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