Anda di halaman 1dari 14

Review Article

Neuromuscular
Complications of
Diabetes Mellitus
Vera Bril, BSc, MD, FRCP(c)
ABSTRACT
Purpose of Review: Diabetes mellitus has become a modern global epidemic, with
steadily increasing prevalence rates related to lifestyle such that 27% of individuals
aged 65 years or older have diabetes mellitus, 95% of whom have type 2. This article
reviews the effects of diabetes mellitus on the neuromuscular system.
Recent Findings: Diabetes mellitus leads to diverse forms of peripheral neuropathy as
the major neuromuscular complication. Both focal and diffuse types of neuropathy can
develop, with the most common form being diabetic sensorimotor polyneuropathy.
Small fibers are damaged early in the development of diabetic sensorimotor
polyneuropathy and are not assessed by nerve conduction studies. Small fiber damage
occurs even in the prediabetes stage. No disease-modifying therapy for diabetic
sensorimotor polyneuropathy is available at this time, but this complication can be
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 sensorimotor 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.

Address correspondence
to Dr Vera Bril, Toronto General
Hospital, 200 Elizabeth St,
5EC-309, Toronto, ON M5G 2C4,
Canada, vera.bril@utoronto.ca.
Relationship Disclosure:
Dr Bril has received grant
support and personal
compensation for consultancy
work from Dainippon
Sumitomo Pharma Co, Ltd;
Eisai, Inc; Eli Lilly and Company;
Pfizer Inc; and Grifols, Canada,
Ltd. Dr Bril has also received
grant support from Cebix
Incorporated, CSL Behring, and
Novartis Corporation, as well
as unrestricted educational
fellow support from Grifols,
Canada, Ltd.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Dr Bril discusses the unlabeled
use of gabapentin, amitriptyline,
morphine, and oxycodone for
the treatment of neuromuscular
complications of diabetes mellitus.
* 2014, American Academy
of Neurology.

Continuum (Minneap Minn) 2014;20(3):531544.

INTRODUCTION
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 radiculoplexus neuropathy, and autonomic
neuropathy, involve primarily the peripheral nervous system. Although reContinuum (Minneap Minn) 2014;20(3):531544

search studies have demonstrated


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,
www.ContinuumJournal.com

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

531

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.

polymyositis, muscular dystrophy, or


inclusion body myositis, among others.
The most common form of neuropathy
in diabetes mellitus is diabetic sensorimotor 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 ulceration, 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 autonomic nerve fibers occurs commonly
as part of DSP, producing erectile dysfunction, cardiac dysfunction, orthostatic
hypotension, bladder dysfunction, gastrointestinal 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

532

type 2 diabetes mellitus.4 About 50%


of patients with diabetes mellitus
develop DSP during the course of
their illness, with significant morbidity and mortality.5Y9 Furthermore, no
disease-modifying treatment is available for DSP. Strict glycemic
control,10Y12 maintained indefinitely,
and attention to potentially modifiable
risk factors (such as hypertension, hyperlipidemia, 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 techniques.14,15 Other forms of diabetic
neuropathyVparticularly the focal neuropathies such as lumbosacral
radiculoplexus neuropathyVrecover
spontaneously, although the course
may be prolonged. Alternatively, patients 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 classification scheme of diabetic neuropathy is
shown in Table 1-1.
DIAGNOSIS
Screening
The diagnosis of diabetic neuropathies can be challenging because of
the diverse manifestations. Also, sophisticated diagnostic techniques continue to evolve.17,18 Simple screening
instruments, such as the monofilament examination, can identify DSP
in the endocrinologists or primary
care physicians office,19 and the test
results have prognostic implications

www.ContinuumJournal.com

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

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 polyneuropathy and small fiber and autonomic 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. Consequently, 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 reflex scores, and sensory examination
tests [light touch, pinprick, temperature, vibration and position sensations]
Continuum (Minneap Minn) 2014;20(3):531544

considered to be due to DSP), can


identify patients with a high probability
of having this condition.23,24 However,
neurologists need to perform a full
evaluation for peripheral neuropathy.25
Clinical Evaluation
A complete neurologic history and examination are required, with attention to
historical factors based on the type and
duration of diabetes mellitus, the level of
glycemic control, the presence of other
complications such as retinopathy or
nephropathy, and the presence of hyperlipidemia and hypertension. Furthermore, to exclude nonYdiabetes-related
causes of peripheral polyneuropathy, a
thorough patient and family history of
nutritional deficiencies, neoplastic processes, paraproteinemias, and kidney
disease, and a patient history of exposures 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 differential of DSP because diabetic neuropathy
is a diagnosis of exclusion (Case 1-1).21
Furthermore, a history concerning autonomic function should be ascertained.
Questions about erectile function, possible 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 patients
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

KEY POINTS

h Regular screening for


diabetic neuropathy is
recommended in
guidelines from
professional bodies
such as the American
Diabetes Association
and the Canadian
Diabetes Association.

h Diabetic neuropathy is a
diagnosis of exclusion.

www.ContinuumJournal.com

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

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 >
_ 40 m/s). The
6 mV), and the sural nerve conduction velocity was 38 m/s (normal >
_
peroneal compound muscle action potential amplitude was 1.5 mV (normal >
5 mV), and the peroneal motor nerve conduction velocity was 39 m/s
_ 40 m/s).
(normal >
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-

534

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 factor, cryoglobulins, erythrocyte sedimentation rate, liver function tests, and kidney
function, might need to be considered in
particular circumstances. Genetic testing
for possible hereditary neuropathies depends on the presentation of both the
patient and family histories.26
If there is a concern about underlying neoplasm, then systemic imaging
studies, such as abdominal ultrasound
and CT scan of the chest, need to be

www.ContinuumJournal.com

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

June 2014

considered. If there is a clinical concern for spinal stenosis or lumbar


radiculopathies, then MRI of the spine
needs to be considered.
Nerve conduction studies. Electrodiagnostic evaluation is necessary to
diagnose and stage DSP reliably. DSP is
the prototype of distal axonal neuropathy, and the evidence base suggests
abnormality of nerve conduction studies
as highly confirmatory for the diagnosis.25 The diagnosis of DSP for research
purposes requires confirmation with objective 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 conduction studies. The addition of other
nerve conduction studies (eg, ulnar,
radial, or femoral) may be necessary
depending on the patients clinical
symptoms. EMG studies may help to
determine whether the neuropathy is
axonal and to exclude other disorders such as radiculopathy. The
presence of DSP is predicted by a
combination of peroneal nerve conduction velocity and sural sensory nerve
action potential amplitude, whereas the
future prediction of DSP is supported by
tibial F-wave latencies, peroneal conduction 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 However, in patients with poorly controlled
type 1 diabetes mellitus, with mean
hemoglobin A1c values of 9.5%, unexpected degrees of conduction velocity
slowing suggestive of demyelination are
observed, and these changes are indicContinuum (Minneap Minn) 2014;20(3):531544

ative of poor control even in those with


long-standing diabetes mellitus.30
Other objective tests (small fiber
tests). In the absence of abnormal
nerve conduction study testing, the
diagnosis of DSP is less definite.25 In
addition, nerve conduction studies are
typically normal in isolated small fiber
neuropathy, which can be the early
manifestation of DSP. Other objective
tests of peripheral nerve function may
help provide confirmation of the diagnosis of a type of diabetic neuropathy,
although most are still under investigation for usefulness (Table 1-2). One
option is to perform quantitative sensory threshold testing, such as thermal
threshold or vibration perception
threshold testing.31 Assessment of
vibration perception thresholds can
be abnormal in patients with normal
nerve conduction studies despite the
fact that both are large fiber test
modalities. This abnormality of large
fiber sensory testing can be related to
abnormality within the CNS affecting
large fiber sensory tracts and is not
specific for peripheral neuropathy. In
such cases, additional investigations
may be necessary. Testing of small
fiber function, including cold detection and heat-as-pain thresholds, can
show abnormality in the presence of
normal nerve conduction studies.32
Other novel small fiber tests that may
become useful are cutaneous axonmediated flare laser Doppler imaging
studies,33 corneal confocal microscopy,34,35 and intraepidermal nerve
fiber density.26,36 These studies appear
to be complementary in the diagnosis
of DSP so that a single noninvasive
small fiber test is insensitive for the
diagnosis of DSP, whereas a combination 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

KEY POINTS

h Nerve conduction studies


remain essential in the
diagnosis and staging of
diabetic neuropathy for
clinical research.

h The diagnosis of
diabetic sensorimotor
polyneuropathy for
research purposes
requires confirmation
with objective tests
such as nerve conduction
studies. This
recommendation has
been endorsed in recent
expert opinion.

h Demyelinating changes
in the nerve conduction
studies should lead to
suspicion of poor
glycemic control in
patients with type 1
diabetes mellitus and
of the presence of
chronic inflammatory
demyelinating
polyneuropathy in
patients with type 2
diabetes mellitus.

h Nerve conduction studies


are normal in small
fiber neuropathy, an
early stage of diabetic
sensorimotor
polyneuropathy.

h If nerve conduction
studies are normal in
suspected diabetic
neuropathy, then
specific small fiber
function tests should be
considered in order to
confirm peripheral
neuropathy.

www.ContinuumJournal.com

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

535

Diabetes Mellitus
KEY POINTS

h Simple tests of
autonomic function
should be considered
in patients with possible
diabetic sensorimotor
polyneuropathy.

TABLE 1-2 Tests for Diabetic Sensorimotor Polyneuropathy

Fiber Type

Test

Result in Diabetic
Sensorimotor
Polyneuropathy

Large

Nerve conduction studies

Axonal changesa

Vibration perception thresholds

Elevated

Small

Quantitative thermal thresholds

Elevated

Corneal confocal microscopy

Reduced nerve fiber length


and density

Cutaneous axon-mediated
laser Doppler flare area

Reduced

Intraepidermal nerve
fiber density

Reduced

Supine and standing


blood pressure

Drop in blood pressure

h Surrogate measures for


diabetic sensorimotor
polyneuropathy include
small fiber tests such as
intraepidermal nerve
fiber density, corneal
confocal microscopy,
quantitative thermal
threshold testing, and
cutaneous axon-mediated
flare laser Doppler
imaging studies.

Autonomic

Supine and standing heart rate

Stable heart rate

RR-variation

Reduced

Sympathetic skin responses

Abnormal

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


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 neuromuscular laboratory can assess autonomic
activity in patients with diabetes mellitus.21 These include postural changes
in blood pressure and heart rate, RRvariation, and sympathetic skin responses. A normal beat-to-beat heart
rate variation with expiration and inspiration of more than 15 beats/min occurs. 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 response reflects the presence of DSP.39

536

Surrogate Markers for


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 measure 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

www.ContinuumJournal.com

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

June 2014

quantitative sensory threshold testing is


not as reliable as nerve conduction
studies.32,42,43 Nonetheless, it is important 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 sampling 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 differential 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 posterior 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 angiography, should be done. It is probable that
noncompressive mononeuropathies are
microvascular in nature and produce
nerve ischemia. In the case of cranial
mononeuropathies, spontaneous recovery 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 atrophy. It is most commonly observed in
patients with well-controlled type 2
diabetes mellitus. The clinical presentation 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):531544

involvement is more widespread in


most cases, leading to the newer nomenclature of diabetic lumbosacral
radiculoplexus neuropathy. The symptoms 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 limitations in ambulation, spontaneous recovery is observed in most cases.
Microscopic vasculitis producing nerve
ischemia may be the underlying pathophysiology of the disorder.44 Perivascular 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 diagnoses, such as intraspinal processes with
polyradicular involvement or compressive causes of plexopathy, and appropriate 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 investigations such as spinal MRI do not
show a structural cause. It is important
to exclude intrathoracic or intraabdominal causes of the pain with
appropriate investigations, and spontaneous resolution is the typical
outcome.
Diabetic cachexia is a rare disorder
manifested by severe diffuse pain and
paresthesia, sensorimotor polyneuropathy, and weight loss in diabetic
www.ContinuumJournal.com

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

537

Diabetes Mellitus
KEY POINT

h Intensive glycemic
control helps minimize
diabetic sensorimotor
polyneuropathy in type
1 diabetes mellitus, and
improved glycemic
control is the only
option also for patients
with type 2 diabetes
mellitus. No other
disease-modifying
treatment is available.
Control of hypertension,
hyperlipidemia, and
elevated body mass
index may be helpful.

538

patients that can be precipitated by


rapid glycemic control with insulin
therapy. Symptomatic recovery is associated with recovery of nerve function,
indicating that the pathogenesis is
likely due to nerve hypoxia but not
irreversible ischemic destruction.45
TREATMENT
For many mononeuropathies, spontaneous resolution is the expected
course. In the case of carpal tunnel
syndrome, nerve conduction studies
cannot distinguish reliably between the
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 patients who have diabetes mellitus with
and without the clinical features of
carpal tunnel syndrome, and the severity 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 presentation. 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 outcomes may not be as good as in
nondiabetic patients. In diabetic lumbosacral radiculoplexus neuropathy, spontaneous 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

variable.49,50 The mainstay of treatment 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 neuropathy,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 beneficial 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 enhanced 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 diabetes mellitus because of a possible tendency 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, particularly in patients with type 1 diabetes
mellitus.13 Finally, diet and exercise
counseling in patients with prediabetes (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.

www.ContinuumJournal.com

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

June 2014

KEY POINT

Case 1-2

h Control of painful

A 68-year-old man presented with an 18-month history of burning pain along


the soles of his feet that he rated as 8/10.The pain was worse when he
was trying to rest and also interfered with his sleep. He had erectile
dysfunction for 1 year but was free of other symptoms. Diabetes mellitus
was diagnosed 3 years ago, and he started a diet and metformin. He had
hypertension and hyperlipidemia. He was a nondrinker and nonsmoker
without a history of toxic exposures or familial neuropathy.
Examination showed a blood pressure of 160/90 mm Hg supine and
155/85 mm Hg standing, with a heart rate of 90 beats/min supine and
100 beats/min standing. His body mass index (BMI) was 35. The peripheral
pulses and skin in the lower limbs were normal. He had blunting of sensations
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 patients
pain to a manageable level but did not completely eliminate the pain.

No effective disease-modifying therapies 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 different phase 3 trials have been contradictory.5,57 Various interventions are
believed by some researchers to have
disease-modifying activity in DSP, but
insufficient evidence exists for any intervention 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 diseasemodifying therapy for DSP exists, several interventions for neuropathic pain
Continuum (Minneap Minn) 2014;20(3):531544

symptoms can be
achieved with
pregabalin, duloxetine,
gabapentin, venlafaxine,
tricyclic antidepressants,
topical capsaicin,
and transcutaneous
electrical nerve
stimulation. Many other
symptomatic treatments
are ineffective or lack
evidence.

in DSP have been shown to be effective. 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 Medicine and Rehabilitation showed benefits from some anticonvulsants (eg,
pregabalin, gabapentin), antidepressants (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 evidence include long-acting capsaicin
www.ContinuumJournal.com

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

539

Diabetes Mellitus
KEY POINTS

h A high placebo effect


is present in patients
with painful diabetic
sensorimotor
polyneuropathy, so
inexpensive and safe
treatments may be
considered if they
provide potential benefit,
although evidence for
their efficacy is lacking.

a
TABLE 1-3 Symptomatic Treatment of Painful Diabetic Neuropathy

Level and
Recommendation

Drug

Dose

Level A, recommended

Pregabalin

300Y600 mg/d

Level B, recommended

Gabapentin

900Y3600 mg/d

h Painful symptoms in
diabetic sensorimotor
polyneuropathy are rarely
eliminated by any
treatment modality, but
pain relief of at least
30% is rated as much
improved and of 50%
as very much improved
by patients.

Sodium valproate

500Y1200 mg/d

Venlafaxine

75Y225 mg/d

Duloxetine

60Y120 mg/d

Amitriptyline

25Y100 mg/d

Dextromethorphan

400 mg/d

Morphine sulphate

Up to 120 mg/d

Tramadol

210 mg/d

Oxycodone

Mean: 37 mg/d
Maximum: 120 mg/d

Capsaicin

0.075% 4 times/d

Isosorbide dinitrate spray


Electrical stimulation

Level B, not recommended

Percutaneous electrical
nerve stimulation
3Y4 times/wk

Oxcarbazepine
Lamotrigine
Lacosamide
Clonidine
Pentoxifylline
Mexiletine
Magnetic field treatment
Low-intensity laser treatment
Reiki therapy

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


stimulation. High-quality studies are
either lacking or negative in many
alternative treatments of DSP, such as
acupuncture or Reiki therapy.58,59 However, the placebo effect is very high in
patients who have painful DSP, accounting for up to 62% of the response, 60 so that any safe and
inexpensive treatment modality should
not be dismissed out of hand if the
patient reports benefit from that treatment. There are several concerns with
the existing evidence base for the treat-

540

ment of painful DSP.58 This is a chronic


disorder, and many of the interventions
have been studied only for short intervals of 4 to 12 weeks; therefore, the longterm efficacy of these interventions
remains unknown. Furthermore, highlevel comparative studies of different
pharmacologic therapies are still required. 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,

www.ContinuumJournal.com

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

June 2014

and those with a 50% reduction in pain


state that they are very much improved.61
For those with autonomic neuropathy, 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, gastrointestinal, genitourinary, and sudomotor 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 neurologic 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 painContinuum (Minneap Minn) 2014;20(3):531544

ful symptoms of DSP is available, and


good evidence supports treatment with
several anticonvulsants, antidepressants,
and opioids.
REFERENCES
1. Pecoraro RE, Reiber GE, Burgess EM. Pathways
to diabetic limb amputation. Basis for
prevention. Diabetes Care 1990;13(5):
513Y521.
2. Singleton JR, Smith AG, Bromberg MB. Painful
sensory polyneuropathy associated with
impaired glucose tolerance. Muscle Nerve
2001;24(9):1225Y1228.
3. Smith AG, Ramachandran P, Tripp S,
Singleton JR. Epidermal nerve innervation
in impaired glucose tolerance and
diabetes-associated neuropathy. Neurology
2001;57(9):1701Y1704.
4. CDC 2011 National Diabetes Fact Sheet.
Publications, Diabetes DDT. http://www.cdc.gov/
diabetes/pubs/pdf/ndfs_2011.pdf. Accessed
August 28, 2013.
5. Boulton AJM, Kempler P, Ametov A, Ziegler D.
Whither pathogenetic treatments for
diabetic polyneuropathy? Diabetes Metab
Res Rev 2013;29(5):327Y333.
6. Tesfaye S, Stevens LK, Stephenson JM, et al.
Prevalence of diabetic peripheral
neuropathy and its relation to glycaemic
control and potential risk factors: the
EURODIAB IDDM Complications Study.
Diabetologia 1996;39(11):1377Y1384.
7. Tesfaye S, Chaturvedi N, Eaton SE, et al.
Vascular risk factors and diabetic neuropathy.
N Engl J Med 2005;352(4):341Y350.
8. Dyck PJ, Overland CJ, Low PA, et al. Signs
and symptoms versus nerve conduction
studies to diagnose diabetic sensorimotor
polyneuropathy: Cl vs. NPhys trial. Muscle
Nerve 2010;42(2):157Y164.
9. Partanen J, Niskanen L, Lehtinen J, et al.
Natural history of peripheral neuropathy
in patients with non-insulin-dependent
diabetes mellitus. N Engl J Med 1995;
333(2):89Y94.
10. The effect of intensive treatment of diabetes
on the development and progression of
long-term complications in insulin-dependent
diabetes mellitus. The Diabetes Control and
Complications Trial Research Group. N Engl J
Med 1993;329(14):977Y986.
11. Albers JW, Feldman EL. Effect of prior
intensive insulin treatment during the
Diabetes Control and Complications Trial
(DCCT) on peripheral neuropathy in type 1
www.ContinuumJournal.com

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

541

Diabetes Mellitus

diabetes during the Epidemiology of


Diabetes Interventions and Complications
(EDIC) Study. Diabetes Care 2010;33(5):
1090Y1096.
12. Shichiri M, Kishikawa H, Ohkubo Y, Wake N.
Long-term results of the Kumamoto Study
on optimal diabetes control in type 2
diabetic patients. Diabetes Care 2000;
23(suppl 2):B21YB29.
13. Tesfaye S, Tandan R, Bastyr EJ3, et al. Factors
that impact symptomatic diabetic peripheral
neuropathy in placebo-administered
patients from two 1-year clinical trials.
Diabetes Care 2007;30(10):2626Y2632.
14. Navarro X, Sutherland DE, Kennedy WR.
Long-term effects of pancreatic transplantation
on diabetic neuropathy. Ann Neurol 1997;
42(5):727Y736.
15. Mehra S, Tavakoli M, Kallinikos PA, et al.
Corneal confocal microscopy detects early
nerve regeneration after pancreas
transplantation in patients with type 1
diabetes. Diabetes Care 2007;30(10):
2608Y2612.
16. Ziegler D, Zentai CP, Perz S, et al. Prediction
of mortality using measures of cardiac
autonomic dysfunction in the diabetic and
nondiabetic population: the MONICA/KORA
Augsburg Cohort Study. Diabetes Care
2008;31(3):556Y561.
17. Perkins BA, Bril V. Diagnosis and management
of diabetic neuropathy. Curr Diab Rep 2002;
2(6):495Y500.
18. Perkins BA, Bril V. Diabetic neuropathy: a
review emphasizing diagnostic methods.
Clin Neurophysiol 2003;114(7):1167Y1175.
19. Perkins BA, Olaleye D, Zinman B, Bril V.
Simple screening tests for peripheral
neuropathy in the diabetes clinic. Diabetes
Care 2001;24(2):250Y256.
20. Perkins BA, Orszag A, Ngo M, et al. Prediction
of incident diabetic neuropathy using the
monofilament examination: a 4-year
prospective study. Diabetes Care 2010;
33(7):1549Y1554.
21. Boulton AJ, Vinik AI, Arezzo JC, et al.
Diabetic neuropathies: a statement by the
American Diabetes Association. Diabetes
Care 2005;28(4):956Y962.
22. Bril V, Perkins B, Toth C. Canadian Diabetes
Association 2013Clinical Practice Guidelines
for the Prevention and Management of
Diabetes in Canada: neuropathy. Can J
Diabetes 2013;37(suppl 1):S142YS144.
23. Bril V, Perkins BA. Validation of the Toronto
Clinical Scoring System for diabetic

542

polyneuropathy. Diabetes Care 2002;25(11):


2048Y2052.
24. Bril V, Tomioka S, Buchanan RA, Perkins BA,
mTCNS Study Group. Reliability and
validity of the modified Toronto Clinical
Neuropathy Score in diabetic sensorimotor
polyneuropathy. Diabet Med 2009;26(3):
240Y246.
25. England JD, Gronseth GS, Franklin G, et al.
Distal symmetric polyneuropathy: a
definition for clinical research: report of the
American Academy of Neurology, the
American Association of Electrodiagnostic
Medicine, and the American Academy of
Physical Medicine and Rehabilitation.
Neurology 2005;64(2):199Y207.
26. England JD, Gronseth GS, Franklin G, et al.
Practice parameter: the evaluation of distal
symmetric polyneuropathy: role of laboratory
and genetic testing (an evidence-based
review). Report of the American Academy of
Neurology, American Association of
Neuromuscular and Electrodiagnostic Medicine,
and American Academy of Physical Medicine
and Rehabilitation. Neurology 2009;72(2):
185Y192.
27. Dyck PJ, Albers JW, Andersen H, et al.
Diabetic polyneuropathies: update on
research definition, diagnostic criteria and
estimation of severity [published online ahead
of print June 21, 2011]. Diabetes Metab
Res Rev. doi:10.1002/dmrr.1226.
28. Weisman A, Bril V, Ngo M, et al. Identification
and prediction of diabetic sensorimotor
polyneuropathy using individual and simple
combinations of nerve conduction study
parameters. PLoS One 2013;8(3):e58783.
29. Dunnigan SK, Ebadi H, Breiner A, et al.
Comparison of diabetes patients with
demyelinating diabetic sensorimotor
polyneuropathy to those diagnosed with
CIDP. Brain Behav 2013;3(6):656Y663.
30. Dunnigan SK, Ebadi H, Breiner A, et al.
Conduction slowing in diabetic sensorimotor
polyneuropathy. Diabetes Care 2013;
36(11):3684Y3690.
31. Kles KA, Bril V. Diagnostic tools for diabetic
sensorimotor polyneuropathy. Curr Diabetes Rev
2006;2(3):353Y361.
32. Zinman LH, Bril V, Perkins BA. Cooling
detection thresholds in the assessment of
diabetic sensory polyneuropathy: comparison
of CASE IV and Medoc instruments.
Diabetes Care 2004;27(7):1674Y1679.
33. Nabavi Nouri M, Ahmed A, Bril V, et al.
Diabetic neuropathy and axon reflex-mediated
neurogenic vasodilatation in type 1 diabetes.
PLoS One 2012;7(4):e34807.

www.ContinuumJournal.com

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

June 2014

34. Ahmed A, Bril V, Orszag A, et al. Detection


of diabetic sensorimotor polyneuropathy
by corneal confocal microscopy in type 1
diabetes: a concurrent validity study.
Diabetes Care 2012;35(4):821Y828.
35. Hertz P, Bril V, Orszag A, et al. Reproducibility
of in vivo corneal confocal microscopy as a
novel screening test for early diabetic
sensorimotor polyneuropathy. Diabet Med
2011;28(10):1253Y1260.
36. Lauria G, Cornblath DR, Johansson O, et al.
EFNS guidelines on the use of skin biopsy in
the diagnosis of peripheral neuropathy. Eur
J Neurol 2005;12(10):747Y758.
37. Breiner A, Lovblom E, Perkins B, et al. Does
the prevailing hypothesis that small-fiber
dysfunction precedes large-fiber dysfunction
apply to type 1 diabetic patients? Diabetes
Care 2014. In press.
38. Orlov S, Bril V, Orszag A, Perkins BA. Heart rate
variability and sensorimotor polyneuropathy
in type 1 diabetes. Diabetes Care 2012;35(4):
809Y816.
39. Bril V, Nyunt M, Ngo M. Limits of the
sympathetic skin response in patients with
diabetic polyneuropathy. Muscle Nerve
2000;23(9):1427Y1430.
40. Polydefkis M, Hauer P, Sheth S, et al. The
time course of epidermal nerve fibre
regeneration: studies in normal controls and
in people with diabetes, with and without
neuropathy. Brain 2004;127(pt 7):
1606Y1615.
41. Hume DA, Lovblom LE, Ahmed A, et al.
Higher magnification lenses versus
conventional lenses for evaluation of diabetic
neuropathy by corneal in vivo confocal
microscopy. Diabetes Res Clin Pract 2012;97(2):
e37Ye40.
42. Bril V, Ellison R, Ngo M, et al. Electrophysiological
monitoring in clinical trials. Roche Neuropathy
Study Group. Muscle Nerve 1998;21(11):
1368Y1373.
43. Bril V, Kojic J, Clark K. Comparison of a
neurothesiometer and vibration in measuring
vibration perception thresholds and relationship
to nerve conduction studies. Diabetes Care
1997;20(9):1360Y1362.
44. Younger DS. Diabetic lumbosacral
radiculoplexus neuropathy: a postmortem
studied patient and review of the literature.
J Neurol 2011;258(7):1364Y1367.
45. Grewal J, Bril V, Lewis GF, et al. Objective
evidence for the reversibility of nerve injury
in diabetic neuropathic cachexia. Diabetes
Care 2006;29(2):473Y474.
Continuum (Minneap Minn) 2014;20(3):531544

46. Perkins BA, Olaleye D, Bril V. Carpal tunnel


syndrome in patients with diabetic
polyneuropathy. Diabetes Care 2002;25(3):
565Y569.
47. Zochodne DW, Isaac D, Jones C. Failure of
immunotherapy to prevent, arrest or reverse
diabetic lumbosacral plexopathy. Acta
Neurol Scand 2003;107(4):299Y301.
48. Chan YC, Lo YL, Chan ES. Immunotherapy for
diabetic amyotrophy. Cochrane Database Syst
Rev 2012;(6):CD006521.
49. Smith AG, Russell J, Feldman EL, et al. Lifestyle
intervention for pre-diabetic neuropathy.
Diabetes Care 2006;29(6):1294Y1299.
50. Gong Q, Gregg EW, Wang J, et al. Long-term
effects of a randomised trial of a 6-year
lifestyle intervention in impaired glucose
tolerance on diabetes-related microvascular
complications: the China Da Qing Diabetes
Prevention Outcome Study. Diabetologia
2011;54(2):300Y307.
51. Effect of intensive diabetes treatment on
nerve conduction in the Diabetes Control
and Complications Trial. Ann Neurol
1995;38(6):869Y880.
52. Writing Team for the Diabetes Control and
Complications Trial/Epidemiology of Diabetes
Interventions and Complications Research
Group. Sustained effect of intensive treatment
of type 1 diabetes mellitus on development
and progression of diabetic nephropathy: the
Epidemiology of Diabetes Interventions and
Complications (EDIC) study. JAMA 2003;
290(16):2159Y2167.
53. Boussageon R, Bejan-Angoulvant T,
Saadatian-Elahi M, et al. Effect of intensive
glucose lowering treatment on all cause
mortality, cardiovascular death, and
microvascular events in type 2 diabetes:
meta-analysis of randomised controlled
trials. BMJ 2011;343:d4169. doi:10.1136/
bmj.d4169.
54. Type 2 diabetes: increased mortality with
low HbA1c. Prescrire Int 2013;22(134):23.
55. Konig M, Lamos EM, Stein SA, Davis SN. An
insight into the recent diabetes trials: what is
the best approach to prevent macrovascular
and microvascular complications? Curr Diabetes
Rev 2013;9(5):371Y381.
56. Callaghan BC, Little AA, Feldman EL,
Hughes RA. Enhanced glucose control for
preventing and treating diabetic neuropathy.
Cochrane Database Syst Rev 2012;6:CD007543.
57. Ziegler D, Low PA, Litchy WJ, et al. Efficacy
and safety of antioxidant treatment with
"-lipoic acid over 4 years in diabetic
polyneuropathy: the NATHAN 1 trial.
Diabetes Care 2011;34(9):2054Y2060.
www.ContinuumJournal.com

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

543

Diabetes Mellitus

58. Bril V, England J, Franklin GM, et al.


Evidence-based guideline: treatment of
painful diabetic neuropathy: report of
the American Academy of Neurology,
the American Association of Neuromuscular
and Electrodiagnostic Medicine, and the
American Academy of Physical Medicine
and Rehabilitation. Neurology 2011;76(20):
1758Y1765.
59. Bo C, Xue Z, Yi G, et al. Assessing the quality
of reports about randomized controlled trials
of acupuncture treatment on Diabetic
Peripheral Neuropathy. PLoS One 2012;7(7):
e38461.

544

60. Hauser W, Bartram-Wunn E, Bartram C, et al.


Systematic review: placebo response in drug
trials of fibromyalgia syndrome and painful
peripheral diabetic neuropathy-magnitude
and patient-related predictors. Pain 2011;
152(8):1709Y1717.
61. Farrar JT, Young JP Jr, LaMoreaux L, et al.
Clinical importance of changes in chronic pain
intensity measured on an 11-point numerical
pain rating scale. Pain 2001;94(2):149Y158.
62. Gibbons CH, Freeman R. Treatment-induced
diabetic neuropathy: a reversible painful
autonomic neuropathy. Ann Neurol 2010;
67(4):534Y541.

www.ContinuumJournal.com

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

June 2014

Anda mungkin juga menyukai