Amplitude of sensory nerve action potential in early stage diabetic peripheral neuropathy: An analysis of 500 cases

Abstract

Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affiliated Hospital of Kunming Medical University in China from June 2008 to September 2013: 221 cases showed symptoms of peripheral neuropathy (symptomatic group) and 279 cases had no symptoms of peripheral impairment (asymptomatic group). One hundred healthy control subjects were also recruited. Nerve conduction studies revealed that distal motor latency was longer, sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude of compound muscle action potential were significantly lower in the median, ulnar, posterior tibial and common peroneal nerve in the diabetic groups compared with control subjects. Moreover, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases (71.6%), among which impairment of the common peroneal nerve was most prominent. Sensory nerve abnormality was more obvious than motor nerve abnormality in the diabetic groups. The amplitude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy. Our results reveal that varying degrees of nerve conduction changes are present in the early, asymptomatic stage of diabetic peripheral neuropathy.

Full text

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NEURAL REGENERATION RESEARCH
July 2014,Volume 9,Issue 14 www.nrronline.org
Amplitude of sensory nerve action potential in early
stage diabetic peripheral neuropathy: an analysis of
500 cases
1 Department of Neurology, the Fourth Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, China
2 Neuroscience Institute, Kunming Medical University, Kunming, Yunnan Province, China
Yunqian Zhang and Jintao Li
contributed equally to this work.
Corresponding author:
Jianlin Wang, M.D., Department of
Neurology, the Fourth Affiliated Hospital
of Kunming Medical University, Kunming
650021, Yunnan Province, China,
2605691027@qq.com.
doi:10.4103/1673-5374.137593
http://www.nrronline.org/
Accepted: 2014-04-29
Yunqian Zhang1, Jintao Li2, Tingjuan Wang1, Jianlin Wang1
Introduction
Diabetic peripheral neuropathy is the most common chronic
complication of diabetes mellitus, with an incidence rate of
about 50 % (Shi et al., 2013; Galuppo et al., 2014; O’Brien
and Karem, 2014; Won et al., 2014; Zhong et al., 2014).
Once symptoms appear, there are few effective therapeu-
tic strategies (Won et al., 2014). Therefore, early discovery
and diagnosis are extremely important. Nerve conduction
studies are the most common method for diagnosis of pe-
ripheral neuropathy (An et al., 2007; Kincaid et al., 2007;
Koçer et al., 2007; Severinsen and Andersen, 2007; Kiziltan
and Benbir, 2008; Løseth et al., 2008, 2010; Uluc et al., 2008;
Asad et al., 2009; Hemmi et al., 2009; Watanabe et al., 2009;
Charles et al., 2010; Dyck et al., 2010; Lee et al., 2010; Suh
et al., 2010; Watanabe et al., 2010; Altun et al., 2011; Dyck
et al., 2011; Koytak et al., 2011; Shin et al., 2011; Heise et al.,
2012; Mondal et al., 2012; Morimoto et al., 2012; Spadella et
al., 2012; Arimura et al., 2013; Joa and Kim, 2013; Koo et al.,
2013; Richardson et al., 2013; Chiles et al., 2014; McLellan
et al., 2014). Heise et al. (2012) found that the combined i
n-
dex, comprising five parameters of nerve conduction, had
greater sensitivity and equivalent specificity compared with
individual parameters in the detection of diabetic polyneu-
ropathy. In another study, Erdoğan et al. (2011) found that
the strength-duration time constant may be useful in the
early stages of neuropathy, since most patients with diabetic
neuropathy had predominant changes in this parameter in
their lower extremities. In our previous electrophysiology
studies, we used several indices that are routinely measured
in diabetic and suspected diabetic patients, with the aim of
facilitating early diagnosis of diabetic peripheral neurop-
athy, reducing treatment costs and improving therapeutic
success. In the present study, we sought to establish a sensi-
tive index for nerve conduction studies in the early diagno-
sis of peripheral neuropathy in 500 patients with diabetes
mellitus.
Subjects and Methods
Subjects
500 diabetic patients who visited the doctor’s office in the
Abstract
Early diagnosis of diabetic peripheral neuropathy is important for the successful treatment of
diabetes mellitus. In the present study, we recruited 500 diabetic patients from the Fourth Affil-
iated Hospital of Kunming Medical University in China from June 2008 to September 2013: 221
cases showed symptoms of peripheral neuropathy (symptomatic group) and 279 cases had no
symptoms of peripheral impairment (asymptomatic group). One hundred healthy control sub-
jects were also recruited. Nerve conduction studies revealed that distal motor latency was longer,
sensory nerve conduction velocity was slower, and sensory nerve action potential and amplitude
of compound muscle action potential were significantly lower in the median, ulnar, posterior
tibial and common peroneal nerve in the diabetic groups compared with control subjects. More-
over, the alterations were more obvious in patients with symptoms of peripheral neuropathy. Of
the 500 diabetic patients, neural conduction abnormalities were detected in 358 cases (71.6%),
among which impairment of the common peroneal nerve was most prominent. Sensory nerve
abnormality was more obvious than motor nerve abnormality in the diabetic groups. The ampli-
tude of sensory nerve action potential was the most sensitive measure of peripheral neuropathy.
Our results reveal that varying degrees of nerve conduction changes are present in the early, as-
ymptomatic stage of diabetic peripheral neuropathy.
Key Words: nerve regeneration; peripheral nerve injury; diabetic peripheral neuropathy; neural con-
duction; electrophysiology; sensory nerve; motor nerve; early diagnosis; neural regeneration
Funding: This work is supported by the Science and Research Fund of Academic Department in
Yunnan Province in China, No. 2011C08.
Zhang YQ, Li JT, Wang TJ, Wang JL. Amplitude of sensory nerve action potential in early stage dia-
betic peripheral neuropathy: an analysis of 500 cases. Neural Regen Res. 2014;9(14):1389-1394.
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Fourth Affiliated Hospital of Kunming Medical University in
China from June 2008 to November 2013 were recruited by
advertisement. All patients’ conditions were consistent with
the diagnostic criteria for diabetes, approved by the World
Health Organization (Wendland et al., 2012). One hundred
healthy control subjects who went to the doctor’s office for
other medical reasons were also recruited. Exclusion criteria:
(1) peripheral neuropathy due to severe liver and kidney
diseases, nutrition deficiency, connective tissue diseases and
other metabolic or hereditary diseases; (2) radiculopathy
due to cervical spondylosis and lumbar intervertebral disc
protrusion; (3) history of long-term alcohol consumption
or prolonged contact with poisonous substances (such as
heavy metals) that could result in peripheral impairment;
(4) history of drugs (such as isoniazid and furaxone) that
may affect neural function. According to the symptoms
of peripheral nerve impairment (such as numbness, pain,
weakness, or burning cooling sensations in the limbs), the
diabetic patients were divided into two groups, symptomatic
and asymptomatic. One hundred healthy control subjects
were also recruited by advertisement. There were no signifi-
cant differences in disease course between the two groups of
patients with diabetes, and no significant differences in gen-
der, age, body height or weight among all three experimental
groups (P > 0.05; Table 1).
The procedures were in accordance with institutional and
regional ethical standards of responsible experimentation
and with the Helsinki Declaration of 1975. The Chinese Eth-
ics Committee approved the age range of adult research par-
ticipants and obtained consent for children aged over 7 years
participating in the trial. Subject approval was obtained for
the electrophysiological test procedures, which were in accor-
dance with the guidelines of the Chinese Ethics Committee.
Analysis of neural conduction
Each subject lay on a bed in a quiet room (22–25°C) with
limbs relaxed. Skin temperature was maintained above 32°C.
Electromyography/evoked potential apparatus (Dantec
Dynamics, Skovlunde, Denmark) was employed in nerve
conduction studies. Motor and sensory nerve conduction of
unilateral or bilateral median nerve, ulnar nerve, posterior
tibial nerve and common peroneal nerve were measured
separately. In the motor nerve conduction test, the sellar
stimulus electrode was placed in front of the stylomastoid
foramen, with the negative pole of the electrode placed at
the distal end of the nerve. The surface electrode was placed
at the proximal end of the nerve, on the muscle belly of the
frontalis, nasalis or orbicularis oris muscles. The groundwire
was placed between the stimulus and recording electrodes.
For sensory nerve conduction tests, a ring electrode was
placed around the end of the fingers or toes, that is, the dis-
tal end of the sensory nerve, and used to stimulate the me-
dian, ulnar and posterior tibial nerves. A surface electrode
was employed to stimulate the common peroneal nerve.
The recording electrode was placed at the proximal end of
the spinal cord using the antegrade method, described pre-
viously (Cui, 2006). Detection parameters were: amplitude
of compound motor action potential, distal motor latency,
amplitude of sensory nerve action potential, and sensory
nerve conduction velocity. Control values corresponded to
the standards of electromyography for age and gender in Pe-
king Union Medical College Hospital in China (Zhang et al.,
2013).
Statistical analysis
Data were analyzed using SPSS 11.5 software (SPSS, Chica-
go, IL, USA) and presented as mean ± SD. Paired t-tests were
used to compare measurement data. Numeration data are
expressed as numbers of nerve fibers (%). A chi-square test
was used to compare rates between two samples. P < 0.05
was considered statistically significant (We used analysis of
variance to compare the data of two experimental groups
and control, and got similar outcome to those of paired
t-tests, so we adopted the results of t-test as the final statisti-
cal outcome).
Results
Motor and sensory nerve conduction in patients with
diabetic peripheral neuropathy
Distal latency of motor nerve conduction in the median, ul-
nar, posterior tibial and common peroneal nerve was longer
in the asymptomatic diabetic group than in healthy controls,
and the amplitude of compound motor action potential was
significantly lower compared with that of the control group
(P < 0.05; Figure 1A). Distal motor latency in the median
and common peroneal nerves in the symptomatic group
was markedly longer than in the asymptomatic group, and
compound motor action potential amplitude in the median
and common peroneal nerve was significantly lower in the
symptomatic group than in asymptomatic patients (P < 0.05;
Figure 1B).
Similarly to the sensory nerve conduction comparison
in the median, ulnar, posterior tibial and common pero-
neal nerve, sensory nerve action potential amplitude and
Table 1 Demographic information of diabetic patients and control subjects
Item
Diabetic patients
Control subjects
Asymptomatic group Symptomatic group
n279 221 100
Gender (n, male/female) 151/128 115/106 48/52
Age (year) 62.3±8.8(34–87) 64.8±9.0(37–89) 61.1±10.8(32–78)
Course of disease (year) 7.7(0.8–18) 8.1(0.1–21) –
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sensory nerve conduction velocity in both diabetic groups
was significantly lower than in healthy controls (P < 0.05).
Importantly, sensory nerve action potential amplitude and
sensory nerve conduction velocity of the median, ulnar, pos-
terior tibial and common peroneal nerves in the symptom-
atic group was significantly lower than in the asymptomatic
group (P < 0.05; Figure 2).
Outcome analysis of nerve conduction studies
Of 500 diabetic patients, 358 (71.6%) exhibited nerve con-
duction abnormalities. The highest rate of abnormality was
found in the common peroneal nerve, followed by the pos-
terior tibial nerve and median nerve, with the ulnar nerve
showing the lowest rate of abnormality (P < 0.05). In the
motor nerve conduction tests, the common peroneal nerve
showed the highest rate of absent waveforms, whereas in
sensory nerve conduction tests, the posterior tibial nerve
was found to have the highest rate of absent waveforms. The
most sensitive index for nerve conduction studies in diabet-
ic patients was sensory nerve action potential, followed by
Figure 1 Motor nerve conduction in diabetic patients with/without peripheral neuropathy and in control subjects.
(A) Distal motor latency (DML); (B) compound muscle action potential (CMAP). Data are presented as mean ± SD. *P < 0.05, vs. NC; #P < 0.05,
vs. ASG (paired t-test). SG: Symptomatic group (n = 221); ASG: asymptomatic group (n = 279); NC: normal control group (n = 100).
Figure 2 Sensory nerve conduction in diabetic patients with/without peripheral neuropathy and in control subjects.
(A) Sensory nerve conduction velocity (SCV); (B) sensory nerve action potential (SNAP). Data are presented as mean ± SD. *P < 0.05, vs. NC; #P <
0.05, vs. ASG (paired t-test). SG: Symptomatic group (n = 221); ASG: asymptomatic group (n = 279); NC: normal control group (n = 100).
Table 2 Abnormal distribution (%) of motor and sensory nerve conduction in diabetic patients with/without peripheral neuropathy and in
control subjects
Nerve Number of nerve fibers Total abnormality
Motor nerve conduction Sensory nerve conduction
χ2P
No wave DML CMAP No wave SCV SNAP
Median 972 52.9 0.3 16.4 13.0 10.6 32.9 42.3 281.006 < 0.05
Ulnar 953 34.5 0 1.8 2.1 0.9 2.9 33.6 334.908 < 0.05
Tibial 912 53.3 0.5 1.1 1.3 28.8 17.8 24.5 603.809 < 0.05
Peroneal 908 60.0 1.8 11.6 21.8 23.7 22.0 36.3 248.002 < 0.05
If amplitude and conductive velocity abnormalities occurred simultaneously in one nerve, one nerve conductive abnormality was counted. A chi-
square test was used for comparison between two samples. DML: Distal motor latency; CMAP: compound motor action potential; SCV: sensory
nerve conduction velocity; SNAP: sensory nerve action potential.
A
DML (ms)
CMAP (mV)
Median Median
*#
*# *#
*#
*#
*#
*
*
*
*
*
*
*
***
SG SGASG ASGNC NC
Ulnar UlnarTibial TibialPeroneal Peroneal
6.0
5.0
4.0
3.0
2.0
1.0
0
25
20
15
10
5
0
B
A
SCV (m/s)
SNAP (mV)
Median Median
*#
*#
*#
*#
*#
*#
*#
*#
*
*
*
*
*
*
*
*
SG SGASG ASGNC NC
Ulnar UlnarTibial TibialPeroneal Peroneal
70
60
50
40
30
20
10
0
35
30
25
20
15
10
5
0
B
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sensory nerve conduction velocity; compound motor action
potential and distal motor latency had relatively low sensi-
tivity. Among the nerve conduction indices, the highest rate
of abnormality was found in median nerve sensory nerve
action potential (Table 2).
Discussion
Diabetic peripheral neuropathy commonly develops insidi-
ously, with various clinical manifestations. In the early stages,
diagnosis is difficult as there are no symptoms. Fortunately,
increasing use of electrophysiological techniques that allow
the identification of sub-clinical pathological changes has
made early diagnosis of diabetic peripheral neuropathy pos-
sible (Liu et al., 2005; Al-Geffari, 2012; Balbinot et al., 2012;
Barriga et al., 2012; Gulichsen et al., 2012; Kuntzer et al.,
2012; Calvet et al., 2013; Fang et al., 2013; Mete et al., 2013;
Papanas et al., 2013; Sellers et al., 2013; Sun et al., 2013; Gor-
don Smith et al., 2014). Electrophysiology has the advantages
of being objective and sensitive, allowing the scope and ex-
tent of affected peripheral nerves to be precisely ascertained
and providing a conclusive diagnosis of diabetic peripheral
neuropathy. Indeed, nerve conduction studies have become
an indispensable tool in the discovery of peripheral nerve
abnormalities. In patients with diabetic peripheral neu-
ropathy, the main abnormality in nerve conduction studies
manifests as reduced amplitude, slowed conductive velocity
or prolonged latent phase, and in severe cases the waveform
is eliminated entirely.
In the present study, we found that the total abnormal
nerve conduction rate in both diabetic groups was 71.6%,
which was in accordance with a previous report (Banthia et
al., 2013). Distal motor latencies in the median, ulnar, poste-
rior tibial and common peroneal nerves in the asymptomat-
ic group were significantly prolonged compared with those
in the control group. Sensory nerve conduction velocity
and amplitudes of sensory nerve action potential and com-
pound motor action potential were all markedly lower in the
asymptomatic group than in controls, suggesting that im-
pairment of sensory and motor axons and the myelin sheath
at the distal end already exists in the early stages of diabetic
peripheral neuropathy, before symptoms emerge. In the
symptomatic group, sensory nerve conduction velocity was
notably slower, distal motor latency in the median and com-
mon peroneal nerves was significantly prolonged and the
amplitude of compound motor action potential was lower
than in the asymptomatic group. These observations indicate
that after symptomatic peripheral nerve impairment emerg-
es in diabetic patients, lesions in the sensory fibers of the
median, ulnar, posterior tibial and common peroneal nerve,
and in the neuraxis and myelin sheath of motor fibers of the
common peroneal nerve, are markedly aggravated compared
with the asymptomatic stage. Importantly, we show for the
first time that in both groups of diabetic patients, sensory
nerves were affected to a greater extent than motor nerves,
indicating that sensory nerves are more vulnerable to dam-
age than motor nerves in diabetic peripheral neuropathy. In
the diabetic groups, posterior tibial and common peroneal
nerve conduction in the lower extremities had a markedly
higher rate of absent waveforms than the median and ulnar
nerves of the upper extremities, implying that the extent of
nerve fiber lesions in the lower extremities is more severe
than that in the upper extremities in diabetic patients. Im-
portantly, we show for the first time that although diabetic
peripheral neuropathy leads to diffuse conductive abnormal-
ity across whole peripheral nerves, the nearer the damage is
to the distal end, the more severe the extent of impairment.
The total rate of abnormality detected in the median, ul-
nar, posterior tibial and common peroneal nerves in diabetic
patients was 60%. The common peroneal nerve was the most
prominently affected. Moreover, among all patients with di-
abetes, the common peroneal nerve showed the highest rate
of absent waveforms, indicating that among the lesioned
peripheral motor nerves in diabetic patients, the common
peroneal nerve was most severely damaged. The posterior
tibial nerve was most severely impaired from the sensory
nerve tests. Comparing all indices of nerve conduction stud-
ies, we found that sensory nerve action potential was the
most sensitive index. In the present study, the median nerve
showed the highest rate of sensory nerve action potential ab-
normality, suggesting that this nerve is the first to be affected
in diabetes. To our knowledge, we are the first to show a
conclusive and simple relationship between peripheral nerve
lesions and electrophysiological indices in different nerves
commonly affected in diabetic peripheral neuropathy. In
practical terms, this will enable earlier diagnosis of the con-
dition.
Liu et al. (2005) studied 700 patients with diabetic periph-
eral neuropathy using nerve conduction studies and found
that the longer the duration of the disease, the greater the
possibility that abnormal electrophysiology will be observed.
The electrophysiological abnormalities observed in the pres-
ent study may be attributed to nutritional and metabolic
disorders resulting from the diabetes itself, leading to im-
pairment of axoplasmic transport in peripheral nerves, pre-
venting distal axons from acquiring sufficient nutrition and
ultimately leading to their degeneration. In a study by Bi et
al. (2008), it was revealed that sensory nerve action potential
amplitude is more sensitive than nerve conduction velocity in
the diagnosis of mild or early diabetic peripheral neuropathy.
Our study confirmed this notion. Importantly, we found that
the abnormal rate of sensory nerve conduction velocity in
diabetic patients was much higher than that of motor nerve
conduction velocity, corresponding with previous studies (Tan
and Tan, 2003; Kles and Bril, 2006; Vinik et al., 2006; Bi et al.,
2008; Charles et al., 2013). These results indicate that nerve
conduction studies should be used as an important index for
the early diagnosis of diabetic peripheral neuropathy.
Taken together, our data demonstrate that various degrees
of peripheral neuropathy occur in both sensory and mo-
tor nerves in the early stages of diabetes, before symptoms
occur. The extent of impairment in the lower extremities is
more severe than that in the upper extremities. Importantly,
the extent of the lesion in sensory nerves is more severe than
that in motor nerves. Symptoms and sensory nerve impair-
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Zhang YQ, et al. / Neural Regeneration Research. 2014;9(14):1389-1394.
ment will worsen with time; therefore, nerve conduction,
especially sensory nerve action potential detection, should
be routinely examined in diabetic patients so that diabetic
peripheral neuropathy can be discovered and treated as early
as possible.
Author contributions: Zhang YQ was responsible for electro-
physiological test. Li JT was responsible for manuscript writing,
revision and trial design. Wang TJ was responsible for experi-
mental collection and statistical analysis. Wang JL was responsi-
ble for trial design, examination and verification of the experi-
mental data, determination of the final draft of this manuscript.
All authors approved the final version of the paper.
Conflicts of interest: None declared.
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Copyedited by Slone-Murphy J, Yajima W, Yu J, Qiu Y, Li CH, Song LP,
Zhao M
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