In this ppt I have tried to give basic idea about Diabetic peripheral and autonomic neuropathy ..from Levine textbook,IWGDF guideline etc Hope it will b helpful for trainee and physician

1. DIABETIC NEUROPATHY
Dr Pankaj Patawari

2. DIABETIC NEUROPATHY
 Diabetic neuropathies are serious, chronic complications of diabetes with
diverse clinical manifestations.
 Identified in patients with Prediabetes
i. Type 1 diabetes mellitus
ii. Type 2 diabetes mellitus

3. Classification of Diabetic Neuropathies
Generalized Symmetrical Polyneuropathies
 Distal sensory or sensorimotor polyneuropathy
 Small – fiber neuropathy
 Autonomic neuropathy
 Large - fiber sensory neuropath
Focal and Asymmetrical Neuropathy
 Cranial neuropathy (single or multiple)
 Truncal neuropathy (thoracic radiculopathy)
 Limb mononeuropathy (single or multiple)
 Lumbosacral radiculoplexopathy (amyotrophy, proximal neuropathy)
Combinations
 Polyradiculoneuropathy
 Diabetic neuropathic cachexia
Dr Pankaj Patawari

4. COMMON RISK FACTORS
 Duration of Diabetes Mellitus
 4-10% by 5 years / up to 50% by 25 years
 Control of Sugar status
 Smoking and Alcohol consumption
 Tobacco use
 Induces vasoconstriction and nerve ischemia
 Age
 Male gender
 Damage to the blood vessels
 Hyperlipidemia
 Mechanical Injury
 Overweight status
 Genetic susceptibility
Dr Pankaj Patawari

5. Causes/Differential
Distal axonal neuropathies
 Vitamin B12 deficiency
 Monoclonal gammopathies
 Vasculitis
 Infectious causes
 Lymphoproliferative disorders
 Paraneoplastic diseases
Small fiber neuropathies (many of these neuropathies)
 Alcoholism
 HIV
 Monoclonal gammopathy
 Phamacologic or environmental toxins
 Sjogren Syndrome
 Systemic or familial amyloidosis
 Sarcoidosis
 Hereditary sensory neuropathy
 Other inherited neuropathies
Demyelinating neuropathies
 Chronic inflammatory demyelinating polyradiculoneuropathy and other demyelinating neuropathies
Multifocal neuropathy
 Other causes of mono neuropathy multiplex
Radiculopathy and plexopathies
 Sarcoidosis
 Amyloidosis
 Vasculitis
 Neoplastic and paraneoplastic causes

6. Normal pain pathways. Left, The ascending pathway of pain transmission. Messages are
transduced by the peripheral ending of the primary afferent nociceptor and then
transmitted to the spinal cord.
Subsequently, messages are relayed via the thalamus to the frontal cortex and
somatosensory cortex. Right, The descending pathway of pain modulation. Pain
modulating impulses from the frontal cortex and hypothalamus ultimately suppress
spinal pain transmission.

7. THREE TYPES OF PAIN
The proposed etiologies of the different types.
a. Dysesthesia pain - Increases firing of damaged or abnormally excited nociceptive fibers, particularly sprouting
regenerating fibers in the cutaneous tissue.
b. Paresthesia pain - Spontaneous activity and increased mechanosensitivity near the cell body of damaged afferents in the
dorsal root ganglion.
c. Paresthesia pain - Ectopic impulses generated from demyelinated patches of myelinated axons.
d. Muscular pain - Ectopic impulses to the muscle generated from demyelinated patches resulting in muscle spasms and
pain.
e. Paresthesia pain - Loss of large myelinated fibers on the effects of the small unmyelinated fibers (modified gate control
hypothesis). Pain signals are transmitted from the spinal cord pain transmission neuron as a result of the input from the
unmyelinated, myelinated, and inhibitor cells.
f. Paresthesia pain – Increased firing of endings of nociceptive afferents that innervate the nerve sheaths themselves (nervi
nervorum). The endoneurial swelling is secondary to endoneurial sodium accumulation and marked nerve hydration.
g. Muscular pain - Reflex loop (Livingston’s vicious cycle) involving a nociceptive input that activates the motor neuron within
the spinal cord causing muscle spasms that in turn activate the muscle nociceptors and feeds back to the spinal cord to
sustain the spasm.

9. The Consensus Development Conference on Standardized Measures in Diabetic
Neuropathy recommended the following five measures to be employed in the
diagnosis of diabetic neuropathy:
1 clinical measures;
2 morphological and biochemical analyses;
3 electrodiagnostic assessment;
4 quantitative sensory testing;
5 autonomic nervous system testing.
1 Clinical measures
Clinical measures include the following:
1 general medical history and neurological history;
2 neurological examination which consists of:
a sensory (pain, light touch, vibration, position);
b motor (graded as normal = 0, weak = 1–4);
c reflex (present or absent);
d autonomic examination (bedside tests including heart rate variation
during deep breathing and postural blood pressure response).

10. Causes for DSPN other than diabetes and referral for a detailed neurological
work-up -
 pronounced asymmetry of the neurological deficits;
 predominant motor deficits, mononeuropathy, cranial nerve involvement;
 rapid development or progression of the neuropathic impairments;
 progression of the neuropathy despite optimal glycemic control;
 development of symptoms and deficits only in the upper limbs;
 family history of non-diabetic neuropathy;
 diagnosis of DSPN cannot be ascertained by clinical examination.

11. Neurological examination
1-MONOFILAMENT TEST
• Each monofilament is marked with a number that represents the decimal
log of 10 times the force in milligrams ranging from 1.65 (000.45 g) to 6.65
(447 g) of linear
• The thicker (higher the number) the monofilament, the more force is
required to cause the buckle.
• Patients without neuropathy should be able to sense the 3.61
monofilament (equivalent to 0.4 gram of linear force).
• The inability to sense monofilaments of 4.17 (equivalent of 1 gram of linear
pressure) or higher is considered consistent with neuropathy (large fiber
modality).
• Inability to sense a monofilament of 5.07 (equivalent to 10 grams of linear
force) is consistent with severe neuropathy and loss of protective
sensation.

12. 10g (5.07) Semmes-Weinstein monofilament
Test 3 different sites (ADA-4 sites)
duration-2s
Don’t use for the next 24 hours after assessing 10-15 patients and replacing it after
using it on 70-90 patients

13. 2-128 Hz Tuning fork
 Apply the tuning fork perpendicularly, with constant pressure (Figure).
 Repeat this application twice, but alternate this with at least one 'mock'
application in which the tuning fork is not vibrating.
 positive -answers at least two out of three
 negative - two out of three answers are incorrect.
 If the patient is unable to sense the vibrations on the toe, repeat the test more
proximally (e.g., malleolus, tibial tuberosity).
 Biothesiometer
 Sensitivity-80% specificity-98%
 16-25v- normal
 >25-grade 1
 >40-grade II
 Vary according to age,gender.

14. 3 Light touch test
This simple test (also called the Ipswich Touch test) can be used to screen for
loss of protective sensation (LOPS),
 The examiner lightly sequentially touches with the tip of hers/his index
finger the tips of the first, third, and fifth toes of both feet for 1–2 s
 When touching, do not push, tap, or poke
 LOPS is likely when light touch is not sensed in ≥ 2 sites

15. 3-Electrodiagnostic
Differentiate ,localisation of lesion.
Limitations
1 measure only function in the largest, fastest
conducting myelinated fibers;
2 have relatively low specificity in detecting
diabetic neuropathy;
3 show relatively high intra-individual variability
for certain parameters (amplitudes);
4 are vulnerable to external factors such as
electrode locations or limb temperature;
5 provide only indirect information about
symptoms and deficits.

16. 2. Morphological assessment
Sural nerve biopsy
 not routinely used
 Used when in doubt
 Limitation-it may result in complication
Skin biopsy
 3-mm punch skin biopsy at the distal leg and quantifying the linear density
of intra-epidermal nerve fiber in at least three 50-μm thick sections per
biopsy, fixed in 2% PLP or Zamboni’s solution, by bright-field
immunohistochemistry or immunofluorescence with anti-protein gene
product 9.5 antibodies (PGP 9.5)
 Quantification of intra-epidermal nerve fiber density closely correlated
with warm- and heat-pain threshold,
 The diagnostic efficiency and predictive values of this technique were very
high

17. Corneal confocal microscopy (CCM)
A rapid, non-invasive, reproducible technique that quantifies small nerve fibres. two-dimensional
images with a lateral resolution of ~2 mm/pixel and final image size of 400 x 400 pixels of the sub-
basal nerve plexus.
Three corneal nerve parameters quantified:
1) CNFD, the total number of major nerves per square millimetre of corneal tissue (no.mm2
);
2) Corneal nerve branch density (CNBD), the number of branches emanating from all major
nerve trunks per square millimetre of corneal tissue (no.mm2
); and
3) Corneal nerve fibre length (CNFL), the total length of all nerve fibres and branches (mm/mm2
)
within the area of corneal tissue.

18. • DIFFERENT PRESENTATION

19. DISTAL SYMMETRICAL POLYNEUROPATHY
Most common form of diabetic neuropathies.
 Sensory deficits predominate
 Stocking-glove distribution.
 Advanced cases, sensation becomes impaired over the anterior chest and
abdomen, producing a truncal wedge-shaped area of sensory loss.
 Autonomic symptoms usually correlate with the severity of the neuropathy.
 Minor motor involvement affecting the distal muscles of the lower extremities.
2 major subgroups
 large-fiber variant
 small-fiber variant
OTHER VARIANTS-
DIABETIC POLYRADICULONEUROPATHY
 Often begins as a distal symmetrical polyneuropathy
 Later involves proximal segments of the PNS including multiple lumbosacral roots,
thoracic posterior primary rami, and (less commonly) cervical myotomes.

20. LARGE FIBER NEUROPATHY SMALL FIBER NEUROPATHY
often asymptomatic, but sensory deficit
may be detected by careful examination
pain of a deep, burning, stinging, aching
character, spontaneous shooting pains
paresthesias allodynia to light touch,
impairment of vibration and joint position
sense
Pain and temperature modalities are
impaired, with relative preservation of
vibration and joint position sensation
diminished muscle stretch reflexes muscle stretch reflexes preserved
ataxia may develop -

21. .

22. IMPAIRED GLUCOSE TOLERANCE NEUROPATHY
It is now clear that peripheral neuropathy can occur before the onset of clinically
diagnosable diabetes mellitus; this is known as impaired glucose tolerance
neuropathy.
TREATMENT-INDUCED NEUROPATHY
 An acute painful neuropathy (burning pain and paresthesias) develop in the distal
lower extremities
 Precipitated following initiation of treatment of a diabetic patient with insulin.
 Spontaneous resolution to follow.
 Pathological studies demonstrate active axonal regeneration, which may act as
generators of spontaneous nerve impulses.
.

23. DIABETIC NEUROPATHIC CACHEXIA
 Acute and severe painful diabetic neuropathy associated with precipitous
severe weight loss, depression, insomnia, and impotence in men.
 More common in men with poor glucose control.
NEUROPATHIC ARTHROPATHY
 Complication seen in patients with diabetes who often have foot ulcers
and autonomic impairment.
 Tends to involve the small joints in the feet.

24. FOCAL AND ASYMMETRICAL NEUROPATHIES
LIMB MONONEUROPATHY
 Single mononeuropathies are caused by two basic mechanisms:
a) Nerve infarction: abrupt onset of pain followed by variable weakness and
atrophy.
b) Entrapment: more common than nerve infarctions.
 Because the primary pathological lesion results in acute axonal degeneration,
recovery tends to be slow.
 The median, ulnar, and fibular nerves are most commonly affected.
 The reason diabetes predisposes to nerve entrapment is unknown.
CRANIAL MONONEUROPATHIES
 A third nerve palsy is the most common.
 Pupillary sparing, the hallmark of diabetic third-nerve palsy, results from ischemic
infarction of the centrifascicular oculomotor axons due to diabetic vasculopathy of
the vasa nervorum.
 The peripherally located pupillary motor fibers are spared as a result of collateral
circulation from the circumferential arteries.
 With decreasing frequency, the fourth, sixth, and seventh nerves are also affected.

25. TRUNCAL NEUROPATHY
 Involves T4 - T12 spinal nerve roots.
 Causes pain (burning, stabbing, boring, belt like pain ) or dysesthesias in
areas of the chest or abdomen.
 Affecting either the entire dermatomal distribution of adjacent spinal
nerves or, restricted areas limited to the distribution of the dorsal or
ventral rami of spinal nerves.
 Bulging of the abdominal wall as a result of weakness of abdominal
muscles may also occur.
 Contact with clothing can be very unpleasant.
 The onset may be either abrupt or gradual.
 The symptoms may persist for several months before gradual and
spontaneous resolution within 4 to 6 months.
 Focal anhidrosis on the trunk correlating with the area of pain is detected
with the help of the thermoregulatory sweat test.

26. MULTIPLE MONONEUROPATHIES
 Involvement of two or more nerves.
 Onset is abrupt in one nerve, and then other nerves are involved sequentially at
irregular intervals.
 Nerve infarction results from occlusion of the vasa nervorum.
DIABETIC AMYOTROPHY / BRUNS GARLAND SYNDROME
 This is debilitating, painful, asymmetrical motor neuropathy with profound atrophy
of proximal leg muscles.
 Pain usually recedes spontaneously long before motor strength begins to improve.
 Involvement of multiple nerve roots or proximal nerve segments.
 Almost always restricted to the lower limbs. In some patients, additional body
region is also affected, mostly the thoracic occasionally cervical region.
 Although a beneficial effect of immunomodulating therapies has been proposed,
controlled studies have shown no positive effect for corticosteroids in enhancing
the recovery of the motor deficit.
 Recovery takes up to 24 months because of the slow rate of axonal regeneration.

27. Focal neuropathies Diffuse neuropathies
A. Ischemic neuropathies
1. Sudden onset
2. Asymmetrical
3. Ischemic etiology
4. Self-limited
5. Examples
a. Mononeuropathies
b. Femoral neuropathies
c. Radiculopathies
d. Plexopathies
e. Cranial neuropathies
B Entrapment neuropathies
1. Gradual onset
2. Usually asymmetrical but can be bilateral
3. Compression etiology
4. Waxing and waning progressive course without
spontaneous recovery
5. Examples
a. Carpal tunnel syndrome
b. Ulnar entrapment (tennis elbow)
c. Lateral cutaneous femoral nerve entrapment
d. Tarsal tunnel syndrome
A. Insidious onset
B. Symmetrical
C. Abnormalities secondary to vascular, metabolic,
structural,
and autoimmune aberrations
D. Progressive without spontaneous recovery
E. Examples
1. Distal-symmetrical polyneuropathy
2. Autonomic neuropathies

28. TREATMENT
Despite major advances in diabetes treatment in general, to date, there is a
paucity of U.S. Food and Drug Administration–approved therapies that
effectively target reversal of the underlying nerve damage.

29. Attempts to treat diabetic neuropathy by manipulating nerve metabolism
have been disappointing.
 Clinical trials of myoinositol supplementation have shown conflicting
results
 Results of aldose reductase inhibitors have so far failed.
 Neurotrophin treatments for diabetic neuropathy, such as nerve growth
factor, have been disappointing

30. Treatment options for painful diabetic neuropathy.
 Pathogenesis-oriented treatment
Compound
/Measure
Dose per day Remarks NNT (95%
CI)
α-Lipoic acid
(thioctic acid)a
Individual adaptation
600 mg i.v. infusion
600–1800 mg orally
Aim: HbA1c ≤6.5–7%
RCT duration: 3 weeks
FSP; RCT duration: 4 yr
-
6.3b
2.8–4.2b

31. Symptomatic Treatment
Compound /
Measure
Dose per Day Remarks NNT (95% CI)
Tricyclic
antidepressants -
Amitriptyline Initial – 10-25 mg/day
Effective – 25-100 mg/day
NNMH: 15 3.6 (3.0–4.4)c
SNRIs
Duloxetine Initial – 20-30 mg/day
Effective – 60-120 mg/day
Effective dose: 60 mg 6.4 (5.2–8.4)c
α2–δ ligands
Pregabalin
Gabapentin
Initial – 25-75 mg, 1-3*/day
Effective - 300–600 mg/day
Initial – 100-300 mg,
1-3*/day
Effective - 900–3600 mg/day
Dose-dependent
effect
Long titration
7.7 (6.5–9.4)c
7.2 (5.9–9.1)c

32. Adverse Effects
Amitriptyline – Common Adverse Effects
Xerostomia, Somnolence, Fatigue, Headache, Dizziness, Insomnia, Orthostatic hypotension, Anorexia, Nausea,
Urinary retention, Constipation, Blurred vision, Accommodation, Disturbance, Mydriasis, Weight gain.
Major Adverse Effects
Delirium, Cardiac arrhythmias, Conduction abnormalities, Myocardial infarction, Heart failure exacerbation,
Stroke, Seizures, Hepatotoxicity, Bone marrow suppression, Suicidal thoughts and behavior, Shift to mania in
bipolar disorder, Neuroleptic malignant syndrome, Serotonin syndrome, Severe hyponatremia, Fragility bone
fractures .
Duloxetine – Common Adverse Effects
Nausea, Somnolence, Dizziness, Constipation, Dyspepsia, Diarrhea, Xerostomia, Anorexia, Headache,
Diaphoresis, Insomnia, Fatigue, Decreased libido.
Major Adverse Effects
Stevens-Johnson syndrome, Hepatotoxicity, Hypertensive crisis, Gastrointestinal hemorrhage, Delirium,
Myocardial infarction, Cardiac arrhythmias, Glaucoma, Suicidal thoughts and behavior, Shift to mania in
patients with bipolar disorder, Seizures, Severe hyponatremia, Fragility bone fractures, Serotonin syndrome,
Neuroleptic malignant syndrome

33. Pregabaline – Common Adverse Effects
Somnolence, Dizziness, Peripheral edema, Headache, Ataxia, Fatigue, Xerostomia, Weight gain
Major Adverse Effects
Angioedema, Hepatotoxicity, Rhabdomyolysis, Suicidal thoughts and behavior, Seizures after rapid
discontinuation, Thrombocytopenia.
Gabapentine – Common Adverse Effects
Somnolence, Dizziness, Ataxia, Fatigue.
Major Adverse Effects
Stevens-Johnson syndrome, Suicidal thoughts and behavior, Seizures after rapid discontinuation.

35. Non pharmacological treatment
 Psychological support
 Physical measures
 Accupuncture
 Transcutaneous electrical nerve stimulation (TENS)
 External muscle stimulation (high-tone therapy)
 Frequency-modulated electromagnetic nerve stimulation (FREMS)
 Electrical spinal cord stimulation
 Surgical decompression
MOST IMPORTANT OF ALL - “Diabetic Neuropathy is The Presence Of Symptoms And/Or Signs Of
Peripheral Nerve Dysfunction In People With Diabetes After The Exclusion Of Other Causes”
BoultonAJM, Gries FA, Jervell JA: Guidelines for the diagnosis and outpatient management of
diabetic peripheral neuropathy. Diabetic Med 15:508–514, 1998
“Also 10-55% patients with diabetic neuropathies may have other conditions that cause similar
manifestations- CIDP, vitamin B12 deficiency, alcoholic neuropathy etc”
Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, Wilson DM, O'BrienPC, Melton LJ 3rd,
Service FJ. The prevalence by staged severity of various types of diabetic neuropathy,
retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy
Study. Neurology. 1993 Apr;43(4):817-24.

36. AUTONOMIC NUEROPATHY AND ITS PRESENTATION
Diabetic autonomic neuropathy (AN) is among the least acknowledged and interpreted
complications of diabetes despite its substantial negative effect on survival and quality
of life in people with diabetes.

37. Hypoglycaemia unawareness: Though literature has shown negative correlation of AN
with hypoglycaemia unawareness, recent evidence has shown attenuation of
epinephrine release with hypoglycaemia and blunted response and release of plasma
pancreatic polypeptidase in patients with AN
Hypoglycaemic autonomic failure: Attenuation of epinephrine and other counter
regulatory hormones in patients with hypoglycaemia unawareness is defined as
hypoglycaemic autonomic failure. Presence of AN further attenuates this response and
increases the severity of this incidence. The strict glycaemic control aggravates
hypoglycaemic autonomic faillure.
Impaired microvascular blood flow to the skin:
 Microvascular insufficiency results in abnormal contraction of the arterioles and
arteries of the skin.
 Laser Doppler flowmetry is a non-invasive method of assessing the changes in
microvascular blood flow with mental arithmetic, cold pressor, heating, and
handgrip.
 Dry skin leading to fissures and ulcer development helps in further seedling of
infection and gangrene.
 AN also causes increased osteoclastic activity and reduced bone density.

38. .

40. .

41. • Thank you

43. CORNERSTONES OF FOOT ULCER PREVENTION
There are five key elements that underpin efforts to prevent foot ulcers:
1. Identifying the at-risk foot
2. Regularly inspecting and examining the at-risk foot
3. Educating the patient, family and healthcare professionals
4. Ensuring routine wearing of appropriate footwear
5. Treating risk factors for ulceration
1-Identifying the at-risk foot-
History: Previous ulcer/lower extremity amputation, claudication
• Vascular status: palpation of pedal pulses
• Loss of protective sensation (LOPS): assess with one of the following techniques
(see addendum for details):
- Pressure perception: Semmes-Weinstein 10 gram monofilament
- Vibration perception: 128 Hz tuning fork
- When monofilament or tuning fork are not available test tactile sensation: lightly touch the
tips of the toes of the patient with the tip of your index finger for 1–2 seconds

44. 2. Regularly inspecting and examining the at-risk foot (IWGDF risk 1 or higher)
In a person with diabetes with loss of protective sensation or peripheral artery disease (IWGDF
risk 1-3) perform a more comprehensive examination, including the following:
• History: inquiring about previous ulcer/lower extremity amputation, end stage renal disease,
previous foot education, social isolation, poor access to healthcare and financial constraints, foot
pain (with walking or at rest) or numbness, claudication
• Vascular status: palpation of pedal pulses
• Skin: assessing for skin colour, temperature, presence of callus or oedema, pre-ulcerative signs
• Bone/joint: check for deformities (e.g., claw or hammer toes), abnormally large bony prominences,
or limited joint mobility. Examine the feet with the patient both lying down and standing up
• Assessment for loss of protective sensation (LOPS), if on a previous examination protective
sensation was intact
• Footwear: ill-fitting, inadequate, or lack of footwear.
• Poor foot hygiene, e.g. improperly cut toenails, unwashed feet, superficial fungal infection, or unclean
socks
• Physical limitations that may hinder foot self-care (e.g. visual acuity, obesity)
• Foot care knowledge

45. Education-
person in this task. Persons who have substantial visual impairment or physical inability to visualise
their feet cannot adequately do the inspection
• Explain the need to perform daily foot inspection of the entire surface of both feet, including areas
between the toes
• Ensure the patient knows how to notify the appropriate healthcare professional if measured foot
temperature is perceptibly increased, or if a blister, cut, scratch or ulcer has developed
• Review the following practices with the patient:
- Avoid walking barefoot, in socks without footwear, or in thin-soled slippers, whether at home
or outside
- Do not wear shoes that are too tight, have rough edges or uneven seams
- Visually inspect and manually feel inside all shoes before you put them on
- Wear socks/stocking without seams (or with the seams inside out); do not wear tight or kneehigh
socks (compressive stocking should only be prescribed in collaboration with the foot care
team), and change socks daily
- Wash feet daily (with water temperature always below 37°C), and dry them carefully, especially
between the toes
- Do not use any kind of heater or a hot-water bottle to warm feet
- Do not use chemical agents or plasters to remove corns and calluses; see the appropriate