NEUROPATHY AND DM

Sheryl Ray B. Yang-Zamora

Dysserie Krystal Palermo-Rivera
 a demonstrable disorder, either clinically
evident or subclinical, that occurs in the
Diabetic setting of diabetes mellitus without other
neuropathy causes for peripheral neuropathy.
owing to the variety of the clinical syndromes with possible overlaps, there is no universally
accepted classification.
PATHOGENETIC MECHANISMS
PATHOGENETIC MECHANISMS

1 Increased flux through the polyol pathway

that leads to accumulation of sorbitol and
fructose, myo-inositol depletion, and
reduction in
Na K -ATPase activity.
+ +
 PATHOGENETIC MECHANISMS

2
Increased flux through the polyol pathway that
leads to accumulation of sorbitol and fructose,
myo-inositol depletion, and reduction in
Na+K+-ATPase activity.
Disturbances in n-6 essential fatty acid
and prostaglandin metabolism that result
in alterations of nerve membrane structure
and microvascular and hemorrheological
abnormalities.
 PATHOGENETIC MECHANISMS

3
Increased flux through the polyol pathway that Disturbances in n-6 essential fatty acid and
leads to accumulation of sorbitol and fructose, prostaglandin metabolism that result in alterations of
myo-inositol depletion, and reduction in nerve membrane structure and microvascular and
Endoneural microvascular deficits with
Na+K+-ATPase activity. hemorrheological abnormalities.

subsequent ischemia and hypoxia, generation

of reactive oxygen species (oxidative stress),
activation of the redox-sensitive transcription
factor NF- κB, and increased activity of
protein kinase C (PKC).
 PATHOGENETIC MECHANISMS

4
Increased flux through the polyol pathway that Disturbances in n-6 essential fatty acid and
leads to accumulation of sorbitol and fructose, prostaglandin metabolism that result in alterations of
myo-inositol depletion, and reduction in nerve membrane structure and microvascular and
Deficits in neurotrophism leading to reduced
Na+K+-ATPase activity. hemorrheological abnormalities.

expression and depletion of neurotrophic

Endoneural microvascular deficits with subsequent
factors
ischemia and hypoxia, such
generation asoxygen
of reactive nerve growth factor (NGF),
species (oxidative stress), activation of the redox-sensitive
neurotrophin-3
transcription factor NF- κB, and increased activity of (NT-3), and insulin-like
protein kinase C (PKC).
growth factor (IGF) and alterations in axonal
transport.
 PATHOGENETIC MECHANISMS

5
Increased flux through the polyol pathway that
leads to accumulation of sorbitol and fructose,
myo-inositol depletion, and reduction in
Na+K+-ATPase activity.
Disturbances in n-6 essential fatty acid and
prostaglandin metabolism that result in alterations of
nerve membrane structure and microvascular and
hemorrheological abnormalities.

Accumulation of non-enzymatic advanced

Endoneural microvascular deficits with subsequent
Deficits in neurotrophism leading to reduced expression and
ischemia and hypoxia, generation of reactive oxygen
glycation end- products (AGEs) on nerve
species (oxidative stress), activation of the redox-sensitive
transcription factor NF- κB, and increased activity of
depletion of neurotrophic factors such as nerve growth factor
(NGF), neurotrophin-3 (NT-3), and insulin-like growth factor
(IGF) and alterations in axonal transport.
and/or vessel proteins.
protein kinase C (PKC).
 PATHOGENETIC MECHANISMS

6
Increased flux through the polyol pathway that
leads to accumulation of sorbitol and fructose,
myo-inositol depletion, and reduction in
Na+K+-ATPase activity.
Disturbances in n-6 essential fatty acid and
prostaglandin metabolism that result in alterations of
nerve membrane structure and microvascular and
hemorrheological abnormalities.

Immunological processes with autoantibodies

Endoneural microvascular deficits with subsequent
to generation
ischemia and hypoxia, vagalof reactive
nerve, oxygensympathetic ganglia, and
Deficits in neurotrophism leading to reduced expression and
depletion of neurotrophic factors such as nerve growth factor
species (oxidative stress), activation of the redox-sensitive
adrenal
transcription factor NF- κB, andmedulla
increased activity in
protein kinase C (PKC).
of addition to inflammatory
(NGF), neurotrophin-3 (NT-3), and insulin-like growth factor
(IGF) and alterations in axonal transport.

changes.
Accumulation of non-enzymatic advanced glycation
end- products (AGEs) on nerve and/or vessel
proteins.
 PATHOGENETIC MECHANISMS
Increased flux through the polyol pathway that
leads to accumulation of sorbitol and fructose,
myo-inositol depletion, and reduction in
Na+K+-ATPase activity.
Endoneural microvascular deficits with subsequent
ischemia and hypoxia, generation of reactive oxygen
species (oxidative stress), activation of the redox-sensitive
transcription factor NF- κB, and increased activity of
protein kinase C (PKC).
Accumulation of non-enzymatic advanced glycation
end- products (AGEs) on nerve and/or vessel
proteins.
Disturbances in n-6 essential fatty acid and
prostaglandin metabolism that result in alterations of
nerve membrane structure and microvascular and
hemorrheological abnormalities.
Deficits in neurotrophism leading to reduced expression and
depletion of neurotrophic factors such as nerve growth factor
(NGF), neurotrophin-3 (NT-3), and insulin-like growth factor
(IGF) and alterations in axonal transport.
Immunological processes with autoantibodies to
vagal nerve, sympathetic ganglia, and adrenal
medulla in addition to inflammatory changes.
 PATHOGENETIC MECHANISMS

n-6 essential fatty acid and

POLYOL PATHWAY prostaglandin

Endoneural microvascular
Neurotrophism Deficits
deficits and ROS

AGE Accumulation Immunological Processes

“Total hyperglycemic exposure is perhaps the
most important risk covariate"
 DEFINITION

Diabetic distal ADA

is the presence of symptoms and/or signs of peripheral
symmetrical nerve dysfunction in people with diabetes after the
exclusion of other causes.
sensorimotor
polyneuropathy HOLT
(DSPN) is a symmetrical, length-dependent sensorimotor polyneuropathy
attributable to metabolic and microvessel alterations as a result
of chronic hyperglycemia exposure (diabetes) and cardiovascular
risk covariates
ETIOLOGICAL FACTORS
Poor glycemic
Visceral Obesity
control
Diabetic distal Diabetes Duration Height
symmetrical
sensorimotor
Hypertension Age
polyneuropathy
(DSPN)
Smoking Hypoinsulinemia

Dyslipidemia
Diabetic distal symmetrical sensorimotor
polyneuropathy (DSPN)

 represents the most relevant clinical manifestation, affecting ∼30% of

hospital- based populations with diabetes and 20% of community-based
individuals with diabetes

 related to both lower extremity impairments such as diminished position

sense and functional limitations such as walking ability

 Pain associated with diabetic neuropathy exerts a substantial impact on

the quality of life, particularly by causing considerable interference in
sleep and enjoyment of life
 Diabetic distal symmetrical sensorimotor
polyneuropathy (DSPN)

Trials
 In the DIAD study, both sensory deficits and neuropathic pain were
independent predictors of cardiac death or non-fatal myocardial
infarction

 History of neuropathy was the most important predictor for

increased mortality in people with type 2 diabetes (T2DM)
allocated to very intensive diabetes therapy aimed at HbA1c <6.0%
in the ACCORD trial
Diabetic distal symmetrical sensorimotor polyneuropathy
(DSPN)

 typically develops as a dying-back neuropathy, affecting the

most distal extremities (toes) first. The neuropathic process then
extends proximally up the limbs and later it may also affect the
anterior abdominal wall and then spread laterally around the
trunk.

 Occasionally the upper limbs are involved, with the fingertips

being affected first (glove-and-stocking distribution)

 The pain was most often described as “burning/hot,” “electric,”

“sharp,” “achy,” and “tingling,” and was worse at night-time and
when tired or stressed
Definitions of minimal criteria for typical DPN
1. Possible DSPN. The presence of symptoms or signs of DSPN may include the
following: symptoms– decreased sensation, positive neuropathic sensory symptoms (e.g.,
“asleep numbness,” prickling or stabbing, burning or aching pain) predominantly in the
toes, feet, or legs; or signs–symmetric decrease of distal sensation or unequivocally
decreased or absent ankle reflexes.

2. Probable DSPN. The presence of a combination of symptoms and signs of neuropathy

include any two or more of the following: neuropathic symptoms, decreased distal
sensation, or unequivocally decreased or absent ankle reflexes.

3. Confirmed DSPN. The presence of an abnormality of NC and a symptom or

symptoms or a sign or signs of neuropathy confirm DSPN. If NC is normal, a validated
measure of small fiber neuropathy (SFN) (with class 1 evidence) may be used.

4. Subclinical DSPN. The presence of no signs or symptoms of neuropathy are

confirmed with abnormal NCs or a vali- dated measure of SFN
It is the loss of the “gift of pain” that permits
patients with plantar neuropathic ulcers to walk
on the lesions, inducing chronicity, frequently
complicated by infection
  has been described as a separate clinical entity
[21]. It is encountered infrequently in both
people with type 1 diabetes mellitus (T1DM)
and T2DM, presenting with continuous burning
Acute Painful pain particularly in the soles (“like walking on
Neuropathy burning sand”) with nocturnal exacerbation.

 A characteristic feature is cutaneous contact

discomfort with clothes and sheets,
Acute Painful  The syndrome of acute painful neuropathy seems
to be equivalent to “diabetic cachexia” as
Neuropathy described by Ellenberg
 Insulin Neuritis
 used by Caravati
 precipitation of acute painful neuropathy several weeks
following the institution of insulin treatment.
 In the most recent series, the term treatment-induced
neuropathy in diabetes (TIND) has been used to describe this
Acute Painful relatively rare iatrogenic small-fiber neuropathy with
neuropathic pain and autonomic involvement caused by an
Neuropathy abrupt improvement in glycemic control in the setting of
chronic hyperglycemia.

2–3% over 3 months = 20% risk

HbA1c >4% over 3 months = > 80% risk
  Most of the focal and multifocal neuropathies
tend to occur in people with long-term diabetes
Focal and who are middle aged or older.

multifocal  Cranial Neuropathy

 Mononeuropathy of the Limbs
neuropathies  Diabetic Truncal Neuropathy
 Diabetic Amyotrophy
  Palsies of the third cranial nerve (diabetic
ophthalmoplegia) are painful in about 50% of
Cranial cases. The onset is usually abrupt. The pain is
felt behind and above the eye, and at times
Neuropathy precedes the ptosis and diplopia

 Full resolution is the rule and generally takes

place within 3–5 months.
  Focal lesions affecting the limb nerves, most
commonly the ulnar, median, radial, and
Mononeuropathy of peroneal, may be painful, particularly if of acute
the limbs onset, as may entrapment neuropathies such as
the carpal tunnel syndrome that is associated
with painful paresthesia
  presents with an abrupt onset, with pain or
dysesthesias being the heralding feature,
sometimes accompanied by cutaneous sensory
Diabetic Truncal impairment or hyperesthesia.
 Pain has been described as deep, aching, or
Neuropathy boring, but the descriptors jabbing, burning,
sensitive skin, and tearing have also been used.
 The neuropathy is almost always unilateral
 Diabetic
Amyotrophy
Asymmetric or symmetric
proximal muscle weakness and
muscle wasting (iliopsoas,
obturator, and adductor muscles)
are easily recognized clinically in
the syndrome of lower limb
proximal motor neuropathy
  diffuse degenerative lesions in the CNS including
demyelination and loss of axon cylinders in the posterior
columns, degeneration of cortical neurons, and
abnormalities in the midbrain and cerebellum, which have
been described as “diabetic myelopathy” and “diabetic
Central encephalopathy”

nervous system  degree of dysfunction along the somatosensory afferent

pathways in persons with T1DM is not related to the
dysfunction duration of diabetes or glycemic control

 characterized by an alteration of the cortical sensory

complex and peripheral rather than spinal or supraspinal
conduction deficits
DIABETIC AUTONOMIC NEUROPATHIES

Major clinical manifestations of diabetic autonomic

neuropathy include: hypoglycemia unawareness, resting
tachycardia, orthostatic hypotension, gastroparesis,
constipation, diarrhea, fecal incontinence, erectile dysfunction,
neurogenic bladder, and sudomotor dysfunction with either
increased or decreased sweating.
CARDIAC AUTONOMIC NEUROPATHY

 CAN prevalence is very low in newly diagnosed patients with

type 1 diabetes, CAN prevalence increases substantially with
diabetes duration

 present in patients with impaired glucose tolerance, insulin

resistance, or metabolic syndrome

 is an independent risk factor for cardiovascular mortality,

arrhythmia, silent ischemia, any major cardiovascular event, and
myocardial dysfunction

 CAN independently predicts the progression of diabetic

nephropathy and chronic kidney disease in diabetes
CARDIAC AUTONOMIC NEUROPATHY

The most common symptoms of CAN occur upon standing and

include light- headedness, weakness, palpitations, faintness, and
syncope
GASTROINTESTINAL NEUROPATHIES

Gastrointestinal neuropathies may involve any portion of the

gastrointestinal tract with manifestations including esophageal
dysmotility, gastroparesis (delayed gastric emptying), constipation,
diarrhea, and fecal incontinence.

symptoms of gastroparesis, such as early satiety, fullness, bloating,

nausea, vomiting, dyspepsia, and ab- dominal pain.
 UROGENITAL NEUROPATHIES

 includes sexual dysfunction and bladder dysfunction.

 In men, diabetic autonomic neuropathy may cause erectile

dysfunction (ED) and/or retrograde ejaculation. ED is three times
more common in men with diabetes than those without the
disease

 Sexual dysfunction is also more common in women with diabetes

 UROGENITAL NEUROPATHIES

Lower Urinary Tract Symptoms

Lower urinary tract symptoms manifest as urinary incontinence and

bladder dysfunction (nocturia, frequent urination, urination urgency,
weak urinary stream) and is linked to the presence of diabetic
neuropathy in both men and women
 SUDOMOTOR DYSFUNCTION

 Sudomotor dysfunction may manifest as dry skin,

anhidrosis, or heat intolerance.

 A rare form of sudomotor dysfunction is gustatory

sweating that comprises excessive sweating limited
exclusively to the head and neck region triggered by
food consumption or, in some cases, the smell of food.