VASCULAR COMPLICATIONS OF DIABETES - PART 4 pot

65
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
Fig. 7.1 Effects of ramipril on cardiovascular outcomes in people with diabetes –
MICRO-HOPE. Lancet 2000; 355: 253–259.
0.16
Myocardial infarction
Stroke
Cardiovascular death
0.12
Kaplan-M
0 08
0.04
0
0 500 1000 20001500
0.08
0.06
Kaplan-M
0 04
0.02
0
0 500 1000 20001500
0.12
0.09
Kaplan-M
0 06
0.03
0
0 500 1000
Duration of follow-up (days)
20001500
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES

66
Revascularization
Urgent revascularization is usually undertaken in refractory unstable angina
that fails to settle despite optimum medical therapy. In 90–95% medical
therapy stabilizes the situation. However, early intervention, with angiogra-
phy and angioplasty where appropriate, has now been shown to be superior
to medical treatment alone. One study compared thrombolysis within 30
minutes of admission with primary angioplasty within 90 minutes. After six
months of follow-up, patients in the angioplasty group fared better on all
measures: the mortality rate was 6.2%, compared with 7.1% for TPA; the rate
of recurrent ACS was 5.3%, compared with 10.6% for TPA; and the stroke
rate was 2.2%, compared with 4% for TPA. Length of time in hospital also
was shorter for the angioplasty group: 4.5 days compared with 6 days for
those who received TPA. These differences, though small, represent signifi-
cant improvements in outcome. When available and performed by experi-
enced operators at high-volume centers, primary percutaneous coronary
intervention (PPCI) saves 20 lives and results in 60 fewer events for every
1,000 patients treated. ‘Time is muscle’ and most hospitals do not have these
facilities, so unless transfer and urgent PPCI can be achieved within 90 min-
utes, thrombolysis remains the treatment of choice.
Surgery and angioplasty have similar results – vein grafting only improves
prognosis in patients with triple vessel disease or LV dysfunction. There is no
evidence that diabetics need an alternative strategy except that the Bypass
Angioplasty Revascularization Investigation (BARI) study suggested that
people with diabetes did less well with angioplasty – this remains to be con-
firmed. The BARI 2 Diabetes (BARI 2D) trial has not yet reported but will
compare whether attenuation of insulin resistance can arrest or retard pro-
gression of coronary artery disease compared with treatment targeted to the
same level of glycaemic control with an insulin-providing approach. It is
designed also to determine whether early revascularization reduces mortality

and morbidity in patients with type 2 diabetes whose cardiac symptoms are
mild and stable. The role of other antiplatelet agents such as clopidogrel, or
angioplasty followed by drug-eluting stents remains uncertain. Comparisons
of restenosis after angioplasty have shown slightly higher rates in people with
diabetes compared to non-diabetics. This difference is probably explained by
the older ages of those with diabetes in these studies.
Statins
Statins have transformed the management of hyperlipidaemia reducing both
total mortality, coronary events and need for revascularization. What is clear
is that this is not due to cholesterol lowering alone. They have significant anti-
inflammatory effects reducing C-reactive protein (CRP) and probably stabi-
lize atheromatous plaques.
67
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
Several clinical trials have now looked at the effect of initiating a statin with-
in hours and days of a coronary event and the findings suggest there may be sig-
nificant benefits. The RECIFE (Reduction of Cholesterol in Ischaemia and
Function of the Endothelium) trial looked at the effect of rapidly lowering cho-
lesterol on endothelial function days after a coronary event. Patients admitted
with MI or unstable angina were randomized to placebo or pravastatin 40mg
within 10 days. Endothelial function was assessed by measuring flow-mediated
dilatation of the brachial artery, which increased by 42% with pravastatin com-
pared with placebo. More excitingly, other short-term studies with pravastatin
40mg and atorvastatin 80mg initiated within four days have shown significant
reductions in coronary events in as little as 16 weeks. Larger trials are on-going
which will help to determine if these preliminary findings are confirmed and if
this is a class effect. Not all statins have been demonstrated to lower CRP, and
smooth muscle cell proliferation (which may help stabilize plaques) is inhibit-
ed by some statins in vivo but not by pravastatin.
Potential but unproven interventions such as use of antioxidants, treat-

ment of homocysteinaemia (with folic acid) or hypertriglyceridaemia remain
untested. In the HOPE study vitamin E conferred no benefit.
Peripheral vascular disease
The Wisconsin Epidemiological Study of Diabetic Retinopathy (WESDR)
included nearly 3,000 people with diabetes (1,200 type 1 patients diagnosed
under 30 years) and showed an association between rising HbA1
C
and risk of
lower limb amputation. However, neither DCCT nor UKPDS were powered
to look at PVD or an amputation as an end-point – DCCT patients were
young and few had macrovascular events; UKPDS patients with significant
peripheral vascular disease at diagnosis were excluded from the study. There
was a non-significant (16%) reduction in fatal and non-fatal MIs in the inten-
sively treated group after 15 years and there was no difference between the
intensive and conventional treatment groups in the proportion of patients
who had evidence of peripheral vascular disease by Doppler blood pressure or
absent peripheral pulses. No controlled trials have been undertaken with dia-
betic patients to assess the effects of risk factor modification on the regression
of vascular disease, however, smoking cessation is associated with improve-
ment of symptoms in non-diabetics. Among patients with symptomatic PVD,
continued smoking is associated with worsening claudication, limb-threaten-
ing ischaemia and amputation, and the need for revascularization. Patency
rates are lower following revascularization in patients who continue to smoke
and survival is reduced. The effects of management of hyperlipidaemia and
hypertension on the progression of PVD has not been fully evaluated but an
analysis of the Scandinavian Simvastin Survival Study (4S) study showed that
the incidence of ‘new or worsening claudication’ was significantly lower in
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES
68
CHD patients treated with simvastatin (Fig. 7.2). In the Physician’s Health

study, low doses of aspirin resulted in a 54% reduction in the risk of periph-
eral arterial surgery, compared with placebo, but no study has shown any
improvement in claudication symptoms with antiplatelet agents. Drug treat-
ment for claudication has generally been disappointing but a new agent,
cilostazol, (a phosphodiesterase III inhibitor with antiplatelet, antithrombot-
ic and vasodilatory effects), looks promising. Phase III studies involving just
over 2,000 patients (approximately 25% with diabetes) using doses of
between 50 and 100mg twice daily, showed improvement in maximal walking
distance in most but not all studies. Pain-free walking distance and quality of
life were improved and cilostazol was significantly better than both placebo
and oxpentifylline 400mg tid (Fig. 7.3).
Peripheral vascular disease is a contributory factor in most diabetic foot
ulcers, and evidence exists that a combination of a dedicated multidisciplinary
foot service and the utilization of specialist footwear can reduce both ulceration
and amputation rates.
Cerebrovascular disease
In UKPDS each 1% reduction in HbA1
C
was associated with a 37% decrease in
risk for microvascular complications and a 21% decrease in the risk of any dia-
betes related end-point or death. The association with glycaemia was less steep
for stroke and heart failure (Fig. 7.4), for which hypertension is a much more
important contributory factor but nevertheless improved glycaemia reduced
Fig. 7.2 Effect of simvastatin on incidence of ‘new or worsening’ intermittent
claudication in the Scandinavian Simvastatin Survival (4S) study. Am J Cardiol
1998; 81: 333–335.
Percentage (%)
4.0 Placebo
Simvastatin
RR = 0.62

P<0.008
3.0
2.0
1.0
0
012
Years
345
69
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
the incidence of stroke. Unfortunately, acute stroke management in the person
with diabetes is based on extrapolation of the data from non-diabetics as there
are, as yet, no prospective studies of stroke management in diabetics. Trials
have shown that thrombolytic therapy started within six hours of the onset of
symptoms of ischaemic stroke reduces the proportion of patients who die or
remain dependent on others, up to six months later, (61.5% vs. 68% of control
patients not given thrombolysis). Results were more impressive if treatment
was started within three hours (56.6% vs. 70.7%). Alteplase seemed superior to
streptokinase but overall there was an increased risk of symptomatic intracra-
nial haemorrhage (9.6% vs 2.6%). Overall, the risk of dying within two weeks
was increased in those receiving thrombolytic therapy (20.9% vs. 11.9%) despite
the improvement in the composite end-point of death or dependency. Whether
people with diabetes benefit similarly from thrombolysis is not known. Use of
anticoagulant therapy with unfractionated or low-molecular weight heparin for
acute ischaemic stroke is associated with an increase in haemorrhagic stroke but
with no positive benefit in terms of mortality or dependency.
Hyperglycaemia on admission is associated with a worse outcome and
although the benefits of treatment of hyperglycaemia in this situation are
unknown, a DIGAMI-style glucose and insulin infusion would seem sensible
(trials are ongoing).

Fig. 7.3 Maximal walking distance in patients with claudication treated with cilostazol
or oxpentifylline or placebo. Circulation 1998; 98 (Suppl 1): 1012, Abstract 58.
Maximal walking distance mean % change from baselin
e
70
(Mean ± 95% confidence interval)
Cilostazol 100

mg bid
Oxpentifylline 400

mg tid
Placebo
60
50
40
30
20
10
0
Baseline 4 8 12 16 20 24
Weeks of treatment
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES
70
Secondary prevention data is based entirely on general population studies
with none having been conducted in people with diabetes alone. Targets sim-
ilar for those of diabetic patients with CHD are appropriate. The dose of
aspirin required is uncertain. The European Stroke Prevention Study showed
that, in the general population, aspirin and sustained-release dipyridamole
are an equally effective secondary prevention in reducing the risk of stroke

Fig. 7.4 Hazard ratios (with 95% confidence intervals) showing association between
mean HbA1
C
and various micro- and macrovascular complications in the UKPDS trial.
BMJ 2000; 321: 405–441, with permission.
10
P<0.0001
12% decrease per
1% reduction in HbA1
c
14% decrease per
1% reduction in HbA1
c
19% decrease per
1% reduction in HbA1
c
37% decrease per
1% reduction in HbA1
c
16% decrease per
1% reduction in HbA1
c
43% decrease per
1% reduction in HbA1
c
Fatal and non-fatal myocardial
infarction
Fatal and non-fatal stroke
Amputation or death from
peripheral vascular disease

Heart failure
Microvascular end points Cataract extraction
P<0.035
1
0.5
10
1
0.5
10
1
0.5
5678910 5678910
Updated mean HbA1
c
concentration
Hazard ratioHazard ratioHazard ratio
P<0.0001 P<0.0001
P<0.0001 P<0.021
71
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
and/or death. However, doubts exist because of the relatively low dose of
aspirin used and the exclusion of one centre from the study because of scien-
tific fraud. In the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic
Events (CAPRIE) study, 7.2% of those treated with clopidogrel 75mg/day had
an event compared with 7.7% of patients receiving aspirin 325mg/day. So, if
the patient has a cerebrovascular incident whilst on aspirin, addition of
dipyridamole may be justified; where patients have a true aspirin allergy
clopidogrel is probably the most appropriate choice.
There are a number of studies where stroke prevention has been a signifi-
cant secondary end-point. The UKPDS hypertension study, in which the tar-

get for tight blood pressure control was <150/85, showed a 44% reduction in
strokes compared to the less tight blood pressure control group (target blood
pressure <180/105) (Fig. 7.5).
Ramipril 10mg daily in the diabetic sub-group (Micro-HOPE) of the
HOPE study reduced the number of strokes from 6.1% to 4.2% (a 33% rela-
tive risk reduction) in a cohort of patients most of whom had established
CHD. The difference in blood pressure between the ramipril and placebo
groups at the end of the study was only 2.5/1.0. Some commentators say this
is insufficient to account for the difference in stroke rates, but as these were
based on casual readings rather than 24-hour profiles it remains uncertain
whether the benefit is due to blood pressure lowering or a different mode of
vascular protection by ACE-Is.
In both CARE and LIPID (secondary prevention studies in patients with
previous MI or angina) pravastatin 40mg reduced the risk of fatal and non-
fatal cerebrovascular accidents by 31% and 20% respectively. The numbers
with diabetes, however, were too small to analyse as a separate group.
Nephropathy
The DCCT showed a 39% reduction in the occurrence of microalbuminuria
and a 54% reduction in albuminuria in the intensive therapy arm for both
adults and adolescents with type 1 diabetes. Similarly, the UKPDS showed a
slowing of renal decline in the tight glycaemic control group with type 2 dia-
betes (Fig. 7.6). Type 2 patients with microalbuminuria or proteinuria are less
likely to progress to ESRF but, as with type 1 diabetes, blood pressure manage-
ment is the mainstay of treatment to reduce the decline in renal function.
ACE-Is are indicated in type 1 patients with persistent microalbuminuria or
proteinuria, irrespective of initial blood pressure (Fig. 7.7) and are first line
agents in type 2 diabetes if microalbuminuria or proteinuria is present, though
lowering blood pressure is the priority. Renoprotection by ACE-Is is probably
a class effect. Angiotensin receptor antagonists (ARAs) achieve similar reduc-
tions in blood pressure and proteinuria as ACE-Is. There have been only three

randomized double-blind studies lasting more than one year using ARAs as
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES
72
anti-hypertensive treatment for people with diabetes. None showed a signifi-
cant reduction in total or cardiovascular mortality. In the RENAAL study
there was a statistical reduction in progression to end-stage renal failure in
those that were treated with ARAs but the placebo group had higher blood
pressure throughout the study which may account for the worse outcomes.
Fig. 7.5 Hazard ratios (with 95% confidence intervals) showing association between
mean systolic blood pressure and various micro- and macrovascular complications in
the UKPDS study. BMJ 2000; 321: 413–417, with permission.
10
P<0.0001
12% decrease per 10mmHg
reduction in systolic blood pressure
13% decrease per 10mmHg
reduction in systolic blood pressure
16% decrease per 10mmHg
reduction in systolic blood pressure
19% decrease per 10mmHg
reduction in systolic blood pressure
12% decrease per 10mmHg
reduction in systolic blood pressure
Fatal and non-fatal myocardial
infarction
Fatal and non-fatal stroke
Amputation or death from
peripheral vascular disease
Heart failure
Microvascular end points Cataract extraction

P<0.0001
1
0.5
10
1
0.5
10
1
0.5
110 130 140 150 160 170
120
110 120 130 140
Updated mean systolic blood pressure (mmHg)
150 160 170
Hazard ratioHazard ratioHazard ratio
P<0.0001 P<0.041
P<0.0001 P<0.0028
73
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
To achieve a target blood pressure of <130/80 for patients with
nephropathy may require several anti-hypertensive agents and for young
people blood pressure targets may be set even lower to achieve a blood pres-
sure <90
th
centile for age.
Fig. 7.7 Effect of captopril on progression of microalbuminuria in normotensive
patients with type 1 diabetes. Diabetologia 1996; 39: 587–593.
0.3
0.2
0.1

0
0.5
0.4
3
113
109
Baseline
114
111
n at risk:
Placebo
Captopril
6
108
104
9
98
96
12
91
90
15
86
89
21
69
77
18
78
85

24
40
41
Proportion with event
Month
Fig. 7.6 Effect of glycaemic control on creatinine increase in UKPDS. Lancet 1998;
352: 837–853.
Conventional therapy
Intensive therapy
3
2
1
0
4
3
P=0.54
P=0.14
P=0.034
74% risk reduction
P=0.099
P=0.0052
Patients (%)
69
Years
12 15
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES
74
Retinopathy
The DCCT demonstrated beyond doubt that good glycaemic control retard-
ed the onset of microvascular complications and delayed progression of those

complications already present. Almost a half of patients in the intensive treat-
ment arm achieved an HbA1
C
of 6.1% or less at least once during the study,
giving a mean of approximately 7% for the duration of the study. From five
years into the study there was a 50% reduction in the cumulative incidence of
retinopathy in the primary prevention cohort and a 54% reduction in pro-
gression in the secondary prevention arm compared to the conventional
treatment group (mean HbA1
C
8.9%) (Figs. 7.8 & 7.9). Intensive therapy
reduced the risk of pre-proliferative and proliferative retinopathy by 47% and
the need for photocoagulation by 56%.
In the UKPDS, hypertensive patients were assigned to either tight or mod-
erate blood pressure control over nine years. The group randomized to tight
blood pressure control (mean 144/82 mmHg) experienced a 47% reduction in
the risk of losing three lines of vision compared to the group with standard
Fig. 7.8 Cumulative incidence of sustained change in retinopathy in patients with
IDDM receiving intensive or conventional therapy in the primary prevention arm of
the DCCT. Year of study refers to sample sizes at different years of the study. NEJM
1993; 329: 977–986.
40
30
20
0
10
60
Conventional
Intensive
P<0.001

50
0
Conventional
Intensive
123
375
342
4
Year of study
5
220
202
67
79
78
8 9
52
49
Patients (%)
75
CHAPTER 7 • EVIDENCE-BASED INTERVENTIONS
blood pressure control (mean BP 154/87 mmHg). There was also a 34% reduc-
tion in the risk of progression of retinopathy status. The EURODIAB
Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus
(EUCLID), also comparing tight with moderate blood pressure control, pro-
duced similar results, i.e. a significantly reduced risk of blindness and reduced
rate of progression of retinopathy in those patients randomized to more
intensively controlled blood pressure. Use of an ACE-I may reduce the pro-
gression of retinopathy, independently of blood pressure reduction, especial-
ly in normotensive type 1 diabetics.

Neuropathy
In the primary prevention cohort of the DCCT, intensive therapy delayed the
appearance of neuropathy at 5 years by 69%. Ten per cent of the conventional
treatment group developed neuropathy compared to 3% in the conventional
group. Progression (as judged by clinical findings and nerve conduction stud-
ies) was reduced by 59%.
Fig. 7.9 Cumulative incidence of sustained change in retinopathy in patients with
IDDM receiving intensive or conventional therapy in the secondary prevention arm of
the DCCT. Year of study refers to sample sizes at different years of the study. NEJM
1993; 329: 977–986.
40
30
20
0
10
60
Conventional
Intensive
P<0.001
50
0
Conventional
Intensive
123
348
354
4
Year of study
5
324

335
67
128
136
8 9
79
93
Patients (%)
In UKPDS, however, no differences were observed between treatment
groups. Aldose reductase inhibitors have not been found to give sustained or
clinically relevant improvements in nerve function.
CONCLUSION
The last two decades have seen the publication of a large number of well
designed, randomized controlled trials which have identified interventions
that can prevent or retard the progression of the micro- and macrovascular
complications of diabetes. The combination of intensified glycaemic control
and aggressive treatment of hypertension and hyperlipidaemia offers the per-
son with diabetes the chance to extend life-expectancy and improve quality of
life. Health organizations, pharmaceutical companies and politicians must
work closely together to devise strategies aimed at preventing type 2 diabetes
and setting up health surveillance systems that identify patients early in their
disease, prior to the onset of complications, so that these interventions can
have the maximum benefit. Nevertheless, these treatments require great com-
mitment from both patient and health professionals and are, for most of the
world’s diabetic population at present, unaffordable.
FURTHER READING
Klein R. Hyperglycaemia and microvascular and macrovascular disease in diabetes. Diabetes
Care 1995; 18(2) 258–268.
The Diabetes Control and Complications Trial Research Group. The effect of intensive
treatment of diabetes on the development and progression of long-term complications

in insulin dependent diabetes mellitus. NEJM 1993; 329: 977–986.
UK Prospective Diabetes Study (UKPDS) Group Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complica-
tions in patients with type 2 diabetes (UKPDS 33). The Lancet 1998; 352: 837–853.
SECTION I • MICRO- AND MACROVASCULAR COMPLICATIONS OF DIABETES
76
SECTION II
DIABETIC
NEUROPATHIES
Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition
Edited by Richard Donnelly, Edward Horton
Copyright © 2005 by Blackwell Publishing Ltd
Table 8.1 Classification of diabetic neuropathy.
7979
CHAPTER 8
CLASSIFICATION AND CLINICAL FEATURES
OF NEUROPATHY
Rayaz A. Malik MB.ChB, PhD, MRCP
79
INTRODUCTION
Diabetic neuropathy may simply be defined as the presence of symptoms
and/or signs of peripheral nerve dysfunction in people with diabetes after the
exclusion of other causes. It can only be diagnosed with a careful clinical
examination, and absence of symptoms cannot be equated with absence of
neuropathy. Diabetic neuropathy should not be diagnosed on one symptom,
sign or test alone: a minimum of two abnormalities (from symptoms, signs,
nerve conduction abnormalities, quantitative sensory tests or quantitative
autonomic tests) is recommended.
CLASSIFICATION
The preferred clinical classification is outlined in Table 8.1.

Generalized symmetrical polyneuropathies
Chronic sensorimotor neuropathy is the commonest manifestation of the dia-
betic neuropathies. Positive painful symptoms tend to be intermittent and more
pronounced at night. Patients may also experience ‘negative’ symptoms such as
numbness and unsteadiness due to disturbed proprioception and abnormal
muscle sensory function resulting in repetitive minor trauma, falls or Charcot’s
neuroarthropathy. Neurological examination demonstrates a symmetrical sen-
sory loss to all modalities in a stocking distribution which in severe cases may
extend to the knees and hands. This is accompanied by reduced or absent ankle
Classification of diabetic neuropathy
Generalized symmetrical polyneuropathies
Sensorimotor (chronic)
Acute sensory
Hyperglycemic neuropathy
Autonomic neuropathy
Focal and multifocal neuropathies
Cranial
Thoracolumbar radiculoneuropathy
Focal limb
Proximal motor (amyotrophy)
Superimposed chronic inflammatory demyelinating neuropathy (CIDP)
Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition
Edited by Richard Donnelly, Edward Horton
Copyright © 2005 by Blackwell Publishing Ltd
SECTION II • DIABETIC NEUROPATHIES
80
and knee reflexes, respectively. Autonomic dysfunction may manifest as dry
skin. Motor weakness is unusual, although small muscle wasting can be seen in
the feet and hands in severe neuropathy. The ‘at-risk’ foot for neuropathic ulcer-
ation might also have a high arch (pes cavus) and clawing of the toes.

Acute Sensory neuropathy is chararacterized by severe sensory symptoms
(hyperaesthesiae, dysaesthesia), allodynia on sensory testing, preserved
strength and occasionally reduced ankle reflexes. Pain is the outstanding
complaint in all patients which may be accompanied by severe weight loss
and depression. Relatively rapid alterations in glycaemic control as a result of
ketoacidosis, weight loss and eating disorders or a sudden improvement in
blood sugars by either insulin or oral hypoglycemic agents (insulin neuritis)
may precipitate an acute or sub-acute onset of debilitating symptoms which
resolve in less than a year. The pathogenesis is unclear although epineurial
arterio-venous shunts and proliferating “new vessels” have been observed in
such patients suggesting that endoneurial ischemia precipitated by the sud-
den improvement of glycaemic control may cause this condition.
Hyperglycaemic neuropathy: Rapidly reversible distal uncomfortable sen-
sory symptoms may be accompanied by abnormalities of nerve conduction in
patients with recently diagnosed or transiently poorly controlled diabetes
with recovery following restoration of euglycaemia.
Autonomic neuropathy
Diabetic autonomic neuropathy is common though rarely severely sympto-
matic and results in significant morbidity and mortality. The cardiovascular,
gastrointestinal, urogenital, sudomotor and pupillomotor systems may be
involved alone or in combination. The most common dysautonomic condi-
tions together with their symptoms are listed in Table 8.2.
Staging
The agreed clinical stages of diabetic neuropathy are shown in Table 8.3.
Focal and multifocal neuropathies
Entrapment neuropathies occur in older type 2 diabetic patients. Carpal tun-
nel syndrome is the most common entrapment neuropathy encountered in
diabetic patients as a result of median nerve compression under the trans-
verse carpal ligament. Whilst an electrophysiological deficit can be demon-
strated in 20–30% of patients it is symptomatic in only 5.8%. Painful paraes-

thesiae of the fingers may progress to a deep-seated ache, which radiates up
the forearm and arm with nocturnal exacerbation. Demyelination occurs and
treatment options include wrist splints, injections of cortisone into the carpal
tunnel and surgical decompression by sectioning the transverse carpal liga-
Table 8.3 Staging severity of diabetic neuropathy.
Table 8.2 Clinical features of autonomic neuropathies.
CHAPTER 8 • CLASSIFICATION AND CLINICAL FEATURES OF NEUROPATHY
81
Clinical features of autonomic neuropathies
System Feature Symptoms
Cardiovascular Orthostatic hypotension Dizziness, lightheadedness, pre-
syncope and syncope.
Exercise intolerance Early fatigue/weakness on
exercise
Gastrointestinal Hypomotility Dysphagia and heartburn, early
satiety, nausea, vomiting,
belching, bloating, constipation
Hypermotility Diaorrhea (nocturnal),
incontinence
Urogenital Bladder dysfunction Frequency, urgency, nocturia,
urinary retention/ incontinence
Sexual dysfunction Erectile dysfunction, ejaculatory
failure, retrograde ejaculation,
vaginal dryness
Sudomotor Sweating abnormalities Anhydrosis, heat intolerance,
gustatory sweating.
Pupillomotor Visual abnormalities Visual blurring,
impaired adaptation to light
Autonomic afferent Reduced visceral sensation Silent myocardial ischemia,
abdominal crises

Staging severity of diabetic neuropathy
N0 = No objective evidence of diabetic neuropathy
N1 = Asymptomatic polyneuropathy
N1a no symptoms or signs but neuropathic test abnormalities
N1b test abnormalities
1
+ neuropathy impairment on neurological exam
N2 = Symptomatic neuropathy
N2a symptoms, signs and test abnormality
N2b N2a + significant ankle dorsiflexor weakness
N3 = Disabling polyneuropathy
1
nerve conduction, QST or autonomic test abnormalities.
SECTION II • DIABETIC NEUROPATHIES
82
ment. These provide variable degrees of pain relief but do not necessarily ben-
efit muscle wasting or sensory loss. Ulnar neuropathy occurs in 2.1% of
patients as a result of ulnar nerve compression in the cubital tunnel. Painful
paraesthesiae in the 4
th
and 5
th
digits may be associated with hypothenar and
interosseous muscle wasting. Both demyelination and axonal degeneration
occur and management is conservative as the results of surgery are poor.
Other entrapment neuropathies involve the radial, common peroneal, lateral
femoral cutaneous and very rarely sciatic and obturator nerves.
Cranial neuropathies are extremely rare (0.05%) and occur in older indi-
viduals with a long duration of diabetes. For the ocular neuropathies cranial
nerves III (3.3%), IV (3.3%) and VI (2.1%) are affected. Oculomotor nerve palsy

presents with acute diplopia, ptosis and pupillary sparing which resolves over
approximately 2.5 months but can recur in 25% of patients. Subperineurial
microfasciculation and demyelination have been shown to occur. 6–48% of
patients with idiopathic facial neuropathy or Bell’s palsy have diabetes. Acute
onset weakness of facial muscles, widening of the palpebral fissure and second-
ary corneal irritation may be accompanied by a disturbance in taste and hyper-
acusis. Concomitant hypertension and severity of paralysis determine the
degree of recovery at one year. There are reports of an increased frequency of
trigeminal neuralgia and hearing loss as a result of VIII nerve involvement.
Diabetic amyotrophy occurs in patients with type 2 diabetes aged 50–60
years and presents with severe pain and uni- or bilateral muscle weakness and
atrophy in the proximal thigh muscles. Electrophysiology shows spontaneous
fibrillation, alterations in the amplitude of the motor unit potential, a reduc-
tion in femoral nerve conduction velocity and an attenuated compound mus-
cle action potential of the quadriceps muscle. Recent reports have demonstrat-
ed centro-fascicular degeneration of the intermediate cutaneous nerve of the
thigh with an inflammatory infiltrate and occlusion of epineurial blood vessels
with features of a necrotizing vasculitis (arteriolar, venular and capillary wall
infiltration with inflammatory cells) with haemosiderin deposition (Fig. 8.1).
Based on the observations of a vasculitis in a proportion of patients, immuno-
suppressive therapy has been recommended using initial intravenous, followed
by high dose oral corticosteroids, or intravenous immunoglobulin.
Diabetic truncal radiculoneuropathy affects middle-aged to elderly dia-
betic patients. Pain occurs in a girdle like distribution over the lower thoracic
or abdominal wall and is of an aching or burning quality, superimposed with
lancinating stabs in a unilateral and rarely bilateral distribution. Profound
weight loss may accompany the onset of symptoms. Clinical examination
demonstrates heterogeneous neurological findings ranging from no abnor-
mality to sensory loss and hyperaesthesia in a complete dermatomal pattern.
Electromyography demonstrates denervation potentials in the intercostal,

anterior abdominal wall, and paraspinal muscles. The natural history is for
83
CHAPTER 8 • CLASSIFICATION AND CLINICAL FEATURES OF NEUROPATHY
spontaneous resolution within 4–6 months. An improvement in glycaemic
control has been advocated, as has immunosuppressive therapy with corti-
costeroids, or intravenous immunoglobulin.
CHRONIC INFLAMMATORY DEMYELINATING
POLYNEUROPATHY (CIDP)
Diabetic patients occasionally develop clinical and electrodiagnostic features
suggestive of CIDP. Thus if an unusually severe and progressive polyneu-
ropathy develops in diabetic patients one must consider CIDP. Current elec-
trodiagnostic and pathological criteria appear to be insufficient for defining
many cases of CIDP and therefore certainly should not be relied on to differ-
entiate from diabetic polyneuropathy. The presence of increased numbers of
macrophages suggestive of a macrophage-associated demyelination may be
helpful as this is a characteristic feature of CIDP not observed in diabetic
polyneuropathy. Treatment requires long-term immunomodulatory therapy
with combinations of corticosteroids, azathioprine, plasmapharesis and
intravenous immune globulin which produces relatively rapid and substan-
tial improvement in neurological deficits and electrophysiology.
Fig. 8.1 Light microscopic H&E section showing epineurial arteriolar and venular wall
infiltration with inflammatory cells and haemorrhage.
SECTION II • DIABETIC NEUROPATHIES
84
FURTHER READING
Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies: technical
review. Diabetes Care 2004; 27: 1458–1486.
Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes
Care 2003; 26: 1553–1579.
CHAPTER 9

PATHOPHYSIOLOGY OF DIABETIC
NEUROPATHY
Rayaz A. Malik MB.ChB, PhD, MRCP
85
Studies in animal models and cultured cells provide a conceptual framework
for the pathogenesis of experimental diabetic neuropathy. However, transla-
tional studies in diabetic patients continue to generate much debate and con-
troversy over the cause(s) and treatment of human diabetic neuropathy.
Hyperglycaemia
Longitudinal data from the Rochester cohort supports the contention that the
duration and severity of exposure to hyperglycaemia are related to the severi-
ty rather than the onset of neuropathy. Similarly, in a study of newly diagnosed
patients with type 2 diabetes followed from base-line for a period of 10 years,
the overall severity but not the development of neuropathy was related to the
degree of hyperglycaemia. Although recent studies in patients with impaired
glucose tolerance (IGT) suggest that even minor degrees of glucose dysmetab-
olism may lead to the development of neuropathy. In patients with IGT sural
nerve amplitude and myelinated fiber density do not differ from those with
normal glucose tolerance. Although, of 121 patients with a painful neuropathy
and electrodiagnostic evidence of axonal injury and epidermal nerve fibre
abnormalities, 25% had impaired glucose tolerance. Intensive insulin therapy
or pancreatic transplantation improves neuropathy in patients with type 1 dia-
betes. This is not proven in type 2 diabetes as both the VA Cooperative Study
on type 2 Diabetes Mellitus (VACSDM) and Steno-2 study failed to demon-
strate an improvement in somatic neuropathy.
Polyol Pathway
Animal models of diabetes consistently demonstrate an association between
increased flux through the polyol pathway and a reduction in nerve conduc-
tion velocity which can be ameliorated with aldose reductase inhibitors
(ARIs). In humans the situation is not clear and in one of the earliest stud-

ies, sorbitol and fructose levels were increased in only one third of the sural
nerve biopsies studied and could not be related to clinical, neurophysiolog-
ical, or pathological severity of neuropathy. A significant increase in glucose,
fructose and sorbitol was observed in post-mortem sciatic nerves from dia-
betic patients and in nerves obtained at amputation, though the actual con-
centrations differed markedly in these two studies. In a recent study of
patients with normal glucose tolerance, IGT and type 2 diabetes only, the
diabetic patients demonstrated an elevation in nerve sorbitol, suggestive of a
glycaemic threshold for activation of this pathway. Linear regression analy-
sis has demonstrated a significant inverse correlation between nerve sorbitol
and myelinated fibre density. It also appears that those at greatest risk of
Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition
Edited by Richard Donnelly, Edward Horton
Copyright © 2005 by Blackwell Publishing Ltd
SECTION II • DIABETIC NEUROPATHIES
86
developing the complications are those with a higher set-point for aldose
reductase activity. Furthermore, polymorphisms in the promoter region of
the aldose reductase gene leading to a highly significant decrease in the fre-
quency of the Z+2 allele have been demonstrated in patients with overt neu-
ropathy compared to those without neuropathy. A meta-analysis of all ran-
domized controlled trials of ARIs was disappointing. It identified 19 trials,
testing four different ARIs for 4–208 weeks (median 24 weeks) and demon-
strated a small but statistically significant reduction in decline of median
(0.66 m/s 95% CI 0.18–1.14m/s) and peroneal (0.53 m/s 95% CI 0.02-
1.04m/s) motor nerve conduction velocity (NCV) without benefit in senso-
ry nerves. More recent trial data has been more encouraging and seems to
show that the degree of aldose reductase inhibition may determine the
improvement observed. Thus zenarestat demonstrated a dose-dependent
increment in sural nerve sorbitol suppression accompanied by significant

improvement in NCV, and in doses producing >80% sorbitol suppression
there was a significant increase in the density of small-diameter myelinated
fibres of the sural nerve. More recently, fidarestat, a potent ARI significant-
ly improved median nerve F-wave conduction velocity (FCV) and minimal
latency as well as symptoms of numbness, spontaneous pain, paraesthesiae
and hyperaesthesiae.
Myoinositol
Myoinositol deficiency has been proposed to play an important role in the
pathogenesis of diabetic neuropathy on the basis of data in experimental dia-
betes. This has not been borne out in human nerve biopsies with no study to
date showing a reduction in myoinositol levels.
Glycation
Hyperglycaemia results in the formation of advanced glycation end-prod-
ucts (AGEs), which in turn act on specific receptors (RAGE), inducing
monocytes and endothelial cells to increase the production of cytokines and
adhesion molecules. Glycation has also recently been shown to have an effect
on matrix metalloproteinases (MMPs), in particular MMP-2 which degrades
type IV collagen, membrane type 1 MMP, tissue inhibitors of MMPs
(TIMP)-1 and -2, and transforming growth factor β (TGF-β‚). Glycation also
prevents epidermal growth factor auto-phosphorylation and activates extra
cellular signal-regulated kinases (ERKs). In experimental diabetes these
changes can be prevented by AGE inhibitors such as the nucleophilic com-
pounds pyridoxamine, tenilsetam, 2, 3-diaminophenazone or aminoguani-
dine. Alternatively the administration of recombinant RAGE hinders the
AGE-RAGE interaction. Sural nerves obtained from diabetic and non-dia-
betic amputation specimens demonstrate significantly elevated pentosidine
CHAPTER 9 • PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY
87
levels in both cytoskeletal and myelin protein. Enhanced staining for car-
boxymethyllysine has been demonstrated in the perineurium, endothelial

cells and pericytes of endoneurial microvessels as well as myelinated and
unmyelinated fibres of sural nerves of patients with type 2 diabetes.
Pyrraline, an advanced glycation end product is also increased in post-
mortem samples of optic nerve from diabetic patients. Intervention trials
have focused on nephropathy and no trial data is currently available for
human diabetic neuropathy.
Oxidative stress
There is emerging evidence that single-nucleotide polymorphisms of the
genes for mitochondrial (SOD2) and extracellular (SOD3) superoxide dis-
mutases may confer an increased risk for the development of neuropathy.
Alpha-lipoic acid (LA), a powerful antioxidant that scavenges hydroxyl rad-
icals, superoxide and peroxyl radicals and regenerates glutathione has been
shown (ALADIN-II study) to improve symptomatic neuropathy and, over
two years sural SNCV, SNAP and tibial MNCV. In ALADIN-III 509 diabet-
ic patients were randomized to LA intravenously for three weeks, followed
by oral treatment, compared to placebo. Whilst the total symptom score
remained unchanged, an improvement in the neuropathy impairment score
was observed after three weeks of i.v. therapy, which was maintained until
the end of the study. Most recently the SYDNEY study has demonstrated a
significant improvement in the neuropathy symptom score, neuropathy
impairment score and one attribute of nerve conduction after daily i.v. with
racemic LA for five days/week for 14 treatments.
Vascular factors
Large vessel revascularization studies have shown an improvement in NCV
in one but not another study. Although in the latter study at long-term fol-
low up a prevention of worsening of peroneal NCV was shown. In a double-
blind placebo controlled clinical trial of trandalopril over 12 months, per-
oneal motor NCV, M-wave amplitude F-wave latency and sural nerve ampli-
tude improved significantly. Although in the Appropriate Blood Pressure
Control in Diabetes (ABPCD) trial the effects of intensive versus moderate

blood pressure control with either nisoldipine or enalapril were assessed and
surprisingly failed to prevent progression of not only diabetic neuropathy
but also nephropathy and retinopathy.
Protein kinase C-β
1, 2-diacylglycerol (DAG) induced activation pf protein kinase C (PKC). In par-
ticular, PKC-β, has been proposed to play a major role in diabetic neuropathy.
Although in nerves from diabetic animals a fall in DAG levels and a consistent
SECTION II • DIABETIC NEUROPATHIES
88
pattern of change in PKC activity has not been observed, inhibition of PKC-β
corrects reduced nerve blood flow and NCV. Based on the findings of a phase
II clinical trial demonstrating some benefit in diabetic patients with neuropa-
thy, multi-centre randomized, double-blind, placebo controlled trials are
underway, and are due to complete in 2006.
Hydroxymethylglutaryl CoA reductase inhibitors
An increasing body of evidence suggests that conventional risk factors for
macrovascular disease such as deranged lipids are important in the patho-
genesis and progression of human diabetic neuropathy. Recent studies show
that hydroxymethylglutaryl CoA reductase inhibitors may enhance endothe-
lial cell nitric oxide bioavailability and prevent AGE-induced NF-kb induced
protein-1 activation and up-regulation of vascular endothelial growth factor
(VEGF) mRNA, thus ameliorating experimental diabetic neuropathy. Thus
simvastatin has shown a trend towards slower progression of neuropathy
measured by vibration perception threshold but no change in clinical neu-
ropathy. As a caution, recent case studies suggest a link between statin use
and an increased risk of peripheral neuropathy.
GROWTH FACTORS
Neurotrophins
Neurotrophins promote the survival of specific neuronal populations by induc-
ing morphological differentiation, enhancing nerve regeneration, stimulating

neurotransmitter expression, and altering the physiological characteristics of
neurones. Studies in experimental models of diabetes demonstrate a depletion
of nerve growth factor (NGF) and NT3 which if corrected ameliorates NCV
deficits. Although initially studies in the skin of patients with diabetic neuropa-
thy demonstrated a depletion of NGF, subsequent studies have shown a signif-
icant increase in skin NGF mRNA and NT3 concentrations with normal sciat-
ic nerve ciliary neurotrophic factor levels. In situ hybridization studies have also
demonstrated an increased expression of trkA, the high-affinity receptor for
NGF, and trkC, the receptor for NT3, in the skin of diabetic patients. Despite
these apparently contradictory findings, a phase II clinical trial of recombinant
human NGF in 250 patients with diabetic neuropathy demonstrated a signifi-
cant improvement in the sensory component of the neurological examination
and two quantitative sensory tests. However, a phase III trial in 1,019 diabetic
patients with sensory polyneuropathy failed to demonstrate a significant bene-
fit. Recently a randomized, double-blind, placebo controlled study of brain-
derived neurotrophic factor (rhBDNF) in 30 diabetic patients demonstrated no
significant improvement in nerve conduction and quantitative sensory and
autonomic function tests, including the cutaneous axon-reflex.