EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

OBJECTIVE: To develop evidence-based recommendations for the management of fibromyalgia syndrome. METHODS: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. RESULTS: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. CONCLUSIONS: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.

Mitochondrial myopathy with succinate dehydrogenase and aconitase deficiency. Abnormalities of several iron-sulfur proteins.

Recently, we described a patient with severe exercise intolerance and episodic myoglobinuria, associated with marked impairment of succinate oxidation and deficient activity of succinate dehydrogenase and aconitase in muscle mitochondria (1). We now report additional enzymatic and immunological characterization of mitochondria. In addition to severe deficiency of complex II, manifested by reduction of succinate dehydrogenase and succinate:coenzyme Q oxidoreductase activities to 12 and 22% of normal, respectively, complex III activity was reduced to 37% and rhodanese to 48% of normal. Furthermore, although complex I activity was not measured, immunoblot analysis of complex I showed deficiency of the 39-, 24-, 13-, and 9-kD peptides with lesser reductions of the 51- and 18-kD peptides. Immunoblots of complex III showed markedly reduced levels of the mature Rieske protein in mitochondria and elevated levels of its precursor in the cytosol, suggesting deficient uptake into mitochondria. Immunoreactive aconitase was also low. These data, together with the previous documentation of low amounts of the 30-kD iron-sulfur protein and the 13.5-kD subunit of complex II, compared to near normal levels of the 70-kD protein suggest a more generalized abnormality of the synthesis, import, processing, or assembly of a group of proteins containing iron-sulfur clusters.

Deficiency of skeletal muscle succinate dehydrogenase and aconitase. Pathophysiology of exercise in a novel human muscle oxidative defect.

We evaluated a 22-yr-old Swedish man with lifelong exercise intolerance marked by premature exertional muscle fatigue, dyspnea, and cardiac palpitations with superimposed episodes lasting days to weeks of increased muscle fatigability and weakness associated with painful muscle swelling and pigmenturia. Cycle exercise testing revealed low maximal oxygen uptake (12 ml/min per kg; healthy sedentary men = 39 +/- 5) with exaggerated increases in venous lactate and pyruvate in relation to oxygen uptake (VO2) but low lactate/pyruvate ratios in maximal exercise. The severe oxidative limitation was characterized by impaired muscle oxygen extraction indicated by subnormal systemic arteriovenous oxygen difference (a-v O2 diff) in maximal exercise (patient = 4.0 ml/dl, normal men = 16.7 +/- 2.1) despite normal oxygen carrying capacity and Hgb-O2 P50. In contrast maximal oxygen delivery (cardiac output, Q) was high compared to sedentary healthy men (Qmax, patient = 303 ml/min per kg, normal men 238 +/- 36) and the slope of increase in Q relative to VO2 (i.e., delta Q/delta VO2) from rest to exercise was exaggerated (delta Q/delta VO2, patient = 29, normal men = 4.7 +/- 0.6) indicating uncoupling of the normal approximately 1:1 relationship between oxygen delivery and utilization in dynamic exercise. Studies of isolated skeletal muscle mitochondria in our patient revealed markedly impaired succinate oxidation with normal glutamate oxidation implying a metabolic defect at the level of complex II of the mitochondrial respiratory chain. A defect in Complex II in skeletal muscle was confirmed by the finding of deficiency of succinate dehydrogenase as determined histochemically and biochemically. Immunoblot analysis showed low amounts of the 30-kD (iron-sulfur) and 13.5-kD proteins with near normal levels of the 70-kD protein of complex II. Deficiency of succinate dehydrogenase was associated with decreased levels of mitochondrial aconitase assessed enzymatically and immunologically whereas activities of other tricarboxylic acid cycle enzymes were increased compared to normal subjects. The exercise findings are consistent with the hypothesis that this defect impairs muscle oxidative metabolism by limiting the rate of NADH production by the tricarboxylic acid cycle.

The prevalences of cytochrome c oxidase negative and superpositive fibres and ragged-red fibres in the trapezius muscle of female cleaners with and without myalgia and of female healthy controls.

The association of cytochrome c oxidase negative fibres (COX-negative) and ragged-red fibres (RR-fibres) with work related trapezius myalgia has been proposed. Hitherto studies have been small or without control groups. The aim of the present study was to investigate the prevalences of RR-fibres and COX-negative fibres in female cleaners with (n=25) and without (n=23) trapezius myalgia and in clinically healthy female teachers (n=21). The cleaners did mainly floor cleaning requiring monotonous loading on the trapezius muscle. A questionnaire covering background data and aspects of pain (prevalence, duration, intensity and influence on daily living) was answered. Biopsies were obtained from the trapezius muscle by an open surgical technique. The three groups did not differ in prevalence of COX-negative or COX-superpositive (i.e. type-I fibres with extremely strong brownish reaction in both the COX and SDH/COX stainings) fibres. The prevalence of COX-negative fibres was age dependent. Two subgroups of RR-fibres were present when stained for COX; COX-negative (73%) and COX-superpositive (26%) fibres. Forty-two percent of the COX-negative fibres were RR-fibres and 79% of the COX-superpositive were RR-fibres. A significantly (P=0.002) higher proportion of the COX-superpositive fibres in the cleaners were RR-fibres compared to the teachers. Multivariate regression analysis revealed that age, occupation as cleaner and a tender point in the trapezius were significantly associated with increased prevalences of RR-fibres; a cleaner with a tender point had a 4.35 higher prevalence of RR-fibres compared to a teacher without a tender point. No correlations between other pain related variables and prevalence of RR-fibres were noted. In conclusion, RR-fibres but not COX-negative or COX-superpositive fibres were correlated with cleaning work tasks and with a tender point in the trapezius.

Quantitative EMG and muscle tension in painful muscles in fibromyalgia.

Examinations were performed in 22 female fibromyalgic patients and in 9 healthy controls. The biceps brachii, trapezius, and tibial anterior muscles were examined electromyographically. The changes found were minor and non-specific. This implies that there is no important loss of motor units and no conspicuous muscle fiber degeneration in fibromyalgia. Our investigation also failed to demonstrate any electrically detectable muscle activity in muscles where the patients during the examination reported pain (paraspinal, trapezius and tibial anterior muscles). This means that muscle tension cannot be a prominent pathogenetic factor in fibromyalgia and that factors other than muscle tension are responsible for maintaining the pain in fibromyalgia.

Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome.

Levels of substance P were determined in the cerebrospinal fluid (CSF) in 15 patients with chronic fatigue syndrome (CFS). All values were within normal range. This is in contrast to fibromyalgia (FM). The majority of patients with FM have increased substance P values in the CSF. The results support the notion that FM and CFS are different disorders in spite of overlapping symptomatology.

Low-dose prednisolone treatment in Duchenne and Becker muscular dystrophy.

Forty-one boys, aged 4.0-19.4 yr, with Duchenne or Becker muscular dystrophy, took part in a 12-month randomized, double-blind cross-over trial in which the patients received 0.35 mg kg-1 day-1 prednisolone for six months and placebo for six months. One patient stopped the treatment because of excessive weight gain. The boys were assessed every third month with a comprehensive test battery of muscle force and function. The results support earlier reports that prednisolone treatment can either improve muscle force and function or diminish the deterioration of muscle function in both Becker and Duchenne muscular dystrophy.

Malignant hyperthermia susceptibility without central core disease (CCD) in a family where CCD is diagnosed.

Central Core Disease (CCD) is a myopathy closely linked to malignant hyperthermia (MH) susceptibility. We present a family with a girl suffering from CCD. Due to the CCD diagnosis, all available relatives were investigated for MH-susceptibility. No other family member has CCD. In vitro contracture tests revealed that several relatives are MH-susceptible. Thus our results suggest that healthy members of families with CCD could be at risk for being malignant hyperthermia susceptible.

Phospholipase A2 activity in dystrophinopathies.

Phospholipase A2 activity in human muscle with or without dystrophin abnormality was studied. The results showed an increased phospholipase A2 activity in Duchenne muscular dystrophy (DMD) patients (1160 +/- 160, P < 0.01) compared to controls (< 200 U mg-1). DMD fetal muscle showed normal levels, but levels then increased dramatically postnatally. Highest levels were found at 5 yr of age (10 times normal) and then declined to 1.5-2 times normal by age 10. Steroid treatment did not change the phospholipase A2 levels significantly. In patients with abnormal dystrophin, i.e. Becker muscular dystrophy, phospholipase A2 activity was increased in the age group 3-15 (920 +/- 230 U mg-1, P < 0.01), while older patients (17-49) showed a non-significant (220 +/- 60 U mg-1) increase. The lack of phospholipase A2 activation in fetuses with DMD, indicates that activation is not a direct consequence of dystrophin deficiency. Phospholipase A2 activity has been shown to be connected to the formation of several inflammatory mediators such as prostaglandins, leukotriens, platelet activating factor and lysophospholipids. Phospholipase A2 activation may therefore play an important role in the development of inflammation and necrosis, with subsequent fibrosis and massive loss of muscle function, which develops in Duchenne and Becker muscular dystrophy.

Impaired oxidative metabolism increases adenine nucleotide breakdown in McArdle's disease.

Two patients with muscle phosphorylase deficiency [McArdle's disease (McA)] were studied during bicycle exercise at 40 (n = 2) and 60 W (n = 1). Peak heart rate was 170 and 162 beats/min, corresponding to approximately 90% of estimated maximal heart rate. Muscle samples were taken at rest and immediately after exercise from the quadriceps femoris. Lactate content remained low in both muscle and blood. Acetylcarnitine, which constitutes a readily available form of acetyl units and thus a substrate for the tricarboxylic acid cycle, was very low in McA patients both at rest and during exercise, corresponding to approximately 17 and 11%, respectively, of that in healthy subjects. Muscle NADH was unchanged during exercise in McA patients in contrast to healthy subjects, in whom NADH increases markedly at high exercise intensities. Despite low lactate levels, arterial plasma NH3 and muscle inosine 5'-monophosphate increased more steeply relative to work load in McA patients than in healthy subjects. The low postexercise levels of lactate, acetylcarnitine, and NADH in McA patients support the idea that exercise performance is limited by the availability of oxidative fuels. Increases in muscle inosine 5'-monophosphate and plasma NH3 indicate that lack of glycogen as an oxidative fuel is associated with adenine nucleotide breakdown and increased deamination of AMP. It is suggested that the early onset of fatigue in McA patients is caused by an insufficient rate of ADP phosphorylation, resulting in transient increases in ADP.

A pilot study of body awareness programs in the treatment of fibromyalgia syndrome.

OBJECTIVE: To compare in a pilot study the effect of two physical therapies, the Mensendieck system (MS) and body awareness therapy (BAT) according to Roxendal, in fibromyalgia patients and to investigate differences in effect between the two interventions. METHODS: Twenty female patients were randomized to either MS or BAT in a program lasting 20 weeks. Evaluations were tender point examination and questionnaires, including visual analog scales (pain intensity at worst site, muscular stiffness, evening fatigue, and global health), Fibromyalgia Impact Questionnaire (FIQ), Coping Strategies Questionnaire, Quality of Life Scales, Arthritis Self-Efficacy Scale (ASES), and disability before, immediately after, and at 6 and 18 months follow-up. RESULTS: The BAT group had improved global health at 18 months follow-up, but lower results than the MS group. The MS group had improved FIQ, ASES other symptoms, and pain at worst site at 18 months follow-up. CONCLUSION: In the present pilot study, MS was associated with more positive changes than BAT.

The impact of time after portacaval shunt in the rat on behavior, brain serotonin, and brain and muscle histology.

We investigated open field behavior, cellular fluorescence of brain serotonin and serotonin metabolism in different regions of the central nervous system (CNS), and brain and muscle histology in rats 3 weeks or 6 months after surgical end-to-side portacaval shunt (PCS). The results revealed a similar disturbance of the CNS serotonin at 3 weeks and 6 months after PCS in the rat. Progressive neurohistological changes were present between 3 weeks and 6 months after PCS. The open field behavioral impairment appeared, however, to diminish with time. There was no evidence from muscle biopsies that lesions in the muscles or in the peripheral nerves contributed to the motor disturbance.

The distribution of intermediate filament protein (skeletin) in normal and diseased human skeletal muscle--an immunohistochemical and electron-microscopic study.

The presence of intermediate filaments in various mature and immature eukaryotic cells is well documented. By using antibodies against the intermediate (skeletin) filaments of cow heart Purkinje fibres, we have in the present work analyzed the distribution of skeletin in normal and diseased skeletal muscle fibres. Antiskeletin proved to be a useful tool for the identification of regenerating fibres in Duchenne muscular dystrophy. In mature muscle fibres with well-preserved myofibrils, skeletin had an intermyofibrillar localization at the Z-disk level where intermediate filaments were demonstrated. The presence of skeletin was also demonstrated around the rods of muscle fibres in nemaline myopathy biopsies, but the rods themselves did not show any cross-reactivity. This report exemplifies the usefulness of antibodies in muscle pathology.

Early infant death in nemaline (rod) myopathy.

Congenital 'floppy infant' syndrome with very early death is uncommon. It is here described in a girl. Histopathological examination of a muscle biopsy at the age of 10 days showed rods and infiltration of inflammatory cells. Death occurred at 5 weeks of age. Electron microscopy of the necropsy material showed widened Z disks and rods of Z disk density with a typical transverse periodicity of 18-20 nm. The differential diagnosis between nemaline (rod) myopathy and infantile polymyositis is discussed. Nemaline (rod) myopathy should always be considered in cases of the congenital 'floppy infant' syndrome.

Evaluation of four outpatient educational programmes for patients with longstanding fibromyalgia.

OBJECTIVE: Four programmes based on educational and cognitive principles but with a variation in total length and number of staff/patient contact hours were compared in order to gain further insight into the importance of the format of the programme for the final outcome. DESIGN: A prospective non-randomized intervention study with 191 persons with fibromyalgia. Data were collected before, after and at 1-year follow-up. Participants served as their own controls. Results within and between the programmes were calculated. METHODS: Clinical investigations before and after intervention. Questionnaires were answered before, after and at 1-year follow-up. RESULTS: Most instruments showed no significant improvements after the programme. However, some improvements were found in important variables such as attitudes, self-efficacy, vitality and "days feeling well". Results were unchanged at the 1-year follow-up and 16 persons had started working. Seven had ceased working. Participants reported frequent use of coping strategies in everyday life. No major differences could be found between the programmes. CONCLUSIONS: More comprehensive programmes did not produce better results at group level. Also short and less costly interventions based on educational and cognitive principles were valuable for persons with longstanding fibromyalgia. More attention must be given to evaluating the clinical effect of programmes.

Effects of hyperbaric oxygen treatment in post-ischemic muscle. A quantitative morphological study.

In the post-ischemic muscle, hyperbaric oxygen (HBO) treatments have been shown to reduce post-ischemic edema and enhance aerobic metabolism. In the present paper histological, histochemical and ultrastructural methods were used to study the influences of HBO treatment on the morphology of post-ischemic skeletal muscle. The changes were also quantified using morphometry. The circulation of the rat hindlimb was interrupted for 3 hours and muscle biopsies were taken 5 and 12 hours post-ischemia. Light microscopy showed signs of ischemic changes in the muscle. Morphometrically, the area with activity of the muscle enzyme phosphorylase was greatly reduced post-ischemia. HBO treatment at 2.5 atmospheres of absolute pressure (ATA) for 45 min significantly increased muscle cross sectional area with a positive phosphorylase reaction 5 hours post-ischemia. Three HBO treatments were necessary to maintain this effect, 12 hours post-ischemia. Ultrastructurally, the ischemic changes seen using light microscopy were confirmed. Morphometrically, there was a significant increase of mitochondrial size in the ischemic muscle compared with the control uninjured muscle but HBO did not markedly reduce these ultrastructural changes. It was concluded that the reduction of phosphorylase activity, a sensitive marker for muscle cell damage, is to a great extent prevented by HBO treatment in the post-ischemic phase.

[Fibromyalgia--a new name for a syndrome with diffuse muscular disorders]. / Fibromyalgi--nytt namn på syndrom med diffusa muskelbesvär.

This new name for an old and common disease has introduced fresh criteria and initiated clinical and basic research. The present clinical knowledge of the diagnosis and treatment is reviewed. Morphological and biochemical findings in the muscle of fibromyalgia patients have shown an unevenly distributed reduction of the oxygen tension. Hypoxia in the muscle sensitizes nociceptors, resulting in hyperalgesia with a diffuse distribution of pain symptoms. These are difficult for the individual to localize and are often combined with muscle stiffness and increased fatigability. These symptoms correspond to complaints received from fibromyalgia patients.

The muscle in fibromyalgia--a review of Swedish studies.

In Sweden, several studies have been performed in patients with fibromyalgia to study muscle morphology, chemistry and physiology in order to understand the origin of the most prominent symptoms in fibromyalgia: muscle pain, muscle fatigue and muscle stiffness. These studies have shown changes indicating disturbed microcirculation, mitochondrial damage and a reduced content of high energy phosphates. Thus, there may be an energy deficiency state in the resting painful muscle in fibromyalgia. Pain analysis has supported the idea that there is a nociceptive origin of the pain. Our hypothesis is that any condition that could lead to constant muscle hypoxia, e.g., through establishment of abnormal motor patterns, might be a possible cause of fibromyalgic pain.