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.
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
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Diabetes Mellitus
KEY POINTS
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.
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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
KEY POINTS
h Diabetic neuropathy is a
diagnosis of exclusion.
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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.
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KEY POINTS
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 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.
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Diabetes Mellitus
KEY POINTS
h Simple tests of
autonomic function
should be considered
in patients with possible
diabetic sensorimotor
polyneuropathy.
Fiber Type
Test
Result in Diabetic
Sensorimotor
Polyneuropathy
Large
Axonal changesa
Elevated
Small
Elevated
Cutaneous axon-mediated
laser Doppler flare area
Reduced
Intraepidermal nerve
fiber density
Reduced
Autonomic
RR-variation
Reduced
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).
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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.
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KEY POINT
Case 1-2
h Control of painful
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.
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Diabetes Mellitus
KEY POINTS
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
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.
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