Keywords:
Charcot-Marie-Tooth Disease - Pain
Palavras-chave:
Doença de Charcot-Marie-Tooth - Dor
INTRODUCTION
Charcot-Marie-Tooth disease (CMT) is a hereditary peripheral neuropathy that has heterogeneous
genetic and clinical expression, Its prevalence is at least 1 in 2,500 individuals
or 1 in 1,214, depending on the ethnicity and evaluation method. The classic phenotype
of CMT disease includes normal initial development, followed by gradual distal weakness
and atrophy and sensory loss arising between the first and second decades of life,
with a reduction in deep tendon reflexes and skeletal deformities in the feet[1],[2],[3],[4].
CMT type 1A (CMT1A) is the most common hereditary neuropathy and accounts for 40 to
60% of all cases with a confirmed molecular diagnosis. It is caused by a duplication
on chromosome 17p11.2, which encodes the peripheral myelin protein gene (PMP22), with
a dominant pattern of inheritance. It is a demyelinating form of CMT, presenting with
a homogeneous reduction in the motor conduction velocity and a significant reduction
in amplitude due to secondary axonal loss[1],[5],[6],[7],[8]. Despite the growing number of studies on possible treatments, there is still no
treatment available for CMT1A.
Sensory symptoms, and in particular pain, are relevant in relation to quality of life
and can represent an important issue in management of CMT disease[5],[9],[10],[11]. Despite being underdiagnosed, pain is a common complaint in these patients. However,
few studies have evaluated the real pathophysiology of this symptom and there are,
to date, no studies that have comprehensively evaluated its characteristics and classification[9],[10],[11],[12].
The aims of this study were to investigate the prevalence and characteristics of pain
in a sample of patients with CMT1A and to correlate the intensity and type of pain
with clinical findings, in order to ascertain its impact on quality of life.
METHODS
This was an observational, cross-sectional and descriptive study.
Patients
A convenience sample of 19 patients with a molecular diagnosis of CMT1A participated
in this study. They were recruited from a larger study (n = 48) on patients with CMT
disease that was carried out at the Clinical Research Unit in Neurology (NeuroUPC)
of the Universidade Federal Fluminense (UFF), Brazil, from September 2018 to October
2019, after approval by the UFF research ethics committee and after the participating
patients or their guardians had signed a free and informed consent statement.
Patients with other causes of polyneuropathy (diabetes, B12 hypovitaminosis or hypothyroidism)
were excluded from this study.
Assessment
All the patients underwent a neurological evaluation consisting of an anamnesis and
a physical examination, and genetic tests were considered to confirm the CMT1A disease.
All the patients underwent laboratory tests and nerve conduction studies.
Specific questionnaires were used to assess the following variables: pain intensity,
using a visual analogue scale (VAS); type of pain, using the Leeds Assessment of Neuropathic
Symptoms and Signs (LANSS) and the Douler Neuropathique 4 (DN4); impact on quality
of life, using the SF-36 scale; and severity of CMT disease, using the Charcot-Marie-Tooth
Neuropathy Score 2 (CMTNS2).
The VAS consisted of a horizontal line of 10 centimeters, on which 0 represented 'no
pain' and 10 represented 'unbearable pain'. The scores obtained were categorized as
follows: 1 to 3 as mild pain, 3 to 8 as moderate pain and 8 to 10 as severe pain[13].
We used two different instruments to assess the type of pain, with the objective of
obtaining greater data reliability. In this regard, it is important to remember that
the sensitivity and specificity of the scales used predict possible failures: LANSS
presents 85% sensitivity and 80% specificity; while DN4 presents 100% sensitivity
and 93.2% specificity in its version validated for Portuguese[14],[15],[16],[17],[18]. LANSS aims to differentiate neuropathic pain from nociceptive pain and is based
on analysis on assessments of sensory descriptors and sensory deficits[14],[15],[16].
From the LANSS and DN4 questionnaires, types of pain can be categorized into neuropathic
or nociceptive pain. Therefore, we assessed the coefficient of correlation between
these types. Since the specific scales do not include mixed pain as a separate type,
we evaluated a correlation between mixed pain and the clinical evaluation, according
to the data collected in the anamnesis and physical examination. Hence, we were able
to categorize the type of pain as neuropathic, nociceptive or mixed pain.
To this end, we used the clinical characteristics proposed by Nascimento and Schestatsky.
We considered nociceptive pain to be a form of pain that was limited to the joint
that was additional to mechanical pain, as pain that appeared during movement or in
a static posture (standing or sitting) or that improved with rest. We also considered
that nociceptive pain could be exacerbated by digital pressure and that imaging examinations
at the same pain site would show myofascial or joint alterations[19],[20],[21]. In order to verify the characteristics of neuropathic pain, we observed whether,
on physical examination, the pain pathway respected nerve territories or whether there
was any change in sensitivity in the painful area. The most common descriptors of
neuropathic pain were also taken into account: in addition to pain that worsened at
night, spontaneous pain that was unrelated to movement or static posture[14],[22],[23].
For assessment of pain and its impact on the quality of life, the SF-36 questionnaire
was used, which considers eight domains of pain. The resulting values range from 0
to 100, where 0 represents the greatest impact and 100 represents the least impact[24].
The “Charcot-Marie-Tooth Neuropathy Score 2” (CMTNS2) is a validated tool that has
the aim of ascertaining the impairment caused by Charcot-Marie-Tooth disease through
assessing signs and symptoms, along with neurophysiological data. It uses an index
that guides attribution of a score, which classifies the patients' involvement as
mild (≤ 10), moderate (11-20) or severe (> 20)[25].
Regarding the patients’ degree of muscle strength, we categorized the presence of
muscle weakness as a Medical Research Council (MRC) score < 5.
Statistical analysis and data processing
The data were collected and stored in a source document and database. Central trend
measurements were used to characterize the values, together with the basic demographic
data.
Independent samples, t tests and chi-square tests were performed to correlate the
pain location with muscle weakness, type of pain and orthopedic abnormalities/atrophy.
RESULTS
A description of the study population is shown in [Table 1].
Table 1
Demographic data of patients with Charcot-Marie-Tooth disease type 1A.
|
TOTAL
|
SD
|
|
n
|
19
|
|
|
Age (years)
|
40.8 (14-77)
|
± 15.6
|
|
Female sex
|
14 (73.6%)
|
-
|
|
In employment
|
12 (63.1%)
|
-
|
|
Years since symptom onset
|
24.2 (0-53)
|
± 17.6
|
|
Usage of pain medication
|
4 (21 %)
|
-
|
|
Corrective surgeries
|
2 (10.4%)
|
-
|
|
Use of gait assistive device
|
1 (5.2%)
|
-
|
|
Wheelchair
|
0
|
-
|
|
Orthosis
|
3 (15.7%)
|
-
|
|
History of fractures
|
6 (31.5%)
|
-
|
|
Scoliosis
|
3 (15.7%)
|
-
|
|
Pes cavus
|
15 (78.9%)
|
-
|
|
Hammer toes
|
9 (47.3%)
|
-
|
|
Peroneal atrophy
|
8 (42.1%)
|
-
|
|
Hand atrophy
|
10 (52.6%)
|
-
|
|
Tremor
|
10 (52.6%)
|
-
|
|
CMTNS2
|
|
Mild
|
4 (21%)
|
-
|
|
Moderate
|
12 (63.1%)
|
-
|
|
Severe
|
3 (15.7%)
|
-
|
SD: standard deviation.
Pain was a symptom in 16 out of the 19 patients (84.2%), as shown in [Figure 1]. The mean age of the pain group was 41.9 ± 16.0 years, and the mean duration of
symptoms since the onset of the disease was 22.8 ± 18.9 years.
Figure 1 Prevalence of pain complaints among patients with Charcot-Marie-Tooth disease type
1A.
The pain intensity according to the VAS scale was moderate (56.2%), with a mean score
of 3.56 ± 2.98.
According to the LANSS questionnaire, 75% of patients (n = 12) had nociceptive pain
and 4 patients had neuropathic pain (25%), with a mean score of 7.13 ± 5.61.
Differently, in the DN4 questionnaire, a majority of the patients (9 individuals;
56.2%) had neuropathic pain (DN4 ≥ 4), while 7 patients (43.7%) had nociceptive pain,
with a mean score of 3.56 ± 2.60.
Correlation of the data from the specific scales with the data obtained through clinical
evaluations showed that one patient whose characteristics of pain ascertained from
the anamnesis and physical examination were entirely nociceptive, was scored as presenting
neuropathic pain in both questionnaires (LANSS and DN4), thus representing a false
positive. This patient had joint pain in the knees, and an imaging examination showed
joint edema in both knees.
In addition, we found that, according to the clinical evaluation, seven patients (43.7%)
had mixed pain, while eight patients had exclusively nociceptive pain (50%) and one
patient had exclusively neuropathic pain, representing 6.2%. We considered these results,
obtained through clinical evaluation, to be the standard for defining the type of
pain ([Table 2]).
Table 2
Relationship between pain location and type of pain, according to the clinical evaluation,
using the chi-square test.
|
Pain location
|
Frequency (n = 16)
|
Type of pain
|
p-value
|
|
Neuropathic (n = 1)
|
Nociceptive (n = 8)
|
Mixed (n = 7)
|
|
Feet
|
10 (62.5%)
|
1
|
2
|
7
|
0.008
|
|
Legs
|
9 (56.2%)
|
0
|
5
|
4
|
0.493
|
|
Knees
|
6 (37.5%)
|
0
|
3
|
3
|
0.710
|
|
Low back
|
5 (31.2%)
|
0
|
2
|
3
|
0.595
|
|
Neck
|
4 (25%)
|
0
|
2
|
2
|
0.827
|
|
Chest
|
3 (18.7%)
|
0
|
2
|
1
|
0.768
|
|
Hips
|
3 (18.7%)
|
0
|
1
|
2
|
0.644
|
|
Hands
|
3 (18.7%)
|
0
|
2
|
2
|
0.827
|
|
Head
|
2 (12.5%)
|
1
|
1
|
0
|
0.018
|
|
Forearm
|
2 (12.5%)
|
0
|
1
|
2
|
0.644
|
Pain correlations with the VAS scale and the SF-36 domains showed a significant negative
correlation, thus demonstrating that the greater the intensity of pain was, the greater
the impairment in quality of life also was, in all domains ([Table 3]).
Table 3
Correlations between pain intensity on visual analogue scale (VAS) and quality-of-life
descriptors (SF-36).
|
Domain
|
Rho
|
p-value
|
|
General health
|
-0.531
|
0.034
|
|
Limitation due to physical aspects
|
-0.721
|
0.002
|
|
Functional capacity
|
-0.684
|
0.003
|
|
Mental health
|
-0.804
|
<0.01
|
|
Vitality
|
-0.762
|
0.001
|
|
Social aspects
|
-0.674
|
0.004
|
|
Bodily pain
|
-0.638
|
0.008
|
|
Limitation due to emotional aspects
|
-0.543
|
0.030
|
Orthopedic abnormalities and atrophy were observed in 14 patients with pain (87.5%):
pes cavus in 13 patients (81.2%), hammer toes in seven (43.7%), peroneal atrophy in
six (37.5%) and hand atrophy in eight (50.0%). There was no relationship with the
type of pain, according to the relationship between the clinical evaluation and specific
scales.
Most of the CMT patients with pain complaints had moderate disease severity according
to the CMTNS2 severity scale (n = 9; 56.25%), while four patients were ranked as mild
(25%) and three as severe (18.7%), with no significant correlation between the severity
of the disease and the intensity and type of pain.
DISCUSSION
The prevalence of pain was previously ascertained in a few studies that had proposed
to evaluate this subject. In the present study, the prevalence of pain was 84.2%.
Comparatively, in another study conducted on a sample of patients with CMT1A, the
prevalence of pain was 88%[25]. An Italian study observed that 56% of individuals with CMT had pain, and that pain
was the main symptom in 15 (28.8%) of these individuals[26].
Regarding the intensity of pain, 56.2% of our cases had moderate pain. Comparatively,
another study observed that 79.4% of the patients presented this result[8]. We believe that one possible reason why these patients’ pain was of moderate level
may have been the slow evolution of their neuropathy, which may have enabled these
individuals to use adaptive strategies for their activities of daily living.
In our study, the pain was assessed as having predominantly nociceptive characteristics
according to the LANSS scale (75%). This differed from the assessment using the DN4
scale, which found neuropathic pain in a majority of the patients (56.25%).
In comparing our results with those from a study conducted in Italy and the United
Kingdom, which evaluated the characteristics of pain in 49 patients with Charcot-Marie-Tooth
disease type 1A[25], using the LANSS questionnaire, similar proportions were found in that study, such
that only 18% of their patients had neuropathic pain. In another study that evaluated
neuropathic pain[24] using the DN4 pain assessment tool, 62.5% of their patients presented this type
of pain, compared with 56.2% of the sample in our study.
We can consider that the need to evaluate mixed pain is a limitation of the scales
used, since their outcomes only allow dichotomous results for characterizing the type
of pain. Therefore, we saw a need to corroborate these results by using those obtained
through clinical evaluation, given that clinical results can be considered “sovereign”.
Among our patients, a majority showed exclusively nociceptive characteristics (50.0%;
n = 8), while seven patients had mixed pain (43.7%) and one patient had exclusively
neuropathic pain (6.2%).
We correlated the other SF-36 domains with pain intensity and found statistically
significant negative correlations for all domains, thus corroborating the hypothesis
that the greater the pain intensity was, the greater the impact was on patients' quality
of life. The subjectivity of pain symptoms still poses a great challenge with regard
to evaluating and understanding pain, but investigation of pain symptoms is necessary
because of their direct relationship with predictors of quality of life.
The pain locations most frequently found in the present study corroborate the hypothesis
that pain in CMT disease is distal, peripheral and symmetrical. Pain was an important
symptom in our study, albeit only of moderate intensity. Feet, legs and knees were
the most frequent pain location and the greater the pain was, the greater the impact
was in patient´s quality of life. Regarding its characteristics, the pain was of nociceptive
origin in most of the individuals, according to two assessment methods (LANSS and
clinical assessment), although the results showed that neuropathic pain was also present.
There may also have been a mixed pattern of pain, which could only be verified through
clinical evaluation.
So far, this is the largest study to have evaluated the pain of patients with Charcot-Marie-Tooth
disease in Brazil. However, further research with larger samples or new tools for
assessing pain is necessary in order to continue to investigate the pathophysiological
aspects of pain and possible preventive measures for biomechanical changes that may
cause or perpetuate pain, given its impact on the quality of life.
