George A, Schneider-Gold C, Zier S, Reiners K, Sommer C. Musculoskeletal Pain in Patients With Myotonic Dystrophy Type 2. Arch Neurol. 2004;61(12):1938-1942. doi:10.1001/archneur.61.12.1938
Myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM) is an autosomal dominant multisystem disorder. Musculoskeletal pain is one of its frequent symptoms but also occurs in other chronic noninflammatory muscle disorders (OMD).
To characterize the phenotype of DM2/PROMM-associated musculoskeletal pain and to test whether it shows features distinct from OMD.
Outpatient clinic for patients with neuromuscular disorders, university hospital.
Twenty-four patients with DM2/PROMM (12 women and 12 men; median age, 57 years) and 24 age- and sex-matched patients with OMD consecutively recruited during a 3-year period were examined for musculoskeletal pain.
Standardized pain assessment; McGill Pain Questionnaire; depression score; and quantification of pain thresholds to blunt pressure on limb muscles with analgometer.
Unlike patients with OMD who have musculoskeletal pain, patients with DM2/PROMM distinguished a wide spectrum of coexisting pain types. The major pain type in patients with DM2/PROMM was exercise-related, temperature-modulated, and palpation-induced, whereas, cramps were rare. In 8 of the patients with DM2/PROMM and in 3 of the patients with OMD, musculoskeletal pain was the most disabling symptom.
Besides many similarities, DM2/PROMM-associated musculoskeletal pain shows features distinct from OMD.
Myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM) is an autosomal dominant multisystem disorder.1,2 The genetic defect of DM2 has been identified in 2001.3 Musculoskeletal pain is one of the frequent symptoms in DM2/PROMM.2,4 Its character has been colorfully described.2,4- 8 Painful symptoms in DM2/PROMM are regarded as “peculiar.” They fluctuate in duration, location, and intensity and are mostly unresponsive to standard analgesic treatment. Systematic analyses of DM2/PROMM-associated pain are unavailable.
Musculoskeletal pain occurs also in other chronic, noninflammatory muscle disorders (OMD).9 It can result from musculoskleletal imbalance secondary to muscle weakness or from depression. Experimental studies provide evidence that overexercise, ischemia, or dystrophy change the milieu adjacent to muscle afferents, which become sensitized or excited.10 However, these mechanisms may not explain (1) why some muscular dystrophies are typically associated with pain and others are not, and (2) why muscle pain occurs as an early symptom in the absence of muscle weakness.
We hypothesized that DM2/PROMM-associated musculoskeletal pain shows a typical pattern distinct from OMD. We addressed this question for 2 reasons. First, a distinct phenotype may indicate a particular pathophysiology, which is disease-related and genetically driven. Distinct mechanisms may require different treatment strategies. Second, the knowledge of specific painful symptoms related to DM2/PROMM may offer additional insights into how musculoskeletal pain is generated. To test our hypothesis, we examined 24 patients with DM2/PROMM and 24 age- and sex-matched patients with OMD for musculoskeletal pain with standardized tools.11
Twenty-four patients fulfilling the diagnostic criteria for DM2/PROMM12 were treated at our institution between August 1, 1999, and May 31, 2002, and were consecutively recruited. The diagnosis was genetically confirmed.13 Twelve women and 12 men from 17 families were studied. Twenty-one patients were seen in clinical follow-ups, 3 at first presentation. Clinical examination included muscle strength evaluation using the Medical Research Council scale. The level of serum creatine kinase was determined. Neurophysiological testing included electromyography in the quadriceps femoris and anterior tibial muscle and nerve conduction studies on the sural and tibial nerves using standard techniques. Clinical and genetic data have been reported in 2003.13 The study was approved by the local university ethics committee. Written informed consent was obtained from all patients and control subjects prior to the examination.
Twenty-four age- and sex-matched patients with OMD were consecutively recruited between January 1, 2000, and May 31, 2002, as a disease-control group. The diagnoses were muscular dystrophy (MD) type Becker (n = 1); facioscapulohumeral MD (n = 2); limb-girdle MD (n = 4); MD unclassified type (n = 4); generalized myotonia (n = 1); potassium-aggravated myotonia (n = 2); acid maltase deficiency (n = 1); myophosphorylase deficiency (n = 1); mitochondrial myopathy (n = 3); late adult-onset type 2 distal myopathy (n = 1); centronuclear myopathy (n = 1); hereditary inclusion body myopathy (n = 1); and proximal myopathy of unknown etiology (n = 2). Twenty patients had a diagnostic muscle biopsy. Eight patients were seen in clinical follow-ups, 16 at first presentation. The patients were negative for the myotonic dystrophy type 1 and DM2 mutation. Their demographic and clinical data were not significantly different from the patients with DM2/PROMM (Table 1). Twenty-four age- and sex-matched healthy volunteers (12 women and 12 men; median age, 49 years; range, 29-75 years) served as controls for pressure-pain–threshold (PPT) measurements and depression scores.
We used the McGill Pain Questionnaire (MPQ)14,15 because it provides qualitative and quantitative data on various aspects of pain in a standardized way.11 The General Depression Score16 was used to reveal depressive symptoms. The algometer was used to identify local mechanical hyperalgesia.17
The patients were asked if they were suffering from or had ever realized a painful or an unpleasant sensation localized to the musculoskeletal system. They indicated whether muscle weakness, myotonia, or pain was the most disabling feature in their daily life activities and rated their subjective impairment by each of these symptoms on a visual analog scale. Subsequently, the MPQ, the depression score, and muscle-specific questions were offered. The patients indicated whether the sensation was (1) painful, (2) unpleasant but not painful, or (3) unusual but not unpleasant. The questionnaire was completed for each type of pain (P) marked as P1, P2, etc. For MPQ pain descriptor analysis, the number of words chosen (NWC), and the pain rating index based on the rank values (PRI-R) were documented.14 Other pain disorders and current pain treatments were documented.
We used an algometer according to Fischer17 to quantify the threshold of pain elicited by blunt pressure to a muscle. The method of PPT measurement was validated in patients and healthy volunteers (data not shown). We examined the deltoid, the extensor digitorum communis, the quadriceps femoris, and the tibialis anterior muscles on both sides. The pressure value at which the subject experienced pain was recorded in kilograms per square centimeters. According to Fischer,17 a PPT below 3 kg/cm2 or a difference from the contralateral PPT exceeding 2 kg/cm2 indicates mechanical hyperalgesia. As the algometer was unavailable from the beginning of the study, PPT was determined in 13 patients with DM2/PROMM and 16 patients with OMD. This may cause error in analysis when comparing the mean PPT values between groups. The demographic and clinical data of the subgroups were not significantly different from the total sample of 24 patients with DM2/PROMM or OMD. Each subject served as his or her own control to identify local mechanical hyperalgesia.
We used the Mann-Whitney test for non-normally distributed data and parametric statistics for data with gaussian distribution (tested with InStat, GraphPad Software, version 6.0; GraphPad Software Inc, San Diego, Calif). Fisher exact test was used for dichotomic values and the unpaired t test with 2-sided P values for mean MPQ-PRI, NWC, and PPT values. The MPQ variables from patients with DM2/PROMM who have musculoskeletal pain (n = 23) were compared with MPQ data from patients with OMD who have musculoskeletal pain (n = 18). Statistical significance was assumed at P<.05.
Musculoskeletal pain was frequent in patients with DM2/PROMM and in patients with OMD (Table 2). Unlike patients with OMD who have musculoskeletal pain, most patients with DM2/PROMM distinguished multiple types of pain of varying site (Table 3), character (Table 4), and temporal pattern (Table 5). Exercise-related pain was frequent in patients with DM2/PROMM and in patients with OMD (Table 6). Cold- and palpation-induced pain was frequent in patients with DM2/PROMM but rare in patients with OMD. Seven patients with DM2/PROMM and 7 patients with OMD reported painful muscle stiffness. In 3 patients with DM2/PROMM, pain was associated with cold dysesthesias of the whole limb.
Fifteen patients with DM2/PROMM and 10 patients with OMD felt handicapped by muscle weakness and musculoskeletal pain. In 8 patients with DM2/PROMM and 3 patients with OMD, musculoskeletal pain was the most disabling feature. Standard analgesics were mostly reported as ineffective. Most patients were not receiving pain medication at the time of examination.
None of the most frequent types of musculoskeletal pain was related to the patients’ demographic, clinical, or neurophysiological data. Two patients with DM2/PROMM and 2 patients with OMD who had plantar dysesthesias showed reduced sural nerve compound action potentials. Two patients with DM2/PROMM and 2 patients with OMD had a depression score indicating moderate depression.
Six of the 13 patients with DM2/PROMM and 1 of the 16 patients with OMD tested for PPT had local mechanical hyperalgesia to blunt pressure confined to 1 muscle (PPT range, 1.7-2.3 kg/cm2). Mean PPT values in patients with DM2/PROMM were not significantly different from patients with OMD or healthy controls (unpaired t test; data not shown).
Our study demonstrates a wide spectrum of coexisting types of musculoskeletal pain in patients with DM2/PROMM. Many features were frequent in patients with DM2/PROMM and in patients with OMD such as exercise-related or stiffness-associated pain. Several features were frequent in patients with DM2/PROMM but rare in patients with OMD such as cold- or palpation-induced pain. A few features were frequent in patients with DM2/PROMM but absent in patients with OMD such as radiating pain or pain lasting for several days. These data indicate that some, but not all, features of DM2/PROMM-associated musculoskeletal pain are distinct from OMD.
Unexpectedly, exercise-related pain was common in our patients with DM2/PROMM. This has not yet been described but is well known in glycogen storage myopathies,9 dystrophinopathies,18,19 or mitochondrial disease.20 It suggests that shared mechanisms may underlie exercise-related pain states. Instead, a pain radiating to the thighs2 might be typical for DM2/PROMM. Also, local musculoskeletal tenderness frequent in our patients with DM2/PROMM but rare in patients with OMD appears to be a distinctive feature. These data suggest that particular pathophysiological mechanisms underlie DM2/PROMM-associated musculoskeletal pain. Disease-related mechanisms might also explain why in the present study sites of muscle pain and muscle weakness (indicating a muscle pathologic condition) did not closely correspond. Furthermore, distinct mechanisms may require different therapeutic approaches. Our data suggest that massages can be deleterious in patients with DM2/PROMM owing to musculoskeletal mechanical hyperalgesia whereas they might be helpful in patients with OMD.
The following aspects may limit the conclusion that our findings in 24 patients with DM2/PROMM are representative for the phenotype of DM2/PROMM-associated musculoskeletal pain in general. First, in 3 families with DM2/PROMM, several members were evaluated. Shared genetic cofactors or recognized behavioral biasing could have overrepresented some features. However, data analysis of 17 index patients from 17 families with DM2/PROMM led to corresponding results. Second, in 2 patients with DM2/PROMM and in 2 patients with OMD, moderate depression and sensory polyneuropathy might have contributed to musculoskeletal pain. However, this may not explain the differences between patients with DM2/PROMM and patients with OMD.
Mean MPQ ratings in our patients with DM2/PROMM reached a range reported for other pain disorders.14 Besides episodic or paroxysmal pain, in many patients with DM2/PROMM, pain persisted for more than 6 months, indicating chronic pain states. Together with the pain-induced impairment of daily life activities, these and previous data2,4 indicate that musculoskeletal pain is not only a frequent but also an important medical problem in DM2/PROMM.
Correspondence: Claudia Sommer, MD, Neurologische Klinik der Universität, Josef-Schneider-Strausse 11, 97080 Würzburg, Germany (firstname.lastname@example.org).
Accepted for Publication: March 25, 2004.
Author Contributions:Study concept and design: George, Schneider-Gold, and Sommer. Acquisition of data: George, Schneider-Gold, Zier, and Sommer. Analysis and interpretation of data: George, Schneider-Gold, Reiners, and Sommer. Drafting of the manuscript: George, Schneider-Gold, Zier, and Sommer. Critical revision of the manuscript for important intellectual content: George, Schneider-Gold, Reiners, and Sommer. Statistical analysis: George. Administrative, technical, and material support: Schneider-Gold, Zier, Reiners, and Sommer. Study supervision: Schneider-Gold and Sommer.
Acknowledgment: We acknowledge the paramount contribution and are grateful to Kenneth Ricker, MD, who sadly died on July 7, 2004, while the manuscript was in press, for delineating the type of pain in patients with DM2/PROMM. The expert technical assistance of E. Huetz in constructing the algometer is gratefully acknowledged. We thank K. Toyka, MD, for critical reading of the manuscript; M. Beck, MD, and C. Wessig, MD, for clinical examinations in a group of patients with DM2/PROMM; W. Kress, PhD, Institute of Human Genetics, Minneapolis, Minn, for molecular genetic studies; and A. Spahn, Rechenzentrum, University of Wuerzburg, for help with statistical analysis.