RESEARCH ARTICLE

Peripheral neuropathy in patients with

multiple sclerosis
Adnan Khan1, Saadat Kamran2, Georgios Ponirakis1, Naveed Akhtar2, Rabia Khan2,
Pooja George2, Blessy M. Babu2, Faiza M. Ibrahim2, Ioannis N. Petropoulos1, Beatriz
G. Canibano2, Stacy S. Wilins2, Dirk Deleu2, Ashfaq Shuaib2,3, Rayaz A. Malik1*
1 Weill Cornell Medicine-Qatar, Qatar Foundation, Education City, Doha, Qatar, 2 Institute of Neuroscience,
Hamad General Hospital, Doha, Qatar, 3 Department of Neurology, University of Alberta, Edmonton, Alberta,
Canada

a1111111111 * ram2045@qatar-med.cornell.edu
a1111111111
a1111111111
a1111111111 Abstract
a1111111111

Objectives
To determine the prevalence and severity of neuropathic pain, sudomotor dysfunction and
OPEN ACCESS abnormal vibration perception in patients with MS.
Citation: Khan A, Kamran S, Ponirakis G, Akhtar N,
Khan R, George P, et al. (2018) Peripheral Methods
neuropathy in patients with multiple sclerosis. 73 patients with MS and 32 age-matched healthy controls underwent assessment of expanded
PLoS ONE 13(3): e0193270. https://doi.org/
10.1371/journal.pone.0193270
disability severity score (EDSS), DN4 to assess neuropathic pain, electrochemical skin conduc-
tance (ESC) to assess sudomotor function and vibration perception threshold (VPT).
Editor: Sam Eldabe, James Cook University
Hospital, UNITED KINGDOM
Results
Received: October 8, 2017
Patients with MS had a higher DN4 score (p < 0.001) with 14% fulfilling the criteria for neuro-
Accepted: February 7, 2018
pathic pain elevated VPT (p < 0.001) and lower ESC on the feet (p < 0.001) and hands (p <
Published: March 7, 2018 0.001) compared to control participants. ESC on the feet (32% of MS patients) and hands
Copyright: © 2018 Khan et al. This is an open (30% of MS patients) were lower, and DN4 (77% of MS patients) and VPT (64% of MS
access article distributed under the terms of the patients) were greater than 2SD of the healthy control values, respectively. EDSS correlated
Creative Commons Attribution License, which
with the number of relapses (r = 0.564, p < 0.001), VPT (r = –0.457, < 0.001) and ESC on
permits unrestricted use, distribution, and
reproduction in any medium, provided the original the feet (r = –0.268, p = 0.023).
author and source are credited.

Data Availability Statement: Data are available

Conclusions
from figshare (https://figshare.com/s/ Patients with multiple sclerosis have evidence of sudomotor dysfunction and elevated vibra-
9a7938564b35bd9b4cb6). All other relevant data
tion perception, which were associated with neurological disability from MS.
are within the paper and its Supporting Information
files.

Funding: This work was supported by Qatar

Foundation-BMRP 20038654 and Multiple
Sclerosis Innovation 2016-201701.10249.POT to
Dr Rayaz A Malik. Introduction
Competing interests: The authors have declared Multiple sclerosis (MS) is considered to be a progressive inflammatory disease characterized
that no competing interests exist. by demyelination in the central nervous system including the optic nerves. However, we and

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 Neuropathy in multiple sclerosis

others have recently demonstrated significant small fibre damage in patients with MS [1–3]. A
recent study has also demonstrated a significant reduction in intraepidermal nerve fibre den-
sity in patients with MS [4]. Sudomotor dysfunction has been described in clinically isolated
syndrome [5] and abnormal sweating is a feature of MS [6]. Impaired sudomotor function cor-
relates with the severity of clinical disability in MS [7, 8] and is associated with sweat gland
denervation [9]. Patients with MS also exhibit the Uhthoff phenomenon, characterized by a
worsening of neurological deficits when patients are exposed to heat, suggestive of vasomotor
dysfunction.
Sudomotor dysfunction can be quantified using the thermoregulatory sweat test (TST),
sympathetic skin response (SSR) or quantitative sudomotor axon reflex test (QSART) [10].
Sudoscan™ is a simple non-invasive technique that quantifies sudomotor function by measure-
ment of electrochemical sweat conductance (ESC) on the hands and feet and has been used to
study diabetic neuropathy [11] and more recently transthyretin familial amyloid polyneuropa-
thy [12] and Fabry disease [13].
Abnormalities in thermal and vibration sensation were shown to be associated with
impaired somatosensory evoked potentials in patients with MS many years ago [14]. Interest-
ingly, a recent study has shown that patients at increased risk of MS have an elevated vibration
perception threshold, even though MRI and OCT are still normal [15]. A recent study has also
demonstrated significant abnormalities in proprioceptive, tactile and vibration perception,
with altered balance in patients with MS [16]. Moreover, vibration perception threshold was
found to be greater in MS patients with walking disability and was related to the 6 min walk
test, the Timed Up and Go test and the Berg balance scale [17]. Hand sensation assessed using
the Semmes-Weinstein monofilament, duration of vibration with 128-Hz frequency tuning
fork, and distance of two-point discrimination has been associated with upper extremity
strength and function in patients with MS [18]. Impaired vibration perception correlates with
EDSS in relapsing-remitting MS, but not progressive MS [19].
Neuropathic pain in patients with MS has been attributed to central abnormalities and yet
MS patients with neuropathic pain have significant abnormalities in thermal thresholds [20].
Indeed, a recent experimental study has demonstrated significant injury to peripheral sensory
neurons in autoimmune encephalomyelitis, an experimental model of MS [21]. Furthermore,
in a large and detailed phenotyping study of 302 patients with MS, 14% had neuropathic pain
according to the DN4 and this was associated with more severe MS and abnormal laser evoked
potentials [22].
Thus, a substantial body of data suggests that there is evidence of peripheral neuropathy,
particularly, small fibre dysfunction in patients with MS. We have undertaken a detailed evalu-
ation of neuropathic pain, sudomotor function and vibration perception in relation to the type
and severity of MS.

Research design and methods

Selection of patients
73 patients with MS attending the neurology outpatient clinic at Hamad General Hospital in
Doha, Qatar and 32 healthy age and gender-matched controls were studied. This study
adhered to the tenets of the declaration of Helsinki and was approved by the Institutional
Review Board of Weill Cornell Medicine-Qatar (approval no. 15–00064). Informed, written
consent was obtained from all participants before participation in the study. Patients with a
diagnosis of MS (fulfilling the 2010 revised McDonald Criteria) and aged 18–65 were included
in the study. Patients were classified into those with clinically isolated syndrome (CIS, n = 8),
relapsing-remitting MS (RRMS, n = 48) and secondary progressive MS (SPMS, n = 19), based

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 Neuropathy in multiple sclerosis

on the clinical course. Other causes of peripheral neuropathy (family history, diabetes, vitamin
B12/folate deficiency, electrophoresis, ANA, alcohol excess) were excluded. Participants on
medication, which could affect sudomotor function, were excluded.

Neurological evaluation
The neurological status of subjects with MS was assessed using the expanded disability status
scale (EDSS). Disease duration was calculated as years from onset to the last assessment of dis-
ability. A Timed 25-foot Walk Test (T25FW), Nine- Hole Peg Test (9-HPT) and the oral Sym-
bol Digit Modality Test (SDMT) were performed in all participants.
The DN4-interview questionnaire (0–10) was used to identify neuropathic pain [23]. Vibra-
tion perception threshold (VPT) was assessed using a Neurothesiometer (Horwell; Scientific
Laboratory Supplies, Wilfrod, Nottingham, U.K.) with an average of three consecutive read-
ings on the great toe for each foot. Sudoscan™ (Impeto Medical, Paris, France) was used to
measure sudomotor function [24]. The test was performed in a temperature controlled room
with a room temperature of 25 ± 2 C˚. For the Sudoscan assessment, patients were advised to
simultaneously place their bare hands and feet on two sets of large-area nickel electrode plates
for 3 minutes without movement. The electrochemical skin conductance (ESC), expressed in
microSiemens (μS), is the ratio between the current generated and the constant DC stimulus
(4 V) applied to the electrodes. At low voltages (<10 V), the stratum corneum is electrically
insulating and only sweat glands are conductive.

Statistical analysis
All statistical analyses were performed using SPSS and graphic illustrations were generated
using Prism 6 (version 6.0g for Window, Graphpad software Inc., CA, USA). Normality of the
distribution of data was examined using the Kolmogorov-Smirnov test and by visual inspec-
tion of histogram and normal Q-Q plot. Data is expressed as the mean ± standard deviation
(Table 1). The data used for statistical analysis in this study are available on (https://figshare.
com/s/9a7938564b35bd9b4cb6).
To assess within and between-group differences, we used one-way ANOVA (non-paramet-
ric, Kruskal-Wallis test) and Tundden T3 for posthoc test corrections. Chi-square (X2) test for
demographic variables. Student t-test was used to compare healthy controls to patients with
MS. Spearman rank test was used and expressed as a correlation coefficient (r) to estimate the
strength of the relationship between clinical disability (EDSS) and neuropathy assessment.
P < 0.05 was considered to be significant.

Results
The clinical, demographic and peripheral neuropathy assessment parameters of the partici-
pants in the study are given in Table 1.

Clinical, neurological and peripheral neuropathy assessment

MS patients and healthy control (HC) participants were age-matched and there were no signif-
icant demographic differences between the two groups. Patients with MS had a disease dura-
tion of 7.72 ± 3.97 years with 1.82 ± 2.09 relapses and an EDSS of 1.49 ± 1.82. They had a
significant reduction in the SDMT score (40.23 ± 13.19 vs 52.32 ± 8.37, p < 0.001), longer
T25FW (7.29 ± 4.19 vs 3.50 ± 0.62, p < 0.001) and 9-HPT (23.90 ± 5.82 vs 18.58 ± 2.35,
p < 0.001) compared with control participants.

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 Neuropathy in multiple sclerosis

Table 1. Demographic and neurological assessment in Healthy Controls (HC) compared to patients with multiple sclerosis (MS) and also subdivided into those
with CIS, RRMS and SPMS.
Parameters HC MS CIS RRMS SPMS
(number of patients) (n = 32) (n = 73) (n = 8) (n = 46) (n = 19)
Age (years) 33.29 ± 4.49 36.68 ± 9.44 36.63 ± 7.27 34.74 ± 8.68 39.84 ± 9.18
Gender (M/F) 13/19 25/48 3/5 14/32 8/11

MS Duration (years) – 7.72 ± 3.97 4.00 ± 2.94 7.59 ± 3.55 9.73 ± 4.08§

Relapses (number) – 1.82 ± 2.09 – 1.08 ± 0.93 3.75 ± 2.67¥

EDSS (score) – 1.49 ± 1.82 0.75 ± 0.65 0.73 ± 0.93 3.63 ± 2.11§,¥

† ‡
Symbol Digit Modality Test (score) 52.32 ± 8.37 40.23 ± 13.19 44.40 ± 9.76 42.53 ± 12.35 33.14 ± 14.31‡

† ‡ ‡
25 Foot Walk Test 3.50 ± 0.62 7.29 ± 4.19 6.20 ± 1.18 6.41 ± 2.68 10.16 ± 6.71‡
9-HP Test (seconds) 18.58 ± 2.35 23.90 ± 5.82† 22.38 ± 1.34‡ 22.85 ± 5.39¥ 26.97 ± 7.11‡
Peripheral Neuropathy Assessment
Parameters HC MS CIS RRMS SPMS
(number of patients) (n = 32) (n = 73) (n = 8) (n = 46) (n = 19)

VPT 3.55 ± 1.32 9.64 ± 8.20† 12.46 ± 10.26 7.77 ± 7.15‡ 13.07 ± 8.99 ‡

†
Feet ESC (μS) 79.23 ± 5.90 69.08 ± 17.47 66.63 ± 22.51 73.28 ± 13.79 59.33 ± 20.72‡

Hands ESC (μS) 72.30 ± 8.31 62.10 ± 17.14† 59.00 ± 19.85 64.87 ± 15.63‡ 55.89 ±19.11‡

† ‡
DN4 0.09 ± 0.30 1.83 ± 1.80 1.75 ± 1.58 1.76 ± 1.87 2.05 ± 1.78‡

Results are expressed as mean ± SD. Statistically significant differences between different types of MS groups using ANOVA

p < 0.05

p < 0.01

p < 0.001.
‡
Post hoc results differ significantly from healthy control group (p < 0.05).
§
Post hoc results differ significantly from CIS (p < 0.05).
¥
Post hoc results differ significantly from RRMS (p < 0.05).
†
Results differ significantly from healthy controls (p < 0.001).

https://doi.org/10.1371/journal.pone.0193270.t001

Patients with MS had a significantly greater DN4 score (1.83 ± 1.80 vs 0.09 ± 0.30, p < 0.001),
with 14% fulfilling the criteria for neuropathic pain, lower ESC on the feet (69.08 ± 17.47 vs
79.23 ± 5.90, p < 0.001) and hands (62.10 ± 17.14 vs 72.30 ± 8.31, p < 0.001) and elevated VPT
(9.64 ± 8.20 vs 3.55 ± 1.32, p < 0.001) compared to control participants (Fig 1).

Fig 1. ESC in the feet (A) and hands (B), VPT (C) and DN4 (D) in healthy controls compared to patients with MS
and according to the sub-type of MS.
https://doi.org/10.1371/journal.pone.0193270.g001

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 Neuropathy in multiple sclerosis

ESC on the feet (32% of MS patients) and hands (30% of MS patients) were lower, and DN4
(77% of MS patients) and VPT (64% of MS patients) were greater than 2SD of the healthy con-
trols, respectively.

Different types of MS
The time from diagnosis of MS was significantly shorter in patients with CIS compared to
SPMS (p < 0.05). EDSS was significantly higher in SPMS vs CIS (p < 0.001) and RRMS
(p < 0.001). There were no differences in age, gender, SDMT score, T25FW, 9-HPT, VPT,
ESC on the hands and feet or DN4 between different MS subtypes.

Correlation of EDSS and peripheral neuropathy parameters

There was no correlation between EDSS and age, MS duration, SDMT, DN4 and ESC on the
hands. However, EDSS correlated with the number of relapses (r = 0.564, p < 0.001), T25FW
(r = 0.360, p = 0.01), VPT (r = –0.457, < 0.001) and ESC on the feet (r = –0.268, p = 0.023).
There was no correlation between ESC on the feet and the number of relapses, T25FW and
9-HPT, but it did correlate with age (r = –0.405, p < 0.001), MS duration (r = –0.387, p <
0.004) and SDMT (r = 0.292, p = 0.036). There was no correlation between ESC on the hands
and the number of relapses, T25FW and 9-HPT, but there was a correlation with MS duration
(r = –0.334, p = 0.014). VPT correlated with age (r = 0.354, p = 0.003) and 9-HPT (r = 0.367,
p = 0.008) and DN4 correlated with age (r = –0.371, p = 0.001).

Discussion
This study demonstrates an increased prevalence of sudomotor dysfunction and elevated
vibration perception in patients with MS. Although the severity of abnormality is mild, a sub-
stantial proportion of patients with MS show significant evidence of abnormality in both ESC
and VPT and 14% have evidence of neuropathic pain.
This study confirms previous studies showing sudomotor dysfunction in patients with MS
[6, 8]. Indeed, an abnormality in QSART has been demonstrated in 32.7% of patients with CIS
[25]. We also demonstrate correlations between the different measures of neuropathy and the
severity of MS, but no difference between the sub-types of MS. In the present study, we show
sudomotor dysfunction using Sudoscan and add MS to the many neurological conditions that
this device can be used to identify sudomotor dysfunction and hence a small fibre neuropathy.
Whilst we show a mild elevation in vibration perception threshold, surprisingly this was
present in 64% of patients with mild MS and correlated with disease severity. This is in accord
with earlier studies showing that 64% had an abnormal vibration perception [26] and that 26%
of patients with mild MS had an elevated vibration perception thresholds in the feet [27]. Ele-
vated vibration perception threshold rather than thermal thresholds have also been correlated
with somatosensory evoked potentials in patients with MS [28]. Whilst the elevated VPT may
be attributed to dorsal column involvement, this would not explain the presence of neuro-
pathic pain and sudomotor dysfunction.
Evoked potentials have been proposed as an objective means to assess disease severity and
monitor progression or regression in clinical trials of patients with MS [29]. In a recent study
of 34 patients with MS, elevated vibration perception threshold correlated with the 6 minute
walk test, Timed Up and Go test and the Berg balance scale [30]. However, in our study, there
was no correlation between VPT and the timed 25-foot walk test.
Several studies have reported neuropathic pain in patients with MS [22, 31]. Our study has
also demonstrated an identical 14% prevalence of neuropathic pain in patients with MS, but
there was no correlation to EDSS [32]. This is in agreement with a recent study that found an

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 Neuropathy in multiple sclerosis

increased prevalence of neuropathic pain in MS patients, which was also not associated with
EDSS [33]. Indeed, some studies have shown an association between pain and EDSS [34] while
others have not [35].
The findings of the present study in patients with MS merit larger longitudinal studies to
assess the underlying basis of both small and large fibre neuropathy in relation to disease sub-
type, severity and progression.

Supporting information
S1 File. Data of the peripheral neuropathy in patients with multiple sclerosis.xlsx.
(ZIP)

Author Contributions
Data curation: Adnan Khan, Pooja George, Blessy M. Babu, Faiza M. Ibrahim, Stacy S. Wilins,
Dirk Deleu.
Formal analysis: Adnan Khan.
Funding acquisition: Ioannis N. Petropoulos, Rayaz A. Malik.
Investigation: Adnan Khan, Saadat Kamran, Georgios Ponirakis, Naveed Akhtar, Beatriz G.
Canibano, Stacy S. Wilins, Dirk Deleu, Ashfaq Shuaib.
Methodology: Adnan Khan, Ashfaq Shuaib, Rayaz A. Malik.
Project administration: Saadat Kamran, Rabia Khan, Rayaz A. Malik.
Resources: Ashfaq Shuaib.
Supervision: Saadat Kamran, Ashfaq Shuaib, Rayaz A. Malik.
Validation: Ioannis N. Petropoulos, Rayaz A. Malik.
Visualization: Beatriz G. Canibano.
Writing – original draft: Adnan Khan.
Writing – review & editing: Adnan Khan, Rayaz A. Malik.

References
1. Bitirgen G, Akpinar Z, Malik RA, Ozkagnici A. Use of corneal confocal cicroscopy to detect corneal
nerve Loss and increased dendritic cells in patients with multiple sclerosis. JAMA Ophthalmology.
2017; 135(7): 777–782. https://doi.org/10.1001/jamaophthalmol.2017.1590 PMID: 28570722
2. Petropoulos IN, Kamran S, Li Y, Khan A, Ponirakis G, Akhtar N, et al. Corneal confocal microscopy: An
imaging endpoint for axonal degeneration in multiple sclerosis. Investigative Ophthalmology & Visual
Science. 2017; 58(9): 3677–3681.
3. Mikolajczak J, Zimmermann H, Kheirkhah A, Kadas EM, Oberwahrenbrock T, Muller R, et al. Patients
with multiple sclerosis demonstrate reduced subbasal corneal nerve fibre density. Multiple Sclerosis
Journal. 2017: 23(14): 1847–1853. https://doi.org/10.1177/1352458516677590 PMID: 27811337
4. Jahanroshan J, Kurne A, Erdem-Ozdamar S, Tan E. The Evaluation of Small Fibers in Multiple Sclero-
sis (P3. 374). Neurology. 2017; 88(16 Supplement):P3. 374.
5. Crnošija L, Adamec I, Lovrić M, Junaković A, Krbot Skorić M, Lušić I, et al. Autonomic dysfunction in
clinically isolated syndrome suggestive of multiple sclerosis. Clinical Neurophysiology. 2016; 127
(1):864–9. https://doi.org/10.1016/j.clinph.2015.06.010 PMID: 26138149
6. Pintér A, Cseh D, Sárközi A, Illigens BM, Siepmann T. Autonomic dysregulation in multiple sclerosis.
International Journal of Molecular Sciences. 2015; 16(8):16920–52. https://doi.org/10.3390/
ijms160816920 PMID: 26213927

PLOS ONE | https://doi.org/10.1371/journal.pone.0193270 March 7, 2018 6/8

 Neuropathy in multiple sclerosis

7. Gutrecht J, Suarez GA, Denny BE. Sympathetic skin response in multiple sclerosis. Journal of the Neu-
rological Sciences. 1993; 118(1):88–91. PMID: 8229055
8. Saari A, Tolonen U, Pääkkö E, Suominen K, Pyhtinen J, Sotaniemi KA, et al. Sympathetic skin
responses in multiple sclerosis. Acta Neurologica Scandinavica. 2008; 118(4):226–31. https://doi.org/
10.1111/j.1600-0404.2008.01003.x PMID: 18355393
9. Gin H, Baudoin R, Raffaitin CH, Rigalleau V, Gonzalez C. Non-invasive and quantitative assessment of
sudomotor function for peripheral diabetic neuropathy evaluation. Diabetes & Metabolism. 2011; 37
(6):527–32.
10. Saari A, Tolonen U, Pääkkö E, Suominen K, Jauhiainen J, Sotaniemi KA, et al. Sudomotor dysfunction
in patients with optic neuritis. Clinical Autonomic Research. 2010; 20(3):199–204. https://doi.org/10.
1007/s10286-009-0052-z PMID: 20213266
11. Vinik AI, Nevoret M-L, Casellini C. The new age of sudomotor function testing: a sensitive and specific
biomarker for diagnosis, estimation of severity, monitoring progression, and regression in response to
intervention. Frontiers in Endocrinology. 2015; 6(94).
12. Castro J, Miranda B, Castro I, de Carvalho M, Conceição I. The diagnostic accuracy of Sudoscan in
transthyretin familial amyloid polyneuropathy. Clinical Neurophysiology. 2016; 127(5):2222–7. https://
doi.org/10.1016/j.clinph.2016.02.013 PMID: 27072093
13. Sahuc P, Chiche L, Dussol B, Pouget J, Franques J. sudoscan as a noninvasive tool to assess sudomo-
tor dysfunction in patients with Fabry disease: results from a case–control study. Therapeutics and clini-
cal risk management. 2016; 12:135. https://doi.org/10.2147/TCRM.S99241 PMID: 26893567
14. Meh D, Denislic M. Correlation between temperature and vibration thresholds and somatosensory
evoked potentials. Electromyography and clinical neurophysiology. 1999; 40(3):131–4.
15. Xia Z, Steele SU, Bakshi A, Clarkson SR, White CC, Schindler MK, et al. Assessment of Early Evidence
of Multiple Sclerosis in a Prospective Study of Asymptomatic High-Risk Family Members. JAMA neurol-
ogy. 2017; 74(3):293–300. https://doi.org/10.1001/jamaneurol.2016.5056 PMID: 28114441
16. Jamali A, Sadeghi-Demneh E, Fereshtenajad N, Hillier S. Somatosensory impairment and its associa-
tion with balance limitation in people with multiple sclerosis. Gait & Posture. 2017.
17. Uszynski M, Purtill H, Coote S. Relationship between foot vibration threshold and walking and balance
functions in people with multiple sclerosis (PwMS). Gait & posture. 2015; 41(1):228–32.
18. Guclu-Gunduz A, Citaker S, Nazliel B, Irkec C. Upper extremity function and its relation with hand sen-
sation and upper extremity strength in patients with multiple sclerosis. NeuroRehabilitation. 2012; 30
(4):369–74. https://doi.org/10.3233/NRE-2012-0768 PMID: 22672953
19. Newsome SD, Wang JI, Kang JY, Calabresi PA, Zackowski KM. Quantitative measures detect sensory
and motor impairments in multiple sclerosis. Journal of the neurological sciences. 2011; 305(1):103–11.
20. Österberg A, Boivie J. Central pain in multiple sclerosis–sensory abnormalities. European Journal of
Pain. 2010; 14(1):104–10. https://doi.org/10.1016/j.ejpain.2009.03.003 PMID: 19359204
21. Wang I-C, Chung C-Y, Liao F, Chen C-C, Lee C-H. Peripheral sensory neuron injury contributes to neu-
ropathic pain in experimental autoimmune encephalomyelitis. Scientific Reports. 2017; 7.
22. Truini A, Galeotti F, La Cesa S, Di Rezze S, Biasiotta A, Di Stefano G, et al. Mechanisms of pain in multi-
ple sclerosis: a combined clinical and neurophysiological study. PAIN®. 2012; 153(10):2048–54.
23. Spallone V, Morganti R, D’amato C, Greco C, Cacciotti L, Marfia G. Validation of DN4 as a screening
tool for neuropathic pain in painful diabetic polyneuropathy. Diabetic Medicine. 2012; 29(5):578–85.
https://doi.org/10.1111/j.1464-5491.2011.03500.x PMID: 22023377
24. Ayoub H, Griveau S, Lair V, Brunswick P, Cassir M, Bedioui F. Electrochemical characterization of
nickel electrodes in phosphate and carbonate electrolytes in view of assessing a medical diagnostic
device for the detection of early diabetes. Electroanalysis. 2010; 22(21):2483–90.
25. Habek M, Crnošija L, Lovrić M, Junaković A, Skorić MK, Adamec I. Sympathetic cardiovascular and
sudomotor functions are frequently affected in early multiple sclerosis. Clinical autonomic research.
2016; 26(6):385–93. https://doi.org/10.1007/s10286-016-0370-x PMID: 27448576
26. Muller R. The clinical aspects of disseminated sclerosis. Acta psychiatrica et neurologica Scandinavica
Supplementum. 1950; 74:32–47.
27. Halonen P, Panelius M, Halonen JP, Lang H. Vibratory perception threshold in patients with mild multi-
ple sclerosis. Acta neurologica scandinavica. 1986; 74(1):63–5. PMID: 3766118
28. Leocani L, Martinelli V, Natali-Sora MG, Rovaris M, Comi G. Somatosensory evoked potentials and
sensory involvement in multiple sclerosis: comparison with clinical findings and quantitative sensory
tests. Multiple Sclerosis Journal. 2003; 9(3):275–9. https://doi.org/10.1191/1352458503ms908oa
PMID: 12814174

PLOS ONE | https://doi.org/10.1371/journal.pone.0193270 March 7, 2018 7/8

 Neuropathy in multiple sclerosis

29. Leocani L, Comi G. Clinical neurophysiology of multiple sclerosis. Handbook of clinical neurology. 2014;
122:671–9. https://doi.org/10.1016/B978-0-444-52001-2.00028-5 PMID: 24507539
30. Uszynski M, Purtill H, Coote S. Relationship between foot vibration threshold and walking and balance
functions in people with multiple sclerosis Gait & Posture. 41(1):228–32. https://doi.org/10.1016/j.
gaitpost.2014.10.010 PMID: 25455206
31. Solaro C, Brichetto G, Amato M, Cocco E, Colombo B, D’aleo G, et al. The prevalence of pain in multiple
sclerosis A multicenter cross-sectional study. Neurology. 2004; 63(5):919–21. PMID: 15365151
32. Fernández-de-las-Peñas C, Ortega-Santiago R, Ortı́z-Gutiérrez R, Caminero AB, Salom-Moreno J,
Arendt-Nielsen L. Widespread pressure pain hypersensitivity in patients with multiple sclerosis with and
without pain as sign of central sensitization. The Clinical Journal of Pain. 2015; 31(1):66–72. https://doi.
org/10.1097/AJP.0000000000000084 PMID: 24525905
33. Güler T, Garip Y, Yılmaz Z, Güler A. Neuropathic Pain in Patients with Multiple Sclerosis: Its Association
with Clinical Variables and Its Impact on Quality of Life. Journal of Physical Medicine & Rehabilitation
Sciences/Fiziksel Tup ve Rehabilitasyon Bilimleri Dergisi. 2016; 19(1).
34. Grau-Lopez L, Sierra S, Martinez-Caceres E, Ramo-Tello C. Analysis of the pain in multiple sclerosis
patients. Neurologı́a (English Edition). 2011; 26(4):208–13.
35. Beiske A, Pedersen E, Czujko B, Myhr KM. Pain and sensory complaints in multiple sclerosis. European
Journal of Neurology. 2004; 11(7):479–82. https://doi.org/10.1111/j.1468-1331.2004.00815.x PMID:
15257687

PLOS ONE | https://doi.org/10.1371/journal.pone.0193270 March 7, 2018 8/8