Ueda 2016 diabetic peripheral neuropathies - alaa abdel salam

1. Diabetic Peripheral neuropathy
Prof. Alaa Abdel-Salam Dawood
Prof. of Endocrinology and Diabetes
Menofia University

2. Definition
DPN is defined as the presence of
symptoms and/or signs of peripheral
nerve dysfunction in people with diabetes
after the exclusion of other causes.

3. ClassificationRapidly reversible
1.Hyperglycemic neuropathy
Generalized symmetric polyneuropathy
1.Acute sensory neuropathy
2.Chronic sensorimotor neuropathy or distal symmetric
polyneuropathy
a.Small-fiber neuropathy
b.Large-fiber neuropathy
3.Autonomic neuropathy
Focal and multifocal neuropathies
1.Focal-limb neuropathy
2.Cranial neuropathy
3.Proximal-motor neuropathy (amyotrophy )
4.Truncal radiculoneuropathy
5.Coexisting chronic inflammatory demyelinating neuropathy
(CIDP)

4. Rapidly reversible
Hyperglycemic neuropathy
 Reversible abnormalities of nerve
function presents with distal sensory
symptoms.
 It may occur in patients with recently
diagnosed or poorly controlled diabetes.
 No structural abnormalities, as recovery
soon follows restoration of euglycemia.

5. Generalized symmetric polyneuropathy
Acute sensory neuropathy
 Acute sensory (painful) neuropathy is characterized by
severe pain, cachexia, weight loss, depression and,
erectile dysfunction.
 It may appear at any time in the course of both type 1 and
type 2 diabetes, associated with poor glycemic control or
after sudden improvement of glycemia and associated
with the onset of insulin therapy (insulin neuritis(.
 It is self-limiting and responds to simple symptomatic
treatment.
 Normal clinical examination, except for allodynia and,
occasionally, reduced ankle reflexes .

6. Acute sensory neuropathy
 Pathology: has not been determined, one hypothesis suggests
that changes in blood glucose flux produces alterations in
epineurial blood flow, leading to ischemia. Other authors
relate this syndrome to diabetic lumbosacral radiculoplexus
neuropathy (DLRPN) and propose an immune mediated
mechanism.
 Management: achieving blood glucose stability. Resolution of
symptoms occurs within one year.

7. Chronic Sensorimotor Neuropathy or Distal
Symmetric Polyneuropathy (DPN)
 DPN is the most common form of the diabetic
neuropathies.
 It is seen in both type 1 and type 2 DM and it may be
already present at the time of diagnosis of type 2 DM.
 Several studies have also suggested that impaired glucose
tolerance (IGT) may lead to polyneuropathy (reporting
rates between 30 and 50%).

8. Chronic Sensorimotor Neuropathy or Distal
Symmetric Polyneuropathy (DPN)
 Sensory symptoms are more prominent than motor and
usually involve the lower limbs.
 These include pain, hyperesthesiae, burning and sharp
stabbing sensations; similar but less severe to those described
in acute sensory neuropathy.
 Numbness in feet and legs leading in time to painless foot
ulcers and subsequent amputations if the neuropathy is not
promptly recognized and treated.
 Unsteadiness: due to abnormal propioception.

9. Chronic Sensorimotor Neuropathy or Distal
Symmetric Polyneuropathy (DPN)
 On physical examination a symmetrical stock and glove
distribution of sensory abnormalities in both lower and upper
limbs is usually seen.
 Deep tendon reflexes may be absent or reduced specially on
the lower extremities.
 Mild muscle wasting may be seen but severe weakness is rare
and should raise the question of a possible non-diabetic
etiology of the neuropathy.
 DPN is frequently accompanied by autonomic neuropathy
(decreased sweating, dry skin, impaired skin blood flow
with cold feet) .

10. Diagnosis
 One or more of the following can be used to assess sensory
function: pinprick, temperature, vibration perception (using
128-Hz tuning fork) and 10-g monofilament pressure test.

11. Diagnosis
Electrophysiologic measures (NCV):
 Electrophysiological studies play a key role in ruling out
other causes of neuropathy and are essential for the
identification of focal and multifocal neuropathies .
 There is evidence that small, unmyelinated fibers are not
diagnosed by routine NCV studies.
 Skin biopsy enables a direct study of small fibers, which
cannot be evaluated by NCV studies.
 Though minimally invasive (3-mm diameter punch
biopsies)

12. Loss of cutaneous nerve fibers that stain
positive for the neuronal antigen protein
gene product 9.5 (PGP 9.5) in metabolic
syndrome and diabetes

13. Multiple Metabolic Pathways may
Contribute to Diabetic Polyneuropathy
Boulton AJM, et al. Diabetes Care. 2004;27:1548–1586.
Diabetes
Hyperglycemia
Polyol pathway Glycation Oxidative stressPKCß
Diabetic neuropathy
Direct neurotoxicity Vasculopathy/ischemia

14. Treatment
Treatment of DN should be targeted towards a
number of different aspects:
 Treatment of specific underlying pathogenic
mechanisms;
 Treatment of symptoms and improvement in
QOL;
 Prevention of progression and complications
of neuropathy .

15. Pathopyshiology
 Microangiopathy,
 Increased polyol flux through the aldose reductase pathway
 Abnormal signaling from advanced glycation endproducts,
 Deficient neuronal growth factors
 Increased oxidative stress targeting neuronal mitochondria.
 Immune mechanism and genetic susceptibility

16. Control of hyperglycemia and metabolic
abnormalities
 The Diabetes Control and Complication Trial (DCCT) research
group reported that clinical and electrophysiological evidence of
neuropathy was reduced by 50% in those treated intensively
with insulin.
 In the UK Prospective Diabetes Study (UKPDS), control of
blood glucose was associated with improvement in vibration
perception.
 The EURODIAB, a prospective study that included 3,250
patients across Europe, has shown that the treatment of
neuropathy should include measures to reduce macrovascular
risk factors, including hyperglycemia, blood pressure and lipid
control and lifestyle modifications including exercise and weight
reduction, smoking cessation, and avoidance of excess alcohol
consumption.

17. Pathogenetic treatments
 aldose reductase inhibitors (ARIs).
 α-lipoic acid
 Benfotiamine
 Gamma linolenic acid
 PKC-β inhibitor
 Growth factors
 Immune therapy

18. Anti-oxidative stress
 Therapies known to reduce oxidative stress are
therefore recommended: aldose reductase
inhibitors (ARIs), α-lipoic acid, benfotiamine

19.  ARIs reduce the flux of glucose through the polyol
pathway, inhibiting tissue accumulation of sorbitol and
fructose.
 Unpleasant side effect limit the use of this group.
 Epalrestat is approved in Japan

20.  Alpha-Lipoic acid (thioctic acid) has been used for its
antioxidant properties.
 A number of studies show its favorable influence on
microcirculation and reversal of symptoms of
neuropathy. A meta-analysis (1,258 patients) concluded
that 600 mg of i.v., α-Lipoic acid daily significantly
reduced symptoms of neuropathy and improved
neuropathic deficits.
Benfotiamine is a transketolase activator that reduces
tissue AGEs. Several independent pilot studies have
demonstrated its effectiveness in diabetic
polyneuropathy.

21.  Gamma linolenic acid is an important constituent of the
neuronal membrane and has shown to preserve nerve
blood flow.
 Some trials show significant improvement and others
not.
 Protein kinase C (PKC) is activated by hyperglycemia
resulting in increased production of vasoconstrictive,
angiogenic, and chemotactic cytokines (TGF-β), VEGF,
endothelin (ET-1), and ICAMs).
Ruboxistaurin (a PKC-β inhibitor) showed improvement in
symptom scores. Its benefit has not been successfully
improved in phase III trials.

22.  There is increasing evidence that there is a deficiency of
nerve growth factor (NGF) in diabetes, as well as the
dependent neuropeptides substance P (SP) and
calcitonin gene-related peptide (CGRP).
 Clinical trials with NGF have not been successful.
Growth factor

23. Immune therapy
 It was reported a 12% incidence of a predominantly
motor form of neuropathy in patients with diabetes
associated with monosialoganglioside antibodies (anti
GM1 antibodies).
 Some data support a predictive role of the presence of
antineuronal antibodies on the later development of
neuropathy. There may be selected cases, particularly
those with autonomic neuropathy, evidence of
antineuronal autoimmunity that may benefit from
intravenous immunoglobulin or large dose steroids .

24. Hyperbaric oxygen
Its use is still debatable as the pathogenesis in diabetic
foot is impaired oxygen delivery to the tissue, so this
therapy might be effective in neuropathy by promoting
oxygen delivery from plasma to the affected tissues.

25. Diabetic neuropathies:
prospects for the future
 There are new areas being explored in an
attempt to
 enhance blood flow via vasa nervorum, such as the
prostacyclin analogue beraprost, blockade of
thromboxane A2
 drugs that normalize Na/K-ATPase activity, such as
cilostazol, a potent phosphodiesterase inhibitor
 Gene Therapy
 Erythropoietin therapy
 C peptide

26. Treatment of symptoms and
improvement in quality of life
-Tricyclic agents (TCAs)
-Serotonin–norepinephrine reuptake inhibitors
(SNRIs)
-γ-aminobutyric acid (GABA) analogues (gabapentin
or pregabalin)
-Sodium channel blocker: carbamazepine
-Opioids
-Topical treatments

27. Mechanisms of Action and Dosing of the Drugs for
Neuropathic Pain
Medication Mechanism of
action
Starting
dose
Titration Maximum
recommended
dose
TCAs
Nortriptyline and
desipramine
(amitriptyline, and
imipramine)
Serotonin and
noradrenalin
reuptake inhibition,
sodium channel
block, N-methyl- d-
aspartate receptor
antagonist
10-25 mg
at bedtime
Increase by
10-25 mg
every 3-7 d as
tolerated
150 mg/d;
further titration
guided by blood
concentration of
the drug and its
active metabolite
SNRIs
Duloxetine
Serotonin and
noradrenalin
reuptake inhibition
30 mg
once daily
Increase to 60
mg once daily
after 1 wk
120 mg/d

28. Mechanisms of Action and Dosing of the Drugs for
Neuropathic Pain
Medication Mechanism of
action
Starting
dose
Titration Maximum
recommended
dose
Gabapentinoids
Gabapentin
Calcium channel a2
-d ligand, which
reduces release of
presynaptic
transmitters
100-300
mg at
bedtime
Increase by
100-300 mg 3
times daily
every 1-7 d. as
tolerated
3600 mg/d
(divided into 3
doses)
Pregabalin Calcium channel a2
-d ligand, which
reduces release of
presynaptic
transmitters
75 mg
twice daily
Increase to
300 mg/d after
3-7 d, then by
150 mg/d
every 3-7 d as
tolerated
600 mg/d
(divided into 2-3
doses)
Sodium channel
blockers
Carbamazepine
Sodium channel
block
100 mg
twice daily
Increase by
100 mg twice
daily every 3-
7 d as
tolerated
1200 mg/d;
further titration
guided by blood
concentration of
the drug

29. Analgesics, topical
 Lidocaine
 Capsaicin cream (Natural chemical derived
from plants of Solanaceae family. By depleting
and preventing reaccumulation of substance P in
peripheral sensory neurons, may render skin and
joints insensitive to pain. Substance P thought to
be chemomediator of pain transmission from
periphery to CNS.

30. Guidelines
AAN [2011] NICE
[2013]
EFNS
[2010]
NeuPSIG
IASP
[2010]
TCAs Second line First line First line First line
SNRIs Second line First line First line First line
GABA
analogues
First line First line First line First line
Tramadol Second line
AAN, American Academy of Neurology;
EFNS, European Federation of Neurological Societies;
NeuPSIG IASP, Neuropathic Pain Special Interest Group of the
International Association for the Study of Pain;
NICE, National Institute for Health and Care Excellence.

31. Special situation

32. Using of Drugs for Neuropathic Pain in special situation
Medication Dosing in renal impairment Dosing in hepatic
impairment
TCAs
Nortriptyline and
desipramine
(amitriptyline, and
imipramine)
Reduced dose and slow titration
recommended; titration guided by
blood concentration of the drug and
its active metabolite
Pharmacokinetics
depends on hepatic
blood flow; caution
should be exercised when
dosing in patients with
hepatic impairment
SNRIs
Duloxetine
No dosage adjustment needed for
patients with creatinine clearance of
30-80 mL/min; contraindicated for
patients with creatinine clearance
<30 mL/min
Not be used in patients
with hepatic impairment

33. Using of Drugs for Neuropathic Pain in special situiation
Medication Dosing in renal impairment Dosing in hepatic
impairment
Gabapentinoids
Gabapentin
Creatinine clearance
≥80 mL/min: maximum dose, 900-
3600 mg/d
50-79 mL/min: maximum dose, 600-
1800 mg/d
30-49 mL/min: maximum dose, 300-
900 mg/d
15-29 mL/min: maximum dose, 150-
600 mg/d
<15 mL/min: maximum dose, 150-
300 mg/d
After hemodialysis, additional
dose needed
No dosage
adjustment required
for
patients with hepatic
impairment

34. Using of Drugs for Neuropathic Pain in special situation
Medication Dosing in renal impairment Dosing in hepatic
impairment
Pregabalin Creatinine clearance
≥60 mL/min: start with 150 mg,
maximum dose, 600 mg/d
30-60 mL/min: start with 75 mg,
maximum dose, 300 mg/d
15-29 mL/min: start with 25 mg,
maximum dose, 150 mg/d
<15 mL/min: start with 25 mg,
maximum dose, 75 mg/d
After hemodialysis, additional
dose needed
No dosage adjustment
required for
patients with hepatic
impairment
Sodium channel
blockers
Carbamazepine
Reduced dose needed in patients with
moderate or severe renal impairment
Contraindicated in
patients with hepatic
impairment

35. Cardiac patients
 TCA: orthostatic hypotension, arrhythmias.
 Duloxetine is associated with an increase in BP. This may
be due to the noradrenergic effect of duloxetine.
Therefore, in patients with known hypertension, BP
monitoring is recommended, especially during the first
month of treatment.
 Pregabalin: Reported congestive heart failure in some
patients, mostly seen in elderly patients with
cardiovascular compromise. Pregabalin should be used
with caution in these patients. Discontinuation of
pregabalin therapy may resolve the reaction. In addition,
use of pregabalin with angiotensin-converting enzyme
inhibitors may increase the risk of developing angioedema.

36. Prevention and treatment of
complications
 Regular foot inspection daily;
 foot protection and ulcer prevention by wearing padded
socks
 selection of proper footwear;
 avoidance of sun-heated surfaces, hot bathwater or
sleeping with feet in front of heaters.
 Nails should be cut transversely and preferably by a
podiatrist.

37. SUMMARY
 PDN is common and is associated with significant
impairment in the quality of life of diabetic patients.
 Despite its high burden, it remains underdiagnosed and
undertreated.
 Whilst a number of treatment which repairs nerves exist,
none are satisfactory.
 Various symptomatic treatments have been proposed to
manage neuropathic pain but few have been found to be
effective.

38. Thank You