Small Fiber Neuropathy Associated with Hyperlipidemia: Utility of Cutaneous Silent Periods and Autonomic Tests

Abstract

Background. Established electrophysiological methods have limited clinical utility in the diagnosis of small fiber neuropathy. The cutaneous silent period (CSP) may be useful as a method for the evaluation of smaller and unmyelinated fiber dysfunctions. Hyperlipidemia is a very rare cause of small fiber neuropathy. In this study, hyperlipidemia and small fiber neuropathy in symptomatic patients with normal nerve conduction studies were evaluated with autonomic tests and cutaneous silent periods. Methods. Twenty-five patients with clinically suspected small fiber neuropathy and 23 healthy volunteers were included. CSP latency and duration, as well as CSP latency difference of the upper and lower extremities, were examined. Two tests were used to assess the autonomic nervous system, namely, the R-R interval variation test in basal and profound breath conditions and the sympathetic skin response. Results. Twenty-five patients with clinically suspected small fiber neuropathy and normal nerve conduction studies were compared with 23 controls. In the upper extremities, patients had prolonged CSP latencies (P = 0.034) and shortened CSP durations (P = 0.039), whereas in the lower extremities, patients had shortened CSP durations (P = 0.001). The expiration-to-inspiration ratios were also reduced in patients groups. There was no significant difference between sympathetic skin response latencies and amplitude of the case and control groups. Conclusion. Our findings indicate that CSP may become a useful technique for the assessment of small fiber neuropathy in hyperlipidemic patients.

Full text

Research Article
Small Fiber Neuropathy Associated with Hyperlipidemia:
Utility of Cutaneous Silent Periods and Autonomic Tests
G. Morkavuk and A. Leventoglu
Ufuk University Medical School, Department of Neurology, Mevlana Bulvarı No. 86-88, Balgat, 06500 Ankara, Turkey
Correspondence should be addressed to A. Leventoglu; alevleventoglu@hotmail.com
Received  January ; Accepted  February ; Published  March 
Academic Editors: T. Kato and Y. Sunada
Copyright ©  G. Morkavuk and A. Leventoglu. is is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
Background. Established electrophysiological methods have limited clinical utility in the diagnosis of small ber neuropathy. e
cutaneous silent period (CSP) may be useful as a method for the evaluation of smaller and unmyelinated ber dysfunctions.
Hyperlipidemia is a very rare cause of small ber neuropathy. In this study, hyperlipidemia and small ber neuropathy in
symptomatic patients with normal nerve conduction studies were evaluated with autonomic tests and cutaneous silent periods.
Methods. Twenty-ve patients with clinically suspected small ber neuropathy and  healthy volunteers were included. CSP latency
and duration, as well as CSP latency dierence of the upper and lower extremities, were examined. Two tests were used to assess the
autonomic nervous system, namely, the R-Rinterval variation test in basal and profound breath conditions and the sympathetic
skin response. Results. Twenty-ve patients with clinically suspected small ber neuropathy and normal nerve conduction studies
were compared with  controls. In the upper extremities, patients had prolonged CSP latencies (𝑃 = 0.034) and shortened CSP
durations (𝑃 = 0.039), whereas in the lower extremities, patients had shortened CSP durations (𝑃 = 0.001). e expiration-to-
inspiration ratios were also reduced in patients groups. ere was no signicant dierence between sympathetic skin response
latencies and amplitude of the case and control groups. Conclusion. Our ndings indicate that CSP may become a useful technique
for the assessment of small ber neuropathy in hyperlipidemic patients.
1. Introduction
Small ber neuropathy (SFN) can be dened as generalized
peripheral neuropathy, where small myelinated A-delta and
unmyelinated C nerve bers are specically more aected
alone or compared with large bers. Patients with SFN refer
to the neurology clinics with generally positive sensory com-
plaints such as burning, stinging and pain in the feet, and/or
autonomic symptoms. e neurological examination in
SFN is either completely normal or just impaired pain-
temperature sensation is found.
A number of methods are required for early detection
and treatment of SFN. e methods for assessing small
ber dysfunction are limited despite its clinical signicance.
eir clinical use is limited, since most of these methods are
invasive or time consuming or require special equipment.
While mainly pain and temperature sensations are
aected in small ber neuropathy, the manifestation may
also be accompanied by autonomic dysfunction. In addition,
routine nerve conduction studies showing the large ber
functions are within the normal limits.
Cutaneous silent period is an inhibitory spinal reex
characterized by a short-term interruption in voluntary
muscle activity following a strong stimulation of a sensory
nerve in the skin. ere is strong evidence suggesting that the
aerent arm and leg of the CSP are formed by somatic small
bers (A-delta) [–]. us, the CSP might be useful for the
functional assessment of somatic small bers.
e etiology of SFN includes toxic, inammatory/
infectious, hereditary causes, amyloidosis, nutritional, and
metabolic such as diabetes mellitus, impaired glucose toler-
ance, Vitamin B and B deciency, and hyperlipidemia. e
association of lipid abnormalities and peripheral neuropathy
hasbeenreportedinmanyreports[–]. Only few reports
have suggested the correlation between hyperlipidemia and
SFN [].
Hindawi Publishing Corporation
ISRN Neurology
Volume 2014, Article ID 579242, 6 pages
http://dx.doi.org/10.1155/2014/579242

ISRN Neurology
e aim of this study is to determine small ber dys-
functions with CSP, sympathetic skin response, and R-R
interval in hyperlipidemic patients and to compare these
results between hyperlipidemic patients and asymptomatic
controls.
2. Materials and Methods
2.1. Study Population. e study population consisted of
hyperlipidemic patients and healthy volunteers. Inclusion
and exclusion criteria were applied to patients. e informed
consent of patients for electrophysiological testing was
obtained from all participants before inclusion.
Forty-eight subjects, consisting of  patients ( females
andmales)fulllingtheabove-mentionedinclusionand
exclusion criteria and  healthy controls ( females and 
males), were included in the study. A detailed medical history
was obtained and systemic and neurologic examinations were
performed. Patients were excluded if they had a history of
any specic peripheral nerve, muscle disease, neuromuscular
junction disease, cervical spondylosis, spine surgery, central
nervous system disease, including stroke, dementia, or medi-
cal conditions associated with peripheral neuropathy, such as
DM, metabolic disorders, alcohol abuse, and malignancy.
Allofthepatientswereevaluatedintermsofage,
sex, weight, body mass index, history of hypertension and
diabetes, smoking, fasting plasma glucose and second-hour
plasma glucose aer a meal, and lipid prole, including,
total cholesterol, triglyceride, LDL-cholesterol and HDL-
cholesterol, and electrocardiogram. Laboratory investiga-
tions included complete blood count, renal and liver function
tests, thyroid function tests, vitamin-B level, folic acid level,
erythrocyte sedimentation rate, and rheumatoid factor. All
the patients were fully examined by means of neurological
examination and autonomic ndings, that is, evaluations
for heart rate, blood pressure. An examiner evaluated each
patient with hyperlipidemia using the Michigan Neuropathy
Screening Instrument (MNSI) [], Michigan Autonomic
Symptom Screening (MASS), Neuropathy Symptom Score
(NSS) [], and DN test []. e study protocol was in
compliance with the Helsinki Declaration of Human Rights
and approved by the Ethics Committee of Ankara University,
andalltheparticipantsprovidedwritteninformedconsent.
2.2. Electrophysiological Evaluation. All electrophysiological
data were recorded using a Medelec Synergy EMG machine
(MEDELEC Synergy, USA) in the electrophysiology labora-
tory in the Ufuk University Medical Faculty Department of
Neurology.
2.3. Nerve Conduction Study (NCS). Each patient’s skin
temperature was conrmed to be ≥∘Conthedorsumofthe
hands and feet. Conventional surface electrode techniques
were used for each nerve conduction study. All the patients
and controls, motor conduction studies were performed from
the bilateral common peroneal and posterior tibial nerves,
and sensory conduction was studied in the bilateral sural,
supercial peroneal nerves in the lower extremities []. In
the upper extremities, motor and sensory nerve conduction
study in median and ulnar nerves were evaluated. Sensory
nerves were studied orthodromically in upper extremities.
Bilateral sural nerve conductions were evaluated antidromi-
cally. Latencies, amplitudes, and velocity parameters were
determined for motor and sensory nerves. e latency of the
sensory nerve action potential (SNAP) was measured to peak
of the negative deection and used to calculate the conduc-
tion velocity. Compound muscle action potentials (CMAP)
and SNAP amplitudes were measured from the positive peak
tothenegativepeakusingsupramaximalpercutaneousnerve
stimulation with surface recordings. e latencies for com-
pound muscle action potentials were determined as the onset
ofthenegativedeectionfromthebaseline,andthelatencies
of the sensory action potentials were determined as the
negative peak. Filter setting were  Hz– kHz for motor
studies and  Hz– kHz for sensory studies.
2.4. Heart Rate Variability in Response to Deep Breathing
(Expiration to Inspiration Ratio (E/I)). e expiration to
inspiration (E/I) ratio is recommended to be sucient
for the evaluation of cardiac autonomic neuropathy [].
Recordings were made in the morning aer subjects were
suciently relaxed. Aer giving proper instructions and
sucient training, the subjects were made to lie in supine
position and through verbal signal they were asked to breathe
maximally allowing ve seconds for inspiration and ve sec-
onds for expiration for one minute. e parasympathetic test
employed in this study was heart rate response to deep breath-
ing at  respiratory cycles per minute. e average of ve
recordings at rest was termed as R% and that of two record-
ings during deep breathing as D%. e dierence between
D%andR%(D-R)andtheratioofD-R%(D/R)werealso
calculated.
2.5.SympatheticSkinResponse. e test were performed with
thesubjectsupineandrelaxedinasemidarkenedroom,in
room temperature controlled at  to ∘C(skintemperature
was maintained at ∘C). e skin temperature was measured
and if under ∘C, the limbs were warmed. A standard
active electrode was attached to the palm and sole and the
reference electrode to the dorsum of the hand and foot.
e stimuli used were single electrical stimulus at the wrist
contralateral to the recording side []. Stimuli were delivered
unexpectedly and in irregular intervals of more than min
to prevent habituation. e latency was measured from
the onset of the stimulus artifact to the onset of the rst
negative deection and expressed in seconds. e amplitude
was measured from the baseline to the negative peak and
expressed in mV. e response was considered absent if
no consistent voltage change occurred using a sensitivity
of  𝜇V per division aer three trials at maximum stimuli
intensity. In our study, the amplitudes were not included in
the analysis because the amplitudes had extent variability
even in the same subject in repeated measurements due to
possible habituation phenomena. Response latencies were
considered pathological when more than  SD above the
mean latency of the control group.

ISRN Neurology 
T1
T1
46.4 ms
d
d
96.2 ms
T2
T2
142.6 ms
(a)
T2
T2
T1
T1
d
d
86.6 ms
114.6 ms
28.0 ms
(b)
F : (a) CSP recording from APB muscles in control subject; (b) in hyperlipidemic patient, prolonged CSP latency with reduced duration
was showed in the APB muscles recording. (T, CSP latency; T, end of the CSP duration, d, CSP duration).
2.6. CSP Evaluation. e CSP was recorded in the right
upper and the lower extremities. Filters were  Hz– kHz,
sweep speed was  ms, and sensitivity was  𝜇V.  e
median sensory nerve was stimulated with a standard painful
stimulus ( mA intensity, ms duration) through a bar
electrode xed on the second digit of the right hand and the
response was recorded with an electrode xed on the belly
of the contracting abductor pollicis brevis muscle (Figure ).
e sural nerve was stimulated supercially lateral to the
external malleolus in the right lower extremity and record-
ings were obtained from the anterior tibial muscle through
bar electrode [,].
2.7. Statistical Analyses. Statistical analyses were performed
using SPSS . for Windows (SPSS Inc., Chicago, IL, USA).
Normally distributed data were analyzed by parametric
tests (𝑡-test and 𝑡-test for dependent samples). e gender
distribution of the two groups was assessed by a chi-square
test. CuSP latency and duration were established as the mean
from four recordings. e mean, median, standard deviation,
and minimal and maximal values were calculated. Student’s
paired test, Mann-Whitney 𝑈, chi-square test, and analysis
of variance (ANOVA) test were used for comparisons. For
correlation analysis, Spearman’s rank correlation coecients
were used. Statistical signicance level was accepted as 𝑃<
0.05.
3. Results
is study included  patients with neuropathic complaints
( men and  women; mean age, . years) and diagnosed
with isolated hyperlipidemia due to the absence of any disease
that could cause polyneuropathy and whose routine nerve
conduction studies were normal, and  healthy subjects with
no disease ( men and  women; mean age,  years). We
recruited  patients from the hyperlipidemia clinic having
aLDL> mg/dL, triglyceride above  mg/dL, and total
cholesterol > mg/dL with SFN symptoms. ere were no
statistically signicant dierences in age and gender between
thepatientandcontrolgroups.Bodymassindexofstudy
group was signicantly higher compared to control (𝑃=
0.001). Total cholesterol, triglycerides, and LDL-cholesterol
were signicantly higher in patient group compared to
healthy control (𝑃 = 0.001). In the patient group, signicant
positive correlation was found between BMI and cholesterol
and triglycerides levels. ere was no signicant dierence in
HDL-cholesterol and blood pressure between study and con-
trol group. R-Rinterval, sympathetic skin response (in four
extremities), and cutaneous silent period (in abductor pollicis
brevis and tibialis anterior muscles) parameters were ana-
lyzed in all patient and control group. e clinical character-
istics of the subjects are shown in Table .
Prolonged CSP latency with reduced duration was
showed in the abductor pollicis brevis muscles in the patient
(Figure ). e results indicated that upper extremity cuta-
neous silent period latency was longer and the duration was
shortened in the patient group compared with the control
group (𝑃 = 0.034,𝑃 = 0.039, resp.) while no statistically
signicant dierence was found for cutaneous silent period
latency in the lower extremities between two groups, when
the correlation between LDL and total cholesterol level and
cutaneous silent period duration in the lower extremity,
a negative correlation was found between two groups; in
otherwords,itwasfoundthatcutaneoussilentperiod
duration in the lower extremity shortened as the LDL and
total cholesterol levels increased (Tab l e  ). No correlation
was found between triglycerides level and cutaneous silent
period latency and duration in the upper or lower extremity.
Sympathetic skin response could not be achieved in bilateral
lower extremities in  patients in the patient group, and
no statistically signicant dierence was observed between
sympathetic skin response latency and amplitudes in four
extremities between the patient and control group (Ta b l e  ).
And for the R-Rinterval parameters, only E/I ratio was found
statistically signicant between two groups. E/I ratio was
found decreased in the patient group compared with the
control group (𝑃 = 0.02)(Table ). ere were no signi-
cant dierences in sympathetic skin response, MNSI, MASS
and LDL-cholesterol, triglycerides, HDL-cholesterol, and
CSP latency between the patient and the control groups (𝑃>
0.005).

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T : Clinical characteristics of patients and control groups.
Patients
(𝑛=25)
Controls
(𝑛=23)𝑃value
Age 39.1 ± 9.5 36 ± 9 NS
Gender (male %) 52%52%NS
BMI 27.9 ± 5.2 23.1 ± 3.2 .∗
Total cholesterol (mg/dL) 231.3 ± 44.7 142.6 ± 27.5 .∗
Triglycerides (mg/dL) 192.5 ± 101.1 86.8 ± 33.9 .∗
HDL (mg/dL) 46.3 ± 16.3 51 ± 13.6 NS
LDL (mg/dL) 152.5 ± 39.9 82 ± 21 .∗
Neurological examination ndings
Normal %
Reduced ankle tendon reex %
Reduced distally vibration sensation %
Reduced touch sensation at the foot %
Sensorimotor symptom,
Numbness %
Paresthesia/dysesthesia %
Burning pain %
Muscle cramps %
Autonomic symptoms,
Lightheadedness %
Dry mouth/dry eyes %
Pale/blue feet %
Cold feet %
Decreased/absent sweating/feet %
Nausea, vomiting, aer eating a meal %
Persistent diarrhea %
Persistent constipation %
Urinary incontinence %
Erectile dysfunction (male) 
NS: no signicance; BMI: body mass index; HDL: high density cholesterol; LDL: low density cholesterol, ∗𝑃 < 0.05.
T : CSP latency and duration measured from upper and lower
extremities of patients and controls groups.
CSP (ms)
Patient group
(𝑛=25)
mean ±SD
Control group
(𝑛=23)
mean ±SD
𝑃value
Upper extremity
Latency 69.1 ± 15.4 58.6 ± 16.2 0.034∗
Duration 56.6 ± 20.0 67.9 ± 19.9 0.039∗
Lower extremity
Latency 89.9 ± 32.6 88.3 ± 12.3 .
Duration 35.7 ± 20.6 55.6 ± 15.6 0.001∗
SD: standard deviation; CSP: cutaneous silent period, ∗𝑃 < 0.05.
4. Discussion
SFN is a neuropathy selectively involving small diameter
myelinated and unmyelinated nerve bers. Degeneration of
T : Sympathetic skin response, mean latency values in hyper-
lipidemic patients and controls.
Patient group
(mean ±SD)
(𝑛=25)
Control group
(mean ±SD)
(𝑛=23)
𝑃value
Upper limb 1.43 ± 0.1 1.36 ± 0.1 .
Sole latency (sec) 1.58 ± 0.8 1.94 ± 0.1 .
∗𝑃 < 0.05.
small nerve bers can foretell the progression to a more
diuse neuropathy [,], making the early diagnosis of
SFN important for the accurate treatment of patients. Recent
studies have also reported that subclinical involvement of
distal large sensory ber can occur in SFN [,]. e
clinical picture of an isolated small ber neuropathy is charac-
teristic, but the diagnosis is not always easy. Previous studies
proposed that the CSP is easily used to assess tool for small-
diameter neuropathies [].

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T  : Mean 𝑅-𝑅interval variation values in patients and controls.
Patient group
(mean ±SD)
(𝑛=25)
Control group
(mean ±SD)
(𝑛=23)
𝑃value
𝑅%25.2 ± 11.6 22.3 ± 8.3 .
𝐷%33.2 ± 11.4 33.2 ± 9.6 .
𝐷-𝑅1.43 ± 0.55 1.56 ± 0.40 .
𝐷/𝑅1.28 ± 0.16 1.38 ± 0.16 0.021
𝑅%: 𝑅-𝑅interval variation at rest; 𝐷%: during deep breathing, 𝐷−𝑅:the
dierence between 𝐷%and𝑅%; 𝐷/𝑅:theratioof𝐷-𝑅%, ∗𝑃 < 0.05.
Early detection is important in somatic small ber
polyneuropathy and electrophysiological studies on small-
diameter ber functions. However, there are many reasons
why early diagnosis is important, some of which is the deni-
tion of the diagnosis which can lead to a focused screening on
its etiology. Second reason, early disease modifying or symp-
tomatictreatmentscanbestarted.Anotherreason,earlydiag-
nosis and awareness of the SFN can increase patients’ com-
pliance, which is particularly important in the treatment of
neuropathic pain [].
SFN is oen idiopathic and typically presents with
peripheral pain with or without symptoms of autonomic
dysfunction. e most common cause is diabetes or glu-
cose intolerance. Other possible causes include hyperlipi-
demia. Dyslipidemia can also cause peripheral nerve damage.
Elevated serum triglyceride levels are associated with an
increased risk for sensory neuropathy or small ber neuropa-
thy. Diagnosis is made on the basis of the clinical features,
normal nerve conduction studies, and abnormal specialized
tests of small ber function. ese tests include assessment of
epidermal nerve ber density as well as temperature sensation
tests, sudomotor and cardiovagal testing, and sympathetic
skin response. Although the use of the CSP in the diagnosis of
somatic small ber polyneuropathy should be supported with
further studies [–], the patients with hyperlipidemia elec-
trophysiological demonstration of the existence of CSP do not
haveanywork.Inthepresentstudy,nerveconductionstudies,
R-Rinterval, and SSR and CSP evaluations were performed
in hyperlipidemic patients with somatic SFN symptoms
and ndings and healthy controls.
e prolonged CSP latency in patients with hyperlipi-
demic patients compared to healthy controls was similar to
previous studies for diabetic patients []. Changes in the
lower extremity CSP duration in the patients group have been
referred to A-delta nerve ber involvement.
Several theories have been proposed in the literature to
explain the possible relationship between lipid disorders and
peripheral neuropathy; one of them suggests that the function
and structure of the nerve could be aected by abnormal
serum lipids by two mechanisms: rst, by the action of
lipoproteins as enzyme cofactors and as bound intermediate
in the biosynthesis of polysaccharide and proteins. Second,
abnormal serum lipids could remote nerve infarction over fat
embolism or lipid stimulated platelet aggregation []. Wig-
gin et al. reported that in their subjects with mild to moderate
diabetic neuropathy, elevated triglycerides correlated with
sural nerve myelinated ber density loss independent of
disease duration, age, diabetes control, or other variables [].
CSP was studied in patients with various sensory neu-
ropathies. Many investigators were able to demonstrate a
reduction in CSP duration in patients with SFN [,]. Leis
[] reported one patient with a pure sensory neuropathy
causing absent sensory nerve action potentials and recorded
prolonged CSP latency. Syed et al. studied  patients with
Fabry’s disease, a rare disease is X-linked lysosomal storage
disorder caused by abnormal developed small and large
diameter bers. In these patients CSP was normal in the
upper extremity, but CSP of either reduced or increased
duration in the lower extremity. ese authors concluded
that the CSP must be insensitive to SFN in case of mild
and moderate impairments []. Corsi et al. []studied
two patients with hereditary sensory autonomic neuropathy.
ey found that in these patients CSP of reduced duration
couldbegainedwhenstimuliwereappliedtotwodigits.
Yam a n e t al . [ ]havereportedprolongedCSPlatencyin
patients with diabetic neuropathy compared to controls and
they found that CSP duration was shortened and prolonged
CSP latency in diabetic patients with small ber neuropathy.
ese authors concluded that the CSP may be a useful
electrophysiological method for the detection and diagnosis
of small ber neuropathy in diabetic patients. Onal et al.
[] also found similar ndings. ey found normal CSP
in the upper extremity, but CSP of reduced duration and
longer latency in the lower extremity. ey suggested that the
dierence was more signicant in patients with neuropathic
pain. ese authors concluded that the CSP evaluation might
be used to support the diagnosis in diabetic patients with
suspected somatic SFN.
Changes in the upper and lower extremity CSP latency
and duration in SFN have been attributed to A-delta nerve
ber involvement. e ndings support the association
between CSP changes and A-delta nerve bers. We have also
foundthattheCSPlatencyisprolongedandtheCSPduration
is shortened in the lower extremities of hyperlipidemic
patients.
5. Conclusions
CSP may be a useful electrophysiological method for
the diagnosis of small ber neuropathy in hyperlipidemic
patients. erefore, we believe that it would oer an insight
into other studies in the future on diagnosis of SFN due to
hyperlipidemia and contribute to the literature.
Conflict of Interests
e authors declare that there is no conict of interests
regarding the publication of this paper.
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ISRN Neurology
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