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ORIGINAL RESEARCH

Restless Legs Syndrome in Hemodialysis Patients:

Clinical and Electrophysiological Study
Ying Lv 1, *, Kun Zou 2,
*, Shanshan Zhuang 3 , Yang Zhou 1 , Yaping Weng 3 , Enna Mi 1 , Minzhu Xie 1 ,
Long Wang 1
Journal of Multidisciplinary Healthcare downloaded from https://www.dovepress.com/

1
Department of Nephrology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang,People’s Republic of China; 2Department of
Neurology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China; 3Department of Hemodialysis Center, The
First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Ying Lv, Department of Nephrology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Ningbo, Zhejiang, 315010,
People’s Republic of China, Email [email protected]
For personal use only.

Background: Hemodialysis-related restless legs syndrome (HD-RLS) is a common sensorial and motor disorder. The diagnosis of this
disease is based on clinical criteria, and it has recently been proposed to use physiological parameters of the nerves related to the duration
of the F wave as a supplementary diagnostic modality. The aim of the study is to determine the value of these parameters in the diagnosis
of HD-RLS by comparing the differences between patients with HD-RLS and hemodialysis patients without RLS (HD-nRLS).
Methods: A total of 20 HD-RLS patients, 33 HD-nRLS patients, and 30 age-and gender-matched healthy controls (HCs) were
included in the study. The motor nerve conduction of the median and ulnar nerves in the upper limbs, as well as the tibial and peroneal
nerves in the bilateral lower limbs, and the sensory nerve conduction of the sural nerve bilaterally and the superficial peroneal nerve,
along with the F waves of the ulnar nerves, median nerve, and bilateral tibial nerve, were assessed.
Results: Both groups of HD patients had variable levels of axonal degeneration and demyelination, with the HD-RLS patients having
more severe lower limb involvement. The HD-RLS patients showed an extension of the F-wave duration (FWD) of the bilateral tibial,
median, and ulnar nerves, along with an increased ratio between FWD and compound muscle action potential duration (CMAPD).
Conclusion: Peripheral neuropathy occurs in patients with HD-RLS, and the FWD/CMAPD ratio could potentially serve as an
adjunctive diagnostic tool for HD-RLS.
Keywords: Restless legs syndrome, F wave hemodialysis, peripheral neuropathy

Introduction
Restless legs syndrome (RLS) is defined by an uncontrollable compulsion to move and recurrent limb movements,
usually happening at night or during periods of inactivity.1 The pathophysiological mechanisms responsible for RLS are
not fully known and can be categorized into two types: primary RLS and secondary RLS,2 which frequently appears in
patients who are undergoing hemodialysis.3,4 The International Restless Legs Syndrome Study Group (IRLSSG) created
diagnostic criteria for RLS that primarily consider patients’ symptoms and sensations.5 These diagnostic criteria were
revised in 2012 to improve the accuracy of the diagnosis.1 Recently, scholars have proposed that FWD and FWD/
CMAPD values could be used as diagnostic indicators for RLS.6–8 FWD is affected by the quantity of motor neurons and
central excitability drive, whereas FWD/CMAPD is a crucial measure for evaluating motor neuron function.8 Central
sensitization is considered one of the pathogenic mechanisms of RLS, which originates from cortical and subcortical
dysfunction leading to a decrease in descending spinal inhibition,9 thereby causing excessive excitability and dysfunction
in the spinal cord.10 The nerve conduction findings in RLS patients in the aforementioned investigations were within the
normal range. However, peripheral neuropathy (PN) is widely observed in patients with end-stage renal disease
(ESRD).11 Hence, the purpose of this work was to detect PN in HD-RLS by nerve conduction investigations and to
ascertain the significance of FWD and FWD/CMAPD ratio in the RLS diagnosis in HD patients.

Journal of Multidisciplinary Healthcare 2024:17 5251–5258 5251

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Methods
Subjects
The study included 20 HD-RLS patients, 33 HD-nRLS patients, and 30 HCs matched in age and gender without any RLS
symptoms. The criteria for inclusion of HD patients were being 18 years of age or older and undergoing a minimum of 90
days of hemodialysis therapy. The exclusion criteria were Parkinson’s disease, stroke, multiple sclerosis, spinal cord
lesions, rheumatoid arthritis, other autoimmune diseases, and a history of diabetes. HD-RLS patients who match the
diagnostic criteria for RLS established by the IRLSSG, medications or chemicals that can trigger or worsen RLS
symptoms, as well as patients already undergoing drug treatment, are excluded.12 The study complied with the
Declaration of Helsinki and was approved by the Ethics Committee of Affiliated Hospital of Ningbo University
Medical College (Decision No. XJS20220907, Date 14/10/2022), and written informed consent was provided by the
patients.

Electrophysiological Tests
Electrophysiological evaluations were performed in the EMG laboratory using a Danish Dantec Keypoint 9033a07 six-
channel electromyograph (factory no. 40396) that was equipped with surface electrodes. The testing took place from
12:00 to 15:00 at a room temperature ranging from 25 to 28°C. The participants’ skin temperature was maintained within
the range of 32–34 °C, and the patients remained asymptomatic. Research findings suggest that the conduction velocities
of both the median nerve and ulnar nerve are reduced on the side with an arteriovenous fistula.13 Consequently, we
conducted assessments on the opposite upper limb’s left/right median nerve (motor and F-wave), left/right ulnar nerve
(motor and F-wave), both tibial nerves (motor and F-wave), as well as both peroneal nerves (motor) and both superficial
peroneal nerves (sensory) in the lower limb. The following measures were performed: distal sensory latency (DSL),
distal motor latency (DML), conduction velocity (CV), sensory nerve action potential (SNAP) amplitude, and compound
muscle action potential (CMAP) amplitude. The F-wave detection involved delivering a stimulus at a frequency of 1 hz
for 20 repetitions and measuring the shortest latency, longest latency, average latency, amplitude, and duration (from
onset to return to baseline).8

Statistical Analysis
Statistical analysis was performed using SPSS v. 26.0 (Chicago, IL). The measurements with normally distributed data
were shown as EQN, and the count data was expressed as a constitutive ratio. The laboratory results from two groups of
HD patients consist of measures of hemoglobin, albumin, serum iron, transferrin saturation, ferritin, folic acid, and
vitamin B12. Statistical analysis was performed using the independent sample t test for normally distributed data and the
Mann–Whitney U-test for normally distributed data. One-way analysis of variance (ANOVA) assessed the differences
among three groups and performed tests for homogeneity of variance and post hoc comparisons, and gender composition
was tested by Pearson’s chi-squared test. The bilateral tibial nerve, median nerve, and ulnar nerve FWD/CMAPD ratio
were considered the independent variables, while the presence or absence of RLS was considered the outcome variable in
order to construct a receiver operating characteristic curve (ROC).

Results
Demographics and Clinical Characteristics
The demographic and clinical features of the participants are shown in Table 1. The three groups did not exhibit any
notable disparities in terms of age and gender distribution. The HD-RLS patients exhibited a statistically significant
elevation in parathyroid hormone concentration compared to the HD-nRLS patients (P<0.019). Nevertheless, there were
no notable disparities observed in hemoglobin, albumin β2-microglobulin, Kt/V, serum iron, transferrin saturation,
ferritin, folic acid, vitamin B12, and vitamin D between the HD patients.

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Table 1 Demographic Features of the Study Population

Variable HD-RLS(n=20) HD-nRLS (n=33) HCs (n = 30) P-value

Age(years) 56.95±11.00 53.72±15.69 50.92±14.84 0.385a

Female/Male 6/14 10/23 9/21 0.491b
HD duration(years) 5.27±4.21 4.66±3.78 NA 0.590c
Hemoglobin(g/L) 117.3±7.6 111.1±13.7 NA 0.072c
Serum albumin(g/L) 41.15±2.45 40.78±3.63 NA 0.703c
β2-microglobulin(mg/L) 34.56±4.35 31.46±7.31 NA 0.080c
Folic acid(ng/L) 14.33±11.94 11.73±10.28 NA 0.408c
Vitamin B12(pg/mL) 824.5±526.0 741.1±456.8 NA 0.549c
Kt/V 1.466±0.219 1.493±0.264 NA 0.702c
Serum iron(umol/L) 15.11±5.37 14.54±6.36 NA 0.247c
Ferritin(ng/mL) 70.06±64.71 87.32±93.27 NA 0.473c
Transferrin saturation(%) 32.01±11.68 29.78±12.92 NA 0.523c
PTH(pmol/L) 430.4±270.8 252.6±178.5 NA 0.006c
Vitamin D(ng) 36.55±12.51 33.97±15.04 NA 0.525c
Note: Data are presented as the mean±standard deviation (range of minemax). HD-RLS=hemodialysis with restless
legs syndrome;HD-nRLS=hemodialysis without restless legs syndrome;HCs=healthy controls; NA=not applicable.
Kt/V=single chamber urea clearance index PTH=parathyroid hormone a ANOVA. b Fisher’s exact test. c Two-
sample t-tests.

Nerve Conduction Study

In the investigation of motor nerve conduction, both the tibial nerve and common peroneal nerve in the lower limbs of
HD patients from both groups exhibited prolonged DML and decreased CV compared to the HCs, with particularly
pronounced differences observed in the HD-RLS patients. Additionally, there was a decrease in CMAP amplitude
observed in both groups of HD patients compared to the HCs, although the intergroup comparison did not show statistical
significance. Two groups of HD patients exhibited reduced CV in the median nerve compared to the HCs. The HD-RLS
patients also demonstrated prolonged distal motor latency and slowed conduction velocity in the ulnar nerve, along with
decreased CMAP amplitude in both the median and ulnar nerves, as indicated in Table 2. Both groups of HD patients
showed varying degrees of axonal degeneration and demyelination, with greater lower extremity involvement observed
in the HD-RLS patients.
Both groups of HD patients exhibited slower bilateral peroneal nerve CV compared to the HCs in terms of sensory
nerve conduction. The HD-RLS patients demonstrated a more pronounced decrease and displayed prolonged DSL.
Furthermore, within the HD-RLS patients, there was an elongation observed in superficial peroneal nerve DSL and
a reduction in CV, specifically on the left side. Both sides of sural nerve and superficial peroneal nerves exhibited
decreased SNAP amplitudes in the HD-nRLS patients. (Table 3).

Table 2 Comparison of the Motor Nerve Conduction Parameters in the Study Population
Nerve Variables HD-RLS(n=20) HD-nRLS (n=33) HCs (n = 30) P-value
a c
Tibial(left) DML (ms) 3.97±0.56 3.57±0.45 3.43±0.68 0.008
CMAP amplitude (mV) 9.69±3.14 10.44±2.72b 13.85±3.59c <0.001
CV (m/s) 38.77±3.27a 43.09±3.94b 45.70±3.25c <0.001

Tibial(right) DML (ms) 4.00±0.82a 3.55±0.62 3.36±0.51c 0.007

CMAP amplitude (mV) 10.04±2.61 10.44±3.34b 14.12±3.63c <0.001
CV (m/s) 38.49±3.13a 42.73±3.16b 44.81±2.58c 0.001
a b c
Common peroneal (left) DML (ms) 4.39±0.95 3.89±0.47 3.21±0.50 <0.001
CMAP amplitude (mV) 2.89±1.44 2.68±1.17b 4.84±1.62c <0.001
CV (m/s) 38.61±2.97a 42.37±2.80b 44.81±3.64c <0.001

(Continued)

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Table 2 (Continued).

Nerve Variables HD-RLS(n=20) HD-nRLS (n=33) HCs (n = 30) P-value

Common peroneal (right) DML (ms) 4.03±0.69 3.83±0.61b 3.24±0.39c <0.001

CMAP amplitude (mV) 3.78±1.78 3.36±1.36b 4.60±1.65c 0.024
CV (m/s) 38.83±3.81a 41.89±3.80b 44.79±2.61c 0.001

Median DML (ms) 2.02±0.32 1.88±0.25 1.91±0.29 0.222

CMAP amplitude (mV) 8.52±1.85 8.38±2.66b 9.82±2.03 0.054
CV (m/s) 42.36±6.83 42.19±8.91b 48.76±3.07c 0.001

Ulnar DML (ms) 2.88±0.32a 2.52±0.32 2.53±0.37c 0.001

b
CMAP amplitude (mV) 7.52±1.62 7.24±1.59 8.23±1.84 0.100
CV (m/s) 51.71±4.32a 55.81±5.79 55.06±3.25c 0.011
Note: one-way analysis of variance (ANOVA) a:HD-RLS VS HD-nRLS P<0.05 b:HD-nRLS VS HCs P<0.05 c:HCs VS HD-RLS P<0.05.
Abbreviation: DSL, distal sensory latency;SNAP, sensory nerve action potential;CV, conduction velocity; DML, distal motor latency; CMAP,
compound muscle action potential; CV, conduction velocity.

Table 3 Comparison of the Sensory Nerve Conduction Parameters in the Study Population
Nerve Variables HD-RLS(n=20) HD-nRLS (n=33) HCs (n = 30) P-value

Sural(left) DSL (ms) 2.01±0.27 1.85±0.26 1.76±0.29c 0.020

SNAP amplitude (mV) 19.56±8.47 18.72±10.87b 24.79±10.10 0.079
CV (m/s) 49.54±5.21a 53.72±4.32 b 56.27±5.67c <0.001

Sural(right) DSL (ms) 1.90±0.35 1.74±0.29 1.61±0.26c 0.009

SNAP amplitude (mV) 18.08±8.58 15.93±10.23b 21.31±9.64 0.142
CV (m/s) 50.01±5.59a 55.18±4.86b 58.30±5.81c <0.001

Superficial peroneal(left) DSL(ms) 2.19±0.34 2.05±0.31b 1.87±0.26c 0.003

SNAP amplitude (mV) 17.10±6.73 16.43±6.95b 21.13±8.43 0.067
CV (m/s) 44.14±4.59a 48.96±4.61b 53.49±3.91c <0.001

Superficial peroneal(right) DSL (ms) 2.19±0.36a 1.98±0.26 1.84±0.21c <0.001

b
SNAP amplitude (mV) 13.43±6.13 16.35±8.82 21.62±7.87c 0.004
CV (m/s) 45.96±5.35a 50.27±6.42 51.57±4.72c 0.005
Note: one-way analysis of variance (ANOVA) a:HD-RLS VS HD-nRLS P<0.05 b:HD-nRLS VS HCs P<0.05 c:HCs VS HD-RLS P<0.05.
Abbreviation: DSL, distal sensory latency;SNAP, sensory nerve action potential;CV, conduction velocity.

F-Waves
Bilateral tibial nerve F waves showed prolonged minimum, maximum, and mean latencies in both groups of HD patients.
Nevertheless, these alterations were particularly noticeable in patients with HD-RLS. These changes were more
pronounced in HD-RLS patients. Notably, the HD-RLS group had a significantly longer FWD than the HCs. No
statistically significant difference in FWD was found between HD-nRLS patients and HCs and no differences were
observed between the three groups in F-wave amplitude and CMAPD.
The minimum latency, maximum latency, and mean latency of the F wave of the median nerve were longer in the HD-
RLS patients than in the HCs. In addition, the minimum latency, maximum latency, and mean latency of the F wave of
the ulnar nerve in the HD-RLS patients were also longer than those in the HD-nRLS patients and the HCs. The FWD of
both median and ulnar nerves was prolonged in the HD-RLS patients, while no statistically significant difference was
found between the HD-nRLS patients and the HCs. No significant differences were found between the three experimental
groups in terms of F-wave amplitude and CMAPD. (Table 4).
The HD-RLS patients had significantly higher FWD/CMAPD ratios for the bilateral tibial nerves, median nerves, and ulnar
nerves compared to the HD-nRLS patients and the HCs. There was no statistically significant difference in the FWD/CMAPD

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Table 4 Comparison of the F-Wave Parameters in the Study Population

F-wave Variables HD-RLS(n=20) HD-nRLS (n=33) HCs (n = 30) P-value

Tibial Minimum latency (ms) 54.28±4.82a 48.35±4.17b 45.94±3.36c <0.001

(left) Maximum latency (ms) 58.03±4.74a 51.89±4.54b 48.57±3.28c <0.001
Mean latency (ms) 55.97±4.49a 49.86±4.32b 47.22±3.21c <0.001
Maximum amplitude (mV) 331.9±152.2 329.7±164.3 342.0±110.6 0.951
Duration (ms) 28.94±2.55a 15.70±3.01 16.37±2.21c <0.001
CMAP duration(ms) 15.74±1.79 15.19±2.15 15.53±2.17 0.626
FWD/CMAPD 1.85±0.26a 1.05±0.27 1.06±0.10c <0.001

Tibial Minimum latency (ms) 54.80±4.50a 48.89±4.52b 46.54±3.21c <0.001

(right) Maximum latency (ms) 58.33±5.45a 52.31±4.74b 49.37±3.02c <0.001
Mean latency (ms) 56.35±4.59a 50.32±4.54b 47.93±3.03c <0.001
Maximum amplitude (mV) 388.8±155.4 329.6±142.1 363.2±124.1 0.361
Duration (ms) 28.08±2.91a 15.82±2.68 16.25±2.11c <0.001
CMAP duration(ms) 15.59±2.05 14.71±2.09 14.81±2.15 0.499
FWD/CMAPD 1.84±0.26a 1.08±0.26 1.12±0.23c <0.001

Median Minimum latency (ms) 27.48±1.44 26.45±2.35b 24.69±1.74c <0.001

Maximum latency (ms) 30.42±1.52 29.13±2.73 28.21±2.31c 0.009
Mean latency (ms) 28.96±1.53a 27.61±2.38b 26.22±1.87c <0.001
Maximum amplitude (mV) 234.6±96.9 230.3±101.5 237.4±54.7 0.958
Duration (ms) 17.15±4.01a 12.11±1.44 11.59±1.46c <0.001
CMAP duration(ms) 14.93±1.61a 13.46±1.88 13.30±2.03c 0.009
FWD/CMAPD 1.16±0.31a 0.91±0.11 0.87±0.07c <0.001

Ulnar Minimum latency (ms) 28.09±1.73a 25.80±1.53b 24.56±2.34c <0.001

a
Maximum latency (ms) 30.81±1.96 28.27±1.80 27.66±2.63c <0.001
Mean latency (ms) 29.46±1.82a 26.98±1.47 26.01±2.31c <0.001
Maximum amplitude (mV) 308.8±86.5 276.0±87.2 290.1±84.1 0.438
Duration (ms) 17.32±3.32a 12.78±1.79 12.92±1.94c <0.001
CMAP duration(ms) 16.13±1.97 15.01±1.94 14.95±2.47 0.127
FWD/CMAPD 1.08±0.21a 0.86±0.11 0.87±0.10c <0.001
Note: CMAP duration=compound muscle action potential duration;FWD/CMAPD =f-wave duration/compound muscle action
potential duration. One-way analysis of variance (ANOVA) a:HD-RLS VS HD-nRLS P<0.05 b:HD-nRLS VS HCs P<0.05 c:HCs VS
HD-RLS P<0.05.

ratio between the HD-nRLS patients and the HCs. The area under the curve (AUC) for the diagnosis of RLS using FWD/
CMAPD of the left tibial nerve was 0.967, with a sensitivity of 95.0% and a specificity of 93.9%. The AUC for the diagnosis of
RLS by FWD/CMAPD of the right tibial nerve was 0.973, with a sensitivity of 95.0% and a specificity of 87.8%. When
diagnosing RLS using FWD/CMAPD of the median nerve, the AUC value was 0.792, with a sensitivity of 70.0% and specificity
of 96.9%. Similarly, The AUC for the diagnosis of RLS using FWD/CMAPD of the ulnar nerve was 0.825, with a sensitivity of
75.0% and specificity of 93.9%. (Table 5)
Table 5 Sensitivity, Specificity, Positive Predictive Value, and Negative Predictive Value for the Studied Parameters in 20 HD
Patients with RLS
Parameters AUC Sensitivity Specificity PPV NPV Cutoff P-value
(95% CI) (95% CI) (95% CI) (95% CI) (95% CI) value

Tibial FWD/CMAPD(left) 0.967 95.0% 93.9% 90.4% 96.8% 1.41 <0.001

Tibial FWD/CMAPD(right) 0.973 95.0% 87.8% 82.6% 96.6% 1.36 <0.001
Median FWD/CMAPD 0.792 70.0% 96.9% 93.3% 84.2% 1.06 <0.001
Ulnar FWD/CMAPD 0.825 75.0% 93.9% 88.2% 86.1% 1.02 <0.001
Abbreviations: AUC, area under the curve; CI, confidence interval; NPV, negative predictive value; PPV, positive predictive value; CMAPD, compound muscle
action potential duration; FWD, F-wave duration.

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Discussion
The pathogenesis of RLS may be related to spinal cord hyperactivity. Spinal cord hyperexcitability can be caused by
changes in sensory neurons, motor neurons, or other neurons.14–16 In studies of patients with primary RLS, it has been
suggested that FWD/CMAPD ratio could serve as a diagnostic tool for RLS. FWD is generally regulated by two types of
neurons: small-diameter slow-conducting neurons and large-diameter fast-conducting motor neurons.17 In patients with
RLS, prolonged FWD is thought to be related to reduced inhibition of small-diameter motoneurons by inhibitory
interneurons (Renshaw cells) in the midbrain dopaminergic cell cluster A11.17,18 Prolonged FWD suggests increased
motor neuron excitability in RLS patients, while a significant increase in the FWD/CMAPD ratio may indicate changes
in the regulation of motor neurons in the spinal cord.
The results of our investigation indicate that the FWD/CMAPD ratio of bilateral tibial nerves is a very sensitive and
specific diagnostic tool for identifying RLS. The left tibial nerve has a sensitivity of 95.0% and a specificity of 93.9%; the
right tibial nerve has a sensitivity of 95.0% and a specificity of 87.8%. In contrast, the FWD/CMAPD ratio of median and
ulnar nerves displays higher specificity but slightly lower sensitivity in diagnosing RLS. Congiu et al discovered
wonderful disparities within the FWD within the higher and lower limbs and the ratio of FWD/CMAPD among sufferers
with RLS patients and the HCs. The tibial nerve FWD and ratio of FWD/CMAPD have proven an excessive level of
sensitivity and specificity within the analysis of RLS. On the other hand, the ulnar nerve FWD and ratio of FWD/
CMAPD exhibited decreased sensitivity but maintained an excessive level of specificity. Nevertheless, none of the
subjects showed altered nerve conduction study data.7 Similar research found no variations in motor and sensory nerve
conduction between RLS patients and the HCs. Patients with RLS had prolonged FWD of the tibial and ulnar nerves and
an increased FWD/CMAPD ratio.6–8Our study found that the F-wave latency of bilateral tibial, median, and ulnar nerves
in HD-RLS patients was extended compared to HD-nRLS patients, albeit with low sensitivity and specificity for RLS
diagnosis. The FWD/CMAPD ratio possesses greater diagnostic significance and may correlate with motor conduction
anomalies in HD-RLS patients.
In our investigation, HD patients had slower motor and sensory nerve CV, as well as decreased CMAP and SNAP
amplitudes, which indicated the presence of PN. ESRD patients frequently develop PN with pure axonal sensory-motor
neuropathy and mixed sensory-motor neuropathy being the most common kinds,11,19 especially when the lower limbs are
more affected. A study of PN in HD patients discovered that 100% of the group with clear clinical symptoms had
multiple neuropathies, whereas 92.5% of the group without obvious clinical symptoms did. The group with evident
clinical symptoms had prolonged motor nerve DML, low CMAP amplitude, and a delayed CV; sensory nerve responses
were absent, with decreased amplitude or prolonged latency, and a slowed CV.20 Our study revealed similar findings,
with both groups of HD patients exhibiting prolonged DML and decreased CV in the tibial nerve and common peroneal
nerve, particularly more pronounced in the HD-RLS patients. Additionally, the CMAP amplitude decreased in both
patient groups. In HD-RLS patients, there was a deceleration of the median nerve and ulnar nerve CV in the upper limbs,
while CMAP amplitude decreased in HD-nRLS patients. This shows that HD patients have PN in both upper and lower
limbs, and the lesions in HD-RLS patients are more severe.
The correlation between RLS and PN or polyneuropathy (PNP) is a subject of contention. A meta-analysis found that
the occurrence of RLS in patients with PN/PNP ranged from 5.2% to 53.7%, while the occurrence of PN in patients with
RLS ranged from 0% to 87.5%.21 Multiple investigations have verified a significantly greater occurrence of PN in
patients with RLS.22–25 The prevalence of RLS in patients with various PNP etiologies varies significantly across studies.
The occurrence rate of RLS in HD patients with PN ranges from 6.6% to 46.6%,26–28 which is higher than that of the
HCs. The occurrence rate of RLS in patients with diabetic PN/PNP ranges from 10.6% to 40.3%.21 Additionally, the
occurrence rates of RLS associated with PNP-related diseases include systemic sclerosis at 40.7%29 and rheumatoid
arthritis at 25%,30 both higher than those in the control group at 4.9% and 4%, respectively. There is a certain correlation
between PN and RLS, but the pathophysiological mechanism remains unclear. Lanza et al suggest that the pathophysiol­
ogy of RLS may be associated with various mechanisms, such as central inhibitory weakening and peripheral nerve
dysfunction.9 Building on these findings, Gemignani proposed a model for the mechanism of RLS as a disorder of the
flexor reflex circuit,31 wherein abnormal peripheral sensory input can trigger spinal excitability upregulation/

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sensitization, resulting in premature activation of motor patterns during rest. In our study, HD patients have PN in both
upper and lower limbs, which may be related to the increased prevalence of RLS.
The HD-RLS patients had prolonged FWD in the nerves of both upper and lower limbs, in contrast to the HD-nRLS
patients and HCs. However, there was no significant statistical distinction between the HD-nRLS patients and HCs.
These findings indicate that the excitability of spinal motor neurons was heightened in the spinal cord of individuals with
HD-RLS. Previous research has demonstrated that the symptoms of RLS patients are linked to the dysfunction of the
dopaminergic system,32 and that iron is a critical cofactor for tyrosine hydroxylase, the rate-limiting enzyme for
dopamine synthesis.33 MRI phase image approaches has demonstrated a notable decrease in iron accumulation in the
thalamus and dentate nucleus among individuals with idiopathic RLS when compared to the HCs.34 Additionally, HD-
RLS patients exhibit diminished iron deposition in the striatum and cerebellum compared to those with HD-nRLS, and
this comparatively reduced iron deposition may correlate with an elevated risk of RLS in HD patients.35 The study of
cerebral blood flow (CBF) in HD patients showed increased blood flow in the left medial frontal gyrus and bilateral
thalamus and decreased blood flow in the left insular cortex compared to normal controls. Compared with HD-nRLS
patients, HD-RLS patients showed increased CBF in the right primary motor cortex, suggesting abnormal perfusion of
the sensorimotor cortex and basal ganglia associated with altered iron deposition.36 The studies indicate that dysfunction
in the subcortical and/or cortical regions leading to reduced descending spinal cord inhibition may be
a pathophysiological mechanism of RLS. The significant increase in the FWD/CMAPD ratio supports the notion that
the regulation of spinal motor neurons was altered.

Conclusion
HD Patients in both groups experienced peripheral neuropathy, and the HD-RLS group had more profound lesions in the
lower extremities. The bilateral tibial nerve ratio of FWD/CMAP provides a superior level of specificity and sensitivity in
diagnosing HD-RLS. The ratio of FWD/CMAPD can serve as an adjunct diagnostic tool for HD-RLS.

Funding
This work is supported by Zhejiang Province Medical and Health Science and Technology (Grant number:
2023KY1100).

Disclosure
The authors report no conflicts of interest in this work.

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