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Mediterranean Group for the Study of Diabetes -
MGSD Postgraduate Course
Diabetic Neuropathy
Susanna Morano Department of Clinical Sciences -
Endocrinology University La Sapienza - Rome
Padua, February 12-14, 2004
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Diabetic Neuropathy (DN) WHO definition A
disease characterized as a progressive loss of
nerve fibers leading to sensation loss, foot
ulceration, amputation
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Definition of DN "the presence of symptoms
and/or signs of peripheral nerve dysfunction in
people with diabetes after exclusion of other
causes." International Consensus Meeting for
the Outpatient Management of Neuropathy
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Diabetic neuropathy is classified into several
syndromes, each with a distinct pattern of
involvement of the peripheral nerves. It has
been described in patients with primary (types 1
and 2) and secondary diabetes, suggesting a
common etiologic mechanism based on chronic
hyperglycemia.
The role of hyperglycemia in the pathogenesis
of this complication has received strong support
from the Diabetes Control and Complications Trial
(DCCT).
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Metabolic control and diabetic complications
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Pathophysiology The pathophysiological basis
leading to the development of peripheral
neuropathy in diabetes is not understood
completely. Numerous changes have been
demonstrated in both myelinated and unmyelinated
fibers. Multiple hypotheses have been proposed.
It is accepted as a multifactorial process.
Metabolic, vascular, altered neurotrophic
support, and autoimmunity are the most accepted
theories.
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• Metabolic theory
• Hyperglycemia increased levels of
  intracellular glucose in nerves leading
  to saturation of the glycolytic pathway.
• The extra glucose is shunted into the polyol
  pathway and converted to sorbitol and fructose by
  aldose reductase and sorbitol dehydrogenase.
• Accumulation of sorbitol and fructose leads to
• nerve myoinositol,
• membrane Na/K-ATPase activity
• impaired axonal transport, structural breakdown
  of the nerve, slowing of conduction velocities.

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Vascular (ischemic-hypoxic) theory Endoneurial
ischemia develops because of increased
endoneurial vascular resistance to hyperglycemic
blood. Various metabolic factors, including
formation of Advanced Glycosylation End-products
(AGE), also have been implicated, leading to
capillary damage, inhibition of axonal transport,
Na/K-ATPase activity, and finally to axonal
degeneration.
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Altered neurotrophic support theory Normally
neurotrophic factors are important in the
development, maintenance, and regeneration of
nervous tissue. Nerve growth factor (NGF) is the
best studied. This protein promotes survival of
sympathetic and small-fiber neural crestderived
factors in the peripheral nervous system. In
animals with diabetes, both production and
transport of NGF are impaired.
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Autoimmunity theory The postulation that
autoimmunity is a mechanism of developing
diabetic neuropathy has been always of interest.
Autoimmune neuropathy can emerge from
immunogenic alteration of the endothelial
capillary cells and of nervous tissue
components.
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Hyperglycemia
Non-enzymatic glycation
Oxidative stress
Polyol pathway
PKC activation
PGE2
TGF- ?
PAI-1, VEGF
NO NGF
Collagen
Na/K-ATPase
ET-1, AII
Fibronectin
Microvascular occlusion, ischemia
Impaired neural function
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Frequency Diabetic neuropathy can occur at
any age with a higher frequency in male and in
middle-aged diabetic patients. The prevalence of
diabetic polyneuropathy varies widely in the
literature mainly due to different criteria used
for its diagnosis. An estimated 10-65 of
patients with diabetes have some form of
peripheral neuropathy. According to Pirart et
al, neuropathy is estimated to be present in
about 7.5 of patients at the onset of diabetes,
this percentage rising to 45 after 25 years of
the disease.
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History In type 1 diabetes mellitus, distal
polyneuropathy occurs after many years of
chronic hyperglycemia while in type 2 diabetes
mellitus it presents after a few years of poor
glycemic control, and occasionally at the time
of diagnosis. Diabetic neuropathy can present
with sensory, motor, and autonomic symptoms.
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• Sensory symptoms negative or positive.
• Negative sensory symptoms include numbness,
  feeling of wearing gloves or walking on stilts,
  loss of balance, especially with the eyes closed
  and painless injuries.
• Positive symptoms include burning, pricking pain,
  electric shocklike feelings, tightness, and
  hypersensitivity to touch.

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• Motor symptoms can cause distal,
• proximal, or focal weakness.
• Distal motor symptoms include
• impaired fine coordination of the hand,
• inability to open jars or turn keys.
• Proximal weakness include difficulty
• with stairs or in getting up from a
• sitting or lying position, falls due to the
• knee giving way, difficulty raising
• arms above the shoulders.

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• Autonomic symptoms
• sudomotor (dry skin, lack of sweating, excessive
  sweating in defined areas),
• pupillary (poor dark adaptation, sensitivity to
  bright lights),
• cardiovascular (postural light-headedness,
  fainting),
• urinary (urgency, incontinence), gastrointestinal
  (nocturnal diarrhea, constipation, vomiting of
  retained food), sexual (erectile dysfunction and
  ejaculatory failure in men, loss of ability to
  reach sexual climax in women).

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Classification

• A generally accepted classification of diabetic
  neuropathies divides them into symmetric and
  asymmetric neuropathies.
• Development of symptoms depends on total
  hyperglycemic exposure and other risk factors.
  Establishing the diagnosis requires care, since
  5-10 of patients with diabetes have symptoms
  that are not caused by diabetic neuropathy.

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• Symmetric polyneuropathies. Most commonly
  involve several symmetrically distributed
  nerves. The longest peripheral nerves are
  affected for first.
• Sensory symptoms are predominant, while motor,
  and autonomic functions are affected in varying
  degrees
• Commonly it presents as night-time painful
  paresthesias and numbness which begin in the toes
  and ascend proximally in a stockinglike
  distribution
• Anterior aspect of the trunk and the vertex of
  the head possibly affected at a late stage
• Weakness of foot muscles and decreased ankle and
  knee reflexes developing later
• Pain and temperature loss with involvement of
  small fibers, predisposing to development of foot
  ulcers
• Impaired proprioception, vibratory perception,
  and gait (sensory ataxia) with involvement of
  large fibers
• Anhydrosis, bladder atony and unreactive pupils
  possible from autonomic dysfunction

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Asymmetric neuropathies. Include single or
multiple cranial and somatic mononeuropathies
(e.g., median, ulnar), single or multiple
mono-radiculopathies (thoracolumbar and
lumbosacral radiculo-neuropathy), amyotrophy.
These syndromes are distinguished from typical
distal diabetic polyneuropathy by the following
(1) they appear acutely or subacutely, (2) they
have a monophasic course, (3) they are
associated more with type 2 than type 1 diabetes,
(4) some are associated with angitis and
ischemia (e.g, lumbosacral radiculo-neuropathy), 5
) they have a weaker association with
hyperglycemia than symmetric neuropathies.
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Asymmetric neuropathies

• Cranial mononeuropathy
• Commonly nerves involved are the oculomotor,
  facial, and optic.
• Oculomotor neuropathy presents as acute or
  subacute periorbital pain or headache followed by
  diplopia. Muscle weakness typically in
  distribution of a single oculomotor nerve with
  sparing of pupillary reflex. Complete spontaneous
  recovery within 3 months.
• Facial neuropathy presents with acute or subacute
  facial weakness can be recurrent or bilateral
  most recover spontaneously in 3-6 months
• Optic neuropathy (with anterior ischemia)
  presents with acute visual loss or visual field
  defects. Optic disk pale and swollen, associated
  with flame-shaped hemorrhages.

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Asymmetric neuropathies

• Somatic mononeuropathies
• Focal neuropathies in the extremities are caused
  by entrapment or compression of the nerve where
  it crosses common pressure points or by ischemia
  and subsequent infarction of the nerve
• Common sites include the median nerve at the
  wrist (carpal tunnel syndrome), ulnar nerve at
  the elbow, and common peroneal nerve at the
  fibular head
• Nerve infarction appears acutely with focal pain
  associated with weakness and variable sensory
  loss in the distribution of the affected nerve

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Asymmetric neuropathies

• Diabetic polyradiculopathy
• Single or more commonly multiple contiguous
  spinal roots are involved
• Includes 2 syndromes, thoracoabdominal and
  lumbosacral radiculopathies
• Thoracoabdominal neuropathy
• Occurs in patients older than 50 years more
  common in type 2 diabetes
• Presents with chest and/or abdominal pain in the
  distribution of thoracic and/or upper lumbar
  roots
• Burning, stabbing, beltlike, or deep pains are
  more intense at night
• Onset of pain usually unilateral
• Touch possibly hypersensitive contact with
  clothing may be unpleasant
• Weakness presenting as bulging of the abdominal
  wall from abdominal muscle paresis
• Co-existing diabetic distal symmetric
  polyneuropathy often present

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Asymmetric neuropathies

• Lumbosacral radiculopathy
• Occurs in patients older than 50 years and
  predominantly in men
• Significant weight loss in 50 of patients
• Symptoms begin unilaterally later may spread to
  the opposite limb
• Starts as sudden, severe, unilateral pain in the
  lower back or hips and spreads to the anterior
  thigh
• Weakness develops days to weeks later in the hip
  and thigh muscles can lead to profound atrophy
  of the proximal lower limb muscles
• Usually knee reflex is absent ankle reflex may
  be depressed
• Numbness and paresthesias are rare

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Asymmetric neuropathies

• Amiotrophy
• A less common syndrome, is characterized by rapid
  and profound weight loss, severe cutaneous pain,
  worsening at night, by small-fiber neuropathy and
  autonomic dysfunction.
• Symptoms usually improve with prolonged
  hyperglycemia control.
• Pharmacologic treatment is usually not effective.
  Non-pharmacologic treatments have been tried
  with limited success and include sympathectomy,
  spinal cord blockade, and electrical spinal cord
  stimulation.

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Diabetic Somatic Neuropathy
Symmetrical diffuse sensimotor neuropathy
Acute diffuse painful neuropathy
Femoral neuropathy (amyotrophy)
Other acute mononeuropathies
Presseure palsies
Sensory loss 0 / Pain / Tendon
reflexes N / Motor deficit 0 /
Sensory loss 0 / - Pain / Tendon
reflexes N / Motor deficit 0
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Diabetic Neuropathy
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• Physical
• Diabetic polyneuropathy typically develops as
  diffused asymptomatic dysfunction of peripheral
  nerve fibers. The most common early dysfunction
  is abnormal nerve conduction or a reduction of
  the heart beat response to deep breathing or to
  Valsalva maneuver.
• The first clinical sign that usually develops
  with abnormal nerve conduction is decrease or
  loss of ankle reflex or decrease or loss of
  vibratory sensation over the great toes.
• With more severe involvement, the patient
  develops varying degrees and modalities of pain
  sensory loss of the toes, feet, and distal legs,
  deep tendon reflex abnormalities and weakness of
  small foot muscles.

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Diagnosis

• Five criteria are needed to diagnose diabetic
  polyneuropathy.
• The patient is diabetic according to the WHO
  criteria.
• The patient metabolic control is poor.
• Patient has predominantly distal sensorial and
  motor polyneuropathy in lower extremities.
• Diabetic retinopathy or nephropathy can be
  present.
• Other causes of neuropathy are excluded.

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• EXAMINATION
• Patients are screened initially with
• questionnaire (i.e. Neuropathy Impairment
  Score)
• clinical assessment.
• Patients scoring in the abnormal range are
  further assessed by
• neurologic examination
• electrophysiologic studies.

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Clinical Examination (1)

• Inspection of the feet
• skin status colour, thickness, cracking,
  trophic changes
• sweating
• infection (interdigital fungal infection)
• ulceration
• calluses/blistering
• deformity e. g. Charcot joint or claved toes
• muscle atrophy
• arches (standing/lying)

Temperature, foot pulses and joint mobility
should be assessed.
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Foot calluses and deformity sites
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Charcots feet with neuropathic ulcer (painless,
calluses around) and amputation
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Clinical Examination (2)

• Neurological Tests
• Pin prick test using a disposable
  dressmakers pin
• Light touch using a cotton wisp
• Vibration test using a 128 Hz tuning fork
• (initially on the big toe)
• Ankle reflex comparing with the knee
  reflex
• Pressure perception using a monofilament
• (absence of sensation in the foot
  to a 10 gauge
  monofilament risk of ulceration)

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Pressure perception
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Cardiovascular tests for autonomic neuropathy
Normal
Borderline
Abnormal
Test
Deep breathing (beats/min)
11-15
lt10
gt15
Valsalva ratio
1.1-1.2
lt1.1
gt1.2
Lying to standing
1.01-1.03
lt1.0
gt1.03
Systolic blood pressure response to stand up (mm
Hg)
20-29
lt20
gt30
Hearth rate variation with breathing Hearth
rate variation with forced expiration Hearth
rate response to stand up
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Electrophysiologic studies Are the most
sensitive, reliable, and reproducible measures of
nerve function. They also correlate with the
morphologic findings on nerve biopsy. Although
they can define and quantitate nerve dysfunction,
the abnormalities found are not specific to
diabetes.
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• Nerve conduction velocities and electromyography
• Motor nerve conduction velocity abnormalities
  reflect loss of large-diameter myelinated fibers,
  usually preminent in the legs.
• Sensitivity nerve conduction abnormalities may be
  found in the sensory nerves (sural, peroneal,
  median). Overall, these reflect the primary
  pathologic changes of axonal degeneration.
• Electromyographic sampling of distal muscles of
  the lower extremities reveals evidence of
  denervation. Abnormalities in the paraspinal
  muscles by needle examination may reflect
  poly-radiculopathy.

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• Stages of Diabetic Neuropathy
• N 0 - No neuropathy
• N 1a - Asymptomatic neuropathy detected as nerve
  conduction abnormality in at least 2 nerves
• N 1b - N1a and abnormal neurologic examination
• N 2a - Symptomatic mild polyneuropathy sensory,
  motor, or autonomic symptoms patient able to
  heel walk
• N 2b - Severe symptomatic polyneuropathy (as in
  N2a, but patient unable to heel walk)
• N 3 - Disabling polyneuropathy

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• Medical Care
• Consider any patient with clinical evidence of
  diabetic peripheral neuropathy to be at risk of
  insensitive foot ulceration and provide education
  on foot care and a podiatry referral.
• Patients with diabetic peripheral neuropathy
  require more frequent follow-up care, always
  paying particular attention to foot inspection to
  reinforce the educational message of the need for
  regular self-care.
• The provision of regular foot examination and
  reinforcement of the educational message have
  been shown in several studies to have a major
  impact on rates of ulceration and even
  amputation.

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• Current treatments
• Tight and stable glycemic control is probably the
  only one that may provide symptomatic relief as
  well as slow the progression of the neuropathic
  state.
• The stability rather than the actual level of
  glycemia may be more important in relieving
  neuropathic pain.
• Tricyclic drugs are the first-line drugs for the
  relief of painful neuropathic symptoms. The onset
  of symptomatic relief is faster than their
  antidepressive effects.
• A number of other drugs, including carbamazepine,
  phenytoin, gabapentin, mexiletine, and lidocaine,
  have been reported to be useful in the relief of
  painful or paresthetic neuropathic symptoms.
• Topical therapy with capsaicin may be useful in
  some patients, especially those with more
  localized pain.
• Acupuncture has been also employed with good
  results in painful neuropathy.

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• Recent treatment for autonomic dysfunction
• Good results have been obtained with the oral
  inhibitors of type 5 phosphodiesterase enzyme
  (PDE-5), the predominant isoenzyme in human
  corpus cavernosum, in the treatment of diabetic
  erectile dysfunction. Extensive clinical trials
  of these agents in diabetes are currently
  underway.

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Potential future therapies
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Surgical Care Pancreatic transplantation
indicated for patients with diabetes with
end-stage renal disease has yielded
stabilization and in some instances improvement
in motor, sensory, and autonomic neuropathy.
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SEP T6-Cortex before and after pancreatic islet
transplantation
8


m/sec

C
6
D
T
4
2
0
8
4
0
Months from diabetes induction
Rats transplanted after 4 months from diabetes
induction and studied after 4 months from islet
transplantation
Morano S et al, EJ Neurosci, 1996
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SEP L6-Cortex before and after pancreatic islet
transplantation
m/sec
12

C

D
T
8
4
0
0
4
8
Months from diabetes induction
Rats transplanted after 4 months from diabetes
induction and studied after 4 months from islet
transplantation
Morano S et al, EJ Neurosci, 1996
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• Impact of Diabetic Neuropathy
• The economic burden of medical and
• pharmacological care of patients with diabetic
• neuropathy is huge, since neuropathy increases
• the risk of foot ulcer and infection, which in
• turn may lead to amputation.

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Prevention

• The best way to help prevent diabetic neuropathy
  is to take the following actions
• Control diabetes. Try to keep blood sugar at a
  normal level.
• Exercise regularly, according to the health care
  provider's recommendation.
• Stop smoking.
• Limit the amount of alcohol intake because it
  also can cause neuropathy.
• Eat a diet with fruit and vegetables.
• Keep follow-up appointments with the health care
  specialist.