Diabetic Neuropathy: Current Concepts - medIND

Introduction 

* Senior Resident 

** Professor 

Department of Endocrinology and 

Metabolism, Institute of Medical Sciences, 

Banaras Hindu University, 

Varanasi – 221005. 

REVIEW ARTICLE 

Diabetic Neuropathy: Current Concepts 

Neuropathy, a common complication of diabetes 

mellitus, is generally considered to be related to 

duration and severity of hyperglycaemia. However, 

it may also occur acutely even with 

hypoglycaemia 1-3 . Usually more than 50% of 

patients with duration of diabetes of 25 years or 

more are affected, making it as one of the most 

common disease of the nervous system 4 . One of 

the largest published series reported a prevalence 

of 7.5% even at the time of diagnosis of diabetes 4 . 

The prevalence however, increases progressively 

without a plateau. 

Definition 

Diabetic neuropathy has been defined as presence 

of symptoms and/or signs of peripheral nerve 

dysfunction in diabetics after exclusion of other 

causes, which may range from hereditary, 

traumatic, compressive, metabolic, toxic, 

nutritional, infectious, immune mediated, 

neoplastic, and secondary to other systemic 

illnesses. Since the manifestations of diabetic 

neuropathy closely mimic chronic inflammatory 

demyelinating polyneuropathy, alcoholic 

neuropathy, and other endocrine neuropathies, 

hence, before labelling diabetic neuropathy it is 

mandatory to exclude all other causes of 

peripheral nerve dysfunction. 

Classification of diabetic neuropathy 

Since the precise aetiopathogenesis of diabetic 

neuropathy is not well defined, it is difficult to 

classify. However, Boulton and Ward (1986) 5 

SK Bhadada*, RK Sahay*, VP Jyotsna*, JK Agrawal** 

originally proposed a purely clinical and 

descriptive classification. Subsequently, Thomas 6 

gave a simple classification based on anatomical 

characteristics, which is now widely accepted 

(Table-I). 

Table I : Classification of diabetic neuropathy. 

A. Diffuse 

1. Distal symmetric sensori-motor polyneuropathy 

2. Autonomic neuropathy 

a. Sudomotor 

b. Cardiovascular 

c. Gastrointestinal 

d. Genitourinary 

3. Symmetric proximal lower limb motor 

neuropathy (amyotrophy) 

B. Focal 

1. Cranial neuropathy 

2. Radiculopathy/plexopathy 

3. Entrapment neuropathy 

4. Asymmetric lower limb motor neuropathy 

(amyotrophy) 

Clinical characteristics 

1. Distal symmetrical sensori-motor 

polyneuropathy: 

It is the most common type of diabetic neuropathy. 

It involves both small and large fibres and has 

insidious onset. Typically, the most distal parts of 

the extremities are affected first, resulting in a 

stocking pattern of sensory loss 7 . As the sensory 

symptoms advance above the knees, the distal 

upper limbs and later the anterior aspect of trunk 

and subsequently the vertex of the head gets 

involved. 

It is predominantly sensory neuropathy, with 

autonomic involvement which is usually subclinical. 

Clinically apparent motor deficit develops only in

are cases. Its symptoms are extremely variable, 

ranging from severely painful symptoms at one 

extreme to the completely painless variety, which 

may present with an insensitive foot ulcer at the 

other end. The neuropathic symptoms may be 

positive or negative. The negative symptoms are - 

numbness and deadness in the lower limbs while 

the positive symptoms most commonly include 

burning pain, altered and uncomfortable 

temperature perception, paraesthesia, shooting, 

stabbing and lancinating pain, hyperaesthesia and 

allodynia. The feet and legs are most commonly 

affected, rarely less severe similar symptoms are 

experienced in the upper limbs also. 

The sensory symptoms and signs are more 

common than motor symptoms and signs. 

Common motor signs are absent or reduced ankle 

reflex, and minimal distal muscle weakness. Motor 

involvement results in foot deformity. This 

abnormality redistributes weight bearing and leads 

to callus and ulcer formation. The proprioceptive 

loss makes the gait more unsteady and there is a 

sense of walking on cotton wool. 

Acute painful neuropathy is a distinct variant of 

distal sensory neuropathy 8 , presenting acutely with 

severe sensory symptoms with few sensory or 

motor signs and often it follows a period of flux in 

glycaemic control. 

2. Autonomic neuropathy 

Autonomic neuropathy is a serious and often overlooked 

component of diabetic neuropathy. Any 

organ of body which is supplied by autonomic 

nerves can be affected. Studies have confirmed 

the presence of parasympathetic dysfuction in 65% 

of the type 2 diabetic patients 10 years after 

diagnosis and of combined parasympathetic and 

sympathetic neuropathy in 15.2% 9 . Autonomic 

neuropathy is not simply an “all or none” 

phenomenon and its symptoms range from minor 

to severe. The severe form may affect survival and 

can cause sudden death. Among autonomic 

neuropathic symptoms gustatory sweating is most 

common, followed by postural hypotension and 

diarrhoea 10 . Loss of sweating in the feet, sexual 

dysfunction, bladder abnormalities, and 

gastroparesis may also occur (Table II). 

Table II : Symptoms and signs of autonomic 

neuropathy. 

1. Cardiovascular 

Postural hypotension 

Resting tachycardia 

Painless myocardial infarction 

Sudden death (with or without association 

with general anaesthesia) 

Prolonged QT interval 

2. Gastrointestinal 

Oesophageal motor incoordination 

Gastric dysrhythmia, hypomotility 

(gastroparesis diabeticorum) 

Pylorospasm. 

Uncoordinated intestinal motility (diabetic 

diarrhoea, spasm) 

Intestinal hypomotility (constipation) 

Gallbladder hypocontraction (diabetic 

cholecystopathy) 

Anorectal dysfunction (faecal incontinence) 

3. Genitourinary 

Diabetic cystopathy (impaired bladder 

sensation, atonic bladder, post micturition 

dribbling, detrusor hyporeflexia or 

hyperreflexia) 

Male impotence 

Ejaculatory disorders 

Reduced vaginal lubrication, dyspareunia 

4. Respiratory 

Impaired breathing control (?) 

Sleep apnoea ? 

5. Thermoregulatory 

Sudomotor 

Vasomotor 

6. Pupillary 

Miosis 

Disturbances of dilatation 

Argyll Robertson pupil 

306 Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December 2001

3. Proximal motor neuropathy 

It typically affects the elderly males (> 50 year) 

suffering from type 2 diabetes mellitus but it can 

also occur in females and type 1 diabetes mellitus. 

It may be symmetrical or asymmetrical, and with 

or without sensory loss. Patient usually presents 

with difficulty in getting up from squatting position, 

pain in climbing stairs and marked weight loss 

(sometimes upto 40% of original weight). It 

predominantly affects anterior (quadriceps) and 

adductor compartments of thigh. Wasting and 

weakness of quadriceps is so severe that the knee 

often gives way, and patient may fall. This has 

been labelled as diabetic amyotrophy also. 

The cause of diabetic amyotrophy is unknown but 

neurological deficit and anatomical distribution 

suggest nerve root involvement presumably due 

to occlusion of the vasa nervosum and infarction. 

Examination shows wasting and weakness of the 

anterior and adductor compartments of thigh. The 

knee jerk is absent, while the ankle jerk may be 

intact. Sometimes, other muscles, especially the 

anterior tibial and peroneal muscles may also be 

involved 11 . 

4. Focal neuropathies or mono-neuropathies 

The diabetic patients are also susceptible to a 

variety of asymmetric and focal neuropathies. 

a. Cranial Neuropathy : The third, fourth, and 

sixth cranial nerves are commonly involved 12 . 

Elderly patients are the most affected. The third 

cranial nerve palsy presents with eye pain, 

diplopia, and ptosis but pupillary response to light 

is usually spared 1 . The pupillary sparing favours 

vascular aetiology of IIIrd nerve palsy. Exclusion 

of other causes of IIIrd nerve palsy is necessary 

before labelling diabetes as a cause. Spontaneous 

recovery generally occurs within 6-12 weeks, 

although recurrent or bilateral lesion may also 

occur 2 . 

b. Truncal Neuropathy : Symptomatic truncal 

polyneuropathy though less common, tends to 

occur in the setting of long standing diabetes with 

other microvascular complications especially 

peripheral neuropathy. Most of the affected 

individuals are in the 5th or 6th decade of life, 

with a variable duration of diabetes 12 . It usually 

presents with gradual onset of pain and 

dysaesthesia in the lower anterior chest or upper 

abdomen with nocturnal intensification. On 

examination, hypoaesthesia or hyperaesthesia 

may be present in the appropriate thoracic 

segment and abdominal muscle weakness leading 

to abdominal swelling 13 . A careful sensory 

examination of abdomen and thorax is mandatory 

in a diabetic person presenting with unexplained 

thoracoabdominal pain. It resolves, spontaneously 

within 2 to 6 months. 

c. Entrapment neuropathy : Also known as 

pressure palsy, this is relatively uncommon. Median 

nerve is mostly affected and is secondary to soft 

tissue changes associated with limited joint 

mobility. Occasionally ulnar or lateral cutaneous 

nerve of thigh may also be affected. 

Pathogenesis of diabetic neuropathy 

The precise pathogenesis of diabetic peripheral 

neuropathy despite recent advances remains 

obscure; however, consensus is that neuropathy 

in diabetes mellitus is a multifactorial disease 14 . 

The possible aetiologic factors suggested include, 

hyperglycaemia, polyol pathway, non-enzymatic 

glycation, free radical and oxidative stress. 

Available evidence suggests that these various 

pathogenetic factors act synergistically 15 . Many of 

these hypotheses are based on studies of different 

animal models of diabetes, but none of these truly 

reproduce the changes as seen in diabetic 

neuropathies in humans 16 . Generally the nerve 

involvement has been correlated with glycaemic 

control, hyperglycaemia induced metabolic 

derangements and neurophysiological alterations, 

serum lipid changes, vascular coagulation, and 

thrombotic abnormalities 2 . 

a. Hyperglycaemia and polyol pathway 

Long-standing hyperglycaemia is the main 

culprit in the development of diabetic 

neuropathy. This has been shown in the results 

Journal, Indian Academy of Clinical Medicine Vol. 2, No. 4 October-December 2001 307

of the Diabetes Control and Complications 

Trial (DCCT) 17 . This randomised prospective 

study showed significant reduction in the 

development and progression of clinical 

neuropathy (64%), motor conduction velocity 

(44%), and autonomic dysfunction (53%) in 

type-1 diabetics with optimal glycaemic 

control 18 . 

The glucose uptake into peripheral nerve is 

insulin independent, therefore it is 

proportionate to ambient blood glucose 

concentration. The rate-limiting enzyme for 

polyol pathway is aldose reductase, which is 

expressed on Schwann cells. Excess glucose is 

shunted into the polyol pathway and is 

converted to sorbitol and fructose by the 

enzymes aldose reductase and sorbitol 

dehydrogenase respectively 14 . The nerve cell 

membrane is relatively impermeable to sorbitol 

and fructose, which tend to accumulate within 

the nerve 19 . Fructose and sorbitol both being 

osmotically active compounds lead to increase 

in the water content in the nerves. Further the 

oxidation/reduction status of the cell is altered 

with loss of reduced nicotinamide-adenine 

dinucleotide phosphate (NADPH) and 

glutathione stores. It leads to a cascade of 

events like a reduced membrane Na- K ATPase 

activity, intra-axonal sodium accumulation 

which reduces nerve conduction velocity and 

brings about structural breakdown of the 

nerve 14 (Fig. 1). Myoinositol level is decreased 

because elevated levels of both glucose and 

sorbitol compete for the uptake of myoinositol 

in the tissues and cells 20 . Moreover, reduced 

NADPH, a cofactor for the enzyme nitric oxide 

synthase, reduces nitric oxide formation 

leading to decreased vasodilatation, that 

impairs blood supply to the nerve 21 . 

Polyol pathway although appears to be a 

plausible cause for diabetic neuropathy, has 

many pit falls such as (a) the absence of 

morphological changes in diabetic neuropathy 

in humans as compared to animal models 22 , 

(b) an increase, but not decrease, of Na + K + - 

Fig. 1: 

ATPase in the peripheral nerve of 

galactosaemic animals despite a reduction in 

the myo-inositol level 23 , (c) the lack of a 

convincingly demonstrable reduced level of 

myo-inositol in human nerve, and the failure 

of dietary myo-inositol supplementation to 

improve neuropathy in humans 24 , (d) the lack 

of unequivocal improvement from the use of 

a variety of aldose reductase inhibitors 25 . 

b. Advanced glycation end products (AGE) 

In the presence of hyperglycaemia, glucose can 

be incorporated non-enzymatically into 

proteins by an unregulated glycation reaction. 

Patient with normal blood sugar are protected 

by the tight control of blood glucose within 

normal limits. This glycation reaction occurs 

in two steps for formation of HbA 1C . In the first 

step there is formation of PreA 1C the Schiff base; 

it is a rapid and reversible reaction. Second 

step is a slow and irreversible step with the 

formation of HbA 1C , which is a ketoamine.If 

plasma glucose is normal for a week, levels of 

glycated serum proteins decrease by 

approximately 40% while HbA 1C drops by only 

10% 26 . 

The HbA 1C formation is an example of 

glycation of proteins. Like haemoglobin A, 


other body proteins such as plasma albumin, 

lipoproteins, fibrin, collagen, and glycoprotein 

recognition systems of hepatic endothelial cells 

may also undergo non-enzymatic glycation. 

The glycation of proteins alters or impairs their 

function, e.g., glycated LDL is not recognised 

by the normal LDL receptor, and its plasma 

half life is increased. Conversely glycated HDL 

turns over more rapidly than native HDL. 

Glycated collagen is less soluble and more 

resistant to degradation by collagenase than 

native collagen. 

Non-enzymatically glycated proteins slowly 

form fluoroscent cross-linked protein products 

called advanced glycation end products 

(AGEs). AGEs formation is accelerated by high 

ambient glucose concentration and by age. 

Patients with long standing diabetes have levels 

at least twice those of normal subjects 27 . The 

rate of glycation with fructose is seven or eight 

times than that with glucose. The glycation of 

myelin protein may contribute to the 

impairment of nerve conduction 28 . These 

advanced glycation end products are also 

present in peripheral nerves 29 which could 

interfere with axonal transports. 

AGES are also believed to cause tissue damage 

because of their reactivity and protein cross 

linking. Receptors for AGE proteins are 

expressed on endothelial cells, fibroblast, 

mesangial cells, and macrophages 30 . A 

macrophage monocyte receptor for AGE 

mediates the uptake of AGE modified proteins 

and the release of TNFα,IL-1, IGF-1, platelet 

derived growth factor 30 . Endothelial cell has 

AGE receptors which internalises AGE to the 

subepithelium, thereby enhancing permeability 

and endothelium dependent coagulant activity. 

AGE also produce alteration in RBC and 

lipoproteins. 

c. Miscellaneous 

i. Free radical and oxidative stress 

Oxygen free radicals could damage nerve by 

direct toxic effects or perhaps by inhibiting nitric 

oxide (NO) production by the endothelium, 

thereby reducing nerve blood flow. In diabetic 

tissues, free radical generation is enhanced 

by the processes of non-enzymatic glycation 

and polyol pathway, while the ability to 

neutralise free radicals is reduced because 

NADPH is consumed through increased activity 

of aldose reducatse 31 . 

ii. Biochemical abnormalities 

Levels of gamma-linolenic acid (GLA) in nerves 

are reduced, because insulin deficiency and 

hyperglycaemia inhibit the activity of d-6desaturase 

enzyme which governs its 

conversion from linoleic acid. GLA is precursor 

of prostanoids, including potent vasodilator, 

prostacyclin, and its deficiency has been 

implicated in the reduced blood flow of 

diabetic nerves. Supplementation of GLA 

decreases rate of deterioration in nerve 

conduction velocity 32 . Moreover, there is 

depletion of carnitine in diabetic nerves. The 

carnitine deficiency could impair ATP 

production. Administration of acetyl-L-carnitine 

to diabetic rats improves various indices of 

peripheral nerve function. 

iii. Vascular and haemorrheological 

abnormalities 

The endoneural vessels get blocked because of 

hyperplasia and swelling of endothelial cells, 

thickening of vessel wall with debris from 

degenerative pericytes as well as basement 

membrane material, and occlusion of the 

capillary lumen by fibrin or aggregated 

platelets 33 . Further various defects in nerve nitric 

oxide (NO) production, increased “quenching” 

of NO by AGE in the vessel wall, deficiency of 

prostacyclin and increased endothelial 

production of potent vasoconstrictor peptide, 

endothelin – 1 are responsible for increased 

vasoconstriction which in turn causes central 

nerve ischaemia. Glycosylation of RBC 

membrane occurs and that decreases 

malleability of RBC and impairs microcirculation. 


iv. Defects in nerve regeneration 

Peripheral nerves have abundant receptors for 

nerve growth factor (NGF). NGF is responsible 

for regeneration of nerves. Circulating NGF 

concentration is reduced in diabetic patients 

with neuropathy 34 . Treatment with NGF has 

improved peripheral nerve function. Insulin like 

growth factor and neurotrophin – 3 also helps 

in regeneration of nerves. 

Thus regardless of the exact pathogenesis of 

diabetic neuropathy, it is now clear that chronic 

hyperglycaemia has a pivotal role in the 

pathogenesis of diabetic neuropathy. The 

earliest effects of hyperglycaemia are generally 

metabolic while electrophysiologic and 

morphological changes are considered to be 

a late occurrence. Intensive control of blood 

sugar reduces the occurrence of clinical 

neuropathy. However, once diabetic 

neuropathy is established, significant recovery 

usually does not occur, even with good 

glycaemic control. 

Diagnosis of diabetic neuropathy (DN) 

The diagnosis of DN can be made on clinical 

examination but subsequently it needs to be 

confirmed by investigations (non-invasive/ 

invasive). The diagnosis of DN in time is very 

important because effective intervention will be 

possible only during the subclinical or early phase 

of dysfunction. There are two approaches for 

diagnosis of DN (i) Traditional (ii) Newer. 

A. Traditional approaches 

1. Clinical examination : The traditional 

approach to diagnose DN, requires careful 

clinical assessment of “Signs” of sensory, motor, 

and autonomic function deterioration. Clinical 

examination yields a “valid” index of DN quickly, 

but inter-examiner variability limits the 

reproducibility and reliability of test results 35 . 

2. Test of sensory function : In-depth sensory 

examination is required because routine 

clinical examination will only detect 

abnormalities at a relatively advanced stage 

and selective involvement of fibre is not rare. 

Patient co-operation is mandatory for clinical 

examination. 

a. Vibration perception threshold (VPT) : It is 

usually assessed by 128 Hz tuning fork. Only 

large fibres are assessed by the test. Vibration 

perception is usually assessed at the tip of great 

toe or over lateral malleolus. Nowadays more 

sophisticated instruments are available for 

assessment of vibration perception threshold, 

e.g., biosthesiometer, vibrameter. 

Biosthesiometer uses an electromagnet to 

activate a spring loaded stimulator, according 

to an arbitrary scale from 0-50 volts. The risk 

of foot ulceration is increased 3-4 fold if the 

vibration perception threshold exceeds 25 

volts. Vibrameter is also based on the principle 

of biosthesiometer but results are given directly 

in mm of probe displacement. 

b. Light touch sensation : These sensations are 

carried by large myelinated Aα and Aβ fibres. 

Nylon Semmes Weintein mono-filaments are 

used for light touch assessment. A series of 

increasingly thick filaments are tested, and the 

threshold at which the first one can be felt when 

buckling is noted. The inability to feel the 10 

gm filament indicate that patient is prone to 

foot ulceration. 

c. Thermal thresholds : Warm and cold 

sensations should be tested separately. The 

former is mediated by the smallest 

unmyelinated C fibres and the latter by small 

myelinated Aδ fibres. The equipment used for 

thermal threshold assessment are expensive 

and mostly used for research purposes. Pain 

threshold can be determined either by 

application of high or low temperature or by 

using the “Pinchometer” or a series of weighted 

needles. 

d. Tests for autonomic function : Bedside 

cardiovascular tests have been developed to 

evaluate cardiovascular autonomic neuropathy 

(table-III) 36 . These tests are extremely sensitive 


and as many as one fifth of all diabetic patients 

have one or more abnormalities while very few 

suffer from symptomatic autonomic 

neuropathy, when non-specific symptoms such 

as diarrhoea or gastroparesis occur, autonomic 

tests must be abnormal. Other autonomic 

functions like blood pressure response to 

sustained hand grip and pupillary function 

require more sophisticated equipment and are 

mostly used as research tools rather than in 

routine clinical practice. 

e. Electrophysiology : Standard elctrophysiologic 

methods have also been used 

extensively to diagnose and follow the 

progression of DN 37 . Electrophysiology, 

particularly conduction velocity alone, may 

provide a poor measure of early dysfunction 

in some patients, because there is little 

demyelination in the early stages 38 . Although 

response amplitude can be correlated with 

density in a population, the onset of change 

in their measure may not be apparent in 

individual patients because of the considerable 

variability in amplitude measure. 

B. New approaches to the diagnosis of 

diabetic neuropathy 

1. Skin punch biopsy and immunohistochemical 

staining : Skin punch biopsy 

specimens (3-4 mm in diameter) obtained with 

the patient under local lidocaine anaesthesia 

under aseptic technique 39 is fixed in formalin, 

cut into 50 mm frozen sections and processed 

for immuno-histochemistry using commercially 

available polyclonal antibodies directed 

against human protein gene product 9.5. By 

this fibre density can be readily quantified, with 

reported interobserver agreement as high as 

96% 40 . 

Lindberger et al 41 has reported that levels of 

both substance P and calcitonin gene related 

peptide (CGRP) are reduced in skin biopsies 

from diabetic patients before clinical or 

neurophysiologic evidence of neuropathy. Levy 

et al 42 showed that there was a progressive 

loss in the number and area innervated by 

CGRP positive nerve fibres when normal 

subjects were compared with diabetic patients 

with clinical evidence of neuropathy. 

The combination of skin punch biopsy and 

immuno staining with specific antibodies has 

the advantage of minimal trauma to the 

patient, reliability, quantifiability, and a 

demonstrable correlation with clinically defined 

disease severity. 

The classical skin punch biopsy is more useful 

in diabetes because classic insult in diabetic 

somatic neuropathy is dying back of axons. 

This distal to proximal gradient of axonal 

pathology can be better evaluated by 

examination of multiple biopsies. Currently, 

few centres have direct experience with this 

procedure, so available data are less. 

2. Quantitative sensory testing (QST) : It 

facilitates early diagnosis and accurate 

assessment of diabetic neuropathy. In QST, 

standardised sensory testing instruments are 

used to control and deliver specific stimuli at 

designated intensities to test sensory thresholds. 

It is defined as the minimum stimulus energy 

detectable 50% of the time. 

Quantitative sensory testing can be measured 

by i) Computer assisted sensory evaluation 

(Case IV). ii) Physitemp NTE-2a thermal tester. 

iii) Tactile circumferential discriminator. 

QST provides a parametric measure of 

sensory function that can target axons of 

specific fibre diameter. Abnormalities in QST 

reflect axonal pathology or alteration in 

sensory transduction. The latter effect may 

be of interest because recent results show 

that abnormalities in distal peptide 

neurotransmitter levels may occur in 

peripheral nerve fibres of diabetic patients 

before axonal loss is detectable 43 . Davis et 

al 44 showed that QST of vibratory thresholds 

can detect subclinical neuropathy in children 


and adolescents with type 1 diabetes. 

However, there are two important problems 

in QST, firstly, QST is only a semi-objective 

measure, and can be influenced by both 

attention and motivation of the patient and 

secondly, abnormal results from QST can 

result from spinal cord pathology as well as 

cortical lesions. Thus, QST though sensitive 

for peripheral neuropathy, is not specific for 

this condition. 

Treatment of diabetic neuropathy 

Definitive prevention, treatment, or cure of 

diabetic peripheral neuropathies must await the 

discovery of the exact aetiology and effective 

treatment of diabetes, however, the results of 

DCCT and pancreas transplantation studies on 

peripheral neuropathy clearly demonstrate that 

an effective and early treatment of 

hyperglycaemia is currently the only important 

factor in delaying the progression of 

neuropathy. The asymmetric and focal 

neuropathies are either self-limiting or do not 

respond to any treatment modality. So treatment 

is largely directed towards distal symmetric 

sensori-motor polyneuropathies and for 

symptoms related to autonomic neuropathy. 

The treatment of diabetic neuropathy can be 

broadly divided into two major groups : (i) 

Symptomatic treatment (ii) Treatment for nerve 

regeneration. 

Symptomatic treatment 

Pain is the most common symptom, which could 

be superficial, deep, or aching. The management 

of pain is often difficult and disappointing. There 

is no single correct approach to the management 

of any given patient with peripheral neuropathy. 

Often it requires patience on the part of patient 

and physician who must try a variety of different 

medications on a trial and error basis until a 

satisfactory regimen is established. Sometimes 

simple reassurance that the pain is not permanent, 

does produce great relief from pain, pain related 

anxiety, or depression. However, following 

measures can be taken in order of preference for 

pain relief : 

Capsaicin 

Superficial hyperaesthesia with burning and 

lancinating dysaesthetic pain is typical of c-fibre 

pain and may respond to local application of 

capsaicin. Capsaicin is trans-8methyl-N vanilly- 

6-nonemide 45 . Capsaicin is extracted from chilli 

pepper and can be prepared at home by mixing 

three teaspoons of cayenne pepper with a jar full 

of cold cream. Its topical application results in 

depletion of substance P, a principal neurotransmitter 

of poly model nociceptive afferent 

fibres. The mechanism of substance P depletion 

may be secondary to the release of substance P 

from nerve terminals, diminished axonal transport 

of substance P to replenish it in the nerve terminals, 

and inhibition of its synthesis 45 . Capsaicin is 

applied at a dose of 0.075%, four times a day to 

skin over the painful areas. The reported controlled 

studies suggest that the benefits of drug application 

become evident only after four weeks of its use. 

Analgesics 

The analgesics do not have a good reputation in 

the management of diabetic neuropathy. On one 

end they have poor efficacy and at the other end 

they have adverse effects. Long term NSAID 

ingestion causes hepatotoxicity, while narcotic 

analgesia causes addiction and worsening of 

autonomic neuropathic symptoms. 

Tricyclic anti-depressants (TCA) 

Tricyclic anti-depressants (TCA) are the most 

commonly used drugs for pain relief in diabetic 

peripheral neuropathy. Double blind trials of 

the tricyclic anti-depressants have demonstrated 

significant benefits in reducing pain that is 

burning, aching, sharp, throbbing, or stinging 46 . 

The use of amitriptyline is contraindicated in 

patients with heart block, recent myocardial 

infarction, heart failure, urinary tract 

obstruction, orthostatic hypotension, and 

narrow angle glaucoma. It should be started at 


low doses of 10 to 20 mg every night and 

increased gradually until pain control is 

achieved or dose limiting side effects occur. 

Achievement of pain relief may require as much 

as 150 mg of the drug per day for 3 to 6 weeks. 

Withdrawal from amitriptyline must be gradual 

so as to prevent rebound insomnia. These drugs 

act on the central nervous system, preventing 

the reuptake of norepinephrine and serotonin 

at synapses involved in pain inhibition. The 

benefits of tricyclics appear to be unrelated to 

relief of depression. 

Anti-convulsants 

Anti-convulsants are used, if treatment with 

amitriptyline is not successful. Commonly used 

anti-convulsants are carbamazepine, 

clonazepam, phenytoin, and gabapentin. The 

drugs are more effective in lancinating pain. 

Among anti-convulsants, carbamazepine is the 

most commonly used drug. When initiating 

carbamazepine, it is advisable to begin with a 

low dose of 100 mg and then increase gradually 

until there is significant relief of symptoms or 

side effects are encountered. Complete blood 

counts and liver functions should be checked at 

the onset and then on a monthly basis over the 

first three months because leukopenia is a 

common complication. 

Gabapentin has demonstrated significant 

efficacy in a recent multicentre, double blind, 

randomised, placebo-controlled study of 165 

patients with type 1 and type 2 diabetes47 . 

Common adverse effects are dizziness, 

somnolence, and headache. Gabapentin 

should be started at a dose of 300 mg/day and 

gradually increased until symptomatic relief 

occurs or until a maximum dose of 2,400 mg 

per day is reached. Clonazepam is also effective 

in restless leg syndrome. 

Others 

Baclofen (Gamma aminobutyric acid), clonidine 

(α2 adrenergic agonist), lignocaine, and 

tramadol hydrochloride are other drugs used 

in management of diabetic peripheral 

neuropathy. Non-pharmacological therapies 

that have also been tried with limited success 

are sympathectomy, spinal cord blockade, and 

electrical spinal cord stimulation. 

Treatment of autonomic neuropathy 

Treatment of autonomic neuropathy is only 

palliative. With the help of pharmacological and 

non-pharmacological means the quality of life 

can be improved in these patients. 

Postural hypotension 

Mild postural hypotension can be managed with 

simple measures such as a high sodium diet, 

raising the head end of bed during sleep and 

wearing of whole body stockings. The 

pharmacological treatments include the use of 

mineralo-corticoids like fludrocortisone, 

sympathomimetic agents (midodrine, clonidine, 

yohimbine), β blockers with or without intrinsic 

sympathomimetic activity (propranolol, 

pindolol), pressor agents (dihydroergotamine, 

caffeine), prostaglandin synthesis inhibitors 

(indomethacin, ibuprofen, naproxen) and antiserotonergic 

agents 48 . Therapy should be 

initiated with fludrocortisone (0.1 to 0.5 mg) 6 

hourly. A pressor sympathomimetic agent, or a 

prostaglandin synthetase inhibitor can be added 

to the drug regimen of those patients who 

remain symptomatic. Refractory symptoms may 

require a combination of above mentioned 

agents. 

Gastrointestinal problems (oesophageal 

dysmotility/gastroparesis and enteropathy) 

Autonomic damage to the upper gastointestinal 

tract is often asymptomatic. Oesophageal motility 

is sometimes reduced, causing dysphagia and 

heart burn. Gastroparesis, with delayed and 

uncoordinated emptying of the stomach can lead 

to abdominal discomfort, intractable vomiting, 

weight loss, and unstable diabetic control. 


Management of diabetic gastroparesis consists of 

multiple small feedings, reduction in dietary fat, 

good glycaemic control, and prokinetic drugs. The 

prokinetic drugs used for the management of 

gastroparesis are metoclopramide (10-20 mg 6 

hourly), domperidone (10-20 mg 4-6 hourly), 

cisapride (10 mg 8 hourly), and erythromycin (250 

mg 8 hourly). All are given 1/2 hours before meal. 

In patients who are unable to tolerate oral 

medication, metoclopramide or erythromycin can 

be given intravenously. In case of severe 

gastroparesis, patients may require hospitalisation, 

intravenous fluids, parental drugs, and nasogastric 

drainage; sometime they may require intra-jejunal 

feeding. 

Enteropathy includes both diarrhoea and 

constipation. The pathogenesis of diabetic 

diarrhoea includes abnormalities in gastrointestinal 

motility, decreased gut transit time, 

reduced fluid absorption, bacterial overgrowth, 

pancreatic insufficiency, coexistent coeliac disease, 

and abnormalities in bile salt metabolism. The 

pathophysiology of diabetic constipation is poorly 

understood but may reflect loss of post-prandial 

gastrocolic reflex 49 . 

Loperamide, diphenoxylate, or codeine 

phosphate are used for symptomatic treatment 

of diabetic diarrhoea, while clonidine is used 

to reduce α2 adrenergic receptor mediated 

intestinal absorption. A short course of broad 

spectrum antibiotics (ampicillin, tetracycline) is 

helpful for diarrhoea due to bacterial overgrowth. 

Cystopathy 

Patients with neurogenic bladder may not be able 

to sense bladder fullness. The patients should be 

instructed to palpate their bladder. The bladder 

may be emptied by mechanical measures such as 

manual suprapubic pressure (Crede’s maneuver) 

or intermittent self catheterisation. Parasympathomimetic 

agents such as bethanechol are some 

times helpful but often do not help to fully empty 

the bladder. While extended sphincter relaxation 

can be achieved with an α1 blocker such as 

doxazosin. If pharmacological measures fail, 

bladder neck surgery (in males) may help to relieve 

spasm of the internal sphincter. 

Sexual dysfunction in males can be managed with 

intrapenile injection of papaverine and by vacuum 

devices. If these therapies do not help, rigid or 

semirigid prostheses are available. The drug 

sildenafil citrate is now being increasingly used to 

manage erectile dysfunction. Being a potent 

inhibitor of cyclic guanosine monophosphate 

hydrolysis in the corpus covernosum, it therefore 

increases the penile response to sexual stimulation. 

One randomised, double-blind, flexible-dose, 

placebo-controlled study included only patients 

with erectile dysfunction attributed to complications 

of diabetes mellitus (n = 268). Patients were 

started on 50 mg and allowed to adjust the dose 

upto 100 mg or down to 25 mg of sildenafil. There 

were highly statistically significant improvements 

(in frequency of successful penetration during 

sexual activity and maintenance of erections after 

penetration) on sildenafil compared to placebo. 

Table III : Tests of cardiac autonomic function. 

Test 

Parasympathetic (heart rate response) 

Normal Borderline Abnormal 

Valsalva (Valsalva ratio) ≥ 1.21 1.11-1.20 ≤ 1.10 

Deep breathing (max/min HR) ≥ 15 beat/min 11-14 beast/min ≤ 10 beats/min 

Standing (30:15 ratio R-R) ≥ 1.04 1.01-1.03 ≤ 1.00 

Sympathetic (blood pressure response) 

Standing (↓ systolic) ≤10 mm Hg 11-29 mm Hg ≥ 30 mm Hg 

Exercise (↑ diastolic) ≥16 mm Hg 11-15 mm Hg ≤ 10 mm Hg 


57% of sildenafil patients reported improved 

erections versus 10% on placebo. Diary data 

indicated that on sildenafil, 48% of intercourse 

attempts were successful versus 12% on placebo. 

Treatment designed to modify the course of 

diabetes 

The outcome of management of diabetic 

peripheral neuropathy is not very good. However, 

people are trying to prevent neuropathy from 

developing (primary prevention) and to improve 

or even reverse established neuropathic damage 

(secondary prevention). For prevention, optimum 

glycaemic control is most important. The aldose 

reductase inhibitors, essential fatty acids, and 

vasodilator drugs are approaching clinical 

usefulness – while the rest are at an experimental 

stage. 

Optimised glycaemic control 

The DCCT and the UKPDS, both landmark studies 

in the history of diabetes, have shown that good 

control can prevent or delay the onset of diabetic 

peripheral neuropathy. The effectiveness of 

normoglycaemia in improving damaged nerves 

has been documented in some patients who have 

undergone combined pancreatic and renal 

transplantation 50 . 

Aldose reductase inhibitors (ARI) 

The aldose reductase inhibitors prevent conversion 

of glucose to sorbitol in presence of 

hyperglycaemia, Therefore, it prevents the polyol 

pathway cascade. ARIs are alreastat, tolerestat, 

epalrestat, sorbinil, and zopolrestat. There is great 

controversy about the mechanisms of action of 

the ARIs, and suggestions range from altered 

phosphoinositide metabolism and Na + - K + 

adenosine triphosphate activity, through reduced 

glutathione levels, to vasodilation and improved 

blood flow to nerve 51 . However, as compared to 

the marked effect of ARIs on nerve function in 

diabetic animals, the results of clinical trials in 

humans have been less convincing 52 . The results 

of more than 20 clinical trials conducted in past 

15-20 years on the effect of a variety of aldose 

Fig. 2 : 

reductase inhibitors generally have been 

disappointing 53 . 

Gamma linolenic acid (GLA) 

Gamma linolenic acid (GLA) is an important 

constituent of neuronal membrane phospholipids 

as well as a substrate for prostaglandin E and 

prostacyclin formation, which may be important 

for preservation of nerve blood flow. In diabetic 

patients, conversion of linolenic acid to GLA and 

subsequent metabolism is impaired, possibly 

contributing to the pathogenesis of diabetic 

neuropathy. A recent trial used GLA for one year 

and this resulted in significant improvements in 

both clinical measures as well as electrophysiologic 

test results 54 . 

Other measures like advanced glycation end 

products (AGE), N-acetyl-L-carnitine, gangliosides, 

and human intravenous immunoglobulin are still 

under trial. 

Treatment for nerve regeneration 

The agents used for nerve regeneration are 

known as neurotrophic factors. The 

neurotrophic factor is defined as a naturally 

occurring protein that is released by target 

tissues of responsive neurons, binds to specific 

receptors and is retrogradely transported to the 


cell body where it regulates gene expression 

through the actions of second messenger 

systems 55 . 

A large number of neurotrophic factors that 

exert effects on specific neuronal populations 

in the peripheral nervous system have been 

discovered. Some of these factors may prove 

useful for the treatment of diabetic peripheral 

neurophathy. All neurotrophic factors are still 

under trial and none of them is available for 

clinical use. Among the most promising are 

members of the neurotrophin gene familynerve 

growth factor (NGF), brain derived 

neurotrophic factors, neurotrophin, insulin 

like growth factor, and glial cell derived 

neurotrophic factor (Table IV). 

Table IV : Neurotrophic factors. 

Neurotrophins (NT) 

Nerve growth factor 

Brain- derived neurotrophic factor 

NT - 3 

NT-4/5 

NT - 6 

Haematopoietic cytokines 

Ciliary neurotrophic factor 

LIF 

Oncogene M 

Interleukin (IL) - 1 

IL - 3 

IL - 6 

IL - 7 

IL - 9 

IL - 11 

Granulocyte colony- stimulating factor 

Insulin - like growth factors (IGF) 

Insulin 

IGF - I 

IGF - II 

Heparin - binding family 

Acdic fibroblast growth factor (FGF) 

Basic FGF 

int - 2 onc 

hst/k-fgf onc 

FGF - 4 

FGF - 5 

FGF - 6 

Keratinocyte growth factor 

Epidermal growth factor (EGF) family 

EGF 

Transforming growth factor (TGF) - α 

TGF - β family 

TGF - β 1 

TGF - β 2 

TGF - β 3 

Glial - derived neurotrophic factor 

Neurturin 

Persephin 

Activin A 

BMP S 

Tyrosine kinase - associated cytokines 

Platelet - derived growth factor 

Colony - stimulating factor - 1 

Stem cell factor 

BMP = bone morphogenetic protein; LIF = leukaemia 

inhibitory factor. 

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Diabetic Neuropathy: Current Concepts - medIND

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