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Diabetic Peripheral neuropathy
Prof. Alaa Abdel-Salam DawoodProf. of Endocrinology and Diabetes
Menofia University
Definition
DPN is defined as the presence ofsymptoms and/or signs of peripheralnerve dysfunction in people with diabetesafter the exclusion of other causes.
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)
Rapidly reversible Hyperglycemic neuropathy
Reversible abnormalities of nervefunction presents with distal sensorysymptoms.
It may occur in patients with recentlydiagnosed or poorly controlled diabetes.
No structural abnormalities, as recoverysoon follows restoration of euglycemia.
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 .
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.
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%).
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.
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) .
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.
DiagnosisElectrophysiologic 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)
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
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
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 .
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
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.
Pathogenetic treatments
aldose reductase inhibitors (ARIs).
α-lipoic acid
Benfotiamine
Gamma linolenic acid
PKC-β inhibitor
Growth factors
Immune therapy
Anti-oxidative stress
Therapies known to reduce oxidative stress aretherefore recommended: aldose reductaseinhibitors (ARIs), α-lipoic acid, benfotiamine
ARIs reduce the flux of glucose through the polyolpathway, inhibiting tissue accumulation of sorbitol andfructose.
Unpleasant side effect limit the use of this group. Epalrestat is approved in Japan
Alpha-Lipoic acid (thioctic acid) has been used for itsantioxidant properties.
A number of studies show its favorable influence onmicrocirculation and reversal of symptoms ofneuropathy. A meta-analysis (1,258 patients) concludedthat 600 mg of i.v., α-Lipoic acid daily significantlyreduced symptoms of neuropathy and improvedneuropathic deficits.
Benfotiamine is a transketolase activator that reduces
tissue AGEs. Several independent pilot studies have
demonstrated its effectiveness in diabetic
polyneuropathy.
Gamma linolenic acid is an important constituent of theneuronal membrane and has shown to preserve nerveblood flow.
Some trials show significant improvement and othersnot.
Protein kinase C (PKC) is activated by hyperglycemiaresulting in increased production of vasoconstrictive,angiogenic, and chemotactic cytokines (TGF-β), VEGF,endothelin (ET-1), and ICAMs).
Ruboxistaurin (a PKC-β inhibitor) showed improvement insymptom scores. Its benefit has not been successfullyimproved in phase III trials.
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
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 .
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.
Diabetic neuropathies: prospects for the future
There are new areas being explored in anattempt to
enhance blood flow via vasa nervorum, such as theprostacyclin analogue beraprost, blockade ofthromboxane A2
drugs that normalize Na/K-ATPase activity, such ascilostazol, a potent phosphodiesterase inhibitor
Gene Therapy
Erythropoietin therapy
C peptide
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
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
Mechanisms of Action and Dosing of the Drugs for Neuropathic Pain
Medication Mechanism of action
Starting dose
Titration Maximum recommended dose
GabapentinoidsGabapentin
Calcium channel a2 -d ligand, which reduces release of presynaptictransmitters
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 presynaptictransmitters
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
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.
GuidelinesAAN [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 theInternational Association for the Study of Pain;NICE, National Institute for Health and Care Excellence.
Special situation
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
Using of Drugs for Neuropathic Pain in special situiation
Medication Dosing in renal impairment Dosing in hepatic impairment
GabapentinoidsGabapentin
Creatinine clearance ≥80 mL/min: maximum dose, 900-3600 mg/d50-79 mL/min: maximum dose, 600-1800 mg/d30-49 mL/min: maximum dose, 300-900 mg/d15-29 mL/min: maximum dose, 150-600 mg/d<15 mL/min: maximum dose, 150-300 mg/dAfter hemodialysis, additionaldose needed
No dosage adjustment required forpatients with hepatic impairment
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/d30-60 mL/min: start with 75 mg, maximum dose, 300 mg/d15-29 mL/min: start with 25 mg, maximum dose, 150 mg/d<15 mL/min: start with 25 mg, maximum dose, 75 mg/dAfter hemodialysis, additionaldose needed
No dosage adjustment required forpatients with hepatic impairment
Sodium channel blockers Carbamazepine
Reduced dose needed in patients with moderate or severe renal impairment
Contraindicated in patients with hepatic impairment
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 somepatients, mostly seen in elderly patients withcardiovascular compromise. Pregabalin should be usedwith caution in these patients. Discontinuation ofpregabalin therapy may resolve the reaction. In addition,use of pregabalin with angiotensin-converting enzymeinhibitors may increase the risk of developing angioedema.
Prevention and treatment of complications
Regular foot inspection daily;
foot protection and ulcer prevention by wearing paddedsocks
selection of proper footwear;
avoidance of sun-heated surfaces, hot bathwater orsleeping with feet in front of heaters.
Nails should be cut transversely and preferably by apodiatrist.
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.
Thank You