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REVIEW
Diabetes Metab Res Rev 2012; 28(Suppl 1): 814.
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2239
ARTICLE
Solomon Tesfaye*
Dinesh Selvarajah
Shefeld Teaching Hospitals,
Shefeld, UK
*Correspondence to:
Solomon Tesfaye M.D., Room Q26,
Royal Hallamshire Hospital, Glossop
Road, Shefeld S10 2JF, UK.
E-mail: solomon.tesfaye@sth.nhs.uk.
SUMMARY
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.
Although there is now strong evidence for the importance of nerve microvascular
disease in the pathogenesis of DPN, the risk factors for painful DPN are not
known. However, emerging evidence regarding the central correlates of painful
DPN is now afforded by brain imaging.
The diagnosis of DPN begins with a careful history of sensory and motor symptoms. The quality and severity of neuropathic pain if present should be
assessed using a suitable scale. Clinical examination should include inspection
of the feet and evaluation of reexes and sensory responses to vibration, light
touch, pinprick and the 10-g monolament.
Glycaemic control and addressing cardiovascular risk is now considered important
in the overall management of the neuropathic patient. Pharmacological treatment
of painful DPN includes tricyclic compounds, serotoninnorepinephrine reuptake
inhibitors (e.g. duloxetine), anticonvulsants (e.g. pregabalin), opiates, membrane
stabilizers, the antioxidant alpha lipoic acid and others. Over the past 7 years, new
agents with perhaps less side effect proles have immerged. Management of
patients with painful neuropathy must be tailored to individual requirements and will depend on the presence of other co-morbidities. There is
limited literature with regard to combination treatment. Copyright 2012
John Wiley & Sons, Ltd.
Keywords diabetic neuropathy; diabetic peripheral neuropathy; painful diabetic
neuropathy; pathogenesis of diabetic neuropathy; MRI
10
Pathogenesis of DPN
Until recently, there were two schools of thought regarding
the aetiology and pathogenesis of DPN: metabolic versus
vascular. Recent studies, however, have shown that both
vascular factors and metabolic interactions are involved at
all stages of DPN [16]. Nerve bre loss is the cause of
insensitivity in DPN. As revealed by fascicular biopsy
of the sural nerve, nerve bres in patients with diabetes
but no DPN are more numerous than in those with DPN
[16]. Sural nerve biopsies also reveal microvascular
defects in the endoneurial vessels, such as gross basement
membrane thickening, endothelial cell proliferation and
hypertrophy [17] as well as reduced oxygen tension [18]
in patients with DPN compared with those who have diabetes but do not have DPN. Similarly, photography of surgically
exposed sural nerve in vivo reveals microvascular abnormalities in its epineurial arteries and veins (Figure 2) [19],
whereas uorescein angiography reveals arteriosclerosis on
the surface of the nerve and impaired blood ow [19] in
patients with DPN compared with those with diabetes but
no DPN.
Central mechanisms
Central sensitization
Ab-bre sprouting into
lamina II of the dorsal horn
Reduced inhibition via
descending pathways
Sympathetic sprouting
Peripheral sensitization
Altered peripheral blood ow
Axonal atrophy, degeneration
or regeneration
Damage to small bres
Glycaemic ux
11
35
HV
30
Painless DN
25
Painful DPN
20
15
10
5
0
0
10
20
30
40
50
60
70
80
Figure 3. Composite concentration-time proles of the bolus passage of exogenous contrast agent (gadolinium-diethylenetriamine
pentaacetic acid) through the thalamus in each subgroup. DPN,
diabetic peripheral neuropathy; HV, healthy volunteer. Adapted
from Reference [28]
Diabetes Metab Res Rev 2012; 28(Suppl 1): 814.
DOI: 10.1002/dmrr
12
13
Pathogenetic treatments
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 a-lipoic
acid is supported by a meta-analysis and is marketed in
certain countries [44].
Conclusions
Diabetic peripheral neuropathy is common, affecting up to
50% of patients with diabetes. In addition, it accounts for
considerable morbidity, mortality and reduced quality of
life. Glycaemic control is the central component of
treatment, but it is difcult to achieve for many patients.
Because cardiovascular risk factors play a major role in
diabetes and the pathogenesis of DPN, they should be
controlled as well.
Painful DPN is difcult to treat. On the basis of the trial
evidence, rst line therapies include a TCA, the SNRI
duloxetine and the anticonvulsant pregabalin. Combination therapy might be useful for those with more severe
pain, but there is paucity of studies and further research
is required. Studies are also required on direct head-tohead comparative trials and long-term efcacy of drugs,
as most trials have lasted less than 6 months.
Imaging evidence that the CNS is involved in DPN
should open new avenues of investigation. Key target
areas generating or modulating pain in painful DPN
including peripheral small bres with modulation at the
level of the spinal cord, the thalamus and the other pain
matrix areas in the brain require further studies to
develop more effective treatments. The association of
painful DPN with autonomic neuropathy also merits
further investigation. Finally, as available therapies for
pain and nerve impairment are less than satisfactory,
rational therapies that address the underlying pathogenesis
need to be developed.
Conict of Interest
Both S. Tesfaye and D. Selvarajah have received honoraria
from Eli Lilly and Company. S. Tesfaye has also received
honoraria from Pzer.
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