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QXD 10/13/01 5:09 PM Page 520

Journal of Clinical Neuroscience (2001) 8(6), 520–524

© 2001 Harcourt Publishers Ltd
doi: 10.1054/jocn.2001.0893, available online at http://www.idealibrary.com on

Clinical study

The natural history of diabetic peripheral neuropathy

determined by a 12 year prospective study using
vibration perception thresholds
D. V. Coppini1, A. Wellmer2, C. Weng1, P. J. Young3, P. Anand2 FRCP, P. H. Sönksen1
1
Division of Medicine, United Medical and Dental Medical Schools, St. Thomas’ Hospital, London, UK, 2Peripheral Neuropathy Unit, Division of
Neuroscience and Psychological Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK, 3Department of
Health Sciences, University of York, York, UK

Summary The development and long term progression of diabetic peripheral neuropathy was studied using vibration perception threshold
(VPT) as a validated measure. Three hundred and ninety-two patients had a normal age corrected VPT (12.1<3.7 volts) at baseline, with an
age corrected logarithmic VPTscore :12. 19.9% developed an abnormal VPT over a 12 year period, increasing from 14.2<3.7 volts
(VPTscore 10.4<0.6) at baseline to 35.9<9.5 volts (VPTscore 12.6<0.45) at follow up (P:0.0001), and from 10.1<3.7 volts (VPTscore
9.4<0.8) to 14.2<4.7 (VPTscore 9.8<0.8) in the rest. Over 80% thus retained a ‘normal’ VPT after a mean diabetes duration of 16 years
despite only average glycaemic control, suggesting that non-ideal long term glycaemic control leads to neuropathy in a subset of predis-
posed patients. VPT was correlated in 123 diabetic patients with definitive criteria for neuropathy and a range of quantitative sensory and
autonomic tests. 62/63 patients with abnormal VPT fulfilled neuropathy criteria; of patients with normal VPT who fulfilled neuropathy criteria,
all had at least one abnormal thermal threshold test result. We conclude that a combination of log-transformed VPT values (VPTscore 910.1)
and thermal thresholds can identify diabetic patients at risk of developing peripheral neuropathy and select patients likely to benefit from pro-
phylaxis in clinical trials. © 2001 Harcourt Publishers Ltd

Keywords: diabetes mellitus, neuropathy, vibration perception threshold (VPT), VPTscore, risk factors

INTRODUCTION of peripheral neuropathy in subjects with normal age corrected

VPT at baseline and to identify the risk factors.
Adequate epidemiological information about the incidence and
natural history of peripheral neuropathy in diabetic patients is still
lacking, although it is a common and clinically significant compli- PATIENTS AND METHODS
cation. This is mainly due to different methods used to define
All patients (n:985) first attending the diabetes clinic at St. Thomas’
neuropathy and the length of follow up required. Even prevalence
Hospital between 1 January 1982 and 30 September 1985 had a
data varies widely in the literature.1–3 The prospect of prophylaxis
structured and comprehensive standardised first visit record
or new treatments of diabetic neuropathy makes such information
entered on our computer database (Diabeta). This clinic is a gen-
more important, and critical to the design of long term clinical
eral diabetic clinic in South London, and is not attached to a spe-
trials.
cialist foot clinic. Clinical examination of the lower limbs and
The Consensus Development Conference on Standardised
vibration threshold measurements at the great toe using a Bio-
Measures in Diabetic Neuropathy recommended the following
thesiometer (Biomedical Instrument, Newbury, Ohio, USA) were
four measures for the diagnosis of diabetic neuropathy: clinical
performed on all patients at first visit, irrespective of symptoms or
measures, morphological and biochemical analysis, electrodiag-
complications. The voltage reading from the Bio-thesiometer was
nostic assessment and quantitative sensory testing.4 These pro-
entered into the computer which calculates a ‘VPTscore’ by com-
posals, however, are impractical in most routine clinical settings
paring the patient’s value with an age-related normal population.
and are mainly intended for research purposes. We therefore stud-
The VPTscore is calculated by adding a value of ‘10’ (hence pro-
ied the role of vibration threshold as a predictor of future neuro-
ducing a positive number) to the number of standard deviations
pathic complications in a long term and large scale study in
that an individual’s reading is away from the mean of normal sub-
diabetic patients.5,6 We also determined the validity of vibration
jects of the same age. VPT has been shown to vary with age.8,9 In
perception abnormalities as markers of peripheral neuropathy by
normal subjects there is a linear relationship between the loga-
correlating these with standard Dyck neuropathy criteria7 and with
rithm of the Bio-thesiometer reading against age.
a range of other quantitative sensory and autonomic tests. The
The ‘VPTscore’ was calculated by the equation:
main aims of the study were to estimate the rate of development

(log10 bioo) – (log10 biom)

Received 31 October 2000
Accepted 19 January 2001
Correspondence to: Prof. Praveen Anand, Peripheral Neuropathy Unit,
Division of Neuroscience and Psychological Medicine, Imperial College
School of Medicine, Hammersmith Hospital, Du Cane Road, London
W12 0NN, UK. Tel.: ;44 (0)181-383 3309 / 3319; E-mail: P. Anand@ic.ac.uk
(a) VPTscore:10; ᎏᎏᎏ
s
where bioo is the observed reading on the Bio-thesiometer (in
volts), biom is the normalised value (mean of normal subjects) and
s is the residual standard deviation of the normalised value. The
normalised value was calculated from a linear fit to the logarithm
of normal data of Bio-thesiometer reading against age in years.

520
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The natural history of diabetic peripheral neuropathy 521

(slope X age);intercept excluded from subsequent analysis leaving 392 of the original 423
(b) (log10 biom ): ᎏᎏᎏ patients eligible for analysis in the follow up. Insulin-dependent
s
diabetes was defined as onset of diabetes : age 40 years.
Substituting for (log10 biom) in equation (b) To evaluate the validity of VPT as a useful measure of neuropa-
thy, 123 diabetic patients from a separate cohort were studied at
the Royal London Hospital. The age range of patients in this
(log10 bioo)9(slope X age);intercept group was 25 to 69 years (mean 48 years) and 65% were male.
(c) VPTscore:10; ᎏᎏᎏᎏ 70% had insulin dependent diabetes and the mean HbA1c in the
s
cohort was 8.1%. On the basis of neuropathic symptoms, neuro-
logical examination, quantitative sensory and autonomic tests and
The values for the slopes, intercepts and standard deviations (s) at
nerve conduction studies, neuropathy was defined according to
various sites were derived from Bloom et al.8 A VPTscore 912
Dyck’s criteria.7 The methods of quantitative sensory and auto-
corresponds to the 95th percentile, and thus scores above 12 are
nomic function testing have been described previously.11 In brief,
taken to be abnormally high.
foot sole thermal thresholds were tested with computer-driven
Details of lower limb examination were also entered into a
Marstock thermal threshold testing system (Somedic Thermotest,
structured template in the patient’s respective file in Diabeta. Eye
Stockholm). The device was set at a rate of rise in temperature of
fundus examination (through dilated pupils where possible), HbA1
1°C/sec. Thermal thresholds were determined for cool and warm
(Corning method), dipstick urine test results (Albustix), and smok-
sensation, and heat pain, as a mean of four consecutive tests. VPT
ing and alcohol history were also entered. Entry of height and
was measured using a Bio-thesiometer, and light touch was
weight are automatically transformed into a body mass index
assessed using a set of Semmes-Weinstein monofilaments using
(BMI). Retinopathy was present if patients had one or more microa-
the same methods as for the prospective study described above.
neurysms, exudates or preretinal haemorrhages (background
Peak axon-reflex sweating was measured with an Evaporimeter
retinopathy) or had proliferative changes (proliferative retinopathy).
(Servomed, Stockholm) after intradermal injection of nicotine
Glycaemic control over 12 years was based on an average of 15
(0.8 ␮g in 0.2 ml) into the right lateral calf skin. Axon-reflex
HbA1 tests per patient during that period.
vasodilatation (ARV) was determined by measurement of
Smoking risk was assessed by comparing outcome in smokers
increased flux using a laser Doppler device (Perimed PF4,
and non-smokers at baseline, and by calculating the average life-
Stockholm) after intradermal injection of capsaicin (0.5␮g in
time smoking years in patients with and without neuropathy
10 ␮l) into the right lateral calf skin. Sural and peroneal nerve
events at review. The effect of alcohol consumption in patients at
conduction was measured using standard techniques. All studies
baseline was analysed using a cut-off of 6 units weekly.
were approved by the St. Thomas’ and Royal London Hospital
Four hundred and twenty-three patients (43%) were success-
Ethics Committees.
fully recruited to the follow up study. We have previously shown
that this group of patients was adequately representative of the
original cohort of patients.5 All these patients in the follow up STATISTICAL ANALYSIS
study (n:423) were reviewed by one observer (DVC) in 1995
Analyses were conducted with logistic regression, using the NLIN
and VPT measurements were repeated. The Bio-thesiometer was
procedure of the SAS system.12 Sensitivity and specificity values
balanced vertically on the pulp of the great toe to measure the
were also obtained using the CTABLE option with prior probabili-
vibration threshold (average of both toes) and a mean of three
ties set to the observed frequency of cases. In the validation study,
readings was used to derive the value on each patient. The same
the frequency of abnormality on VPT was compared with the fre-
instrument was used to test all patients. Sensory testing using a
quency of abnormality on other tests using the chi-square test.
5.07 Semmes-Weinstein monofilament was also performed on the
dorsum of the great toe. Eight correct responses out of 10 applica-
tions indicated normal sensation; one to seven correct responses RESULTS
indicated reduced sensation (score of 1); and no correct responses
Baseline clinical characteristics of patients entering the prospec-
translated into absent sensation (score of 2). All patients
tive study are presented in Table 1. Normal ankle reflexes were
also underwent a screening examination using the Michigan
present in 93% of patients and cotton wool sensory testing was
Neuropathy Screening Instrument (MNSI). A score 92 has been
intact in all but one patient. None of the patients had a history of
shown to identify patients with diabetic neuropathy.10 A history of
foot ulceration at the baseline visit. Seventy-eight patients
both positive (tingling, burning or increased sensitivity in feet or
(19.9%) developed peripheral neuropathy over a mean 12–year
legs) or negative (reduced feeling in feet) symptoms was also
period. VPT in these patients increased from 14.2<3.7 volts
recorded. A family history of diabetes was recorded as positive
(VPTscore 10.4<0.6) at baseline to 35.9<9.5 volts (VPTscore
only if present in parents or siblings. A history of hypertension
12.6<0.45) at follow up (P:0.0001) and from 10.1<3.7 volts
was recorded if patients had been treated for this. A finger-prick
(VPTscore 9.4<0.8) to 14.2<4.7 (VPTscore 9.8<0.8) in the rest
capillary blood sample was used to measure total cholesterol,
of the patients (P:0.0001) (Table 1).
triglycerides and creatinine levels (Colorimetry method, Cobas
Fifteen (3.8%) patients (all but one patient in the abnormal VPT
Mira analyser, Roche Diagnostics, UK). A first morning urine
group) developed lower extremity complications. Seven patients
sample was tested for proteinuria (Albustix, Bayer Diagnostics,
(1.8%) had active plantar foot or toe ulcers at the time of review
UK). In patients with a negative test, an albumin-creatinine ratio
and eight patients (2%) had either toe or more proximal amputa-
(ACR) was measured on the same sample (Turbidimetry method,
tions over the 12-year period. There was no significant difference
Cobas Mira analyser, Roche Diagnostics, UK). Microalbuminuria
in the number of patients with impalpable pedal pulses in the two
was defined as an ACR93.
groups.
We defined VPT abnormality as a VPTscore at review 912.
Retinopathy at baseline, male gender, tall stature and Caucasian
Subjects with a VPTscore :12 were considered as ‘normal’ for
ethnicity were all independent positive predictors for peripheral
VPT. Thirty-one (7.3%) patients (males 62%; caucasian 87%)
neuropathy (Table 1). Glycaemic control (average HbA1 over 12
who had abnormal VPT by this criterion at the baseline visit were
years) was worse in patients developing an abnormal VPT

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522 Coppini et al.

Table 1 Baseline characteristics of patients with and without future neuropathy

Patients developing ‘Normal’ patients P value

neuropathy (n:78) (n:314)

Male 54 (69.2) 153 (48.7) 0.002

Age* 46.8<9.6 48.3<10.3 0.40
IDDM 26 (33.3) 92 (29.3) 0.30
Caucasian 61 (78.2) 201 (64.1) 0.02
Afro-Caribbean 12 (15.3) 88 (28.0) 0.02
Toe VPT (volts)* 14.2<4.7 10.1<3.7 0.0001
VPTscore* 10.4<0.6 9.4<0.8 0.0001
Absent ankle reflexes 8 (10.2) 25 (8.0) 0.62
Absent cotton wool sensation 1 (1.3) 2 (0.6) 0.53
(feet)
Retinopathy (any grade) 18 (23.1) 42 (13.4) 0.02
Proteinuria (.1;) 7 (9.0) 15 (4.8) 0.12
HbA1* 12.6<2.6 12.1<2.7 0.20
BMI (kg/m2)* 28.1<5.2 27.2<4.4 0.20
Height (cm)* 169.7<8.2 165.9<7.2 0.001
Smokers 14 (17.9) 79 (25.2) 0.30
Alcohol (96 units weekly) 49 (62.8) 186 (59.2) 0.50

Data are n (%) or otherwise specified.

*mean<SD.

Table 2 Characteristics of patients with and without neuropathy at review

Patients with ‘Normal’ patients P value

neuropathy n:78 n:314

Age (years)* 58.0<10.0 60.0<11.8 0.30

Duration* 17.6<7.3 16.1<6.1 0.10
Toe VPT (volts)* 35.9<9.5 15.5<6.6 0.0001
VPTscore* 12.6<0.45 9.8<0.8 0.0001
Abnormal monofilament 36 (46.1) 37 (11.8) 0.0001
Perception (score 1or 2)
MNSI (score 92) 42 (53.8) 33 (10.5) 0.0001
Absent pedal pulses 11 (14.1) 25 (8.0) 0.06
Plantar ulceration 6 (7.7) 1 (0.3) 0.002
Amputations 8 (10.2) 0 (0) 0.0007
Neuropathic symptoms 35 (44.8) 68 (21.6) 0.0001
Hypertension history 14 (17.9) 80 (25.5) 0.20
Retinopathy (any grade) 48 (61.5) 125 (39.8) :0.01
Microalbuminuria (ACR93) 17 (21.8) 85 (27.0%) 0.20
Proteinuria (.1;) 25 (32.1) 75 (23.8) 0.01
Average HbA1 over 12 years* 11.0<1.4 10.4<1.4 0.01
Total cholesterol (mmol/L)* 5.5<0.9 5.4<1.0 0.40
Triglycerides (mmol/L)* 2.4<1.2 2.2<1.1 0.60
Creatinine (␮mol/L)* 103.0<24.7 97.0<21.4 0.10
Family history of diabetes 25 (32.0) 75 (27.1) 0.50
Lifetime smoking years † 17.2 (0-57) 13.8 (0-61) 0.10
Insulin treatment 43 (55.1) 138 (44.0) 0.20
Tablet treatment 30 (38.5) 155 (49.4) 0.08
Diet treatment 5 (6.4) 21 (6.6) 0.60

Data are n (%) or otherwise specified. Paired statistical tests were performed using logistic regression.
* mean<SD. †mean and range.

(11.0<1.4% v. 10.4<1.4%, neuropathy v. normal; P:0.01)
(Table 2). First visit (baseline) HbA1 was not significantly differ-
ent in the two groups. Abnormal clinical tests (monofilament test-
ing and MNSI 9 2) and lower extremity complications were all
strongly associated with an abnormal VPT at review (Table 2). A
VPTscore cut-off 9 10.1 showed overall better (P:0.02) sensi-
tivity (77.3%) and specificity (72.8%) in predicting outcome than
raw VPT values (sensitivity and specificity 63.6% and 68%,
respectively, for VPT of 10 volts). It is interesting to note that a
VPTscore of 10 is the mean value of normal subjects in an age
group. Thus the cut off value to predict an abnormal value
(VPTscore912) at the follow up coincides with the mean value of
normal subjects.
In the second (validation) study, there was a highly significant
correlation of other tests with VPT for abnormal values (Table 3).
Not all tests could be performed on every patient, as the numbers
indicate in the Table. Seventy nine of 94 patients who had all the
appropriate tests fulfilled the Dyck criteria for neuropathy. Only
one out of 63 patients (1.6%) with an abnormal VPT was not diag-
nosed as having neuropathy. The predominant symptom occurring
in patients with neuropathy on Dyck criteria who had normal VPT
was distal limb pain (in 14 out of 17 patients), and there were
abnormalities in thermal thresholds in all such cases. There was a
relatively high proportion of such cases as they were referred to a
neuropathy clinic for management of symptoms.
DISCUSSION
To our knowledge, this is the first long term prospective study
reporting on the natural history of peripheral neuropathy in relation

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The natural history of diabetic peripheral neuropathy 523

Table 3 Correlation of vibration perception threshold (VPT) abnormalities with abnormalities of other tests

Test (n) VPT abnormal (n:76) VPT normal (n:47) P value Regression analysis (on 48 cases with all tests)
␹² test
normal abnormal normal abnormal Correlation of test values with P value
% (n) % (n) % (n) % (n) VPT values (slope (95% CI)

sural nerve action 31.9 (22) 68.1 (47) 79.1 (34) 20.9 (9) :0.0001 90.124 (90.203 to 90.045) :0.003
potential (112)
monofilaments 35.8 (24) 64.2 (43) 74.4 (32) 25.6 (11) :0.0001 0.275 (0.209 to 0.340) :0.0001
(110)
cool perception 47.8 (32) 52.2 (35) 85.4 (35) 14.6 (6) :0.0001 0.204 (0.076 to 0.332) :0.003
threshold (108)
warm perception 16.2 (11) 83.8 (57) 37.5 (15) 62.5 (25) :0.05 0.140 (0.019 to 0.261) :0.03
threshold (108)
axon-reflex 25 (12) 75 (36) 28 (7) 72 (18) ns 90.592 (90.926 to 90.258) :0.001
vasodilatation (73)
Neuropathy defined 1.6 (1) 98.4 (62) 45.2 54.8 <0.001 0.036 (0.023 to 0.049) :0.0001
stages 1–3 (94) (14)* (17)†
normal – no neuropathy
abnormal – neuropathy

* 4/14 (28.6%) and † 14/17 (82.4%) had pain in the feet (P:0.005; Chi-square test).
* 4/14 (28.6%) and † 17/17 (100%) had abnormalities on warm threshold (P:0.0001; Chi-square test).

to quantitative vibration perception threshold testing. Use of
age corrected toe vibration thresholds as a marker of diabetic neu-
ropathy seems both reliable and practical. An abnormal VPT is
clearly related to other abnormal quantitative tests, and we have
previously shown that it is a useful predictor of lower extremity
complications.5 Although clinical tests (cotton wool sensation,
ankle reflexes) were normal in most patients (90%) at baseline,
vibration thresholds and ‘VPTscores’ were then already signifi-
cantly higher in patients who went on to develop an abnormal
VPT. We have previously reported higher vibration threshold mea-
surements at the time of diagnosis in a subset of insulin-dependent
diabetic patients in our cohort who subsequently developed
peripheral neuropathy.13 Vibration thresholds have also been
shown to correlate strongly with clinical scores in other studies.1,2
These findings suggest that subclinical large nerve fibre damage
may be present at an early stage in patients who subsequently
develop neuropathy. Most amputations (7/8) were at toe or fore-
foot level, indicating that these were for reasons of neuropathy
rather than ischaemia.
In our validation study, 62 out of 63 patients with neuropathy by
Dyck criteria had an abnormal VPT. The few patients with a nor-
mal VPT who had neuropathy by Dyck criteria presented with
symptoms of small sensory fibre dysfunction, particularly distal
limb pain, and all of these had at least one abnormal thermal
threshold. Painful diabetic neuropathy may result from dysfunction
of small unmyelinated sensory fibres, with or without dysfunction
of large sensory fibres.14,15 In accord, tests of unmyelinated sen-
sory fibre function were poorly correlated with VPT, especially
axon-reflex vasodilatation. Therefore when careful history taking is
combined with physical examination, VPT testing is a sensitive
and simple way for detecting neuropathy, and a combination of
VPT and thermal threshold appears to detect all cases of neuropa-
thy defined by Dyck criteria as well as subclinical neuropathy.
Patients with retinopathy at baseline were at increased risk of
developing peripheral neuropathy. Impaired blood flow has been
shown in some studies to be an important aetiological feature of
both neuropathy and retinopathy.16,17 Mild retinopathy is easier to
detect than early neuropathy in diabetic patients. Minor retinal
changes in the absence of any significant neurological abnormali-
ties may help identify patients at risk of future neuropathy.
Taller diabetic patients seem more vulnerable to peripheral neu-
ropathy, in keeping with the length-dependent presentation of
diabetic sensory polyneuropathy.18 Caucasian patients seem to be
at higher risk of developing neuropathy than Afro-Caribbean
patients. The risk of amputation in diabetic patients was 2.3 times
greater for blacks than whites in South Carolina,19 and 1.4 times
greater for non-whites in New Jersey20; other risk factors such as
peripheral vascular disease and poor socio-economic status may
play a more important role in foot complications in black patients
in the USA. The number of Asian patients entering the study was
probably too small (3.8%) to assess the overall risk of neuropathy
in this group, but no increase in susceptibility was detected.
The Diabetes Control and Complications Trial (DCCT)21 has
established that a lowering of HbA1c in patients with insulin-
dependent diabetes (IDDM) was associated with a reduction in
subsequent development of clinical neuropathy.21 Although haemo-
globin A1 levels at the baseline visit were not different, mean gly-
caemic control in our cohort of both insulin and non-insulin
dependent diabetic patients was worse in patients subsequently
developing an abnormal VPT, indicating the importance of meta-
bolic control. Of great interest, however, was that over 300 patients
in our cohort (80%) retained a ‘normal’ VPT after an average dia-
betes duration of 16 years despite only average glycaemic control
(mean HbA1 10.4<1.4). In the DCCT, 9.6% of conventionally
treated insulin-dependent patients (mean HbA1c 9.1%) who had no
clinical neuropathy at baseline developed confirmed clinical neu-
ropathy over 6.5 years.22 Although the DCCT represented a
younger and more homogenous population of patients, glycaemic
control in conventionally treated patients was fairly representative
of that seen in our clinics. It seems likely that non-ideal long term
glycaemic control (at least over a 12 year period) leads to neuropa-
thy only in a subset of patients predisposed to this and possibly
other complications. Although we would have liked to study risk
factors for neuropathy for IDDM and NIDDM separately, the num-
ber of IDDM patients with neuropathy (n:26) was too small rela-
tive to the entire cohort to enable this. However, there was no
association between diet, drug or insulin treatment and neuropathy.
In summary, ‘VPTscores’ show overall better sensitivity and
specificity than raw VPT in identifying patients at risk at an early
stage and are likely to be more useful in regular (e.g. annual) moni-
toring of patients. A ‘VPTscore 910.1’ indicates increased risk of
developing neuropathy, and may select patients suitable for clinical
trials and those likely to benefit from potential treatments for
polyneuropathy. Similar long term prospective studies with thermal

© 2001 Harcourt Publishers Ltd Journal of Clinical Neuroscience (2001) 8(6), 520–524
JOCN-157.QXD 10/13/01 5:09 PM Page 524
524 Coppini et al.
threshold tests may help identify patients with early selective small
nerve fibre dysfunction, who may present with pain or autonomic
features.23
ACKNOWLEDGEMENTS
This study was supported by Wyeth Laboratories, Maidenhead,
England, UK; PA and AW gratefully acknowledge support of the
Medical Research Council (UK) and Amgen, Inc., USA.
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