Neuropathy in Diabetes, Is Diabetes always to blame?

Srinivas Rao Paidipally, Dr. Shyam Kalavalapalli, , Prof. VijaySekhar Reddy

Dr. Srinivas Rao Paidipally

Consultant Physician
Department of Endocrinology
Gandhi Medical College
Hyderabad

Dr. Shyam Kalavalapalli

Consultant Endocrinologist
Institute of Diabetes, Endocrinology and Adiposity (IDEA CENTRES)
Hyderabad

Dr. VijaySekhar Reddy

HOD, Department of Endocrinology
Gandhi Medical College
Hyderabad

CORRESPONDING AUTHOR
Dr. Srinivas Rao Paidipally
Department of Endocrinology
Gandhi Medical College, Hyderabad
psrdr@rediffmail.com
Tel. no.: 09989050745

Article points and key words:

Diabetes is the commonest cause of peripheral neuropathy but not

the only one.

It is not uncommon to attribute symptoms of neuropathy to

diabetes and overlook other causes.

Treatment strategy depends on the aetiology of the neuropathy

making it crucial to remember that other causes can co exists.

If the aetiology remains unclear and the clinical picture is atypical a

wider search looking for less common causes should be undertaken.

Diabetes, Peripheral Neuropathy, aetiology, treatment

Abstract
Peripheral neuropathy is a common neurological problem with prevalence
between 2.4% and 8 %( 1).

Diabetes is the commonest cause of

peripheral neuropathy in the developed world. However, it is important to

recognise the possibility of other causes; it is not uncommon to attribute
symptoms of neuropathy to diabetes when in fact there may be other
pathological processes occurring. Studies have indicated that there may
be more than one cause for neuropathy in 10% to 50 %( 2) of diabetes
patients.

This article focuses on the non-diabetic causes of peripheral

neuropathy.

Introduction
Diabetic peripheral neuropathy is the presence of symptoms and/or signs
of peripheral nerve dysfunction in people with diabetes after exclusion of
other causes (Boulton et al 1998). The exclusion of other potential causes
is important in management of the condition.

The Central Nervous system is covered by three layers, dura, arachnoid

and piamater. Parts of the nervous system which lie outside the covering
layers of brain and spinal cord comprise peripheral nervous system. Optic
nerve and olfactory bulb break this rule; they are considered special
extensions of the brain (3). A typical nerve is composed of fascicles which
contain several hundred axons bound by perineurium. Epineurium binds
all the fascicles in a particular nerve. Each axon has a coating of myelin
interrupted by nodes of ranvier. Not all axons are myelinated (3).
There are two main types of nerve fibres relevant for neuropathies, small
and large fibres. Large fibres sub serve joint position sense and vibration,
whereas small fibres carry pain and temperature sensations. Most length
dependent neuropathies are thought to involve large fibres. A typical
symmetrical peripheral neuropathy is thought to be length dependent
process i.e. toes and soles affected before hands (4).
The term peripheral neuropathy is commonly used to indicate a
symmetrical, glove and stocking pattern of sensory loss on a background
of absent ankle reflexes with or without mild weakness distally in the

lower limbs. However the peripheral neuropathy also encompasses

several patterns of pathology of the peripheral nervous system.
ranges

from

problems

at

the

nerve

root

(radiculopathy),

This
plexus

(plexopathy), individual nerves (mononeuropathy eg: common peroneal

nerve

palsy

causing

foot

drop),

multiple

mononeuropathy

and

symmetrical polyneuropathy. It is important to be able to recognise the

pattern of neurological deficit and localise the site of lesion. Neuropathies
can be classified based on time frame as acute (<4 weeks), subacute(48weeks) and chronic(>8 weeks)(5). Based on the pathology they can be
axonal, demyelinating or mixed.
An acute onset neuropathy is most likely to be inflammatory (Gullian
Barre Syndrome, Sarcoidosis), or of vascular aetiology (vasculitis).

On

the other hand chronic neuropathies which evolve over years are likely to
be hereditary (Charcot Marie Tooth) or metabolic (Diabetes).
The deficits in peripheral neuropathy may be grouped under the headings
purely sensory (only sensory symptoms like pins & needles, numbness),
motor (only weakness of involved muscles), mixed (mixture of both
sensory and motor features), autonomic (postural drop of blood pressure,
tachycardia, altered sweating) or a combination of above (5).

The

presenting features can be variable ranging from mild sensory symptoms

of

diabetic

neuropathy

to

acute

symptoms of Guillain Barre Syndrome.

flaccid

paralysis

with

autonomic

Depending on the site of pathology, neuropathies can either be axonal or

demyelinating.

Common causes of acute axonal neuropathy are

vasculitis, toxins (arsenic, thallium). Guillain Barre Syndrome is an acute

demyelinating

illness.

HIV

sometimes

may

present

as

an

acute

demyelinating illness. A list of axonal and demyelinating neuropathies is

given in table 1

Distal symmetrical weakness is commonly seen in axonal neuropathies.

Conversely

in

demyelinating

neuropathies

the

weakness/motor

impairment can be proximal. Loss of tendon reflexes can be seen in both

small and large fibre neuropathy.

Large myelinated nerve fibres sub

serve joint position sense, proprioception as well as reflexes. This explains

the

areflexia

in

patients

with

loss

of

joint

position

sense

and

proprioception and also in patients with demyelinating neuropathies.

In peripheral neuropathies sensory loss can be variable and different
modalities can be affected up to variable extent. With gradual loss of
sensations, subcutaneous tissue thickens; hair growth is reduced, skin
over the extremities can become tight and shiny. With autonomic
involvement the peripheries can become warm and pink (6)

Patients commonly present with a mixture of both sensory and motor

symptoms.

The

differential

diagnosis

for

mixed

sensory

motor

neuropathy is very wide (Table 2). Hence the importance of a relevant

history (including drugs) which narrows down on a differential diagnosis,

aided by a thorough examination (neurological and systemic) cannot be
stressed enough. Most peripheral neuropathies can be diagnosed based
on history, examination and first line investigations looking for a treatable
cause (Haematology FBC, B12, Folate, ESR, U&E, LFT, TFT, blood
glucose). It is also important to remember that Leprosy and Anaemia are
common causes for treatable peripheral neuropathy worldwide.
If the aetiology remains unclear and the clinical picture is atypical or
continues to progress, a wider search looking for less common causes
(Table 3) based on the clinical clues should be undertaken. A referral to
Neurologist and a Neurophysiologist at this stage may be initiated.
It is vital to tie up history, symptoms, signs and the time course together
to work towards the site of lesion in the peripheral nervous system.
Neurophysiology (Nerve Conduction Studies), an extension of the clinical
examination can help to confirm the site and delineate the underlying
pathology (axonal, demyelinating or a mixture of both) and a plausible
diagnosis.
Neurophysiology is helpful in determining if the neuropathy is axonal or
demyelinating and aids in further investigations and management. Nerve
conduction studies are mainly helpful in large fibre pathology; small fibre
neuropathies require quantitative testing to define hot, cold and pain
threshold.
Planning a

treatment

strategy

depends

on

the

aetiology

of

the

neuropathy. Removing the offending agent may be the only thing thats

needed.

Depending on the type of neuropathy treatment can be

symptomatic

or

aggressive

immunosuppression

for

inflammatory

neuropathies. Controlling blood sugars, correcting vitamin deficiencies &

metabolic abnormalities may prevent further worsening of neuropathy.
For inflammatory neuropathies immunosuppression is mainstay of
management.

Long

term

treatment

may

be

needed.

Diagnosing

inflammatory neuropathies in time is critical as delayed diagnosis may

result in significant morbidity and even death. For demyelinating
neuropathies

like

CIDP

treatment

options

include

steroids,

IV

Immunoglobulins and plasma exchange. Vasculitic neuropathies are

treated more aggressively with IV steroids followed by oral steroids and
steroid sparing agents.
Generic treatments for peripheral neuropathy consist of educating patient
about care of the feet, avoiding trauma & ill fitting shoes, referral to
chiropodist & symptomatic treatment for neuropathic pain.
In conclusion, though diabetes remains the most likely cause for
peripheral neuropathy it is vital to remember the possibility of other
causes and if the aetiology remains unclear, the clinical picture is atypical
History of heavy alcohol consumption
a widerofsearch
looking for less common causes should be undertaken.
Symptoms
hypo/hyperthyroidism
Weight loss (symptoms suggestive of malignancy), chemotherapy
HIV infection
The following
red tests
flags(eosinophilia,
can makelow
a diabetic
neuropathy less likely.
Abnormalities
on blood
B12)
Isolated foot drop
Proximal weakness
Bowel and bladder disturbance
Arms affected more than legs
Rapid progression of symptoms

References:
1.Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy.
J Neurol Neurosurg Psychiatry. 1997 Apr;62(4):310-8.
2. Freeman R. Not all neuropathy in diabetes is of diabetic etiology: Curr
Diab Rep. 2009 Dec;9(6):423-31.
3. Adams and Victors/Ropper AH, Brown RH Editors. Principles of
Neurology. 8th edition.London. McGraw Hill 2005 Pg no 1110
4. J England, A Asbur Peripheral neuropathy Lancet 2004; 363: 215161
5. Richard Hughes. Peripheral nerve diseases. Pract Neurol. 2008
Dec;8(6):396-405.
6. Adams and Victors/Ropper AH, Brown RH Editors. Principles of
Neurology. 8th edition.London. McGraw Hill 2005 Pg no 111.
NICE Guidelines
(March
- Neuropathic
pain: the pharmacological
Table 2.7.Differential
diagnosis of
Sensory2010)
motor Neuropathy
(chronic/subacute)
management of neuropathic pain in adults in non-specialist settings.
1. Metabolic - Diabetes, Uraemia, Chronic liver disease, thyroid abnormalities
8 Boulton
AJM,
Gries FA, Jervell JA: Guidelines for the diagnosis and
2. Deficiencies
B12,
Thiamine,
outpatient management of diabetic peripheral neuropathy. Diabetic Med15
: 508-514,199
3. Drugs
& Toxins Alcohol, Anti-infectives, Chemotherapeutic agents, Antiarrhythmics, metals like
arsenicTable 1
4.
Paraneoplastic
Chronic
Axonal neuropathies
Chronic Demyelinating neuropathies
Diabetes
Chronic inflammatory demyelinating Polyradiculopathy
5.
Paraproteinaemic
Alcohol
Hereditary neuropathies like Charcot Marie Tooth
Vitamin deficiency
Multifocal Motor Neuropathy
6.
Infection HIV, Leprosy (developing
world) disease
Drugs
Refsums
Paraneoplastic
Paraproteinaemic neuropathy
7.
Collagen vascular
diseases
Autoimmune
conditions
Drugs (Chloroquine, Amiodarone)
Polyarteritis nodosa
Wegeners granulomatosis
Churg strauss syndrome
Sjogrens syndrome
SLE, Rheumatoid arthritis
8. Hereditary Neuropathies
Charcot Marie Tooth
Hereditary liability to pressure palsy
Metachromatic leukodystrophy
Refsum disease

Table 3 Other less common causes

Neoplasms
Paraprotein
Infections like HIV
Vasculitis
Sjogrens
Sarcoidosis
Amyloidosis (particularly in painful small fibre neuropathies)
Nerve biopsy (?Vasculitic neuropathy)
Lumbar puncture for raised CSF protein
Genetic conditions if hereditary neuropathy suspected