Diabetic Peripheral

Neuropathy

Overview
Diabetic peripheral neuropathy (DPN) affects up to 50% of patients with
diabetes and is a major cause of morbidity and increased mortality.
Its clinical manifestations include painful neuropathic symptoms and
insensitivity, which increases the risk for burns, injuries and foot
ulceration

Several recent studies have implicated poor glycaemic control, duration

of diabetes, hyperlipidaemia (particularly hypertryglyceridaemia),
elevated albumin excretion rates and obesity as risk factors for the
development of DPN.
The diagnosis of DPN begins with a careful history of sensory and motor
symptoms.
Glycaemic control and addressing cardiovascular risk is now considered
important in the overall management of the neuropathic patient.

Definition
The Toronto Consensus Panel on Diabetic Neuropathy recently
defined DPN as a symmetrical, length-dependent
sensorimotor polyneuropathy attributable to metabolic and
microvessel alterations as a result of chronic hyperglycaemia
exposure and cardiovascular risk covariates. An abnormality
of nerve conduction tests, which is frequently subclinical,
appears to be the first objective quantitative indication of the
condition

Pathogenesis DPN
There were two schools of thought regarding the aetiology
and pathogenesis of DPN:
metabolic
vascular.

Microvascular abnormalities in
epineurial vessels in diabetes and
diabetes with DPN. The patient with
DPN has epineurial arterial
attenuation/tortuosity and an
arteriovenous shunt leading to
increased venous pressure and
tortuosity

Mechanisms of DPN
Peripheral mechanisms

Central mechanisms

Changes in sodium channel distribution

and expression

Central sensitization

Changes in calcium channel distribution

and expression

A-fibre sprouting into lamina II of the

dorsal horn

Altered neuropeptide expression

Reduced inhibition via descending

pathways

Sympathetic sprouting
Peripheral sensitization
Altered peripheral blood flow

Axonal atrophy, degeneration or

regeneration
Damage to small fibres
Glycaemic flux

Risk Factors of DPN

Clinical features
Painful symptoms such as burning, tingling (pins and needles or
paraesthesia), shooting (like electric shock) or lancing (stabbing) are
present in around a third of patients with DPN and around 20% of all
diabetic patients
Chronic persistently painful DPN can be extremely distressing and might
be associated with profound depression together with anxiety
Insensitivity, or loss of pain, can lead to foot ulceration and a host of
unintentional but serious injuries.

Imaging Studies
Spinal cord involvement in DPN
Using a non-invasive magnetic resonance (MR) imaging technique,
Eaton et al. reported a significantly lower cord area in the cervical
and upper thoracic regions in subjects with established DPN
compared with healthy nondiabetic control subjects
This study showed that the neuropathic process in diabetes is not
confined to the peripheral nerve and appears to involve the spinal
cord. Of concern is that this occurs early in the neuropathic process

Imaging Studies
Brain MR Spectroscopy
Findings from a research may reflect that there was a thalamic neuronal
dysfunction in DPN, implicating the brain in the neuropathic process.
However, the mechanism of thalamic involvement is unclear.
One possible explanation for thalamic neuronal dysfunction in DPN may be that
loss of afferent input, as a result of peripheral nerve damage.
It may also be equally likely that the observed changes in the thalamus may be
occurring concomitantly to the changes seen in the peripheral nervous system.

Imaging Studies
MR Perfusion Imaging
Although the pathogenesis of thalamic involvement on H-MRS in
DPN is unknown, it is likely that both vascular and metabolic
etiological factors that have been postulated in the pathogenesis of
DPN and other microvascular complications of diabetes may be
involved.
Similar thalamic microvascular abnormalities have been
demonstrated in other chronic pain states and may thus be
important in the pathogenesis of painful DPN.

Imaging Studies
Functional MR imaging
Utilizing fMRI, Wilkinson et al. performed a preliminary study
comprising type 1 diabetic subjects (no DPN, painful DPN and
painless DPN) to test the feasibility of monitoring the brain's
response to the presentation of heat pain in the context of DPN.
The results show that subjects with no DPN had greater BOLD
response than those with painless DPN. Subjects with painful DPN
showed significantly greater response than those with painless DPN.
The primary somatosensory cortex, lateral frontal and cerebellar
regions demonstrated greatest involvement.

Treatments
Achieving and maintaining near-normal glycaemia (HbA1c) as an initial
step.
Apart from glycaemic control, there has been little advance in the
development compounds that can halt the neuropathic process.
Although several disease-modifying agents are under investigation, only
the antioxidant -lipoic acid is supported by a meta-analysis and is
marketed in certain countries

References

Tesfaye S. Recent advances in the management of diabetic symmetrical polyneuropathy. J Diabetes Invest 2010; 2:
3342.
Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of
severity and treatments. Diabetes Care 2010; 33(10): 22852293.
Boulton AJM, Kirsner RS, Vileikyte L. Neuropathic diabetic foot ulcers. N Engl J Med 2004; 351: 4855.
Tesfaye S, Chaturvedi N, Eaton SEM, Witte D, Ward JD, Fuller J. Vascular risk factors and diabetic neuropathy. New
Engl J Med 2005; 352: 341350.
Selvarajah D, Wilkinson ID, Emery CJ, et al. Thalamic neuronal dysfunction and chronic sensorimotor distal
symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia 2008; 51: 20882092.
Eaton SE, Harris ND, Rajbhandari SM, et al. Spinal-cord involvement in diabetic peripheral neuropathy. Lancet 2001;
358(9275): 3536.
Selvarajah D, Wilkinson ID, Emery CJ, et al. Thalamic neuronal dysfunction and chronic sensorimotor distal
symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia 2008; 51: 20882092.