Abstract
Objective
The objective of our study was to describe and evaluate the prevalence of chronic pain in persons with Charcot-Marie-Tooth (CMT) disease during a multidisciplinary consultation at the Center of Reference for Neuromuscular Diseases.
Methodology
This prospective study was conducted between 2008 and 2010, it was a partnership between a Center of Reference for Neuromuscular Diseases (Centre de référence des maladies neuromusculaires [CRMD]) and a Department for the Assessment and Treatment of Pain (Département d’évaluation et de traitement de la douleur [DETD]). The evaluation consisted in a complete assessment of each patient during the first multidisciplinary consultation, with a previously established diagnosis validated by genetic testing, by various specialists: neurologist, PM&R physician, pain management specialist and physiotherapist. The evaluation tools used were Visual Analogical Scale (VAS), Hospital Anxiety and Depression Scale (HAD), DN4 scale, Neuropathic Pain Symptom Inventory (NPSI) (if DN4 ≥ 4), Pain Questionnaire of Saint Antoine (QDSA) (if DN4 < 4), body representation to define the painful areas, Overall Neuropathy Limitations Scale (ONLS), Medical Research Council scale (MRC), Short Questionnaire on Pain (QCD), VAS during transfers, self-care, getting dressed and physiotherapy sessions and quantified use of analgesics.
Results
A total of 50 patients were included (28 women, 22 men); two patients (one man and one woman) were discarded from the study because of missing pain assessment data. Mean age was 47 years (R: 14–85), in average the symptoms had been present for the past 20 years (R: 0.3–68), most patients had little impairment, the mean MRC was 53 (R: 36–60), with CMT1A being predominant (CMT1A: 76.9%, CMTX: 13.5%, CMT2: 5.8%, CMT4: 3.8%). It is noted that 65.4% of patients reported some pain with a mean duration of pain at 140 months (R: 5–660). The mean VAS was 5.5 (R: 1–10), greater than 4 in 79.4% of cases, requiring the use of analgesics in 38.4% of cases (step 1: 60%, step 2: 40% on the WHO pain relief ladder). The predominant location of the pain was distal, peripheral and symmetric (64.7%); furthermore the feet were affected in 80% of cases. DN4 was positive in 40.6% of painful patients. In 62.5% of the cases, the pain did not have an underlying mechanical origin. The emotional impact remained quite modest (HAD: A = 8; D = 5). Patients with CMT1A seemed less affected by pain ( P = 0.03).
Conclusion
This original study describes the pain in patients with CMT disease during a primary multidisciplinary consultation. We see that in 66% of cases, patients do report some pain, this pain is usually moderate, preferentially located in the extremities and is symmetric. In 62.5% of cases, the pain has a neuromuscular origin with a positive DN4 in 50% of cases in this etiology. In our study, patients with CMT1A report less pain than patients with other CMT types. This disease being quite rare (rare disease), the number of patients did not allow us to bring up statistically significant results. The pain must be thoroughly screened for because of its frequency in persons with CMT.
Résumé
Objectifs
Décrire et évaluer la douleur chronique chez des patients porteurs de neuropathie héréditaire de type Charcot-Marie-Tooth (CMT).
Méthodologie
Il s’agit d’une étude prospective conduite entre 2008 et 2010, collaborative entre un centre de référence des maladies neuromusculaires (CRMN) et un département d’évaluation et de traitement de la douleur (DETD), réalisée pour chaque sujet lors de la première consultation pluridisciplinaire, le diagnostic ayant préalablement été confirmé et caractérisé par analyse biologique moléculaire. L’évaluation a consisté en un examen des patients par les différents médecins spécialistes neurologue, MPR, douleur et le kinésithérapeute. Les outils d’évaluation utilisés ont été : EVA, HAD, DN4, NPSI (si DN4 ≥ 4), QDSA (si DN4 < 4), schéma corporel de localisation de la douleur, Overall Neuropathy Limitations Scale (ONLS), échelle de force Medical Research Council (MRC), questionnaire concis de la douleur, EVA douleur lors des transferts, de l’habillage, toilette et de la kinésithérapie, consommation d’antalgiques.
Résultats
Les caractéristiques démographiques de la population étudiée sont : 50 patients (28 femmes, 22 hommes ; deux patients [un homme et une femme] exclus pour données manquantes dans l’évaluation de la douleur), moyenne d’âge de 47 ans (14–85) dont les symptômes évoluent depuis en moyenne 20 ans (0,3–68), peu déficitaires, échelle MRC moyenne de 53 (36–60), avec une prédominance de CMT de type 1A (CMT1A) (1A : 76,9 %, liée à l’X : 13,5 %, 2 : 5,8 %, 4 : 3,8 %). On note que 65,4 % des patients déclarent une douleur, depuis en moyenne 140 mois (5–660). L’EVA moyenne est de 5,5 (1–10), supérieure ou égale à 4 dans 79,4 % des cas, nécessitant des antalgiques dans 38,4 % (palier 1 = 60 %, palier 2 = 40 %). La localisation périphérique distale et symétrique prédomine (64,7 %), atteignant les pieds dans 80 % des cas. On note que 40,6 % des patients douloureux ont un DN4 positif ; 62,5 % des douleurs ne sont pas d’origine mécanique. Le retentissement émotionnel reste faible (HAD : A = 8 ; D = 5). La douleur est moins fréquente dans le type CMT1A ( p = 0,03).
Conclusions
Cette étude originale est descriptive de la douleur des patients CMT lors d’une première consultation pluridisciplinaire. Soixante-six pour cent des patients présentent des douleurs, d’intensité modérée, de localisation préférentiellement distale et symétrique. Les douleurs sont majoritairement d’origine neuromusculaire (62,5 %) avec un DN4 positif dans 50 % des cas dans cette étiologie. Le CMT1A, le plus fréquent, est le moins souvent douloureux. L’effectif de la population étant faible (maladie rare), nous n’avons pas pu mettre en évidence des résultats statistiquement significatifs. La douleur doit cependant être recherchée de façon systématique en raison de sa fréquence.
1
English version
1.1
Introduction
Charcot-Marie-Tooth disease (CMT) is one of the most common inherited neurological disorders (prevalence 1/2500 , 30,000 patients are affected in France). This is a hereditary sensory-motor, demyelinating or axonal, neuropathy and genetically heterogeneous .
There are four main types of CMT diseases: CMT1 (autosomal dominant), CMT2 (genetically heterogeneous), CMTX related to the X chromosome (mutation of the connexin-32 gene on the X chromosome) and CMT4 (autosomal recessive).
CMT1A is the most common type, caused by abnormalities in the myelin sheath (more than 50% of cases ) with duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22) . CMT classification became more and more complex over these past 10 years due to the increasing number of identified loci and genes. Diagnostic strategies have been implemented in order to orientate the genetic testing according to the CMT type.
CMT disease management is based on genetic, electrophysiological (EMG) and even morphological approaches . The intensity of clinical symptoms can vary, starting around the age of 20 preferentially in the lower limbs. The affection is usually symmetric and bilateral. CMT disease is characterized by sensory-motor impairments and progressive muscle atrophy in the extremities (weakness of the foot and lower leg muscles) and often associated to foot deformities (high arches, hammertoes, flat palms and scoliosis). Authors have also reported a loss of aerobic capacities and oxygen consumption associated to muscle weakness . This decrease in muscle strength and aerobic capacities triggers muscle atrophy by denervation and immobilization. In their study, Gimignani et al. reported that sensory disorders were quite common (54% of CMT1 and CMT2); in CMT2 patients the presence of sensory disorders was correlated to a later onset and less severe motor impairments.
The progression of the disease is chronic and slowly progressive, but rarely ever fatal. This evolution can vary greatly for a same CMT type, going from no symptoms to severe impairments requiring a wheelchair. The severity of symptoms differs greatly among individuals and even among family members with the disease. In an Italian study conducted on patients with CMT1A over a 2-year period, the authors reported an aggravation of the distal sensory-motor impairments; but they did not report any negative impact on the quality of life, disability and depression.
The increased fatigue and sensory impairments seem to be compensated by some coping strategies, promoted by the slow progression of the disease.
To date, there are no pharmacological or genetic treatments available to treat this disease; however preventive measures can be implemented: physiotherapy, orthotics, orthopedic surgery and technical aids .
Some specific therapeutic approaches are now used for the most common CMT1A type to provide a “tailored-fit” correction to each patient’s dysfunctions . A recent article by Sereda et al. showed on a murine model that antiprogesterone therapy could decrease PMP22 expression and improve motor impairments. A more complete approach could be based on preventing or at least limiting axonal loss, a mechanism common to all CMT types, with neuroprotective neurotrophic factors. In 2004, Passage et al. reported that long-term treatment with acid ascorbic showed its efficacy in mice PMP22 overexpression, one of the models for the human form of the disease. A study was also conducted on human models, with inconclusive results . In 2001, a consensus conference wrote up recommendations for rehabilitation physiotherapy in neuromuscular diseases (but very few specific studies focused on CMT):
- •
muscle strength training is not contraindicated;
- •
eccentric training should be avoided;
- •
muscle strength training should be conducted below the maximum fatigue threshold, right from the onset of the disease .
An open study on eight patients with CMT, conducted by V. Gautheron et al. in 2006 , consisted in a muscle strength training program on a cycle ergometer three times a week for 12 weeks (incrementing exercises). The results showed improved physical and functional abilities and good exercise tolerance.
Commonly, rehabilitation care management is based on preventive measures: orthotic braces (wrists, hands, tibiotarsal joint, foot soles) in order to prevent stiffness, retractions and deformities. Corrective surgery is rarely indicated .
In neuromuscular diseases, chronic pain occurs in 62% of the cases and the mean intensity of this pain is moderate, anxiety is present in 46% of cases and depression in 16% .
Very few studies focused on pain in this pathology, its frequency varying from 56 to 96%. In CMT disease pain is usually moderate, symmetric and predominant to the lower limbs. Pain is most often neuropathic, with cramps, paresthesia and restlessness. Neuropathic pain in CMT1A is linked to damages in Aδ-type nerve fibers .
The STOPNEP study conducted in France on the general population showed that chronic pain is commonly reported (one third of French people) with 7% of neuropathic pain. Pain is mostly expressed by women (60.5%) with a mean age between 50 to 64 years. In more than 75% of cases, neuropathic pain is caused by low-back pain and neck pain, sometimes associated to spinal cord pain.
The other main etiologies of neuropathic pain are diabetes, herpes zoster, traumatic spinal cord injury, multiple sclerosis, AIDS infection and peripheral nerve lesions. A study conducted in Germany in 2003 on 362,963 persons revealed that the annual incidence of neuropathic pain was 8.2/1000 persons per year affecting predominantly middle-aged women.
The pharmaceutical care management of this pain is symptomatic. Neuropathic pain is usually poorly relieved by common analgesics, usually antidepressant and anti-seizure drugs are associated to the treatment, in accordance with the recommendations written by the French Society on the Study and Treatment of Pain (SFETD) in 2012. The efficacy of these treatment is incomplete and yields numerous and often bothersome adverse side effects. This is why physical therapy is essential in this pathology especially as it is free from adverse events. As in every type of chronic pain, there can be a negative impact on patients’ quality of life, mood and sleep , these factors should be considered when choosing the treatments.
The aim of our study was to describe and evaluate chronic pain and its impact in persons with CMT disease during the first multidisciplinary consultation in the Reference Center for Neuromuscular Diseases (CRMN).
Does this pain have a semiological specificity? A better description of the type of pain seen in CMT disease could improve the care management of this rare pathology where no specific cure is available.
1.2
Patients and methods
1.2.1
Patients
This prospective, descriptive study took place between 2008 and 2010 and was based on a partnership between a CRMN and a department for the evaluation and treatment of pain (DETD). It was conducted during the first multidisciplinary consultation proposed to patients.
The diagnosis of CMT disease was validated on clinical, family, electrophysiological and/or genetic criteria .
Patients with neurological pathologies were excluded from the study. The evaluation consisted in a systematic examination of the patients by a neurologist, PM&R physician, pain specialist and physiotherapist.
1.2.2
Measures
Data collected were:
- •
demographics;
- •
duration of the disease’s progression, type of mutation and genetic data;
- •
history of ankle or foot surgery;
- •
podoscope examination;
- •
Overall Neuropathy Limitations Scale (ONLS) : the use of this functional scale was validated in CMT disease. The total score goes from 0 to 12 (0 = normal). It is divided into two parts: functional score for the upper limbs on 5 points (0 = normal) and functional score for the lower limbs on 7 points (0 = normal);
- •
Medical Research Council (MRC) Score : established on the basis of a complete motor testing of the four limbs according to the classification by the MRC going from 0 to 5: arm abduction, forearm flexion, wrist extension, thigh extension, dorsal flexion of the foot. The score goes from 0 to 60 (normal);
- •
analytic testing (according to the MRC classification) for each muscle of the four limbs;
- •
gait speed on a 10-meter distance (Wade test) ;
- •
Hospital Anxiety and Depression (HAD) scale : self-administered questionnaire evaluating anxiety and depression. Sum of the scores from the D column (0 to 21): depression is likely more than 10. Sum of the scores from the A column (0 to 21): pathological anxiety likely more than 10;
- •
all patients where asked: “Do you feel pain? If yes, how long has this pain been present?” Patients were considered painful regardless of the VAS score.
The evaluation of painful patients included:
- •
use of analgesics (according to the WHO ladder), antidepressants and anti-seizure medicines;
- •
intensity of the pain measured by the VAS , scale going from 0 to 100 mm on a ruler presented to the patient;
- •
spontaneous description of the quality of the pain using one to three qualitative words;
- •
DN4 questionnaire : when the physician suspects neuropathic pain, the DN4 questionnaire is useful for the diagnosis; the physician interviews and examines the patient, then fills out the questionnaire (by scoring 0 for no and 1 for yes) and each of the 10 items (seven questions and three signs that can be found during the examination). The DN4 score goes from 0 (absence of symptoms) to 10 (presence of all the symptoms). The test is positive when the score greater or equal to 4/10 (sensitivity 82.9% and specificity 89.9%);
- •
body representation of the painful areas; the various locations of the pain are axial (neck, back, lower-back), peripheral (proximal and distal) and the head;
- •
short questionnaire on pain (QCD) : self-questionnaire evaluating the impact of pain in various areas: mood, gait, work, relations with others, sleep, desire and will for life;
- •
Neuropathic Pain Symptom Inventory (NPSI) (filled-out if the DN4 ≥ 4) : self-questionnaire describing, during the past 24 hours, the intensity and frequency of spontaneous-type pain (burning, squeezing, compression pain), short painful episodes (electric shock, stabbing), provoked pain (brushing, pressure or contact with a cold object) and abnormal sensations (tingling, crawling);
- •
the short version of the Saint-Antoine Pain Questionnaire (QDSA) (filled out if DN4 < 4) , self-questionnaire scoring the sensory and emotional qualities of the pain;
- •
clinical examination: patients were examined by two pain management specialists and divided into two groups: mechanical pain (osteoarticular pain, by excessive nociception) and non-mechanical pain (neuromuscular) including the rest of the patients.
1.2.3
Statistical analysis
The statistical analysis described each variable according to their nature, qualitative or quantitative. Chi 2 test (or Fisher exact test) was used to test paired 2 × 2 variables to measure their independence, Kruskal-Wallis test was also used. A 5% alpha risk was chosen to interpret the significance of comparisons.
1.3
Results
1.3.1
Description of the population studied (during the first specialized CMT consultation at the CRMN)
Demographics of the population: 50 patients (28 women, 22 men; two patients [one man and one woman] were excluded due to missing data on pain evaluation), mean age 47 years (14–85) with symptoms of disease progressing for a mean of 20 years (0.3–68) ( Table 1 ).
| Non-painful patients | Painful patients | |
|---|---|---|
| Number of patients | 18 | 32 |
| Age (years) | 46 (22–79) | 48 (14–85) |
| Sex (M / W) | 6 / 12 | 16 / 16 |
| Onset of the disease (years) | 20.1 (0.3–55) | 21.3 (3–68) |
| History of foot surgery | 3 | 9 |
| Arched feet | 13 | 25 |
| 10-meter walking test in seconds | 8.5 (6–16) | 8 (4–15) |
| ONLS / 5 | 0.8 (0–3) | 1.4 (0–4) |
| ONLS / 7 | 1.7 (0–4) | 2 (1–6) |
| ONLS / 12 | 2.5 (0–6) | 3.4 (1–10) |
| MRC / 60 | 52.8 (38–60) | 53.2 (36–60) |
| Proximal motor testing of the upper limbs / 5 | 4.9 (4–5) | 4.8 (2–5) |
| Distal motor testing of the upper limbs / 5 | 4.2 (2.9–5) | 4.3 (2–5) |
| Proximal motor testing of the lower limbs / 5 | 4.6 (3.1–5) | 4.5 (2–5) |
| Distal motor testing of the lower limbs / 5 | 2.6 (0–4.8) | 3.1 (0.6–5) |
| Anxiety (HAD) / 21 | 6.8 (2–15) | 8.5 (1–18) |
| Depression (HAD) / 21 | 4.5 (2–11) | 8 (0–13) |
| CMT Types: 1A / 2 / X / 4 | 17 / 0 / 1 / 0 | 21 / 3 / 6 / 2 |
The studied population is representative of the pathology (gender, age, genetics and clinical symptoms) .
The CMT1A type is predominant: CMT1A: 76.9%, CMTX: 13.5%, CMT2: 5.8%, CMT4: 3.8%.
Regarding genetic data (data were missing for four patients), PMP22 is present in 77.1% of the cases, connexin 32: 14.6%, GDAP1 dominant: 6.25%, GDAP1 recessive 2.1%.
The types of mutation found (data were missing in five cases) were:
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duplication of chromosome 17p11.2 for the PMP 22 in all CMT1A types (78.7%);
- •
mutation of the connexin-32 gene: arginine 164 replaces glycine in 8.5% of the cases, PHE 235 CYS: 2.1%, ARG22GLN: 4.3%, ARG 120 TRP: 6.4%.
In the medical history we find that 24% of patients had ankle or feet surgery and 75% have arched feet.
Muscle strength has not decreased much with a mean MRC at 53 (36–60). Muscle weakness (testing ≤ 3) is predominant to the lower limbs and the extremities. Functional capacities are not very impaired in the upper limbs (ONLS / 5; 0 = normal) and upper limbs (ONLS / 7): ONLS / 5 = 1.2 (0–5) and ONLS / 7 = 1.9 (0–6).
The result of the 10-meter walking test was 8 seconds in average (4.5 km/h) (4–16), excluding the non-ambulatory patients.
1.3.2
Description of painful patients
Description of painful patients ( Tables 2 and 3 ):
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66% (32/50) of patients have chronic pain (progressing for over 3 months);
- •
according to the clinical classification 62.5% (20/32) of the pain have a neuromuscular origin ( Table 3 ).
In our study the pain is most often neuromuscular. When the pain is mechanical, the age of the patients is higher (56.2 years in average vs. 43.2) and the disease is older (mean of 4 years more);
- •
two descriptions are most often used to spontaneously describe the pain: “cramps” in 29% of cases and “tearing” in 13.3% of the cases ( Table 4 );
Table 4
Words expressed spontaneously by the patients to describe the type of pain (0 to 3 maximum per patient): at the beginning of the consultation and prior to any other evaluation.
Descriptive words
Mechanical pain
Neuromuscular pain
Cramps
1
8
Tearing
2
2
Prickling
0
2
Burning
2
1
Tiring
0
3
Pounding
1
2
Throbbing
1
2
Pressure
1
1
Heaviness
1
1
Tingling
2
2
Stabbing (knife)
2
0
Giving way
1
1
Crushing
1
0
Stiffness
0
1
Vice
1
0
Discomfort
0
1
Tetany
0
1
Sharp
1
0
Squashing
1
0
Dislocation
0
1
Anesthetic
0
1
Debilitating
0
1
Contracture
1
0
Block
1
0
Irritating
0
1
Paralysis
2
1
Wearisome
1
1
Recurrent
1
0
Electric shock
0
2
Varying
1
0
- •
pain has been progressing for an average of 140 months (5–660);
- •
pain is less frequent for CMT1A type than in other CMT types ( P = 0.03);
- •
mean VAS for the pain is (10–100), greater or equal to 40 in 79.4% of the cases;
- •
38.4% of patients use analgesics: step 1 and step 2 (WHO ladder) in 60% and 40% of the cases. No patient is using step 3 analgesics or anti-seizure drugs. Five percent of patients take an antidepressant for mood disorders;
- •
mean VAS for the pain during transfers is 35/100;
- •
mean VAS for the pain during self-care and getting dressed is 23/100;
- •
the results of the short questionnaire on pain (means for the impact of the pain in various domains) are:
- ∘
mood: 4.6/10,
- ∘
gait: 5.3/10,
- ∘
work: 5.5/10,
- ∘
relations with others: 2.4/10,
- ∘
sleep: 3.4/10,
- ∘
will for life: 3.3/10.
- ∘
| Positive DN4 | Negative DN4 | |
|---|---|---|
| Number of patients | 13 | 19 |
| Age (years) | 48.3 (32–70) | 47.9 (14–85) |
| Sex (M / W) | 5 / 8 | 11 / 8 |
| Onset of the disease (years) | 20.7 (3–56) | 21.8 (3–68) |
| History of foot surgery | 4 | 5 |
| Arched feet | 11 | 14 |
| 10-meter walking test in seconds | 7.8 (6–11) | 8.1 (4–15) |
| ONLS / 5 | 1.5 (1–3) | 1.3 (0–4) |
| ONLS / 7 | 1.9 (1–3) | 2.1 (1–6) |
| ONLS / 12 | 3.4 (2–6) | 3.3 (1–10) |
| MRC / 60 | 53 (48–60) | 53 (36–60) |
| Proximal motor testing of the upper limbs / 5 | 4.9 (4.5–5) | 4.7 (2–5) |
| Distal motor testing of the upper limbs / 5 | 4.3 (2.8–5) | 4.3 (2–5) |
| Proximal motor testing of the lower limbs / 5 | 4.4 (3.2–5) | 4.7 (2–5) |
| Distal motor testing of the lower limbs / 5 | 3 (0.6–5) | 3.1 (0.3–5) |
| Axial pain | 3 | 9 |
| Proximal peripheral pain of the lower limbs (data missing for one case on the DN4 value) | 5 (5 symmetric) | 7 (4 symmetric, missing data for 1 patient, 2 asymmetric) |
| Proximal peripheral pain of the upper limbs | 1 (1 symmetric) | 3 (2 asymmetric, 1 symmetric) |
| Distal peripheral pain of the lower limbs | 10 (10 symmetric) | 10 (8 symmetric, 2 asymmetric) |
| Distal peripheral pain of the upper limbs | 2 (2 symmetric) | 3 (3 symmetric) |
| Mechanical pain | 3 | 9 |
| VAS (/100) | 56 (30–80) | 53 (10–80) |
| QCD / mood (/10) | 4.7 (0–10) | 4.5 (0–10) |
| QCD / gait (/10) | 6.4 (1–9) | 4.6 (0–10) |
| QCD / work (/10) | 6.2 (1–8) | 5 (0–8) |
| QCD / relations to others (/10) | 2.8 (0–7) | 2 (0–8) |
| QCD / sleep (/10) | 4.8 (0–10) | 2.4 (0–10) |
| QCD / will for life (/10) | 4 (0–9) | 2.7 (0–8) |
| VAS transfers (/10) | 3.5 (0–7) | 3.5 (0–8) |
| VAS self-care/getting dressed (/10) | 2.3 (0–7) | 2.3 (0–9) |
| Anxiety (HAD) / 21 | 10.2 (6–16) | 7.3 (1–18) |
| Depression (HAD) / 21 | 6.4 (1–13) | 4.5 (0–13) |
| CMT Types: 1A / 2 / X / 4 | 9 / 2 / 2 / 0 | 12 / 1 / 4 / 2 |
| Mechanical pain | Neuromuscular pain | |
|---|---|---|
| Number of patients | 12 | 20 |
| Age (years) | 56.2 (34–85) | 43.2 (14–75) |
| Sex (M / W) | 3 / 9 | 13 / 7 |
| Onset of the disease (years) | 24.5 (3–68) | 19.4 (3–55) |
| History of foot surgery | 4 | 5 |
| Arched feet | 9 | 16 |
| 10-meter walking test in seconds | 9.4 (6–15) | 7.1 (4–11) |
| ONLS / 5 | 1.6 (0–4) | 1.2 (0–3) |
| ONLS / 7 | 2.2 (1–6) | 1.9 (1–3) |
| ONLS / 12 | 3.8 (1–10) | 3.1 (1–6) |
| MRC / 60 | 51.2 (36–60) | 54.4 (48–60) |
| Proximal motor testing of the upper limbs / 5 | 4.6 (2–5) | 4.9 (4.5–5) |
| Distal motor testing of the upper limbs / 5 | 4 (2–5) | 4.6 (2.9–5) |
| Proximal motor testing of the lower limbs / 5 | 4.2 (2–5) | 4.7 (3.3–5) |
| Distal motor testing of the lower upper limbs / 5 | 2.7 (0.5–3.8) | 3.4 (0.7–4.6) |
| Axial pain | 8 (1 neck, 6 lower back, 6 spine) | 4 (2 neck, 1 lower back, 1 spine) |
| Proximal peripheral pain of the lower limbs | 4 | 8 |
| Proximal peripheral pain of the upper limbs | 2 | 2 |
| Distal peripheral pain of the lower limbs | 5 | 15 |
| Distal peripheral pain of the upper limbs | 0 | 5 |
| Positive DN4 | 3 | 10 |
| VAS (/100) | 56 | 53 |
| QCD / mood (/10) | 5.6 (0–10) | 3.9 (0–10) |
| QCD / gait (/10) | 4.5 (0–10) | 5.8 (0–10) |
| QCD / work (/10) | 5.5 (2–8) | 5.5 (0–8) |
| QCD / relations to others (/10) | 2.7 (0–8) | 2.1 (0–7) |
| QCD / sleep (/10) | 3 (0–10) | 3.6 (0–9) |
| QCD / will for life (/10) | 4.4 (0–8) | 2.6 (0–9) |
| VAS transfers (/10) | 4.2 (0–8) | 3 (0–8) |
| VAS self-care/getting dressed (/10) | 3.2 (0–9) | 1.7 (0–7) |
| Anxiety (HAD) / 21 | 9.6 (3–18) | 7.8 (1–15) |
| Depression (HAD) / 21 | 6.5 (1–13) | 4.5 (0–8) |
| CMT Types: 1A / 2 / X / 4 | 9 / 0 / 1 / 2 | 12 / 3 / 5 / 0 |
Thirteen out of 32 (40.6%) painful patients have a positive DN4 (≥ 4) ( Table 2 ), 50% of neuromuscular pain, according to our clinical classification, has a positive DN4 score ( Tables 3–5 ).
| DN4+ / Mechanical | DN4+ / Neuromuscular | DN4− / Mechanical | DN4− / Neuromuscular | |
|---|---|---|---|---|
| Number of patients | 3 | 10 | 9 | 10 |
| Sex (M/W) | 0/3 | 5/5 | 3/6 | 8/2 |
| Age | 46.7 | 48.9 | 59.4 | 37.5 |
| Onset of the disease (years) | 15.7 | 22.2 | 27.4 | 16.7 |
| ONLS/12 | 2.3 | 3.8 | 4.3 | 2.5 |
| MRC | 57 | 52.5 | 49.3 | 56.4 |
| 10-meter walking test in seconds | 8 | 7.7 | 10 | 6.4 |
| VAS | 53 | 57 | 57 | 50 |
| HAD (A/D) | 12/9 | 9.7/5.6 | 8.9/5.8 | 6/3.5 |
Detailed results of the DN4:
- •
burning-type pain: 75%;
- •
sensation of painful cold: 0%;
- •
electric shock: 41%;
- •
crawling: 82%;
- •
tingling: 61%;
- •
numbness: 23%;
- •
itching: 0%;
- •
hypoesthesia to the touch: 88%;
- •
hypoesthesia to the prick-test: 80%;
- •
allodynia to brushing: 7%.
Location of the pain:
- •
a total of 53 painful areas were described: 41 peripheral locations and 12 axial locations. Five patients described both axial and peripheral locations (14.7%);
- •
description of peripheral pain:
- ∘
25 distal locations (73.5%): 20 to the lower limbs and five to the upper limbs,
- ∘
16 proximal locations (47%): 12 to the lower limbs and four to the upper limbs,
- ∘
80% of the cases for peripheral pain affect the feet more than the hands,
- ∘
in 90% of the cases, peripheral pain is symmetric;
- ∘
- •
description of the axial pain:
- ∘
12 axial locations (37.5%): seven in the lower back, three in the neck and two diffuse spinal pain,
- ∘
the QDSA was done when the DN4 was negative,
- ∘
mean of sensory-type words to qualify the pain 3.1/10,
- ∘
mean of emotional-type words to qualify the pain 4.3/10,
- ∘
the NPSI was done when the DN4 was positive,
the mean score was 40/100, with a predominance of paroxysmal, constriction and paresthesia-type pain.
- ∘
1.3.3
Description of the non-painful population (compared to painful patients)
Painful and non-painful populations are quite similar in age, sex, genetics and duration of the disease ( Table 1 ):
- •
18 patients are non-painful (vs. 32 painful patients);
- •
the disease has been progressing in average for 20.2 years (vs. 21.3 years);
- •
the mean age is 46 years (vs. 48 years);
- •
the sex ratio is six men/12 women (vs. 16 M/16 W);
- •
history of foot surgery: 25% (vs. 75%);
- •
arched feet: 50% (vs. 66%). Painful patients most often have arched feet;
- •
the CTM types are: CMT1A = 17 (vs. 21), CMT2 = 0 (vs. 3), CMT X = 1 (vs. 6), CMT4 = 0 (vs. 2). This repartition is comparable to the commonly established one ;
- •
in the non-painful population, no patient is taking any analgesics, antidepressant or anti-seizure drugs;
- •
mean ONLS / 5 is 0.8 (vs. 1.4);
- •
mean ONLS / 7 is 1.7 (vs. 2);
- •
mean ONLS / 12 is 2.5 (vs. 3.4).
We note a lesser functional impact of the disease in non-painful patients:
- •
mean MRC is 52.8 (vs. 53.2);
- •
for the non-painful patients, motor impairments are greater in the lower limbs: motor function test 2.6 / 5 (vs. 3.1);
- •
the 10-meter walking test is 8.5 seconds in average (vs. 8);
- •
the HAD scale shows a mean score of 6.8 for anxiety (vs. 8.5) and 4.5 for depression (vs. 5.3): no noticeable difference on the anxiety and depression scores between painful and non-painful patients. None of these two populations have any pathological emotional component.
1.4
Discussion
A US study on CMT disease , based on questionnaires sent to patients’ home, found a majority of women in the painful population (64%); this was not found in our study (50/50).
This tendency was also found in the STOPNEP survey and in the German study , both focused on evaluating the frequency of neuropathic pain in the general population.
Analgesic use is low with a predominance of step 1 pain medications with no step 3 analgesics, whereas the study by Carter et al. showed the use of opioids in 23% of cases.
Just like in our study, the literature reports pain frequency going from 70 to 90% with a moderate intensity. The pain is less frequent (56%) in the study by Gemignani et al. .
As expected the location of the pain is symmetric and affecting mostly the feet. Contrarily to our results, in his study Carter reported that spinal and osteoarticular pain were predominant affecting mostly the lower back (70%) followed by the knees (53%), ankles (50%), toes (46%), feet (44%) and hands (7%).
Most pain symptoms have a neuromuscular etiology with only 40% of positive DN4 questionnaires. Let us note that the DN4 only has a specificity of 81.2%, which could explain the discordance.
The Italian study by Gemignani et al. found a much lower frequency for neuropathic pain (11%), pain by excessive nociception is predominant in the CMT1A type (71%).
Just like in the study by Carter , we did not highlight any symptoms that could differentiate the neuropathic pain in CMT disease from other neuropathies.
DN4 is positive in one quarter of the patients with mechanical pain and it is well known that spinal pain is often responsible of neuropathic pain (6 to 32%) .
The frequency of nociceptive pain increases with age and disease progression: this result could be explained by a degenerative affection aggravated by gait disorders caused by distal impairment and musculoskeletal deformities.
Our NPSI components are different from the ones reported in the work of Carter where “dull” and “burning” were the most frequent without any explanation regarding this difference.
In our population, painful patients tend to have more of the following (without any statistically significant different): arched feet, musculoskeletal deformities that could be at the origin of the pain as suggested by Padua et al. or considered as a marker of the disease progression.
Just like in the other studies the pain’s impact on patients’ activities of daily living and mood remains quite low in spite of the progression of the sensory motor deficit.
In CMT disease, age and duration of the symptoms are highly correlated to a deterioration of the quality of life .
In a study conducted in 2005, CMT has been evidenced as the neuromuscular disease having the lowest impact on the patients’ social interactions with others , just like in our study.
1.5
Conclusion
The originality of the study resides both in a systematic and detailed evaluation of the pain and in the large cohort of French patients with this rare, diagnostically validated, disease.
No statistically significant result is highlighted by this study. The CMT1A type tends to be less painful.
Even if pain is a frequent occurrence in CMT, it remains moderate with a low impact on the patients’ daily life. In most cases, the pain has a neuromuscular origin with a positive DN4 in only 50% of the cases. The words most often reported to describe the nature of the pain are “cramps”, just like in the literature.
The psycho-emotional dimension, present in all types of chronic pain, is not found in this study: there were no signs of anxiety or depression, the words used to describe the pain did not bear any emotional characteristics.
The slow progression of the disease probably promotes coping strategies both on a physical and psychological level.
Pain being quite common in CMT disease (neuropathic and/or nociceptive), it must be systematically screened for: DN4, NPSI and QSDA are quick, simple and validated can optimize the care management of this disease.
In light of the high frequency of arched feet in painful patients, we propose an early fitting with corrective sole orthotics in these patients.
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
2
Version française
2.1
Introduction
La maladie de Charcot-Marie-Tooth (CMT) est la plus fréquente des maladies neuromusculaires héréditaires (prévalence : 1/2500 , 30 000 personnes atteintes en France).
Il s’agit d’une neuropathie héréditaire sensitivomotrice, démyélinisante ou axonale, génétiquement hétérogène .
Il existe quatre types de CMT : I (autosomique dominante), II (génétiquement hétérogène), III liée à l’X (mutation du gène de la connexine 32) et IV (autosomique récessive).
Le type Ia (démyélinisant) est de loin le plus fréquent (plus de 50 % : duplication ou mutation du segment 17p11.2, locus du gène codant pour la pmp22 [ peripheral myelin protein ]) .
La classification des CMT est devenue de plus en plus complexe au cours de la dernière décennie, en raison du nombre croissant de loci et de gènes identifiés. Des stratégies de diagnostic ont été mises en place afin d’orienter les analyses moléculaires à réaliser en fonction du type de CMT.
Cela nécessite donc une approche clinique, génétique, électrophysiologique (électromyogramme) et parfois morphologique .
Les signes cliniques sont de sévérité variable, débutant, en général vers 20 ans, aux membres inférieurs. L’atteinte est bilatérale et symétrique.
La maladie de CMT est caractérisée par un déficit sentivomoteur et une amyotrophie progressive des extrémités (péronières et éminences hypothénar), souvent associés à des déformations (pieds creux, orteils en griffes, paumes plates, scoliose).
Il a été constaté une diminution des capacités aérobies et de la consommation d’oxygène associée à une perte de force . La diminution de la force musculaire et des capacités aérobies entraînent une amyotrophie par dénervation et immobilisation.
Dans l’étude de Gimignani et al. , les troubles sensitifs sont fréquents (54 % des CMT I et II) ; chez les patients CMT II, la présence de troubles sensitifs est corrélée à un début plus tardif et à une atteinte motrice moins sévère.
L’évolution est chronique et lentement progressive n’atteignant pas le pronostic vital.
Pour un même type, elle est très variable allant des formes asymptomatiques au handicap sévère nécessitant un fauteuil roulant.
Cette variabilité du phénotype est inter- mais aussi intrafamiliale.
Dans une étude italienne portant sur les CMT1A sur une période de deux ans, il est constaté une aggravation du déficit sensitivomoteur distal mais pas de la qualité de vie, du handicap et de la dépression.
L’augmentation de la fatigue et du déficit sensitif paraît être compensée par des stratégies adaptatives, favorisées par la lente progression de la maladie.
Il n’existe aucun traitement pharmacologique ou génétique curatif actuellement, en revanche des mesures préventives peuvent être prises : kinésithérapie, port d’attelles, chirurgie orthopédique et aides techniques .
Des approches thérapeutiques spécifiques visant à corriger « à la carte » chacun des dysfonctionnements sont néanmoins en cours pour la forme la plus fréquente, le CMT1A. Un article récent de Sereda et al. a par exemple montré, sur un modèle murin, que des anti-progestérones étaient capables de diminuer l’expression de PMP22 et d’améliorer le déficit moteur.
Une approche plus globale pourra consister à prévenir ou du moins limiter la perte axonale, mécanisme commun à toutes les formes de CMT, avec des facteurs neuroprotecteurs ou neurotrophiques.
En 2004, Passage et al. ont montré que le traitement au long cours avec de l’acide ascorbique semble efficace chez les souris surexprimant la PMP22, un des modèles de la forme humaine de la maladie. Une étude a également été réalisée chez l’homme, dont les résultats sont peu probants .
En 2001, une conférence de consensus a élaboré des recommandations sur la kinésithérapie dans les maladies neuromusculaires (mais peu d’études spécifiques sur les CMT) :
- •
l’exercice musculaire n’est pas contre-indiqué ;
- •
il convient d’éviter les exercices de type excentrique ;
- •
le travail musculaire doit se faire en dessous du seuil maximal de fatigue, dès l’apparition de la maladie .
Une étude ouverte sur huit patients porteurs de CMT a été menée par V. Gautheron et al. en 2006 , consistant en un renforcement musculaire sur cycloergomètre trois fois par semaine pendant 12 semaines (exercices en créneau) mettant en évidence une amélioration des capacités physiques et fonctionnelles, avec une bonne tolérance des exercices.
Classiquement, la prise en charge rééducative est également basée sur des mesures préventives : orthèses (poignets, mains, suropédieuses, plantaires) afin de prévenir les enraidissements, les rétractions et les déformations.
La chirurgie correctrice est rarement indiquée .
Dans les maladies neuromusculaires, la fréquence de la douleur chronique est de 62 %, l’intensité moyenne est modérée avec 46 % d’anxiété et 16 % de dépression .
Peu d’études se sont intéressées à la douleur dans cette pathologie, la fréquence variant de 56 à 96 %.
L’intensité de la douleur dans la maladie de CMT est modérée, la localisation est symétrique et prédomine aux membres inférieurs. Les douleurs sont le plus souvent neuropathiques, à type de crampes, paresthésies, impatiences. La douleur neuropathique serait liée, dans le type Ia, à l’atteinte des fibres Aδ .
L’enquête STOPNEP menée en population générale en France montre que la douleur chronique est une plainte fréquente (un tiers des français) avec 7 % de douleurs neuropathiques. La douleur est à prédominance féminine (60,5 %) avec un âge moyen de 50 à 64 ans. Les douleurs neuropathiques sont dues dans plus de 75 % des cas à des lombalgies et cervicalgies, associées parfois à des radiculalgies.
Les autres principales causes de douleurs neuropathiques sont le diabète, le zona, le traumatisme médullaire, la sclérose en plaques, l’infection VIH et les lésions nerveuses périphériques.
Une enquête réalisée en Allemagne en 2003 sur 362 963 personnes relève une incidence annuelle de douleurs neuropathiques de 8,2/1000 personnes par an avec une prédominance chez la femme d’âge moyen.
La prise en charge médicamenteuse des douleurs est symptomatique.
Les douleurs neuropathiques sont habituellement mal soulagées par les antalgiques habituels, le traitement fait donc appel aux antidépresseurs et antiépileptiques, selon les recommandations de la Société francaise d’étude et traitement de la douleur (SFETD) en 2010 . Ces traitements ont une efficacité partielle au prix d’effets indésirables souvent gênants : les thérapeutiques physiques gardent donc toute leur place dans cette pathologie, d’autant qu’elles sont dénuées d’effets secondaires.
Comme dans toute douleur chronique, il peut exister un retentissement sur la qualité de vie, l’humeur et le sommeil , facteurs à prendre en compte pour le choix des traitements.
Le but de notre étude est de décrire, d’évaluer la douleur chronique et son retentissement chez les patients porteurs de CMT lors de la première consultation pluridisciplinaire du centre de référence des maladies neuromusculaires (CRMN).
Ces douleurs ont-elles une spécificité séméiologique ?
Une meilleure description du type de douleur rencontrée dans la maladie de CMT pourrait améliorer la prise en charge de cette pathologie rare dépourvue de traitement curatif spécifique.
2.2
Patients et méthodes
2.2.1
Patients
Il s’agit d’une étude prospective, descriptive conduite entre 2008 et 2010, collaborative entre un CRMN et un département d’évaluation et traitement de la douleur (DETD), réalisée lors d’une première consultation pluridisciplinaire.
Le diagnostic de CMT a été confirmé sur des critères cliniques, familiaux, électrophysiologiques et/ou génétiques .
Les patients porteurs de pathologie neurologique associée ont été exclus de l’étude.
L’évaluation a consisté en un examen systématique des patients par un neurologue, un médecin de MPR, un algologue et un kinésithérapeute.
2.2.2
Mesures
Les données recueillies ont été :
- •
démographiques ;
- •
durée d’évolution de la maladie, type de mutation et génétique ;
- •
antécédents chirurgicaux de la cheville ou du pied ;
- •
examen sur podoscope ;
- •
Overall Neuropathy Limitations Scale (ONLS) : échelle fonctionnelle dont l’utilisation a été validée dans la maladie de CMT. Le score total est sur 12 (0 = normalité). Elle se divise en deux parties : score fonctionnel des membres supérieurs sur 5 points (0 = normalité) et score fonctionnel des membres inférieurs sur 7 points (0 = normalité) ;
- •
score Medical Research Council (MRC) : établi sur la base d’un testing moteur global des quatre membres selon la classification du MRC allant de 0 à 5 : abduction du bras, flexion de l’avant-bras, extension du poignet, flexion de cuisse, extension de jambe, flexion dorsale du pied. Score allant de 0 à 60 (normal) ;
- •
testing analytique (selon la classification du MRC) de chaque muscle des quatre membres ;
- •
vitesse de marche sur 10 m (test de Wade) ;
- •
échelle Hospital Anxiety and Depression Scale (HAD) : autoquestionnaire évaluant l’anxiété et la dépression. Somme des scores de la colonne D (0 à 21) : dépression probable au-dessus de 10. Somme des scores de la colonne A (0 à 21) : anxiété pathologique probable au-dessus de 10 ;
- •
il a été demandé à tous les patients : « Avez-vous une ou des douleurs ? Et si oui, depuis combien de temps ? » Les patients étaient considérés comme douloureux quelle que soit l’intensité à l’EVA.
L’évaluation chez les patients douloureux comprenait :
- •
la consommation d’antalgiques (paliers), d’antidépresseurs et d’antiépileptiques ;
- •
intensité de la douleur par l’échelle visuelle analogique (EVA) , échelle de 0 à 100 mm sur une réglette présentée au patient ;
- •
description spontanée de la douleur par un à trois qualificatifs ;
- •
questionnaire DN4 : lorsque le praticien soupçonne une douleur neuropathique, le questionnaire DN4 est utile au diagnostic ; le praticien interroge et examine le patient, puis remplit le questionnaire lui-même, en cotant 0 pour non et 1 pour oui, pour chacun des dix items (sept questions et trois signes d’examen). Le score DN4 va de 0 (absence de tout symptôme) à 10 (présence de tous les symptômes). Le test est positif pour un score supérieur ou égal à 4/10 (sensibilité à 82,9 % ; spécificité à 89,9 %) ;
- •
schéma corporel des zones douloureuses ; les différentes localisations sont axiale (cervicale, dorsale, lombaire), périphérique (proximale, distale) et la tête ;
- •
questionnaire concis sur les douleurs (QCD) : autoquestionnaire évaluant le retentissement de la douleur dans différents domaines : humeur, marche, travail, relation avec les autres, sommeil, goût de vivre ;
- •
Neuropathic Pain Symptom Inventory (NPSI) (rempli si le DN4 ≥ 4) : autoquestionnaire décrivant, au cours des dernières 24 heures, l’intensité et la fréquence des douleurs spontanées (brûlure, étau, compression), des crises douloureuses brèves (décharge électrique, coups de couteau), des douleurs provoquées (par le frottement, la pression ou le contact avec un objet froid) et des sensations anormales (fourmillements, picotements) ;
- •
la version courte du questionnaire douleur de Saint-Antoine (QDSA) (rempli si le DN4 < 4) , autoquestionnaire notant les qualificatifs sensoriels et émotionnels de la douleur ;
- •
examen clinique : les patients sont examinés par deux médecins algologues et classés en deux groupes : douleur mécanique (ostéoarticulaire, par excès de nociception) et douleur non mécanique (neuromusculaire) incluant le reste des patients.
2.2.3
Analyses statistiques
L’analyse statistique a consisté en une description de chaque variable selon leur nature qualitative ou quantitative. Étude de l’indépendance ou non des variables qualitatives deux à deux : test du Chi 2 (ou test exact de Fisher), test de rang de Kruskal-Wallis. Un risque alpha à 5 % a été choisi pour l’interprétation de la significativité des comparaisons.
2.3
Résultats
2.3.1
Description de la population étudiée (lors de la première consultation spécialisée CMT au CRMN)
Les caractéristiques démographiques de la population sont : 50 patients (28 femmes, 22 hommes ; deux patients [un homme et une femme] exclus pour données manquantes dans l’évaluation de la douleur), moyenne d’âge de 47 ans (14–85) dont les symptômes de la maladie évoluent depuis 20 ans en moyenne (0,3–68) ( Tableau 1 ).
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