Muscle pain as a prominent feature of facioscapulohumeral muscular dystrophy (FSHD): four illustrative case reports
Article Outline
- Abstract
- 1. Introduction
- 2. Patients and methods
- 3. Case reports
- 4. Results
- 5. Discussion
- Acknowledgements
- References
- Copyright
Abstract
Clinical studies of facioscapulohumeral muscular dystrophy (FSHD) rarely report muscle pain as a significant feature of the condition. We report four adult patients with FSHD in whom muscle pain was a presenting complaint and remains their most disabling symptom. These four patients were investigated using a pain questionnaire and diary. Inflammatory and metabolic causes of muscle pain were sought by muscle biopsy and a range of biochemical investigations. All patients reported between three and seven different pains of varying site and nature. None of the group had more than one painfree day per month and all complained of disturbed sleep. While some pains could potentially be attributed to postural problems, others were clearly myalgic in nature, though most often not specifically exercise-related. These myalgic pains could be particularly difficult to control. Results of metabolic investigations and muscle biopsy revealed no clue to the pathogenesis of these pains and there was no evidence for any exceptional inflammatory response. We believe that pain in FSHD is an under-reported but significant symptom and that further work is necessary to determine its prevalence, understand its cause and provide effective treatment.
Keywords: Facioscapulohumeral muscular dystrophy, Muscle pain
1. Introduction
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant condition with a prevalence of approximately 4.4/100 000 [1]. Clinical descriptions of FSHD emphasise variability of age at onset, with infantile and childhood forms recognised 2, 3, and also a wide range of severity. While the predominant muscle involvement is often restricted to a `facioscapulohumeral' distribution, lending the disorder its descriptive name, most patients will eventually develop weakness in their lower limbs. This may be present at presentation and, rarely, may even precede upper limb involvement. Pelvic girdle weakness is common and, if an early problem, may be a poor prognostic sign. Many patients also experience weakness of the anterior tibial and peroneal muscles. If facial muscle involvement is mild, making the diagnosis may present a particular problem, though the asymmetry which is often a feature of the condition can be a clue to the diagnosis in atypical cases [1].
Several reviews delineate the clinical features of FSHD more comprehensively 1, 3, 4, 5, 6. There are, however, few reports in the medical literature of pain as a major feature of the condition. Early reports of pain in association with muscle weakness in a facioscapulohumeral distribution were unable to distinguish whether the association represented a complication of a muscular dystrophy, or a form of polymyositis 7, 8, 9, 10.
We have seen approximately 20 patients (including 6 children) with FSHD in the last year in the paediatric and adult muscle clinics in Newcastle General Hospital. While pain was rarely reported as a problem in the paediatric patients, four adults reported severe multifocal muscle pain as the most disabling aspect of their condition, with several others reporting having had such pain at some stage in their disease. The pains were often extremely serious, disabling and difficult to control. Because of the paucity of information about pain in FSHD, we investigated the pains in these four patients, with the aim of characterising the pain more precisely, excluding any coincidental cause and exploring its pathogenesis. We excluded any evidence of inflammatory or metabolic pathology in association with the muscular dystrophy and the cause of the severe pain we documented therefore remains unknown.
2. Patients and methods
A questionnaire was administered to all patients and a diary was then self-completed over a period of at least 4 weeks (completed by 3/4 patients). As more than one pain was described by all of the patients, they were asked to complete the questionnaire for each type of pain. For each pain the character, persistence, severity (on a scale of 1–10), frequency, site, radiation, precipitating and relieving factors, associated features and disturbance of sleep was documented. All medications used were also documented. Each pain was given a number and a key was provided to aid the completion of the pain diary. In the pain diary, each different pain was documented on a daily basis with details of the site, type, persistence, severity and amount of the day that the pain was present. Daily use of painkillers was also noted.
The cause of the muscle pain was sought through a series of metabolic investigations as follows: (1) ischaemic lactate and ammonia test (screening for disorders of carbohydrate metabolism and AMP deaminase deficiency); (2) fasting serum acylcarnitines (for disorders of β-oxidation and fatty acid metabolism); (3) urine organic and amino acids (for fatty acid and amino acid disorders). Evidence of inflammation was sought by measuring erythrocyte sedimentation rate (ESR), autoantibodies (thyroid microsomal antibodies, antinuclear antibodies, reticulin antibodies, mitochondrial, smooth muscle and GPC antibodies, and rheumatoid factor), serum electrophoresis, immunoglobulins and C-reactive protein. Serum creatine kinase (CK) was measured along with routine biochemistry and haematology. Electromyography (EMG) and nerve conduction studies were performed in two patients (by Dr. Peter Fawcett).
A needle muscle biopsy was obtained from quadriceps and examined using a variety of histological and histochemical techniques to determine fibre morphology, fibre type distribution, presence of myofibrillar ATPase, ragged red fibres, and glycogen and lipid content (haematoxylin and eosin (H&E), succinate dehydrogenase (SDH), cytochrome oxidase (COX), periodic acid-Schiff (PAS), non-specific esterase and Sudan Black B). The muscle was also examined immunocytochemically using antibodies to the N- and C- terminal domains of dystrophin, α- and γ-sarcoglycan, β-dystroglycan, α-2 laminin, β-spectrin and major histocompatibility complex-I (MHC-I). Molecular genetic analysis looking for the small DNA fragment on chromosome 4q associated with 95% of FSHD cases was performed in all patients on DNA extracted from whole blood, digested with EcoRI alone and with EcoRI and BlnI in combination. The digested DNA was run on gels optimised to visualise large DNA fragments, blotted and probed with p13-E11 (a kind gift of Dr. Rune Frants) as described [11].
3. Case reports
3.1. Case 1
This 36-year-old man has a mother and sister affected by FSHD. He achieved normal motor milestones and reached above average sporting fitness throughout his teenage years and early 20s. He had a road traffic accident in his early 30s, after which he began to experience muscle pain. Though pain was an early symptom, the diagnosis was made on the basis of weakness on examination in the context of his family history. By the time he was seen recently he had prominent proximal upper and lower limb pain associated with weakness affecting periscapular, forearm extensor and hamstring groups bilaterally. There was no history of myoglobinuria, but pain has consistently been the most disabling feature of his condition.
Clinical examination was entirely consistent with a diagnosis of FSHD with facial weakness, bilateral and symmetrical wasting of the temporalis, periscapular muscles and triceps, and relative preservation of biceps and the distal forearm muscles. He had normal bulk in his lower limbs and there was no muscle fasciculation or focal muscle tenderness. He had MRC grade 3 weakness in the periscapular region and grade 4− weakness of triceps bilaterally. Distal upper limb and lower limb power was well preserved. His reflexes were normal and there were no sensory signs. Functionally, he could walk on the flat for about 50 yards, and was able to work in a clerical capacity.
On detailed questioning he could distinguish a total of seven disparate pains, four of which were right-sided whilst the remainder were bilateral. The most severe (rated 8 out of 10) was a constant gripping pain in the muscles of his right posterior thigh which was present most of the day and disturbed his sleep. It was exacerbated by prolonged standing or walking but relieved by warmth and swimming. The other pains were intermittent and of variable severity, frequency and character. They ranged from a sharp pain (grade 8/10) in the dorsal aspect of his right forearm (which came on out of the blue once a fortnight and was relieved by rest) to a nagging ache in his chest, neck and shoulders which gradually built to a crescendo as the day progressed but was readily relieved by resting his arms. He had also complained of hip pain, but an X-ray of his right hip showed mild osteoarthritic changes only. Over a 31-day period he had no pain-free days and indeed had pain which lasted all day and night on 10 occasions and pain lasting for most of the day on a further 16 occasions. His daily medications included dothiepin 75 mg orally once per day and dihydrocodeine 30 mg between once and four times per day with variable success. He also claimed some relief from hydrotherapy and a brief course of acupuncture but found a transcutaneous electrical nerve stimulation (TENS) machine unhelpful, mainly because of the multifocal nature of his pain. His mother, who is affected by FSHD, also complains of severe pain as a feature of her condition: his affected sister does not.
3.2. Case 2
This 36-year-old woman has an extensive family history of FSHD traced back to her maternal grandfather. She had normal early motor development but noted pain and weakness affecting her shoulders and proximal upper limbs in childhood. In her late 20s she noticed weakness and pain in her lower limbs. There was no history of myoglobinuria. She continues to work full-time as a hospital nurse, though her pain and right-sided footdrop frequently restrict her activities. On examination she had facial muscle weakness. Her periscapular muscles were wasted but the remainder of her upper and lower limb muscle bulk was normal. There was no evidence of fasciculation seen and no focal muscle tenderness. She had MRC grade 2 weakness of shoulder abduction and external rotation and weakness of tibialis anterior on the right. The remainder of her motor examination was normal, including her tendon reflexes.
Her pain affected her left knee, both upper arms and hips. Although she had a right-sided footdrop, for which she intermittently wore a splint, this was not associated with discomfort. Her hip pain tended to be worse in the morning and was associated with stiffness but was relieved to some extent by swimming and by the use of a TENS machine. The ache in her upper arms however was precipitated by exertion and did not respond to ibuprofen or coproxamol. Her affected relatives do not complain of pain to the same extent as case 2.
3.3. Case 3
This 31-year-old man has no family history of neuromuscular disease. He had normal early motor development and his symptoms began in his mid-20s with a continuous `ache' affecting his periscapular muscles, biceps, triceps and forearm flexors. These symptoms were followed by periscapular muscle wasting and weakness of the shoulder girdle. He has no history of myoglobinuria. He continues to work as a bricklayer, but is severely affected by periods of severe pain. On examination he had mild asymmetrical facial weakness, winging of the scapulae with weakness (MRC grade 4) and wasting of temporalis, periscapular, biceps and triceps muscles bilaterally. He had normal lower limb bulk, but MRC grade 4+ weakness of hip flexion bilaterally. His tendon reflexes were normal.
He complained of pain at six separate sites of which five were bilateral. Three pains were predominantly left sided and the pain in his ankle, which was associated with a foot drop, was exclusively so. The pains in his lower back, anterior thighs and anterior forearms were occasionally associated with nausea, initial insomnia and sleep disturbance. Each pain had a distinct character: the lower back pain was described as sharp and stabbing, while the thigh and shoulder pains were aching and the forearm pain was nagging. All of the pains were relieved by rest. Apart from his anterior thigh pain, which responded to coproxamol (two tablets once to four times per day), he experienced only minimal relief from coproxamol and none from ibuprofen. His left ankle pain was mainly helped by the use of a splint. Over a 56-day period he had no pain-free days and on 42 days experienced pain in at least one site for most of the day.
3.4. Case 4
This 38-year-old man had no family history of neuromuscular disease. He had a normal early motor development, with above average sporting performance until his early 20s. He first noted an ache in his periscapular and proximal lower limb muscles which progressed for a number of years before the onset of muscle weakness in the same regions. He described an `ache' over the insertion of his scapular fixators and a sharp pain deep within his wrist extensors. After a period of sustained exercise, these muscles `throb' for hours to days and may become tender to touch. An exceptional period of weeks of such pain had to be treated with morphine. He has never experienced myoglobinuria.
On examination there was asymmetrical weakness of eye closure, inability to whistle and symmetrical wasting of temporalis, masseter, trapezius and the periscapular muscles. Biceps and triceps bulk were well preserved, and there was no focal tenderness or fasciculations seen. He had MRC grade 3 weakness of abduction, internal and external rotation of the shoulder bilaterally. Triceps were weak (grade 4 bilaterally) but biceps normal. He had grade 4+ weakness of hip flexion and extension, but the remainder of the motor examination including his tendon reflexes was normal. Pain was present at four separate sites including foreams, shoulders, thighs and lower back in a largely symmetrical distribution. Over a 60-day period pain was present for most of the day on 20 days although his sleep was not usually disturbed. Throughout the 60-day period he had only one day when he was entirely pain-free. The pain in his shoulders and limbs was sometimes precipitated by exercise but usually responded to coproxamol (taken on 44 days out of the 60-day period) and he found swimming particularly beneficial. His lower back ache, which was often the most severe and debilitating of his pains, responded neither to coproxamol nor ibuprofen. However he reported a good overall improvement in both pain control and general well-being after starting fluoxetine.
4. Results
Results of full blood count, coagulation studies, renal and bone biochemistry, fasting glucose, ESR, C-reactive protein, serum electrophoresis and immunoglobins were normal in all patients. Serum creatine kinase (normal <175 U/l) was mildly elevated: patient 1 184 U/l, patient 2 326 U/l, patient 3 205 U/l, patient 4 195 U/l. Patients 1 and 4 also had a raised alanine aminotransferase at 108 U/l and 72 U/l, respectively (normal <43 U/l). Patient 1 had borderline hypothyroidism (thyroid stimulating hormone elevated at 5.06 mU/l, normal <4.5mU/l, with a normal free T4). Thyroid microsomal autoantibodies were present (>1 in 6400 titre) but the remainder of the autoantibody screen was normal. Thyroid function tests and autoantibody screen were normal in the other patients. A 12-lead ECG was normal in all patients. An EMG performed in patients 3 and 4 showed chronic myopathic changes only. The presence of myotonia was specifically excluded.
4.1. Metabolic studies
Metabolic studies including a fasting venous lactate, fasting serum acylcarnitines, and urine organic and amino acids were within normal limits in all patients. A forearm exercise test was completely normal in patients 2 and 3 but revealed a normal lactate rise with a flat ammonia response in patients 1 and 4. However, in both of these patients the histochemical examination of muscle was unremarkable, with AMP deaminase activity within normal limits. This histochemical result suggests that the poor ammonia response may have been secondary to suboptimal work load (possibly due to forearm pain).
4.2. Muscle biopsy
Patients 1 and 2 had each undergone one muscle biopsy; patients 3 and 4 each had two biopsies, the initial biopsy in patient 3 being from biceps and the rest all from quadriceps. All revealed changes consistent with a mild chronic dystrophy. The most recent biopsies from all four patients showed no evidence of acute muscle fibre necrosis or of inflammatory cell infiltrates. However, acutely necrotic fibres were seen in the original biopsies from patients 3 and 4; patient 3's first biopsy also showed minor inflammatory (lymphocytic) cell infiltration. The biopsies from patients 1 and 2 showed weak up regulation of MHC-I on occasional fibres, as did the original biopsies from patients 3 and 4, but not their subsequent biopsies. The level and distribution of MHC-I expression seen was consistent with the presence of occasional regenerating muscle fibres. Widespread strong MHC-I upregulation on almost all the muscle fibre population is characteristic of primary inflammatory myopathies and was not seen in any of these FSHD patients.
4.3. Molecular genetics
Molecular genetic analysis showed a short DNA fragment (confirmed as of 4q35 origin by double digestion with EcoRI and BlnI) in patients 1 (approximately 21 kb), 2 (approximately 24 kb) and 3 (approximately 24 kb). A short band was also found in the mother of patient 1. In addition linkage analysis in the family of patient 2 confirmed chromosome 4 localisation of the disease in this pedigree. Samples were not available from the parents of case 3. In case 4, however, DNA analysis using Southern blotting failed to detect a fragment of <40 kb on probing with p13E-11. Further testing by pulsed field gel electrophoresis (Dr. Bakker, Leiden) confirmed that no short band could be detected.
5. Discussion
We have identified four patients with long-standing FSHD in whom pain is the most disabling symptom and was amongst their presenting complaints. Documenting these histories has led us to believe that pain in FSHD is a significant observation and that where it does occur it presents a major problem for management. Patients complained of between three and seven separate pains of varying nature with a quite marked asymmetry of distribution in two patients. While the origin of some types of pain could potentially be attributed to postural problems (especially the pains described in the shoulders, hips and lower back), the forearm and thigh pains appeared to be specifically myalgic and particularly intractable, responding poorly to both analgesia and TENS. The description of the pains varied mainly according to site, with the forearm and thigh pains most often described as having a `sharp' or `stabbing' nature.
All the patients we report described muscle pain as a feature of their condition right from the onset, often predating the diagnosis. None had more than one pain-free day per month, despite taking analgesia most days, and all complained of disturbed sleep. As well as variability of character (from sharp stabbing pains to a dull nagging ache), the pains showed variability of severity and periodicity between sites. On the whole, symptoms were less marked in the summer months.
While the medical literature is largely silent on the topic of pain in association with FSHD, the patient information literature has highlighted the problem in a majority of FSHD patients surveyed in both the Netherlands and France (Patient information literature: FSH Watch, summer 1997). This theme has been developed in a survey of 270 French FSHD patients, where only 5.6% of patients did not report any pain at all, and 32% reported pain, though of unspecified nature, as a problem every day (Urtizberea et al., data submitted for publication). Once we had identified pain as a problem in the four patients reported here we asked routinely, though informally, about the presence of this symptom in other patients with FSHD. Only one of the children with FSHD, most of whom are very severely affected, reported any muscle pain at all. Many adults with FSHD did not report a serious problem with pain, but several reported having had muscle pain previously. Others quite clearly stated that pain was not and had never been a feature of their condition. As we do not have complete ascertainment of all patients with FSHD in our region, we cannot attempt to give a figure for the prevalence of this problem amongst the FSHD population, though this information would undoubtedly be very valuable.
The patients reported here were all ambulant, and did not suffer from unusually severe muscle weakness. Two had a positive family history of FSHD and in case 1, his affected mother (who is not a regular patient of ours) is also reported to suffer from severe and incapacitating muscle pain. The affected relatives of case 2 apparently do not report pain as a significant problem. Previous reports of pain associated with muscle weakness in a facioscapulohumeral distribution are limited, and fail to distinguish conclusively between patients with FSHD and those who may have an unusual form of polymyositis 7, 8, 9, 10. These reports predate the potential to perform a specific diagnostic test for FSHD. Three out of the four patients we report do have the characteristic DNA deletion on chromosome 4 which is associated with FSHD, and the fourth (case 4) has FSHD on clinical grounds, though he has no family history of the disease. We have excluded all the currently immunologically definable alternative forms of muscular dystrophy in this patient (including calpain 3 deficiency, LGMD2A, L.V.B. Anderson, personal communication), EMG examination specifically excluded myotonia, and metabolic studies were all normal. We believe that FSHD remains clinically the most likely diagnosis [12]. Approximately 5% of FSHD, apparently clinically indistinguishable from the chromosome 4-linked form, do not show linkage to chromosome 4q [13]. It would seem, therefore, that pain in association with an FSHD phenotype is not limited to the form with a definable small DNA fragment of chromosome 4q origin.
Postural problems in FSHD may be a cause of pain: for example, humeral subluxation and prominent lumbar lordosis may contribute to the development of shoulder and back pains respectively and may respond in our experience to supportive treatment. We believe however that the myalgic pains reported here, characteristically often an early symptom and clearly multifocal, are a distinct and characteristic entity. Specific muscle pain has a number of different causes and associations. Polymyositis is a sporadic condition associated with muscle inflammation and elevation of creatine kinase. Inflammation has sometimes been noted in muscle biopsies from patients with FSHD 8, 14, but was not a prominent feature in the biopsies reported here, with only weak upregulation of MHC-I immunolabelling, compatible in our experience with most biopsies from patients with FSHD. Similarly the ESR was normal and the CK was not elevated in these patients to the kinds of levels seen in patients with polymyositis – the mild elevation seen in these patients is typically the level found in FSHD 1, 3, 4, 5, 6. Severe muscle pain is also found in some forms of metabolic muscle disease, but we feel that our sets of investigations makes this association very unlikely in this group. Dystrophinopathy may also be associated with muscle pain, though this is usually a cramp-like pain predominantly affecting the calves, and is often exercise related 15, 16, 17, 18, 19. Unfortunately, although we have excluded these alternative causes throughout our investigations, we have not found any clues as to the possible pathogenesis of the pain in FSHD.
Treatment of the pain in the patients we report has been difficult, with a very poor response to conventional first-line analgesic or anti-inflammatory therapy. At least one of the patients had been prescribed morphine to help with pain relief during a particularly severe and long-lasting episode. Three of the patients reported considerable overall benefit from swimming and particularly from hydrotherapy, although unfortunately the latter was not readily available on a long-term basis. All patients complained of a sense of frustration with concomitant depression and irritability. Two of the four patients were treated with antidepressants and reported an improvement not only in their mood but also partial improvement in their pain control. Further psychological analysis of this group might therefore also be of interest.
Polymyositis is treated with steroids or other anti-inflammatory drugs [20]. The literature on the use of steroids in FSHD is not entirely encouraging. Munsat et al. [8]found that CK levels fell and symptoms improved in a small number of FSHD patients treated with steroids, while a recent more systematic study of steroids in FSHD concluded that there was no benefit [21]. However, this study did not address the question of pain specifically at all.
In conclusion, we have reported these patients to draw attention to our belief that pain in FSHD may be an inherent feature of the condition which requires further investigation to establish its prevalence and determine its cause. Most importantly for those affected, this will allow the identification of treatment strategies to control this disabling symptom.
Acknowledgements
Many thanks to Dr. M.A.J. Johnson for analysis of the biopsies and to Mrs. Daisy Haggerty for DNA analysis. Two patients were referred by Dr. D. Bates and Dr. M. Jackson. P.F.C. is funded by the Wellcome Trust and C.P. by Action Research.
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