing erectile dys-
function, cardiac dysfunction, orthostatic
hypotension, bladder dysfunction, gastro-
intestinal dysmotility, and disorders of
vision and sweating. At times, autonomic
neuropathy can present without major
evidence of DSP. This article discusses
the diabetic peripheral neuropathies
in the most detail because that is what
most neurologists will observe in their
daily practice.
SCOPE OF THE PROBLEM
As a result of the epidemic of diabetes
mellitus in the developed world and its
increasing prevalence in developing
countries, DSP now presents a global
burden as the most common form of
polyneuropathy. Currently, 8.3% of the
population has diabetes mellitus, and,
in those aged 65 years and older, the
prevalence is 26.9%.4 Furthermore, 35%
of those aged 20 years or older have
prediabetes.4 It is estimated that 1 in 3
people in the United States will have
diabetes mellitus by 2050 if the current
increase in prevalence continues. In
adults with diabetes mellitus, 95% have
type 2 diabetes mellitus.4 About 50%
of patients with diabetes mellitus
develop DSP during the course of
their illness, with significant morbid-
ity and mortality.5Y9 Furthermore, no
disease-modifying treatment is avail-
able for DSP. Strict glycemic
control,10Y12 maintained indefinitely,
and attention to potentially modifiable
risk factors (such as hypertension, hy-
perlipidemia, smoking, and high body
mass index [BMI]) may help prevent the
progression of DSP,7,13 but so far no
effective therapy that leads to regression
of this disorder exists. Even pancreatic
transplant in patients with type 1
diabetes mellitus does not reverse
DSP, although there is some evidence
of l imi ted ne rve re ge ner ation
using novel measurement techni-
ques.14,15 Other forms of diabetic
neuropathyVparticularly the focal neu-
ropathies such as lumbosacral
radiculoplexus neuropathyVrecover
spontaneously, although the course
may be prolonged. Alternatively, pa-
tients with entrapment neuropathies
such as carpal tunnel syndrome may
benefit from surgical intervention. The
autonomic neuropathies, particularly
cardiac autonomic neuropathy, pose a
threat to life and function; for example,
cardiac autonomic neuropathy increases
the risk of mortality.16 A simple classifi-
cation scheme of diabetic neuropathy is
shown in Table 1-1.
DIAGNOSIS
Screening
The diagnosis of diabetic neuropa-
thies can be challenging because of
the diverse manifestations. Also, so-
phisticated diagnostic techniques con-
tinue to evolve.17,18 Simple screening
instruments, such as the monofila-
ment examination, can identify DSP
in the endocrinologist’s or primary
care physician’s office,19 and the test
results have prognostic implications
June 2014

TABLE 1-1 Types of Diabetic
Neuropathy in
Order of Decreasing
Frequency
b Diffuse
Diabetic sensorimotor
polyneuropathya
Autonomic neuropathy
Small fiber neuropathy
Pandysautonomia
Diabetic cachexia
b Focal
Carpal tunnel syndrome
Ulnar nerve compression
Cranial nerve palsies
(cranial nerves III, VII, and IV)
Lumbosacral radiculoplexus
neuropathy (‘‘femoral
neuropathy,’’ ‘‘diabetic
amyotrophy’’)
Mononeuropathy (eg, peroneal,
radial)
Thoracoabdominal
radiculopathy
a
Diabetic sensorimotor polyneuropathy is
the most common diabetic poly-
neuropathy and small fiber and auto-
nomic neuropathies are usually part of
diabetic sensorimotor polyneuropathy
rather than isolated polyneuropathies.
for the development of DSP.20 These
simple tests of sensation at the toes
identify subjects at high risk for having
or developing polyneuropathy and are
easily and quickly performed. Conse-
quently, such tests can form part of
the routine screening for DSP as
recommended in various professional
guidelines.21,22 A simplified scoring
system, such as the Toronto Clinical
Neuropathy Score (a summed score of
abnormal symptoms [pain, tingling,
numbness, ataxia, weakness, upper
limb symptoms], knee and ankle re-
flex scores, and sensory examination
tests [light touch, pinprick, tempera-
ture, vibration and position sensations]
Continuum (Minneap Minn) 2014;20(3):531–544
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KEY POINTS
considered to be due to DSP), can h Regular screening for
identify patients with a high probability diabetic neuropathy is
of having this condition.23,24 However, recommended in
neurologists need to perform a full guidelines from
evaluation for peripheral neuropathy.25 professional bodies
such as the American
Clinical Evaluation Diabetes Association
A complete neurologic history and ex- and the Canadian
amination are required, with attention to Diabetes Association.
historical factors based on the type and h Diabetic neuropathy is a
duration of diabetes mellitus, the level of diagnosis of exclusion.
glycemic control, the presence of other
complications such as retinopathy or
nephropathy, and the presence of hy-
perlipidemia and hypertension. Further-
more, to exclude nonYdiabetes-related
causes of peripheral polyneuropathy, a
thorough patient and family history of
nutritional deficiencies, neoplastic pro-
cesses, paraproteinemias, and kidney
disease, and a patient history of expo-
sures to toxins such as alcohol and
neurotoxic drugs (eg, amiodarone, vinca
alkaloids, diphenylhydantoin) needs to
be ascertained. This approach will help
exclude other diagnoses in the differen-
tial of DSP because diabetic neuropathy
is a diagnosis of exclusion (Case 1-1).21
Furthermore, a history concerning auto-
nomic function should be ascertained.
Questions about erectile function, possi-
ble orthostatic hypotension, arrhythmia,
bowel or bladder disturbances, sweating
irregularities, and gastrointestinal
dysmotility problems need to be part of
the symptom screen. In addition to a
detailed neurologic examination (with
particular attention to the patient’s
peripheral sensory system, deep tendon
reflexes, and strength), the morphology
of the feet needs to be considered
and the presence of ulcerations or
amputations noted. The peripheral
pulses should be assessed. If there is
any concern about possible syncopal
or presyncopal events, supine and
standing blood pressure and heart rate
should be measured. The pupillary
reactions to light and accommodation
www.ContinuumJournal.com 533
 Diabetes Mellitus

Case 1-1
A 58-year-old mechanic presented with a 2-year history of unsteadiness and
numbness and tingling in his feet. His sensory symptoms had progressed to
above the ankles. He had had two falls in the past 6 months. He denied any
pain, weakness, muscle cramping, or other neurologic symptoms other than
erectile dysfunction. He did not know of any medical illness in his history and
rarely sought medical attention. He drank four beers daily, had a
30-pack/year history of smoking cigarettes, and led a sedentary lifestyle.
Examination showed a body mass index of 33, blood pressure 150/90 mm Hg
supine and standing, and heart rate 85 beats/min supine and 90 beats/min
standing. Ankle reflexes were absent, and he had loss of sensations of pinprick,
temperature, vibration, and light touch to the ankles; he demonstrated a
broad-based gait and was unable to tandem walk. The rest of the examination
was normal.
Laboratory testing showed a normal vitamin B12 level and normal results
for serum immunoelectrophoresis and fasting blood sugar; an abnormal
2-hour glucose tolerance test; and a hemoglobin A1c level of 7.5% (normal G6%).
The sural sensory nerve action potential amplitude was 4 mV (normal > _
6 mV), and the sural nerve conduction velocity was 38 m/s (normal >_ 40 m/s). The
peroneal compound muscle action potential amplitude was 1.5 mV (normal > _
5 mV), and the peroneal motor nerve conduction velocity was 39 m/s
(normal > _ 40 m/s).
The patient was diagnosed with diabetic sensorimotor polyneuropathy
(DSP) and referred to an endocrinologist for treatment of hyperglycemia
and advice on lifestyle modification, nutrition, exercise, and assessment of
other potential risk factors. Given his history of regular ethanol intake and
unsteadiness, a brain MRI was done to assess for the presence of midline
(vermian) cerebellar degeneration, which was observed.
Comment. The neuropathy in this patient led to the diagnosis of type 2
diabetes mellitus. This patient had the classical presentation of DSP with
the confirmatory axonal changes on nerve conduction studies. Given his
degree of ataxia, concurrent disorders needed to be investigated and
excluded, as DSP is a diagnosis of exclusion.

should be noted. The state of the skin in
the lower extremities needs to be
assessed for the presence or absence of
hair and the presence of trophic changes
(such as thin, shiny, and discolored skin)
that may signal the presence of
polyneuropathy. The range of spinal
motion should be evaluated, as well as
gait and posture.
Laboratory Tests
After a clinical evaluation, laboratory
testing should include at a minimum
assessment of vitamin B12 level, serum
immunoelectrophoresis (to exclude
monoclonal gammopathy), and hemo-
globin A1c.26 The hemoglobin A1c will
give an estimate of the average glycemic
control for the past 3 months. Other
tests directed to specific functions such
as antinuclear antibody, rheumatoid fac-
tor, cryoglobulins, erythrocyte sedimenta-
tion rate, liver function tests, and kidney
function, might need to be considered in
particular circumstances. Genetic testing
for possible hereditary neuropathies de-
pends on the presentation of both the
patient and family histories.26
If there is a concern about under-
lying neoplasm, then systemic imaging
studies, such as abdominal ultrasound
and CT scan of the chest, need to be

534 www.ContinuumJournal.com June 2014

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


considered. If there is a clinical con-
cern for spinal stenosis or lumbar
radiculopathies, then MRI of the spine
needs to be considered.
Nerve conduction studies. Electro-
diagnostic evaluation is necessary to
diagnose and stage DSP reliably. DSP is
the prototype of distal axonal neuropa-
thy, and the evidence base suggests
abnormality of nerve conduction studies
as highly confirmatory for the diagno-
sis.25 The diagnosis of DSP for research
purposes requires confirmation with ob-
jective tests such as nerve conduction
studies. This recommendation has been
endorsed in recent expert opinion.27 At a
minimum, upper and lower limb nerve
conduction studies, including motor and
sensory nerves, need to be completed.
The typical screening involves peroneal
and tibial motor, sural sensory, and
median motor and sensory nerve con-
duction studies. The addition of other
nerve conduction studies (eg, ulnar,
radial, or femoral) may be necessary
depending on the patient’s clinical
symptoms. EMG studies may help to
determine whether the neuropathy is
axonal and to exclude other dis-
orders such as radiculopathy. The
presence of DSP is predicted by a
combination of peroneal nerve con-
duction velocity and sural sensory nerve
action potential amplitude, whereas the
future prediction of DSP is supported by
tibial F-wave latencies, peroneal conduc-
tion velocity, and the sum of lower limb
conduction velocities (sural, peroneal, and
tibial).28 In patients with type 2 diabetes
mellitus, demyelinating changes are
unexpected and lead to alternative
diagnoses such as chronic inflammatory
demyelinating polyneuropathy.29 How-
ever, in patients with poorly controlled
type 1 diabetes mellitus, with mean
hemoglobin A1c values of 9.5%, unex-
pected degrees of conduction velocity
slowing suggestive of demyelination are
observed, and these changes are indic-
Continuum (Minneap Minn) 2014;20(3):531–544
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KEY POINTS
ative of poor control even in those with h Nerve conduction studies
long-standing diabetes mellitus.30 remain essential in the
Other objective tests (small fiber diagnosis and staging of
tests). In the absence of abnormal diabetic neuropathy for
nerve conduction study testing, the clinical research.
diagnosis of DSP is less definite.25 In h The diagnosis of
addition, nerve conduction studies are diabetic sensorimotor
typically normal in isolated small fiber polyneuropathy for
neuropathy, which can be the early research purposes
manifestation of DSP. Other objective requires confirmation
tests of peripheral nerve function may with objective tests
help provide confirmation of the diag- such as nerve conduction
nosis of a type of diabetic neuropathy, studies. This
although most are still under investi- recommendation has
been endorsed in recent
gation for usefulness (Table 1-2). One
expert opinion.
option is to perform quantitative sen-
sory threshold testing, such as thermal h Demyelinating changes
threshold or vibration perception in the nerve conduction
studies should lead to
threshold testing.31 Assessment of
suspicion of poor
vibration perception thresholds can
glycemic control in
be abnormal in patients with normal patients with type 1
nerve conduction studies despite the diabetes mellitus and
fact that both are large fiber test of the presence of
modalities. This abnormality of large chronic inflammatory
fiber sensory testing can be related to demyelinating
abnormality within the CNS affecting polyneuropathy in
large fiber sensory tracts and is not patients with type 2
specific for peripheral neuropathy. In diabetes mellitus.
such cases, additional investigations h Nerve conduction studies
may be necessary. Testing of small are normal in small
fiber function, including cold detec- fiber neuropathy, an
tion and heat-as-pain thresholds, can early stage of diabetic
show abnormality in the presence of sensorimotor
normal nerve conduction studies.32 polyneuropathy.
Other novel small fiber tests that may h If nerve conduction
become useful are cutaneous axon- studies are normal in
mediated flare laser Doppler imaging suspected diabetic
studies,33 corneal confocal micros- neuropathy, then
specific small fiber
copy,34,35 and intraepidermal nerve
function tests should be
fiber density.26,36 These studies appear
considered in order to
to be complementary in the diagnosis confirm peripheral
of DSP so that a single noninvasive neuropathy.
small fiber test is insensitive for the
diagnosis of DSP, whereas a combina-
tion of tests gives better diagnostic
results.37 Intraepidermal nerve fiber
density is invasive, expensive, and not
done routinely. Only testing of thermal
thresholds is readily available for clinical
www.ContinuumJournal.com 535
 Diabetes Mellitus

KEY POINTS
h Simple tests of TABLE 1-2 Tests for Diabetic Sensorimotor Polyneuropathy
autonomic function
should be considered Result in Diabetic
in patients with possible Sensorimotor
diabetic sensorimotor Fiber Type Test Polyneuropathy
polyneuropathy. Large Nerve conduction studies Axonal changesa
h Surrogate measures for Vibration perception thresholds Elevated
diabetic sensorimotor Small Quantitative thermal thresholds Elevated
polyneuropathy include
Corneal confocal microscopy Reduced nerve fiber length
small fiber tests such as
and density
intraepidermal nerve
Cutaneous axon-mediated Reduced
fiber density, corneal
laser Doppler flare area
confocal microscopy,
quantitative thermal Intraepidermal nerve Reduced
fiber density
threshold testing, and
cutaneous axon-mediated Autonomic Supine and standing Drop in blood pressure
flare laser Doppler blood pressure
imaging studies. Supine and standing heart rate Stable heart rate
RR-variation Reduced
Sympathetic skin responses Abnormal
a
In patients with type 1 diabetes mellitus that is poorly controlled, slowing of conduction velocity can be
observed. If demyelination is demonstrated in patients with well-controlled type 1 diabetes mellitus or
in patients with type 2 diabetes mellitus irrespective of glycemic control, then other diagnoses should
be considered (eg, chronic inflammatory demyelinating polyneuropathy).

testing, and other noninvasive small Surrogate Markers for

fiber tests are still used mainly for
research purposes.
Autonomic system tests. Testing of
the autonomic nervous system can be
complex and is not done routinely.
However, simple tests in the neuromus-
cular laboratory can assess autonomic
activity in patients with diabetes mel-
litus.21 These include postural changes
in blood pressure and heart rate, RR-
variation, and sympathetic skin re-
sponses. A normal beat-to-beat heart
rate variation with expiration and inspi-
ration of more than 15 beats/min oc-
curs. A reduction in normal RR-variation
to fewer than 10 beats/min is abnormal,
indicating vagal dysfunction, and provides
early evidence of cardiac autonomic
neuropathy that can be observed despite
a lack of clinical abnormalities.21,38 The
absence of the sympathetic skin re-
sponse reflects the presence of DSP.39
536 www.ContinuumJournal.com
Diabetic Sensorimotor
Polyneuropathy
Reliable and valid surrogate markers for
DSP would be helpful in clinical trials to
assess response to therapy and perhaps
in the clinic to allow earlier diagnosis
and interventions. DSP is indolent, and
novel ways to measure disease activity
might improve care delivery to affected
patients. These methods generally mea-
sure small nerve fiber function and
structure, as noted above. Serial punch
biopsies of the skin for intraepidermal
nerve density and morphology might be
a useful surrogate for DSP,36,40 although
this procedure is not yet standard
practice and is invasive and expensive.26
Noninvasive measures, such as corneal
confocal microscopy, might become
useful.34,35,41 None of these measures is
as robust as nerve conduction studies
currently, and even the older method of
June 2014

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

quantitative sensory threshold testing is
not as reliable as nerve conduction
studies.32,42,43 Nonetheless, it is impor-
tant to develop ways to measure small
nerve fiber function and structure as
involvement of small nerve fibers occurs
earliest in DSP, and some patients have
minimal or no demonstrable large fiber
abnormalities. Finally, nerve biopsy sam-
pling of large nerves such as the sural
nerve is not indicated in the routine
diagnosis of DSP.
The diagnosis of mononeuropathies
is straightforward, involving symptoms
and signs within the territory of a single
peripheral nerve, such as the median,
ulnar, radial, or peroneal nerves. For
cranial mononeuropathies, the differen-
tial diagnosis is crucial. For example, in
diabetes mellitus, a pupillary-sparing
third nerve palsy is typically observed.
Involvement of the pupil should lead to
a search for an aneurysm of the poste-
rior communicating artery compressing
the nerve, or some other compressive
or intrinsic third nerve lesion. In this
case, appropriate diagnostic imaging
tests, such as MRI, magnetic resonance
angiography, or conventional angiogra-
phy, should be done. It is probable that
noncompressive mononeuropathies are
microvascular in nature and produce
nerve ischemia. In the case of cranial
mononeuropathies, spontaneous recov-
ery is the rule.
Diabetic Lumbosacral
Radiculoplexus Neuropathy
Diabetic lumbosacral radiculoplexus
neuropathy presents with acute and
severe proximal lower limb pain,
followed by muscle weakness and atro-
phy. It is most commonly observed in
patients with well-controlled type 2
diabetes mellitus. The clinical presenta-
tion often involves the distribution of
the femoral nerve, which led to the
former names of ‘‘diabetic amyotrophy’’
or ‘‘femoral neuropathy.’’ However, the
Continuum (Minneap Minn) 2014;20(3):531–544
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
involvement is more widespread in
most cases, leading to the newer no-
menclature of diabetic lumbosacral
radiculoplexus neuropathy. The symp-
toms can spread to the contralateral
limb, and weight loss can be observed,
as can upper limb changes. Although
the course can be prolonged for
months with major disability and limita-
tions in ambulation, spontaneous re-
covery is observed in most cases.
Microscopic vasculitis producing nerve
ischemia may be the underlying path-
ophysiology of the disorder.44 Peri-
vascular epineural inflammation and
infiltration of adjacent endoneurium
have been observed, and epineurial
microvasculitis without vessel damage
has been described in others. Some
pathologists question the significance
of such microvasculitis. Evidence of
ischemic infarcts is demonstrable in
some patients but not in others.44 It
is important to exclude other diagno-
ses, such as intraspinal processes with
polyradicular involvement or compres-
sive causes of plexopathy, and appro-
priate investigations, such as MRI
scanning of the lumbosacral spine and
pelvis, may need to be done.
Thoracoabdominal radiculopathy is
thought to be a focal radiculopathy
analogous to diabetic lumbosacral
radiculoplexopathy affecting nerve
roots in the thoracic or abdominal
dermatomes. The patients present
with acute radicular pain in the
thoracoabdominal region, and investi-
gations such as spinal MRI do not
show a structural cause. It is important
to exclude intrathoracic or intra-
abdominal causes of the pain with
appropriate investigations, and spon-
taneous resolution is the typical
outcome.
Diabetic cachexia is a rare disorder
manifested by severe diffuse pain and
paresthesia, sensorimotor poly-
neuropathy, and weight loss in diabetic
www.ContinuumJournal.com 537
 Diabetes Mellitus
KEY POINT
h Intensive glycemic patients that can be precipitated by
control helps minimize rapid glycemic control with insulin
diabetic sensorimotor therapy. Symptomatic recovery is asso-
polyneuropathy in type ciated with recovery of nerve function,
1 diabetes mellitus, and indicating that the pathogenesis is
improved glycemic likely due to nerve hypoxia but not
control is the only irreversible ischemic destruction.45
option also for patients
with type 2 diabetes TREATMENT
mellitus. No other For many mononeuropathies, sponta-
disease-modifying
neous resolution is the expected
treatment is available.
course. In the case of carpal tunnel
Control of hypertension,
hyperlipidemia, and
syndrome, nerve conduction studies
elevated body mass cannot distinguish reliably between the
index may be helpful. presence of entrapment of the median
nerve at the carpal tunnel and DSP.46
Similar changes in the median nerve
conduction tests are observed in pa-
tients who have diabetes mellitus with
and without the clinical features of
carpal tunnel syndrome, and the sever-
ity of the changes is related to the
severity of DSP but not to the clinical
features of carpal tunnel syndrome. For
this reason, diagnosis and management
should be based on the clinical presen-
tation. Conservative measures may fail
to relieve the compression, and surgical
release should be considered for both
carpal tunnel syndrome and cubital
tunnel syndrome, although the out-
comes may not be as good as in
nondiabetic patients. In diabetic lumbo-
sacral radiculoplexus neuropathy, spon-
taneous resolution is expected. No
current clinical trial evidence supports
the use of immune therapies in diabetic
lumbosacral radiculoplexus neuropathy,
so IV immunoglobulin, plasma exchange,
or immunosuppressant medications are
not recommended.47,48 Physiotherapy,
analgesia, and supportive therapy are
recommended for this condition.
In small fiber neuropathyVlikely
to be the earliest manifestation of
DSP as well as the form observed in
prediabetesVlifestyle modification
may improve nerve function and
symptoms, although the evidence is
538 www.ContinuumJournal.com
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
variable.49,50 The mainstay of treat-
ment in patients with DSP remains
strict glycemic control maintained
indefinitely. In patients with type 1
diabetes mellitus, good evidence has
shown that intensive glycemic control
minimizes the incidence of neuro-
pathy,10,51 and there appears to be a
metabolic memory effect in that the
beneficial effect of a 5-year period of
intensive diabetes control persists for
more than 10 years after the end of
that treatment.11,52 In patients with
type 2 diabetes mellitus, the benefi-
cial outcomes are less apparent, as
strict glycemic control can be associated
with negative effects such as increased
mortality and no definite change in
DSP.53Y55 However, the findings from a
recent Cochrane review support en-
hanced glucose control in both type 1
and type 2 diabetes mellitus to improve
nerve function: in type 1 diabetes
mellitus to prevent the development of
clinical neuropathy and in type 2 diabe-
tes mellitus because of a possible ten-
dency to reduce the incidence of clinical
neuropathy (Case 1-2).56 Attention to
other modifiable risk factors, such
as hyperlipidemia, hypertension, and
high BMI, may ameliorate DSP, particu-
larly in patients with type 1 diabetes
mellitus.13 Finally, diet and exercise
counseling in patients with predia-
betes (impaired glucose tolerance)
may help reduce symptoms and lead
to peripheral nerve reinnervation.49
A hemoglobin A1c level under 7% in
type 1 diabetes mellitus would minimize
progression of DSP, and a level of
less than 7.5% might be beneficial
in type 2 diabetes mellitus, but these
types of management decisions need to
be formulated by the primary care
physician and endocrinologist providing
diabetes care to these patients.51,55
Surveillance and attention to foot care
are needed to prevent foot ulceration
and amputation.
June 2014
 KEY POINT

Case 1-2 h Control of painful

symptoms can be
A 68-year-old man presented with an 18-month history of burning pain along
achieved with
the soles of his feet that he rated as 8/10.The pain was worse when he
pregabalin, duloxetine,
was trying to rest and also interfered with his sleep. He had erectile
gabapentin, venlafaxine,
dysfunction for 1 year but was free of other symptoms. Diabetes mellitus
tricyclic antidepressants,
was diagnosed 3 years ago, and he started a diet and metformin. He had
topical capsaicin,
hypertension and hyperlipidemia. He was a nondrinker and nonsmoker
and transcutaneous
without a history of toxic exposures or familial neuropathy.
electrical nerve
Examination showed a blood pressure of 160/90 mm Hg supine and
stimulation. Many other
155/85 mm Hg standing, with a heart rate of 90 beats/min supine and
symptomatic treatments
100 beats/min standing. His body mass index (BMI) was 35. The peripheral
are ineffective or lack
pulses and skin in the lower limbs were normal. He had blunting of sensations
evidence.
of pinprick, temperature, vibration, and light touch distally in the toes.
His reflexes and the rest of the neurologic examination were normal.
He had normal nerve conduction studies and elevated cold-detection
thresholds. Laboratory tests showed a hemoglobin A1c level of 8.5% and
normal vitamin B12 and serum immunoelectrophoresis.
The patient was diagnosed with small fiber diabetic polyneuropathy. He
was advised to increase exercise, reduce caloric intake (reduce BMI), and
aim for a hemoglobin A1c level less than 7%. Control of hypertension and
hyperlipidemia were recommended. Pregabalin 75 mg at bedtime was
initiated, with the recommendation for a slow upward titration to a
maximum dose of 300 mg twice daily. After 2 weeks, his pain was 3/10,
and he slept better and was happy with this outcome.
Comment. In this case, early diabetic sensorimotor polyneuropathy
presented as a small fiber neuropathy. The presence of normal ankle reflexes
and nerve conduction studies does not exclude this diagnosis, and a small
fiber test showed neuropathy. Symptomatic treatment reduced the patient’s
pain to a manageable level but did not completely eliminate the pain.

No effective disease-modifying ther- in DSP have been shown to be effec-

apies are available for DSP. Many drugs
that appeared promising in phase 2
trials have failed to demonstrate efficacy
in phase 3 trials, or results from differ-
ent phase 3 trials have been contra-
dictory.5,57 Various interventions are
believed by some researchers to have
disease-modifying activity in DSP, but
insufficient evidence exists for any in-
tervention at this stage. In fact, the
same interventions can have variable
evidence, with positive studies in some
regions of the world and negative
studies in other regions of the world.
Although no specific disease-
modifying therapy for DSP exists, sev-
eral interventions for neuropathic pain
Continuum (Minneap Minn) 2014;20(3):531–544
tive. A recent evidence-based practice
parameter developed by the American
Academy of Neurology, the American
Association of Neuromuscular and
Electrodiagnostic Medicine, and the
American Academy of Physical Medi-
cine and Rehabilitation showed bene-
fits from some anticonvulsants (eg,
pregabalin, gabapentin), antidepres-
sants (eg, amitriptyline, duloxetine),
and opioids (eg, morphine sulphate,
oxycodone).58 See Table 1-3 for a
complete listing and doses used in the
supporting clinical trials. Similar results
have been published by other groups.22
Other interventions with good evi-
dence include long-acting capsaicin
www.ContinuumJournal.com 539

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Diabetes Mellitus

KEY POINTS
h A high placebo effect a
TABLE 1-3 Symptomatic Treatment of Painful Diabetic Neuropathy
is present in patients
with painful diabetic Level and
sensorimotor Recommendation Drug Dose
polyneuropathy, so
Level A, recommended Pregabalin 300Y600 mg/d
inexpensive and safe
Level B, recommended Gabapentin 900Y3600 mg/d
treatments may be
considered if they Sodium valproate 500Y1200 mg/d
provide potential benefit, Venlafaxine 75Y225 mg/d
although evidence for Duloxetine 60Y120 mg/d
their efficacy is lacking. Amitriptyline 25Y100 mg/d
h Painful symptoms in Dextromethorphan 400 mg/d
diabetic sensorimotor Morphine sulphate Up to 120 mg/d
polyneuropathy are rarely
Tramadol 210 mg/d
eliminated by any
Oxycodone Mean: 37 mg/d
treatment modality, but
pain relief of at least Maximum: 120 mg/d
30% is rated as much Capsaicin 0.075% 4 times/d
improved and of 50% Isosorbide dinitrate spray
as very much improved Electrical stimulation Percutaneous electrical
by patients. nerve stimulation
3Y4 times/wk
Level B, not recommended Oxcarbazepine
Lamotrigine
Lacosamide
Clonidine
Pentoxifylline
Mexiletine
Magnetic field treatment
Low-intensity laser treatment
Reiki therapy
a
Reprinted with permission from Bril V, et al. Neurology.58 B 2011, American Academy of Neurology.
www.neurology.org/content/76/20/1758.long.

and transcutaneous electrical nerve ment of painful DSP.58 This is a chronic

stimulation. High-quality studies are
either lacking or negative in many
alternative treatments of DSP, such as
acupuncture or Reiki therapy.58,59 How-
ever, the placebo effect is very high in
patients who have painful DSP, ac-
counting for up to 62% of the re-
sponse, 60 so that any safe and
inexpensive treatment modality should
not be dismissed out of hand if the
patient reports benefit from that treat-
ment. There are several concerns with
the existing evidence base for the treat-
disorder, and many of the interventions
have been studied only for short inter-
vals of 4 to 12 weeks; therefore, the long-
term efficacy of these interventions
remains unknown. Furthermore, high-
level comparative studies of different
pharmacologic therapies are still re-
quired. In addition, it is rare that painful
symptoms are completely eliminated.
Rather, a 30% reduction in pain is
considered a good outcome as this
degree of pain relief relates to patients
reporting that they feel much improved,

540 www.ContinuumJournal.com June 2014

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

and those with a 50% reduction in pain
state that they are very much improved.61
For those with autonomic neuro-
pathy, exclusion of organ-based disease
is required, and often patients need to
be referred to the appropriate specialist
in that field (eg, gastroenterologist,
urologist, cardiologist) for investigation
and management.
One other entity that neurologists
should keep in mind is insulin neuritis,
also known as treatment-induced diabetic
neuropathy. This is the development of
neuropathic symptoms (often painful
peripheral paresthesia) starting soon
after the initiation of insulin therapy
and thought to be related to a rapid
normalization of nerve glucose levels.
Autonomic neuropathy accompanies
insulin neuritis with cardiovascular, gas-
trointestinal, genitourinary, and sudomo-
tor symptoms.62 Spontaneous recovery is
observed after about 18 months of
glycemic control. This entity differs from
diabetic cachexia in that weight loss is
not a feature of insulin neuritis.
SUMMARY
DSP remains the most common neuro-
logic complication of diabetes mellitus.
Optimal glycemic control and attention
to hypertension, hyperlipidemia, BMI,
and foot care are fundamental in those
with type 1 diabetes mellitus. The
benefits of strict glycemic control are
not as evident in those with type 2
diabetes mellitus, although lifestyle
modification may be of benefit. No
disease-modifying intervention has
proven effective in reversing DSP or
even in slowing the progression, beyond
pancreatic transplantation or intensive
glycemic control in type 1 diabetes
mellitus. In prediabetes, attention to
lifestyle modification may modify
polyneuropathy. Attention should be
paid to foot care in order to avoid the
complications of foot ulceration and
amputation. Symptom control for pain-
Continuum (Minneap Minn) 2014;20(3):531–544
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
ful symptoms of DSP is available, and
good evidence supports treatment with
several anticonvulsants, antidepressants,
and opioids.
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