Key words
fibromyalgia syndrome - sleep - quality of life - depression - large fibre neuropathy
Schlüsselwörter
Großfaser-Neuropathie - Fibromyalgie-Syndrom - Schlaf - Lebensqualität - Depression
Introduction
Fibromyalgia (FM) is a common widespread rheumatic disease characterized by
widespread pain, fatigue, sleep disturbances, and cognitive symptoms, as well as
somatic symptoms [1]
[2]. It is the second most common rheumatic
disease after osteoarthritis and its prevalence increases with age and peaks in the
fifth and sixth decade of life, mostly affecting women [3]
[4]. The prevalence of FM has been reported as
2% in the United States, 3.3% in Canada, and 3.6% in Turkey
[5]. Its prevalence also increases, as
socioeconomic and education level decrease [6].
Polyneuropathy (PNP) is a condition which affects the peripheral nervous systems of
both upper and lower limbs. Its nature may be axonal or demyelinating. Reduced
compound muscle action potential (CMAP) and sensory nerve action potential (SNAP)
amplitudes are the major electrophysiological hallmarks of axonal loss, while
increased sensory and motor nerve conduction velocity indicating distal motor
latency and increased minimum F latency suggest demyelinating exposure in PNP [7]
[8].
In recent years, there is growing evidence that peripheral neuropathy is an important
component of FM [9]
[10]
[11]
[12]
[13]. This can also explain burning sensation,
allodynia, stinging, numbness, and hypersensitivity to normal stimuli in FM
patients.
In the present study, we aimed to investigate the incidence of large fiber neuropathy
(LFN) in FM patients and to examine the effect of LFN and FM on pain, quality of
life, sleep quality, disability, and depressive symptoms.
Patients and Methods
This prospective study was conducted at musculoskeletal outpatient clinic of
University of Health Sciences, Umraniye Training and Research Hospital between June
2018 and February 2019. A total of a total of 104 patients presenting with
generalized pain, burning sensation, stinging, numbness, and allodynia who were
diagnosed with FM according to the 2010 American College of Rheumatology (ACR)
diagnostic criteria [2] were included in the
study. All patients included in the study had pain within the last three months
without any other rheumatic disease. The patients were divided into two groups
according to electromyographic (EMG) findings as Group 1 including polyneuropathy
(PNP) patients (n=48) and Group 2 including non-PNP patients as the control
subjects (n=54). Group 1 was also further divided into 2 subgroups as
sensorial PNP (n=28) and sensorimotor PNP (n=20). Those with
diabetes mellitus, vitamin B12 deficiency, malignancies, connective tissue
disorders, and toxic, infectious, or hereditary diseases were excluded from the
study. A written informed consent was obtained from each patient. The study protocol
was approved by the Ethics Committee of University of Health Sciences, Umraniye
Training and Research Hospital. The study was conducted in accordance with the
principles of the Declaration of Helsinki.
Electrophysiological studies
Electrophysiological studies of FM patients with and without PNP were performed
by a single electrophysiologist. Standard motor and sensory nerve conduction
studies (NCS) were performed. The methods described by Falck et al. [14] and Stalberg and Falck [15] were used. Electrophysiological studies
were performed with bilateral sural NCS, right common peroneal, right tibial
nerve, right median-ulnar motor and sensory NCS protocols using the Medelec
Synergy on Nicolet AT2 EMG/EP system (Nicolet Biomedical, Madison, WI,
USA). Surface bar recording and ring electrode recording were used. Median,
ulnar, and sural sensory NCSs were performed using the antidromic method. Motor
NCSs were performed analyzing the CMAP, distal latency, conduction velocity,
mean F-response latency, and F-wave persistence. The median F-response latency
was calculated based on series of 10 responses. Sensory NCSs were performed
measuring the baseline-to-peak latency, baseline-to-peak nerve conduction
velocity (NCV), and SNAP.
The latency of sensory nerve was related to the onset of the first negative
deflection and to the negative peak. The sensory NCV was calculated based on the
latency and the distance between the stimulating and recording electrode. The
amplitude of the SNAP was measured from the baseline to the negative peak.
Stimulation duration was 0.2 ms for motor stimuli and 0.1 ms sensory
stimuli. All NCSs were performed with supramaximal stimulation. The band of
frequencies was 20 Hz-2 kHz in the sensory and
5 Hz-10 kHz in the motor and F-wave studies. Skin temperature
was kept at 31°C to 34°C in all patient groups.
According to EMG findings, neuropathy was defined as damage to the axons (axonal
neuropathy) or the myelin (demyelinating neuropathy), or both (mixed). We used
mean±2 standard deviations (SDs) as the limit for the controls in our
laboratory with 95% confidence interval (CI) and stated the deviation
from normal mean for the individual subject as Z-score (i. e.,
deviations in SD from the normal of mean) [16].
Outcome measurements
Data including demographic and clinical characteristics of the patients were
recorded. Sociodemographic characteristics of the patients were standardized
between the groups. All outcome measurements were evaluated by a single
researcher.
The Visual Analog Scale (VAS), which is a self-rated questionnaire, was used to
evaluate pain severity. The scale ranges from 0 to10. 0 indicates no pain, while
10 indicates unbearable pain [17].
The Short Form-36, which is a multi-item scale and consists of eight subscales
and 36 items, was used to evaluate the quality of life, and physical and mental
health of the patients. The eight subscales are physical functioning, role
limitations due to physical problems, bodily pain, general health perceptions,
vitality, social functioning, role limitations due to emotional problems, and
mental health [18]. The validity and
reliability of the SF-36 in the Turkish population have been shown by Demiral et
al. [19].
The Pittsburgh Sleep Quality Index (PSQI) is a self-rated questionnaire which
evaluates sleep quality and disturbances in the previous month. The overall
score ranges from 0 to 21 and higher scores indicate worse sleep quality [20].
The Beck Depression Inventory (BDI), which is one of the most widely used tools
to assess depressive symptoms, consists of 21 items. The overall scores range
from 0 to 63. The sum of each item score of 0 to 9 denotes normal, 10 to 15 mild
depression, 16 to 23 moderate depression, and 24 to 63 severe depression [21]. The validity and reliability of the
BDI in the Turkish population have been shown by Ulusoy et al. [22].
The Fibromyalgia Impact Questionnaire (FIQ), which is a 10-item, self-rated
instrument, is used to measure functional disability and to evaluate work
performance, pain, fatigue, morning stiffness, anxiety, and depression [23]. The overall score ranges from 0 to 100
and higher scores indicate a greater impact of FM on functioning. The validity
and reliability of the FIQ in the Turkish population have been shown by Sarmer
et al. [24].
The Symptom Severity Scale (SSS) is a self-administered questionnaire with a
score range from 0 to 12. It measures severity of fatigue, cognitive
dysfunction, somatic symptoms, and unrefreshed sleep over the past week each on
a scale from 0 to 3: 0=no problem, 1=mild, 2=moderate,
and 3=severe [2].
The Widespread Pain Index (WPI) is used to measure the extent of bodily pain on a
0 to 19 scale by asking patients if they have had pain or tenderness in 19
different body regions (shoulder girdle, hip, jaw, upper arm, upper leg, lower
arm, and lower leg on each side of the body, as well as upper back, lower back,
chest, neck, and abdomen) over the past week, with each painful or tender region
scoring 1 point [2].
Statistical analysis
Statistical analysis was performed using the SPSS version 20 software (IBM Corp.,
Armonk, NY, USA). Descriptive data were expressed in mean±SD, median
(min-max), or number and frequency. The Student’s t-test was used to
compare the qualitative variables showing normal distribution between the
groups, while the Mann-Whitney U test was used to compare non-normally
distributed variables. The Fisher’s exact test was used to examine
significant differences in the sociodemographic characteristics between the
groups. The Pearson correlation analysis was performed to analyze possible
correlations between the variables. A p value of p<0.05 was
considered statistically significant.
Results
A total of 104 patients with FM were included in this study. Of the patients, 67 were
females and 37 were males with a mean age of 52.21±9.53 (range, 31 to 74)
years. Of all patients, 48 (46.15%) had PNP and 56 (53.85%) had no
PNP. According to EMG findings, 28 patients (58.33%) had sensorial PNP and
20 patients (41.66%) had sensorimotor PNP. There was no statistically
significant difference in baseline sociodemographic characteristics between the
groups (p>0.05). Baseline sociodemographic and clinical characteristics of
the patients are shown in [Table 1].
Table 1 Demographic features of participants.
|
Groups
|
Control
|
PNP
|
|
Sex (M/F); n
|
36/20
|
31/17
|
|
Age (year)
|
Mean±SD
|
50.7±8.84
|
54.0±10.08
|
|
Median (Range)
|
50 (31–71)
|
51 (36–74)
|
There was a statistically significant difference in the VAS, SF-36, BDI, FIQ, and
PSQI scores between Group 1 and Group 2 (p<0.05). However, there was no
statistically significant difference in the VAS, SF-36, BDI, FIQ, and PSQI scores
between the sensorial and sensorimotor PNP groups (p>0.05). The VAS, SF-36,
BDI, FIQ, and PSQI scores are presented in [Table
2] and [3].
Table 2 Comparison of VAS, SF-36, PSQI, BDI, NDI, FACIT, FIQ, SSS
and WPI values between PNP and control groups
|
PNP n:48
|
Control n:54
|
p-values
|
|
Mean±SD
(Median)
|
Mean±SD
(Median)
|
|
VAS
a
|
8.29±1.11
(8.0)
|
4.16±1.76
(4.0)
|
<0.001
|
|
Sf36-PF
b
|
35.31±7.54
(30.0)
|
59.46±15.54
(60.0)
|
<0.001
|
|
Sf36-DPR
b
|
35.42±12.46
(25.0)
|
66.07±18.73
(75.0)
|
<0.001
|
|
Sf36-DER
b
|
38.19±19.43
(33.3)
|
75.00±22.25
(66.7)
|
<0.001
|
|
Sf36-VT
b
|
31.98±6.50
(30.0)
|
55.54±15.34
(62.5)
|
<0.001
|
|
Sf36-MH
b
|
31.42±6.09
(32.0)
|
55.54±16.50
(53.0)
|
<0.001
|
|
Sf36-SF
b
|
31.98±9.14
(25.0)
|
56.21±16.05
(62.5)
|
<0.001
|
|
Sf36-BP
b
|
30.89±6.41
(32.5)
|
56.61±18.92
(57.5)
|
<0.001
|
|
Sf36-GH
b
|
29.48±5.18
(30.0)
|
51.25±14.69
(50.0)
|
<0.001
|
|
PSQI
b
|
15.40±1.99
(16.0)
|
9.23±3.57
(8.0)
|
<0.001
|
|
BDI
b
|
13.15±3.71
(12.5)
|
6.77±2.96
(6.0)
|
<0.001
|
|
FIQ
b
|
65.30±6.18
(65.8)
|
38.70±10.88
(36.7)
|
<0.001
|
|
SSS
b
|
9.83±1.19
(10.0)
|
7.95±0.90
(8.0)
|
<0.001
|
|
WPI
b
|
6.88±1.10
(7.0)
|
6.00±0.93
(6.0)
|
<0.001
|
VAS, visual analog scale; SF-36 PF, short form-36 physical functioning; SF-36
DPR, short form-36 diffuculty physical role; SF-36 PF, short form-36
diffuculty emotional role; SF-36 VT, short form-36 vitality; SF-36 MH, short
form-36 mental health; SF-36 SF, short form-36 social functioning; SF-36 BP,
short form-36 bodily pain; SF-36 GH, short form-36 general health; PSQI,
Pittsburgh Sleep Quality Index; BDI, The Beck Depression Inventory;
SSS,Symptom Severity Scale; WPI, Widespread Pain Index.
a
Independent Sample T Test;
b
Mann Whitney Test; * p<0.05
Table 3 Comparison of VAS, SF-36, PSQI, BDI, NDI, FACIT, FIQ, SSS
and WPI values between Sensorial PNP and Sensorimotor PNP groups
|
Sensorial PNP n:28
|
Sensorimotor PNP n:20
|
p-values
|
|
Mean±SD (Median)
|
Mean±SD (Median)
|
|
VAS
a
|
8.46±1.00
|
8.05±1.23
|
0.231
|
|
Sf36-PF
b
|
34.64±7.44
|
36.25±7.76
|
0.461
|
|
Sf36-DPR
b
|
34.82±12.43
|
36.25±12.76
|
0.695
|
|
Sf36-DER
b
|
36.90±7.44
|
39.99±17.44
|
0.789
|
|
Sf36-VT
b
|
32.86±7.13
|
30.75±5.45
|
0.313
|
|
Sf36-MH
b
|
30.79±5.51
|
32.30±6.88
|
0.226
|
|
Sf36-SF
b
|
32.68±9.05
|
31.00±9.40
|
0.602
|
|
Sf36-BP
b
|
30.54±6.10
|
31.38±6.95
|
0.843
|
|
Sf36-GH
b
|
28.93±4.16
|
30.25±6.38
|
0.355
|
|
PSQI
b
|
15.43±1.73
|
15.35±2.35
|
0.933
|
|
BDI
b
|
13.64±3.32
|
12.45±4.17
|
0.234
|
|
FIQ
b
|
65.41±6.35
|
65.16±6.09
|
0.738
|
|
SSS
b
|
9.89±1.17
|
9.75±1.25
|
0.621
|
|
WPI
b
|
6.79±1.10
|
7.00±1.12
|
0.498
|
VAS, visual analog scale; SF-36 PF, short form-36 physical functioning; SF-36
DPR, short form-36 diffuculty physical role; SF-36 PF, short form-36
diffuculty emotional role; SF-36 VT, short form-36 vitality; SF-36 MH, short
form-36 mental health; SF-36 SF, short form-36 social functioning; SF-36 BP,
short form-36 bodily pain; SF-36 GH, short form-36 general health; PSQI,
Pittsburgh Sleep Quality Index; BDI, The Beck Depression Inventory; FIQ,
Fibromiyalgia Impact Questionnarie; SSS, Symptom Severity Scale;WPI,
Widespread Pain Index.
a
Independent Sample T Test;
b
Mann Whitney Test; *p<0.05
The correlation analysis revealed a moderate, negative, and statistically significant
relationship between the changes in the VAS scores and changes in the SF-36 mental
health (r=−0.434), SF-36 bodily pain (r=−0.501)
scores in the PNP group. In addition, there was a weak, negative, and statistically
significant relationship between the changes in the VAS scores and the changes in
the SF-36 general health (r=−0.287) scores in the PNP group. There
was also a weak, positive, and statistically significant relationship between the
changes in the VAS and the changes in the PSQI (r=0.342) scores in the PNP
group. There was a moderate, positive, and statistically significant relationship
between the changes in the VAS and the changes in the BDI (r=0.413) scores
in the PNP group. There was a weak, negative, and statistically significant
relationship between the changes in the FIQ scores and the changes in the SF-36
mental health (r=−0.355) scores in the PNP group. There was a
moderate, negative, and statistically significant relationship between the changes
in the FIQ scores and the changes in the SF-36 bodily pain
(r=−0.401) and SF-36 general health (r=415) scores in the
PNP group. There was also a weak, positive, and statistically significant
relationship between the changes in the FIQ and the changes in the PSQI
(r=0.331) and BDI (r=379) scores in the PNP group. In addition,
there was a weak, positive, and statistically significant relationship between the
changes in the SSS and the changes in the PSQI (r=0.352) and SF-36 vitality
(r=0.263) scores in the PNP group. In addition, there was a weak, negative,
and statistically significant relationship between the changes in the SSS and the
changes in the SF-36-GH (r=− 0.307) scores in the PNP group.
There was also a weak, positive, and statistically significant relationship between
the changes in the WPI and the changes in the SF-36 vitality
(r=− 0.347) scores in the PNP group. There was a weak,
negative, and statistically significant relationship between the changes in the WPI
and the changes in the SF-36 bodily pain (r=− 0.247) scores
in the PNP group. The results of the correlation analysis of all scales in the PNP
group are summarized in [Table 4].
Table 4 Correlation analysis of SF-36, PSQI and BDI scores with
VAS, FIQ, SSS and WPI scores in PNP groups.
|
|
VAS
|
FIQ
|
SSS
|
WPI
|
|
Sf36-PF
|
r
2
|
−0.215
|
−0.229
|
−0.018
|
−0.213
|
|
p
|
0.143
|
0.117
|
0.905
|
0.147
|
|
Sf36-DPR
|
r
2
|
−0.224
|
−0.181
|
−0.311
|
−0.213
|
|
p
|
0.125
|
0.217
|
0.032
|
0.146
|
|
Sf36-DER
|
r
2
|
−0.232
|
−0.195
|
−0.148
|
0.095
|
|
p
|
0.113
|
0.185
|
0.315
|
0.521
|
|
Sf36-VT
|
r
2
|
−0.067
|
−0.188
|
0.263
|
0.347
|
|
p
|
0.651
|
0.202
|
0.071
|
0.016
|
|
Sf36-MH
|
r
2
|
−0.434
|
−0.355
|
−0.043
|
0.014
|
|
p
|
0.002
|
0.013
|
0.772
|
0.923
|
|
Sf36-SF
|
r
2
|
−0.137
|
−0.188
|
0.070
|
−0.175
|
|
p
|
0.354
|
0.201
|
0.636
|
0.233
|
|
Sf36-BP
|
r
2
|
−0.501
|
−0.401
|
−0.134
|
−0.247
|
|
p
|
0.000
|
0.005
|
0.366
|
0.090
|
|
Sf36-GH
|
r
2
|
−0.287
|
−0.415
|
−0.307
|
−0.179
|
|
p
|
0.048
|
0.003
|
0.034
|
0.223
|
|
PSQI
|
r
2
|
0.342
|
0.331
|
0.352
|
0.120
|
|
p
|
0.017
|
0.021
|
0.014
|
0.416
|
|
BDI
|
r
2
|
0.413
|
0.379
|
0.213
|
−0.079
|
|
p
|
0.003
|
0.008
|
0.146
|
0.595
|
VAS, visual analog scale; SF-36 PF, short form-36 physical functioning; SF-36
DPR, short form-36 diffuculty physical role; SF-36 PF, short form-36
diffuculty emotional role; SF-36 VT, short form-36 vitality; SF-36 MH, short
form-36 mental health; SF-36 SF, short form-36 social functioning; SF-36 BP,
short form-36 bodily pain; SF-36 GH, short form-36 general health; PSQI,
Pittsburgh Sleep Quality Index; BDI, The Beck Depression Inventory;
SSS,Symptom Severity Scale; WPI, Widespread Pain Index. Pearson
correlation analysis *p<0.05
Discussion
In this study, we evaluated the effect of LFN and FM on pain, quality of life, sleep
quality, disability, and depressive symptoms. Our study results showed that FM
presenting with LFN had an adverse effect on pain, quality of life, sleep quality,
and depressive symptoms than those without LFN.
Small fiber neuropathy occurs when damage to the peripheral nerves which affects the
small myelinated (Aδ) fibers or unmyelinated C fibers. The specific fiber
types are involved in both small somatic and autonomic fibers. In the peripheral
nerves, deep senses such as vibration, position sense, and afferent part of the
tendon reflex arc are carried with large myelinated fibers, whereas pain and heat
sense are carried by unmyelinated and small myelinated fibers. Large fiber function
is evaluated by NCS and EMG. Therefore, it is difficult to obtain objective data in
neuropathies where small nerve fibers are selectively captured. Quantitative sensory
testing, bedside tests for the autonomic nervous system, and electrophysiological
examinations, and nerve and skin biopsies can be used to demonstrate SFN. In this
type of neuropathy, clinical, neurological, nerve conduction and EMG studies are
usually normal [25]
[26]. Small nerve fiber neuropathies can occur
without large nerve fiber involvement, although there are some reports showing both
types of neuropathy simultaneously developed or progressed to include large nerve
fibers [27].
Previous studies have well documented that nearly half of FM patients have small
fiber neuropathy (SFN) due to reduced intraepidermal fiber density [10]
[11]
[28]. In most cases, SFN causes sensory
symptoms such as pain, burning, and paresthesia and occur in a length-dependent
(stocking-glove distribution) pattern. Paresthesia may manifest as burning,
stinging, tingling, or hyperesthesia. In addition, allodynia which is the perception
of non-painful stimuli as being painful or hyperalgesia which is the perception of
painful stimuli as being more painful than expected may be seen in these patients.
This can also explain the reason for lesser symptoms in FM patients without
neuropathy than those with neuropathy. Symptoms usually begin at night, leading to
reduced sleep quality. Of note, FM, itself, has been already associated with sleep
disturbances. In addition, SFN may lead to abnormal sweating (reduced or increased)
due to autonomic dysfunction, skin discoloration, dry mouth, dry eye,
gastrointestinal disorders, constipation, and headache [28]
[29]
[30]
[31]. These symptoms can be also attributed to
somatic problems in FM patients.
In a study, Caro et al. [32] divided the
patients into three groups as FM (n=29), FM+rheumatoid arthritis
(RA) (n=26), and non-FM/non-RA (n=40). More than 90%
of the patients in the FM group had sensorimotor PNP, mainly sensorial
and/or axonal PNP. Although similar results were obtained in the
FM+RA group, only 7% of the controls had sensorimotor PNP. In our
study, we also observed sensorial or sensorimotor PNP in 48 (46.15%) of the
FM patients. In another study, complaints of numbness, burning, tingling, morning
stiffness, insomnia, fatigue, and weakness were significantly more common in the FM
group, compared to the controls [33]. Also,
the mean scores of the BDS, FIQ, Leeds Assessment of Neuropathic Symptoms and Signs
(LANSS), and painDETECT were significantly higher in the FM patients. There was also
a statistically significant correlation between the FIQ values and LANSS and the BDS
and painDETECT scores in the FM group. Similarly, in our study, we found
statistically higher BDI, FIQ, VAS, SSS, and WPI scores in the patients with LFN.
In
addition, we found a significant correlation between the FIQ scores and BDI, PSQI,
and SF-36 subscale scores. However, the lack of an electrophysiological study in the
aforementioned study precludes an accurate comparison of those with peripheral
neuropathy to those without. In our study, we confirmed that not every patient with
FM presenting with numbness, burning sensation, and tingling was diagnosed with
peripheral neuropathy as evidenced by electrophysiological studies.
Although EMG and NCSs often produce normal results in SFN patients, it is unlikely
to
definitely rule out SFN based on electrophysiological studies, even in cases without
peripheral neuropathy. Similarly, FM patients with and without peripheral neuropathy
might have SFN, as well. This can explain the reason for the lack of LFN in all FM
patients with neuropathy based on EMG findings.
Although previous studies have demonstrated that nearly half of the patients have
SFN, there is a limited number of studies evaluating FM symptoms in SFN patients in
the literature. In our study, the VAS, BDI, PSQI, and FIQ scores were statistically
significantly higher, while the SF-36 subscale scores were statistically
significantly lower in the FM patients with LFN than those without LFN. This finding
indicates an adverse effect of FM presenting with LFN on pain, quality of life,
sleep quality, disability, and depressive symptoms. Despite this statistically
significant difference between the FM patients with and without LFN, we found no
significant difference in sensorial and sensorimotor symptoms among FM patients.
This can be attributed to the fact that sensorial involvement is much more important
for FM symptoms. In addition, muscle strength, muscle balance, and physical function
can be measured to evaluate motor involvement more accurately.
According to the correlation analysis, we found significant correlations between the
SF-36, BDI, and PSQI and VAS, FIQ, SSS, and WPI scores. This finding indicates the
evident relation of the sleep quality and depressive symptoms with pain, FM
severity, and disability. Based on these results, we suggest that treatment of
peripheral neuropathic pain and alleviate FM symptoms and improve daily living
activities of patients.
Nonetheless, there are some limitations to this study. Further prospective studies
in
large series using electrophysiological studies are needed to evaluate the incidence
of LFN in FM patients and its effect on FM symptoms. In addition, a head-to-head
comparison study investigating the symptom severity and incidence in FM patients
with SFN and LFN would be helpful to gain a better understanding of this topic.
Additionally, the incidence of peripheral neuropathy among FM patients may shed
light into the etiology of FM which has been long discussed. Therefore, further
studies investigating the pathogenesis of FM are warranted. In our study, although
small fiber involvement is not known in the FM patient group, we believe that
showing large fiber involvement would contribute to the pathogenesis. In further
studies, both types of neuropathy involvement should be sought to gain a better
understanding of the pathogenesis.
Conclusion
In conclusion, both LFN and SFN may present with generalized pain, burning sensation,
numbness, and abnormal pain perception and FM presenting with LFN has an adverse
effect on pain, quality of life, sleep quality, disability, and depressive symptoms
than those without LFN, indicating the importance of neuropathy management in FM
patients. In these cases, an effective treatment plan may improve sleep quality,
quality of life, and depressive symptoms.
